instruction stringlengths 34 186 | input stringlengths 2.02k 93.8k | output stringlengths 2 418 | meta_questiontype stringclasses 6 values | meta_inputlicense stringclasses 6 values | meta_pmid stringlengths 8 8 | meta_safetyreportid int64 9.51M 21M | meta_articlepubdate stringlengths 4 10 |
|---|---|---|---|---|---|---|---|
What was the administration route of drug 'MIDAZOLAM'? | Catatonia associated with late-life psychosis successfully treated with lithium: a case report.
BACKGROUND
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition. Its pathogenesis is poorly understood. Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia; however, alternative treatment strategies have not been established in cases where these treatments are either ineffective or unavailable. Here, we report a case of catatonia associated with late-life psychosis, which was successfully treated with lithium.
METHODS
A 66-year-old single man with hearing impairment developed hallucination and delusions and presented with catatonic stupor after a fall. He initially responded to benzodiazepine therapy; however, his psychotic symptoms became clinically evident and benzodiazepine provided limited efficacy. Blonanserin was ineffective, and ECT was unavailable. His catatonic and psychotic symptoms were finally relieved by lithium monotherapy.
CONCLUSIONS
Catatonic symptoms are common in patients with mood disorders, suggesting that lithium may be effective in these cases. Moreover, lithium may be effective for both catatonic and psychotic symptoms, as it normalizes imbalances of excitatory and inhibitory systems in the brain, which underlies major psychosis. Cumulative evidence from further cases is needed to validate our findings.
Background
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition; its pathogenesis is poorly understood [1]. Catatonia was once recognized as a subtype of schizophrenia; however, the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) removed it from all schizophrenia subtypes, and defined it as a specifier of various psychiatric disorders or medical conditions [2]. Indeed, catatonia has been reported to be associated with a variety of medical conditions [3, 4]. Moreover, a previous study has reported that catatonic symptoms were more common in patients with manic or mixed episodes (28–31%) than in those with schizophrenia (10–15%) [5]. A prospective cohort study has also reported the incidence of catatonia to be only 7.6% in patients with schizophrenia [6].
Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia, particularly in acute cases; however, benzodiazepines show limited efficacy in a considerable number of patients [7], and available facilities for ECT are limited. In cases where benzodiazepines are ineffective and ECT is unavailable, a systematic review of alternative treatment strategies proposed glutamate antagonists, antiepileptic drugs, and atypical antipsychotics as first-, second-, and third-line treatments for catatonia, respectively [8]. The proper alternative treatment of catatonia may differ depending on the underlying disease; however, as its pathogenesis is unclear, the pharmacological action of each drug is therefore unknown.
Here, we report a case of catatonia associated with late-life psychosis that was successfully treated with lithium.
Case presentation
The patient was a 66-year-old single man, who worked for a cleaning company, and had hearing impairment; however, there was no evident medical history of psychiatric disorders. He was found lying in front of his apartment and was sent to the emergency room. A physical examination revealed fracture of the left patella and calcaneus, which appeared to be related to trauma. He kept his eyes closed for most of the day and demonstrated no spontaneous speech or reaction. Although his blood tests showed inflammatory reaction, his vital signs were normal, and computed tomography and electroencephalography of his brain showed no significant findings. He had no relatives and there was no life history information of him. According to the information of the neighboring residents, he had exhibited strange behaviors since about 2 months before admission and often annoyed the neighbors. Before his arrival to the emergency department, a neighbor called the police because the patient had stood in front of his apartment for a long time. While in detention, he did not respond to the police interrogations at all; he was found lying in front of his apartment a few hours after police released him. After admission to the emergency department, he was consulted with our department for the assessment of psychotic symptoms by his physician. Including the process leading to hospitalization, he was diagnosed with catatonia based on the presence of stupor, mutism, and negativism which was detected from the information by the police about the patients’ uncooperative behavior during detention. He was started on intravenous administration of 5 mg/day midazolam, which was switched to lorazepam, administered through a feeding tube. He then gradually opened his eyes and started speaking. He stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He was, therefore, suspected to have hallucinations and delusions. He subsequently developed fever, and the blood tests showed an inflammatory reaction with creatine kinase (CK) elevation; antibiotics were accordingly administered for infection at the injury site. The dose of lorazepam was tapered to 2 mg/day because he developed delirium; after normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. His delirium improved, and he was able to eat by himself; however, he spent more time lying down with his eyes closed. Considering the possibility of oversedation, lorazepam was tapered to a dose of 1 mg/day. Since he appeared to have improved slightly, the dose of blonanserin patch was increased to 40 mg/day, and lorazepam was terminated. However, he spent most of his time in bed, and eating became difficult. Although he was a suitable candidate for ECT, it was unavailable in our facility. We tried to transfer the facility where ECT was available; however, it was full. Lithium was, therefore, added, and blonanserin patch was terminated; he opened his eyes and began to move after the dose of lithium was increased to 400 mg/day, and he began to eat and talk. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day, the dose of 400 mg/day was maintained after obtaining informed consent, based on the blood concentration results (Fig. 1). He mentioned that he had graduated from high school and had no history of alcohol or drug abuse. At age 60, he moved to his present apartment after changing jobs, and had developed hallucinations approximately a year before hospitalization. On examination, his mini-mental state examination (MMSE) score was 26; some points were lost on 3-step command (minus 2) and delayed recall (minus 2) tasks, suggesting that there was no remarkable cognitive dysfunction. He was, therefore, transferred to a rehabilitation facility.Fig. 1 Clinical course of a case of catatonia associated with late paraphrenia. A 66-year-old man with catatonic stupor initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident because he stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He subsequently developed delirium with fever and creatine kinase (CK) level elevation and the dose of lorazepam was tapered to 2 mg/day. After normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. The dose of the blonanserin patch was increased to 40 mg/day, and lorazepam was terminated; however, it was not effective. Although he was a suitable candidate for ECT, it was unavailable in our facility. Lithium was, therefore, added, and the blonanserin patch was terminated; his catatonic and psychotic symptoms were finally relieved by lithium monotherapy. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day (0.86 mEq/ml), the dose of 400 mg/day (0.50 mEq/ml) was maintained after obtaining informed consent, based on the blood concentration results. Li blood concentration of lithium, CK creatine kinase
Discussion and conclusions
This report describes the case of a single elderly man with hearing impairment, who developed hallucination and delusions and presented with catatonia at the last minute before his fall. There were no remarkable brain organic abnormalities which possibly cause catatonic symptoms, suggesting that his psychotic and catatonic symptoms were not derived from either trauma or drugs used after admission. His premorbid social function was almost normal enough to work for cleaning company, and the results of cognitive function tests performed after his psychiatric symptoms improved showed that he did not have remarkable neurocognitive impairment leading to social dysfunction. He had sensory deficit, which is common in late paraphrenia [9], and developed psychotic symptoms after 60 years of age without any evident history of psychiatric disorders. This suggested that his catatonia occurred because of late-life psychosis called as late paraphrenia, which has been recognized to be independent of schizophrenia [10]. Although the patient showed no remarkable cognitive dysfunction in MMSE, we could not rule out the possibility of neurocognitive deficit of the patient because there was no other neurocognitive examination of the patient to assess cognitive impairment. A previous review of paraphrenia has reported that the pathology of paraphrenia is similar to that of the neurofibrillary tangles, which are the predominant form of senile dementia [11]. His psychotic episode could have represented the prodromal symptoms of dementia; he therefore needs to be followed up closely for the progressive of cognitive dysfunction in the future.
The patient had initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident; however, its efficacy was limited. Some patients with catatonia fail to respond to benzodiazepines, with approximately 30% of patients showing only partial response [12, 13]; in particular, cases that occur secondary to schizophrenia have been reported to be less likely to respond to benzodiazepines [14, 15]. Moreover, benzodiazepine use is not suitable for elderly patients, considering the risk of delirium. Atypical antipsychotics have been recommended as one of the alternative treatment strategies for catatonia [8]; however, blonanserin did not improve his catatonia. Finally, both his catatonic and psychotic symptoms were completely resolved by lithium monotherapy. Catatonic symptoms are more common in patients with mood disorders than in those with schizophrenia [5], suggesting that lithium may be effective for catatonia. Although previous case reports advocate the effectiveness of lithium in preventing recurrence of catatonia [16, 17], there is no evidence of its effectiveness in the acute phase.
Although the pathogenesis of catatonia remains poorly understood, the neurochemical hypothesis suggests that alterations in various neurotransmission systems, including gamma-aminobutyric acid (GABA) and glutamate, play a role [18, 19]. Even if the effects of benzodiazepines on the GABA system in the brain are limited, ECT has a high response rate, suggesting that catatonia may be the final common outcome for abnormal brain seizure activity [20]. In the present case, antiepileptic drugs which are candidates of the alternative treatment strategies for catatonia [8] were not administrated due to no remarkable abnormalities of electroencephalography. Finally, lithium was used because the effect of benzodiazepine was limited and ECT was unavailable. A previous study, using induced pluripotent stem cells (iPSCs) derived from neuronal cells of patients with bipolar disorders, has reported that the hyperexcitability phenotype of young neurons was selectively reversed by lithium only in lithium responders [21]. Moreover, a recent study using iPSCs derived from monozygotic twins discordant for major psychosis has suggested that lithium may normalize unbalanced specification of excitatory and inhibitory neurons in major psychosis neural circuits, by activating the Wnt signaling pathway [22]. In the present case of catatonia associated with late-life psychosis, lithium, although not as fast-acting as ECT, was effective for both catatonic and psychotic symptoms, as it normalized unbalanced specification of excitatory and inhibitory systems in the brain.
To the best of our knowledge, this is the first report on the efficacy of lithium in the acute phase of catatonia. There was a previous report of lithium therapy for catatonia features in autism spectrum disorder patients [23] and the another reported the case of catatonia cause by lithium overdose [24], suggesting that the action and effects of lithium on neurons numerous and diverse. Future studies are needed to elucidate the pathogenesis of catatonia to identify the most reliable treatment.
Abbreviations
ECTElectroconvulsive therapy
iPSCsInduced pluripotent stem cells
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank to all staff involved in the medical care of this patient.
Authors’ contributions
HS and JT were involved in the management of the patient. This case report was written by HS. MH and MI revised the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The data used for this case report is available from the corresponding authors on reasonable request.
Ethics approval and consent to participate
Ethics committee in Kansai Rosai Hospital approved for the publication of this case report.
Consent for publication
Written informed consent has been obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests. This edit was made to conform to the format of the journal guidelines. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33602282 | 19,733,655 | 2021-02-18 |
What was the outcome of reaction 'Delirium'? | Catatonia associated with late-life psychosis successfully treated with lithium: a case report.
BACKGROUND
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition. Its pathogenesis is poorly understood. Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia; however, alternative treatment strategies have not been established in cases where these treatments are either ineffective or unavailable. Here, we report a case of catatonia associated with late-life psychosis, which was successfully treated with lithium.
METHODS
A 66-year-old single man with hearing impairment developed hallucination and delusions and presented with catatonic stupor after a fall. He initially responded to benzodiazepine therapy; however, his psychotic symptoms became clinically evident and benzodiazepine provided limited efficacy. Blonanserin was ineffective, and ECT was unavailable. His catatonic and psychotic symptoms were finally relieved by lithium monotherapy.
CONCLUSIONS
Catatonic symptoms are common in patients with mood disorders, suggesting that lithium may be effective in these cases. Moreover, lithium may be effective for both catatonic and psychotic symptoms, as it normalizes imbalances of excitatory and inhibitory systems in the brain, which underlies major psychosis. Cumulative evidence from further cases is needed to validate our findings.
Background
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition; its pathogenesis is poorly understood [1]. Catatonia was once recognized as a subtype of schizophrenia; however, the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) removed it from all schizophrenia subtypes, and defined it as a specifier of various psychiatric disorders or medical conditions [2]. Indeed, catatonia has been reported to be associated with a variety of medical conditions [3, 4]. Moreover, a previous study has reported that catatonic symptoms were more common in patients with manic or mixed episodes (28–31%) than in those with schizophrenia (10–15%) [5]. A prospective cohort study has also reported the incidence of catatonia to be only 7.6% in patients with schizophrenia [6].
Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia, particularly in acute cases; however, benzodiazepines show limited efficacy in a considerable number of patients [7], and available facilities for ECT are limited. In cases where benzodiazepines are ineffective and ECT is unavailable, a systematic review of alternative treatment strategies proposed glutamate antagonists, antiepileptic drugs, and atypical antipsychotics as first-, second-, and third-line treatments for catatonia, respectively [8]. The proper alternative treatment of catatonia may differ depending on the underlying disease; however, as its pathogenesis is unclear, the pharmacological action of each drug is therefore unknown.
Here, we report a case of catatonia associated with late-life psychosis that was successfully treated with lithium.
Case presentation
The patient was a 66-year-old single man, who worked for a cleaning company, and had hearing impairment; however, there was no evident medical history of psychiatric disorders. He was found lying in front of his apartment and was sent to the emergency room. A physical examination revealed fracture of the left patella and calcaneus, which appeared to be related to trauma. He kept his eyes closed for most of the day and demonstrated no spontaneous speech or reaction. Although his blood tests showed inflammatory reaction, his vital signs were normal, and computed tomography and electroencephalography of his brain showed no significant findings. He had no relatives and there was no life history information of him. According to the information of the neighboring residents, he had exhibited strange behaviors since about 2 months before admission and often annoyed the neighbors. Before his arrival to the emergency department, a neighbor called the police because the patient had stood in front of his apartment for a long time. While in detention, he did not respond to the police interrogations at all; he was found lying in front of his apartment a few hours after police released him. After admission to the emergency department, he was consulted with our department for the assessment of psychotic symptoms by his physician. Including the process leading to hospitalization, he was diagnosed with catatonia based on the presence of stupor, mutism, and negativism which was detected from the information by the police about the patients’ uncooperative behavior during detention. He was started on intravenous administration of 5 mg/day midazolam, which was switched to lorazepam, administered through a feeding tube. He then gradually opened his eyes and started speaking. He stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He was, therefore, suspected to have hallucinations and delusions. He subsequently developed fever, and the blood tests showed an inflammatory reaction with creatine kinase (CK) elevation; antibiotics were accordingly administered for infection at the injury site. The dose of lorazepam was tapered to 2 mg/day because he developed delirium; after normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. His delirium improved, and he was able to eat by himself; however, he spent more time lying down with his eyes closed. Considering the possibility of oversedation, lorazepam was tapered to a dose of 1 mg/day. Since he appeared to have improved slightly, the dose of blonanserin patch was increased to 40 mg/day, and lorazepam was terminated. However, he spent most of his time in bed, and eating became difficult. Although he was a suitable candidate for ECT, it was unavailable in our facility. We tried to transfer the facility where ECT was available; however, it was full. Lithium was, therefore, added, and blonanserin patch was terminated; he opened his eyes and began to move after the dose of lithium was increased to 400 mg/day, and he began to eat and talk. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day, the dose of 400 mg/day was maintained after obtaining informed consent, based on the blood concentration results (Fig. 1). He mentioned that he had graduated from high school and had no history of alcohol or drug abuse. At age 60, he moved to his present apartment after changing jobs, and had developed hallucinations approximately a year before hospitalization. On examination, his mini-mental state examination (MMSE) score was 26; some points were lost on 3-step command (minus 2) and delayed recall (minus 2) tasks, suggesting that there was no remarkable cognitive dysfunction. He was, therefore, transferred to a rehabilitation facility.Fig. 1 Clinical course of a case of catatonia associated with late paraphrenia. A 66-year-old man with catatonic stupor initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident because he stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He subsequently developed delirium with fever and creatine kinase (CK) level elevation and the dose of lorazepam was tapered to 2 mg/day. After normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. The dose of the blonanserin patch was increased to 40 mg/day, and lorazepam was terminated; however, it was not effective. Although he was a suitable candidate for ECT, it was unavailable in our facility. Lithium was, therefore, added, and the blonanserin patch was terminated; his catatonic and psychotic symptoms were finally relieved by lithium monotherapy. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day (0.86 mEq/ml), the dose of 400 mg/day (0.50 mEq/ml) was maintained after obtaining informed consent, based on the blood concentration results. Li blood concentration of lithium, CK creatine kinase
Discussion and conclusions
This report describes the case of a single elderly man with hearing impairment, who developed hallucination and delusions and presented with catatonia at the last minute before his fall. There were no remarkable brain organic abnormalities which possibly cause catatonic symptoms, suggesting that his psychotic and catatonic symptoms were not derived from either trauma or drugs used after admission. His premorbid social function was almost normal enough to work for cleaning company, and the results of cognitive function tests performed after his psychiatric symptoms improved showed that he did not have remarkable neurocognitive impairment leading to social dysfunction. He had sensory deficit, which is common in late paraphrenia [9], and developed psychotic symptoms after 60 years of age without any evident history of psychiatric disorders. This suggested that his catatonia occurred because of late-life psychosis called as late paraphrenia, which has been recognized to be independent of schizophrenia [10]. Although the patient showed no remarkable cognitive dysfunction in MMSE, we could not rule out the possibility of neurocognitive deficit of the patient because there was no other neurocognitive examination of the patient to assess cognitive impairment. A previous review of paraphrenia has reported that the pathology of paraphrenia is similar to that of the neurofibrillary tangles, which are the predominant form of senile dementia [11]. His psychotic episode could have represented the prodromal symptoms of dementia; he therefore needs to be followed up closely for the progressive of cognitive dysfunction in the future.
The patient had initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident; however, its efficacy was limited. Some patients with catatonia fail to respond to benzodiazepines, with approximately 30% of patients showing only partial response [12, 13]; in particular, cases that occur secondary to schizophrenia have been reported to be less likely to respond to benzodiazepines [14, 15]. Moreover, benzodiazepine use is not suitable for elderly patients, considering the risk of delirium. Atypical antipsychotics have been recommended as one of the alternative treatment strategies for catatonia [8]; however, blonanserin did not improve his catatonia. Finally, both his catatonic and psychotic symptoms were completely resolved by lithium monotherapy. Catatonic symptoms are more common in patients with mood disorders than in those with schizophrenia [5], suggesting that lithium may be effective for catatonia. Although previous case reports advocate the effectiveness of lithium in preventing recurrence of catatonia [16, 17], there is no evidence of its effectiveness in the acute phase.
Although the pathogenesis of catatonia remains poorly understood, the neurochemical hypothesis suggests that alterations in various neurotransmission systems, including gamma-aminobutyric acid (GABA) and glutamate, play a role [18, 19]. Even if the effects of benzodiazepines on the GABA system in the brain are limited, ECT has a high response rate, suggesting that catatonia may be the final common outcome for abnormal brain seizure activity [20]. In the present case, antiepileptic drugs which are candidates of the alternative treatment strategies for catatonia [8] were not administrated due to no remarkable abnormalities of electroencephalography. Finally, lithium was used because the effect of benzodiazepine was limited and ECT was unavailable. A previous study, using induced pluripotent stem cells (iPSCs) derived from neuronal cells of patients with bipolar disorders, has reported that the hyperexcitability phenotype of young neurons was selectively reversed by lithium only in lithium responders [21]. Moreover, a recent study using iPSCs derived from monozygotic twins discordant for major psychosis has suggested that lithium may normalize unbalanced specification of excitatory and inhibitory neurons in major psychosis neural circuits, by activating the Wnt signaling pathway [22]. In the present case of catatonia associated with late-life psychosis, lithium, although not as fast-acting as ECT, was effective for both catatonic and psychotic symptoms, as it normalized unbalanced specification of excitatory and inhibitory systems in the brain.
To the best of our knowledge, this is the first report on the efficacy of lithium in the acute phase of catatonia. There was a previous report of lithium therapy for catatonia features in autism spectrum disorder patients [23] and the another reported the case of catatonia cause by lithium overdose [24], suggesting that the action and effects of lithium on neurons numerous and diverse. Future studies are needed to elucidate the pathogenesis of catatonia to identify the most reliable treatment.
Abbreviations
ECTElectroconvulsive therapy
iPSCsInduced pluripotent stem cells
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank to all staff involved in the medical care of this patient.
Authors’ contributions
HS and JT were involved in the management of the patient. This case report was written by HS. MH and MI revised the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The data used for this case report is available from the corresponding authors on reasonable request.
Ethics approval and consent to participate
Ethics committee in Kansai Rosai Hospital approved for the publication of this case report.
Consent for publication
Written informed consent has been obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests. This edit was made to conform to the format of the journal guidelines. | Recovering | ReactionOutcome | CC BY | 33602282 | 19,742,073 | 2021-02-18 |
What was the outcome of reaction 'Delusion'? | Catatonia associated with late-life psychosis successfully treated with lithium: a case report.
BACKGROUND
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition. Its pathogenesis is poorly understood. Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia; however, alternative treatment strategies have not been established in cases where these treatments are either ineffective or unavailable. Here, we report a case of catatonia associated with late-life psychosis, which was successfully treated with lithium.
METHODS
A 66-year-old single man with hearing impairment developed hallucination and delusions and presented with catatonic stupor after a fall. He initially responded to benzodiazepine therapy; however, his psychotic symptoms became clinically evident and benzodiazepine provided limited efficacy. Blonanserin was ineffective, and ECT was unavailable. His catatonic and psychotic symptoms were finally relieved by lithium monotherapy.
CONCLUSIONS
Catatonic symptoms are common in patients with mood disorders, suggesting that lithium may be effective in these cases. Moreover, lithium may be effective for both catatonic and psychotic symptoms, as it normalizes imbalances of excitatory and inhibitory systems in the brain, which underlies major psychosis. Cumulative evidence from further cases is needed to validate our findings.
Background
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition; its pathogenesis is poorly understood [1]. Catatonia was once recognized as a subtype of schizophrenia; however, the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) removed it from all schizophrenia subtypes, and defined it as a specifier of various psychiatric disorders or medical conditions [2]. Indeed, catatonia has been reported to be associated with a variety of medical conditions [3, 4]. Moreover, a previous study has reported that catatonic symptoms were more common in patients with manic or mixed episodes (28–31%) than in those with schizophrenia (10–15%) [5]. A prospective cohort study has also reported the incidence of catatonia to be only 7.6% in patients with schizophrenia [6].
Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia, particularly in acute cases; however, benzodiazepines show limited efficacy in a considerable number of patients [7], and available facilities for ECT are limited. In cases where benzodiazepines are ineffective and ECT is unavailable, a systematic review of alternative treatment strategies proposed glutamate antagonists, antiepileptic drugs, and atypical antipsychotics as first-, second-, and third-line treatments for catatonia, respectively [8]. The proper alternative treatment of catatonia may differ depending on the underlying disease; however, as its pathogenesis is unclear, the pharmacological action of each drug is therefore unknown.
Here, we report a case of catatonia associated with late-life psychosis that was successfully treated with lithium.
Case presentation
The patient was a 66-year-old single man, who worked for a cleaning company, and had hearing impairment; however, there was no evident medical history of psychiatric disorders. He was found lying in front of his apartment and was sent to the emergency room. A physical examination revealed fracture of the left patella and calcaneus, which appeared to be related to trauma. He kept his eyes closed for most of the day and demonstrated no spontaneous speech or reaction. Although his blood tests showed inflammatory reaction, his vital signs were normal, and computed tomography and electroencephalography of his brain showed no significant findings. He had no relatives and there was no life history information of him. According to the information of the neighboring residents, he had exhibited strange behaviors since about 2 months before admission and often annoyed the neighbors. Before his arrival to the emergency department, a neighbor called the police because the patient had stood in front of his apartment for a long time. While in detention, he did not respond to the police interrogations at all; he was found lying in front of his apartment a few hours after police released him. After admission to the emergency department, he was consulted with our department for the assessment of psychotic symptoms by his physician. Including the process leading to hospitalization, he was diagnosed with catatonia based on the presence of stupor, mutism, and negativism which was detected from the information by the police about the patients’ uncooperative behavior during detention. He was started on intravenous administration of 5 mg/day midazolam, which was switched to lorazepam, administered through a feeding tube. He then gradually opened his eyes and started speaking. He stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He was, therefore, suspected to have hallucinations and delusions. He subsequently developed fever, and the blood tests showed an inflammatory reaction with creatine kinase (CK) elevation; antibiotics were accordingly administered for infection at the injury site. The dose of lorazepam was tapered to 2 mg/day because he developed delirium; after normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. His delirium improved, and he was able to eat by himself; however, he spent more time lying down with his eyes closed. Considering the possibility of oversedation, lorazepam was tapered to a dose of 1 mg/day. Since he appeared to have improved slightly, the dose of blonanserin patch was increased to 40 mg/day, and lorazepam was terminated. However, he spent most of his time in bed, and eating became difficult. Although he was a suitable candidate for ECT, it was unavailable in our facility. We tried to transfer the facility where ECT was available; however, it was full. Lithium was, therefore, added, and blonanserin patch was terminated; he opened his eyes and began to move after the dose of lithium was increased to 400 mg/day, and he began to eat and talk. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day, the dose of 400 mg/day was maintained after obtaining informed consent, based on the blood concentration results (Fig. 1). He mentioned that he had graduated from high school and had no history of alcohol or drug abuse. At age 60, he moved to his present apartment after changing jobs, and had developed hallucinations approximately a year before hospitalization. On examination, his mini-mental state examination (MMSE) score was 26; some points were lost on 3-step command (minus 2) and delayed recall (minus 2) tasks, suggesting that there was no remarkable cognitive dysfunction. He was, therefore, transferred to a rehabilitation facility.Fig. 1 Clinical course of a case of catatonia associated with late paraphrenia. A 66-year-old man with catatonic stupor initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident because he stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He subsequently developed delirium with fever and creatine kinase (CK) level elevation and the dose of lorazepam was tapered to 2 mg/day. After normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. The dose of the blonanserin patch was increased to 40 mg/day, and lorazepam was terminated; however, it was not effective. Although he was a suitable candidate for ECT, it was unavailable in our facility. Lithium was, therefore, added, and the blonanserin patch was terminated; his catatonic and psychotic symptoms were finally relieved by lithium monotherapy. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day (0.86 mEq/ml), the dose of 400 mg/day (0.50 mEq/ml) was maintained after obtaining informed consent, based on the blood concentration results. Li blood concentration of lithium, CK creatine kinase
Discussion and conclusions
This report describes the case of a single elderly man with hearing impairment, who developed hallucination and delusions and presented with catatonia at the last minute before his fall. There were no remarkable brain organic abnormalities which possibly cause catatonic symptoms, suggesting that his psychotic and catatonic symptoms were not derived from either trauma or drugs used after admission. His premorbid social function was almost normal enough to work for cleaning company, and the results of cognitive function tests performed after his psychiatric symptoms improved showed that he did not have remarkable neurocognitive impairment leading to social dysfunction. He had sensory deficit, which is common in late paraphrenia [9], and developed psychotic symptoms after 60 years of age without any evident history of psychiatric disorders. This suggested that his catatonia occurred because of late-life psychosis called as late paraphrenia, which has been recognized to be independent of schizophrenia [10]. Although the patient showed no remarkable cognitive dysfunction in MMSE, we could not rule out the possibility of neurocognitive deficit of the patient because there was no other neurocognitive examination of the patient to assess cognitive impairment. A previous review of paraphrenia has reported that the pathology of paraphrenia is similar to that of the neurofibrillary tangles, which are the predominant form of senile dementia [11]. His psychotic episode could have represented the prodromal symptoms of dementia; he therefore needs to be followed up closely for the progressive of cognitive dysfunction in the future.
The patient had initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident; however, its efficacy was limited. Some patients with catatonia fail to respond to benzodiazepines, with approximately 30% of patients showing only partial response [12, 13]; in particular, cases that occur secondary to schizophrenia have been reported to be less likely to respond to benzodiazepines [14, 15]. Moreover, benzodiazepine use is not suitable for elderly patients, considering the risk of delirium. Atypical antipsychotics have been recommended as one of the alternative treatment strategies for catatonia [8]; however, blonanserin did not improve his catatonia. Finally, both his catatonic and psychotic symptoms were completely resolved by lithium monotherapy. Catatonic symptoms are more common in patients with mood disorders than in those with schizophrenia [5], suggesting that lithium may be effective for catatonia. Although previous case reports advocate the effectiveness of lithium in preventing recurrence of catatonia [16, 17], there is no evidence of its effectiveness in the acute phase.
Although the pathogenesis of catatonia remains poorly understood, the neurochemical hypothesis suggests that alterations in various neurotransmission systems, including gamma-aminobutyric acid (GABA) and glutamate, play a role [18, 19]. Even if the effects of benzodiazepines on the GABA system in the brain are limited, ECT has a high response rate, suggesting that catatonia may be the final common outcome for abnormal brain seizure activity [20]. In the present case, antiepileptic drugs which are candidates of the alternative treatment strategies for catatonia [8] were not administrated due to no remarkable abnormalities of electroencephalography. Finally, lithium was used because the effect of benzodiazepine was limited and ECT was unavailable. A previous study, using induced pluripotent stem cells (iPSCs) derived from neuronal cells of patients with bipolar disorders, has reported that the hyperexcitability phenotype of young neurons was selectively reversed by lithium only in lithium responders [21]. Moreover, a recent study using iPSCs derived from monozygotic twins discordant for major psychosis has suggested that lithium may normalize unbalanced specification of excitatory and inhibitory neurons in major psychosis neural circuits, by activating the Wnt signaling pathway [22]. In the present case of catatonia associated with late-life psychosis, lithium, although not as fast-acting as ECT, was effective for both catatonic and psychotic symptoms, as it normalized unbalanced specification of excitatory and inhibitory systems in the brain.
To the best of our knowledge, this is the first report on the efficacy of lithium in the acute phase of catatonia. There was a previous report of lithium therapy for catatonia features in autism spectrum disorder patients [23] and the another reported the case of catatonia cause by lithium overdose [24], suggesting that the action and effects of lithium on neurons numerous and diverse. Future studies are needed to elucidate the pathogenesis of catatonia to identify the most reliable treatment.
Abbreviations
ECTElectroconvulsive therapy
iPSCsInduced pluripotent stem cells
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank to all staff involved in the medical care of this patient.
Authors’ contributions
HS and JT were involved in the management of the patient. This case report was written by HS. MH and MI revised the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The data used for this case report is available from the corresponding authors on reasonable request.
Ethics approval and consent to participate
Ethics committee in Kansai Rosai Hospital approved for the publication of this case report.
Consent for publication
Written informed consent has been obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests. This edit was made to conform to the format of the journal guidelines. | Recovered | ReactionOutcome | CC BY | 33602282 | 19,733,655 | 2021-02-18 |
What was the outcome of reaction 'Hallucination'? | Catatonia associated with late-life psychosis successfully treated with lithium: a case report.
BACKGROUND
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition. Its pathogenesis is poorly understood. Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia; however, alternative treatment strategies have not been established in cases where these treatments are either ineffective or unavailable. Here, we report a case of catatonia associated with late-life psychosis, which was successfully treated with lithium.
METHODS
A 66-year-old single man with hearing impairment developed hallucination and delusions and presented with catatonic stupor after a fall. He initially responded to benzodiazepine therapy; however, his psychotic symptoms became clinically evident and benzodiazepine provided limited efficacy. Blonanserin was ineffective, and ECT was unavailable. His catatonic and psychotic symptoms were finally relieved by lithium monotherapy.
CONCLUSIONS
Catatonic symptoms are common in patients with mood disorders, suggesting that lithium may be effective in these cases. Moreover, lithium may be effective for both catatonic and psychotic symptoms, as it normalizes imbalances of excitatory and inhibitory systems in the brain, which underlies major psychosis. Cumulative evidence from further cases is needed to validate our findings.
Background
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition; its pathogenesis is poorly understood [1]. Catatonia was once recognized as a subtype of schizophrenia; however, the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) removed it from all schizophrenia subtypes, and defined it as a specifier of various psychiatric disorders or medical conditions [2]. Indeed, catatonia has been reported to be associated with a variety of medical conditions [3, 4]. Moreover, a previous study has reported that catatonic symptoms were more common in patients with manic or mixed episodes (28–31%) than in those with schizophrenia (10–15%) [5]. A prospective cohort study has also reported the incidence of catatonia to be only 7.6% in patients with schizophrenia [6].
Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia, particularly in acute cases; however, benzodiazepines show limited efficacy in a considerable number of patients [7], and available facilities for ECT are limited. In cases where benzodiazepines are ineffective and ECT is unavailable, a systematic review of alternative treatment strategies proposed glutamate antagonists, antiepileptic drugs, and atypical antipsychotics as first-, second-, and third-line treatments for catatonia, respectively [8]. The proper alternative treatment of catatonia may differ depending on the underlying disease; however, as its pathogenesis is unclear, the pharmacological action of each drug is therefore unknown.
Here, we report a case of catatonia associated with late-life psychosis that was successfully treated with lithium.
Case presentation
The patient was a 66-year-old single man, who worked for a cleaning company, and had hearing impairment; however, there was no evident medical history of psychiatric disorders. He was found lying in front of his apartment and was sent to the emergency room. A physical examination revealed fracture of the left patella and calcaneus, which appeared to be related to trauma. He kept his eyes closed for most of the day and demonstrated no spontaneous speech or reaction. Although his blood tests showed inflammatory reaction, his vital signs were normal, and computed tomography and electroencephalography of his brain showed no significant findings. He had no relatives and there was no life history information of him. According to the information of the neighboring residents, he had exhibited strange behaviors since about 2 months before admission and often annoyed the neighbors. Before his arrival to the emergency department, a neighbor called the police because the patient had stood in front of his apartment for a long time. While in detention, he did not respond to the police interrogations at all; he was found lying in front of his apartment a few hours after police released him. After admission to the emergency department, he was consulted with our department for the assessment of psychotic symptoms by his physician. Including the process leading to hospitalization, he was diagnosed with catatonia based on the presence of stupor, mutism, and negativism which was detected from the information by the police about the patients’ uncooperative behavior during detention. He was started on intravenous administration of 5 mg/day midazolam, which was switched to lorazepam, administered through a feeding tube. He then gradually opened his eyes and started speaking. He stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He was, therefore, suspected to have hallucinations and delusions. He subsequently developed fever, and the blood tests showed an inflammatory reaction with creatine kinase (CK) elevation; antibiotics were accordingly administered for infection at the injury site. The dose of lorazepam was tapered to 2 mg/day because he developed delirium; after normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. His delirium improved, and he was able to eat by himself; however, he spent more time lying down with his eyes closed. Considering the possibility of oversedation, lorazepam was tapered to a dose of 1 mg/day. Since he appeared to have improved slightly, the dose of blonanserin patch was increased to 40 mg/day, and lorazepam was terminated. However, he spent most of his time in bed, and eating became difficult. Although he was a suitable candidate for ECT, it was unavailable in our facility. We tried to transfer the facility where ECT was available; however, it was full. Lithium was, therefore, added, and blonanserin patch was terminated; he opened his eyes and began to move after the dose of lithium was increased to 400 mg/day, and he began to eat and talk. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day, the dose of 400 mg/day was maintained after obtaining informed consent, based on the blood concentration results (Fig. 1). He mentioned that he had graduated from high school and had no history of alcohol or drug abuse. At age 60, he moved to his present apartment after changing jobs, and had developed hallucinations approximately a year before hospitalization. On examination, his mini-mental state examination (MMSE) score was 26; some points were lost on 3-step command (minus 2) and delayed recall (minus 2) tasks, suggesting that there was no remarkable cognitive dysfunction. He was, therefore, transferred to a rehabilitation facility.Fig. 1 Clinical course of a case of catatonia associated with late paraphrenia. A 66-year-old man with catatonic stupor initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident because he stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He subsequently developed delirium with fever and creatine kinase (CK) level elevation and the dose of lorazepam was tapered to 2 mg/day. After normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. The dose of the blonanserin patch was increased to 40 mg/day, and lorazepam was terminated; however, it was not effective. Although he was a suitable candidate for ECT, it was unavailable in our facility. Lithium was, therefore, added, and the blonanserin patch was terminated; his catatonic and psychotic symptoms were finally relieved by lithium monotherapy. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day (0.86 mEq/ml), the dose of 400 mg/day (0.50 mEq/ml) was maintained after obtaining informed consent, based on the blood concentration results. Li blood concentration of lithium, CK creatine kinase
Discussion and conclusions
This report describes the case of a single elderly man with hearing impairment, who developed hallucination and delusions and presented with catatonia at the last minute before his fall. There were no remarkable brain organic abnormalities which possibly cause catatonic symptoms, suggesting that his psychotic and catatonic symptoms were not derived from either trauma or drugs used after admission. His premorbid social function was almost normal enough to work for cleaning company, and the results of cognitive function tests performed after his psychiatric symptoms improved showed that he did not have remarkable neurocognitive impairment leading to social dysfunction. He had sensory deficit, which is common in late paraphrenia [9], and developed psychotic symptoms after 60 years of age without any evident history of psychiatric disorders. This suggested that his catatonia occurred because of late-life psychosis called as late paraphrenia, which has been recognized to be independent of schizophrenia [10]. Although the patient showed no remarkable cognitive dysfunction in MMSE, we could not rule out the possibility of neurocognitive deficit of the patient because there was no other neurocognitive examination of the patient to assess cognitive impairment. A previous review of paraphrenia has reported that the pathology of paraphrenia is similar to that of the neurofibrillary tangles, which are the predominant form of senile dementia [11]. His psychotic episode could have represented the prodromal symptoms of dementia; he therefore needs to be followed up closely for the progressive of cognitive dysfunction in the future.
The patient had initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident; however, its efficacy was limited. Some patients with catatonia fail to respond to benzodiazepines, with approximately 30% of patients showing only partial response [12, 13]; in particular, cases that occur secondary to schizophrenia have been reported to be less likely to respond to benzodiazepines [14, 15]. Moreover, benzodiazepine use is not suitable for elderly patients, considering the risk of delirium. Atypical antipsychotics have been recommended as one of the alternative treatment strategies for catatonia [8]; however, blonanserin did not improve his catatonia. Finally, both his catatonic and psychotic symptoms were completely resolved by lithium monotherapy. Catatonic symptoms are more common in patients with mood disorders than in those with schizophrenia [5], suggesting that lithium may be effective for catatonia. Although previous case reports advocate the effectiveness of lithium in preventing recurrence of catatonia [16, 17], there is no evidence of its effectiveness in the acute phase.
Although the pathogenesis of catatonia remains poorly understood, the neurochemical hypothesis suggests that alterations in various neurotransmission systems, including gamma-aminobutyric acid (GABA) and glutamate, play a role [18, 19]. Even if the effects of benzodiazepines on the GABA system in the brain are limited, ECT has a high response rate, suggesting that catatonia may be the final common outcome for abnormal brain seizure activity [20]. In the present case, antiepileptic drugs which are candidates of the alternative treatment strategies for catatonia [8] were not administrated due to no remarkable abnormalities of electroencephalography. Finally, lithium was used because the effect of benzodiazepine was limited and ECT was unavailable. A previous study, using induced pluripotent stem cells (iPSCs) derived from neuronal cells of patients with bipolar disorders, has reported that the hyperexcitability phenotype of young neurons was selectively reversed by lithium only in lithium responders [21]. Moreover, a recent study using iPSCs derived from monozygotic twins discordant for major psychosis has suggested that lithium may normalize unbalanced specification of excitatory and inhibitory neurons in major psychosis neural circuits, by activating the Wnt signaling pathway [22]. In the present case of catatonia associated with late-life psychosis, lithium, although not as fast-acting as ECT, was effective for both catatonic and psychotic symptoms, as it normalized unbalanced specification of excitatory and inhibitory systems in the brain.
To the best of our knowledge, this is the first report on the efficacy of lithium in the acute phase of catatonia. There was a previous report of lithium therapy for catatonia features in autism spectrum disorder patients [23] and the another reported the case of catatonia cause by lithium overdose [24], suggesting that the action and effects of lithium on neurons numerous and diverse. Future studies are needed to elucidate the pathogenesis of catatonia to identify the most reliable treatment.
Abbreviations
ECTElectroconvulsive therapy
iPSCsInduced pluripotent stem cells
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank to all staff involved in the medical care of this patient.
Authors’ contributions
HS and JT were involved in the management of the patient. This case report was written by HS. MH and MI revised the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The data used for this case report is available from the corresponding authors on reasonable request.
Ethics approval and consent to participate
Ethics committee in Kansai Rosai Hospital approved for the publication of this case report.
Consent for publication
Written informed consent has been obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests. This edit was made to conform to the format of the journal guidelines. | Recovered | ReactionOutcome | CC BY | 33602282 | 19,733,655 | 2021-02-18 |
What was the outcome of reaction 'Sedation complication'? | Catatonia associated with late-life psychosis successfully treated with lithium: a case report.
BACKGROUND
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition. Its pathogenesis is poorly understood. Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia; however, alternative treatment strategies have not been established in cases where these treatments are either ineffective or unavailable. Here, we report a case of catatonia associated with late-life psychosis, which was successfully treated with lithium.
METHODS
A 66-year-old single man with hearing impairment developed hallucination and delusions and presented with catatonic stupor after a fall. He initially responded to benzodiazepine therapy; however, his psychotic symptoms became clinically evident and benzodiazepine provided limited efficacy. Blonanserin was ineffective, and ECT was unavailable. His catatonic and psychotic symptoms were finally relieved by lithium monotherapy.
CONCLUSIONS
Catatonic symptoms are common in patients with mood disorders, suggesting that lithium may be effective in these cases. Moreover, lithium may be effective for both catatonic and psychotic symptoms, as it normalizes imbalances of excitatory and inhibitory systems in the brain, which underlies major psychosis. Cumulative evidence from further cases is needed to validate our findings.
Background
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition; its pathogenesis is poorly understood [1]. Catatonia was once recognized as a subtype of schizophrenia; however, the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) removed it from all schizophrenia subtypes, and defined it as a specifier of various psychiatric disorders or medical conditions [2]. Indeed, catatonia has been reported to be associated with a variety of medical conditions [3, 4]. Moreover, a previous study has reported that catatonic symptoms were more common in patients with manic or mixed episodes (28–31%) than in those with schizophrenia (10–15%) [5]. A prospective cohort study has also reported the incidence of catatonia to be only 7.6% in patients with schizophrenia [6].
Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia, particularly in acute cases; however, benzodiazepines show limited efficacy in a considerable number of patients [7], and available facilities for ECT are limited. In cases where benzodiazepines are ineffective and ECT is unavailable, a systematic review of alternative treatment strategies proposed glutamate antagonists, antiepileptic drugs, and atypical antipsychotics as first-, second-, and third-line treatments for catatonia, respectively [8]. The proper alternative treatment of catatonia may differ depending on the underlying disease; however, as its pathogenesis is unclear, the pharmacological action of each drug is therefore unknown.
Here, we report a case of catatonia associated with late-life psychosis that was successfully treated with lithium.
Case presentation
The patient was a 66-year-old single man, who worked for a cleaning company, and had hearing impairment; however, there was no evident medical history of psychiatric disorders. He was found lying in front of his apartment and was sent to the emergency room. A physical examination revealed fracture of the left patella and calcaneus, which appeared to be related to trauma. He kept his eyes closed for most of the day and demonstrated no spontaneous speech or reaction. Although his blood tests showed inflammatory reaction, his vital signs were normal, and computed tomography and electroencephalography of his brain showed no significant findings. He had no relatives and there was no life history information of him. According to the information of the neighboring residents, he had exhibited strange behaviors since about 2 months before admission and often annoyed the neighbors. Before his arrival to the emergency department, a neighbor called the police because the patient had stood in front of his apartment for a long time. While in detention, he did not respond to the police interrogations at all; he was found lying in front of his apartment a few hours after police released him. After admission to the emergency department, he was consulted with our department for the assessment of psychotic symptoms by his physician. Including the process leading to hospitalization, he was diagnosed with catatonia based on the presence of stupor, mutism, and negativism which was detected from the information by the police about the patients’ uncooperative behavior during detention. He was started on intravenous administration of 5 mg/day midazolam, which was switched to lorazepam, administered through a feeding tube. He then gradually opened his eyes and started speaking. He stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He was, therefore, suspected to have hallucinations and delusions. He subsequently developed fever, and the blood tests showed an inflammatory reaction with creatine kinase (CK) elevation; antibiotics were accordingly administered for infection at the injury site. The dose of lorazepam was tapered to 2 mg/day because he developed delirium; after normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. His delirium improved, and he was able to eat by himself; however, he spent more time lying down with his eyes closed. Considering the possibility of oversedation, lorazepam was tapered to a dose of 1 mg/day. Since he appeared to have improved slightly, the dose of blonanserin patch was increased to 40 mg/day, and lorazepam was terminated. However, he spent most of his time in bed, and eating became difficult. Although he was a suitable candidate for ECT, it was unavailable in our facility. We tried to transfer the facility where ECT was available; however, it was full. Lithium was, therefore, added, and blonanserin patch was terminated; he opened his eyes and began to move after the dose of lithium was increased to 400 mg/day, and he began to eat and talk. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day, the dose of 400 mg/day was maintained after obtaining informed consent, based on the blood concentration results (Fig. 1). He mentioned that he had graduated from high school and had no history of alcohol or drug abuse. At age 60, he moved to his present apartment after changing jobs, and had developed hallucinations approximately a year before hospitalization. On examination, his mini-mental state examination (MMSE) score was 26; some points were lost on 3-step command (minus 2) and delayed recall (minus 2) tasks, suggesting that there was no remarkable cognitive dysfunction. He was, therefore, transferred to a rehabilitation facility.Fig. 1 Clinical course of a case of catatonia associated with late paraphrenia. A 66-year-old man with catatonic stupor initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident because he stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He subsequently developed delirium with fever and creatine kinase (CK) level elevation and the dose of lorazepam was tapered to 2 mg/day. After normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. The dose of the blonanserin patch was increased to 40 mg/day, and lorazepam was terminated; however, it was not effective. Although he was a suitable candidate for ECT, it was unavailable in our facility. Lithium was, therefore, added, and the blonanserin patch was terminated; his catatonic and psychotic symptoms were finally relieved by lithium monotherapy. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day (0.86 mEq/ml), the dose of 400 mg/day (0.50 mEq/ml) was maintained after obtaining informed consent, based on the blood concentration results. Li blood concentration of lithium, CK creatine kinase
Discussion and conclusions
This report describes the case of a single elderly man with hearing impairment, who developed hallucination and delusions and presented with catatonia at the last minute before his fall. There were no remarkable brain organic abnormalities which possibly cause catatonic symptoms, suggesting that his psychotic and catatonic symptoms were not derived from either trauma or drugs used after admission. His premorbid social function was almost normal enough to work for cleaning company, and the results of cognitive function tests performed after his psychiatric symptoms improved showed that he did not have remarkable neurocognitive impairment leading to social dysfunction. He had sensory deficit, which is common in late paraphrenia [9], and developed psychotic symptoms after 60 years of age without any evident history of psychiatric disorders. This suggested that his catatonia occurred because of late-life psychosis called as late paraphrenia, which has been recognized to be independent of schizophrenia [10]. Although the patient showed no remarkable cognitive dysfunction in MMSE, we could not rule out the possibility of neurocognitive deficit of the patient because there was no other neurocognitive examination of the patient to assess cognitive impairment. A previous review of paraphrenia has reported that the pathology of paraphrenia is similar to that of the neurofibrillary tangles, which are the predominant form of senile dementia [11]. His psychotic episode could have represented the prodromal symptoms of dementia; he therefore needs to be followed up closely for the progressive of cognitive dysfunction in the future.
The patient had initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident; however, its efficacy was limited. Some patients with catatonia fail to respond to benzodiazepines, with approximately 30% of patients showing only partial response [12, 13]; in particular, cases that occur secondary to schizophrenia have been reported to be less likely to respond to benzodiazepines [14, 15]. Moreover, benzodiazepine use is not suitable for elderly patients, considering the risk of delirium. Atypical antipsychotics have been recommended as one of the alternative treatment strategies for catatonia [8]; however, blonanserin did not improve his catatonia. Finally, both his catatonic and psychotic symptoms were completely resolved by lithium monotherapy. Catatonic symptoms are more common in patients with mood disorders than in those with schizophrenia [5], suggesting that lithium may be effective for catatonia. Although previous case reports advocate the effectiveness of lithium in preventing recurrence of catatonia [16, 17], there is no evidence of its effectiveness in the acute phase.
Although the pathogenesis of catatonia remains poorly understood, the neurochemical hypothesis suggests that alterations in various neurotransmission systems, including gamma-aminobutyric acid (GABA) and glutamate, play a role [18, 19]. Even if the effects of benzodiazepines on the GABA system in the brain are limited, ECT has a high response rate, suggesting that catatonia may be the final common outcome for abnormal brain seizure activity [20]. In the present case, antiepileptic drugs which are candidates of the alternative treatment strategies for catatonia [8] were not administrated due to no remarkable abnormalities of electroencephalography. Finally, lithium was used because the effect of benzodiazepine was limited and ECT was unavailable. A previous study, using induced pluripotent stem cells (iPSCs) derived from neuronal cells of patients with bipolar disorders, has reported that the hyperexcitability phenotype of young neurons was selectively reversed by lithium only in lithium responders [21]. Moreover, a recent study using iPSCs derived from monozygotic twins discordant for major psychosis has suggested that lithium may normalize unbalanced specification of excitatory and inhibitory neurons in major psychosis neural circuits, by activating the Wnt signaling pathway [22]. In the present case of catatonia associated with late-life psychosis, lithium, although not as fast-acting as ECT, was effective for both catatonic and psychotic symptoms, as it normalized unbalanced specification of excitatory and inhibitory systems in the brain.
To the best of our knowledge, this is the first report on the efficacy of lithium in the acute phase of catatonia. There was a previous report of lithium therapy for catatonia features in autism spectrum disorder patients [23] and the another reported the case of catatonia cause by lithium overdose [24], suggesting that the action and effects of lithium on neurons numerous and diverse. Future studies are needed to elucidate the pathogenesis of catatonia to identify the most reliable treatment.
Abbreviations
ECTElectroconvulsive therapy
iPSCsInduced pluripotent stem cells
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank to all staff involved in the medical care of this patient.
Authors’ contributions
HS and JT were involved in the management of the patient. This case report was written by HS. MH and MI revised the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The data used for this case report is available from the corresponding authors on reasonable request.
Ethics approval and consent to participate
Ethics committee in Kansai Rosai Hospital approved for the publication of this case report.
Consent for publication
Written informed consent has been obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests. This edit was made to conform to the format of the journal guidelines. | Recovered | ReactionOutcome | CC BY | 33602282 | 19,742,073 | 2021-02-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Immune-mediated adrenal insuficiency'. | Symptomatic methemoglobinemia in a patient with metastatic clear cell renal cell carcinoma treated with pembrolizumab and axitinib combination therapy: a case report.
BACKGROUND
Combination regimens that include immune checkpoint (ICI) and vascular endothelial growth factor (VEGF) inhibition have opened the door to new treatment opportunities for patients with metastatic renal cell carcinoma (mRCC). While these treatment options have provided improved tolerability and better outcomes compared to older regimens, many patients still experience a myriad of treatment-related adverse events. Given that these regimens were recently approved for mRCC, the complete side effect profile may not be fully elucidated yet.
METHODS
We report a case of a 73-year old White male with mRCC who was managed with an ICI-VEGF inhibitor combination regimen. He experienced a partial response (Fig. 1) but had side effects including symptomatic cyanosis diagnosed as methemoglobinemia which led to treatment discontinuation. Upon holding his therapy, his methemoglobinemia and cyanosis resolved.
CONCLUSIONS
Combination VEGF-ICI therapy provide novel regimens for advanced solid tumor malignancies including mRCC. While shown to have improved efficacy in clinical trials, it is crucial that oncologists uncover the full side effect profile of these novel agents especially as their use becomes more standard in the management of advanced malignancies. To our knowledge, this is the first reported case of a patient experiencing symptomatic methemoglobinemia as an adverse event associated with a VEGF-ICI combination regimen. While the cause of this side effect is unclear, in this paper we attempt to elucidate a process that is in line with the mechanism of action of these therapies to explain how these agents, specifically the axitinib, could have caused the methemoglobin to rise to a symptomatic level.
Background
Vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) are small molecules that inhibit tyrosine kinase receptors involved in the VEGF pathway [1]. These types of TKIs are pathway-specific inhibitors of the angiogenic signaling process that cancers depend upon to obtain access to nutrients and to metastasize [2]. Blocking VEGF from malignant tissue effectively causes transient hypoxia, cutting off access to nutrients vital for oncogenesis. TKIs are integral to the treatment of numerous cancers including metastatic renal cell carcinoma (mRCC) [3]. Pembrolizumab is a programmed death-1 (PD-1) inhibitor that is in a class of medications called immune checkpoint inhibitors (ICIs). These agents increase T-cell activation, improving T-cell-mediated clearance of malignant cells and are used in several malignancies including mRCC [4–6]. PD-1 and VEGF-TKI combination therapy have shown efficacy and received FDA approval as the standard treatment for advanced RCC through the phase 3 KEYNOTE-426 clinical trial [7, 8]. This regimen, however, is not without side effects which can significantly impact patient quality of life and cause treatment discontinuation [5]. In the KEYNOTE-426 trial, the most commonly cited adverse events associated with pembrolizumab-axitinib were diarrhea, hypertension, fatigue and hypothyroidism [8]. In this report we are presenting, to our best knowledge, the first case of a patient with mRCC who developed cyanosis diagnosed as methemoglobinemia while on pembrolizumab-axitinib treatment. This case displays a rare but severe adverse event that could be related to ICI and VEGF-TKI combination therapy.
Case presentation
A 73-year-old White male was diagnosed with pT2NxMx clear cell RCC (ccRCC) and underwent radical nephrectomy in November of 2007. Given his family history of malignancy, he underwent genetic testing and was found to be positive for CHEK2, ATM, BLM and MLH1 mutations. He then presented twelve years later with biopsy-proven recurrence of his ccRCC in the pancreas, liver and lung. He was started on combination therapy consisting of pembrolizumab 200 mg IV q3 weeks and axitinib 5mg PO BID [8, 9]. As seen in Fig. 1, his scans two months after treatment initiation showed partial response in his metastases per RECIST v1.1. His course was complicated four months after initiation by adverse events including cystitis, hematuria, fatigue, polycythemia and peri-oral cyanosis without hypoxia. His primary care physician initiated cyanosis work-up and laboratory tests were obtained. This included a complete blood-cell count with differential, which showed a positive test for methemoglobinemia displaying a percent methemoglobin level of 3.7% exceeding the 1.5% cutoff for positivity. Additional complete blood cell-count values showed a normal erythropoietin (EPO) level and an elevated hemoglobin of 18.4 with a hematocrit of 53.8. The secondary polycythemia experienced concomitantly with the methemoglobinemia was attributed to a combination of the axitinib therapy and an RCC-associated paraneoplastic syndrome. Upon holding his axitinib for 1 week, the patient’s symptoms resolved. Follow-up laboratory tests similarly showed normalization of the residual polycythemia with a subsequent hemoglobin of 15.3 and hematocrit of 47.4. While the MetHb level was only mildly elevated during the treatment period, the patient was highly symptomatic and this reaction prompted medication adjustments. He was restarted on the same combination therapy with a reduced dose of axitinib from 5 to 3 mg. His adverse symptoms recurred and were intolerable shortly after resuming. He discontinued the pembrolizumab-axitinib therapy and transitioned three weeks later to an ipilimumab 1mg/kg IVBP and nivolumab 3mg/kg IVBP combination regimen. This subsequent regimen was discontinued due to poor tolerability from immune-related adverse events including hypothyroidism and adrenal insufficiency. His follow-up scans in January showed sustained partial response, but progression of disease in June of 2020 within the liver metastasis. In September of 2020, the patient is still alive and has begun local Y90 radiation therapy and awaits upcoming surveillance scans.Fig. 1 Axial contrast enhanced computed tomography scan of the abdomen and pelvis. Interval decreases in size of liver metastases with reference measurements are as follows: T11: 1.6 × 1.9 cm metastasis of liver towards the dome compared to baseline of 3.7 × 3.4 cm. T12: 1.6 × 2.2 cm metastasis towards the dome more centrally compared to baseline of 3.3 × 3.5 cm. L1: 2.1 × 2.1 cm metastasis inferior right hepatic lobe compared to baseline of 3.2 × 3.9 cm
Discussion
In this case, we presented a mRCC patient who had partial response to treatment with pembrolizumab and axitinib. Despite the response, he experienced recurrent cyanosis without hypoxia diagnosed as acquired methemoglobinemia, leading to treatment discontinuation. There have been no reported cases of methemoglobinemia related to either PD-1-inhibitors or VEGF-TKIs. However, our analysis of the clinical notes and labs are in line with the treating physician’s suspicion that the methemoglobinemia was most likely attributed to the axitinib. It is important to note that these symptoms resolved within seven days of holding axitinib and recurred at the lower dose. The amount of methemoglobin measured in the patient’s blood overtime can be appreciated in Fig. 2. This case could provide evidence of a rare, but significant side effect of anti-VEGF therapy when used in combination with ICI. It is important for medical oncologists to be aware of this adverse event so they can formulate the best response for their patients in the clinic.Fig. 2 Patient’s percent level of methemoglobin relative to normal hemoglobin based on sequential complete blood-cell counts with differential
Hemoglobin (Hb) is the oxygen carrying molecule within red blood cells (RBCs). Methemoglobin (MetHb) is a type of Hb containing an oxidized ferric (Fe3+) atom that is less effective at releasing oxygen compared to the normal ferrous (Fe2+) bound heme [10]. RBCs are frequently exposed to oxidizing agents, such as free radicals, metabolites and drug intermediates. These molecules shift the iron in their heme rings from 2+ to 3+, which forms MetHb. To combat this, the RBC contains a large reservoir cytochrome-based reducing enzymes to counteract these oxidizing particles [11]. Methemoglobinemia is a state where the percentage of MetHb relative to normal Hb rises to a symptomatic level [11]. There are two main forms of methemoglobinemia: inherited and acquired. These conditions are associated with either a genetic or an induced deficiency of these RBC reducing enzymes. The acquired form is more common and is most often due to medications such as dapsone, which form potent oxidizing agents when metabolized by cytochrome P450 enzymes in the liver [12, 13]. This patient’s medication list showed no notable agents that could have been associated with the patient’s adverse hematologic side effects. There was also no evidence of any past or familial hematologic disorders playing a role in the patient’s adverse reaction. Family history was only significant for past malignancies, which was supported by genetic mutation findings. Methemoglobinemia can also be a difficult syndrome to diagnose due to its wide spectrum of symptomology ranging from minor cyanosis to life-threatening hypoxemia [10]. This is additionally complicated within the context of RCC as RBC syndromes, such as polycythemia and anemia, are much more common amongst this patient population. For most patients, methemoglobinemia becomes symptomatic when MetHb levels rise to 10–20% rather than the 3.7% experienced by the patient in our case report. However, as stated earlier, methemoglobinemia has a wide range of symptomology and, especially for those burdened by metastatic cancer, intensive VEGF therapy and other hematologic disorders, this symptom threshold could be significantly lower for complex oncology patients.
Between the two agents comprising the patient’s treatment regimen, axitinib is more likely the culprit for the methemoglobinemia. Unlike pembrolizumab, axitinib has a short half-life of roughly 3–6 hours in vivo [14]. The patient’s markedly rapid clinical improvement upon holding axitinib supports our theory that it may have been the inciting factor in this patient’s methemoglobinemia. Additionally, axitinib can induce polycythemia and other RBC dysfunction in patients with ccRCC due to complex interactions between hypoxia inducible factor 1 alpha (HIF-1a), VEGF and EPO [15, 16]. In fact, some studies suggesting hemoglobin values could be used as biomarkers for axitinib treatment response [17]. The etiology of this patient’s methemoglobinemia is unclear at this time. However, there are a few plausible explanations for an increase in oxidizing agents that could have produced enough MetHb to become symptomatic. The partial regression noted in this patient’s metastatic lesions could have released large quantities of intracellular oxidizing components from the malignant cells as a result of a favorable response. The combination of cell lysis and T cell expansion may have led to a concomitant release of oxidizing agents that overwhelmed the RBC reducing enzymes. Additionally, while there is little evidence of axitinib or its metabolites acting as oxidizers, axitinib is metabolized by multiple cytochrome P450 enzymes which could form oxidizing agents in a similar mechanism to a dapsone-induced methemoglobinemia [14]. While the true cause of this adverse reaction is not currently known, it was likely a multifactorial event incited by an increase in oxidizing agents that overwhelmed the reducing capacity of this patient’s RBCs.
Conclusion
Combination immune therapy provides an exciting new treatment option for mRCC patients that combines the benefits of multiple potent therapies for an even greater treatment effect. These agents can provide clinical oncologists with additional treatment options for aggressive malignancies like mRCC. However, it is crucial that medical oncologists appreciate the benefits and costs these treatment regimens impose on patients. Adverse events, such as the one presented in this case report, can be life-threatening and have significant impacts on the patient’s prognosis and quality of life. Current trials utilizing PD-1 and VEGF-TKI combination therapy have presented promising results and FDA approval for patients with advanced RCC [8]. This case presents one such example of a RCC patient who experienced a rare but important adverse hematologic event. The novelty of this presentation is both a strength and a weakness in this case study. The resulting methemoglobinemia for this patient could have equally been involved with another underlying disease process as it could be a true side effect of VEGF-TKI and ICI combination therapy. Current clinical trials should make ongoing efforts to note these uncommon side effects to better appreciate the side-effect profile of these novel agents. Cases, such as this one, can hopefully assist practicing oncologists to recognize the rare and potentially severe side effect of methemoglobinemia in mRCC patients treated with ICI and VEGF-TKI combination therapy.
Patient perspective
“I was given pembrolizumab by intravenous means every 21 days for three months. I also was placed on 5 MG tablets of Axitinib. The combination did have great success with decreasing and/or eliminating a tumor from my pancreas and two on my liver. However, the side effects caused me to have to stop the therapy. The first symptom was a loss of appetite which in turn lead to fatigue, tiredness, loss of weight, and loss of voice volume. There was no sickness, I just didn’t feel well. My lips and eye whites turned blue and I was ultimately diagnosed with methemoglobinemia. I was weak, needed weekly infusions of fluid, and ultimately had to quit the therapy after three months. There was never any pain from anything. Dehydration became my biggest issue as I spend most of my time sleeping and not wanting to eat. I found success managing this situation with my general practitioner who is an internist specializing in kidney and diabetes. It is best to start this journey with a good oncologist that will take the time to determine what is happening with your systems. I was fortunate enough to find great doctor(s)."
Abbreviations
mRCCMetastatic renal cell carcinoma
ccRCCClear cell renal cell carcinoma
HbHemoglobin
MetHbMethemoglobin
PD-1Programmed cell death protein-1
VEGFVascular endothelial growth factor
HIF-1aHypoxia inducible factor-1-alpha
Fe3+Ferric
Fe2+Ferrous
RBCRed blood cell
EPOErythropoietin
TKITyrosine-kinase inhibitor
ICIImmune checkpoint inhibitor
IMDCInternational metastatic renal cell carcinoma database consortium
OSOverall survival
PFSProgression-free survival
RECISTv1.1Response evaluation criteria in solid tumors version 1.1
ECOG PSEastern Cooperative Oncology Group performance status
C-statisticsUno’s Concordance Statistics
PD-L1Programmed death ligand-1
FDAFood and Drug Administration
CHEK2Checkpoint kinase 2 gene
ATMAtaxia-telangiesctasia gene
BLMBloom gene
MLH1MMR gene
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors' contributions
TAO was involved in the identification and selection of patients, outline, data acquisition, analysis, figures, online research, writing and editing of the manuscript. DJM was involved in the writing, editing, data acquisition, administrative support and provided advisory over the manuscript. STE was involved in administrative support and editing of the manuscript. All remaining authors were involved in the care of the patients in this study, interpretation and analysis of study results, and editing the manuscript. All authors reviewed and accepted the final version of the manuscript.
Funding
This work was supported by the Breen Foundation and National Institutes of Health/ National Cancer Institute and the Biostatistics and Bioinformatics Shared Resource of the Winship Cancer Institute of Emory University under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Availability of data and materials
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
Mehmet A. Bilen has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Genomic Health, Nektar, and Sanofi and has received grants to his institution from Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, Seattle Genetics, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peleton Therapeutics, and Pfizer for work performed as outside of the current study. | IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY | 33602288 | 19,742,851 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Immune-mediated hypothyroidism'. | Symptomatic methemoglobinemia in a patient with metastatic clear cell renal cell carcinoma treated with pembrolizumab and axitinib combination therapy: a case report.
BACKGROUND
Combination regimens that include immune checkpoint (ICI) and vascular endothelial growth factor (VEGF) inhibition have opened the door to new treatment opportunities for patients with metastatic renal cell carcinoma (mRCC). While these treatment options have provided improved tolerability and better outcomes compared to older regimens, many patients still experience a myriad of treatment-related adverse events. Given that these regimens were recently approved for mRCC, the complete side effect profile may not be fully elucidated yet.
METHODS
We report a case of a 73-year old White male with mRCC who was managed with an ICI-VEGF inhibitor combination regimen. He experienced a partial response (Fig. 1) but had side effects including symptomatic cyanosis diagnosed as methemoglobinemia which led to treatment discontinuation. Upon holding his therapy, his methemoglobinemia and cyanosis resolved.
CONCLUSIONS
Combination VEGF-ICI therapy provide novel regimens for advanced solid tumor malignancies including mRCC. While shown to have improved efficacy in clinical trials, it is crucial that oncologists uncover the full side effect profile of these novel agents especially as their use becomes more standard in the management of advanced malignancies. To our knowledge, this is the first reported case of a patient experiencing symptomatic methemoglobinemia as an adverse event associated with a VEGF-ICI combination regimen. While the cause of this side effect is unclear, in this paper we attempt to elucidate a process that is in line with the mechanism of action of these therapies to explain how these agents, specifically the axitinib, could have caused the methemoglobin to rise to a symptomatic level.
Background
Vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) are small molecules that inhibit tyrosine kinase receptors involved in the VEGF pathway [1]. These types of TKIs are pathway-specific inhibitors of the angiogenic signaling process that cancers depend upon to obtain access to nutrients and to metastasize [2]. Blocking VEGF from malignant tissue effectively causes transient hypoxia, cutting off access to nutrients vital for oncogenesis. TKIs are integral to the treatment of numerous cancers including metastatic renal cell carcinoma (mRCC) [3]. Pembrolizumab is a programmed death-1 (PD-1) inhibitor that is in a class of medications called immune checkpoint inhibitors (ICIs). These agents increase T-cell activation, improving T-cell-mediated clearance of malignant cells and are used in several malignancies including mRCC [4–6]. PD-1 and VEGF-TKI combination therapy have shown efficacy and received FDA approval as the standard treatment for advanced RCC through the phase 3 KEYNOTE-426 clinical trial [7, 8]. This regimen, however, is not without side effects which can significantly impact patient quality of life and cause treatment discontinuation [5]. In the KEYNOTE-426 trial, the most commonly cited adverse events associated with pembrolizumab-axitinib were diarrhea, hypertension, fatigue and hypothyroidism [8]. In this report we are presenting, to our best knowledge, the first case of a patient with mRCC who developed cyanosis diagnosed as methemoglobinemia while on pembrolizumab-axitinib treatment. This case displays a rare but severe adverse event that could be related to ICI and VEGF-TKI combination therapy.
Case presentation
A 73-year-old White male was diagnosed with pT2NxMx clear cell RCC (ccRCC) and underwent radical nephrectomy in November of 2007. Given his family history of malignancy, he underwent genetic testing and was found to be positive for CHEK2, ATM, BLM and MLH1 mutations. He then presented twelve years later with biopsy-proven recurrence of his ccRCC in the pancreas, liver and lung. He was started on combination therapy consisting of pembrolizumab 200 mg IV q3 weeks and axitinib 5mg PO BID [8, 9]. As seen in Fig. 1, his scans two months after treatment initiation showed partial response in his metastases per RECIST v1.1. His course was complicated four months after initiation by adverse events including cystitis, hematuria, fatigue, polycythemia and peri-oral cyanosis without hypoxia. His primary care physician initiated cyanosis work-up and laboratory tests were obtained. This included a complete blood-cell count with differential, which showed a positive test for methemoglobinemia displaying a percent methemoglobin level of 3.7% exceeding the 1.5% cutoff for positivity. Additional complete blood cell-count values showed a normal erythropoietin (EPO) level and an elevated hemoglobin of 18.4 with a hematocrit of 53.8. The secondary polycythemia experienced concomitantly with the methemoglobinemia was attributed to a combination of the axitinib therapy and an RCC-associated paraneoplastic syndrome. Upon holding his axitinib for 1 week, the patient’s symptoms resolved. Follow-up laboratory tests similarly showed normalization of the residual polycythemia with a subsequent hemoglobin of 15.3 and hematocrit of 47.4. While the MetHb level was only mildly elevated during the treatment period, the patient was highly symptomatic and this reaction prompted medication adjustments. He was restarted on the same combination therapy with a reduced dose of axitinib from 5 to 3 mg. His adverse symptoms recurred and were intolerable shortly after resuming. He discontinued the pembrolizumab-axitinib therapy and transitioned three weeks later to an ipilimumab 1mg/kg IVBP and nivolumab 3mg/kg IVBP combination regimen. This subsequent regimen was discontinued due to poor tolerability from immune-related adverse events including hypothyroidism and adrenal insufficiency. His follow-up scans in January showed sustained partial response, but progression of disease in June of 2020 within the liver metastasis. In September of 2020, the patient is still alive and has begun local Y90 radiation therapy and awaits upcoming surveillance scans.Fig. 1 Axial contrast enhanced computed tomography scan of the abdomen and pelvis. Interval decreases in size of liver metastases with reference measurements are as follows: T11: 1.6 × 1.9 cm metastasis of liver towards the dome compared to baseline of 3.7 × 3.4 cm. T12: 1.6 × 2.2 cm metastasis towards the dome more centrally compared to baseline of 3.3 × 3.5 cm. L1: 2.1 × 2.1 cm metastasis inferior right hepatic lobe compared to baseline of 3.2 × 3.9 cm
Discussion
In this case, we presented a mRCC patient who had partial response to treatment with pembrolizumab and axitinib. Despite the response, he experienced recurrent cyanosis without hypoxia diagnosed as acquired methemoglobinemia, leading to treatment discontinuation. There have been no reported cases of methemoglobinemia related to either PD-1-inhibitors or VEGF-TKIs. However, our analysis of the clinical notes and labs are in line with the treating physician’s suspicion that the methemoglobinemia was most likely attributed to the axitinib. It is important to note that these symptoms resolved within seven days of holding axitinib and recurred at the lower dose. The amount of methemoglobin measured in the patient’s blood overtime can be appreciated in Fig. 2. This case could provide evidence of a rare, but significant side effect of anti-VEGF therapy when used in combination with ICI. It is important for medical oncologists to be aware of this adverse event so they can formulate the best response for their patients in the clinic.Fig. 2 Patient’s percent level of methemoglobin relative to normal hemoglobin based on sequential complete blood-cell counts with differential
Hemoglobin (Hb) is the oxygen carrying molecule within red blood cells (RBCs). Methemoglobin (MetHb) is a type of Hb containing an oxidized ferric (Fe3+) atom that is less effective at releasing oxygen compared to the normal ferrous (Fe2+) bound heme [10]. RBCs are frequently exposed to oxidizing agents, such as free radicals, metabolites and drug intermediates. These molecules shift the iron in their heme rings from 2+ to 3+, which forms MetHb. To combat this, the RBC contains a large reservoir cytochrome-based reducing enzymes to counteract these oxidizing particles [11]. Methemoglobinemia is a state where the percentage of MetHb relative to normal Hb rises to a symptomatic level [11]. There are two main forms of methemoglobinemia: inherited and acquired. These conditions are associated with either a genetic or an induced deficiency of these RBC reducing enzymes. The acquired form is more common and is most often due to medications such as dapsone, which form potent oxidizing agents when metabolized by cytochrome P450 enzymes in the liver [12, 13]. This patient’s medication list showed no notable agents that could have been associated with the patient’s adverse hematologic side effects. There was also no evidence of any past or familial hematologic disorders playing a role in the patient’s adverse reaction. Family history was only significant for past malignancies, which was supported by genetic mutation findings. Methemoglobinemia can also be a difficult syndrome to diagnose due to its wide spectrum of symptomology ranging from minor cyanosis to life-threatening hypoxemia [10]. This is additionally complicated within the context of RCC as RBC syndromes, such as polycythemia and anemia, are much more common amongst this patient population. For most patients, methemoglobinemia becomes symptomatic when MetHb levels rise to 10–20% rather than the 3.7% experienced by the patient in our case report. However, as stated earlier, methemoglobinemia has a wide range of symptomology and, especially for those burdened by metastatic cancer, intensive VEGF therapy and other hematologic disorders, this symptom threshold could be significantly lower for complex oncology patients.
Between the two agents comprising the patient’s treatment regimen, axitinib is more likely the culprit for the methemoglobinemia. Unlike pembrolizumab, axitinib has a short half-life of roughly 3–6 hours in vivo [14]. The patient’s markedly rapid clinical improvement upon holding axitinib supports our theory that it may have been the inciting factor in this patient’s methemoglobinemia. Additionally, axitinib can induce polycythemia and other RBC dysfunction in patients with ccRCC due to complex interactions between hypoxia inducible factor 1 alpha (HIF-1a), VEGF and EPO [15, 16]. In fact, some studies suggesting hemoglobin values could be used as biomarkers for axitinib treatment response [17]. The etiology of this patient’s methemoglobinemia is unclear at this time. However, there are a few plausible explanations for an increase in oxidizing agents that could have produced enough MetHb to become symptomatic. The partial regression noted in this patient’s metastatic lesions could have released large quantities of intracellular oxidizing components from the malignant cells as a result of a favorable response. The combination of cell lysis and T cell expansion may have led to a concomitant release of oxidizing agents that overwhelmed the RBC reducing enzymes. Additionally, while there is little evidence of axitinib or its metabolites acting as oxidizers, axitinib is metabolized by multiple cytochrome P450 enzymes which could form oxidizing agents in a similar mechanism to a dapsone-induced methemoglobinemia [14]. While the true cause of this adverse reaction is not currently known, it was likely a multifactorial event incited by an increase in oxidizing agents that overwhelmed the reducing capacity of this patient’s RBCs.
Conclusion
Combination immune therapy provides an exciting new treatment option for mRCC patients that combines the benefits of multiple potent therapies for an even greater treatment effect. These agents can provide clinical oncologists with additional treatment options for aggressive malignancies like mRCC. However, it is crucial that medical oncologists appreciate the benefits and costs these treatment regimens impose on patients. Adverse events, such as the one presented in this case report, can be life-threatening and have significant impacts on the patient’s prognosis and quality of life. Current trials utilizing PD-1 and VEGF-TKI combination therapy have presented promising results and FDA approval for patients with advanced RCC [8]. This case presents one such example of a RCC patient who experienced a rare but important adverse hematologic event. The novelty of this presentation is both a strength and a weakness in this case study. The resulting methemoglobinemia for this patient could have equally been involved with another underlying disease process as it could be a true side effect of VEGF-TKI and ICI combination therapy. Current clinical trials should make ongoing efforts to note these uncommon side effects to better appreciate the side-effect profile of these novel agents. Cases, such as this one, can hopefully assist practicing oncologists to recognize the rare and potentially severe side effect of methemoglobinemia in mRCC patients treated with ICI and VEGF-TKI combination therapy.
Patient perspective
“I was given pembrolizumab by intravenous means every 21 days for three months. I also was placed on 5 MG tablets of Axitinib. The combination did have great success with decreasing and/or eliminating a tumor from my pancreas and two on my liver. However, the side effects caused me to have to stop the therapy. The first symptom was a loss of appetite which in turn lead to fatigue, tiredness, loss of weight, and loss of voice volume. There was no sickness, I just didn’t feel well. My lips and eye whites turned blue and I was ultimately diagnosed with methemoglobinemia. I was weak, needed weekly infusions of fluid, and ultimately had to quit the therapy after three months. There was never any pain from anything. Dehydration became my biggest issue as I spend most of my time sleeping and not wanting to eat. I found success managing this situation with my general practitioner who is an internist specializing in kidney and diabetes. It is best to start this journey with a good oncologist that will take the time to determine what is happening with your systems. I was fortunate enough to find great doctor(s)."
Abbreviations
mRCCMetastatic renal cell carcinoma
ccRCCClear cell renal cell carcinoma
HbHemoglobin
MetHbMethemoglobin
PD-1Programmed cell death protein-1
VEGFVascular endothelial growth factor
HIF-1aHypoxia inducible factor-1-alpha
Fe3+Ferric
Fe2+Ferrous
RBCRed blood cell
EPOErythropoietin
TKITyrosine-kinase inhibitor
ICIImmune checkpoint inhibitor
IMDCInternational metastatic renal cell carcinoma database consortium
OSOverall survival
PFSProgression-free survival
RECISTv1.1Response evaluation criteria in solid tumors version 1.1
ECOG PSEastern Cooperative Oncology Group performance status
C-statisticsUno’s Concordance Statistics
PD-L1Programmed death ligand-1
FDAFood and Drug Administration
CHEK2Checkpoint kinase 2 gene
ATMAtaxia-telangiesctasia gene
BLMBloom gene
MLH1MMR gene
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors' contributions
TAO was involved in the identification and selection of patients, outline, data acquisition, analysis, figures, online research, writing and editing of the manuscript. DJM was involved in the writing, editing, data acquisition, administrative support and provided advisory over the manuscript. STE was involved in administrative support and editing of the manuscript. All remaining authors were involved in the care of the patients in this study, interpretation and analysis of study results, and editing the manuscript. All authors reviewed and accepted the final version of the manuscript.
Funding
This work was supported by the Breen Foundation and National Institutes of Health/ National Cancer Institute and the Biostatistics and Bioinformatics Shared Resource of the Winship Cancer Institute of Emory University under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Availability of data and materials
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
Mehmet A. Bilen has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Genomic Health, Nektar, and Sanofi and has received grants to his institution from Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, Seattle Genetics, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peleton Therapeutics, and Pfizer for work performed as outside of the current study. | IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY | 33602288 | 19,742,851 | 2021-02-19 |
What was the administration route of drug 'IPILIMUMAB'? | Symptomatic methemoglobinemia in a patient with metastatic clear cell renal cell carcinoma treated with pembrolizumab and axitinib combination therapy: a case report.
BACKGROUND
Combination regimens that include immune checkpoint (ICI) and vascular endothelial growth factor (VEGF) inhibition have opened the door to new treatment opportunities for patients with metastatic renal cell carcinoma (mRCC). While these treatment options have provided improved tolerability and better outcomes compared to older regimens, many patients still experience a myriad of treatment-related adverse events. Given that these regimens were recently approved for mRCC, the complete side effect profile may not be fully elucidated yet.
METHODS
We report a case of a 73-year old White male with mRCC who was managed with an ICI-VEGF inhibitor combination regimen. He experienced a partial response (Fig. 1) but had side effects including symptomatic cyanosis diagnosed as methemoglobinemia which led to treatment discontinuation. Upon holding his therapy, his methemoglobinemia and cyanosis resolved.
CONCLUSIONS
Combination VEGF-ICI therapy provide novel regimens for advanced solid tumor malignancies including mRCC. While shown to have improved efficacy in clinical trials, it is crucial that oncologists uncover the full side effect profile of these novel agents especially as their use becomes more standard in the management of advanced malignancies. To our knowledge, this is the first reported case of a patient experiencing symptomatic methemoglobinemia as an adverse event associated with a VEGF-ICI combination regimen. While the cause of this side effect is unclear, in this paper we attempt to elucidate a process that is in line with the mechanism of action of these therapies to explain how these agents, specifically the axitinib, could have caused the methemoglobin to rise to a symptomatic level.
Background
Vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) are small molecules that inhibit tyrosine kinase receptors involved in the VEGF pathway [1]. These types of TKIs are pathway-specific inhibitors of the angiogenic signaling process that cancers depend upon to obtain access to nutrients and to metastasize [2]. Blocking VEGF from malignant tissue effectively causes transient hypoxia, cutting off access to nutrients vital for oncogenesis. TKIs are integral to the treatment of numerous cancers including metastatic renal cell carcinoma (mRCC) [3]. Pembrolizumab is a programmed death-1 (PD-1) inhibitor that is in a class of medications called immune checkpoint inhibitors (ICIs). These agents increase T-cell activation, improving T-cell-mediated clearance of malignant cells and are used in several malignancies including mRCC [4–6]. PD-1 and VEGF-TKI combination therapy have shown efficacy and received FDA approval as the standard treatment for advanced RCC through the phase 3 KEYNOTE-426 clinical trial [7, 8]. This regimen, however, is not without side effects which can significantly impact patient quality of life and cause treatment discontinuation [5]. In the KEYNOTE-426 trial, the most commonly cited adverse events associated with pembrolizumab-axitinib were diarrhea, hypertension, fatigue and hypothyroidism [8]. In this report we are presenting, to our best knowledge, the first case of a patient with mRCC who developed cyanosis diagnosed as methemoglobinemia while on pembrolizumab-axitinib treatment. This case displays a rare but severe adverse event that could be related to ICI and VEGF-TKI combination therapy.
Case presentation
A 73-year-old White male was diagnosed with pT2NxMx clear cell RCC (ccRCC) and underwent radical nephrectomy in November of 2007. Given his family history of malignancy, he underwent genetic testing and was found to be positive for CHEK2, ATM, BLM and MLH1 mutations. He then presented twelve years later with biopsy-proven recurrence of his ccRCC in the pancreas, liver and lung. He was started on combination therapy consisting of pembrolizumab 200 mg IV q3 weeks and axitinib 5mg PO BID [8, 9]. As seen in Fig. 1, his scans two months after treatment initiation showed partial response in his metastases per RECIST v1.1. His course was complicated four months after initiation by adverse events including cystitis, hematuria, fatigue, polycythemia and peri-oral cyanosis without hypoxia. His primary care physician initiated cyanosis work-up and laboratory tests were obtained. This included a complete blood-cell count with differential, which showed a positive test for methemoglobinemia displaying a percent methemoglobin level of 3.7% exceeding the 1.5% cutoff for positivity. Additional complete blood cell-count values showed a normal erythropoietin (EPO) level and an elevated hemoglobin of 18.4 with a hematocrit of 53.8. The secondary polycythemia experienced concomitantly with the methemoglobinemia was attributed to a combination of the axitinib therapy and an RCC-associated paraneoplastic syndrome. Upon holding his axitinib for 1 week, the patient’s symptoms resolved. Follow-up laboratory tests similarly showed normalization of the residual polycythemia with a subsequent hemoglobin of 15.3 and hematocrit of 47.4. While the MetHb level was only mildly elevated during the treatment period, the patient was highly symptomatic and this reaction prompted medication adjustments. He was restarted on the same combination therapy with a reduced dose of axitinib from 5 to 3 mg. His adverse symptoms recurred and were intolerable shortly after resuming. He discontinued the pembrolizumab-axitinib therapy and transitioned three weeks later to an ipilimumab 1mg/kg IVBP and nivolumab 3mg/kg IVBP combination regimen. This subsequent regimen was discontinued due to poor tolerability from immune-related adverse events including hypothyroidism and adrenal insufficiency. His follow-up scans in January showed sustained partial response, but progression of disease in June of 2020 within the liver metastasis. In September of 2020, the patient is still alive and has begun local Y90 radiation therapy and awaits upcoming surveillance scans.Fig. 1 Axial contrast enhanced computed tomography scan of the abdomen and pelvis. Interval decreases in size of liver metastases with reference measurements are as follows: T11: 1.6 × 1.9 cm metastasis of liver towards the dome compared to baseline of 3.7 × 3.4 cm. T12: 1.6 × 2.2 cm metastasis towards the dome more centrally compared to baseline of 3.3 × 3.5 cm. L1: 2.1 × 2.1 cm metastasis inferior right hepatic lobe compared to baseline of 3.2 × 3.9 cm
Discussion
In this case, we presented a mRCC patient who had partial response to treatment with pembrolizumab and axitinib. Despite the response, he experienced recurrent cyanosis without hypoxia diagnosed as acquired methemoglobinemia, leading to treatment discontinuation. There have been no reported cases of methemoglobinemia related to either PD-1-inhibitors or VEGF-TKIs. However, our analysis of the clinical notes and labs are in line with the treating physician’s suspicion that the methemoglobinemia was most likely attributed to the axitinib. It is important to note that these symptoms resolved within seven days of holding axitinib and recurred at the lower dose. The amount of methemoglobin measured in the patient’s blood overtime can be appreciated in Fig. 2. This case could provide evidence of a rare, but significant side effect of anti-VEGF therapy when used in combination with ICI. It is important for medical oncologists to be aware of this adverse event so they can formulate the best response for their patients in the clinic.Fig. 2 Patient’s percent level of methemoglobin relative to normal hemoglobin based on sequential complete blood-cell counts with differential
Hemoglobin (Hb) is the oxygen carrying molecule within red blood cells (RBCs). Methemoglobin (MetHb) is a type of Hb containing an oxidized ferric (Fe3+) atom that is less effective at releasing oxygen compared to the normal ferrous (Fe2+) bound heme [10]. RBCs are frequently exposed to oxidizing agents, such as free radicals, metabolites and drug intermediates. These molecules shift the iron in their heme rings from 2+ to 3+, which forms MetHb. To combat this, the RBC contains a large reservoir cytochrome-based reducing enzymes to counteract these oxidizing particles [11]. Methemoglobinemia is a state where the percentage of MetHb relative to normal Hb rises to a symptomatic level [11]. There are two main forms of methemoglobinemia: inherited and acquired. These conditions are associated with either a genetic or an induced deficiency of these RBC reducing enzymes. The acquired form is more common and is most often due to medications such as dapsone, which form potent oxidizing agents when metabolized by cytochrome P450 enzymes in the liver [12, 13]. This patient’s medication list showed no notable agents that could have been associated with the patient’s adverse hematologic side effects. There was also no evidence of any past or familial hematologic disorders playing a role in the patient’s adverse reaction. Family history was only significant for past malignancies, which was supported by genetic mutation findings. Methemoglobinemia can also be a difficult syndrome to diagnose due to its wide spectrum of symptomology ranging from minor cyanosis to life-threatening hypoxemia [10]. This is additionally complicated within the context of RCC as RBC syndromes, such as polycythemia and anemia, are much more common amongst this patient population. For most patients, methemoglobinemia becomes symptomatic when MetHb levels rise to 10–20% rather than the 3.7% experienced by the patient in our case report. However, as stated earlier, methemoglobinemia has a wide range of symptomology and, especially for those burdened by metastatic cancer, intensive VEGF therapy and other hematologic disorders, this symptom threshold could be significantly lower for complex oncology patients.
Between the two agents comprising the patient’s treatment regimen, axitinib is more likely the culprit for the methemoglobinemia. Unlike pembrolizumab, axitinib has a short half-life of roughly 3–6 hours in vivo [14]. The patient’s markedly rapid clinical improvement upon holding axitinib supports our theory that it may have been the inciting factor in this patient’s methemoglobinemia. Additionally, axitinib can induce polycythemia and other RBC dysfunction in patients with ccRCC due to complex interactions between hypoxia inducible factor 1 alpha (HIF-1a), VEGF and EPO [15, 16]. In fact, some studies suggesting hemoglobin values could be used as biomarkers for axitinib treatment response [17]. The etiology of this patient’s methemoglobinemia is unclear at this time. However, there are a few plausible explanations for an increase in oxidizing agents that could have produced enough MetHb to become symptomatic. The partial regression noted in this patient’s metastatic lesions could have released large quantities of intracellular oxidizing components from the malignant cells as a result of a favorable response. The combination of cell lysis and T cell expansion may have led to a concomitant release of oxidizing agents that overwhelmed the RBC reducing enzymes. Additionally, while there is little evidence of axitinib or its metabolites acting as oxidizers, axitinib is metabolized by multiple cytochrome P450 enzymes which could form oxidizing agents in a similar mechanism to a dapsone-induced methemoglobinemia [14]. While the true cause of this adverse reaction is not currently known, it was likely a multifactorial event incited by an increase in oxidizing agents that overwhelmed the reducing capacity of this patient’s RBCs.
Conclusion
Combination immune therapy provides an exciting new treatment option for mRCC patients that combines the benefits of multiple potent therapies for an even greater treatment effect. These agents can provide clinical oncologists with additional treatment options for aggressive malignancies like mRCC. However, it is crucial that medical oncologists appreciate the benefits and costs these treatment regimens impose on patients. Adverse events, such as the one presented in this case report, can be life-threatening and have significant impacts on the patient’s prognosis and quality of life. Current trials utilizing PD-1 and VEGF-TKI combination therapy have presented promising results and FDA approval for patients with advanced RCC [8]. This case presents one such example of a RCC patient who experienced a rare but important adverse hematologic event. The novelty of this presentation is both a strength and a weakness in this case study. The resulting methemoglobinemia for this patient could have equally been involved with another underlying disease process as it could be a true side effect of VEGF-TKI and ICI combination therapy. Current clinical trials should make ongoing efforts to note these uncommon side effects to better appreciate the side-effect profile of these novel agents. Cases, such as this one, can hopefully assist practicing oncologists to recognize the rare and potentially severe side effect of methemoglobinemia in mRCC patients treated with ICI and VEGF-TKI combination therapy.
Patient perspective
“I was given pembrolizumab by intravenous means every 21 days for three months. I also was placed on 5 MG tablets of Axitinib. The combination did have great success with decreasing and/or eliminating a tumor from my pancreas and two on my liver. However, the side effects caused me to have to stop the therapy. The first symptom was a loss of appetite which in turn lead to fatigue, tiredness, loss of weight, and loss of voice volume. There was no sickness, I just didn’t feel well. My lips and eye whites turned blue and I was ultimately diagnosed with methemoglobinemia. I was weak, needed weekly infusions of fluid, and ultimately had to quit the therapy after three months. There was never any pain from anything. Dehydration became my biggest issue as I spend most of my time sleeping and not wanting to eat. I found success managing this situation with my general practitioner who is an internist specializing in kidney and diabetes. It is best to start this journey with a good oncologist that will take the time to determine what is happening with your systems. I was fortunate enough to find great doctor(s)."
Abbreviations
mRCCMetastatic renal cell carcinoma
ccRCCClear cell renal cell carcinoma
HbHemoglobin
MetHbMethemoglobin
PD-1Programmed cell death protein-1
VEGFVascular endothelial growth factor
HIF-1aHypoxia inducible factor-1-alpha
Fe3+Ferric
Fe2+Ferrous
RBCRed blood cell
EPOErythropoietin
TKITyrosine-kinase inhibitor
ICIImmune checkpoint inhibitor
IMDCInternational metastatic renal cell carcinoma database consortium
OSOverall survival
PFSProgression-free survival
RECISTv1.1Response evaluation criteria in solid tumors version 1.1
ECOG PSEastern Cooperative Oncology Group performance status
C-statisticsUno’s Concordance Statistics
PD-L1Programmed death ligand-1
FDAFood and Drug Administration
CHEK2Checkpoint kinase 2 gene
ATMAtaxia-telangiesctasia gene
BLMBloom gene
MLH1MMR gene
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors' contributions
TAO was involved in the identification and selection of patients, outline, data acquisition, analysis, figures, online research, writing and editing of the manuscript. DJM was involved in the writing, editing, data acquisition, administrative support and provided advisory over the manuscript. STE was involved in administrative support and editing of the manuscript. All remaining authors were involved in the care of the patients in this study, interpretation and analysis of study results, and editing the manuscript. All authors reviewed and accepted the final version of the manuscript.
Funding
This work was supported by the Breen Foundation and National Institutes of Health/ National Cancer Institute and the Biostatistics and Bioinformatics Shared Resource of the Winship Cancer Institute of Emory University under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Availability of data and materials
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
Mehmet A. Bilen has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Genomic Health, Nektar, and Sanofi and has received grants to his institution from Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, Seattle Genetics, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peleton Therapeutics, and Pfizer for work performed as outside of the current study. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33602288 | 19,742,851 | 2021-02-19 |
What was the administration route of drug 'NIVOLUMAB'? | Symptomatic methemoglobinemia in a patient with metastatic clear cell renal cell carcinoma treated with pembrolizumab and axitinib combination therapy: a case report.
BACKGROUND
Combination regimens that include immune checkpoint (ICI) and vascular endothelial growth factor (VEGF) inhibition have opened the door to new treatment opportunities for patients with metastatic renal cell carcinoma (mRCC). While these treatment options have provided improved tolerability and better outcomes compared to older regimens, many patients still experience a myriad of treatment-related adverse events. Given that these regimens were recently approved for mRCC, the complete side effect profile may not be fully elucidated yet.
METHODS
We report a case of a 73-year old White male with mRCC who was managed with an ICI-VEGF inhibitor combination regimen. He experienced a partial response (Fig. 1) but had side effects including symptomatic cyanosis diagnosed as methemoglobinemia which led to treatment discontinuation. Upon holding his therapy, his methemoglobinemia and cyanosis resolved.
CONCLUSIONS
Combination VEGF-ICI therapy provide novel regimens for advanced solid tumor malignancies including mRCC. While shown to have improved efficacy in clinical trials, it is crucial that oncologists uncover the full side effect profile of these novel agents especially as their use becomes more standard in the management of advanced malignancies. To our knowledge, this is the first reported case of a patient experiencing symptomatic methemoglobinemia as an adverse event associated with a VEGF-ICI combination regimen. While the cause of this side effect is unclear, in this paper we attempt to elucidate a process that is in line with the mechanism of action of these therapies to explain how these agents, specifically the axitinib, could have caused the methemoglobin to rise to a symptomatic level.
Background
Vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) are small molecules that inhibit tyrosine kinase receptors involved in the VEGF pathway [1]. These types of TKIs are pathway-specific inhibitors of the angiogenic signaling process that cancers depend upon to obtain access to nutrients and to metastasize [2]. Blocking VEGF from malignant tissue effectively causes transient hypoxia, cutting off access to nutrients vital for oncogenesis. TKIs are integral to the treatment of numerous cancers including metastatic renal cell carcinoma (mRCC) [3]. Pembrolizumab is a programmed death-1 (PD-1) inhibitor that is in a class of medications called immune checkpoint inhibitors (ICIs). These agents increase T-cell activation, improving T-cell-mediated clearance of malignant cells and are used in several malignancies including mRCC [4–6]. PD-1 and VEGF-TKI combination therapy have shown efficacy and received FDA approval as the standard treatment for advanced RCC through the phase 3 KEYNOTE-426 clinical trial [7, 8]. This regimen, however, is not without side effects which can significantly impact patient quality of life and cause treatment discontinuation [5]. In the KEYNOTE-426 trial, the most commonly cited adverse events associated with pembrolizumab-axitinib were diarrhea, hypertension, fatigue and hypothyroidism [8]. In this report we are presenting, to our best knowledge, the first case of a patient with mRCC who developed cyanosis diagnosed as methemoglobinemia while on pembrolizumab-axitinib treatment. This case displays a rare but severe adverse event that could be related to ICI and VEGF-TKI combination therapy.
Case presentation
A 73-year-old White male was diagnosed with pT2NxMx clear cell RCC (ccRCC) and underwent radical nephrectomy in November of 2007. Given his family history of malignancy, he underwent genetic testing and was found to be positive for CHEK2, ATM, BLM and MLH1 mutations. He then presented twelve years later with biopsy-proven recurrence of his ccRCC in the pancreas, liver and lung. He was started on combination therapy consisting of pembrolizumab 200 mg IV q3 weeks and axitinib 5mg PO BID [8, 9]. As seen in Fig. 1, his scans two months after treatment initiation showed partial response in his metastases per RECIST v1.1. His course was complicated four months after initiation by adverse events including cystitis, hematuria, fatigue, polycythemia and peri-oral cyanosis without hypoxia. His primary care physician initiated cyanosis work-up and laboratory tests were obtained. This included a complete blood-cell count with differential, which showed a positive test for methemoglobinemia displaying a percent methemoglobin level of 3.7% exceeding the 1.5% cutoff for positivity. Additional complete blood cell-count values showed a normal erythropoietin (EPO) level and an elevated hemoglobin of 18.4 with a hematocrit of 53.8. The secondary polycythemia experienced concomitantly with the methemoglobinemia was attributed to a combination of the axitinib therapy and an RCC-associated paraneoplastic syndrome. Upon holding his axitinib for 1 week, the patient’s symptoms resolved. Follow-up laboratory tests similarly showed normalization of the residual polycythemia with a subsequent hemoglobin of 15.3 and hematocrit of 47.4. While the MetHb level was only mildly elevated during the treatment period, the patient was highly symptomatic and this reaction prompted medication adjustments. He was restarted on the same combination therapy with a reduced dose of axitinib from 5 to 3 mg. His adverse symptoms recurred and were intolerable shortly after resuming. He discontinued the pembrolizumab-axitinib therapy and transitioned three weeks later to an ipilimumab 1mg/kg IVBP and nivolumab 3mg/kg IVBP combination regimen. This subsequent regimen was discontinued due to poor tolerability from immune-related adverse events including hypothyroidism and adrenal insufficiency. His follow-up scans in January showed sustained partial response, but progression of disease in June of 2020 within the liver metastasis. In September of 2020, the patient is still alive and has begun local Y90 radiation therapy and awaits upcoming surveillance scans.Fig. 1 Axial contrast enhanced computed tomography scan of the abdomen and pelvis. Interval decreases in size of liver metastases with reference measurements are as follows: T11: 1.6 × 1.9 cm metastasis of liver towards the dome compared to baseline of 3.7 × 3.4 cm. T12: 1.6 × 2.2 cm metastasis towards the dome more centrally compared to baseline of 3.3 × 3.5 cm. L1: 2.1 × 2.1 cm metastasis inferior right hepatic lobe compared to baseline of 3.2 × 3.9 cm
Discussion
In this case, we presented a mRCC patient who had partial response to treatment with pembrolizumab and axitinib. Despite the response, he experienced recurrent cyanosis without hypoxia diagnosed as acquired methemoglobinemia, leading to treatment discontinuation. There have been no reported cases of methemoglobinemia related to either PD-1-inhibitors or VEGF-TKIs. However, our analysis of the clinical notes and labs are in line with the treating physician’s suspicion that the methemoglobinemia was most likely attributed to the axitinib. It is important to note that these symptoms resolved within seven days of holding axitinib and recurred at the lower dose. The amount of methemoglobin measured in the patient’s blood overtime can be appreciated in Fig. 2. This case could provide evidence of a rare, but significant side effect of anti-VEGF therapy when used in combination with ICI. It is important for medical oncologists to be aware of this adverse event so they can formulate the best response for their patients in the clinic.Fig. 2 Patient’s percent level of methemoglobin relative to normal hemoglobin based on sequential complete blood-cell counts with differential
Hemoglobin (Hb) is the oxygen carrying molecule within red blood cells (RBCs). Methemoglobin (MetHb) is a type of Hb containing an oxidized ferric (Fe3+) atom that is less effective at releasing oxygen compared to the normal ferrous (Fe2+) bound heme [10]. RBCs are frequently exposed to oxidizing agents, such as free radicals, metabolites and drug intermediates. These molecules shift the iron in their heme rings from 2+ to 3+, which forms MetHb. To combat this, the RBC contains a large reservoir cytochrome-based reducing enzymes to counteract these oxidizing particles [11]. Methemoglobinemia is a state where the percentage of MetHb relative to normal Hb rises to a symptomatic level [11]. There are two main forms of methemoglobinemia: inherited and acquired. These conditions are associated with either a genetic or an induced deficiency of these RBC reducing enzymes. The acquired form is more common and is most often due to medications such as dapsone, which form potent oxidizing agents when metabolized by cytochrome P450 enzymes in the liver [12, 13]. This patient’s medication list showed no notable agents that could have been associated with the patient’s adverse hematologic side effects. There was also no evidence of any past or familial hematologic disorders playing a role in the patient’s adverse reaction. Family history was only significant for past malignancies, which was supported by genetic mutation findings. Methemoglobinemia can also be a difficult syndrome to diagnose due to its wide spectrum of symptomology ranging from minor cyanosis to life-threatening hypoxemia [10]. This is additionally complicated within the context of RCC as RBC syndromes, such as polycythemia and anemia, are much more common amongst this patient population. For most patients, methemoglobinemia becomes symptomatic when MetHb levels rise to 10–20% rather than the 3.7% experienced by the patient in our case report. However, as stated earlier, methemoglobinemia has a wide range of symptomology and, especially for those burdened by metastatic cancer, intensive VEGF therapy and other hematologic disorders, this symptom threshold could be significantly lower for complex oncology patients.
Between the two agents comprising the patient’s treatment regimen, axitinib is more likely the culprit for the methemoglobinemia. Unlike pembrolizumab, axitinib has a short half-life of roughly 3–6 hours in vivo [14]. The patient’s markedly rapid clinical improvement upon holding axitinib supports our theory that it may have been the inciting factor in this patient’s methemoglobinemia. Additionally, axitinib can induce polycythemia and other RBC dysfunction in patients with ccRCC due to complex interactions between hypoxia inducible factor 1 alpha (HIF-1a), VEGF and EPO [15, 16]. In fact, some studies suggesting hemoglobin values could be used as biomarkers for axitinib treatment response [17]. The etiology of this patient’s methemoglobinemia is unclear at this time. However, there are a few plausible explanations for an increase in oxidizing agents that could have produced enough MetHb to become symptomatic. The partial regression noted in this patient’s metastatic lesions could have released large quantities of intracellular oxidizing components from the malignant cells as a result of a favorable response. The combination of cell lysis and T cell expansion may have led to a concomitant release of oxidizing agents that overwhelmed the RBC reducing enzymes. Additionally, while there is little evidence of axitinib or its metabolites acting as oxidizers, axitinib is metabolized by multiple cytochrome P450 enzymes which could form oxidizing agents in a similar mechanism to a dapsone-induced methemoglobinemia [14]. While the true cause of this adverse reaction is not currently known, it was likely a multifactorial event incited by an increase in oxidizing agents that overwhelmed the reducing capacity of this patient’s RBCs.
Conclusion
Combination immune therapy provides an exciting new treatment option for mRCC patients that combines the benefits of multiple potent therapies for an even greater treatment effect. These agents can provide clinical oncologists with additional treatment options for aggressive malignancies like mRCC. However, it is crucial that medical oncologists appreciate the benefits and costs these treatment regimens impose on patients. Adverse events, such as the one presented in this case report, can be life-threatening and have significant impacts on the patient’s prognosis and quality of life. Current trials utilizing PD-1 and VEGF-TKI combination therapy have presented promising results and FDA approval for patients with advanced RCC [8]. This case presents one such example of a RCC patient who experienced a rare but important adverse hematologic event. The novelty of this presentation is both a strength and a weakness in this case study. The resulting methemoglobinemia for this patient could have equally been involved with another underlying disease process as it could be a true side effect of VEGF-TKI and ICI combination therapy. Current clinical trials should make ongoing efforts to note these uncommon side effects to better appreciate the side-effect profile of these novel agents. Cases, such as this one, can hopefully assist practicing oncologists to recognize the rare and potentially severe side effect of methemoglobinemia in mRCC patients treated with ICI and VEGF-TKI combination therapy.
Patient perspective
“I was given pembrolizumab by intravenous means every 21 days for three months. I also was placed on 5 MG tablets of Axitinib. The combination did have great success with decreasing and/or eliminating a tumor from my pancreas and two on my liver. However, the side effects caused me to have to stop the therapy. The first symptom was a loss of appetite which in turn lead to fatigue, tiredness, loss of weight, and loss of voice volume. There was no sickness, I just didn’t feel well. My lips and eye whites turned blue and I was ultimately diagnosed with methemoglobinemia. I was weak, needed weekly infusions of fluid, and ultimately had to quit the therapy after three months. There was never any pain from anything. Dehydration became my biggest issue as I spend most of my time sleeping and not wanting to eat. I found success managing this situation with my general practitioner who is an internist specializing in kidney and diabetes. It is best to start this journey with a good oncologist that will take the time to determine what is happening with your systems. I was fortunate enough to find great doctor(s)."
Abbreviations
mRCCMetastatic renal cell carcinoma
ccRCCClear cell renal cell carcinoma
HbHemoglobin
MetHbMethemoglobin
PD-1Programmed cell death protein-1
VEGFVascular endothelial growth factor
HIF-1aHypoxia inducible factor-1-alpha
Fe3+Ferric
Fe2+Ferrous
RBCRed blood cell
EPOErythropoietin
TKITyrosine-kinase inhibitor
ICIImmune checkpoint inhibitor
IMDCInternational metastatic renal cell carcinoma database consortium
OSOverall survival
PFSProgression-free survival
RECISTv1.1Response evaluation criteria in solid tumors version 1.1
ECOG PSEastern Cooperative Oncology Group performance status
C-statisticsUno’s Concordance Statistics
PD-L1Programmed death ligand-1
FDAFood and Drug Administration
CHEK2Checkpoint kinase 2 gene
ATMAtaxia-telangiesctasia gene
BLMBloom gene
MLH1MMR gene
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors' contributions
TAO was involved in the identification and selection of patients, outline, data acquisition, analysis, figures, online research, writing and editing of the manuscript. DJM was involved in the writing, editing, data acquisition, administrative support and provided advisory over the manuscript. STE was involved in administrative support and editing of the manuscript. All remaining authors were involved in the care of the patients in this study, interpretation and analysis of study results, and editing the manuscript. All authors reviewed and accepted the final version of the manuscript.
Funding
This work was supported by the Breen Foundation and National Institutes of Health/ National Cancer Institute and the Biostatistics and Bioinformatics Shared Resource of the Winship Cancer Institute of Emory University under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Availability of data and materials
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
Mehmet A. Bilen has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Genomic Health, Nektar, and Sanofi and has received grants to his institution from Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, Seattle Genetics, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peleton Therapeutics, and Pfizer for work performed as outside of the current study. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33602288 | 19,742,851 | 2021-02-19 |
What was the dosage of drug 'IPILIMUMAB'? | Symptomatic methemoglobinemia in a patient with metastatic clear cell renal cell carcinoma treated with pembrolizumab and axitinib combination therapy: a case report.
BACKGROUND
Combination regimens that include immune checkpoint (ICI) and vascular endothelial growth factor (VEGF) inhibition have opened the door to new treatment opportunities for patients with metastatic renal cell carcinoma (mRCC). While these treatment options have provided improved tolerability and better outcomes compared to older regimens, many patients still experience a myriad of treatment-related adverse events. Given that these regimens were recently approved for mRCC, the complete side effect profile may not be fully elucidated yet.
METHODS
We report a case of a 73-year old White male with mRCC who was managed with an ICI-VEGF inhibitor combination regimen. He experienced a partial response (Fig. 1) but had side effects including symptomatic cyanosis diagnosed as methemoglobinemia which led to treatment discontinuation. Upon holding his therapy, his methemoglobinemia and cyanosis resolved.
CONCLUSIONS
Combination VEGF-ICI therapy provide novel regimens for advanced solid tumor malignancies including mRCC. While shown to have improved efficacy in clinical trials, it is crucial that oncologists uncover the full side effect profile of these novel agents especially as their use becomes more standard in the management of advanced malignancies. To our knowledge, this is the first reported case of a patient experiencing symptomatic methemoglobinemia as an adverse event associated with a VEGF-ICI combination regimen. While the cause of this side effect is unclear, in this paper we attempt to elucidate a process that is in line with the mechanism of action of these therapies to explain how these agents, specifically the axitinib, could have caused the methemoglobin to rise to a symptomatic level.
Background
Vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) are small molecules that inhibit tyrosine kinase receptors involved in the VEGF pathway [1]. These types of TKIs are pathway-specific inhibitors of the angiogenic signaling process that cancers depend upon to obtain access to nutrients and to metastasize [2]. Blocking VEGF from malignant tissue effectively causes transient hypoxia, cutting off access to nutrients vital for oncogenesis. TKIs are integral to the treatment of numerous cancers including metastatic renal cell carcinoma (mRCC) [3]. Pembrolizumab is a programmed death-1 (PD-1) inhibitor that is in a class of medications called immune checkpoint inhibitors (ICIs). These agents increase T-cell activation, improving T-cell-mediated clearance of malignant cells and are used in several malignancies including mRCC [4–6]. PD-1 and VEGF-TKI combination therapy have shown efficacy and received FDA approval as the standard treatment for advanced RCC through the phase 3 KEYNOTE-426 clinical trial [7, 8]. This regimen, however, is not without side effects which can significantly impact patient quality of life and cause treatment discontinuation [5]. In the KEYNOTE-426 trial, the most commonly cited adverse events associated with pembrolizumab-axitinib were diarrhea, hypertension, fatigue and hypothyroidism [8]. In this report we are presenting, to our best knowledge, the first case of a patient with mRCC who developed cyanosis diagnosed as methemoglobinemia while on pembrolizumab-axitinib treatment. This case displays a rare but severe adverse event that could be related to ICI and VEGF-TKI combination therapy.
Case presentation
A 73-year-old White male was diagnosed with pT2NxMx clear cell RCC (ccRCC) and underwent radical nephrectomy in November of 2007. Given his family history of malignancy, he underwent genetic testing and was found to be positive for CHEK2, ATM, BLM and MLH1 mutations. He then presented twelve years later with biopsy-proven recurrence of his ccRCC in the pancreas, liver and lung. He was started on combination therapy consisting of pembrolizumab 200 mg IV q3 weeks and axitinib 5mg PO BID [8, 9]. As seen in Fig. 1, his scans two months after treatment initiation showed partial response in his metastases per RECIST v1.1. His course was complicated four months after initiation by adverse events including cystitis, hematuria, fatigue, polycythemia and peri-oral cyanosis without hypoxia. His primary care physician initiated cyanosis work-up and laboratory tests were obtained. This included a complete blood-cell count with differential, which showed a positive test for methemoglobinemia displaying a percent methemoglobin level of 3.7% exceeding the 1.5% cutoff for positivity. Additional complete blood cell-count values showed a normal erythropoietin (EPO) level and an elevated hemoglobin of 18.4 with a hematocrit of 53.8. The secondary polycythemia experienced concomitantly with the methemoglobinemia was attributed to a combination of the axitinib therapy and an RCC-associated paraneoplastic syndrome. Upon holding his axitinib for 1 week, the patient’s symptoms resolved. Follow-up laboratory tests similarly showed normalization of the residual polycythemia with a subsequent hemoglobin of 15.3 and hematocrit of 47.4. While the MetHb level was only mildly elevated during the treatment period, the patient was highly symptomatic and this reaction prompted medication adjustments. He was restarted on the same combination therapy with a reduced dose of axitinib from 5 to 3 mg. His adverse symptoms recurred and were intolerable shortly after resuming. He discontinued the pembrolizumab-axitinib therapy and transitioned three weeks later to an ipilimumab 1mg/kg IVBP and nivolumab 3mg/kg IVBP combination regimen. This subsequent regimen was discontinued due to poor tolerability from immune-related adverse events including hypothyroidism and adrenal insufficiency. His follow-up scans in January showed sustained partial response, but progression of disease in June of 2020 within the liver metastasis. In September of 2020, the patient is still alive and has begun local Y90 radiation therapy and awaits upcoming surveillance scans.Fig. 1 Axial contrast enhanced computed tomography scan of the abdomen and pelvis. Interval decreases in size of liver metastases with reference measurements are as follows: T11: 1.6 × 1.9 cm metastasis of liver towards the dome compared to baseline of 3.7 × 3.4 cm. T12: 1.6 × 2.2 cm metastasis towards the dome more centrally compared to baseline of 3.3 × 3.5 cm. L1: 2.1 × 2.1 cm metastasis inferior right hepatic lobe compared to baseline of 3.2 × 3.9 cm
Discussion
In this case, we presented a mRCC patient who had partial response to treatment with pembrolizumab and axitinib. Despite the response, he experienced recurrent cyanosis without hypoxia diagnosed as acquired methemoglobinemia, leading to treatment discontinuation. There have been no reported cases of methemoglobinemia related to either PD-1-inhibitors or VEGF-TKIs. However, our analysis of the clinical notes and labs are in line with the treating physician’s suspicion that the methemoglobinemia was most likely attributed to the axitinib. It is important to note that these symptoms resolved within seven days of holding axitinib and recurred at the lower dose. The amount of methemoglobin measured in the patient’s blood overtime can be appreciated in Fig. 2. This case could provide evidence of a rare, but significant side effect of anti-VEGF therapy when used in combination with ICI. It is important for medical oncologists to be aware of this adverse event so they can formulate the best response for their patients in the clinic.Fig. 2 Patient’s percent level of methemoglobin relative to normal hemoglobin based on sequential complete blood-cell counts with differential
Hemoglobin (Hb) is the oxygen carrying molecule within red blood cells (RBCs). Methemoglobin (MetHb) is a type of Hb containing an oxidized ferric (Fe3+) atom that is less effective at releasing oxygen compared to the normal ferrous (Fe2+) bound heme [10]. RBCs are frequently exposed to oxidizing agents, such as free radicals, metabolites and drug intermediates. These molecules shift the iron in their heme rings from 2+ to 3+, which forms MetHb. To combat this, the RBC contains a large reservoir cytochrome-based reducing enzymes to counteract these oxidizing particles [11]. Methemoglobinemia is a state where the percentage of MetHb relative to normal Hb rises to a symptomatic level [11]. There are two main forms of methemoglobinemia: inherited and acquired. These conditions are associated with either a genetic or an induced deficiency of these RBC reducing enzymes. The acquired form is more common and is most often due to medications such as dapsone, which form potent oxidizing agents when metabolized by cytochrome P450 enzymes in the liver [12, 13]. This patient’s medication list showed no notable agents that could have been associated with the patient’s adverse hematologic side effects. There was also no evidence of any past or familial hematologic disorders playing a role in the patient’s adverse reaction. Family history was only significant for past malignancies, which was supported by genetic mutation findings. Methemoglobinemia can also be a difficult syndrome to diagnose due to its wide spectrum of symptomology ranging from minor cyanosis to life-threatening hypoxemia [10]. This is additionally complicated within the context of RCC as RBC syndromes, such as polycythemia and anemia, are much more common amongst this patient population. For most patients, methemoglobinemia becomes symptomatic when MetHb levels rise to 10–20% rather than the 3.7% experienced by the patient in our case report. However, as stated earlier, methemoglobinemia has a wide range of symptomology and, especially for those burdened by metastatic cancer, intensive VEGF therapy and other hematologic disorders, this symptom threshold could be significantly lower for complex oncology patients.
Between the two agents comprising the patient’s treatment regimen, axitinib is more likely the culprit for the methemoglobinemia. Unlike pembrolizumab, axitinib has a short half-life of roughly 3–6 hours in vivo [14]. The patient’s markedly rapid clinical improvement upon holding axitinib supports our theory that it may have been the inciting factor in this patient’s methemoglobinemia. Additionally, axitinib can induce polycythemia and other RBC dysfunction in patients with ccRCC due to complex interactions between hypoxia inducible factor 1 alpha (HIF-1a), VEGF and EPO [15, 16]. In fact, some studies suggesting hemoglobin values could be used as biomarkers for axitinib treatment response [17]. The etiology of this patient’s methemoglobinemia is unclear at this time. However, there are a few plausible explanations for an increase in oxidizing agents that could have produced enough MetHb to become symptomatic. The partial regression noted in this patient’s metastatic lesions could have released large quantities of intracellular oxidizing components from the malignant cells as a result of a favorable response. The combination of cell lysis and T cell expansion may have led to a concomitant release of oxidizing agents that overwhelmed the RBC reducing enzymes. Additionally, while there is little evidence of axitinib or its metabolites acting as oxidizers, axitinib is metabolized by multiple cytochrome P450 enzymes which could form oxidizing agents in a similar mechanism to a dapsone-induced methemoglobinemia [14]. While the true cause of this adverse reaction is not currently known, it was likely a multifactorial event incited by an increase in oxidizing agents that overwhelmed the reducing capacity of this patient’s RBCs.
Conclusion
Combination immune therapy provides an exciting new treatment option for mRCC patients that combines the benefits of multiple potent therapies for an even greater treatment effect. These agents can provide clinical oncologists with additional treatment options for aggressive malignancies like mRCC. However, it is crucial that medical oncologists appreciate the benefits and costs these treatment regimens impose on patients. Adverse events, such as the one presented in this case report, can be life-threatening and have significant impacts on the patient’s prognosis and quality of life. Current trials utilizing PD-1 and VEGF-TKI combination therapy have presented promising results and FDA approval for patients with advanced RCC [8]. This case presents one such example of a RCC patient who experienced a rare but important adverse hematologic event. The novelty of this presentation is both a strength and a weakness in this case study. The resulting methemoglobinemia for this patient could have equally been involved with another underlying disease process as it could be a true side effect of VEGF-TKI and ICI combination therapy. Current clinical trials should make ongoing efforts to note these uncommon side effects to better appreciate the side-effect profile of these novel agents. Cases, such as this one, can hopefully assist practicing oncologists to recognize the rare and potentially severe side effect of methemoglobinemia in mRCC patients treated with ICI and VEGF-TKI combination therapy.
Patient perspective
“I was given pembrolizumab by intravenous means every 21 days for three months. I also was placed on 5 MG tablets of Axitinib. The combination did have great success with decreasing and/or eliminating a tumor from my pancreas and two on my liver. However, the side effects caused me to have to stop the therapy. The first symptom was a loss of appetite which in turn lead to fatigue, tiredness, loss of weight, and loss of voice volume. There was no sickness, I just didn’t feel well. My lips and eye whites turned blue and I was ultimately diagnosed with methemoglobinemia. I was weak, needed weekly infusions of fluid, and ultimately had to quit the therapy after three months. There was never any pain from anything. Dehydration became my biggest issue as I spend most of my time sleeping and not wanting to eat. I found success managing this situation with my general practitioner who is an internist specializing in kidney and diabetes. It is best to start this journey with a good oncologist that will take the time to determine what is happening with your systems. I was fortunate enough to find great doctor(s)."
Abbreviations
mRCCMetastatic renal cell carcinoma
ccRCCClear cell renal cell carcinoma
HbHemoglobin
MetHbMethemoglobin
PD-1Programmed cell death protein-1
VEGFVascular endothelial growth factor
HIF-1aHypoxia inducible factor-1-alpha
Fe3+Ferric
Fe2+Ferrous
RBCRed blood cell
EPOErythropoietin
TKITyrosine-kinase inhibitor
ICIImmune checkpoint inhibitor
IMDCInternational metastatic renal cell carcinoma database consortium
OSOverall survival
PFSProgression-free survival
RECISTv1.1Response evaluation criteria in solid tumors version 1.1
ECOG PSEastern Cooperative Oncology Group performance status
C-statisticsUno’s Concordance Statistics
PD-L1Programmed death ligand-1
FDAFood and Drug Administration
CHEK2Checkpoint kinase 2 gene
ATMAtaxia-telangiesctasia gene
BLMBloom gene
MLH1MMR gene
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors' contributions
TAO was involved in the identification and selection of patients, outline, data acquisition, analysis, figures, online research, writing and editing of the manuscript. DJM was involved in the writing, editing, data acquisition, administrative support and provided advisory over the manuscript. STE was involved in administrative support and editing of the manuscript. All remaining authors were involved in the care of the patients in this study, interpretation and analysis of study results, and editing the manuscript. All authors reviewed and accepted the final version of the manuscript.
Funding
This work was supported by the Breen Foundation and National Institutes of Health/ National Cancer Institute and the Biostatistics and Bioinformatics Shared Resource of the Winship Cancer Institute of Emory University under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Availability of data and materials
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
Mehmet A. Bilen has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Genomic Health, Nektar, and Sanofi and has received grants to his institution from Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, Seattle Genetics, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peleton Therapeutics, and Pfizer for work performed as outside of the current study. | 1MG/KG | DrugDosageText | CC BY | 33602288 | 19,742,851 | 2021-02-19 |
What was the dosage of drug 'NIVOLUMAB'? | Symptomatic methemoglobinemia in a patient with metastatic clear cell renal cell carcinoma treated with pembrolizumab and axitinib combination therapy: a case report.
BACKGROUND
Combination regimens that include immune checkpoint (ICI) and vascular endothelial growth factor (VEGF) inhibition have opened the door to new treatment opportunities for patients with metastatic renal cell carcinoma (mRCC). While these treatment options have provided improved tolerability and better outcomes compared to older regimens, many patients still experience a myriad of treatment-related adverse events. Given that these regimens were recently approved for mRCC, the complete side effect profile may not be fully elucidated yet.
METHODS
We report a case of a 73-year old White male with mRCC who was managed with an ICI-VEGF inhibitor combination regimen. He experienced a partial response (Fig. 1) but had side effects including symptomatic cyanosis diagnosed as methemoglobinemia which led to treatment discontinuation. Upon holding his therapy, his methemoglobinemia and cyanosis resolved.
CONCLUSIONS
Combination VEGF-ICI therapy provide novel regimens for advanced solid tumor malignancies including mRCC. While shown to have improved efficacy in clinical trials, it is crucial that oncologists uncover the full side effect profile of these novel agents especially as their use becomes more standard in the management of advanced malignancies. To our knowledge, this is the first reported case of a patient experiencing symptomatic methemoglobinemia as an adverse event associated with a VEGF-ICI combination regimen. While the cause of this side effect is unclear, in this paper we attempt to elucidate a process that is in line with the mechanism of action of these therapies to explain how these agents, specifically the axitinib, could have caused the methemoglobin to rise to a symptomatic level.
Background
Vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) are small molecules that inhibit tyrosine kinase receptors involved in the VEGF pathway [1]. These types of TKIs are pathway-specific inhibitors of the angiogenic signaling process that cancers depend upon to obtain access to nutrients and to metastasize [2]. Blocking VEGF from malignant tissue effectively causes transient hypoxia, cutting off access to nutrients vital for oncogenesis. TKIs are integral to the treatment of numerous cancers including metastatic renal cell carcinoma (mRCC) [3]. Pembrolizumab is a programmed death-1 (PD-1) inhibitor that is in a class of medications called immune checkpoint inhibitors (ICIs). These agents increase T-cell activation, improving T-cell-mediated clearance of malignant cells and are used in several malignancies including mRCC [4–6]. PD-1 and VEGF-TKI combination therapy have shown efficacy and received FDA approval as the standard treatment for advanced RCC through the phase 3 KEYNOTE-426 clinical trial [7, 8]. This regimen, however, is not without side effects which can significantly impact patient quality of life and cause treatment discontinuation [5]. In the KEYNOTE-426 trial, the most commonly cited adverse events associated with pembrolizumab-axitinib were diarrhea, hypertension, fatigue and hypothyroidism [8]. In this report we are presenting, to our best knowledge, the first case of a patient with mRCC who developed cyanosis diagnosed as methemoglobinemia while on pembrolizumab-axitinib treatment. This case displays a rare but severe adverse event that could be related to ICI and VEGF-TKI combination therapy.
Case presentation
A 73-year-old White male was diagnosed with pT2NxMx clear cell RCC (ccRCC) and underwent radical nephrectomy in November of 2007. Given his family history of malignancy, he underwent genetic testing and was found to be positive for CHEK2, ATM, BLM and MLH1 mutations. He then presented twelve years later with biopsy-proven recurrence of his ccRCC in the pancreas, liver and lung. He was started on combination therapy consisting of pembrolizumab 200 mg IV q3 weeks and axitinib 5mg PO BID [8, 9]. As seen in Fig. 1, his scans two months after treatment initiation showed partial response in his metastases per RECIST v1.1. His course was complicated four months after initiation by adverse events including cystitis, hematuria, fatigue, polycythemia and peri-oral cyanosis without hypoxia. His primary care physician initiated cyanosis work-up and laboratory tests were obtained. This included a complete blood-cell count with differential, which showed a positive test for methemoglobinemia displaying a percent methemoglobin level of 3.7% exceeding the 1.5% cutoff for positivity. Additional complete blood cell-count values showed a normal erythropoietin (EPO) level and an elevated hemoglobin of 18.4 with a hematocrit of 53.8. The secondary polycythemia experienced concomitantly with the methemoglobinemia was attributed to a combination of the axitinib therapy and an RCC-associated paraneoplastic syndrome. Upon holding his axitinib for 1 week, the patient’s symptoms resolved. Follow-up laboratory tests similarly showed normalization of the residual polycythemia with a subsequent hemoglobin of 15.3 and hematocrit of 47.4. While the MetHb level was only mildly elevated during the treatment period, the patient was highly symptomatic and this reaction prompted medication adjustments. He was restarted on the same combination therapy with a reduced dose of axitinib from 5 to 3 mg. His adverse symptoms recurred and were intolerable shortly after resuming. He discontinued the pembrolizumab-axitinib therapy and transitioned three weeks later to an ipilimumab 1mg/kg IVBP and nivolumab 3mg/kg IVBP combination regimen. This subsequent regimen was discontinued due to poor tolerability from immune-related adverse events including hypothyroidism and adrenal insufficiency. His follow-up scans in January showed sustained partial response, but progression of disease in June of 2020 within the liver metastasis. In September of 2020, the patient is still alive and has begun local Y90 radiation therapy and awaits upcoming surveillance scans.Fig. 1 Axial contrast enhanced computed tomography scan of the abdomen and pelvis. Interval decreases in size of liver metastases with reference measurements are as follows: T11: 1.6 × 1.9 cm metastasis of liver towards the dome compared to baseline of 3.7 × 3.4 cm. T12: 1.6 × 2.2 cm metastasis towards the dome more centrally compared to baseline of 3.3 × 3.5 cm. L1: 2.1 × 2.1 cm metastasis inferior right hepatic lobe compared to baseline of 3.2 × 3.9 cm
Discussion
In this case, we presented a mRCC patient who had partial response to treatment with pembrolizumab and axitinib. Despite the response, he experienced recurrent cyanosis without hypoxia diagnosed as acquired methemoglobinemia, leading to treatment discontinuation. There have been no reported cases of methemoglobinemia related to either PD-1-inhibitors or VEGF-TKIs. However, our analysis of the clinical notes and labs are in line with the treating physician’s suspicion that the methemoglobinemia was most likely attributed to the axitinib. It is important to note that these symptoms resolved within seven days of holding axitinib and recurred at the lower dose. The amount of methemoglobin measured in the patient’s blood overtime can be appreciated in Fig. 2. This case could provide evidence of a rare, but significant side effect of anti-VEGF therapy when used in combination with ICI. It is important for medical oncologists to be aware of this adverse event so they can formulate the best response for their patients in the clinic.Fig. 2 Patient’s percent level of methemoglobin relative to normal hemoglobin based on sequential complete blood-cell counts with differential
Hemoglobin (Hb) is the oxygen carrying molecule within red blood cells (RBCs). Methemoglobin (MetHb) is a type of Hb containing an oxidized ferric (Fe3+) atom that is less effective at releasing oxygen compared to the normal ferrous (Fe2+) bound heme [10]. RBCs are frequently exposed to oxidizing agents, such as free radicals, metabolites and drug intermediates. These molecules shift the iron in their heme rings from 2+ to 3+, which forms MetHb. To combat this, the RBC contains a large reservoir cytochrome-based reducing enzymes to counteract these oxidizing particles [11]. Methemoglobinemia is a state where the percentage of MetHb relative to normal Hb rises to a symptomatic level [11]. There are two main forms of methemoglobinemia: inherited and acquired. These conditions are associated with either a genetic or an induced deficiency of these RBC reducing enzymes. The acquired form is more common and is most often due to medications such as dapsone, which form potent oxidizing agents when metabolized by cytochrome P450 enzymes in the liver [12, 13]. This patient’s medication list showed no notable agents that could have been associated with the patient’s adverse hematologic side effects. There was also no evidence of any past or familial hematologic disorders playing a role in the patient’s adverse reaction. Family history was only significant for past malignancies, which was supported by genetic mutation findings. Methemoglobinemia can also be a difficult syndrome to diagnose due to its wide spectrum of symptomology ranging from minor cyanosis to life-threatening hypoxemia [10]. This is additionally complicated within the context of RCC as RBC syndromes, such as polycythemia and anemia, are much more common amongst this patient population. For most patients, methemoglobinemia becomes symptomatic when MetHb levels rise to 10–20% rather than the 3.7% experienced by the patient in our case report. However, as stated earlier, methemoglobinemia has a wide range of symptomology and, especially for those burdened by metastatic cancer, intensive VEGF therapy and other hematologic disorders, this symptom threshold could be significantly lower for complex oncology patients.
Between the two agents comprising the patient’s treatment regimen, axitinib is more likely the culprit for the methemoglobinemia. Unlike pembrolizumab, axitinib has a short half-life of roughly 3–6 hours in vivo [14]. The patient’s markedly rapid clinical improvement upon holding axitinib supports our theory that it may have been the inciting factor in this patient’s methemoglobinemia. Additionally, axitinib can induce polycythemia and other RBC dysfunction in patients with ccRCC due to complex interactions between hypoxia inducible factor 1 alpha (HIF-1a), VEGF and EPO [15, 16]. In fact, some studies suggesting hemoglobin values could be used as biomarkers for axitinib treatment response [17]. The etiology of this patient’s methemoglobinemia is unclear at this time. However, there are a few plausible explanations for an increase in oxidizing agents that could have produced enough MetHb to become symptomatic. The partial regression noted in this patient’s metastatic lesions could have released large quantities of intracellular oxidizing components from the malignant cells as a result of a favorable response. The combination of cell lysis and T cell expansion may have led to a concomitant release of oxidizing agents that overwhelmed the RBC reducing enzymes. Additionally, while there is little evidence of axitinib or its metabolites acting as oxidizers, axitinib is metabolized by multiple cytochrome P450 enzymes which could form oxidizing agents in a similar mechanism to a dapsone-induced methemoglobinemia [14]. While the true cause of this adverse reaction is not currently known, it was likely a multifactorial event incited by an increase in oxidizing agents that overwhelmed the reducing capacity of this patient’s RBCs.
Conclusion
Combination immune therapy provides an exciting new treatment option for mRCC patients that combines the benefits of multiple potent therapies for an even greater treatment effect. These agents can provide clinical oncologists with additional treatment options for aggressive malignancies like mRCC. However, it is crucial that medical oncologists appreciate the benefits and costs these treatment regimens impose on patients. Adverse events, such as the one presented in this case report, can be life-threatening and have significant impacts on the patient’s prognosis and quality of life. Current trials utilizing PD-1 and VEGF-TKI combination therapy have presented promising results and FDA approval for patients with advanced RCC [8]. This case presents one such example of a RCC patient who experienced a rare but important adverse hematologic event. The novelty of this presentation is both a strength and a weakness in this case study. The resulting methemoglobinemia for this patient could have equally been involved with another underlying disease process as it could be a true side effect of VEGF-TKI and ICI combination therapy. Current clinical trials should make ongoing efforts to note these uncommon side effects to better appreciate the side-effect profile of these novel agents. Cases, such as this one, can hopefully assist practicing oncologists to recognize the rare and potentially severe side effect of methemoglobinemia in mRCC patients treated with ICI and VEGF-TKI combination therapy.
Patient perspective
“I was given pembrolizumab by intravenous means every 21 days for three months. I also was placed on 5 MG tablets of Axitinib. The combination did have great success with decreasing and/or eliminating a tumor from my pancreas and two on my liver. However, the side effects caused me to have to stop the therapy. The first symptom was a loss of appetite which in turn lead to fatigue, tiredness, loss of weight, and loss of voice volume. There was no sickness, I just didn’t feel well. My lips and eye whites turned blue and I was ultimately diagnosed with methemoglobinemia. I was weak, needed weekly infusions of fluid, and ultimately had to quit the therapy after three months. There was never any pain from anything. Dehydration became my biggest issue as I spend most of my time sleeping and not wanting to eat. I found success managing this situation with my general practitioner who is an internist specializing in kidney and diabetes. It is best to start this journey with a good oncologist that will take the time to determine what is happening with your systems. I was fortunate enough to find great doctor(s)."
Abbreviations
mRCCMetastatic renal cell carcinoma
ccRCCClear cell renal cell carcinoma
HbHemoglobin
MetHbMethemoglobin
PD-1Programmed cell death protein-1
VEGFVascular endothelial growth factor
HIF-1aHypoxia inducible factor-1-alpha
Fe3+Ferric
Fe2+Ferrous
RBCRed blood cell
EPOErythropoietin
TKITyrosine-kinase inhibitor
ICIImmune checkpoint inhibitor
IMDCInternational metastatic renal cell carcinoma database consortium
OSOverall survival
PFSProgression-free survival
RECISTv1.1Response evaluation criteria in solid tumors version 1.1
ECOG PSEastern Cooperative Oncology Group performance status
C-statisticsUno’s Concordance Statistics
PD-L1Programmed death ligand-1
FDAFood and Drug Administration
CHEK2Checkpoint kinase 2 gene
ATMAtaxia-telangiesctasia gene
BLMBloom gene
MLH1MMR gene
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors' contributions
TAO was involved in the identification and selection of patients, outline, data acquisition, analysis, figures, online research, writing and editing of the manuscript. DJM was involved in the writing, editing, data acquisition, administrative support and provided advisory over the manuscript. STE was involved in administrative support and editing of the manuscript. All remaining authors were involved in the care of the patients in this study, interpretation and analysis of study results, and editing the manuscript. All authors reviewed and accepted the final version of the manuscript.
Funding
This work was supported by the Breen Foundation and National Institutes of Health/ National Cancer Institute and the Biostatistics and Bioinformatics Shared Resource of the Winship Cancer Institute of Emory University under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Availability of data and materials
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
Mehmet A. Bilen has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Genomic Health, Nektar, and Sanofi and has received grants to his institution from Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, Seattle Genetics, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peleton Therapeutics, and Pfizer for work performed as outside of the current study. | 3MG/KG | DrugDosageText | CC BY | 33602288 | 19,742,851 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal exposure during delivery'. | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | ESCITALOPRAM OXALATE, NITROFURANTOIN\NITROFURANTOIN MONOHYDRATE, SERTRALINE HYDROCHLORIDE, VITAMINS | DrugsGivenReaction | CC BY | 33602307 | 19,062,877 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypoglycaemia'. | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | DINOPROSTONE, ESCITALOPRAM OXALATE, MINERALS\VITAMINS, NITROFURANTOIN\NITROFURANTOIN MONOHYDRATE, OXYTOCIN, SERTRALINE HYDROCHLORIDE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33602307 | 19,025,209 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypoxia'. | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | DINOPROSTONE, ESCITALOPRAM OXALATE, MINERALS\VITAMINS, NITROFURANTOIN\NITROFURANTOIN MONOHYDRATE, OXYTOCIN, SERTRALINE HYDROCHLORIDE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33602307 | 19,025,209 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure during pregnancy'. | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | CLARITHROMYCIN, DINOPROSTONE, ESCITALOPRAM OXALATE, OXYTOCIN, SERTRALINE HYDROCHLORIDE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33602307 | 19,027,415 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neonatal hypoxia'. | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | CLARITHROMYCIN, DINOPROSTONE, ESCITALOPRAM OXALATE, OXYTOCIN, SERTRALINE HYDROCHLORIDE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33602307 | 19,027,415 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Overdose'. | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | DINOPROSTONE, ESCITALOPRAM OXALATE, NITROFURANTOIN\NITROFURANTOIN MONOHYDRATE, OXYTOCIN, SERTRALINE HYDROCHLORIDE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33602307 | 19,039,103 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pregnancy'. | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | ESCITALOPRAM OXALATE, NITROFURANTOIN MONOHYDRATE, SERTRALINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33602307 | 19,718,564 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory depression'. | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | DINOPROSTONE, ESCITALOPRAM OXALATE, MINERALS\VITAMINS, NITROFURANTOIN\NITROFURANTOIN MONOHYDRATE, OXYTOCIN, SERTRALINE HYDROCHLORIDE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33602307 | 19,025,209 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Umbilical cord abnormality'. | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | ESCITALOPRAM OXALATE, NITROFURANTOIN MONOHYDRATE, SERTRALINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33602307 | 19,718,564 | 2021-02-19 |
What was the administration route of drug 'CLARITHROMYCIN'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Transplacental | DrugAdministrationRoute | CC BY | 33602307 | 19,027,415 | 2021-02-19 |
What was the administration route of drug 'DINOPROSTONE'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Transplacental | DrugAdministrationRoute | CC BY | 33602307 | 18,962,434 | 2021-02-19 |
What was the administration route of drug 'ESCITALOPRAM OXALATE'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Transplacental | DrugAdministrationRoute | CC BY | 33602307 | 19,718,564 | 2021-02-19 |
What was the administration route of drug 'MINERALS\VITAMINS'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Transplacental | DrugAdministrationRoute | CC BY | 33602307 | 19,025,209 | 2021-02-19 |
What was the administration route of drug 'NITROFURANTOIN MONOHYDRATE'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Transplacental | DrugAdministrationRoute | CC BY | 33602307 | 19,718,564 | 2021-02-19 |
What was the administration route of drug 'NITROFURANTOIN\NITROFURANTOIN MONOHYDRATE'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Transplacental | DrugAdministrationRoute | CC BY | 33602307 | 18,962,434 | 2021-02-19 |
What was the administration route of drug 'OXYTOCIN CITRATE'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Transplacental | DrugAdministrationRoute | CC BY | 33602307 | 18,962,434 | 2021-02-19 |
What was the administration route of drug 'OXYTOCIN'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Transplacental | DrugAdministrationRoute | CC BY | 33602307 | 19,025,209 | 2021-02-19 |
What was the administration route of drug 'SERTRALINE HYDROCHLORIDE'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Transplacental | DrugAdministrationRoute | CC BY | 33602307 | 19,718,564 | 2021-02-19 |
What was the administration route of drug 'SODIUM CHLORIDE'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Transplacental | DrugAdministrationRoute | CC BY | 33602307 | 18,962,434 | 2021-02-19 |
What was the administration route of drug 'VITAMINS'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Transplacental | DrugAdministrationRoute | CC BY | 33602307 | 19,062,877 | 2021-02-19 |
What was the dosage of drug 'CLARITHROMYCIN'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | 100 MG, 1X/DAY | DrugDosageText | CC BY | 33602307 | 19,027,415 | 2021-02-19 |
What was the dosage of drug 'NITROFURANTOIN\NITROFURANTOIN MONOHYDRATE'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | 100 MILLIGRAM, QD | DrugDosageText | CC BY | 33602307 | 19,039,103 | 2021-02-19 |
What was the dosage of drug 'OXYTOCIN CITRATE'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | 0.02 IU/ML | DrugDosageText | CC BY | 33602307 | 18,962,434 | 2021-02-19 |
What was the dosage of drug 'OXYTOCIN'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | 20 UNITS OF OXYTOCIN IN 1000ML OF SODIUM CHLORIDE INFUSION WAS FORMULATED AND .. | DrugDosageText | CC BY | 33602307 | 19,039,103 | 2021-02-19 |
What was the outcome of reaction 'Cyanosis neonatal'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 19,718,564 | 2021-02-19 |
What was the outcome of reaction 'Cyanosis'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 19,062,877 | 2021-02-19 |
What was the outcome of reaction 'Foetal exposure during pregnancy'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 19,025,209 | 2021-02-19 |
What was the outcome of reaction 'Hypoglycaemia neonatal'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 19,718,564 | 2021-02-19 |
What was the outcome of reaction 'Hypoglycaemia'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 19,025,209 | 2021-02-19 |
What was the outcome of reaction 'Hypoxia'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 19,025,209 | 2021-02-19 |
What was the outcome of reaction 'Maternal exposure during pregnancy'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 19,027,415 | 2021-02-19 |
What was the outcome of reaction 'Motor dysfunction'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 19,718,564 | 2021-02-19 |
What was the outcome of reaction 'Neonatal behavioural syndrome'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 19,025,209 | 2021-02-19 |
What was the outcome of reaction 'Neonatal hypoxia'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 19,027,415 | 2021-02-19 |
What was the outcome of reaction 'Neonatal respiratory depression'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 18,962,434 | 2021-02-19 |
What was the outcome of reaction 'Neonatal respiratory distress'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 19,718,564 | 2021-02-19 |
What was the outcome of reaction 'Overdose'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 19,039,103 | 2021-02-19 |
What was the outcome of reaction 'Respiratory depression'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 19,025,209 | 2021-02-19 |
What was the outcome of reaction 'Respiratory distress'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 19,062,877 | 2021-02-19 |
What was the outcome of reaction 'Umbilical cord abnormality'? | Respiratory depression in a neonate born to mother on maximum dose sertraline: a case report.
BACKGROUND
Mood and anxiety disorders are common in women of childbearing age, especially during the peripartum period. As more women seek medical management for these conditions, there is an increasing need for studies to better examine the effects of exposure to selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, on newborns at the time of delivery.
METHODS
We report the case of a term Caucasian infant born to a 17-year-old white female taking 100 mg of sertraline daily for depression and anxiety who exhibited respiratory depression and hypoxia after an uncomplicated vaginal delivery. The neonate was treated with the use of continuous positive airway pressure (CPAP) and supplemental oxygen and subsequently the symptoms resolved without complication.
CONCLUSIONS
We present this case with the suspicion of poor neonatal adjustment syndrome as the possible cause of the respiratory depression and hypoxia in this newborn.
Introduction
It is estimated that 15%–21% of peripartum women screen positive for perinatal mood disorders and that 14% of women of reproductive age (18–44 years old) screen positive for major or minor depression [1, 2]. In pregnant women who meet criteria for major or minor depression, lack of treatment has been associated with an increased risk of adverse outcomes for the infant, particularly during the later second or early third trimesters [3]. Current guidelines suggest antidepressant medication as the initial treatment of choice in both pregnant and postpartum patients. While the choice of antidepressant is based on a variety of criteria, SSRIS, specifically sertraline, are the mainstay of treatment as they are better studied and enjoy the support of more years of data. We report a case of transient hypoxia and perinatal depression in an infant born to a 17-year-old female who at the time of delivery was taking 100 mg of sertraline for symptoms of anxiety and depression.
Case presentation
A 17-year-old white female gravida 1 para 0-0-0-0 with a past medical history of depression, panic attacks and right nephrolithiasis presented to a rural community hospital at 38 weeks 4 days for induction of labor. She had been receiving routine prenatal care. Patient’s pregnancy was complicated by right nephrolithiasis, young maternal age, a slipped disc in the lumbar spine and chlamydia during pregnancy. The decision was made to proceed with induction of labor at 38 weeks and 4 days rather than waiting for 39 weeks secondary to the patient’s nephrolithiasis and back pain from a slipped disc. This decision was made with the assistance of physicians who were board certified in maternal fetal medicine. Medications at the time of induction included sertraline 100 mg daily, macrobid 100 mg daily for urinary tract infections, and prenatal vitamins. She claimed compliance with these medications and denied any other medications, vitamins, or supplements. She had previously been prescribed escitalopram for her depression and anxiety but switched to sertraline 50 mg daily 4 months prior to delivery. Prior to this she had been on escitalopram for greater than two years. She felt that symptoms were not adequately controlled, so the dose of sertraline was later increased to 100 mg daily 2 months and 17 days prior to delivery. The last 100 mg dose of sertraline was given 5 h and 26 min prior to delivery. The patient denied use of tobacco, alcohol, or illicit drugs during pregnancy.
Patient was induced via 10 mg topical vaginal dinoprostone given one time and allowed to dilate. Subsequently she underwent an amniotomy after she was placed on oxytocin 20 unit in 1000 mL sodium chloride 0.9% infusion given at the rate of 1munit/min. She was allowed to progress through the normal stages of labor with no maternal or fetal complications. Continuous fetal monitoring was performed per hospital protocol, and tracing fluctuated between category I and category II without any unexpected decelerations or tracing abnormalities. At no time was cesarean section considered as fetal status appeared reassuring. There was no indication for biophysical profile during labor. Delivery occurred spontaneously. After delivery of the head it was noted that there was a loose nuchal cord which was easily slipped over the head of the infant and resolved. She gave birth vaginally to a 3373 g male infant at 0226 with APGAR scores of 3 at 1 min, 6 at 5 min and 8 at 10 min.
At the time of delivery, the newborn exhibited motor depression, cyanosis, and minimal respiratory effort. It was noted that the umbilical cord only had two vessels upon inspection. A pulse oximeter was placed at 2 min to monitor oxygenation and at four minutes it was noted that the infant was euglycemic with a blood sugar of 110 mg/dL. At nine minutes the infant continued to exhibit grunting, retractions, and tachypnea consistent with respiratory distress. He was found to have a respiratory rate of 30 and 82% oxygen saturation. He was then placed on 10 L of supplemental oxygen via simple bag mask. At ten minutes the APGAR score was 8, with points taken off due to cyanotic extremities and continued poor respiratory effort. The infant was then transferred to the neonatal intensive care unit (NICU) at 0240 for further evaluation and monitoring. In the NICU there was a sustained period of hypoglycemia which was initially noted at 0605 with a blood glucose of 42 mg/dL. Other than this, laboratory values and physical exam was normal for the duration of the hospitalization. The neonate remained on 2 L oxygen via nasal cannula until 1200 and was lowered to 1 L oxygen via nasal cannula which was continued for an additional 3.5 h. At this point the infant was weaned off supplemental oxygen and would not require it for the remainder of the hospitalization. The hypoglycemia persisted due to poor feeding with measurements of 63 mg/dL at 1202 and 68 mg/dL at 1803. At this point both the oxygen saturation and blood sugars both normalized and would continue to stay within normal limits until the patient discharged the following day at 1430. The patient was instructed to follow up with the pediatrician 2 days after discharge.
Outcome
The pediatrician noted that there were no symptoms of respiratory distress or complications of the hypoxia in the newborn at 4 days postpartum.
Discussion
As women of reproductive age are at an elevated risk for depression and anxiety, The American College of Obstetricians and Gynecologists issued a committee opinion in 2015 that recommends for the screening of depression both during pregnancy and postpartum [4]. This recommendation, as well as the changing attitudes towards mental health and its treatment, has led to an increase in women receiving treatment for peripartum depression and anxiety.
Current guidelines suggest antidepressant medication as the initial treatment of choice for peripartum depression, with psychotherapy as an acceptable alternative or adjuvant provided that the patient does not complain of suicidal ideation or significant cognitive impairment. The choice of antidepressant is informed by a number of considerations (tolerability, prior efficacy and use, potential fetal adverse effects, potential maternal adverse effects, use at conception, etc...). The most widely used class of medication has been selective serotonin reuptake inhibitors (SSRIs), with the exception of paroxetine [5]. About 80% of pregnant patients treated for depression in the first trimester receive SSRIs as opposed to other classes of antidepressants such as SSRIs, or monoamine reuptake inhibitors. Out of all the medications in pregnancy three SSRIs, sertraline, fluoxetine, and escitalopram, were among the twenty most commonly prescribed drugs in pregnancy, with sertraline being the drug of choice for treatment of anxiety and depression [6, 7]. While these three drugs have similar efficacy and a similar side effect profiles, they differ in their pharmacokinetic (PK) properties (Table 1) [8]. Many SSRIs have active metabolites, including sertraline and fluoxetine meaning that they may continue to exhibit effects until they are excreted. Metabolites are primarily excreted renally in urine, as well as through the gastrointestinal tract in fecal matter [9].Table 1 Pharmacokinetics of three most prescribed SSRIs
Drug Pharmaco-kinetics Half life Time to 99% metabolised [days] Estimated exposure to parent drug [%] Estimated exposure to metabolite [%] Active metabolite [%] Time to peak concentration [h]
Escitalopran1 Linear 27-33 h 6.1 73 70 No 3-4
Fluoxetine Non-linear 1-4 days 25 58-73 63-71 Yes 6-8
Sertraline Linear 26 h 5.4 29-73 29-63% Yes 4-10
While numerous studies that demonstrate the lack of significant teratogenicity of SSRI use during pregnancy and confirm their safety during lactation, there are few to show the effects of their use at the time of or immediately prior to the time of delivery [10]. Studies have shown that exposure to SSRIs during pregnancy is associated with increased infant morbidity which necessitates admission to the NICU as well as a collection of transient symptoms referred to as poor neonatal adjustment syndrome (PNAS) [11]. This syndrome is characterized by, but not limited to, respiratory distress, hypoxia, seizures, and limpness (Table 2) [12]. Early clinical and research findings of this syndrome led to a 2004 warning by The United States Food and Drug Administration recommending that SSRIs be tapered 7–10 days prior to delivery [13]. Currently, the tapering of SSRIs prior to delivery is not recommended as there is insufficient evidence to suggest that doing so is beneficial [14–16]. While the pathophysiology of PNAS is not fully understood, these symptoms appear similar to those seen in adults overdosing or withdrawing from SSRIs. There are few studies that have assessed the safety during the third trimester, but current literature suggests that there is an increased risk of perinatal complications including respiratory distress, irritability and feeding problems [17]. Additionally, in a study of 700,000 infants with antenatal exposure to SSRIs, when controlled for all other factors, were more likely to manifest central nervous related symptoms, respiratory distress, hypoglycemia, and persistent pulmonary hypertension [3]. From studies looking at fetal cord blood and amniotic fluid versus maternal plasma concentrations of SSRIs we know that varying concentrations of the parent drug and metabolites of SSRIs pass through the placenta (Table 1). For sertraline, the estimated exposure of 29–73% of the parent drug and 29–63% of the active metabolite [18].Table 2 Symptoms of Poor Neonatal Adjustment Syndrome, Selective Serotonin Reuptake Inhibitor Overdose and Selective Serotonin Reuptake Inhibitor withdrawal
PNAS SSRI overdose SSRI withdrawal
Autonomic Instability
Diaphoresisa,b
Exaggerated Moro Reflex
Feeding difficulties
Fevera
Gastrointestinal Disturbancea,b
Hypoglycaemia
Increased Muscle Tonea
Insomniaa
Irritabilitya,b
Limpness
Persistent Crying
Poor thermoregulation
Respiratory Distress
Seizuresa
Sleep Disturbanceb
Tachycardiaa
Tachypnoeab
Tremorsb
Agitation
Anythmia
Clonus
Confusion
Diaphoresisa
Fevera
Gastrointestinal disturbancea
Headache
Hyperreflexia
Hypertension
Increased Muscle Tonea
Insomniaa
Irritabilitya
Loss of consciousness
Loss of muscle coordination
Mydriasis
Piloerection
Seizuresa
Shivering
Tachycardiaa
Tachypnoea
Twitching
Agitation
Ataxia
Diaphoresisb
Dizziness
Gastrointestinal Upsetb
Headache
Insomniab
Irritabilityb
Lethargy
Nausea
Paraesthesia
Sleep disturbanceb
Tremorb
aOverlapping symptoms between PNAS and SSRI overdose
bOverlapping symptoms between PNAS and SSRI withdrawal
Few studies have assessed the effects at the time of delivery, but research consistently shows the use of SSRIs during pregnancy are related to a variety of neonatal complications including respiratory distress. We were able to find no specific studies addressing neonatal symptoms that were thought to be from maternal ingestion of sertraline prior to delivery, other than those addressing withdrawal from sertraline. Further research is additionally needed to elucidate whether these complications represent a direct serotonergic effect on an immature nervous system or are a product of drug overdose or withdrawal. Many of the symptoms of an SSRI overdose and withdrawal overlap with those of PNAS (Table 2). Symptoms such as gastrointestinal upset, tremors, sleep disturbances, tremors or twitching are seen in all three, while symptoms unique to PNAS include hypoglycemia, respiratory distress, and tachypnea [19, 20]. In order to have symptoms of withdrawal, discontinuation of the drug would need to occur with sufficient time prior to delivery for the active component to be fully metabolized or excreted from both maternal and fetal circulation. It is currently not well understood how the timeline of overdose or withdrawal is altered by transport across the placenta or by altered levels of fetal metabolism. The time required for >99.00% of a drug to be excreted depends on the half-life and pharmacokinetics of the drug, ranging from 5.4 days with sertraline up to 25 days with fluoxetine (Table 1). Therapeutic doses of SSRIs are based on an adult cytochrome P450 mediated metabolism, this system is not fully functioning and develops at different rates during the postnatal period. While many of these cytochromes develop rapidly after birth, at the time of birth they are not fully functional. This window of time between birth and full development of a cytochrome P450 (CYP450) system could potentially lead to reduced metabolism and increased concentrations in the neonate. The cytochrome primarily responsible for metabolism of SSRIs is CYP2D6, as well as CYP3A4. While CYP2D6 starts at low levels in the fetus and rapidly develops in the first month postpartum, the CYP3A system has a transition from CYP3A7 to CYP3A4 which reaches 30–50% at 3–12 months of age [21]. Metabolites from the cytochrome P450 system are then excreted renally in the urine, as well as by the gastrointestinal tract in fecal matter. While nephrons are structurally complete by 36 weeks gestation, the newborn kidney is still functionally immature. During the first weeks of life renal function undergoes a rapid maturation, reaching a mature glomerular filtration rate corrected for body size by 12 months of age [22]. During pregnancy, there are increased rates of maternal cytochrome P450 expression and activity and during labor there continues to be transplacental blood exchange allowing for adequate metabolism and excretion of the drug. But after delivery, there is no longer blood exchange between the mother and infant, leaving any parent drug or metabolite in the infant’s blood. This leaves a period where the infant has both reduced levels of cytochrome activity and kidney function, creating a window of vulnerability to the drugs' effects.
In this case we see that the patient had been treated with sertraline, the last dose of which was given 5 h and 26 min prior to delivery. This time is sufficient to allow for peak concentration of the drug to be reached in maternal circulation and move through the placenta into fetal circulation and amniotic fluid. Without fully functional mechanisms to metabolize the parent drug or excrete the active metabolite, a window of vulnerability was present in the neonate to the effects of sertraline. Research currently demonstrates the link between the use of SSRIs during pregnancy and PNAS. Despite not fully understanding the pathophysiology it cannot be ignored that the symptoms of PNAS overlap with those known to be caused by an overdose of SSRIs. In this case the neonate presented with transient respiratory depression, hypoxia, feeding difficulties and hypoglycemia, all of which are consistent with a diagnosis of PNAS. Without other clear etiologies for these symptoms, it is reasonable to conclude that they can be linked to the use of high dose sertraline at the time of delivery.
Conclusions
Mood and anxiety disorders are common in women of childbearing age and there are increased rates in those during the peripartum period. As treatment with antidepressant medications, particularly SSRIs, is widely accepted as the first line treatment in pregnant women it is paramount that we fill the current gap in knowledge of the consequences of exposure to SSRIs and other antidepressants on newborns at the time of delivery. These medications are some of the most commonly prescribed drugs during pregnancy, consequently there is a need for further studies to evaluate the potential effects and risks of usage.
Abbreviations
APGARAppearance, Pulse, Grimace, Activity and Respiration
NICUNeonatal intensive care unit
SSRISelective serotonin reuptake inhibitor
PNASPoor neonatal adjustment syndrome
CYP450Cytochrome p450
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ethics approval and consent to participate
This project was reviewed by the Marchand Institute IRB committee in September of 2020 and approved from an ethical standpoint.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.
Competing interests
All authors deny any competing interests in regards to this paper. | Recovered | ReactionOutcome | CC BY | 33602307 | 19,718,564 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood pressure increased'. | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | BETAMETHASONE, ENOXAPARIN SODIUM, INSULIN ASPART, INSULIN DETEMIR | DrugsGivenReaction | CC BY | 33602315 | 19,235,870 | 2021-02-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'COVID-19'. | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | BETAMETHASONE, ENOXAPARIN SODIUM, INSULIN ASPART, INSULIN DETEMIR | DrugsGivenReaction | CC BY | 33602315 | 19,235,870 | 2021-02-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cholestasis of pregnancy'. | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | BETAMETHASONE, ENOXAPARIN SODIUM, INSULIN ASPART, INSULIN DETEMIR | DrugsGivenReaction | CC BY | 33602315 | 19,235,870 | 2021-02-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Low birth weight baby'. | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | ASPIRIN, BETAMETHASONE, ENOXAPARIN, INSULIN ASPART, INSULIN DETEMIR, URSODIOL | DrugsGivenReaction | CC BY | 33602315 | 19,187,682 | 2021-02-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Placental insufficiency'. | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | BETAMETHASONE, ENOXAPARIN SODIUM, INSULIN ASPART, INSULIN DETEMIR | DrugsGivenReaction | CC BY | 33602315 | 19,235,870 | 2021-02-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary haemorrhage neonatal'. | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | ASPIRIN, BETAMETHASONE, ENOXAPARIN SODIUM, INSULIN ASPART, INSULIN DETEMIR, URSODIOL | DrugsGivenReaction | CC BY | 33602315 | 19,240,246 | 2021-02-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'SARS-CoV-2 test positive'. | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | ASPIRIN, BETAMETHASONE, ENOXAPARIN SODIUM, INSULIN ASPART, INSULIN DETEMIR, URSODIOL | DrugsGivenReaction | CC BY | 33602315 | 19,240,104 | 2021-02-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sepsis neonatal'. | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | ASPIRIN, BETAMETHASONE, ENOXAPARIN SODIUM, INSULIN ASPART, INSULIN DETEMIR, URSODIOL | DrugsGivenReaction | CC BY | 33602315 | 19,240,246 | 2021-02-18 |
What was the administration route of drug 'ASPIRIN'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Transplacental | DrugAdministrationRoute | CC BY | 33602315 | 19,240,104 | 2021-02-18 |
What was the administration route of drug 'BETAMETHASONE'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Transplacental | DrugAdministrationRoute | CC BY | 33602315 | 19,240,104 | 2021-02-18 |
What was the administration route of drug 'ENOXAPARIN SODIUM'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Transplacental | DrugAdministrationRoute | CC BY | 33602315 | 19,240,104 | 2021-02-18 |
What was the administration route of drug 'ENOXAPARIN'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Transplacental | DrugAdministrationRoute | CC BY | 33602315 | 19,187,682 | 2021-02-18 |
What was the administration route of drug 'INSULIN ASPART'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Transplacental | DrugAdministrationRoute | CC BY | 33602315 | 19,240,104 | 2021-02-18 |
What was the administration route of drug 'INSULIN DETEMIR'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Transplacental | DrugAdministrationRoute | CC BY | 33602315 | 19,240,104 | 2021-02-18 |
What was the administration route of drug 'URSODIOL'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Transplacental | DrugAdministrationRoute | CC BY | 33602315 | 19,240,104 | 2021-02-18 |
What was the dosage of drug 'URSODIOL'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | 300 MILLIGRAM, BID | DrugDosageText | CC BY | 33602315 | 19,187,682 | 2021-02-18 |
What was the outcome of reaction 'Blood pressure increased'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33602315 | 19,235,870 | 2021-02-18 |
What was the outcome of reaction 'COVID-19'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33602315 | 19,235,870 | 2021-02-18 |
What was the outcome of reaction 'Cholestasis of pregnancy'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33602315 | 19,235,870 | 2021-02-18 |
What was the outcome of reaction 'Foetal exposure during pregnancy'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33602315 | 19,240,104 | 2021-02-18 |
What was the outcome of reaction 'Maternal exposure during pregnancy'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33602315 | 19,235,870 | 2021-02-18 |
What was the outcome of reaction 'Placental insufficiency'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33602315 | 19,235,870 | 2021-02-18 |
What was the outcome of reaction 'Pneumothorax'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Fatal | ReactionOutcome | CC BY | 33602315 | 19,240,246 | 2021-02-18 |
What was the outcome of reaction 'Pulmonary haemorrhage'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33602315 | 19,240,104 | 2021-02-18 |
What was the outcome of reaction 'SARS-CoV-2 test positive'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33602315 | 19,240,104 | 2021-02-18 |
What was the outcome of reaction 'Sepsis neonatal'? | Maternal and fetal effects of COVID-19 virus on a complicated triplet pregnancy: a case report.
BACKGROUND
Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case.
METHODS
The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition.
CONCLUSIONS
This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.
Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has spread throughout the world. Unfortunately, there is still limited scientific evidence on the manifestations and potential impact of this virus on pregnancy. In this article, we aim to report the maternal and fetal effects of the virus on a complicated triplet pregnancy.
Case
A 38 year-old Iranian woman with a triplet (three chorionic and three amniotic) pregnancy was hospitalized at 29 weeks and 2 days gestational age due to one-time high blood pressure at 140/90mmHg and elevated liver enzymes. A week before admission, she had been hospitalized in another hospital for about 5 days to evaluate the cause of increased liver enzymes. She had a 2-year history of primary infertility and had become pregnant by ovulation induction, and also had a 5-year history of hypothyroidism, which was euthyroid during pregnancy. She had also been diagnosed with gestational diabetes a month before admission, which was being treated with 16 units of insulin daily (6 units Levemir and 10 units NovoRapid), so her blood glucose levels were maintained in a normal range, and glycated hemoglobin concentration was 5.6 %. She was at risk for preeclampsia due to her advanced age and triplet pregnancy, so aspirin was administered. On the other hand, due to hospitalization for more than 3 days, she was at increased risk of deep vein thrombosis and was treated with enoxaparin. Additionally, given the possibility of iatrogenic preterm delivery, she had received a course of betamethasone for fetal lung maturation.
Two weeks before hospitalization, liver enzymes increased to four times the normal levels: alanine amino transferase (ALT) 218 units per liter (U/L) and aspartate amino transferase (AST) 283 U/L. After a thorough evaluation and ruling out preeclampsia, and due to a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid (300 mg twice a day) from 1 week before hospitalization. Lab tests at admission included the following: ALT = 94 U/L, AST = 57 U/L, total bilirubin = 0.7, direct bilirubin = 0.1, and lactate dehydrogenase (LDH) = 276 U/L. Other tests including white blood cell count, hemoglobin, platelet, serum creatinine, and urinalysis were in the normal range. She underwent 24-hour Holter blood pressure monitoring, and among all measurements, only 18.8% of systolic and 15.6% of diastolic blood pressure exceeded the set limit of 140 and 90 mmHg, respectively. Echocardiographic findings were quite normal, and 24-hour urine protein was also reported in the normal range. On the second day of hospitalization, an ultrasound exam was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses. One of the fetuses had increased umbilical artery resistance (pulsatility index [PI] > 95%) and estimated weight below 5%, but umbilical cord and middle cerebral artery findings were normal in the other two fetuses. On the fourth day of hospitalization, the patient developed fever and cough. The following day, due to the persistent fever and cough and also an onset of myalgia, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted on nasopharyngeal swabs for SARS-CoV-2 nucleic acid. All steps including sample collection, processing and laboratory testing were based on World Health Organization (WHO) guidelines. Chest X-ray and computed tomography scan were not performed due to the patient’s lack of consent.
The result of RT-PCR was positive for the SARS-CoV-2 virus. However, the patient’s clinical symptoms were mild. She had a mild fever, with maximum temperature of 38.3 °C. She had no complaint of shortness of breath, diarrhea, nausea or vomiting, her respiratory rate was 18–20 per minute, and oxygen saturation was above 95% at all times. On the same day that she developed clinical symptoms, an ultrasound exam was performed: the fetus who already had increased umbilical artery resistance showed an exacerbated condition involving absent umbilical artery end-diastolic flow, and another fetus showed umbilical artery resistance (PI > 95%), but umbilical cord and middle cerebral artery findings were normal in the third fetus, and biophysical scores and amniotic fluid were normal in all three fetuses. Based on these findings, the patient underwent serial ultrasound exams, and unfortunately, exacerbated umbilical flow resistance in the second fetus also progressed to absent umbilical artery end-diastolic flow (Fig. 1). However, Doppler and biophysical scores were normal in all fetuses. Finally, 6 days after the beginning of clinical symptoms, the biophysical scores declined in the two fetuses with absent umbilical artery end-diastolic flow, so the patient underwent cesarean section due to rapid deterioration of fetal conditions and exacerbated placental insufficiency. The first baby was born weighing 1320 g with umbilical cord pH 7.25, and her 5-minute APGAR [appearance, pulse, grimace, activity, respiration] score was 4; the second baby was born weighing 1600 g with umbilical cord pH 7.23, and his 5-minute APGAR score was 7; the third baby was born weighing 1250 g with umbilical cord pH 7.21, and her 5-minute APGAR score was 6. In order to protect the babies from infection with the virus, delayed cord clamping was not performed, skin-to-skin contact of mother and babies was not practiced, and the babies were separated from the mother immediately after birth. All three babies were intubated and were admitted to the neonatal intensive care unit (NICU), where they were kept in separate, isolated rooms. RT-PCR of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was carried out for all three newborns immediately after birth. The mother was discharged 3 days after cesarean section, and 2 weeks later she had recovered completely without any complications.Fig. 1 Fetal umbilical artery resistance during hospitalization
Two of the babies, weighing 1250 and 1320 g, each received three doses and the other baby received two doses of surfactant. All three newborns developed clinical symptoms of sepsis and pulmonary hemorrhage. The primary results of the COVID-19 test were negative for all three newborns. Because of the poor general conditions of the newborns, and considering the false-negative probability of the initial test, the COVID-19 test was repeated immediately after receiving the first test results, and the result was positive for the baby who weighed 1600 g and also had better umbilical cord and placental circulation before birth. Unfortunately, we did not examine the umbilical cord blood and amniotic fluid samples for the virus, so we cannot conclusively link the COVID-19 RT-PCR positive test in this fetus to vertical transmission, but because the babies were completely isolated and had no suspected exposure during the period between the two tests, the possibility of vertical transmission cannot be ignored.
The baby who weighed 1320 g died 3 days after birth with collapsed white lung and sepsis. The baby who weighed 1250 g also had symptoms of sepsis and died 13 days after birth. The baby who weighed 1600 g and had a positive COVID-19 test eventually recovered and was discharged in good general condition 3 weeks after birth.
Discussion
We report the case of a woman with a triplet pregnancy who was infected with COVID-19. Despite the presence of some comorbidity, she had only mild symptoms of COVID-19 infection, but rapid and progressive placental insufficiency occurred simultaneously with the peak maternal infectious disease symptoms. A COVID-19 test was positive in one baby, who was discharged in good condition 3 weeks after birth, and negative in two other babies, who died 3 and 13 days after birth.
A recently published study identified maternal age and underlying diseases as risk factors for severity of COVID-19 symptoms [1]; however, other studies have reported maternal mortality in women without underlying disease [2, 3]. In our previous prospective cohort study of COVID-19-infected pregnant women, we did not have any maternal deaths, and there were no differences in underlying disease between COVID-19-infected and non-infected pregnant women [4]. However, studies in this area are insufficient, and further research is needed.
Available data about COVID-19 vertical transmission is still contradictory. At the beginning of the pandemic, no vertical transmission was reported [5]; however, some cases of probable vertical transmission have recently been noted [6–8]. In a recent review of 50 studies, the virus test was positive in 17 cases of neonatal secretions, eight cases of placental tissue, three cases of breast milk and one case of amniotic fluid, and anti-SARS-CoV-2 antibodies were positive in three infants [9]. Therefore, the possibility of vertical transmission should be considered.
Delayed positive tests in newborns have also been reported in other studies [2, 6–8]. In most reports, the positive test occurred with a delay of 16–72 hours after birth; therefore, we recommend that all infants born to COVID-19-infected mothers be retested within the next hours if the test immediately after birth is negative. In our study, SARS-CoV-2 PCR tests for the babies were negative immediately after birth, and interestingly, changed to delayed positive in one baby who during the time between the first and second tests was completely isolated and had no suspected exposure. Unfortunately, we did not test the placenta, umbilical cord or amniotic fluid samples for the virus, and this is a limitation of our study.
Our case was a triplet pregnancy. Most previous studies are in singleton pregnancies, although there are also some reports of twin pregnancies [10–12].
Some have hypothesized that maternal respiratory failure and hypoxia may transiently reduce uterine placental blood flow [13, 14], but in our case, the mother did not have severe illness. However, there was severe placental insufficiency in two of the fetuses, both of whom had negative COVID-19 test results. Interestingly, it was the largest fetus with better placental circulation who was infected. On the other hand, although this woman had several underlying factors for placental insufficiency, and umbilical artery resistance was noted in one of the fetuses before maternal infection, the rapid and progressive placental insufficiency occurring during the last days of pregnancy and simultaneously with the peak maternal infectious disease should be taken into account. Although this pregnancy was a complicated one and there were several risk factors for placental insufficiency, the conceivable and hypothetical impact of COVID-19 on uterine circulation and fetal hypoxia should also be considered.
Conclusion
There are still insufficient data about COVID-19 in pregnancy. Our case was a complicated triplet pregnancy; however, COVID-19 symptoms in the mother were mild. Given the rapid and progressive placental insufficiency after COVID-19 infection, it seems prudent that in cases of pregnancy with COVID-19 infection, in addition to assessing and managing the mother, special attention should be given to the possibility of acute placental insufficiency and subsequent fetal hypoxia. The possibility of vertical transmission should also be considered.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the patient for allowing us to publish this report.
Authors’ contributions
MR, AA and RP are perinatologists, and TS is an infectious disease specialist, all of whom managed the patient. ZF is a neonatologist who managed the newborns. RP and ASH drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they have no funding source for this case report.
Availability of data and materials
Data are available from the electronic health record at Arash hospital.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethical number IR.TUMS.VCR.REC.1398.1057), and written informed consent was obtained from the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Fatal | ReactionOutcome | CC BY | 33602315 | 19,240,246 | 2021-02-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maculopathy'. | Maculopathy Secondary to Pentosan Polysulfate Use: A Single-Center Experience.
To investigate the prevalence of retinal pathology in patients with a history of exposure to pentosan polysulfate sodium (PPS).
Patients exposed to PPS and seen in the ophthalmology clinic at Northwestern University during 1/1/2002 to 1/1/2019 were identified from electronic health records (EHR) by an electronic data warehouse (EDW) search. Visual acuity (VA), reasons for clinic visit, ocular conditions, and duration of exposure to PPS were noted. Chart review was performed for fundus exam findings and ophthalmologic imaging, specifically fundus photography, fundus autofluorescence, and ocular coherence tomography (OCT) images. When OCT or fundus photography was available, studies were evaluated by two independent graders.
A total of 131 patients who were exposed to PPS and seen at the Northwestern Ophthalmology clinic were identified in the EHR. Forty patients of 131 had imaging. Patients with imaging or fundus examination suspicious for PPS maculopathy were placed into the suspect group. Of the 40 patients that had imaging, 5 (12.5%) had features suspicious for PPS maculopathy. Of the remaining 91, 5 (5.4%) had macular pigmentary changes described on fundus exam. Among the 10 patients in the suspect group, the average duration of PPS use was 4.2 years (range 0.3-11.6 years, interquartile range 5.5 years) and the average cumulative dose was 380g (range 29-1092g, interquartile range 132g).
A novel drug-induced maculopathy has been associated with PPS use with a distinct clinical constellation that can be accurately identified with multimodal imaging.
Introduction
Interstitial cystitis (IC) or bladder pain syndrome is a chronic condition that causes pain or pressure in the bladder, predominantly in women.1 The pathophysiology of this disease is still unknown. In the US, 2.7–6.5% of the population is affected by IC.1 Antihistamines, tricyclic antidepressants, cyclosporine, bacille Calmette-Guérin, nitric oxide, and pentosane polysulfate (PPS) have all been used to treat IC.2 PPS is a sulfated polysaccharide, with a structure similar to heparin and glycosaminoglycan and is the only United States Food and Drug Administration (FDA)-approved drug for IC, typically dosed at 100mg three times per day.3 It works as a mucosal protecting agent in the bladder to provide symptomatic relief by binding to the uroepithelium and reducing permeability to decrease irritation from toxins.3
Long-term studies on PPS report nausea, diarrhea, and headache as the common adverse effects.3 Pearce et al recently described a unique pigmentary maculopathy associated with chronic exposure to PPS in which toxic changes to the retina in 6 out of 38 patients studied at a single center were described.4 They noted changes in the retinal pigment epithelium including parafoveal pigmented deposits, paracentral atrophy, and hyperreflective lesions.4 Further studies have shown that key features of PPS-associated maculopathy include a hypoautofluorescent peripapillary halo on imaging and early involvement of the central macula.5 Prior to understanding the new maculopathy, several patients were diagnosed as having macular dystrophies and hereditary maculopathies.5 Prospective studies by Wang et al and Vora et al have reported the prevalence of PPS-associated maculopathy to be 20% and 23.1% respectively.6,7 Theorized mechanisms include the antagonism of the fibroblastic growth factor pathway in the retina by PPS, specifically in the retinal pigmental epithelium layer (RPE), PPS being directly toxic to the retina, or interaction between PPS and the glycosaminoglycans in the photoreceptor layer of the retina.8,9 Although PPS was approved by the FDA in 1996, it was only recently in June of 2020 that the FDA released an updated label to include retinal pigmentary changes as a warning and adverse effect of the drug.
This study reports retinal changes noted in patients on PPS, for any duration of the drug, at a tertiary-care center to add to the previously reported single-center case series. The current state of identification of this disease, steps to understand the association versus causation between PPS and pigmentary maculopathy, and changes to improve identification of this condition are also discussed.
Methods
A retrospective study was performed on patients from the Northwestern Medicine EPIC electronic health records (EHR) by using an Electronic Data Warehouse (EDW) search. The study cohort included patients aged 18–95 years who had been exposed to PPS and seen in the Northwestern ophthalmology clinic from January 1, 2002 to January 1, 2019. An EDW query was performed to obtain visual acuities, duration of drug, dose of drug, other health conditions, and demographics for patients in the study group. Patient charts were reviewed by study team members for fundus findings documented in the examination and ophthalmologic imaging, specifically multimodal imaging including fundus photography, fundus autofluorescence, and ocular coherence tomography (OCT) images. When imaging was available, the images were evaluated by at least two independent ophthalmologists. In cases where imaging was not available, patient charts were reviewed for fundus examinations with clinical documentation of macular pigmentary changes such as pigmentary clumping or mottling. Subjective complaints were not utilized to identify suspicious findings. Patients with fundus exam or imaging findings suspicious for PPS-associated maculopathy as described by Pearce et al were separated into the suspect group for further evaluation.
This study was approved by the Institutional Review Board of Northwestern University. All data accessed complied with relevant data protection and privacy regulations. Descriptive statistics were used to summarize patient demographics. Continuous measures were summarized with means and standard deviations (SD), and categorical measures were summarized with frequencies and percentages. SAS version 9.4 (SAS Institute, Cary, NC) was used for all statistical analyses.
Results
The study cohort comprised a total of 262 eyes of 131 patients. One hundred and eleven (84.7%) patients were female, and the cohort’s average age was 59.5 (±16.1) years old (range: 21–90). Demographic data are shown in Table 1. Of the 131 patients, 40 patients (30.5%) had imaging while 91 (69.5%) did not. Of the 40 patients with imaging on file, 5 (12.5%) had findings suspicious for PPS-associated maculopathy and of the 91 patients without imaging, 82 patients had documented fundus examinations and 5 (6.1%) of such patients were noted to have macular pigmentary changes. The 5 patients with imaging findings suspicious for PPS maculopathy and the other 5 patients with macular pigmentary changes were separated into a suspect group.Table 1 Characteristics of Patients Taking Pentosan Polysulfate Sodium
All Patients Patients in Suspect Group Patients without Suspicious Features
N Mean SD N Mean SD N Mean SD
Age (years) 131 59.5 16.1 10 (7.6%) 67.3 12.0 121 (92.4%) 58.5 16.3
Gender
Male 20 (15.3%) 2 (20%) 20 18 (14.9%) 17.5
Female 111 (84.7%) 8 (80%) 80 103 (85.1%) 82.5
Range (Interquartile Range) Mean Median Range (Interquartile Range) Mean Median Range (Interquartile Range) Mean Median
Visual acuity logMAR 0–1.6 0.19 0.1 0–1.6 0.19 0.1 0–1.6 0.19 0.1
PPS duration (years) 0.1–19.1 (5.3) 3.7 2.0 0.3–11.6 (5.5) 4.2 3.0 0.1–19.1 (5.3) 3.6 1.7
Cumulative dose (g) 0.3–2086 (468.1) 430.2 272.7 29–1092 (132) 380 319 0.3–2086 (645.7) 442 188.1
Individual examination and imaging findings for the suspect group and their classification based on degree of suspicion as described in a recent paper by Hanif et al are shown in Table 2.10 Patients 8 and 9 had the most striking findings including pigmentary changes around the fovea (Figures 1 and 2) with both hyper- and hypoautofluorescent pigmentary changes associated with vitelliform/hyperreflective lesions on OCT. Patient 8 had multiple studies over a 5 year period documenting progression of RPE atrophy in the late stage of the disease. (Figure 3).Table 2 Clinical Findings in Patients Suspicious for PPS-Associated Maculopathy
Patient # Clinical Exam Findings Image Type and Findings Category per Hanif et al Reason for Examination
Patient 1 RPE mottling Fundus photo; paracentral macular pigmented spots 2 Glaucoma suspect
Patient 2 Mild RPE mottling OCT; retinal pigment epithelial mottling 3 Diabetic screening exam
Patient 3 Retinal pigment epithelial mottling OCT; retinal pigment epithelial mottling 2 Open angle glaucoma
Patient 4 Early age-related macular degeneration No imaging available 2 Nuclear cataract
Patient 5 Normal macula OCT; retinal pigment epithelial mottling and mild pigment clumping 2 Nuclear cataract
Patient 6 Parafoveal pale yellow spots No imaging available 2 Dry age-related macular degeneration
Patient 7 Very fine central drusen No imaging available 3 Posterior vitreous detachment
Patient 8 Multiple drusen, pigmentary atrophy, pigment mottling FAF, OCT; Reticular hypo- and hyperautofluorescent spots, pigment mottling, large areas of confluent RPE atrophy, Focal RPE enlargement 1 Dry age-related macular degeneration
Patient 9 Multiple drusen, pigment mottling FAF, OCT: Reticular hypo- and hyperautofluorescent spots, pigment mottling, subretinal hyperreflective deposits 1 Pigmentary retinal dystrophy
Patient 10 Drusen, hard drusen, ERM, mild pigmentary change No imaging available 3 Drusen
Abbreviations: N/A, not available; OCT, ocular coherence tomography; FAF, fundus autofluorescence.
Figure 1 (Patient 9) Fundus photography: Fundus autofluorescence at early stage of disease showing pigment mottling, reticular hypoautofluorescent and hyperautofluorescent spots, and focal areas of RPE enlargement.
Figure 2 (Patient 8) OCT: Later stage of the disease shows large areas of confluent RPE atrophy.
Figure 3 (Patient 8) Fundus autofluorescence at presentation and 4 years later, depicting the increase in areas of RPE atrophy.
The average logMAR visual acuity (VA) for all 131 patients was 0.19. The mean duration of PPS use and mean cumulative dose in the suspect group were 4.2 years and 380g respectively and in the non-suspect group were 3.6 years and 442g (Table 1). Common other diagnoses for which patients were seen in the ophthalmology clinic included ocular surface issues (blepharitis, dry eye syndrome, meibomian gland dysfunction) (n=37), cataract: pre- or post-op (n=30), glaucoma/ocular hypertension (n=7), diabetic retinopathy surveillance (n=6), uveitis (n=8), and other issues including posterior vitreous detachment, retinal tear, esotropia, and migraine (n=23).
Discussion
Our study evaluated the prevalence of retinal pathology in a cohort of patients who had been exposed to PPS and examined in a tertiary care setting. Pearce et al described a potential association between chronic use of PPS and the development of a vision-threatening maculopathy,4 and Hanif et al recently reported a strong causal relationship between the two.4,9,10 An associated study with 35 patients noted that this maculopathy is associated with long-term exposure to PPS with a median of 15 years and a range of 3–22 years.10 Common symptoms of the maculopathy included difficulty reading, metamorphopsia, impaired dark adaptation, and nyctalopia.11 While several studies have shown the association of PPS to a maculopathy, some studies have discussed the possibility of IC causing the maculopathy itself.12,13
Given these findings, we conducted a retrospective chart review at our institution to look for evidence of retinal pathology in patients with PPS. Our suspect group was found to have been taking PPS for an average of 4.2 years and an average dosage 380g respectively while the non-suspect group took it for an average of 3.6 years at 442g. However, the median cumulative dosage for the non-suspect group was lower than that of the suspect group at 188.1g as opposed to 317g. This suggests that a majority of patients without pigmentary changes had lower exposure to the drug, with either a shorter duration and/or lower doses when compared to those in the suspect group.
Two patients from our cohort had fundus findings that were consistent with the maculopathy described by Pearce et al. However, it is of note that even patients with as little as 0.3 years on the drug had evidence of pigmentary changes documented in their chart. In our study cohort, age, gender, visual acuity, and duration of drug therapy were not found to be significant factors in the development of PPS-related maculopathy.
Although this is a retrospective analysis, this emphasizes the need to start monitoring patients on PPS early on as well as documenting a baseline comprehensive eye exam to identify any changes that occur during the use of the drug. When pathology was noted, it was commonly diagnosed as age-related macular degeneration or pattern dystrophy. Such diagnoses were also noted in the prior study by Hanif et al.8 Imaging analyses reported by Hadad et al showed that all patients (n=17) using 100mg of PPS daily for at least 3 years had mottling changes of the retina on near-infrared imaging, 75% of patients showed a hypoautofluorescence defect in the macula similar to those reported by Pearce et al,4 and hyperreflectivity, thickening of the foci of the RPE, and a flying saucer macular sign were also noted on OCT imaging.14
A recent prospective study by Wang et al found that patients with a cumulative dosage over 1500g had a significant risk of developing a PPS-associated maculopathy.6 They recommend baseline ophthalmological examinations with multimodal imaging of patients who are to receive PPS in a cumulative dose of about 500g. In our study cohort, Patient 9 was found to have prominent macular pigmentary findings that were consistent with the previously described PPS-associated maculopathy. However, this patient only had a cumulative dosage of 304.4g. Further study is needed to determine at what cumulative dosage patients become at risk for the development of PPS-associated macular changes.
Additionally, some patients in our suspect group were examined in the clinic post-drug cessation, so it is unclear at which point in their course of treatment pigmentary changes developed. A recent case study discussed the possibility of progressing maculopathy after discontinuation of the drug, where a 67-year-old woman with a history of PPS use for 18 years presented with worsening vision despite stopping the drug at the age of 62.15 Additionally, a retrospective study by Shah et al proposed that pigmentary changes can continue to develop for at least ten years after the cessation of PPS.16 Longitudinal study is required to understand the course of the PPS-associated maculopathy development.
Strengths of our work include the fact that our study cohort includes all patients taking PPS seen at the Northwestern Ophthalmology clinic during our study period, not just those seen in by a retina specialist. This prevented potential bias towards the existence of retinal findings. We were able to establish a relationship between the drug and macular pathology, and confirm recent findings by other authors. Lastly, since it was a retrospective study, there was minimal selection or recall bias. There are limitations to our study. Given that it was a single center study, the number of patients included in the analysis were limited. Consequently, our non-suspect group does not serve strictly as a control group because patients in both the suspect and non-suspect group experienced ocular comorbidities. This is one likely explanation for the lack of difference in average visual acuity between the two groups. Additionally, dates of medication discontinuation may not always be entered into the appropriate sections of the EHR and patients occasionally discontinue their medications on their own. The last date of PPS use was missing in the EHR for 48% of our patients, who may or may not have discontinued the drug. This affected our analysis for the true duration and cumulative dosage of the drug. Because of the retrospective nature of this study, data was derived from the existing EHR. Consequently, not all patients in the cohort had imaging on file, likely because conditions for which they were seen in the ophthalmology clinic frequently did not warrant any multimodal or posterior segment imaging. Even when posterior segment examination was performed, mild findings of early stages of the retinopathy could be easily missed. Educating eye providers is critical in early identification of patients who are on the drug, improving detection of new changes that develop during therapy, and ensuring regular follow up. Further, patients should be counseled on the potential side effects of the drug along with a careful consideration of the risks and benefits prior to starting PPS therapy. Lyons et al also recommend prescribing the lowest dose and duration of the medication if the decision to start PPS is made.17
Our study adds to the growing body of work that supports the presence of a distinct pigmentary maculopathy associated with chronic usage of PPS. Future study is warranted, and guidelines are in the process of being established for the screening for PPS-associated maculopathy. A prospective analysis employing baseline ophthalmologic exams, regular follow-up, along with multimodal imaging is important in understanding the course of the disease while patients are on the medication as well as after discontinuation.
Acknowledgments
Saena A. Sadiq, BS for her work which was critical in the revision of the manuscript, including additional literature review and incorporation of new findings into the manuscript, updating the tables, and reformatting the images.
Disclosure
The authors have no proprietary or commercial interest in any of the materials discussed in this article and report no conflicts of interest in this work. | PENTOSAN POLYSULFATE SODIUM | DrugsGivenReaction | CC BY-NC | 33603329 | 18,923,799 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'No adverse event'. | Hummingbird Study: Results from an Exploratory Trial Assessing the Performance and Acceptance of a Digital Medicine System in Adults with Schizophrenia, Schizoaffective Disorder, or First-Episode Psychosis.
Symptoms of psychotic disorders can complicate efforts to accurately evaluate patients' medication ingestion. The digital medicine system (DMS), composed of antipsychotic medication co-encapsulated with an ingestible sensor, wearable sensor patches, and a smartphone application, was developed to objectively measure medication ingestion. We assessed performance and acceptance of the DMS in subjects with psychotic disorders.
This was an 8-week open-label, single-arm, multicenter, Phase 4 pragmatic study (NCT03568500; EudraCT #2017-004602-17). Eligible adults were diagnosed with schizophrenia, schizoaffective disorder, or first-episode psychosis; were receiving aripiprazole, quetiapine, olanzapine, or risperidone; and could use the DMS with the application downloaded on a personal smartphone. The primary endpoint was good patch coverage, defined as the proportion of days over the assessment period where ≥80.0% of patch data was available, or an ingestion was detected. Exploratory endpoints included a survey on user satisfaction, used to assess acceptance of the DMS. Safety analyses included the incidence of treatment-emergent adverse events (TEAEs).
From May 25, 2018 to March 22, 2019, 55 subjects were screened and 44 were enrolled. Good patch coverage was achieved on 63.4% of days assessed and the DMS generated an adherence metric of ≥80.0%, reflecting the percentage of ingestion events expected when good patch coverage was reported. Most subjects (53.5%) were satisfied with the DMS. Medical device skin irritations were the only TEAEs reported.
The DMS had sufficient performance in, and acceptance from, subjects with psychotic disorders and was generally well tolerated.
Introduction
Schizophrenia is a psychotic disorder that presents global health challenges and is among the leading causes of disability.1,2 The global prevalence of schizophrenia has increased from approximately 13 million people in 1990 to over 20 million in 2016.3 In Europe, the economic burden of psychotic disorders was estimated to be €93.9 billion in 2010.4 Schizophrenia, schizoaffective disorder, and first-episode psychosis are similarly presenting mental illnesses.5 Schizophrenia consists of psychosis, which can present as multiple symptoms, such as delusions, hallucinations, disorganized behavior, and a lack of awareness of disease.5 Schizoaffective disorder involves schizophrenia symptoms in the presence of major depressive episodes, with or without bipolar mania.5 First-episode psychosis refers to a period after an initial psychotic episode and recovery.5 The therapeutic goals for schizophrenia and other psychotic disorders include symptom control and relapse prevention.1,6 Antipsychotics, such as aripiprazole, olanzapine, quetiapine, and risperidone, are considered the first-line pharmacotherapy for these psychotic disorders.1,6
Adherence to therapy is a major challenge in patients with psychotic disorders.7 An estimated 41–50% of patients with schizophrenia, and approximately 55% of patients with first-episode psychosis, are not fully adherent with their medication.7,8 Psychotic symptoms, such as unawareness of illness, poor memory, depression, paranoid delusions, and hallucinations, could underlie nonadherence in these patients.1,7 Poor adherence to antipsychotics has been associated with higher rates of violence, hospital admission, substance abuse, and an increased risk of mortality.9,10 Many tools are used to measure adherence, such as self-reporting, direct visualization, biomarkers and metabolites, pharmacy prescription data, and medication event-monitoring systems.10 Electronic adherence monitoring (EAM), which measures when medication is accessed, has been considered the gold standard of adherence measurement, and a recent meta-analysis found that EAM-measured adherence to oral antipsychotics was approximately 70%.11 These adherence tools, however, may be associated with disadvantages.12,13 For example, self-reporting and observational methods may be affected by patients reporting incorrect information or tampering with an adherence device (either purposefully or by accident), and measuring drug metabolism through assays can be expensive and intrusive.12,13
The digital medicine system (DMS) measures ingestion of a medication using an ingestible sensor that is either embedded within a tablet14,15 or embedded within an inert tablet and co-encapsulated with an oral medication tablet.16 After ingestion of the tablet, the sensor is activated by stomach fluid and sends a signal to a wearable sensor patch attached to the patient’s torso.16 A smartphone application collects these data from the patch via Bluetooth and transfers them to a secure digital health data server.16 The data can be accessed by patients through the smartphone application or by healthcare providers and caregivers through separate web portals.16 The DMS is intended to encourage greater self-management of mental illness by helping the patient and their healthcare provider track their medication-taking behaviors to support informed treatment discussions.16
Incorporating smartphones in adherence management offers new opportunities and benefits—most patients with psychosis who own mobile phones use them daily, and smartphone ownership, while lower among those with psychosis than in the general population, is also growing.17–19 Although studies have shown that patients with schizophrenia may not have negative experiences with mobile devices,20 data collection could present a barrier for patients with paranoia or who are uncomfortable with this information being shared.17 Data collection also introduces numerous complex ethical issues regarding the privacy and security of patient information, which must be addressed to ensure patient and public trust in digital medicine.17 To protect patient privacy, the DMS is patient-centric, and allows specific authorization as to which healthcare providers, caregivers, and family members can access the information collected. The DMS uses industry-standard encryption protocols for data transmission from the patch to the mobile device, and from devices to the server; DMS data can be accessed only through the sponsor’s servers, which are also protected with industry-standard security features.
In previous Phase 2 clinical studies, the DMS was evaluated in the United States (US) in subjects with schizophrenia, bipolar I disorder, and major depressive disorder who were considered clinically stable and were receiving oral aripiprazole.21,22 The first DMS used aripiprazole paired with a sensor and was approved in the US as monotherapy for schizophrenia or bipolar 1 disorder, and as an adjunctive treatment for major depressive disorder.23 The DMS in this study used ingestible and wearable sensors certified by the British Standards Institute for use in Europe as class IIa medical devices (Conformité Européenne #559,373).24
In this phase 4 pragmatic study (the Hummingbird Study), we evaluated the clinical utility of the DMS in patients diagnosed with schizophrenia, schizoaffective disorder, or first-episode psychosis potentially presenting with acute mental illness, who were receiving oral aripiprazole, olanzapine, quetiapine, or risperidone, and who also had a smartphone to use in the study. This study was performed using the National Health Service (NHS) Mental Health Trusts in the United Kingdom (UK), which presented an opportunity to evaluate the DMS in a different treatment system outside of the US.
Methods
Study Design and Participants
This was an 8-week open-label, single-arm, multicenter, phase 4 pragmatic study performed at 5 NHS Foundation Trusts in the UK. The study was conducted in accordance with local laws, the International Conference on Harmonization Good Clinical Practice Consolidated Guideline, and the Declaration of Helsinki. The study protocol was approved by the London – City and East Research Ethics Committee and was registered with ClinicalTrials.gov (NCT 03568500) and with EudraCT (#2017-004602-17). All subjects provided written informed consent prior to participating in the study.
Subjects for this study were identified using database searches conducted at each study site per provider discretion, from a range of clinical populations, including those being treated by acute-care teams or by community services. Key eligibility criteria included subjects being aged between 18 to 65 years; having a diagnosis of schizophrenia, schizoaffective disorder, or first-episode psychosis; and having a prescription for oral aripiprazole, olanzapine, quetiapine, or risperidone. Eligible subjects were able to complete onboarding and use the DMS by downloading and using the application on their personal smartphone with internet connectivity. Subjects were excluded from the study if they had an intellectual developmental delay or disorder, major neurocognitive disorder, or another condition that might impact the subject’s ability to participate in the trial or interact with the DMS, or if they were advised to not participate in the trial per their healthcare provider’s judgement. Full eligibility criteria and the study design have been previously published.16
Procedures
Subjects were screened for up to 1 week, followed by an 8-week assessment period while using the DMS (Appendix s-Figure-1). A safety follow-up telephone call was performed 2 weeks after the last visit. The DMS included a drug–device combination of the patient’s prescribed oral antipsychotic medication tablet co-encapsulated with an ingestible event marker (IEM) embedded in an inert tablet (Proteus Digital Health Inc., Redwood City, CA), a sensor patch (Disposable Wearable Sensor version 5 [DW-5], Proteus Digital Health Inc., Redwood City, CA) that was applied to the torso to detect ingestion of the antipsychotic, and a smartphone application for subjects with a web portal for healthcare providers (Otsuka Medical software version 2.1; Otsuka Pharmaceutical Development and Commercialization, Inc., Princeton, NJ). This study was conducted using both Android and iOS versions of the smartphone application. An integrated call center was available to answer any technical questions on the use of the DMS from the study subjects and participating investigators or site staff.
Outcomes
The primary endpoint was the mean proportion of days with good patch coverage. Good patch coverage was defined as either having the patch worn with data collected for 80.0% or greater of the time or having an IEM detected within a given day of the assessment period. The primary endpoint was calculated per subject as days of good patch coverage divided by all assessment days (from first drug intake date until the last drug intake date for each subject). Each subject’s coverage value was then averaged to calculate a mean for each of the 3 diagnostic categories, as well as for the overall study population. The secondary endpoint of adherence metric was calculated as the mean proportion of each subject’s number of detected IEMs divided by the expected number of IEMs on assessment days of good patch coverage.
Exploratory endpoints related to device performance were the mean proportion of days that subjects wore the patch during the assessment period, and the mean number of IEMs registered on the digital health data server divided by the expected number of IEMs during the assessment period. Exploratory endpoints related to acceptance were responses to the Subject Usability and Satisfaction Scale on week 8. Other exploratory endpoints assessed included changes from baseline to week 8 in Patient Activation Measure-Mental Health (PAM-MH)25 and Clinical Global Impression-Severity of Illness Scale (CGI-S)26 scores as measured in subjects with baseline and postbaseline scores. The number of times per day that subjects used the application and the number of times per week that healthcare providers used the web portal were also captured.
Safety was assessed as the incidence of adverse events (AEs), treatment-emergent adverse events (TEAEs), serious AEs, and reports of suicide or suicidal ideation. All AEs were classified using preferred terms of the standardized Medical Dictionary for Regulatory Activities version 22.0. TEAEs of medical device (patch) site irritation were graded by the healthcare provider using the Skin Irritation Scoring System (grades 0–7).27
Statistical Analyses
As this was a feasibility study, no statistical comparisons or power calculations were performed. A sample size of 60 subjects was planned for this study with an anticipated discontinuation rate of 25.0%. Performance and acceptance analyses were assessed in the intent-to-treat population, which was defined as all subjects who entered the trial and used the DMS. Safety analyses were performed in the safety population, which was defined similarly to the intent-to-treat population. Descriptive statistics were used for all endpoints. Continuous variables were summarized by means, medians, or ranges, and relevant quartiles, standard deviations (SD), or standard errors of the mean. Categorical variables were summarized using frequency distributions. No imputation was performed for other missing data, unless specified otherwise.
Role of the Funding Source
All aspects of the trial (design; data collection, analysis, and interpretation; writing the report; and decision to submit the paper for publication) were managed by the sponsor, including oversight of the contract research organization. The corresponding author (JCF) had full access to all data in the study and had final responsibility for the decision to submit for publication.
Results
Subjects
From May 25, 2018 to March 22, 2019, 55 subjects were screened and 44 were enrolled in the trial, of whom 54.5% (24/44) completed the trial (Figure 1). One subject discontinued from the trial without ingesting any study medication. Most subjects had a diagnosis of schizophrenia (40.9%; 18/44), followed by first-episode psychosis (36.4%; 16/44), and schizoaffective disorder (22.7%; 10/44; Table 1). All but 1 of the subjects enrolled received antipsychotic medication (Table 1). Overall, subjects used the DMS for 1760 days (aripiprazole group: 711 days; olanzapine group: 865 days; quetiapine group: 184 days [no subjects enrolled used risperidone]). Of the 20 subjects who discontinued the trial early, 65.0% (13/20) used the Android version of the application, 15.0% (3/20) used the iOS version, and 20.0% (4/20) did not report the version. Further, of those who discontinued the trial early, 85.0% (17/20) contacted the call center (a total of 100 calls) for assistance with patch-related issues. Six subjects withdrew consent; of these, one felt uncomfortable wearing the patch and taking medication, and another found it difficult to cope with the technology, reporting that it made them feel “anxious.”Table 1 Subject Demographics and Baseline Characteristics
Characteristics Enrolled Subjects
(n = 44)
Mean age, years (SD) 34.4 (10.7)
Sex
Female 15 (34.1)
Male 29 (65.9)
Race
Black 8 (18.2)
White 35 (79.5)
Other 1 (2.3)
Psychiatric disease
Schizophrenia 18 (40.9)
Schizoaffective disorder 10 (22.7)
First-episode psychosis 16 (36.4)
Antipsychotic taken
Aripiprazole 18 (40.9)
Olanzapine 19 (43.2)
Quetiapine 6 (13.6)
Risperidone 0
None received 1 (2.3)a
≥ 1 Medications taken at baseline 43 (100.0)b
Notes: Data are presented as n (%), unless otherwise specified. aOne subject discontinued the study without receiving treatment. bBased on the 43 subjects who received the digital medicine system.
Abbreviation: SD, standard deviation.
Figure 1 Subject disposition. aOf the subjects enrolled, 43 received a treatment and were included in the intent-to-treat and safety sample analyses.
Performance
For the 8-week assessment period, the mean proportion of days with good patch coverage was 63.4% (SD: 26.6) for the overall population (Table 2). No noticeable difference was observed between psychiatric conditions with respect to the proportion of time with good patch coverage over the assessment period (Table 2). A decline in the proportion of time with good patch coverage from weeks 1–4, then followed by an increase from weeks 4–5, was observed in all groups over the assessment period, except for subjects with schizoaffective disorder. Subjects with schizoaffective disorder exhibited a decrease in time with good patch coverage during weeks 1–2, followed by a rebound during weeks 2–5 to a greater value than for the first week (Figure 2). A decline in time with good patch coverage was observed over weeks 5–8 in all groups regardless of psychiatric condition (Figure 2). For the overall population, the mean proportion of days over the 8-week assessment period that subjects wore the patch was 55.1% (SD: 27.8) (Table 2). No noticeable differences in the proportion of time that subjects wore the patch were observed between psychiatric conditions (Table 2).Table 2 Summary of Digital Medicine System Performance Endpoints Related to Patch Wear (Intent-to-Treat Population)
Endpoint Schizophrenia (n = 18) Schizoaffective Disorder (n = 9) First-Episode Psychosis (n = 16) Overall (n = 43)
Proportion of days with good patch coverage (primary endpoint)
Mean (SD) 64.3 (20.2) 63.0 (37.7) 62.5 (27.5) 63.4 (26.6)
Median (Q1, Q3) 62.0 (49.1, 85.7) 76.8 (42.4, 98.2) 67.3 (50.7, 74.6) 66.7 (48.3, 85.7)
Range 26.7–92.9 0.0–100.0 7.3–100.0 0.0–100.0
Proportion of days that subjects wore the patch
Mean (SD) 59.0 (22.5) 53.1 (37.6) 51.9 (28.4) 55.1 (27.8)
Median (Q1, Q3) 62.4 (42.9, 84.2) 43.0 (22.6, 87.8) 56.5 (37.3, 65.2) 58.3 (39.9, 84.2)
Range 22.4–86.7 1.7–98.8 2.7–99.2 1.7–99.2
Note: Data are presented as %.
Abbreviations: Q, quartile; SD, standard deviation.
Figure 2 Proportion of time with good patch coverage over the assessment period (intent-to-treat population). Data are means ± standard error.
Note: Arrow represents scheduled provider visit during week 4.
The proportion of IEMs ingested and registered on the digital health data server over the 8-week assessment period was 56.4% (SD: 25.6) for the overall population (Table 3). For subjects with schizophrenia or with first-episode psychosis, the proportions of IEMs registered on the digital health data server were comparable (Table 3). Subjects with schizoaffective disorder had the lowest proportion of IEMs registered (Table 3). The mean adherence metric for the 8-week assessment period was 86.6% (SD: 14.5) for the overall population (Table 3). Subjects with schizophrenia and first-episode psychosis had relatively consistent adherence metrics over the assessment period (Figure 3). Subjects with schizoaffective disorder, however, had a lower mean and higher variability in adherence metrics compared with other psychiatric conditions over the assessment period (Table 3; Figure 3).Table 3 Summary of Digital Medicine System Endpoints Based on IEM Detection (Intent-to-Treat Population)
Schizophrenia (n = 18) Schizoaffective Disorder (n = 9) First-Episode Psychosis (n = 16) Overall (n = 43)
Adherence metric based on digital health dataa
Mean (SD) 88.9 (8.1) 72.3 (25.7) 91.0 (7.4) 86.6 (14.5)
Median (Q1, Q3) 89.8 (84.3, 95.5) 79.6 (66.7, 87.5) 92.2 (87.3, 96.4) 89.3 (83.3, 94.7)
Range 69.0–100.0 14.3–96.4 75.0–100.0 14.3–100.0
Proportion of IEMs ingestedb
Mean (SD) 58.4 (17.5) 50.2 (37.4) 57.6 (26.8) 56.4 (25.6)
Median (Q1, Q3) 58.0 (49.1, 72.2) 66.7 (12.5, 69.6) 60.9 (46.3, 65.2) 60.0 (45.6, 69.6)
Range 24.1–88.5 0.0–96.4 5.5–100.0 0.0–100.0
Notes: Data are presented as %. aOne subject in the schizoaffective disorder group was excluded because they had 0 days of good patch coverage. bIngested IEMs were registered on the digital health data server.
Abbreviations: IEM, ingestible event marker; Q, quartile; SD, standard deviation.
Figure 3 Adherence metric over the assessment period (intent-to-treat population). aOne subject in the schizoaffective disorder group was excluded because they had 0 days of good patch coverage. Data are means ± standard error. Arrow represents scheduled provider visit during week 4.
Acceptance
When surveyed on their experience of the DMS, 53.5% (23/43) of subjects were somewhat satisfied, satisfied, or extremely satisfied with the DMS, and 51.2% (22/43) of subjects found the DMS somewhat helpful, helpful, or extremely helpful in managing their condition (Appendix s-Table 1). Proportions of subjects who reported it somewhat easy, easy, or extremely easy to use the DMS: 69.8% (30/43); to apply the patch, 67.4% (29/43); and to use the mobile application, 60.5% (26/43; Appendix s-Table 1).
When asked about the patch, 60.5% (26/43) of subjects somewhat agreed, agreed, or strongly agreed with not minding the patch, and 58.1% (25/43) of subjects needed assistance in changing and pairing patches (Appendix s-Table 1). An insignificant decrease in mean PAM-MH scores from baseline (64.5) to week 8 or early termination (63.6) was observed. No change in the mean CGI-S score from baseline (2.6) to week 8 or early termination (2.6) was observed. Overall, subjects used the smartphone application 0.5 times per day (SD: 0.3), and healthcare providers accessed the web portal 1.8 times per week (SD: 0.8).
Data from the call center indicated that 11 subjects telephoned 34 times for patch-related issues, and 9 times for issues related to smartphone application usage. Further, research or clinical staff telephoned the call center 23 times for patch-related issues during onsite visits for subjects in need of assistance with the system.
Safety
Over the 8-week assessment period, AEs were reported in 9 subjects (Table 4). No deaths, serious AEs, or AEs related to suicide or suicidal ideation were reported during the study (Table 4). TEAEs were reported in 9 subjects, all of which were associated with medical device site irritation due to the adhesive patch (Table 4). Most of these TEAEs were considered mild in severity. One TEAE was considered of moderate intensity and resolved after discontinuation of the DMS. Four subjects discontinued the study due to a TEAE (Table 4). Most (88.9% [8/9]) patch-related skin irritation scores were from 0–2, which were not considered medically significant (Table 5).Table 4 Summary of Safety (Safety Population)
Parameter Aripiprazole (n = 18) Olanzapine (n = 19) Quetiapine (n = 6) Overall (n = 43)
Subjects with AEs 4 (22.2) 2 (10.5) 3 (50.0) 9 (20.9)
Subjects with serious AEs 0 0 0 0
Deaths 0 0 0 0
Subjects with TEAEs 4 (22.2) 2 (10.5) 3 (50.0) 9 (20.9)
Leading to study discontinuation 1 (5.6) 1 (5.3) 2 (33.3) 4 (9.3)
Medical device site irritationa 4 (22.2) 2 (10.5) 3 (50.0) 9 (20.9)
Notes: Data are presented as n (%). aMedical device site irritation due to the adhesive patch.
Abbreviations: AE, adverse event; TEAE, treatment-emergent adverse event.
Table 5 Skin Irritation Scoring System for Patch-Related Skin TEAEs (Safety Population)
Scoring System Overall
(n = 43)a
0: No evidence of skin irritation 3 (7.0)
1: Minimal erythema, barely visible 2 (4.7)
2: Definite erythema, readily visible; minimal edema or minimal papular response 3 (7.0)
3: Erythema and papules 1 (2.3)
4: Definite edema 0
5: Erythema, edema, and papules 0
6: Vesicular eruption 0
7: Strong reaction spreading beyond the test site 0
Notes: Data are presented as n (%). a8 Subjects answered the skin irritation questionnaire; scores were limited to 1 per subject, except for 1 subject who reported 2 scores.
Abbreviation: TEAE, treatment-emergent adverse event.
Discussion
In this phase 4 pragmatic study in subjects with schizophrenia, schizoaffective disorder, or first-episode psychosis who were receiving aripiprazole, olanzapine, or quetiapine, good patch coverage with the DMS was reported 63.4% of the time over the 8-week assessment period. Overall, the DMS generated an adherence metric of 80.0% or greater, reflecting the percentage of IEMs detected that would be expected when good patch coverage was reported. The DMS was generally well-tolerated in this study population and no new safety findings were reported. The incidence of TEAEs (20.9%), which were all associated with patch-related skin reactions, was consistent with reports from previous trials with the DMS (32.8%21 and 34.7%22). Together, these results support the use of the DMS in a broader population of patients and with different types of antipsychotics than seen in previous clinical trials.21,22 Specifically, this study included patients with schizoaffective disorder or first-episode psychosis and those who may have presented with acute illness. Moreover, these findings suggest that the DMS could be successfully used with aripiprazole and other oral antipsychotics, such as olanzapine and quetiapine.
The proportion of time that subjects had good patch coverage in this study (63.4%) was lower compared with a previous 8-week phase 2 trial with the DMS (80.1%).22 Moreover, a lower proportion of time spent wearing the patch was reported in this study (55.1%) compared with previous phase 2 trials with the DMS (70.7%21 and 77.9%22). Although the proportion of time with good patch coverage appeared to decline from baseline to week 8, an increase between weeks 4–5 was noticed in all subjects, regardless of psychiatric condition. This increase may have been due to the scheduled interaction with a healthcare provider at week 4, which suggests that healthcare providers could increase patient engagement during visits, possibly by reviewing ingestion data of their patients using the web portal. A possible explanation for why less patch wear was reported in this study compared with previous reports may be related to issues with pairing the patch and smartphone application, as indicated by the number of calls from subjects and healthcare providers to the call center.
To our knowledge, this was the first study to evaluate the DMS where subjects could use their own smartphone, which included the iOS and Android application platforms. Compatibility of the DMS with various smartphones across diverse subject demographics may have resulted in user error and affected subjects’ ability to successfully engage with the smartphone application and pair patches. Additionally, this study had fewer scheduled interactions or touchpoints with healthcare providers (3 interactions) compared with previous clinical trials with the DMS (4 to 5 interactions).21,22 This study also included subjects with acute mental illness, whereas previous trials recruited only subjects who were already on stable antipsychotic doses and did not have acute psychotic symptoms.21,22 These features of the study design provided a more real-world setting to evaluate performance and acceptance of the DMS. Issues with pairing patches with the smartphone application, the fewer number of touchpoints, and the inclusion of subjects with acute mental illness may have negatively influenced patch coverage metrics in this study.
In this study, the DMS showed good acceptance in the overall subject population, as evidenced by responses to the user-experience survey. Overall, subjects were satisfied with using the DMS and generally found its components easy to use. However, less than half of subjects found it easy to pair the patch with the smartphone application, and over half of subjects needed help with changing or pairing patches. This may indicate a lack of familiarity with pairing Bluetooth devices, or that compatibility issues between the patch and smartphone application were encountered. Acknowledging the limitations of cross-study comparisons, the proportion of subjects in this study who were satisfied with the DMS (53.5%) and found it helpful in managing their condition (51.2%) appeared to be lower compared with a previous phase 2 study in subjects with schizophrenia who were stable on medication (78.3% and 70.0%, respectively).21 These findings may be explained by similar factors that affected patch coverage. Specifically, having fewer scheduled interactions, the inclusion of subjects with acute mental illness, and issues related to pairing the patch to the smartphone application may explain why fewer subjects were satisfied with the DMS in this study compared with prior reports.
The proportion of IEMs detected (56.4%) and the adherence metric (86.6%) in this study were similar to findings in previous phase 2 trials with the DMS (59.4% and 73.9%–88.6%, respectively).21,22 These results, along with considerations that this study included different populations, acutely ill subjects, and the use of different types of smartphones suggest that the DMS could be a clinically useful tool to measure intake of medication in diverse populations with varying disease severity. This is beneficial, as accurate measurements of adherence can be particularly challenging in patients with severe mental illness.7
A potential limitation of this study was the small sample size, especially in the group with schizoaffective disorder (n=10), which could have contributed to the wide variability in the proportion of time with good patch coverage and adherence metric observed in this group. Also, allowing subjects to use their own smartphone that was compatible with the application could have led to lower-than-planned enrollment. A limitation pertaining to patient comfort with data collection is that paranoid symptoms were not assessed, thus conclusions cannot be drawn on whether patients with paranoia could use the DMS successfully. Further, patients were excluded if they had a condition judged to impair their ability to engage with the DMS, which could have included patients who refused to comply with data collection policies. Of note, 2 patients withdrew consent due to discomfort with the DMS, although it is unclear if this was due to paranoia, discomfort with data collection, or another reason. Another limitation may be that information on the smartphone operating systems and reasons for which subjects and healthcare providers contacted the call center were not fully collected. Such data could have been useful to better understand the source of compatibility issues between the patch and smartphone application, which may have affected the performance and acceptance of the DMS. Moreover, to gain better insights to the real-world applicability of the DMS, future studies could benefit from enrolling more subjects per psychiatric condition and collecting more information on smartphones used in the study and related technical issues. These studies could also be enhanced by examining the impact of sharing the DMS’s data with patients, both on adherence metrics and the quality of their relationships with healthcare providers. Lastly, a more user-friendly design may be necessary to reach a broader population of patients who have serious mental illnesses and concerns with the process of data collection.
Conclusions
Overall, the DMS observed good patch coverage and high treatment adherence metrics over the 8-week assessment period. Most subjects were satisfied with using the DMS and generally found its components easy to use. Moreover, the DMS was associated with a safety profile that was comparable to that of previous reports.21,22 Together, these findings suggest that the DMS could be a useful tool to measure intake of various antipsychotics, including olanzapine and quetiapine, in addition to aripiprazole. However, compared with previous studies,21,22 the lower values for patch-related endpoints and subject satisfaction21,22 suggest that regular clinical contact, more support and engagement from the care team, and better training may be required to reinforce performance and acceptance of the DMS in patients with psychotic disorders. This study reflects use of the DMS in a more real-world setting where patients would likely use their own smartphone. A goal for future studies is to better understand smartphone ownership in patient populations to help optimize testing processes of the DMS’s smartphone application. Further evaluation of the DMS in larger clinical trials including different types of antipsychotics and patients with various psychotic disorders may be necessary to establish its clinical utility and to determine its impact on improving treatment adherence in patients with serious mental illness.
Acknowledgments
The authors thank the patients, patient advisers, and NHS staff from all 5 participating sites (Oxford Health NHS Foundation Trust, Northumberland, Tyne and Wear NHS Foundation Trust, Southern Health NHS Foundation Trust, South London and Maudsley NHS Foundation Trust, and Surrey and Borders Partnership NHS Foundation Trust) for their contributions to the study methodology. SS is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.
Data Sharing Statement
Data collected for this study will not be made available to others.
Ethics Approval and Informed Consent
This study protocol and informed consent forms were approved by the London – Central and East ethics committee.
Consent for Publication
No patient data are identifiable, thus no consent is required.
Author Contributions
JCF, NC, JK, TS, SS, PP, SR, and TP-S contributed to study conception design and data collection. All authors contributed to data analysis and interpretation, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.
Disclosure
JCF, NC, JK, HF, TS, and TP-S are employees of Otsuka Pharmaceutical. SR has received honoraria from Otsuka and Lundbeck LLC, Deerfield, IL for educational sessions. SS has received honoraria from Lundbeck for educational sessions. PP has received honoraria from Otsuka. The authors report no other conflicts of interest in this work. | ARIPIPRAZOLE | DrugsGivenReaction | CC BY-NC | 33603385 | 19,918,305 | 2021 |
What is the weight of the patient? | Hyperlipidemia Caused by Voriconazole: A Case Report.
Voriconazole has been widely used in clinical practice for nearly 20 years. The adverse reactions caused by voriconazole have been reported gradually, such as visual impairment, hepatotoxicity, skin rash. At present, there are few reports about triazole antifungal drugs causing the increase of triglyceride and total cholesterol. Thus, the present study reported a case of chronic pulmonary aspergillosis with significantly increased blood lipids after treatment with voriconazole. In this case, the patient's total cholesterol was normal, and triglyceride was 2.64 times of the upper limit of the reference value at the time of admission. On the 30th day after oral administration of voriconazole 200mg q12h, triglyceride and total cholesterol were 4.55 times and 3.31 times of the baseline levels, respectively, with the trough concentration of voriconazole of 6.6 μ g/mL. After 28 days of voriconazole withdrawal and itraconazole administration, triglyceride decreased to 1.45 times of baseline level and total cholesterol decreased to the normal range. After another 24 days of treatment with voriconazole 200mg q12h, triglyceride increased again to 3.25 times of the baseline level and cholesterol was within the normal range. At the same time, the trough concentration of voriconazole was 3.2 μ g/mL. After 14 days of treatment with voriconazole 100mg q12h, the triglyceride level recovered to the baseline level, with the trough concentration of voriconazole of 1.5 μ g/mL. The Naranjo's rating scale was used, the final score was 10 points, indicating that the causal relationship between voriconazole and dyslipidemia was positive, which was likely to be related to the trough concentration of voriconazole.
Introduction
Voriconazole (VRCZ) is the second generation of triazole antifungal drug that exerts antifungal effects by inhibiting 14 -sterol demethylation via cytochrome P450 in fungi to inhibit the biosynthesis of ergosterol. The common adverse reactions of VRCZ include hepatotoxicity and visual impairment, which are often related to the concentration of the drug. However, the effect of voriconazole on lipid metabolism has not been reported. Thus, the present study reported a case of chronic pulmonary aspergillosis (CPA) with significantly increased blood lipids after treatment with VRCZ and reviewed and analyzed the case of dyslipidemia caused by triazole antifungal drugs.
Case Description
A 44-year-old female patient, 148 cm height and 43 kg weight, was admitted to the First Affiliated Hospital, Zhejiang University School of Medicine for “blood in sputum for 11 months.” Chest computed tomography (CT) of the patient showed dilatation of the bronchi in both lungs and nodular high-density shadows and air crescent sign in some cavities (Figure 1); hence, diagnosis of aspergilloma was considered. The patient was positive for specific IgG of Aspergillus fumigatus and galactomannan (GM) positive for alveolar lavage fluid in the right upper lobe. Subsequently, A. fumigatus was cultured, and the diagnosis was CPA. Voriconazole (VRCZ) tablets (200 mg every 12 hours) were taken orally from January 22, 2019. The patient had a history of rheumatoid arthritis and regularly administered leflunomide tablets 10 mg QD for a long duration and had a history of sinus tachycardia, as well as metoprolol sustained-release tablets (47.5mg QD) for a long period.Figure 1 Chest CT image of the patient showed multiple dilatation of the bronchi with infection in the right lung. As shown by the arrow, aspergilloma can be seen in the dilated bronchus, showing air crescent sign.
Before administering VRCZ, the liver enzymes and the total cholesterol were normal, while the triglyceride was 2.64-fold of the upper limit of the reference value. After ingesting VRCZ tablets for 14 days, the liver enzyme levels were higher, while the blood lipids were similar to the baseline values. After administering the tablets for 30 days, the symptoms of blood in sputum disappeared. And the liver enzymes were normal while the blood lipids were significantly higher than the baseline values. Simultaneously, the trough concentration of VRCZ was 6.6 μg/mL. Considering the possibility of hyperlipidemia caused by the drug, VRCZ was withdrawn, and itraconazole (200 mg every 12 hours) was administered.
After 28 days of itraconazole treatment, the liver enzymes and blood lipids recovered to baseline levels. While, the patient’s symptoms of blood in sputum occurred.Then, the patient was given VRCZ tablets (200 mg every 12 hours) again.
After 24 days of VRCZ treatment, the liver enzyme levels were normal while triglycerides increased significantly, and the trough concentration of VRCZ was 3.2 μg/mL. The symptom of blood in sputum was improved significantly. The increase in blood lipids may be related to the trough concentration of VRCZ. The patient agreed to continue taking VRCZ tablets after communication. Therefore, the therapeutic regimen of voriconazole was adjusted to 100 mg every 12 hours. After 49 days of this therapeutic regimen, the liver enzymes and blood lipids recovered to the baseline levels again, with the trough concentration of voriconazole of 1.5 μg/mL. After 155 days of continuous use of antifungal agents, considering the full course, the voriconazole was withdrawn. During the administration and after the withdrawal of VRCZ, the liver enzymes and blood lipids were similar to the baseline levels. During the whole treatment process, the diet and living habits of the patients were consistent with those before the treatment, and no significant change was detected in height and weight compared to those before the treatment. During the treatment, the specific values of liver enzymes, total cholesterol, and triglyceride of the patient are shown in Table 1, Figure 2.Table 1 The Specific Values of Liver Enzymes, Total Cholesterol and Triglyceride of the Patient During the Treatment
Laboratory Indicators Day 0 Day 14 Day 30 Day 60 Day 84 Day 130
Total cholesterol (mmol/L) (3.14–5.86) 3.6 3.65 11.93 4.59 4.66 3.26
Triglycerides (mmol/L) (0.3–1.7) 4.5 4.51 20.51 6.56 14.64 4.84
Aspartate aminotransferase (U/L) (13–35) 11 18 28 19 16 15
Alanine aminotransferase (U/L) (7.40) 22 54 16 10 12 7
Trough concentration of VRCZ (μg/mL) NA NA 6.6 NA 3.2 1.5
Abbreviation: NA, not available.
Figure 2 Changes in triglyceride, cholesterol, and trough concentration of VRCZ during treatment.
According to the treatment process of the patient, Naranjo′s rating scale was used to evaluate the adverse reactions, and the final score was 10 points, establishing a positive correlation between VRCZ and dyslipidemia, which was likely to be related to the trough concentration of VRCZ.1
Discussion
CPA is an uncommon and problematic pulmonary disease. Long-term oral antifungal therapy (voriconazole or itraconazole) is recommended for CPA to improve overall health status and respiratory symptoms, arrest haemoptysis and prevent progression.2 VRCZ is the second generation of triazole antifungal drug that has been widely used in clinical practice for about 20 years. In addition to common adverse reactions, such as visual impairment, hepatotoxicity, and skin rash,3–5 unique reactions, such as phototoxic skin diseases and malignant tumors, periostitis, hair loss, alopecia, and nail changes,6 have also been found with long-term use. However, adverse reactions of hyperlipidemia have not yet been reported. Hong and Lin7 reported a case of dyslipidemia in a 48-year-old female patient caused by itraconazole. In the second week after taking itraconazole, the patient showed elevated triglycerides and total cholesterol and normal alanine aminotransferase (ALT) and glutamic oxaloacetic transaminase (AST). The blood lipids recovered to normal 1–2 months after the withdrawal of itraconazole.
Presently, only one study7 has reported triazole antifungal drugs causing the increase in triglyceride and total cholesterol, and the mechanism is yet unclear. Studies have shown that among triazoles, VRCZ has the strongest affinity for steroid 24-hydroxylase (CYP46A1) and inhibits the conversion of cholesterol to 24-hydroxycholesterol in the brain.8,9 However, bile acids are generated from cholesterol through cholesterol 7 α hydroxylase (CYP7A1), which is a critical metabolic pathway of cholesterol in the human body. Therefore, the inhibition of cholesterol metabolism in the brain by voriconazole cannot explain the cause of elevated serum cholesterol in this patient.10,11 In addition, cytochrome P4503A (CYP3A) is the only enzyme that converts retinoic acid to cis-9-retinoic acid, and cis-9-retinoic acid is the only ligand of retinoic acid X receptor (RXR). When combined, the upregulation of apoptosis and differentiation and proliferation of adipocytes is inhibited. After the inhibition of CYP3A, the synthesis of cis-9-retinoic acid is reduced, leading to a decrease in RXR activity, thus resulting in the decreased differentiation and the increase of apoptosis of peripheral adipocytes.12 As a CYP3A inhibitor, the commonly used ritonavir has a high incidence of hypertriglyceridemia, which is related to this mechanism. However, whether the abnormal increase of triglycerides is related to VRCZ as a CYP3A drug is yet to be verified. When the patient was given VRCZ again, and when the trough concentration of the drug was half of the first dose, serum cholesterol recovered to the baseline level, and serum triglyceride level also recovered to normal with the decrease in the trough concentration of VRCZ. However, current studies still cannot explain the causes of VRCZ-induced dyslipidemia, and further research is needed.
Although drug-induced hyperlipidemia is clinically common, VRCZ has not been reported previously to cause hyperlipidemia. Based on the data of this case, it is inferred that VRCZ-induced hyperlipidemia is a reversible concentration-dependent adverse reaction. In addition, the side effects of drug-induced hyperlipidemia require large scale population studies to observe whether it has implications for patients with cardiovascular and cerebrovascular disease especially in terms of incidence to stroke and myocardial infraction.
Conclusion
We clearly observed drug-induced hyperlipidemia caused by voriconazole in a patient with chronic pulmonary aspergillosis.The level of triglycerides and cholesterol was positively correlated with the trough concentration of voriconazole. Therapeutic drug monitoring and blood lipid level monitoring were both important during the use of voriconazole.
Ethics Approval and Consent for Publication
This study has been reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital of Zhejiang University (ref#2020-1502). The patient provided informed consent for publication of the clinical details including lung CT images, and written informed consent was obtained.
Author Contributions
All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare that they have no conflicts of interest. | 43 kg. | Weight | CC BY-NC | 33603412 | 19,030,841 | 2021 |
What was the administration route of drug 'VORICONAZOLE'? | Hyperlipidemia Caused by Voriconazole: A Case Report.
Voriconazole has been widely used in clinical practice for nearly 20 years. The adverse reactions caused by voriconazole have been reported gradually, such as visual impairment, hepatotoxicity, skin rash. At present, there are few reports about triazole antifungal drugs causing the increase of triglyceride and total cholesterol. Thus, the present study reported a case of chronic pulmonary aspergillosis with significantly increased blood lipids after treatment with voriconazole. In this case, the patient's total cholesterol was normal, and triglyceride was 2.64 times of the upper limit of the reference value at the time of admission. On the 30th day after oral administration of voriconazole 200mg q12h, triglyceride and total cholesterol were 4.55 times and 3.31 times of the baseline levels, respectively, with the trough concentration of voriconazole of 6.6 μ g/mL. After 28 days of voriconazole withdrawal and itraconazole administration, triglyceride decreased to 1.45 times of baseline level and total cholesterol decreased to the normal range. After another 24 days of treatment with voriconazole 200mg q12h, triglyceride increased again to 3.25 times of the baseline level and cholesterol was within the normal range. At the same time, the trough concentration of voriconazole was 3.2 μ g/mL. After 14 days of treatment with voriconazole 100mg q12h, the triglyceride level recovered to the baseline level, with the trough concentration of voriconazole of 1.5 μ g/mL. The Naranjo's rating scale was used, the final score was 10 points, indicating that the causal relationship between voriconazole and dyslipidemia was positive, which was likely to be related to the trough concentration of voriconazole.
Introduction
Voriconazole (VRCZ) is the second generation of triazole antifungal drug that exerts antifungal effects by inhibiting 14 -sterol demethylation via cytochrome P450 in fungi to inhibit the biosynthesis of ergosterol. The common adverse reactions of VRCZ include hepatotoxicity and visual impairment, which are often related to the concentration of the drug. However, the effect of voriconazole on lipid metabolism has not been reported. Thus, the present study reported a case of chronic pulmonary aspergillosis (CPA) with significantly increased blood lipids after treatment with VRCZ and reviewed and analyzed the case of dyslipidemia caused by triazole antifungal drugs.
Case Description
A 44-year-old female patient, 148 cm height and 43 kg weight, was admitted to the First Affiliated Hospital, Zhejiang University School of Medicine for “blood in sputum for 11 months.” Chest computed tomography (CT) of the patient showed dilatation of the bronchi in both lungs and nodular high-density shadows and air crescent sign in some cavities (Figure 1); hence, diagnosis of aspergilloma was considered. The patient was positive for specific IgG of Aspergillus fumigatus and galactomannan (GM) positive for alveolar lavage fluid in the right upper lobe. Subsequently, A. fumigatus was cultured, and the diagnosis was CPA. Voriconazole (VRCZ) tablets (200 mg every 12 hours) were taken orally from January 22, 2019. The patient had a history of rheumatoid arthritis and regularly administered leflunomide tablets 10 mg QD for a long duration and had a history of sinus tachycardia, as well as metoprolol sustained-release tablets (47.5mg QD) for a long period.Figure 1 Chest CT image of the patient showed multiple dilatation of the bronchi with infection in the right lung. As shown by the arrow, aspergilloma can be seen in the dilated bronchus, showing air crescent sign.
Before administering VRCZ, the liver enzymes and the total cholesterol were normal, while the triglyceride was 2.64-fold of the upper limit of the reference value. After ingesting VRCZ tablets for 14 days, the liver enzyme levels were higher, while the blood lipids were similar to the baseline values. After administering the tablets for 30 days, the symptoms of blood in sputum disappeared. And the liver enzymes were normal while the blood lipids were significantly higher than the baseline values. Simultaneously, the trough concentration of VRCZ was 6.6 μg/mL. Considering the possibility of hyperlipidemia caused by the drug, VRCZ was withdrawn, and itraconazole (200 mg every 12 hours) was administered.
After 28 days of itraconazole treatment, the liver enzymes and blood lipids recovered to baseline levels. While, the patient’s symptoms of blood in sputum occurred.Then, the patient was given VRCZ tablets (200 mg every 12 hours) again.
After 24 days of VRCZ treatment, the liver enzyme levels were normal while triglycerides increased significantly, and the trough concentration of VRCZ was 3.2 μg/mL. The symptom of blood in sputum was improved significantly. The increase in blood lipids may be related to the trough concentration of VRCZ. The patient agreed to continue taking VRCZ tablets after communication. Therefore, the therapeutic regimen of voriconazole was adjusted to 100 mg every 12 hours. After 49 days of this therapeutic regimen, the liver enzymes and blood lipids recovered to the baseline levels again, with the trough concentration of voriconazole of 1.5 μg/mL. After 155 days of continuous use of antifungal agents, considering the full course, the voriconazole was withdrawn. During the administration and after the withdrawal of VRCZ, the liver enzymes and blood lipids were similar to the baseline levels. During the whole treatment process, the diet and living habits of the patients were consistent with those before the treatment, and no significant change was detected in height and weight compared to those before the treatment. During the treatment, the specific values of liver enzymes, total cholesterol, and triglyceride of the patient are shown in Table 1, Figure 2.Table 1 The Specific Values of Liver Enzymes, Total Cholesterol and Triglyceride of the Patient During the Treatment
Laboratory Indicators Day 0 Day 14 Day 30 Day 60 Day 84 Day 130
Total cholesterol (mmol/L) (3.14–5.86) 3.6 3.65 11.93 4.59 4.66 3.26
Triglycerides (mmol/L) (0.3–1.7) 4.5 4.51 20.51 6.56 14.64 4.84
Aspartate aminotransferase (U/L) (13–35) 11 18 28 19 16 15
Alanine aminotransferase (U/L) (7.40) 22 54 16 10 12 7
Trough concentration of VRCZ (μg/mL) NA NA 6.6 NA 3.2 1.5
Abbreviation: NA, not available.
Figure 2 Changes in triglyceride, cholesterol, and trough concentration of VRCZ during treatment.
According to the treatment process of the patient, Naranjo′s rating scale was used to evaluate the adverse reactions, and the final score was 10 points, establishing a positive correlation between VRCZ and dyslipidemia, which was likely to be related to the trough concentration of VRCZ.1
Discussion
CPA is an uncommon and problematic pulmonary disease. Long-term oral antifungal therapy (voriconazole or itraconazole) is recommended for CPA to improve overall health status and respiratory symptoms, arrest haemoptysis and prevent progression.2 VRCZ is the second generation of triazole antifungal drug that has been widely used in clinical practice for about 20 years. In addition to common adverse reactions, such as visual impairment, hepatotoxicity, and skin rash,3–5 unique reactions, such as phototoxic skin diseases and malignant tumors, periostitis, hair loss, alopecia, and nail changes,6 have also been found with long-term use. However, adverse reactions of hyperlipidemia have not yet been reported. Hong and Lin7 reported a case of dyslipidemia in a 48-year-old female patient caused by itraconazole. In the second week after taking itraconazole, the patient showed elevated triglycerides and total cholesterol and normal alanine aminotransferase (ALT) and glutamic oxaloacetic transaminase (AST). The blood lipids recovered to normal 1–2 months after the withdrawal of itraconazole.
Presently, only one study7 has reported triazole antifungal drugs causing the increase in triglyceride and total cholesterol, and the mechanism is yet unclear. Studies have shown that among triazoles, VRCZ has the strongest affinity for steroid 24-hydroxylase (CYP46A1) and inhibits the conversion of cholesterol to 24-hydroxycholesterol in the brain.8,9 However, bile acids are generated from cholesterol through cholesterol 7 α hydroxylase (CYP7A1), which is a critical metabolic pathway of cholesterol in the human body. Therefore, the inhibition of cholesterol metabolism in the brain by voriconazole cannot explain the cause of elevated serum cholesterol in this patient.10,11 In addition, cytochrome P4503A (CYP3A) is the only enzyme that converts retinoic acid to cis-9-retinoic acid, and cis-9-retinoic acid is the only ligand of retinoic acid X receptor (RXR). When combined, the upregulation of apoptosis and differentiation and proliferation of adipocytes is inhibited. After the inhibition of CYP3A, the synthesis of cis-9-retinoic acid is reduced, leading to a decrease in RXR activity, thus resulting in the decreased differentiation and the increase of apoptosis of peripheral adipocytes.12 As a CYP3A inhibitor, the commonly used ritonavir has a high incidence of hypertriglyceridemia, which is related to this mechanism. However, whether the abnormal increase of triglycerides is related to VRCZ as a CYP3A drug is yet to be verified. When the patient was given VRCZ again, and when the trough concentration of the drug was half of the first dose, serum cholesterol recovered to the baseline level, and serum triglyceride level also recovered to normal with the decrease in the trough concentration of VRCZ. However, current studies still cannot explain the causes of VRCZ-induced dyslipidemia, and further research is needed.
Although drug-induced hyperlipidemia is clinically common, VRCZ has not been reported previously to cause hyperlipidemia. Based on the data of this case, it is inferred that VRCZ-induced hyperlipidemia is a reversible concentration-dependent adverse reaction. In addition, the side effects of drug-induced hyperlipidemia require large scale population studies to observe whether it has implications for patients with cardiovascular and cerebrovascular disease especially in terms of incidence to stroke and myocardial infraction.
Conclusion
We clearly observed drug-induced hyperlipidemia caused by voriconazole in a patient with chronic pulmonary aspergillosis.The level of triglycerides and cholesterol was positively correlated with the trough concentration of voriconazole. Therapeutic drug monitoring and blood lipid level monitoring were both important during the use of voriconazole.
Ethics Approval and Consent for Publication
This study has been reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital of Zhejiang University (ref#2020-1502). The patient provided informed consent for publication of the clinical details including lung CT images, and written informed consent was obtained.
Author Contributions
All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare that they have no conflicts of interest. | Oral | DrugAdministrationRoute | CC BY-NC | 33603412 | 19,027,008 | 2021 |
What was the outcome of reaction 'Hyperlipidaemia'? | Hyperlipidemia Caused by Voriconazole: A Case Report.
Voriconazole has been widely used in clinical practice for nearly 20 years. The adverse reactions caused by voriconazole have been reported gradually, such as visual impairment, hepatotoxicity, skin rash. At present, there are few reports about triazole antifungal drugs causing the increase of triglyceride and total cholesterol. Thus, the present study reported a case of chronic pulmonary aspergillosis with significantly increased blood lipids after treatment with voriconazole. In this case, the patient's total cholesterol was normal, and triglyceride was 2.64 times of the upper limit of the reference value at the time of admission. On the 30th day after oral administration of voriconazole 200mg q12h, triglyceride and total cholesterol were 4.55 times and 3.31 times of the baseline levels, respectively, with the trough concentration of voriconazole of 6.6 μ g/mL. After 28 days of voriconazole withdrawal and itraconazole administration, triglyceride decreased to 1.45 times of baseline level and total cholesterol decreased to the normal range. After another 24 days of treatment with voriconazole 200mg q12h, triglyceride increased again to 3.25 times of the baseline level and cholesterol was within the normal range. At the same time, the trough concentration of voriconazole was 3.2 μ g/mL. After 14 days of treatment with voriconazole 100mg q12h, the triglyceride level recovered to the baseline level, with the trough concentration of voriconazole of 1.5 μ g/mL. The Naranjo's rating scale was used, the final score was 10 points, indicating that the causal relationship between voriconazole and dyslipidemia was positive, which was likely to be related to the trough concentration of voriconazole.
Introduction
Voriconazole (VRCZ) is the second generation of triazole antifungal drug that exerts antifungal effects by inhibiting 14 -sterol demethylation via cytochrome P450 in fungi to inhibit the biosynthesis of ergosterol. The common adverse reactions of VRCZ include hepatotoxicity and visual impairment, which are often related to the concentration of the drug. However, the effect of voriconazole on lipid metabolism has not been reported. Thus, the present study reported a case of chronic pulmonary aspergillosis (CPA) with significantly increased blood lipids after treatment with VRCZ and reviewed and analyzed the case of dyslipidemia caused by triazole antifungal drugs.
Case Description
A 44-year-old female patient, 148 cm height and 43 kg weight, was admitted to the First Affiliated Hospital, Zhejiang University School of Medicine for “blood in sputum for 11 months.” Chest computed tomography (CT) of the patient showed dilatation of the bronchi in both lungs and nodular high-density shadows and air crescent sign in some cavities (Figure 1); hence, diagnosis of aspergilloma was considered. The patient was positive for specific IgG of Aspergillus fumigatus and galactomannan (GM) positive for alveolar lavage fluid in the right upper lobe. Subsequently, A. fumigatus was cultured, and the diagnosis was CPA. Voriconazole (VRCZ) tablets (200 mg every 12 hours) were taken orally from January 22, 2019. The patient had a history of rheumatoid arthritis and regularly administered leflunomide tablets 10 mg QD for a long duration and had a history of sinus tachycardia, as well as metoprolol sustained-release tablets (47.5mg QD) for a long period.Figure 1 Chest CT image of the patient showed multiple dilatation of the bronchi with infection in the right lung. As shown by the arrow, aspergilloma can be seen in the dilated bronchus, showing air crescent sign.
Before administering VRCZ, the liver enzymes and the total cholesterol were normal, while the triglyceride was 2.64-fold of the upper limit of the reference value. After ingesting VRCZ tablets for 14 days, the liver enzyme levels were higher, while the blood lipids were similar to the baseline values. After administering the tablets for 30 days, the symptoms of blood in sputum disappeared. And the liver enzymes were normal while the blood lipids were significantly higher than the baseline values. Simultaneously, the trough concentration of VRCZ was 6.6 μg/mL. Considering the possibility of hyperlipidemia caused by the drug, VRCZ was withdrawn, and itraconazole (200 mg every 12 hours) was administered.
After 28 days of itraconazole treatment, the liver enzymes and blood lipids recovered to baseline levels. While, the patient’s symptoms of blood in sputum occurred.Then, the patient was given VRCZ tablets (200 mg every 12 hours) again.
After 24 days of VRCZ treatment, the liver enzyme levels were normal while triglycerides increased significantly, and the trough concentration of VRCZ was 3.2 μg/mL. The symptom of blood in sputum was improved significantly. The increase in blood lipids may be related to the trough concentration of VRCZ. The patient agreed to continue taking VRCZ tablets after communication. Therefore, the therapeutic regimen of voriconazole was adjusted to 100 mg every 12 hours. After 49 days of this therapeutic regimen, the liver enzymes and blood lipids recovered to the baseline levels again, with the trough concentration of voriconazole of 1.5 μg/mL. After 155 days of continuous use of antifungal agents, considering the full course, the voriconazole was withdrawn. During the administration and after the withdrawal of VRCZ, the liver enzymes and blood lipids were similar to the baseline levels. During the whole treatment process, the diet and living habits of the patients were consistent with those before the treatment, and no significant change was detected in height and weight compared to those before the treatment. During the treatment, the specific values of liver enzymes, total cholesterol, and triglyceride of the patient are shown in Table 1, Figure 2.Table 1 The Specific Values of Liver Enzymes, Total Cholesterol and Triglyceride of the Patient During the Treatment
Laboratory Indicators Day 0 Day 14 Day 30 Day 60 Day 84 Day 130
Total cholesterol (mmol/L) (3.14–5.86) 3.6 3.65 11.93 4.59 4.66 3.26
Triglycerides (mmol/L) (0.3–1.7) 4.5 4.51 20.51 6.56 14.64 4.84
Aspartate aminotransferase (U/L) (13–35) 11 18 28 19 16 15
Alanine aminotransferase (U/L) (7.40) 22 54 16 10 12 7
Trough concentration of VRCZ (μg/mL) NA NA 6.6 NA 3.2 1.5
Abbreviation: NA, not available.
Figure 2 Changes in triglyceride, cholesterol, and trough concentration of VRCZ during treatment.
According to the treatment process of the patient, Naranjo′s rating scale was used to evaluate the adverse reactions, and the final score was 10 points, establishing a positive correlation between VRCZ and dyslipidemia, which was likely to be related to the trough concentration of VRCZ.1
Discussion
CPA is an uncommon and problematic pulmonary disease. Long-term oral antifungal therapy (voriconazole or itraconazole) is recommended for CPA to improve overall health status and respiratory symptoms, arrest haemoptysis and prevent progression.2 VRCZ is the second generation of triazole antifungal drug that has been widely used in clinical practice for about 20 years. In addition to common adverse reactions, such as visual impairment, hepatotoxicity, and skin rash,3–5 unique reactions, such as phototoxic skin diseases and malignant tumors, periostitis, hair loss, alopecia, and nail changes,6 have also been found with long-term use. However, adverse reactions of hyperlipidemia have not yet been reported. Hong and Lin7 reported a case of dyslipidemia in a 48-year-old female patient caused by itraconazole. In the second week after taking itraconazole, the patient showed elevated triglycerides and total cholesterol and normal alanine aminotransferase (ALT) and glutamic oxaloacetic transaminase (AST). The blood lipids recovered to normal 1–2 months after the withdrawal of itraconazole.
Presently, only one study7 has reported triazole antifungal drugs causing the increase in triglyceride and total cholesterol, and the mechanism is yet unclear. Studies have shown that among triazoles, VRCZ has the strongest affinity for steroid 24-hydroxylase (CYP46A1) and inhibits the conversion of cholesterol to 24-hydroxycholesterol in the brain.8,9 However, bile acids are generated from cholesterol through cholesterol 7 α hydroxylase (CYP7A1), which is a critical metabolic pathway of cholesterol in the human body. Therefore, the inhibition of cholesterol metabolism in the brain by voriconazole cannot explain the cause of elevated serum cholesterol in this patient.10,11 In addition, cytochrome P4503A (CYP3A) is the only enzyme that converts retinoic acid to cis-9-retinoic acid, and cis-9-retinoic acid is the only ligand of retinoic acid X receptor (RXR). When combined, the upregulation of apoptosis and differentiation and proliferation of adipocytes is inhibited. After the inhibition of CYP3A, the synthesis of cis-9-retinoic acid is reduced, leading to a decrease in RXR activity, thus resulting in the decreased differentiation and the increase of apoptosis of peripheral adipocytes.12 As a CYP3A inhibitor, the commonly used ritonavir has a high incidence of hypertriglyceridemia, which is related to this mechanism. However, whether the abnormal increase of triglycerides is related to VRCZ as a CYP3A drug is yet to be verified. When the patient was given VRCZ again, and when the trough concentration of the drug was half of the first dose, serum cholesterol recovered to the baseline level, and serum triglyceride level also recovered to normal with the decrease in the trough concentration of VRCZ. However, current studies still cannot explain the causes of VRCZ-induced dyslipidemia, and further research is needed.
Although drug-induced hyperlipidemia is clinically common, VRCZ has not been reported previously to cause hyperlipidemia. Based on the data of this case, it is inferred that VRCZ-induced hyperlipidemia is a reversible concentration-dependent adverse reaction. In addition, the side effects of drug-induced hyperlipidemia require large scale population studies to observe whether it has implications for patients with cardiovascular and cerebrovascular disease especially in terms of incidence to stroke and myocardial infraction.
Conclusion
We clearly observed drug-induced hyperlipidemia caused by voriconazole in a patient with chronic pulmonary aspergillosis.The level of triglycerides and cholesterol was positively correlated with the trough concentration of voriconazole. Therapeutic drug monitoring and blood lipid level monitoring were both important during the use of voriconazole.
Ethics Approval and Consent for Publication
This study has been reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital of Zhejiang University (ref#2020-1502). The patient provided informed consent for publication of the clinical details including lung CT images, and written informed consent was obtained.
Author Contributions
All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare that they have no conflicts of interest. | Recovered | ReactionOutcome | CC BY-NC | 33603412 | 19,027,008 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Encephalopathy'. | Encephalopathy Induced by Preventive Administration of Acyclovir in a Man with Symptomatic Multiple Myeloma and Renal Dysfunction.
Acyclovir (ACV) neurotoxicity is a neuropsychiatric condition induced by the anti-herpetic drugs ACV and valacyclovir (VACV). It is presumed that elevated blood levels of ACV and its metabolite 9-carboxymethoxymethylguanine are involved in the development of ACV-induced encephalopathy; age and renal dysfunction are risk factors. Here, we report a case of encephalopathy caused by the administration of VACV for herpes zoster prophylaxis in a patient with renal dysfunction owing to multiple myeloma.
Renal dysfunction was diagnosed in a 70-year-old man visiting our hospital for a medical checkup. His creatinine clearance rate was 8 mL/min. He was diagnosed with symptomatic multiple myeloma, and bortezomib/dexamethasone (BD) therapy for multiple myeloma and VACV for herpes zoster prophylaxis were initiated. We administered 500 mg/day of VACV three times a week, a lower dosage than recommended, after adjusting for his renal impairment. His renal function was monitored twice per week during therapy. During the second course of BD therapy, 6 weeks after starting treatment, he was hospitalized owing to impaired consciousness (Glasgow Coma Scale score: E2, V4, M4), and his BD and VACV therapy were suspended. Brain magnetic resonance imaging and cerebrospinal fluid analysis showed no abnormalities. Three days after discontinuing BD and VACV therapy, his consciousness recovered completely, and impaired consciousness did not recur after resuming BD therapy. His clinical diagnosis was thus ACV-induced encephalopathy.
VACV is often prescribed to patients with multiple myeloma receiving BD therapy to prevent herpes zoster. ACV-induced encephalopathy is commonly observed in patients with renal dysfunction; especially among patients with multiple myeloma with Bence-Jones proteinuria, renal tubules are easily damaged and plasma ACV concentrations are likely to increase and induce ACV-induced encephalopathy. Careful monitoring of the level of consciousness is necessary during preventive ACV therapy in patients with renal dysfunction.
Introduction
Acyclovir (ACV) neurotoxicity is a neuropsychiatric condition induced by the administration of the anti-herpetic drugs ACV and valacyclovir (VACV).1 VACV is the prodrug of ACV. Usually, various neuropsychiatric symptoms, such as disturbance of consciousness, tremor, and myoclonus, occur within 2 days after initiating the therapy.1–3 Hallucinations are also common.1–3 It is presumed that elevated blood levels of ACV and its metabolite, 9-carboxymethoxymethylguanine (CMMG), are involved in the development of ACV-induced encephalopathy4 and that age and renal dysfunction are risk factors.5
Bortezomib/dexamethasone (BD) therapy is one of the standard regimens for patients with symptomatic multiple myeloma who have severe renal impairment.6 In bortezomib-containing regimens, low-dose oral ACV is recommended for herpes zoster prophylaxis.7,8
We present a case of encephalopathy caused by the administration of VACV for herpes zoster prophylaxis in a patient with renal dysfunction due to multiple myeloma.
Case Presentation
Renal dysfunction was diagnosed in a 70-year-old man who visited our hospital for a medical checkup. His serum creatinine level and creatinine clearance rate were 8.78 mg/dL (normal range: 0.53–1.02 mg/dL) and 8 mL/min (normal range: 80–180 mL/min), respectively. He was diagnosed with Bence–Jones protein λ-type multiple myeloma based on the presence of 40% plasma cells in his bone marrow (10% or more of plasma cells is considered definitive of the disease) and Bence–Jones proteinuria (M proteinuria of 4.8 g/day). Additionally, the diagnosis of symptomatic multiple myeloma (International Staging System stage 3) was based on the presence of renal dysfunction. Renal biopsy revealed cast nephropathy known as myeloma kidney, in which large amounts of Bence–Jones proteins formed casts that blocked the tubules (Figure 1). BD therapy was initiated with concurrent VACV for herpes zoster prophylaxis. We administered a reduced dose VACV of 500 mg three times a week because of the patient’s renal impairment, based on the drug information on VACV provided in the UpToDate database.9 His renal function was monitored twice per week during therapy. Six weeks later, during his second course of BD therapy, the patient was hospitalized because of impaired consciousness. He displayed no other symptoms during hospitalization.Figure 1 Histology of kidney tissue showing myeloma cast nephropathy. (A) Hematoxylin and eosin stain (magnification ×200). (B) Periodic acid-Schiff stain (magnification ×400).
On admission, his vital signs were as follows: Glasgow Coma Scale score, E2, V4, M4; body temperature, 36.5°C; blood pressure, 145/79 mmHg; pulse rate, 73 beats/min; respiratory rate, 15 breaths/min; and SpO2, 96%. His vital signs were normal, and there were no remarkable neurological abnormalities except for disturbance of consciousness. Table 1 summarizes the results of patient’s blood test on admission. The results, including renal function, were unchanged. Brain magnetic resonance imaging and cerebrospinal fluid analysis—cell counts 1/µL, protein 40 mg/dL, glucose 98 mg/dL, reference blood glucose level 125 mg/dL—revealed no abnormalities. There was no new electrolyte, endocrine hormone abnormality, or suggestion of epilepsy. Therefore, we suspected drug-induced disturbance of consciousness and suspended the BD and VACV therapy. Three days after discontinuing the drugs, his level of consciousness returned to normal, and the BD therapy was restarted after 20 days of drug interruption. The Naranjo score10 for estimating the probability of adverse drug reactions was 7 points. In this scoring system, ≥ 9 points indicate “high probability for adverse reactions” and 5–8 points indicate “probability for adverse reactions”.10 In all Japan, the laboratories do not have facilities to measure ACV/CMMG levels. Though his blood level of ACV could not be measured, the clinical diagnosis was ACV neurotoxicity based on his response to the suspension of the therapy, the high Naranjo score, and the lack of other contributing factors. We theorized that ACV blood levels gradually increased over the long-term administration of oral VACV owing to renal dysfunction. Figure 2 illustrates his clinical course.Table 1 Results of the Patient’s Admission Blood Tests
Parameters Result Reference Range
White blood cell count 15.278 × 103/µL 4.50–7.50 × 103/µL
Neutrophils 89.2%
Lymphocytes 5.8%
Hemoglobin 7.2 g/dL 11.3–15.2 g/dL
Hematocrit 21.7% 36–45%
Platelets 173 × 103/µL 130–350 × 103/µL
C-reactive protein 0.06 mg/dL ≤0.60 mg/dL
Total protein 6.7 g/dL 6.9–8.4 g/dL
Albumin 3.9 g/dL 3.9–5.1 g/dL
Aspartate aminotransferase 15 U/L 11–30 U/L
Alanine aminotransferase 15 U/L 4–30 U/L
Lactate dehydrogenase 235 U/L 109–216 U/L
Creatine phosphokinase 55 U/L 40–150 U/L
Blood nitrogen urea 69.7 mg/dL 8–20 mg/dL
Creatinine 7.71 mg/dL 0.63–1.03 mg/dL
Creatinine clearance 8.8 mL/min >60 mL/min
Sodium 136 mEq/L 136–148 mEq/L
Potassium 4.6 mEq/L 3.6–5.0 mEq/L
Glucose 155 mg/dL 70–109 mg/dL
Figure 2 Clinical course of the patient after starting bortezomib/dexamethasone therapy. BD therapy: Bortezomib was administered at a dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 with dexamethasone (20 mg) administered on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12. The 21-day regimen administered in 2 cycles was defined as 1 course.
The patient underwent 9 cycles of BD therapy and achieved complete remission. We administered 250 mg of famciclovir for herpes zoster prophylaxis, three times a week, between cycles 4 to 9. One year after the end of treatment, he remained in remission. His creatinine level recovered and remained stable at 4–5 mg/dL in response to the treatment. He did not exhibit any sequelae of ACV encephalopathy.
Discussion
We presented a case of ACV-induced encephalopathy caused by the administration of VACV for herpes zoster during the treatment of multiple myeloma in a man with renal dysfunction. To the best of our knowledge, this is the first report of ACV neurotoxicity in a patient taking low-dose VACV for herpes zoster prophylaxis. This case illustrates that ACV or VACV should be used with caution in patients with myeloma-associated renal dysfunction, even if used in low doses for herpes zoster prophylaxis.
In all Japan, the laboratories do not have facilities to measure ACV/CMMG levels. However, we diagnosed ACV-induced encephalopathy based on his clinical course, the high Naranjo score, the lack of other contributing factors. ACV or VACV can cause renal tubular obstruction secondary to crystal-induced nephropathy, and direct action of the ACV aldehyde can cause acute kidney injury; these can lead to increased blood concentrations of ACV and CMMG and cause encephalopathy.2,11 In this case, our patient exhibited Bence–Jones proteinuria. Increased excretion of Bence–Jones proteins may have damaged the tubular epithelium or formed casts that blocked the renal tubules, leading to myeloma cast nephropathy. It is the most common cause of myeloma-associated renal injury and may cause renal dysfunction.12,13 Though the renal dysfunction in our patient was stable at a low level, we theorized that long-term preventive oral VACV therapy gradually led to increased plasma concentrations of ACV and CMMG, resulting in encephalopathy.
In this case, the VACV prophylaxis resulted in ACV-induced encephalopathy, even though we administered it at a dose lower than the recommended dose for patients with renal dysfunction. ACV-induced encephalopathy has been observed in patients administered with extremely high doses (10 mg/kg every hour) of the drug or in cases of renal failure without dose adjustment.4 It has often been reported in elderly people and patients with impaired renal function,5 but it has occurred in patients without renal dysfunction and young patients.14 In all cases, ACV-induced encephalopathy developed owing to the ACV or VACV treatment for herpes simplex or zoster virus. There were no reports that ACV-induced encephalopathy developed with prophylactic administration. Myeloma kidney with Bence–Jones proteinuria causes kidney renal tubular damage, which is disproportionate to the degree of renal impairment suggested by the creatinine level. Thus, it is presumed that it inhibits the excretion of drugs, including ACV, in renal tubules, resulting in an elevated blood concentration. It is difficult to measure ACV and CMMG blood levels. Therefore, even with the recommended level of ACV or VACV prophylaxis for renal impairment, it is not possible to predict ACV neurotoxicity, such as impaired consciousness and impaired renal function.
In conclusion, among patients with multiple myeloma with Bence–Jones proteinuria, the renal tubules are easily damaged, and the plasma concentration of ACV is likely to increase and induce ACV neurotoxicity. Careful monitoring of the level of consciousness is necessary during preventive ACV therapy in patients with renal dysfunction.
Abbreviations
ACV, acyclovir; BD, bortezomib/dexamethasone; CMMG, 9-carboxymethoxymethylguanine; VACV, valacyclovir.
Data Sharing Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Consent for Publication
Written informed consent was obtained from the patient for the publication of this case report and accompanying images.
Author Contributions
All authors contributed to the conception, study design, execution, acquisition of data, analysis and interpretation, drafting and revising the article, and critically reviewing the article; provided final approval of the version to be published; and agreed to be accountable for all aspects of the work.
Disclosure
The authors declare that they have no conflicts of interest. | VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33603447 | 19,083,394 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxic encephalopathy'. | Encephalopathy Induced by Preventive Administration of Acyclovir in a Man with Symptomatic Multiple Myeloma and Renal Dysfunction.
Acyclovir (ACV) neurotoxicity is a neuropsychiatric condition induced by the anti-herpetic drugs ACV and valacyclovir (VACV). It is presumed that elevated blood levels of ACV and its metabolite 9-carboxymethoxymethylguanine are involved in the development of ACV-induced encephalopathy; age and renal dysfunction are risk factors. Here, we report a case of encephalopathy caused by the administration of VACV for herpes zoster prophylaxis in a patient with renal dysfunction owing to multiple myeloma.
Renal dysfunction was diagnosed in a 70-year-old man visiting our hospital for a medical checkup. His creatinine clearance rate was 8 mL/min. He was diagnosed with symptomatic multiple myeloma, and bortezomib/dexamethasone (BD) therapy for multiple myeloma and VACV for herpes zoster prophylaxis were initiated. We administered 500 mg/day of VACV three times a week, a lower dosage than recommended, after adjusting for his renal impairment. His renal function was monitored twice per week during therapy. During the second course of BD therapy, 6 weeks after starting treatment, he was hospitalized owing to impaired consciousness (Glasgow Coma Scale score: E2, V4, M4), and his BD and VACV therapy were suspended. Brain magnetic resonance imaging and cerebrospinal fluid analysis showed no abnormalities. Three days after discontinuing BD and VACV therapy, his consciousness recovered completely, and impaired consciousness did not recur after resuming BD therapy. His clinical diagnosis was thus ACV-induced encephalopathy.
VACV is often prescribed to patients with multiple myeloma receiving BD therapy to prevent herpes zoster. ACV-induced encephalopathy is commonly observed in patients with renal dysfunction; especially among patients with multiple myeloma with Bence-Jones proteinuria, renal tubules are easily damaged and plasma ACV concentrations are likely to increase and induce ACV-induced encephalopathy. Careful monitoring of the level of consciousness is necessary during preventive ACV therapy in patients with renal dysfunction.
Introduction
Acyclovir (ACV) neurotoxicity is a neuropsychiatric condition induced by the administration of the anti-herpetic drugs ACV and valacyclovir (VACV).1 VACV is the prodrug of ACV. Usually, various neuropsychiatric symptoms, such as disturbance of consciousness, tremor, and myoclonus, occur within 2 days after initiating the therapy.1–3 Hallucinations are also common.1–3 It is presumed that elevated blood levels of ACV and its metabolite, 9-carboxymethoxymethylguanine (CMMG), are involved in the development of ACV-induced encephalopathy4 and that age and renal dysfunction are risk factors.5
Bortezomib/dexamethasone (BD) therapy is one of the standard regimens for patients with symptomatic multiple myeloma who have severe renal impairment.6 In bortezomib-containing regimens, low-dose oral ACV is recommended for herpes zoster prophylaxis.7,8
We present a case of encephalopathy caused by the administration of VACV for herpes zoster prophylaxis in a patient with renal dysfunction due to multiple myeloma.
Case Presentation
Renal dysfunction was diagnosed in a 70-year-old man who visited our hospital for a medical checkup. His serum creatinine level and creatinine clearance rate were 8.78 mg/dL (normal range: 0.53–1.02 mg/dL) and 8 mL/min (normal range: 80–180 mL/min), respectively. He was diagnosed with Bence–Jones protein λ-type multiple myeloma based on the presence of 40% plasma cells in his bone marrow (10% or more of plasma cells is considered definitive of the disease) and Bence–Jones proteinuria (M proteinuria of 4.8 g/day). Additionally, the diagnosis of symptomatic multiple myeloma (International Staging System stage 3) was based on the presence of renal dysfunction. Renal biopsy revealed cast nephropathy known as myeloma kidney, in which large amounts of Bence–Jones proteins formed casts that blocked the tubules (Figure 1). BD therapy was initiated with concurrent VACV for herpes zoster prophylaxis. We administered a reduced dose VACV of 500 mg three times a week because of the patient’s renal impairment, based on the drug information on VACV provided in the UpToDate database.9 His renal function was monitored twice per week during therapy. Six weeks later, during his second course of BD therapy, the patient was hospitalized because of impaired consciousness. He displayed no other symptoms during hospitalization.Figure 1 Histology of kidney tissue showing myeloma cast nephropathy. (A) Hematoxylin and eosin stain (magnification ×200). (B) Periodic acid-Schiff stain (magnification ×400).
On admission, his vital signs were as follows: Glasgow Coma Scale score, E2, V4, M4; body temperature, 36.5°C; blood pressure, 145/79 mmHg; pulse rate, 73 beats/min; respiratory rate, 15 breaths/min; and SpO2, 96%. His vital signs were normal, and there were no remarkable neurological abnormalities except for disturbance of consciousness. Table 1 summarizes the results of patient’s blood test on admission. The results, including renal function, were unchanged. Brain magnetic resonance imaging and cerebrospinal fluid analysis—cell counts 1/µL, protein 40 mg/dL, glucose 98 mg/dL, reference blood glucose level 125 mg/dL—revealed no abnormalities. There was no new electrolyte, endocrine hormone abnormality, or suggestion of epilepsy. Therefore, we suspected drug-induced disturbance of consciousness and suspended the BD and VACV therapy. Three days after discontinuing the drugs, his level of consciousness returned to normal, and the BD therapy was restarted after 20 days of drug interruption. The Naranjo score10 for estimating the probability of adverse drug reactions was 7 points. In this scoring system, ≥ 9 points indicate “high probability for adverse reactions” and 5–8 points indicate “probability for adverse reactions”.10 In all Japan, the laboratories do not have facilities to measure ACV/CMMG levels. Though his blood level of ACV could not be measured, the clinical diagnosis was ACV neurotoxicity based on his response to the suspension of the therapy, the high Naranjo score, and the lack of other contributing factors. We theorized that ACV blood levels gradually increased over the long-term administration of oral VACV owing to renal dysfunction. Figure 2 illustrates his clinical course.Table 1 Results of the Patient’s Admission Blood Tests
Parameters Result Reference Range
White blood cell count 15.278 × 103/µL 4.50–7.50 × 103/µL
Neutrophils 89.2%
Lymphocytes 5.8%
Hemoglobin 7.2 g/dL 11.3–15.2 g/dL
Hematocrit 21.7% 36–45%
Platelets 173 × 103/µL 130–350 × 103/µL
C-reactive protein 0.06 mg/dL ≤0.60 mg/dL
Total protein 6.7 g/dL 6.9–8.4 g/dL
Albumin 3.9 g/dL 3.9–5.1 g/dL
Aspartate aminotransferase 15 U/L 11–30 U/L
Alanine aminotransferase 15 U/L 4–30 U/L
Lactate dehydrogenase 235 U/L 109–216 U/L
Creatine phosphokinase 55 U/L 40–150 U/L
Blood nitrogen urea 69.7 mg/dL 8–20 mg/dL
Creatinine 7.71 mg/dL 0.63–1.03 mg/dL
Creatinine clearance 8.8 mL/min >60 mL/min
Sodium 136 mEq/L 136–148 mEq/L
Potassium 4.6 mEq/L 3.6–5.0 mEq/L
Glucose 155 mg/dL 70–109 mg/dL
Figure 2 Clinical course of the patient after starting bortezomib/dexamethasone therapy. BD therapy: Bortezomib was administered at a dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 with dexamethasone (20 mg) administered on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12. The 21-day regimen administered in 2 cycles was defined as 1 course.
The patient underwent 9 cycles of BD therapy and achieved complete remission. We administered 250 mg of famciclovir for herpes zoster prophylaxis, three times a week, between cycles 4 to 9. One year after the end of treatment, he remained in remission. His creatinine level recovered and remained stable at 4–5 mg/dL in response to the treatment. He did not exhibit any sequelae of ACV encephalopathy.
Discussion
We presented a case of ACV-induced encephalopathy caused by the administration of VACV for herpes zoster during the treatment of multiple myeloma in a man with renal dysfunction. To the best of our knowledge, this is the first report of ACV neurotoxicity in a patient taking low-dose VACV for herpes zoster prophylaxis. This case illustrates that ACV or VACV should be used with caution in patients with myeloma-associated renal dysfunction, even if used in low doses for herpes zoster prophylaxis.
In all Japan, the laboratories do not have facilities to measure ACV/CMMG levels. However, we diagnosed ACV-induced encephalopathy based on his clinical course, the high Naranjo score, the lack of other contributing factors. ACV or VACV can cause renal tubular obstruction secondary to crystal-induced nephropathy, and direct action of the ACV aldehyde can cause acute kidney injury; these can lead to increased blood concentrations of ACV and CMMG and cause encephalopathy.2,11 In this case, our patient exhibited Bence–Jones proteinuria. Increased excretion of Bence–Jones proteins may have damaged the tubular epithelium or formed casts that blocked the renal tubules, leading to myeloma cast nephropathy. It is the most common cause of myeloma-associated renal injury and may cause renal dysfunction.12,13 Though the renal dysfunction in our patient was stable at a low level, we theorized that long-term preventive oral VACV therapy gradually led to increased plasma concentrations of ACV and CMMG, resulting in encephalopathy.
In this case, the VACV prophylaxis resulted in ACV-induced encephalopathy, even though we administered it at a dose lower than the recommended dose for patients with renal dysfunction. ACV-induced encephalopathy has been observed in patients administered with extremely high doses (10 mg/kg every hour) of the drug or in cases of renal failure without dose adjustment.4 It has often been reported in elderly people and patients with impaired renal function,5 but it has occurred in patients without renal dysfunction and young patients.14 In all cases, ACV-induced encephalopathy developed owing to the ACV or VACV treatment for herpes simplex or zoster virus. There were no reports that ACV-induced encephalopathy developed with prophylactic administration. Myeloma kidney with Bence–Jones proteinuria causes kidney renal tubular damage, which is disproportionate to the degree of renal impairment suggested by the creatinine level. Thus, it is presumed that it inhibits the excretion of drugs, including ACV, in renal tubules, resulting in an elevated blood concentration. It is difficult to measure ACV and CMMG blood levels. Therefore, even with the recommended level of ACV or VACV prophylaxis for renal impairment, it is not possible to predict ACV neurotoxicity, such as impaired consciousness and impaired renal function.
In conclusion, among patients with multiple myeloma with Bence–Jones proteinuria, the renal tubules are easily damaged, and the plasma concentration of ACV is likely to increase and induce ACV neurotoxicity. Careful monitoring of the level of consciousness is necessary during preventive ACV therapy in patients with renal dysfunction.
Abbreviations
ACV, acyclovir; BD, bortezomib/dexamethasone; CMMG, 9-carboxymethoxymethylguanine; VACV, valacyclovir.
Data Sharing Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Consent for Publication
Written informed consent was obtained from the patient for the publication of this case report and accompanying images.
Author Contributions
All authors contributed to the conception, study design, execution, acquisition of data, analysis and interpretation, drafting and revising the article, and critically reviewing the article; provided final approval of the version to be published; and agreed to be accountable for all aspects of the work.
Disclosure
The authors declare that they have no conflicts of interest. | BORTEZOMIB, DEXAMETHASONE, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33603447 | 19,085,824 | 2021 |
What was the dosage of drug 'BORTEZOMIB'? | Encephalopathy Induced by Preventive Administration of Acyclovir in a Man with Symptomatic Multiple Myeloma and Renal Dysfunction.
Acyclovir (ACV) neurotoxicity is a neuropsychiatric condition induced by the anti-herpetic drugs ACV and valacyclovir (VACV). It is presumed that elevated blood levels of ACV and its metabolite 9-carboxymethoxymethylguanine are involved in the development of ACV-induced encephalopathy; age and renal dysfunction are risk factors. Here, we report a case of encephalopathy caused by the administration of VACV for herpes zoster prophylaxis in a patient with renal dysfunction owing to multiple myeloma.
Renal dysfunction was diagnosed in a 70-year-old man visiting our hospital for a medical checkup. His creatinine clearance rate was 8 mL/min. He was diagnosed with symptomatic multiple myeloma, and bortezomib/dexamethasone (BD) therapy for multiple myeloma and VACV for herpes zoster prophylaxis were initiated. We administered 500 mg/day of VACV three times a week, a lower dosage than recommended, after adjusting for his renal impairment. His renal function was monitored twice per week during therapy. During the second course of BD therapy, 6 weeks after starting treatment, he was hospitalized owing to impaired consciousness (Glasgow Coma Scale score: E2, V4, M4), and his BD and VACV therapy were suspended. Brain magnetic resonance imaging and cerebrospinal fluid analysis showed no abnormalities. Three days after discontinuing BD and VACV therapy, his consciousness recovered completely, and impaired consciousness did not recur after resuming BD therapy. His clinical diagnosis was thus ACV-induced encephalopathy.
VACV is often prescribed to patients with multiple myeloma receiving BD therapy to prevent herpes zoster. ACV-induced encephalopathy is commonly observed in patients with renal dysfunction; especially among patients with multiple myeloma with Bence-Jones proteinuria, renal tubules are easily damaged and plasma ACV concentrations are likely to increase and induce ACV-induced encephalopathy. Careful monitoring of the level of consciousness is necessary during preventive ACV therapy in patients with renal dysfunction.
Introduction
Acyclovir (ACV) neurotoxicity is a neuropsychiatric condition induced by the administration of the anti-herpetic drugs ACV and valacyclovir (VACV).1 VACV is the prodrug of ACV. Usually, various neuropsychiatric symptoms, such as disturbance of consciousness, tremor, and myoclonus, occur within 2 days after initiating the therapy.1–3 Hallucinations are also common.1–3 It is presumed that elevated blood levels of ACV and its metabolite, 9-carboxymethoxymethylguanine (CMMG), are involved in the development of ACV-induced encephalopathy4 and that age and renal dysfunction are risk factors.5
Bortezomib/dexamethasone (BD) therapy is one of the standard regimens for patients with symptomatic multiple myeloma who have severe renal impairment.6 In bortezomib-containing regimens, low-dose oral ACV is recommended for herpes zoster prophylaxis.7,8
We present a case of encephalopathy caused by the administration of VACV for herpes zoster prophylaxis in a patient with renal dysfunction due to multiple myeloma.
Case Presentation
Renal dysfunction was diagnosed in a 70-year-old man who visited our hospital for a medical checkup. His serum creatinine level and creatinine clearance rate were 8.78 mg/dL (normal range: 0.53–1.02 mg/dL) and 8 mL/min (normal range: 80–180 mL/min), respectively. He was diagnosed with Bence–Jones protein λ-type multiple myeloma based on the presence of 40% plasma cells in his bone marrow (10% or more of plasma cells is considered definitive of the disease) and Bence–Jones proteinuria (M proteinuria of 4.8 g/day). Additionally, the diagnosis of symptomatic multiple myeloma (International Staging System stage 3) was based on the presence of renal dysfunction. Renal biopsy revealed cast nephropathy known as myeloma kidney, in which large amounts of Bence–Jones proteins formed casts that blocked the tubules (Figure 1). BD therapy was initiated with concurrent VACV for herpes zoster prophylaxis. We administered a reduced dose VACV of 500 mg three times a week because of the patient’s renal impairment, based on the drug information on VACV provided in the UpToDate database.9 His renal function was monitored twice per week during therapy. Six weeks later, during his second course of BD therapy, the patient was hospitalized because of impaired consciousness. He displayed no other symptoms during hospitalization.Figure 1 Histology of kidney tissue showing myeloma cast nephropathy. (A) Hematoxylin and eosin stain (magnification ×200). (B) Periodic acid-Schiff stain (magnification ×400).
On admission, his vital signs were as follows: Glasgow Coma Scale score, E2, V4, M4; body temperature, 36.5°C; blood pressure, 145/79 mmHg; pulse rate, 73 beats/min; respiratory rate, 15 breaths/min; and SpO2, 96%. His vital signs were normal, and there were no remarkable neurological abnormalities except for disturbance of consciousness. Table 1 summarizes the results of patient’s blood test on admission. The results, including renal function, were unchanged. Brain magnetic resonance imaging and cerebrospinal fluid analysis—cell counts 1/µL, protein 40 mg/dL, glucose 98 mg/dL, reference blood glucose level 125 mg/dL—revealed no abnormalities. There was no new electrolyte, endocrine hormone abnormality, or suggestion of epilepsy. Therefore, we suspected drug-induced disturbance of consciousness and suspended the BD and VACV therapy. Three days after discontinuing the drugs, his level of consciousness returned to normal, and the BD therapy was restarted after 20 days of drug interruption. The Naranjo score10 for estimating the probability of adverse drug reactions was 7 points. In this scoring system, ≥ 9 points indicate “high probability for adverse reactions” and 5–8 points indicate “probability for adverse reactions”.10 In all Japan, the laboratories do not have facilities to measure ACV/CMMG levels. Though his blood level of ACV could not be measured, the clinical diagnosis was ACV neurotoxicity based on his response to the suspension of the therapy, the high Naranjo score, and the lack of other contributing factors. We theorized that ACV blood levels gradually increased over the long-term administration of oral VACV owing to renal dysfunction. Figure 2 illustrates his clinical course.Table 1 Results of the Patient’s Admission Blood Tests
Parameters Result Reference Range
White blood cell count 15.278 × 103/µL 4.50–7.50 × 103/µL
Neutrophils 89.2%
Lymphocytes 5.8%
Hemoglobin 7.2 g/dL 11.3–15.2 g/dL
Hematocrit 21.7% 36–45%
Platelets 173 × 103/µL 130–350 × 103/µL
C-reactive protein 0.06 mg/dL ≤0.60 mg/dL
Total protein 6.7 g/dL 6.9–8.4 g/dL
Albumin 3.9 g/dL 3.9–5.1 g/dL
Aspartate aminotransferase 15 U/L 11–30 U/L
Alanine aminotransferase 15 U/L 4–30 U/L
Lactate dehydrogenase 235 U/L 109–216 U/L
Creatine phosphokinase 55 U/L 40–150 U/L
Blood nitrogen urea 69.7 mg/dL 8–20 mg/dL
Creatinine 7.71 mg/dL 0.63–1.03 mg/dL
Creatinine clearance 8.8 mL/min >60 mL/min
Sodium 136 mEq/L 136–148 mEq/L
Potassium 4.6 mEq/L 3.6–5.0 mEq/L
Glucose 155 mg/dL 70–109 mg/dL
Figure 2 Clinical course of the patient after starting bortezomib/dexamethasone therapy. BD therapy: Bortezomib was administered at a dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 with dexamethasone (20 mg) administered on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12. The 21-day regimen administered in 2 cycles was defined as 1 course.
The patient underwent 9 cycles of BD therapy and achieved complete remission. We administered 250 mg of famciclovir for herpes zoster prophylaxis, three times a week, between cycles 4 to 9. One year after the end of treatment, he remained in remission. His creatinine level recovered and remained stable at 4–5 mg/dL in response to the treatment. He did not exhibit any sequelae of ACV encephalopathy.
Discussion
We presented a case of ACV-induced encephalopathy caused by the administration of VACV for herpes zoster during the treatment of multiple myeloma in a man with renal dysfunction. To the best of our knowledge, this is the first report of ACV neurotoxicity in a patient taking low-dose VACV for herpes zoster prophylaxis. This case illustrates that ACV or VACV should be used with caution in patients with myeloma-associated renal dysfunction, even if used in low doses for herpes zoster prophylaxis.
In all Japan, the laboratories do not have facilities to measure ACV/CMMG levels. However, we diagnosed ACV-induced encephalopathy based on his clinical course, the high Naranjo score, the lack of other contributing factors. ACV or VACV can cause renal tubular obstruction secondary to crystal-induced nephropathy, and direct action of the ACV aldehyde can cause acute kidney injury; these can lead to increased blood concentrations of ACV and CMMG and cause encephalopathy.2,11 In this case, our patient exhibited Bence–Jones proteinuria. Increased excretion of Bence–Jones proteins may have damaged the tubular epithelium or formed casts that blocked the renal tubules, leading to myeloma cast nephropathy. It is the most common cause of myeloma-associated renal injury and may cause renal dysfunction.12,13 Though the renal dysfunction in our patient was stable at a low level, we theorized that long-term preventive oral VACV therapy gradually led to increased plasma concentrations of ACV and CMMG, resulting in encephalopathy.
In this case, the VACV prophylaxis resulted in ACV-induced encephalopathy, even though we administered it at a dose lower than the recommended dose for patients with renal dysfunction. ACV-induced encephalopathy has been observed in patients administered with extremely high doses (10 mg/kg every hour) of the drug or in cases of renal failure without dose adjustment.4 It has often been reported in elderly people and patients with impaired renal function,5 but it has occurred in patients without renal dysfunction and young patients.14 In all cases, ACV-induced encephalopathy developed owing to the ACV or VACV treatment for herpes simplex or zoster virus. There were no reports that ACV-induced encephalopathy developed with prophylactic administration. Myeloma kidney with Bence–Jones proteinuria causes kidney renal tubular damage, which is disproportionate to the degree of renal impairment suggested by the creatinine level. Thus, it is presumed that it inhibits the excretion of drugs, including ACV, in renal tubules, resulting in an elevated blood concentration. It is difficult to measure ACV and CMMG blood levels. Therefore, even with the recommended level of ACV or VACV prophylaxis for renal impairment, it is not possible to predict ACV neurotoxicity, such as impaired consciousness and impaired renal function.
In conclusion, among patients with multiple myeloma with Bence–Jones proteinuria, the renal tubules are easily damaged, and the plasma concentration of ACV is likely to increase and induce ACV neurotoxicity. Careful monitoring of the level of consciousness is necessary during preventive ACV therapy in patients with renal dysfunction.
Abbreviations
ACV, acyclovir; BD, bortezomib/dexamethasone; CMMG, 9-carboxymethoxymethylguanine; VACV, valacyclovir.
Data Sharing Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Consent for Publication
Written informed consent was obtained from the patient for the publication of this case report and accompanying images.
Author Contributions
All authors contributed to the conception, study design, execution, acquisition of data, analysis and interpretation, drafting and revising the article, and critically reviewing the article; provided final approval of the version to be published; and agreed to be accountable for all aspects of the work.
Disclosure
The authors declare that they have no conflicts of interest. | ON DAYS 1, 4, 8 AND 11 | DrugDosageText | CC BY-NC | 33603447 | 19,085,824 | 2021 |
What was the dosage of drug 'DEXAMETHASONE'? | Encephalopathy Induced by Preventive Administration of Acyclovir in a Man with Symptomatic Multiple Myeloma and Renal Dysfunction.
Acyclovir (ACV) neurotoxicity is a neuropsychiatric condition induced by the anti-herpetic drugs ACV and valacyclovir (VACV). It is presumed that elevated blood levels of ACV and its metabolite 9-carboxymethoxymethylguanine are involved in the development of ACV-induced encephalopathy; age and renal dysfunction are risk factors. Here, we report a case of encephalopathy caused by the administration of VACV for herpes zoster prophylaxis in a patient with renal dysfunction owing to multiple myeloma.
Renal dysfunction was diagnosed in a 70-year-old man visiting our hospital for a medical checkup. His creatinine clearance rate was 8 mL/min. He was diagnosed with symptomatic multiple myeloma, and bortezomib/dexamethasone (BD) therapy for multiple myeloma and VACV for herpes zoster prophylaxis were initiated. We administered 500 mg/day of VACV three times a week, a lower dosage than recommended, after adjusting for his renal impairment. His renal function was monitored twice per week during therapy. During the second course of BD therapy, 6 weeks after starting treatment, he was hospitalized owing to impaired consciousness (Glasgow Coma Scale score: E2, V4, M4), and his BD and VACV therapy were suspended. Brain magnetic resonance imaging and cerebrospinal fluid analysis showed no abnormalities. Three days after discontinuing BD and VACV therapy, his consciousness recovered completely, and impaired consciousness did not recur after resuming BD therapy. His clinical diagnosis was thus ACV-induced encephalopathy.
VACV is often prescribed to patients with multiple myeloma receiving BD therapy to prevent herpes zoster. ACV-induced encephalopathy is commonly observed in patients with renal dysfunction; especially among patients with multiple myeloma with Bence-Jones proteinuria, renal tubules are easily damaged and plasma ACV concentrations are likely to increase and induce ACV-induced encephalopathy. Careful monitoring of the level of consciousness is necessary during preventive ACV therapy in patients with renal dysfunction.
Introduction
Acyclovir (ACV) neurotoxicity is a neuropsychiatric condition induced by the administration of the anti-herpetic drugs ACV and valacyclovir (VACV).1 VACV is the prodrug of ACV. Usually, various neuropsychiatric symptoms, such as disturbance of consciousness, tremor, and myoclonus, occur within 2 days after initiating the therapy.1–3 Hallucinations are also common.1–3 It is presumed that elevated blood levels of ACV and its metabolite, 9-carboxymethoxymethylguanine (CMMG), are involved in the development of ACV-induced encephalopathy4 and that age and renal dysfunction are risk factors.5
Bortezomib/dexamethasone (BD) therapy is one of the standard regimens for patients with symptomatic multiple myeloma who have severe renal impairment.6 In bortezomib-containing regimens, low-dose oral ACV is recommended for herpes zoster prophylaxis.7,8
We present a case of encephalopathy caused by the administration of VACV for herpes zoster prophylaxis in a patient with renal dysfunction due to multiple myeloma.
Case Presentation
Renal dysfunction was diagnosed in a 70-year-old man who visited our hospital for a medical checkup. His serum creatinine level and creatinine clearance rate were 8.78 mg/dL (normal range: 0.53–1.02 mg/dL) and 8 mL/min (normal range: 80–180 mL/min), respectively. He was diagnosed with Bence–Jones protein λ-type multiple myeloma based on the presence of 40% plasma cells in his bone marrow (10% or more of plasma cells is considered definitive of the disease) and Bence–Jones proteinuria (M proteinuria of 4.8 g/day). Additionally, the diagnosis of symptomatic multiple myeloma (International Staging System stage 3) was based on the presence of renal dysfunction. Renal biopsy revealed cast nephropathy known as myeloma kidney, in which large amounts of Bence–Jones proteins formed casts that blocked the tubules (Figure 1). BD therapy was initiated with concurrent VACV for herpes zoster prophylaxis. We administered a reduced dose VACV of 500 mg three times a week because of the patient’s renal impairment, based on the drug information on VACV provided in the UpToDate database.9 His renal function was monitored twice per week during therapy. Six weeks later, during his second course of BD therapy, the patient was hospitalized because of impaired consciousness. He displayed no other symptoms during hospitalization.Figure 1 Histology of kidney tissue showing myeloma cast nephropathy. (A) Hematoxylin and eosin stain (magnification ×200). (B) Periodic acid-Schiff stain (magnification ×400).
On admission, his vital signs were as follows: Glasgow Coma Scale score, E2, V4, M4; body temperature, 36.5°C; blood pressure, 145/79 mmHg; pulse rate, 73 beats/min; respiratory rate, 15 breaths/min; and SpO2, 96%. His vital signs were normal, and there were no remarkable neurological abnormalities except for disturbance of consciousness. Table 1 summarizes the results of patient’s blood test on admission. The results, including renal function, were unchanged. Brain magnetic resonance imaging and cerebrospinal fluid analysis—cell counts 1/µL, protein 40 mg/dL, glucose 98 mg/dL, reference blood glucose level 125 mg/dL—revealed no abnormalities. There was no new electrolyte, endocrine hormone abnormality, or suggestion of epilepsy. Therefore, we suspected drug-induced disturbance of consciousness and suspended the BD and VACV therapy. Three days after discontinuing the drugs, his level of consciousness returned to normal, and the BD therapy was restarted after 20 days of drug interruption. The Naranjo score10 for estimating the probability of adverse drug reactions was 7 points. In this scoring system, ≥ 9 points indicate “high probability for adverse reactions” and 5–8 points indicate “probability for adverse reactions”.10 In all Japan, the laboratories do not have facilities to measure ACV/CMMG levels. Though his blood level of ACV could not be measured, the clinical diagnosis was ACV neurotoxicity based on his response to the suspension of the therapy, the high Naranjo score, and the lack of other contributing factors. We theorized that ACV blood levels gradually increased over the long-term administration of oral VACV owing to renal dysfunction. Figure 2 illustrates his clinical course.Table 1 Results of the Patient’s Admission Blood Tests
Parameters Result Reference Range
White blood cell count 15.278 × 103/µL 4.50–7.50 × 103/µL
Neutrophils 89.2%
Lymphocytes 5.8%
Hemoglobin 7.2 g/dL 11.3–15.2 g/dL
Hematocrit 21.7% 36–45%
Platelets 173 × 103/µL 130–350 × 103/µL
C-reactive protein 0.06 mg/dL ≤0.60 mg/dL
Total protein 6.7 g/dL 6.9–8.4 g/dL
Albumin 3.9 g/dL 3.9–5.1 g/dL
Aspartate aminotransferase 15 U/L 11–30 U/L
Alanine aminotransferase 15 U/L 4–30 U/L
Lactate dehydrogenase 235 U/L 109–216 U/L
Creatine phosphokinase 55 U/L 40–150 U/L
Blood nitrogen urea 69.7 mg/dL 8–20 mg/dL
Creatinine 7.71 mg/dL 0.63–1.03 mg/dL
Creatinine clearance 8.8 mL/min >60 mL/min
Sodium 136 mEq/L 136–148 mEq/L
Potassium 4.6 mEq/L 3.6–5.0 mEq/L
Glucose 155 mg/dL 70–109 mg/dL
Figure 2 Clinical course of the patient after starting bortezomib/dexamethasone therapy. BD therapy: Bortezomib was administered at a dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 with dexamethasone (20 mg) administered on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12. The 21-day regimen administered in 2 cycles was defined as 1 course.
The patient underwent 9 cycles of BD therapy and achieved complete remission. We administered 250 mg of famciclovir for herpes zoster prophylaxis, three times a week, between cycles 4 to 9. One year after the end of treatment, he remained in remission. His creatinine level recovered and remained stable at 4–5 mg/dL in response to the treatment. He did not exhibit any sequelae of ACV encephalopathy.
Discussion
We presented a case of ACV-induced encephalopathy caused by the administration of VACV for herpes zoster during the treatment of multiple myeloma in a man with renal dysfunction. To the best of our knowledge, this is the first report of ACV neurotoxicity in a patient taking low-dose VACV for herpes zoster prophylaxis. This case illustrates that ACV or VACV should be used with caution in patients with myeloma-associated renal dysfunction, even if used in low doses for herpes zoster prophylaxis.
In all Japan, the laboratories do not have facilities to measure ACV/CMMG levels. However, we diagnosed ACV-induced encephalopathy based on his clinical course, the high Naranjo score, the lack of other contributing factors. ACV or VACV can cause renal tubular obstruction secondary to crystal-induced nephropathy, and direct action of the ACV aldehyde can cause acute kidney injury; these can lead to increased blood concentrations of ACV and CMMG and cause encephalopathy.2,11 In this case, our patient exhibited Bence–Jones proteinuria. Increased excretion of Bence–Jones proteins may have damaged the tubular epithelium or formed casts that blocked the renal tubules, leading to myeloma cast nephropathy. It is the most common cause of myeloma-associated renal injury and may cause renal dysfunction.12,13 Though the renal dysfunction in our patient was stable at a low level, we theorized that long-term preventive oral VACV therapy gradually led to increased plasma concentrations of ACV and CMMG, resulting in encephalopathy.
In this case, the VACV prophylaxis resulted in ACV-induced encephalopathy, even though we administered it at a dose lower than the recommended dose for patients with renal dysfunction. ACV-induced encephalopathy has been observed in patients administered with extremely high doses (10 mg/kg every hour) of the drug or in cases of renal failure without dose adjustment.4 It has often been reported in elderly people and patients with impaired renal function,5 but it has occurred in patients without renal dysfunction and young patients.14 In all cases, ACV-induced encephalopathy developed owing to the ACV or VACV treatment for herpes simplex or zoster virus. There were no reports that ACV-induced encephalopathy developed with prophylactic administration. Myeloma kidney with Bence–Jones proteinuria causes kidney renal tubular damage, which is disproportionate to the degree of renal impairment suggested by the creatinine level. Thus, it is presumed that it inhibits the excretion of drugs, including ACV, in renal tubules, resulting in an elevated blood concentration. It is difficult to measure ACV and CMMG blood levels. Therefore, even with the recommended level of ACV or VACV prophylaxis for renal impairment, it is not possible to predict ACV neurotoxicity, such as impaired consciousness and impaired renal function.
In conclusion, among patients with multiple myeloma with Bence–Jones proteinuria, the renal tubules are easily damaged, and the plasma concentration of ACV is likely to increase and induce ACV neurotoxicity. Careful monitoring of the level of consciousness is necessary during preventive ACV therapy in patients with renal dysfunction.
Abbreviations
ACV, acyclovir; BD, bortezomib/dexamethasone; CMMG, 9-carboxymethoxymethylguanine; VACV, valacyclovir.
Data Sharing Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Consent for Publication
Written informed consent was obtained from the patient for the publication of this case report and accompanying images.
Author Contributions
All authors contributed to the conception, study design, execution, acquisition of data, analysis and interpretation, drafting and revising the article, and critically reviewing the article; provided final approval of the version to be published; and agreed to be accountable for all aspects of the work.
Disclosure
The authors declare that they have no conflicts of interest. | ON DAYS 1 AND 2, 4 AND 5, 8 AND 9, AND 11 AND 12 | DrugDosageText | CC BY-NC | 33603447 | 19,085,824 | 2021 |
What was the outcome of reaction 'Toxic encephalopathy'? | Encephalopathy Induced by Preventive Administration of Acyclovir in a Man with Symptomatic Multiple Myeloma and Renal Dysfunction.
Acyclovir (ACV) neurotoxicity is a neuropsychiatric condition induced by the anti-herpetic drugs ACV and valacyclovir (VACV). It is presumed that elevated blood levels of ACV and its metabolite 9-carboxymethoxymethylguanine are involved in the development of ACV-induced encephalopathy; age and renal dysfunction are risk factors. Here, we report a case of encephalopathy caused by the administration of VACV for herpes zoster prophylaxis in a patient with renal dysfunction owing to multiple myeloma.
Renal dysfunction was diagnosed in a 70-year-old man visiting our hospital for a medical checkup. His creatinine clearance rate was 8 mL/min. He was diagnosed with symptomatic multiple myeloma, and bortezomib/dexamethasone (BD) therapy for multiple myeloma and VACV for herpes zoster prophylaxis were initiated. We administered 500 mg/day of VACV three times a week, a lower dosage than recommended, after adjusting for his renal impairment. His renal function was monitored twice per week during therapy. During the second course of BD therapy, 6 weeks after starting treatment, he was hospitalized owing to impaired consciousness (Glasgow Coma Scale score: E2, V4, M4), and his BD and VACV therapy were suspended. Brain magnetic resonance imaging and cerebrospinal fluid analysis showed no abnormalities. Three days after discontinuing BD and VACV therapy, his consciousness recovered completely, and impaired consciousness did not recur after resuming BD therapy. His clinical diagnosis was thus ACV-induced encephalopathy.
VACV is often prescribed to patients with multiple myeloma receiving BD therapy to prevent herpes zoster. ACV-induced encephalopathy is commonly observed in patients with renal dysfunction; especially among patients with multiple myeloma with Bence-Jones proteinuria, renal tubules are easily damaged and plasma ACV concentrations are likely to increase and induce ACV-induced encephalopathy. Careful monitoring of the level of consciousness is necessary during preventive ACV therapy in patients with renal dysfunction.
Introduction
Acyclovir (ACV) neurotoxicity is a neuropsychiatric condition induced by the administration of the anti-herpetic drugs ACV and valacyclovir (VACV).1 VACV is the prodrug of ACV. Usually, various neuropsychiatric symptoms, such as disturbance of consciousness, tremor, and myoclonus, occur within 2 days after initiating the therapy.1–3 Hallucinations are also common.1–3 It is presumed that elevated blood levels of ACV and its metabolite, 9-carboxymethoxymethylguanine (CMMG), are involved in the development of ACV-induced encephalopathy4 and that age and renal dysfunction are risk factors.5
Bortezomib/dexamethasone (BD) therapy is one of the standard regimens for patients with symptomatic multiple myeloma who have severe renal impairment.6 In bortezomib-containing regimens, low-dose oral ACV is recommended for herpes zoster prophylaxis.7,8
We present a case of encephalopathy caused by the administration of VACV for herpes zoster prophylaxis in a patient with renal dysfunction due to multiple myeloma.
Case Presentation
Renal dysfunction was diagnosed in a 70-year-old man who visited our hospital for a medical checkup. His serum creatinine level and creatinine clearance rate were 8.78 mg/dL (normal range: 0.53–1.02 mg/dL) and 8 mL/min (normal range: 80–180 mL/min), respectively. He was diagnosed with Bence–Jones protein λ-type multiple myeloma based on the presence of 40% plasma cells in his bone marrow (10% or more of plasma cells is considered definitive of the disease) and Bence–Jones proteinuria (M proteinuria of 4.8 g/day). Additionally, the diagnosis of symptomatic multiple myeloma (International Staging System stage 3) was based on the presence of renal dysfunction. Renal biopsy revealed cast nephropathy known as myeloma kidney, in which large amounts of Bence–Jones proteins formed casts that blocked the tubules (Figure 1). BD therapy was initiated with concurrent VACV for herpes zoster prophylaxis. We administered a reduced dose VACV of 500 mg three times a week because of the patient’s renal impairment, based on the drug information on VACV provided in the UpToDate database.9 His renal function was monitored twice per week during therapy. Six weeks later, during his second course of BD therapy, the patient was hospitalized because of impaired consciousness. He displayed no other symptoms during hospitalization.Figure 1 Histology of kidney tissue showing myeloma cast nephropathy. (A) Hematoxylin and eosin stain (magnification ×200). (B) Periodic acid-Schiff stain (magnification ×400).
On admission, his vital signs were as follows: Glasgow Coma Scale score, E2, V4, M4; body temperature, 36.5°C; blood pressure, 145/79 mmHg; pulse rate, 73 beats/min; respiratory rate, 15 breaths/min; and SpO2, 96%. His vital signs were normal, and there were no remarkable neurological abnormalities except for disturbance of consciousness. Table 1 summarizes the results of patient’s blood test on admission. The results, including renal function, were unchanged. Brain magnetic resonance imaging and cerebrospinal fluid analysis—cell counts 1/µL, protein 40 mg/dL, glucose 98 mg/dL, reference blood glucose level 125 mg/dL—revealed no abnormalities. There was no new electrolyte, endocrine hormone abnormality, or suggestion of epilepsy. Therefore, we suspected drug-induced disturbance of consciousness and suspended the BD and VACV therapy. Three days after discontinuing the drugs, his level of consciousness returned to normal, and the BD therapy was restarted after 20 days of drug interruption. The Naranjo score10 for estimating the probability of adverse drug reactions was 7 points. In this scoring system, ≥ 9 points indicate “high probability for adverse reactions” and 5–8 points indicate “probability for adverse reactions”.10 In all Japan, the laboratories do not have facilities to measure ACV/CMMG levels. Though his blood level of ACV could not be measured, the clinical diagnosis was ACV neurotoxicity based on his response to the suspension of the therapy, the high Naranjo score, and the lack of other contributing factors. We theorized that ACV blood levels gradually increased over the long-term administration of oral VACV owing to renal dysfunction. Figure 2 illustrates his clinical course.Table 1 Results of the Patient’s Admission Blood Tests
Parameters Result Reference Range
White blood cell count 15.278 × 103/µL 4.50–7.50 × 103/µL
Neutrophils 89.2%
Lymphocytes 5.8%
Hemoglobin 7.2 g/dL 11.3–15.2 g/dL
Hematocrit 21.7% 36–45%
Platelets 173 × 103/µL 130–350 × 103/µL
C-reactive protein 0.06 mg/dL ≤0.60 mg/dL
Total protein 6.7 g/dL 6.9–8.4 g/dL
Albumin 3.9 g/dL 3.9–5.1 g/dL
Aspartate aminotransferase 15 U/L 11–30 U/L
Alanine aminotransferase 15 U/L 4–30 U/L
Lactate dehydrogenase 235 U/L 109–216 U/L
Creatine phosphokinase 55 U/L 40–150 U/L
Blood nitrogen urea 69.7 mg/dL 8–20 mg/dL
Creatinine 7.71 mg/dL 0.63–1.03 mg/dL
Creatinine clearance 8.8 mL/min >60 mL/min
Sodium 136 mEq/L 136–148 mEq/L
Potassium 4.6 mEq/L 3.6–5.0 mEq/L
Glucose 155 mg/dL 70–109 mg/dL
Figure 2 Clinical course of the patient after starting bortezomib/dexamethasone therapy. BD therapy: Bortezomib was administered at a dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 with dexamethasone (20 mg) administered on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12. The 21-day regimen administered in 2 cycles was defined as 1 course.
The patient underwent 9 cycles of BD therapy and achieved complete remission. We administered 250 mg of famciclovir for herpes zoster prophylaxis, three times a week, between cycles 4 to 9. One year after the end of treatment, he remained in remission. His creatinine level recovered and remained stable at 4–5 mg/dL in response to the treatment. He did not exhibit any sequelae of ACV encephalopathy.
Discussion
We presented a case of ACV-induced encephalopathy caused by the administration of VACV for herpes zoster during the treatment of multiple myeloma in a man with renal dysfunction. To the best of our knowledge, this is the first report of ACV neurotoxicity in a patient taking low-dose VACV for herpes zoster prophylaxis. This case illustrates that ACV or VACV should be used with caution in patients with myeloma-associated renal dysfunction, even if used in low doses for herpes zoster prophylaxis.
In all Japan, the laboratories do not have facilities to measure ACV/CMMG levels. However, we diagnosed ACV-induced encephalopathy based on his clinical course, the high Naranjo score, the lack of other contributing factors. ACV or VACV can cause renal tubular obstruction secondary to crystal-induced nephropathy, and direct action of the ACV aldehyde can cause acute kidney injury; these can lead to increased blood concentrations of ACV and CMMG and cause encephalopathy.2,11 In this case, our patient exhibited Bence–Jones proteinuria. Increased excretion of Bence–Jones proteins may have damaged the tubular epithelium or formed casts that blocked the renal tubules, leading to myeloma cast nephropathy. It is the most common cause of myeloma-associated renal injury and may cause renal dysfunction.12,13 Though the renal dysfunction in our patient was stable at a low level, we theorized that long-term preventive oral VACV therapy gradually led to increased plasma concentrations of ACV and CMMG, resulting in encephalopathy.
In this case, the VACV prophylaxis resulted in ACV-induced encephalopathy, even though we administered it at a dose lower than the recommended dose for patients with renal dysfunction. ACV-induced encephalopathy has been observed in patients administered with extremely high doses (10 mg/kg every hour) of the drug or in cases of renal failure without dose adjustment.4 It has often been reported in elderly people and patients with impaired renal function,5 but it has occurred in patients without renal dysfunction and young patients.14 In all cases, ACV-induced encephalopathy developed owing to the ACV or VACV treatment for herpes simplex or zoster virus. There were no reports that ACV-induced encephalopathy developed with prophylactic administration. Myeloma kidney with Bence–Jones proteinuria causes kidney renal tubular damage, which is disproportionate to the degree of renal impairment suggested by the creatinine level. Thus, it is presumed that it inhibits the excretion of drugs, including ACV, in renal tubules, resulting in an elevated blood concentration. It is difficult to measure ACV and CMMG blood levels. Therefore, even with the recommended level of ACV or VACV prophylaxis for renal impairment, it is not possible to predict ACV neurotoxicity, such as impaired consciousness and impaired renal function.
In conclusion, among patients with multiple myeloma with Bence–Jones proteinuria, the renal tubules are easily damaged, and the plasma concentration of ACV is likely to increase and induce ACV neurotoxicity. Careful monitoring of the level of consciousness is necessary during preventive ACV therapy in patients with renal dysfunction.
Abbreviations
ACV, acyclovir; BD, bortezomib/dexamethasone; CMMG, 9-carboxymethoxymethylguanine; VACV, valacyclovir.
Data Sharing Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Consent for Publication
Written informed consent was obtained from the patient for the publication of this case report and accompanying images.
Author Contributions
All authors contributed to the conception, study design, execution, acquisition of data, analysis and interpretation, drafting and revising the article, and critically reviewing the article; provided final approval of the version to be published; and agreed to be accountable for all aspects of the work.
Disclosure
The authors declare that they have no conflicts of interest. | Recovered | ReactionOutcome | CC BY-NC | 33603447 | 19,085,824 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment noncompliance'. | Evidence of Nonadherence in Cases of Pseudoresistant Hypertension.
Resistant hypertension (RH) is characterized by the use of three or more antihypertensive drugs without reaching the goal of controlling blood pressure (BP). For a definitive diagnosis of RH, it is necessary to exclude causes of pseudoresistance, including the white-coat effect, errors in BP measurement, secondary hypertension, therapeutic inertia, and poor adherence to lifestyle changes and pharmacological treatment. Herein, we report the history of a patient with long-standing uncontrolled BP, even when using seven antihypertensive drugs. Causes of secondary hypertension that justified the high BP levels were investigated, in addition to the other causes of pseudo-RH. In view of the difficult-to-control BP situation, it was decided to hospitalize the patient for better investigation. After 5 days, he had BP control with practically the same medications previously used. Finally, all factors related to the presence of pseudo-RH are discussed, especially poor adherence to treatment. Poor adherence to antihypertensive treatment is common in daily medical practice, and its investigation is of fundamental importance for better management of BP.
Introduction
Globally, hypertension is one of the most important risk factors of cardiovascular disease, stroke, chronic kidney disease, incapacity, and death.1 It is highly prevalent, and as such deserves attention from health professionals with regard to proper diagnosis and handling, with the aim of controlling blood pressure (BP) levels. Its prevalence is estimated to be around 31% in the Brazilian population when considering hypertension with BP values ≥140/90 mmHg.2,3 If we take into consideration the last US guideline that considers hypertension with BP levels ≥130/80 mmHg, prevalence in the US population is 46%, according to NHANES (2013–2016).1,4
Nowadays, even with modern antihypertensive therapy, there is a form of presentation of hypertension in which BP control is not achieved, known as resistant hypertension (RH). It is defined as BP remaining above the recommended targets with the use of three or more antihypertensives of different classes, including a renin–angiotensin system blocker (angiotensin-converting enzyme inhibitor) or angiotensin-receptor blocker), a long-acting calcium channel blocker, and a long-acting thiazide diuretic, all at maximum recommended and tolerated doses, with appropriate frequency, dosage, and proven adherence by the patient.5,6
RH individuals represent a group at higher risk of target-organ damage, cardiovascular morbidity, and mortality. In 2012, the Brazilian Society of Cardiology issued its first position on RH, which included recommendations for diagnosis, evaluation, and treatment.7 Since then, a large number of studies on RH have improved our understanding of its pathogenesis, evaluation, and treatment, and new statements of position have been published.5,6 Nevertheless, the real prevalence of RH remains still controversial, mainly because of the difficulty in identifying cases of “pseudoresistance”.8,9
For correct diagnosis of RH, it is necessary to rule out factors that may interfere with BP control, such as accuracy of BP measurement, white-coat effect, adherence to pharmacological and nonpharmacological treatment, inadequate therapeutic regimen, and therapeutic inertia, in addition to the use of medications that increase BP and causes of secondary hypertension.5,6 As such, the first step in the correct diagnosis of true RH is to exclude these factors.Among them, pharmacological nonadherence is a well-known and highly prevalent behavioral cause of poor BP control.10–15
Medication adherence is defined as the process by which patients take their medications as prescribed, and comprises three components: initiation, implementation, and discontinuation.16 Initiation is the time from prescription until the first dose of the medication is taken. The implementation of the doses corresponds to day-to day-execution, ie, it reflects the daily use of medications. In turn, discontinuation represents the end of therapy, when the patient does not take the next dose and the treatment is interrupted thereafter. Finally, persistence is the length of time between initiation and the last dose immediately preceding discontinuation.16 Thenceforward, three major types of deviations from given instructions can occur and are particularly common: noninitiation, short persistence, and poor execution.15,17 Generally, poor execution is a typical consequence of occasional forgetfulness or negligence, results in more or less prolonged periods of treatment interruptions characterizing unintentional nonadherence, and represents a majority of cases. Usually, unintentional nonadherence results from a lack of understanding or other educational, mental, or physical personal problems. On the other hand, intentional nonadherence is an active process in which an individual actively or consciously chooses to forego prescribed antihypertensive drugs (either to skip some doses, modify, or discontinue).15,17,18 All these aspects of adherence to medication have a direct and major influence on the quality of BP control in RH, the most critical being of course noninitiation and a lack of persistence.15 In the specific case of antihypertensive drugs in pseudo-RH, intentional nonadherence easily escapes detection and can be costly to diagnose and to correct.17
Nowadays, indirect and direct methods are used for assessment of nonadherence to BP-lowering drugs. Indirect methods are less invasive and cheaper. They include patient interviews, patient diaries, questionnaires, self-reports, pill count, assessment of the patient’s response, measurement of physiological markers, review of prescriptions, and electronic medication monitoring.15,17,19,20 In turn, direct methods are more invasive and expensive, and include the direct observation of patients during the use of lowering-BP drugs and measurement of levels of antihypertensive drugs or their metabolites in the blood or in the urine.15,17,19,20 This case report discusses several stages of clinical investigation and complementary exams that must be performed, including nonadherence assessment, which are fundamental tasks for the diagnosis of pseudoresistance to treatment.
Case Report
The patient was a 56-year-old white woman with a 4-year history of hypertension with uncontrolled BP. In addition, she had had Hashimoto’s thyroiditis for about 10 years. She denied a history of smoking or drinking. She was taking valsartan (320 mg/day), hydrochlorothiazide (75 mg/day), methyldopa (1,500 mg/day), atenolol (100 mg/day), spironolactone (25 mg/day), and levothyroxine sodium (300 µg/day) at initial consultation. She was intolerant to angiotensin-converting enzyme inhibitors because of cough and amlodipine due to lower-limb edema. The patient told us that she was taking all the medications correctly. The degree of adherence was determined using the eight-item Morisky Medication Adherence Scale (MMAS8) translated into Brazilian Portuguese, and the patient was considered to have high adherence (eight points) on this test.21–23
Her physical examination revealed BP 230/160 mmHg (mean of three measures) in both arms, heart rate 80 bpm, body mass index 29.3 kg/m2, and waist circumference 94 cm. The BP measure in the lower limbs did not show a significant difference in relation to upper limbs. She had no abnormalities of the heart, lungs, or abdomen. According to initial complementary exams, the patient presented fasting glycemia 101 mg/dL, sodium 142 mEq/L, potassium 4.4 mEq/L, creatinine 0.8 mg/dL, estimated glomerular filtration rate (CKD-EPI) 89.3 mL/min/1.73 m2, normal routine urine, microalbuminuria 230 mg/24 h (normal <30 mg/24 h), total cholesterol 148 mg/dL, HDL cholesterol 38 mg/dL, LDL cholesterol 86 mg/dL, and triglycerides 122 mg/dL. The 24-hour urinary sodium measure was 164 mEq/L (ideal level <100 mEq/L). Other exam results were thyroid-stimulating hormone 40.89 mU/L, free T4 0.75 ng/dL, parathyroid hormone 58.86 pg/mL (normal 10–65 pg/mL), vitamin D 30.8 ng/mL, and serum calcium 9.2 mg/dL (normal 8–10 mg/dL).
Electrocardiography was normal, with sinus rhythm and heart rate of 74 bpm. Echocardiography showed structural and functional normality. Ambulatory BP monitoring (ABPM) revealed 24-hour mean BP of 204/130 mmHg, awake BP of 207/133 mmHg, and 193/122 mmHg BP during sleep, with attenuated nocturnal dipping in systolic and diastolic BP. The patient had hypertensive retinopathy (grade 2 Keith–Wagener–Barker classification). All investigations for secondary hypertension were negative. Therefore, primary hyperaldosteronism, renovascular hypertension, renal disease, obstructive sleep apnea, pheochromocytoma, acromegaly, and Cushing’s disease were excluded, as shown in Table 1. Four weeks prior to investigation for hyperaldosteronism, her thiazide diuretic, renin–angiotensin system blocker, and mineralocorticoid-receptor antagonist were stopped for screening this condition, in accordance with guidelines.4–6Table 1 Results of Investigation of Secondaryµ Hypertension
Result Reference
Aldosterone 12.5 ng/dL 3.4–27.3 ng/dL
Plasma renin activity (PRA) 1.6 ng/mL/h 0.5–6 ng/mL/h
Aldosterone:PRA ratio 7.81 <27
Urinary metanephrine 212.2 µg/24h <280 µg/24h
Urinary normetanephrine 417.9 µg/24h <732 µg/24h
Plasma adrenaline 10.6 pg/mL <90 pg/mL
Plasma noradrenaline 100.6 pg/mL <460 pg/mL
Plasma dopamine 30.1 pg/mL <30 pg/mL
Cortisol 8.04 µg/dL 6.2–19.4
Growth hormone 0.12 ng/mL <3.61 ng/mL
IFG1 (somatomedin) 116 ng/mL 123–406 ng/mL
Renal ultrasonography Normal —
Renal Doppler velocimetry Normal —
Polysomnography Normal —
During outpatient follow-up, hydrochlorothiazide was exchanged for chlorthalidone (25 mg/day), and nitrendipine (20 mg/day) was added to her antihypertensive treatment. Nevertheless, the patient had several BP elevations of up to 290/180 mmHg and a hospital admission with hypertensive encephalopathy, even with the use of valsartan (320 mg/day), chlortalidone (25 mg/day), nitrendipine (20 mg/day), methyldopa (1,500 mg/day), atenolol (100 mg/day), and spironolactone (150 mg/day). Moreover, she was also using diazepam (10 mg/day) and levothyroxine sodium (300 µg/day). On hospital discharge, methyldopa was exchanged for clonidine (600 µg/day), and hydralazine (150 mg/day) was added to the therapy regimen.
A careful interview and investigation of nonadherence was performed, and given that the patient stated that she had taken all the prescribed medications, a hypothesis of intestinal absorption disturbance was arrived at as the cause of the lack of control of hypertension and thyroid function. However, all functional, anatomic, and histopathologic investigation for malabsorption syndromes gave negative results (upper digestive endoscopy and colonoscopy, both with normal biopsies, antitissue transglutaminase IgA and IgG antibodies and antigliadin IgA antibodies were nonreagents upon testing for celiac disease).
Considering the difficulty in controlling the hypertension and due to the high cardiovascular risk presented by the patient (target-organ damage), the team opted to hospitalize her for the purpose of observing her evolution and performing other investigations. The usual biochemical tests were normal. She maintained her previous weight. During the hospitalization, there was a progressive control of BP levels around the fifth day of admission with administration of the same drugs previously used by the patient (valsartan 320 mg/day, chlortalidone 25 mg/day, nitrendipine 20 mg/day, atenolol 100 mg/day, clonidine (600 µg/day, hydralazine (150 mg/day, and spironolactone 150 mg/day); Figure 1). She was discharged after 10 days with controlled BP. The patient was referred for psychiatric evaluation, where she was diagnosed with recurrent depressive disorder and medicated. Subsequently, she was referred for follow-up with psychology. About 30 days after discharge, BP remained high with the same drugs used in hospital.Figure 1 Evolution of systolic blood pressure (solid line), diastolic blood pressure (dashed line), and heart rate (gray line) in hospital.
Discussion
In the present report, we discuss the case of a middle-aged female patient with a history of uncontrolled hypertension in the long term and all the diagnostic steps involved in the investigation of RH with the exclusion of confounding factors, including causes of pseudoresistance. It is common to find individuals with elevated BP in an outpatient clinic specialized in hypertension, even when using three or more antihypertensive drugs, a fact that fulfills the initial definition of RH and is compatible with the description of the patient, who was using five antihypertensive drugs. Therefore, for true RH diagnosis, it was necessary to exclude causes of pseudoresistance following diagnostic investigation (Table 2). Pseudo-RH is attributed to six principal etiologies — white-coat effect, errors in BP measurement, failure of drug prescription, use of drugs that increase BP, poor adhesion to lifestyle changes, and pharmacological treatment — besides the presence of secondary hypertension causes.Table 2 Steps in the Diagnostic Assessment of Resistant Hypertension to Exclude Pseudoresistance to Treatment
To Investigate
1. ABPM/HBPM White-coat effect
2. BP-measurement technique Measure errors
Cuff size
3. Medical prescription Inadequate combinations
Inappropriate doses
4. Drugs that increase BP Nonsteroidal anti-inflammatories
Corticosteroids
Sympathomimetics
Amphetamines
Oral contraceptives
Cyclosporine, tacrolimus
Recombinant human erythropoietin
Licorice
Cocaine
5. Nonadherence Lifestyle changes
Pharmacological treatment
6. Secondary hypertension Specific tests
7. General biochemical exams Sodium, potassium
Creatinine (and eGFR)
Glycemia (and HbA1c for diabetes)
Lipids
Routine urine
24-hour urinary sodium
Microalbuminuria
TSH, free thyroxine
Abbreviations: ABPM/HBPM, ambulatory BP monitoring/home BP monitoring; BP, blood pressure; eGFR, estimated glomerular filtration rate (CKD-EPI); HbA1c, glycated hemoglobin; TSH, thyroid-stimulating hormone.
The first step in investigation of RH would be to request ABPM or home BPM, in order to evaluate the white-coat effect as a cause of pseudoresistance. The ABPM of our patient showed elevated BP levels during 24 hours awake and during sleep, a fact that excluded the white-coat effect. The nocturnal dipping was attenuated, and the BP means in all the periods were above the recommended levels, according to guidelines. Studies have shown that 30%–50% of hypertensive individuals considered resistant in fact show a white-coat effect.24,25 Moreover, ABPM is important in performing therapeutic adjustment, detecting nondipper patterns (prognostic marker in RH), and introducing nightly doses of antihypertensive drugs (chronotherapy) to reverse the adverse pattern of nocturnal dipping.5,6,25–27 All these situations highlight the need to request ABPM or home BPM for individuals suspected of RH.
Secondly, errors in accuracy of BP measurements, which are mainly related to technical issues and the use of inadequately sized cuffs, should be observed carefully to avoid overestimating BP.5,6,28,29 Bhatt et al showed that approximately 33% of uncontrolled RH individuals were falsely identified as having RH based on triage BP measurements.30 The following procedures are fundamental steps for attaining the best accuracy in BP measurement.3–6,29 Measurements should be taken with a calibrated aneroid sphygmomanometer or automatic digital device. The cuff should be placed so that the lower edge is 3 cm above the elbow crease and the bladder centered over the brachial artery. A cuff compatible with the circumference of the arm should be used, considering that these patients are generally obese or overweight. Preferably, the arm should be bare and supported with the BP cuff positioned at heart level. A mean of three BP measurements taken in a sitting position after 5–10 minutes of rest should be performed. For aneroid sphygmomanometry, consider the phase I and V (disappearance) Korotkoff sounds to identify systolic and diastolic BP, respectively. Also, where an aneroid device is being used, the inflation pressure must reach 30 mmHg above the level at which the radial pulse is extinguished, and a cuff-deflation rate of 2 mmHg per beat must be used. A minimum of 1–2 minutes is recommended between readings to avoid venous congestion. BP should be measured in both arms to detect possible differences due to peripheral vascular disease.
In sequence, other causes that should be evaluated for a pseudoresistance diagnosis are failures in drug prescription with inadequate drug and dose combinations,28,31 especially subutilization of appropriate diuretics.32 Nevertheless, in the evolution of this case, the patient was using seven drugs with adequate doses, among them a thiazide diuretic (chlorthalidone) and spironolactone, which is considered the fourth drug for RH treatment.5,6 On the other hand, a report of drug-induced side effects or a clinical response to antihypertensive drugs may be proof that drugs have been taken.33 Therefore, in the present case, a β-blocker was prescribed; however, the patient’s ambulatory heart rate was >70 bpm, ie, she did not present bradycardia, possibly indicating nonadherence to treatment. Additionally, during the hospitalization, her heart rate reduced to <70 bpm, indicating clinical response to β-blocker use (Figure 1).
Drugs that increase BP should always be investigated and discontinued when possible. Other factors that are strong predictors of hypertension, such as excessive ingestion of salt, obesity, and physical inactivity, should also be monitored and lifestyle changes implemented.5,6,29 A DASH (dietary approaches to stop hypertension) diet, weight loss, and physical activity are important tools for improved BP control, but adherence is a difficult barrier to overcome.3–6 In the present report, the patient was overweight, and 24-hour urinary sodium was above the ideal level, showing that she had poor adherence to lifestyle changes.
During the investigation stages of true RH, it is also necessary to rule out causes of secondary hypertension. The most common etiologies were evaluated and discounted. chronic kidney disease was also ruled out, since renal function was normal (eGFR 89.3 mL/min/1.73 m2). In relation to biochemical tests performed since the basal evaluation, an important alteration in thyroid function was observed, indicating that it had not responded to the reposition with thyroid hormone. Thyroid hormones act on the cardiovascular system, promoting impact on cardiac function. Hypothyroidism is associated with decreased cardiac output because of impaired relaxation of vascular smooth muscle and decreased nitric oxide production. This leads to systemic vascular resistance increase and consequently increased diastolic BP.34 Nevertheless, from our point of view, hypothyroidism could not explain the high BP levels as the likely cause of secondary hypertension, since BP was controlled during the hospitalization, suggesting nonadherence to the use of medications, including the thyroid hormone.
In spite of the fact that the patient had no gastroenterology signals or symptoms, malabsorption syndrome was considered a possible justification for no responses to thyroid or hypertension treatment. However, the complementary investigation showed no alterations in functional or histopathologic gastrointestinal tract exams. Therefore, considering the high cardiovascular risk (target-organ damage and previous hypertensive emergency),35 the patient was admitted, in order to perform better investigation and improve BP control. As reported earlier, BP levels reduced progressively during the first 5 days, with BP controlled. From our perspective, this was evidence that the patient was not taking the drugs correctly, neither for hypertension nor hypothyroidism. Additionally, the low-sodium diet during hospitalization may have contributed to the reduction in BP. On the other hand, the BP control while in hospital also removes other reasons for the extremely elevated BP, including possible causes of secondary hypertension. Although a careful interview with the patient had been carried out to investigate adherence and she had stated that she was using the drugs correctly (high adherence to MMAS8 scale),21–23 there were probably errors in the use of the medications, due to forgetfulness, confusion or even the option of not using them, which is why we requested a follow-up with psychiatry/psychology. The patient was diagnosed with a psychiatric disorder, which could explain the nonadherence to lifestyle changes and pharmacological treatment.
RH is difficult to diagnose in daily medical practice; therefore, it is necessary to evaluate all the possible causes, including poor adherence to treatment. Drug nonadherence is highly relevant in cases of pseudo-RH. Indeed, when BP does not decrease despite the prescription of at least three antihypertensive drugs, including a diuretic, physicians face two major challenges: is the patient not responding to therapy, or is the patient not taking drugs as recommended, characterizing a nonadherer? True resistance to pharmacotherapy is relatively uncommon, a situation that led us to ask if drugs work in individuals who do not take them.17 Drug nonadherence is highly prevalent in patients with pseudo-RH, and it must also be excluded before definitive diagnosis of RH.10,11 Studies have shown that 50–80% of patients have no complete adherence.8,10,11 Our group has demonstrated that about 86% have presented poor adherence to both medication and nonmedication treatment, and emotional factors were the most reported (69.12%) among patients’ reasons for nonadherence to treatment36 a fact also observed in two European centers, which demonstrated that emotional impact was an important predictor of BP control.37
Several methods are used for assessment of adherence to BP-lowering drugs, but they have different degrees of accuracy. Figure 2 shows the indirect (noninvasive) and direct (invasive) methods used for evaluation of adherence to antihypertensive drugs.15,17,20 During the investigation of adherence to BP-lowering drugs, a careful patient interview is very important, including questionnaires and pill count, but questionnaires are known to be inaccurate, and in recent evaluations the ability of doctors to detect nonadherence is very low, compatible with another case report.17 On the other hand, therapeutic drug monitoring (TDM) is considered direct, invasive, and expensive, but most accurate method for evaluating intentional nonadherence. TDM measures the drug or metabolite (biomarkers) concentration in body fluids (blood or urine).15,17,20 For this objective, liquid chromatography–mass spectrometry analysis can be used.15,17,20 A recent study evaluated if there were concordance between TDM and self-reported adherence in individuals with RH, and no concordance was found, pointing to the low accuracy of the indirect method.12 However, TDM needs to be realized with the informed consent of patients and tends to induce white-coat adherence, ie, patients tend to increase adherence a few days before and after a consultation.15,17,20 This method is not available in our center.Figure 2 Methods of evaluation of drug adherence according to accuracy. The last three selected methods are considered invasive.
In following up this case, we used other direct methods to evaluate adherence to BP-lowering drugs, eg, directly observed therapy, which was originally developed for treatment of tuberculosis.38 With this method,15,17,20 the pharmacodynamic effect of administered BP-lowering drug is relatively easy to measure, simply by observing BP over time, since the peak effect on BP is within the first 3–4 hours, with gradual dissipation over the next 24–48 hours, quite suitable for diagnosis of intentional nonadherence to antihypertensive drugs. We advocate that hospitalization be used as a substitute, very similar to the original method, and this was the method that showed the nonadherence in our case.
Pharmacological nonadherence is related to several factors, such as the large pill, dosing complexity, costs, adverse reactions with multidrug antihypertensive regimens, bad patient–clinician relationships, and clinician inertia with reduced insistence on adherence when individuals present consistently suboptimal adherence.39,40 Other factors related to poor adherence are mainly old age and low education. Older individuals and those with low education have difficulty understanding the importance of following the advice of health professionals, as well as remembering the recommended dosage and correct times to take the pills.8,10,11,39,40 Our patient had not completed elementary education, which is in line with the literature.
Drug associations and the assistance of a multidisciplinary team capable of guiding appropriate use of medication and monitoring changes in lifestyle are often able to minimize this issue.3,4 Transparent clinician–patient discussion without blame, observation of prescription refills and tablet counts, hospitalization, and if possible biochemical assays of medications or their metabolites in urine or plasma must be part of nonadherence investigation. It is important to highlight that there is no gold standard for investigation of adherence, and to overcome each method’s limitations, a combination of measures should be used.15,17,20 Therefore, multifactorial conditions can be mitigated through health-education policies that value the instruction of individuals, using clear language and amusing material, if necessary, to explain the consequences of uncontrolled BP resulting from poor adherence to treatment. An effective doctor–patient relationship also presents an important strategy for winning over the patient and convincing them of the need for therapy, in addition to family involvement in the line of care, especially in the case of elderly patients.
Our patient did not have characteristics compatible with the typical presentation of RH, which occurs predominantly in men aged >55 years, in individuals who are black, have diabetes, are obese, or have stage 3 or higher chronic kidney disease.5,6,29 Considering the elevated BP levels in the office and on 24-hour ABPM, the optimized therapeutic strategies used in the prehospitalization treatment with consequent lack of BP control and the assessment of nonadherence using the inpatient (directly observed therapy method), with evident reduction in BP and heart rate, we can conclude that we were facing a case of pseudo-RH, due to the patient’s lack of adherence to drug treatment on a daily basis.
Consent Statement
We confirm that the patient provided informed consent for the case details to be published, and institutional approval was not required.
Acknowledgments
The authors wish to thank DE Morisky, who gave permission for use of the MMAS8 for this study.
The MMAS8 scale, content, name, and trademarks are protected by US copyright and trademark laws. Permission for use of the scale and its coding is required. A license agreement is available from MMAR, Donald E. Morisky, ScD, ScM, MSPH, 294 Lindura Court, Las Vegas, NV, USA, dmorisky@gmail.com.
Disclosure
The authors report no conflicts of interest in this work. | ATENOLOL, CHLORTHALIDONE, CLONIDINE, DIAZEPAM, HYDRALAZINE HYDROCHLORIDE, HYDROCHLOROTHIAZIDE, LEVOTHYROXINE SODIUM, METHYLDOPA, NITRENDIPINE, SPIRONOLACTONE, VALSARTAN | DrugsGivenReaction | CC BY-NC | 33603455 | 19,951,351 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | The Recurrent Liver Disorder of a Pregnant Mother: Intrahepatic Cholestasis of Pregnancy - A Case Report and Literature Review.
Intrahepatic cholestasis of pregnancy (ICP) is a form of liver disease which is unique to pregnancy with a worldwide prevalence ranging from 0.3% and 5.6% of pregnancies. It is presented with skin pruritus and elevated total serum bile salt and liver function test with unknown etiologic agent but suggested hormonal, environmental and genetic risk factors.
A 31-year-old Gravida III and Para II mother came to University of Gondar specialized hospital at the outpatient clinic in January 2019 with complain of generalized pruritus along with jaundice at 24 weeks gestational age (GA). She presented with singleton and intrauterine pregnancy with a history of one neonatal loss, one living child, and elevated bilirubin, on admission blood serum test showed elevated serum transaminases, and bilirubin. At 30 weeks GA her bilirubin total and bilirubin direct tests were 4.52 mg/dl and 3.45 mg/dl respectively. At 34 weeks GA her bilirubin values became elevated. At 37 weeks GA fetal delivery was carried out via successful caesarean section with an indication of non-reassuring fetal heart rate pattern after induction with oxytocin. The outcome was stable for both mother and baby. After a two week follow up in the outpatient set up, her liver biochemistry test was normal, and free of the clinical features with normal physical growth and intact primitive reflexes of a newborn.
Presenting with a typical marker of increased liver function tests, bilirubin values and pruritus as a clinical feature, ICP was diagnosed. After an attempt at an oxytocin induction, an effective cesarean section was performed to deliver a live female baby, weighing 2.8 kg. The case disappeared after three weeks follow up in the puerperium.
Background
As described by Ahlfeld (1883), intrahepatic cholestasis of pregnancy (ICP), is a frequent jaundice in pregnancy that can be relieved following delivery, it may reoccur in subsequent pregnancies.1 ICP is a common pregnancy-related liver disease seen in the second and third trimesters of pregnancy.2 Clinically it characterized by a rash and an itching sensation all over the body, particularly on the hands and feet. Elevated liver enzymes, including serum aminotransferases and/or elevated serum bile acid levels (>or = 10 micromol/L) are usually spontaneously relieved after delivery, and no later than one month post-partum. ICP may reoccur in subsequent pregnancies.3 ICP is a liver disease unique to pregnancy with a global prevalence ranging from 0.3% and 5.6% of pregnancies. Its prevalence differs from one country to the other and is more common in countries like Chile and Bolivia.1,4
Even though, the pathogenesis of ICP is not well defined and its etiology is multifaceted, it is related to abnormal biliary transport across the canalicular membrane. Available literature suggest that genetic, environmental, hormonal, and exogenous factors all play a role in the occurrence of ICP.5–7 Even though ICP will not usually have severe and complex outcomes, it has been associated mostly with preterm delivery, meconium staining of amniotic fluid, fetal bradycardia, fetal distress and fetal demise.1,3,6,8–11 The underlying mechanisms associated with poor fetal outcome are largely unknown. Poor fetal outcomes, including asphyxia events and spontaneous preterm delivery, have been shown to be associated with elevated maternal total serum bile acids (TBA) (40 micromole/L) in pregnancy.3,12
It is controversial to set the standardized and the most optimal management for women with ICP.9 But pharmacotherapy, antenatal fetal monitoring, analysis of the bile acid and early elective delivery are the currently proposed management options, so as to reduce poor outcomes for both mother and baby.1,9,11,13
Case Presentation
A 31-year-old Gravida III and Para II mother came to the outpatient clinic of the University of Gondar specialized hospital, North West Ethiopia, in January 2019 complaining of pruritus (mainly under the breasts, on the neck, palms of the hands and soles of the feet) along with jaundice at 24 weeks gestational age (GA). She had a history of antenatal care follow up at a nearby health center. She presented to us with singleton and intrauterine pregnancy.
On arrival, she was screened for both subjective and objective data for her current and past obstetric, medical, surgical, gynecological, social, personal and family history. She had a history of early neonatal loss and one living child, her bilirubin value was elevated, she suffered pruritus and hepatomegaly in her previous pregnancies. She had a personal and family history of pruritus during pregnancy. From her previous personal history, she reported a history of similar features that resembled her current clinical presentation. The rest of her laboratory investigations and physical examination results, including vital signs (blood pressure 100/70 mmHg), were in their normal range and she arranged for her next follow up after being provided with an antihistamine drug and offered counseling and health education to ensure the best outcome for her pregnancy. At 30 weeks GA, she was assessed for any complaints, including the worsening of pruritus and underwent liver biochemistry tests. Based on this, her bilirubin total and bilirubin direct tests were 4.52 mg/dl and 3.45 mg/dl respectively. Other complete blood count tests and urinalysis were within the normal range. The progress of the pregnancy was also assessed using ultrasound and showed no any abnormality. At 34 weeks GA her bilirubin values became elevated, whereas her liver function test on both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were 83U/L and 75 U/L, respectively. The value of prothrombin time (PT) and partial thromboplastin time (PTT) were 12.2 and 34.6 seconds, respectively. Urine bilirubin, urobilinogen, urine nitrite, and Hepatitis B surface antigen (HBS-antigen) tests were negative. But there was no opportunity for a TBA laboratory test.
As a result of having some abnormally elevated liver biochemistry tests, and the clinical features of the patient's current and past obstetric history, a decision was made to admitthe patient to the obstetric ward after a diagnosis of ICP was made. After admission various checks were carried out, including: weekly fetal surveillance with ultrasound and using a kick chart; administration of four doses of dexamethasone 12 hours apart to accelerate fetal lung maturation at 33 weeks GA; administration of antihistamine drugs to alleviate the suffering from pruritus; and psychological reassurance of the patient. The patient's clinical symptoms were not improved after administering antihistamine drugs and she suffered from severe pruritus following the administration of dexamethasone. At 37 weeks GA, the obstetrician and midwives had a detailed discussion and decided to deliver the baby. Initially the cervix was ripened with a Foley catheter so as to have an acceptable BISHOP score and then induction of labor with oxytocin was carried out. During this time a non-reassuring fetal heart rate pattern was detected with a cardiotocograph (CTG) and was confirmed with ultrasound. Finally, a successful caesarean section was done performed to deliver a 2.8 kg live female baby with an APGAR score of 8 and 9 in the 1st and 5th minutes, respectively. Following delivery, the patient remained inhospital for a week and was discharged to home with both mother and baby in stable conditions. The evaluation of the patient during the puerperium two weeks after giving birth was good, with the normalization of the liver biochemistry tests and the disappearance of the pruritus. The bilirubin total, ALT and AST decreased to 1.1 mg/dl, 32 U/L, and 31 U/L respectively. The evaluation of the baby was also good, with normal physical development.
Discussion and Conclusion
With the unknown etiology of ICP, various factors are indicated to be associated with high prevalence of ICP; these factors include genetics, the environment, coexisting liver and biliary tract conditions or abnormal metabolism of bile acid due to the high secretion of estrogen during pregnancy, hyper emesis gravidarum, multiple pregnancies and over stimulation of ovarian or oral contraception. The most frequent ICP complication to the fetus is preterm delivery.3,8 Especially the risk of preterm delivery is significantly higher for those patients with total bile acids (TBA)>40 µmol/l.3 It was found that the mechanism of preterm delivery with ICP is that bile acid activity results in an increased sensitivity of the uterine muscle to oxytocin and in the increased oxytocin receptor expression. Having a TBA >11 mol/L in the third trimester of pregnancy is a direct indicative of ICP. The measurement of bile acid concentration is a basic test aimed at diagnosis and therapy monitoring of the ICP. Meanwhile, the activity of alcohol dehydrogenase (ADH) isoenzymes could be considered as having a positive interaction in the sera of women with intrahepatic cholestasis14 and having a history of allergic reactions may mean they are more likely to develop ICP15 but for our patient there was no history of allergic reactions. Hence it is better to consider such a test while suspecting and detecting this case. ICP has its own differential diagnoses including fatty liver disease, hepatobiliary disorder, HELLP syndrome, skin disease, renal pruritus and hyper emesis gravidarum. As a result, it is better to consider all these and differing diagnoses while anticipating ICP. In the management of ICP, the major role should be preventing still birth and minimizing the adverse effects of ICP clinical features on the mother. As various literatures suggest,8,11 there is no definitive cure for ICP other than alleviating the suffering from pruritus with drugs like Ursodeoxycholic acid (UDCA),2 antihistamines and delivering the baby as early as possible (from 37–38 weeks GA) as the clinical features of ICP will regress and disappear after delivery.
Finally, ICP is a cholestatic liver disease unique to pregnancy with a variable worldwide prevalence ranging between 0.3% and 5.6% of pregnancies. After confirming the diagnosis of ICP with a liver biochemistry test indicating total serum bile acid and its signs and symptoms as a clinical feature, close follow up of the patient is mandatory so as to prevent and minimize the adverse outcomes of ICP. For our patient after a serial laboratory test and weekly fetal surveillance, a trial of induction with oxytocin was performed and finally an effective cesarean section was carried out to deliver a 2.8 kg living female baby with an indication of non-reassuring fetal heart rate pattern. ICP regressed and disappeared at the three week follow up in the puerperium.
Acknowledgment
We would like to acknowledge University of Gondar Department of Obstetrics and Gynecology as well as school of midwifery for allowing us to report on this case. Our deepest gratitude goes to our patient for her cooperation on revealing both her subjective and objective data, as well as her permission for us to publish this article.
Abbreviations
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GA, gestational age; ICP, intrahepatic cholestasis of pregnancy; PT, prothrombin time; PTT, partial thromboplastin time; TBA, total serum bile acid.
Data Sharing Statement
The data used to support the findings of this study are available from the corresponding author upon formal request.
Ethical Approval and Consent to Participate
The Ethical clearance letter was obtained from the Institutional Review Board of the University of Gondar. Patient consent was taken with written informed consent form and she was volunteer to participate.
Consent for Publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declared that they did not have any competing interest. | DEXAMETHASONE | DrugsGivenReaction | CC BY-NC | 33603498 | 19,786,053 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'. | The Recurrent Liver Disorder of a Pregnant Mother: Intrahepatic Cholestasis of Pregnancy - A Case Report and Literature Review.
Intrahepatic cholestasis of pregnancy (ICP) is a form of liver disease which is unique to pregnancy with a worldwide prevalence ranging from 0.3% and 5.6% of pregnancies. It is presented with skin pruritus and elevated total serum bile salt and liver function test with unknown etiologic agent but suggested hormonal, environmental and genetic risk factors.
A 31-year-old Gravida III and Para II mother came to University of Gondar specialized hospital at the outpatient clinic in January 2019 with complain of generalized pruritus along with jaundice at 24 weeks gestational age (GA). She presented with singleton and intrauterine pregnancy with a history of one neonatal loss, one living child, and elevated bilirubin, on admission blood serum test showed elevated serum transaminases, and bilirubin. At 30 weeks GA her bilirubin total and bilirubin direct tests were 4.52 mg/dl and 3.45 mg/dl respectively. At 34 weeks GA her bilirubin values became elevated. At 37 weeks GA fetal delivery was carried out via successful caesarean section with an indication of non-reassuring fetal heart rate pattern after induction with oxytocin. The outcome was stable for both mother and baby. After a two week follow up in the outpatient set up, her liver biochemistry test was normal, and free of the clinical features with normal physical growth and intact primitive reflexes of a newborn.
Presenting with a typical marker of increased liver function tests, bilirubin values and pruritus as a clinical feature, ICP was diagnosed. After an attempt at an oxytocin induction, an effective cesarean section was performed to deliver a live female baby, weighing 2.8 kg. The case disappeared after three weeks follow up in the puerperium.
Background
As described by Ahlfeld (1883), intrahepatic cholestasis of pregnancy (ICP), is a frequent jaundice in pregnancy that can be relieved following delivery, it may reoccur in subsequent pregnancies.1 ICP is a common pregnancy-related liver disease seen in the second and third trimesters of pregnancy.2 Clinically it characterized by a rash and an itching sensation all over the body, particularly on the hands and feet. Elevated liver enzymes, including serum aminotransferases and/or elevated serum bile acid levels (>or = 10 micromol/L) are usually spontaneously relieved after delivery, and no later than one month post-partum. ICP may reoccur in subsequent pregnancies.3 ICP is a liver disease unique to pregnancy with a global prevalence ranging from 0.3% and 5.6% of pregnancies. Its prevalence differs from one country to the other and is more common in countries like Chile and Bolivia.1,4
Even though, the pathogenesis of ICP is not well defined and its etiology is multifaceted, it is related to abnormal biliary transport across the canalicular membrane. Available literature suggest that genetic, environmental, hormonal, and exogenous factors all play a role in the occurrence of ICP.5–7 Even though ICP will not usually have severe and complex outcomes, it has been associated mostly with preterm delivery, meconium staining of amniotic fluid, fetal bradycardia, fetal distress and fetal demise.1,3,6,8–11 The underlying mechanisms associated with poor fetal outcome are largely unknown. Poor fetal outcomes, including asphyxia events and spontaneous preterm delivery, have been shown to be associated with elevated maternal total serum bile acids (TBA) (40 micromole/L) in pregnancy.3,12
It is controversial to set the standardized and the most optimal management for women with ICP.9 But pharmacotherapy, antenatal fetal monitoring, analysis of the bile acid and early elective delivery are the currently proposed management options, so as to reduce poor outcomes for both mother and baby.1,9,11,13
Case Presentation
A 31-year-old Gravida III and Para II mother came to the outpatient clinic of the University of Gondar specialized hospital, North West Ethiopia, in January 2019 complaining of pruritus (mainly under the breasts, on the neck, palms of the hands and soles of the feet) along with jaundice at 24 weeks gestational age (GA). She had a history of antenatal care follow up at a nearby health center. She presented to us with singleton and intrauterine pregnancy.
On arrival, she was screened for both subjective and objective data for her current and past obstetric, medical, surgical, gynecological, social, personal and family history. She had a history of early neonatal loss and one living child, her bilirubin value was elevated, she suffered pruritus and hepatomegaly in her previous pregnancies. She had a personal and family history of pruritus during pregnancy. From her previous personal history, she reported a history of similar features that resembled her current clinical presentation. The rest of her laboratory investigations and physical examination results, including vital signs (blood pressure 100/70 mmHg), were in their normal range and she arranged for her next follow up after being provided with an antihistamine drug and offered counseling and health education to ensure the best outcome for her pregnancy. At 30 weeks GA, she was assessed for any complaints, including the worsening of pruritus and underwent liver biochemistry tests. Based on this, her bilirubin total and bilirubin direct tests were 4.52 mg/dl and 3.45 mg/dl respectively. Other complete blood count tests and urinalysis were within the normal range. The progress of the pregnancy was also assessed using ultrasound and showed no any abnormality. At 34 weeks GA her bilirubin values became elevated, whereas her liver function test on both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were 83U/L and 75 U/L, respectively. The value of prothrombin time (PT) and partial thromboplastin time (PTT) were 12.2 and 34.6 seconds, respectively. Urine bilirubin, urobilinogen, urine nitrite, and Hepatitis B surface antigen (HBS-antigen) tests were negative. But there was no opportunity for a TBA laboratory test.
As a result of having some abnormally elevated liver biochemistry tests, and the clinical features of the patient's current and past obstetric history, a decision was made to admitthe patient to the obstetric ward after a diagnosis of ICP was made. After admission various checks were carried out, including: weekly fetal surveillance with ultrasound and using a kick chart; administration of four doses of dexamethasone 12 hours apart to accelerate fetal lung maturation at 33 weeks GA; administration of antihistamine drugs to alleviate the suffering from pruritus; and psychological reassurance of the patient. The patient's clinical symptoms were not improved after administering antihistamine drugs and she suffered from severe pruritus following the administration of dexamethasone. At 37 weeks GA, the obstetrician and midwives had a detailed discussion and decided to deliver the baby. Initially the cervix was ripened with a Foley catheter so as to have an acceptable BISHOP score and then induction of labor with oxytocin was carried out. During this time a non-reassuring fetal heart rate pattern was detected with a cardiotocograph (CTG) and was confirmed with ultrasound. Finally, a successful caesarean section was done performed to deliver a 2.8 kg live female baby with an APGAR score of 8 and 9 in the 1st and 5th minutes, respectively. Following delivery, the patient remained inhospital for a week and was discharged to home with both mother and baby in stable conditions. The evaluation of the patient during the puerperium two weeks after giving birth was good, with the normalization of the liver biochemistry tests and the disappearance of the pruritus. The bilirubin total, ALT and AST decreased to 1.1 mg/dl, 32 U/L, and 31 U/L respectively. The evaluation of the baby was also good, with normal physical development.
Discussion and Conclusion
With the unknown etiology of ICP, various factors are indicated to be associated with high prevalence of ICP; these factors include genetics, the environment, coexisting liver and biliary tract conditions or abnormal metabolism of bile acid due to the high secretion of estrogen during pregnancy, hyper emesis gravidarum, multiple pregnancies and over stimulation of ovarian or oral contraception. The most frequent ICP complication to the fetus is preterm delivery.3,8 Especially the risk of preterm delivery is significantly higher for those patients with total bile acids (TBA)>40 µmol/l.3 It was found that the mechanism of preterm delivery with ICP is that bile acid activity results in an increased sensitivity of the uterine muscle to oxytocin and in the increased oxytocin receptor expression. Having a TBA >11 mol/L in the third trimester of pregnancy is a direct indicative of ICP. The measurement of bile acid concentration is a basic test aimed at diagnosis and therapy monitoring of the ICP. Meanwhile, the activity of alcohol dehydrogenase (ADH) isoenzymes could be considered as having a positive interaction in the sera of women with intrahepatic cholestasis14 and having a history of allergic reactions may mean they are more likely to develop ICP15 but for our patient there was no history of allergic reactions. Hence it is better to consider such a test while suspecting and detecting this case. ICP has its own differential diagnoses including fatty liver disease, hepatobiliary disorder, HELLP syndrome, skin disease, renal pruritus and hyper emesis gravidarum. As a result, it is better to consider all these and differing diagnoses while anticipating ICP. In the management of ICP, the major role should be preventing still birth and minimizing the adverse effects of ICP clinical features on the mother. As various literatures suggest,8,11 there is no definitive cure for ICP other than alleviating the suffering from pruritus with drugs like Ursodeoxycholic acid (UDCA),2 antihistamines and delivering the baby as early as possible (from 37–38 weeks GA) as the clinical features of ICP will regress and disappear after delivery.
Finally, ICP is a cholestatic liver disease unique to pregnancy with a variable worldwide prevalence ranging between 0.3% and 5.6% of pregnancies. After confirming the diagnosis of ICP with a liver biochemistry test indicating total serum bile acid and its signs and symptoms as a clinical feature, close follow up of the patient is mandatory so as to prevent and minimize the adverse outcomes of ICP. For our patient after a serial laboratory test and weekly fetal surveillance, a trial of induction with oxytocin was performed and finally an effective cesarean section was carried out to deliver a 2.8 kg living female baby with an indication of non-reassuring fetal heart rate pattern. ICP regressed and disappeared at the three week follow up in the puerperium.
Acknowledgment
We would like to acknowledge University of Gondar Department of Obstetrics and Gynecology as well as school of midwifery for allowing us to report on this case. Our deepest gratitude goes to our patient for her cooperation on revealing both her subjective and objective data, as well as her permission for us to publish this article.
Abbreviations
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GA, gestational age; ICP, intrahepatic cholestasis of pregnancy; PT, prothrombin time; PTT, partial thromboplastin time; TBA, total serum bile acid.
Data Sharing Statement
The data used to support the findings of this study are available from the corresponding author upon formal request.
Ethical Approval and Consent to Participate
The Ethical clearance letter was obtained from the Institutional Review Board of the University of Gondar. Patient consent was taken with written informed consent form and she was volunteer to participate.
Consent for Publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declared that they did not have any competing interest. | DEXAMETHASONE | DrugsGivenReaction | CC BY-NC | 33603498 | 19,786,053 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Live birth'. | The Recurrent Liver Disorder of a Pregnant Mother: Intrahepatic Cholestasis of Pregnancy - A Case Report and Literature Review.
Intrahepatic cholestasis of pregnancy (ICP) is a form of liver disease which is unique to pregnancy with a worldwide prevalence ranging from 0.3% and 5.6% of pregnancies. It is presented with skin pruritus and elevated total serum bile salt and liver function test with unknown etiologic agent but suggested hormonal, environmental and genetic risk factors.
A 31-year-old Gravida III and Para II mother came to University of Gondar specialized hospital at the outpatient clinic in January 2019 with complain of generalized pruritus along with jaundice at 24 weeks gestational age (GA). She presented with singleton and intrauterine pregnancy with a history of one neonatal loss, one living child, and elevated bilirubin, on admission blood serum test showed elevated serum transaminases, and bilirubin. At 30 weeks GA her bilirubin total and bilirubin direct tests were 4.52 mg/dl and 3.45 mg/dl respectively. At 34 weeks GA her bilirubin values became elevated. At 37 weeks GA fetal delivery was carried out via successful caesarean section with an indication of non-reassuring fetal heart rate pattern after induction with oxytocin. The outcome was stable for both mother and baby. After a two week follow up in the outpatient set up, her liver biochemistry test was normal, and free of the clinical features with normal physical growth and intact primitive reflexes of a newborn.
Presenting with a typical marker of increased liver function tests, bilirubin values and pruritus as a clinical feature, ICP was diagnosed. After an attempt at an oxytocin induction, an effective cesarean section was performed to deliver a live female baby, weighing 2.8 kg. The case disappeared after three weeks follow up in the puerperium.
Background
As described by Ahlfeld (1883), intrahepatic cholestasis of pregnancy (ICP), is a frequent jaundice in pregnancy that can be relieved following delivery, it may reoccur in subsequent pregnancies.1 ICP is a common pregnancy-related liver disease seen in the second and third trimesters of pregnancy.2 Clinically it characterized by a rash and an itching sensation all over the body, particularly on the hands and feet. Elevated liver enzymes, including serum aminotransferases and/or elevated serum bile acid levels (>or = 10 micromol/L) are usually spontaneously relieved after delivery, and no later than one month post-partum. ICP may reoccur in subsequent pregnancies.3 ICP is a liver disease unique to pregnancy with a global prevalence ranging from 0.3% and 5.6% of pregnancies. Its prevalence differs from one country to the other and is more common in countries like Chile and Bolivia.1,4
Even though, the pathogenesis of ICP is not well defined and its etiology is multifaceted, it is related to abnormal biliary transport across the canalicular membrane. Available literature suggest that genetic, environmental, hormonal, and exogenous factors all play a role in the occurrence of ICP.5–7 Even though ICP will not usually have severe and complex outcomes, it has been associated mostly with preterm delivery, meconium staining of amniotic fluid, fetal bradycardia, fetal distress and fetal demise.1,3,6,8–11 The underlying mechanisms associated with poor fetal outcome are largely unknown. Poor fetal outcomes, including asphyxia events and spontaneous preterm delivery, have been shown to be associated with elevated maternal total serum bile acids (TBA) (40 micromole/L) in pregnancy.3,12
It is controversial to set the standardized and the most optimal management for women with ICP.9 But pharmacotherapy, antenatal fetal monitoring, analysis of the bile acid and early elective delivery are the currently proposed management options, so as to reduce poor outcomes for both mother and baby.1,9,11,13
Case Presentation
A 31-year-old Gravida III and Para II mother came to the outpatient clinic of the University of Gondar specialized hospital, North West Ethiopia, in January 2019 complaining of pruritus (mainly under the breasts, on the neck, palms of the hands and soles of the feet) along with jaundice at 24 weeks gestational age (GA). She had a history of antenatal care follow up at a nearby health center. She presented to us with singleton and intrauterine pregnancy.
On arrival, she was screened for both subjective and objective data for her current and past obstetric, medical, surgical, gynecological, social, personal and family history. She had a history of early neonatal loss and one living child, her bilirubin value was elevated, she suffered pruritus and hepatomegaly in her previous pregnancies. She had a personal and family history of pruritus during pregnancy. From her previous personal history, she reported a history of similar features that resembled her current clinical presentation. The rest of her laboratory investigations and physical examination results, including vital signs (blood pressure 100/70 mmHg), were in their normal range and she arranged for her next follow up after being provided with an antihistamine drug and offered counseling and health education to ensure the best outcome for her pregnancy. At 30 weeks GA, she was assessed for any complaints, including the worsening of pruritus and underwent liver biochemistry tests. Based on this, her bilirubin total and bilirubin direct tests were 4.52 mg/dl and 3.45 mg/dl respectively. Other complete blood count tests and urinalysis were within the normal range. The progress of the pregnancy was also assessed using ultrasound and showed no any abnormality. At 34 weeks GA her bilirubin values became elevated, whereas her liver function test on both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were 83U/L and 75 U/L, respectively. The value of prothrombin time (PT) and partial thromboplastin time (PTT) were 12.2 and 34.6 seconds, respectively. Urine bilirubin, urobilinogen, urine nitrite, and Hepatitis B surface antigen (HBS-antigen) tests were negative. But there was no opportunity for a TBA laboratory test.
As a result of having some abnormally elevated liver biochemistry tests, and the clinical features of the patient's current and past obstetric history, a decision was made to admitthe patient to the obstetric ward after a diagnosis of ICP was made. After admission various checks were carried out, including: weekly fetal surveillance with ultrasound and using a kick chart; administration of four doses of dexamethasone 12 hours apart to accelerate fetal lung maturation at 33 weeks GA; administration of antihistamine drugs to alleviate the suffering from pruritus; and psychological reassurance of the patient. The patient's clinical symptoms were not improved after administering antihistamine drugs and she suffered from severe pruritus following the administration of dexamethasone. At 37 weeks GA, the obstetrician and midwives had a detailed discussion and decided to deliver the baby. Initially the cervix was ripened with a Foley catheter so as to have an acceptable BISHOP score and then induction of labor with oxytocin was carried out. During this time a non-reassuring fetal heart rate pattern was detected with a cardiotocograph (CTG) and was confirmed with ultrasound. Finally, a successful caesarean section was done performed to deliver a 2.8 kg live female baby with an APGAR score of 8 and 9 in the 1st and 5th minutes, respectively. Following delivery, the patient remained inhospital for a week and was discharged to home with both mother and baby in stable conditions. The evaluation of the patient during the puerperium two weeks after giving birth was good, with the normalization of the liver biochemistry tests and the disappearance of the pruritus. The bilirubin total, ALT and AST decreased to 1.1 mg/dl, 32 U/L, and 31 U/L respectively. The evaluation of the baby was also good, with normal physical development.
Discussion and Conclusion
With the unknown etiology of ICP, various factors are indicated to be associated with high prevalence of ICP; these factors include genetics, the environment, coexisting liver and biliary tract conditions or abnormal metabolism of bile acid due to the high secretion of estrogen during pregnancy, hyper emesis gravidarum, multiple pregnancies and over stimulation of ovarian or oral contraception. The most frequent ICP complication to the fetus is preterm delivery.3,8 Especially the risk of preterm delivery is significantly higher for those patients with total bile acids (TBA)>40 µmol/l.3 It was found that the mechanism of preterm delivery with ICP is that bile acid activity results in an increased sensitivity of the uterine muscle to oxytocin and in the increased oxytocin receptor expression. Having a TBA >11 mol/L in the third trimester of pregnancy is a direct indicative of ICP. The measurement of bile acid concentration is a basic test aimed at diagnosis and therapy monitoring of the ICP. Meanwhile, the activity of alcohol dehydrogenase (ADH) isoenzymes could be considered as having a positive interaction in the sera of women with intrahepatic cholestasis14 and having a history of allergic reactions may mean they are more likely to develop ICP15 but for our patient there was no history of allergic reactions. Hence it is better to consider such a test while suspecting and detecting this case. ICP has its own differential diagnoses including fatty liver disease, hepatobiliary disorder, HELLP syndrome, skin disease, renal pruritus and hyper emesis gravidarum. As a result, it is better to consider all these and differing diagnoses while anticipating ICP. In the management of ICP, the major role should be preventing still birth and minimizing the adverse effects of ICP clinical features on the mother. As various literatures suggest,8,11 there is no definitive cure for ICP other than alleviating the suffering from pruritus with drugs like Ursodeoxycholic acid (UDCA),2 antihistamines and delivering the baby as early as possible (from 37–38 weeks GA) as the clinical features of ICP will regress and disappear after delivery.
Finally, ICP is a cholestatic liver disease unique to pregnancy with a variable worldwide prevalence ranging between 0.3% and 5.6% of pregnancies. After confirming the diagnosis of ICP with a liver biochemistry test indicating total serum bile acid and its signs and symptoms as a clinical feature, close follow up of the patient is mandatory so as to prevent and minimize the adverse outcomes of ICP. For our patient after a serial laboratory test and weekly fetal surveillance, a trial of induction with oxytocin was performed and finally an effective cesarean section was carried out to deliver a 2.8 kg living female baby with an indication of non-reassuring fetal heart rate pattern. ICP regressed and disappeared at the three week follow up in the puerperium.
Acknowledgment
We would like to acknowledge University of Gondar Department of Obstetrics and Gynecology as well as school of midwifery for allowing us to report on this case. Our deepest gratitude goes to our patient for her cooperation on revealing both her subjective and objective data, as well as her permission for us to publish this article.
Abbreviations
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GA, gestational age; ICP, intrahepatic cholestasis of pregnancy; PT, prothrombin time; PTT, partial thromboplastin time; TBA, total serum bile acid.
Data Sharing Statement
The data used to support the findings of this study are available from the corresponding author upon formal request.
Ethical Approval and Consent to Participate
The Ethical clearance letter was obtained from the Institutional Review Board of the University of Gondar. Patient consent was taken with written informed consent form and she was volunteer to participate.
Consent for Publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declared that they did not have any competing interest. | DEXAMETHASONE | DrugsGivenReaction | CC BY-NC | 33603498 | 19,786,053 | 2021 |
What was the dosage of drug 'DEXAMETHASONE'? | The Recurrent Liver Disorder of a Pregnant Mother: Intrahepatic Cholestasis of Pregnancy - A Case Report and Literature Review.
Intrahepatic cholestasis of pregnancy (ICP) is a form of liver disease which is unique to pregnancy with a worldwide prevalence ranging from 0.3% and 5.6% of pregnancies. It is presented with skin pruritus and elevated total serum bile salt and liver function test with unknown etiologic agent but suggested hormonal, environmental and genetic risk factors.
A 31-year-old Gravida III and Para II mother came to University of Gondar specialized hospital at the outpatient clinic in January 2019 with complain of generalized pruritus along with jaundice at 24 weeks gestational age (GA). She presented with singleton and intrauterine pregnancy with a history of one neonatal loss, one living child, and elevated bilirubin, on admission blood serum test showed elevated serum transaminases, and bilirubin. At 30 weeks GA her bilirubin total and bilirubin direct tests were 4.52 mg/dl and 3.45 mg/dl respectively. At 34 weeks GA her bilirubin values became elevated. At 37 weeks GA fetal delivery was carried out via successful caesarean section with an indication of non-reassuring fetal heart rate pattern after induction with oxytocin. The outcome was stable for both mother and baby. After a two week follow up in the outpatient set up, her liver biochemistry test was normal, and free of the clinical features with normal physical growth and intact primitive reflexes of a newborn.
Presenting with a typical marker of increased liver function tests, bilirubin values and pruritus as a clinical feature, ICP was diagnosed. After an attempt at an oxytocin induction, an effective cesarean section was performed to deliver a live female baby, weighing 2.8 kg. The case disappeared after three weeks follow up in the puerperium.
Background
As described by Ahlfeld (1883), intrahepatic cholestasis of pregnancy (ICP), is a frequent jaundice in pregnancy that can be relieved following delivery, it may reoccur in subsequent pregnancies.1 ICP is a common pregnancy-related liver disease seen in the second and third trimesters of pregnancy.2 Clinically it characterized by a rash and an itching sensation all over the body, particularly on the hands and feet. Elevated liver enzymes, including serum aminotransferases and/or elevated serum bile acid levels (>or = 10 micromol/L) are usually spontaneously relieved after delivery, and no later than one month post-partum. ICP may reoccur in subsequent pregnancies.3 ICP is a liver disease unique to pregnancy with a global prevalence ranging from 0.3% and 5.6% of pregnancies. Its prevalence differs from one country to the other and is more common in countries like Chile and Bolivia.1,4
Even though, the pathogenesis of ICP is not well defined and its etiology is multifaceted, it is related to abnormal biliary transport across the canalicular membrane. Available literature suggest that genetic, environmental, hormonal, and exogenous factors all play a role in the occurrence of ICP.5–7 Even though ICP will not usually have severe and complex outcomes, it has been associated mostly with preterm delivery, meconium staining of amniotic fluid, fetal bradycardia, fetal distress and fetal demise.1,3,6,8–11 The underlying mechanisms associated with poor fetal outcome are largely unknown. Poor fetal outcomes, including asphyxia events and spontaneous preterm delivery, have been shown to be associated with elevated maternal total serum bile acids (TBA) (40 micromole/L) in pregnancy.3,12
It is controversial to set the standardized and the most optimal management for women with ICP.9 But pharmacotherapy, antenatal fetal monitoring, analysis of the bile acid and early elective delivery are the currently proposed management options, so as to reduce poor outcomes for both mother and baby.1,9,11,13
Case Presentation
A 31-year-old Gravida III and Para II mother came to the outpatient clinic of the University of Gondar specialized hospital, North West Ethiopia, in January 2019 complaining of pruritus (mainly under the breasts, on the neck, palms of the hands and soles of the feet) along with jaundice at 24 weeks gestational age (GA). She had a history of antenatal care follow up at a nearby health center. She presented to us with singleton and intrauterine pregnancy.
On arrival, she was screened for both subjective and objective data for her current and past obstetric, medical, surgical, gynecological, social, personal and family history. She had a history of early neonatal loss and one living child, her bilirubin value was elevated, she suffered pruritus and hepatomegaly in her previous pregnancies. She had a personal and family history of pruritus during pregnancy. From her previous personal history, she reported a history of similar features that resembled her current clinical presentation. The rest of her laboratory investigations and physical examination results, including vital signs (blood pressure 100/70 mmHg), were in their normal range and she arranged for her next follow up after being provided with an antihistamine drug and offered counseling and health education to ensure the best outcome for her pregnancy. At 30 weeks GA, she was assessed for any complaints, including the worsening of pruritus and underwent liver biochemistry tests. Based on this, her bilirubin total and bilirubin direct tests were 4.52 mg/dl and 3.45 mg/dl respectively. Other complete blood count tests and urinalysis were within the normal range. The progress of the pregnancy was also assessed using ultrasound and showed no any abnormality. At 34 weeks GA her bilirubin values became elevated, whereas her liver function test on both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were 83U/L and 75 U/L, respectively. The value of prothrombin time (PT) and partial thromboplastin time (PTT) were 12.2 and 34.6 seconds, respectively. Urine bilirubin, urobilinogen, urine nitrite, and Hepatitis B surface antigen (HBS-antigen) tests were negative. But there was no opportunity for a TBA laboratory test.
As a result of having some abnormally elevated liver biochemistry tests, and the clinical features of the patient's current and past obstetric history, a decision was made to admitthe patient to the obstetric ward after a diagnosis of ICP was made. After admission various checks were carried out, including: weekly fetal surveillance with ultrasound and using a kick chart; administration of four doses of dexamethasone 12 hours apart to accelerate fetal lung maturation at 33 weeks GA; administration of antihistamine drugs to alleviate the suffering from pruritus; and psychological reassurance of the patient. The patient's clinical symptoms were not improved after administering antihistamine drugs and she suffered from severe pruritus following the administration of dexamethasone. At 37 weeks GA, the obstetrician and midwives had a detailed discussion and decided to deliver the baby. Initially the cervix was ripened with a Foley catheter so as to have an acceptable BISHOP score and then induction of labor with oxytocin was carried out. During this time a non-reassuring fetal heart rate pattern was detected with a cardiotocograph (CTG) and was confirmed with ultrasound. Finally, a successful caesarean section was done performed to deliver a 2.8 kg live female baby with an APGAR score of 8 and 9 in the 1st and 5th minutes, respectively. Following delivery, the patient remained inhospital for a week and was discharged to home with both mother and baby in stable conditions. The evaluation of the patient during the puerperium two weeks after giving birth was good, with the normalization of the liver biochemistry tests and the disappearance of the pruritus. The bilirubin total, ALT and AST decreased to 1.1 mg/dl, 32 U/L, and 31 U/L respectively. The evaluation of the baby was also good, with normal physical development.
Discussion and Conclusion
With the unknown etiology of ICP, various factors are indicated to be associated with high prevalence of ICP; these factors include genetics, the environment, coexisting liver and biliary tract conditions or abnormal metabolism of bile acid due to the high secretion of estrogen during pregnancy, hyper emesis gravidarum, multiple pregnancies and over stimulation of ovarian or oral contraception. The most frequent ICP complication to the fetus is preterm delivery.3,8 Especially the risk of preterm delivery is significantly higher for those patients with total bile acids (TBA)>40 µmol/l.3 It was found that the mechanism of preterm delivery with ICP is that bile acid activity results in an increased sensitivity of the uterine muscle to oxytocin and in the increased oxytocin receptor expression. Having a TBA >11 mol/L in the third trimester of pregnancy is a direct indicative of ICP. The measurement of bile acid concentration is a basic test aimed at diagnosis and therapy monitoring of the ICP. Meanwhile, the activity of alcohol dehydrogenase (ADH) isoenzymes could be considered as having a positive interaction in the sera of women with intrahepatic cholestasis14 and having a history of allergic reactions may mean they are more likely to develop ICP15 but for our patient there was no history of allergic reactions. Hence it is better to consider such a test while suspecting and detecting this case. ICP has its own differential diagnoses including fatty liver disease, hepatobiliary disorder, HELLP syndrome, skin disease, renal pruritus and hyper emesis gravidarum. As a result, it is better to consider all these and differing diagnoses while anticipating ICP. In the management of ICP, the major role should be preventing still birth and minimizing the adverse effects of ICP clinical features on the mother. As various literatures suggest,8,11 there is no definitive cure for ICP other than alleviating the suffering from pruritus with drugs like Ursodeoxycholic acid (UDCA),2 antihistamines and delivering the baby as early as possible (from 37–38 weeks GA) as the clinical features of ICP will regress and disappear after delivery.
Finally, ICP is a cholestatic liver disease unique to pregnancy with a variable worldwide prevalence ranging between 0.3% and 5.6% of pregnancies. After confirming the diagnosis of ICP with a liver biochemistry test indicating total serum bile acid and its signs and symptoms as a clinical feature, close follow up of the patient is mandatory so as to prevent and minimize the adverse outcomes of ICP. For our patient after a serial laboratory test and weekly fetal surveillance, a trial of induction with oxytocin was performed and finally an effective cesarean section was carried out to deliver a 2.8 kg living female baby with an indication of non-reassuring fetal heart rate pattern. ICP regressed and disappeared at the three week follow up in the puerperium.
Acknowledgment
We would like to acknowledge University of Gondar Department of Obstetrics and Gynecology as well as school of midwifery for allowing us to report on this case. Our deepest gratitude goes to our patient for her cooperation on revealing both her subjective and objective data, as well as her permission for us to publish this article.
Abbreviations
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GA, gestational age; ICP, intrahepatic cholestasis of pregnancy; PT, prothrombin time; PTT, partial thromboplastin time; TBA, total serum bile acid.
Data Sharing Statement
The data used to support the findings of this study are available from the corresponding author upon formal request.
Ethical Approval and Consent to Participate
The Ethical clearance letter was obtained from the Institutional Review Board of the University of Gondar. Patient consent was taken with written informed consent form and she was volunteer to participate.
Consent for Publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declared that they did not have any competing interest. | UNK (4 DOSES, 12 HOURS APART) | DrugDosageText | CC BY-NC | 33603498 | 19,786,053 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dystonia'. | Clozapine Efficacy in a Case of Severe Treatment-Resistant Postpartum Psychosis.
The postpartum period is a difficult time for mother and family. Unfortunately, in some cases, two psychiatric complications may occur: postpartum psychoses (PPP) with a prevalence of 0.2% and a very low incidence of 0.25-0.50 per 1000 deliveries, and post-natal depressions with an incidence of 10 to 20% per 1000 deliveries. The onset of postpartum psychosis is in the first 4 weeks after childbirth with symptoms such as emotional lability, cognitive disorganization, delusional beliefs and hallucinations. It requires hospitalization due to the high risk of suicide and infanticide. The studies reveal that the treatment can include FGAs (first-generation antipsychotics), such as haloperidol, and SGAs (second-generation antipsychotics), such as olanzapine, quetiapine and risperidone. The literature is scarce in what resistant PPP is concerned and no such cases treated with clozapine have been reported, according to our knowledge. The present case report focuses on a female diagnosed with PPP who was treated with clozapine due to the lack of response to adequate dosage of 2 second-generation antipsychotics.
We present the case of a 30-year-old primiparous woman on her 3rd day after delivery, admitted in the psychiatric emergency unit for agitation, intrusive thoughts with a content frequently related to the infant, ideas of reference, disorganized speech, bizarre behavior, verbal stereotypes, insomnia and anxiety. Due to lack of response to adequate dosage of 2 second-generation antipsychotics, clozapine was initiated up to 250 mg/day. The symptoms remitted in the next 5 days and the patient was discharged. After discharge, at the patient's request, clozapine was replaced by olanzapine. Visit at 1 year revealed full remission of symptoms.
Although data is extremely limited, clozapine has been shown to be effective and safe in a severe case of treatment-resistant PPP.
Background
The postpartum period is a difficult time for mother and family. Unfortunately, in some cases, two psychiatric complications may occur: postpartum psychoses (PPP) with a prevalence of 0.2% and a very low incidence of 0.25–0.50 per 1000 deliveries and post-natal depressions with an incidence of 10 to 20% per 1000 deliveries. The postpartum psychosis is not only rare, but it is also not officially recognized as a distinct disorder in DSM-5.1,2
The onset of postpartum psychosis (a psychiatric emergency) is in the first 4 weeks after childbirth; it is marked by symptoms such as emotional lability, cognitive disorganization, delusional beliefs and hallucinations and it is most likely an overt presentation of bipolar disorder.3 It requires hospitalization due to the high risk of suicide and infanticide.4 Infanticide is associated with imperative hallucinations that command to kill the child or delusions that the child is possessed.5
The risk of developing psychosis is higher in the first 30 days after childbirth, especially in primiparous. Women who are already vulnerable as a result of genetics or stressful environmental exposure are susceptible to mental disease in this period and this was attributed to neuro-hormonal factors.6 The levels of estrogen and oxytocin gradually rise during the pregnancy and drop sharply after delivery, returning to normal within 3 weeks. Considering that the occurrence of psychosis is associated in time with the abrupt decline of the two hormones, an increased sensitivity of dopamine receptors due to the sudden decrease in estrogen levels has been involved. Given the putative role of estradiol and oxytocin in the pathophysiology, both estrogens (sometimes associated with progesterone) and oxytocin have been tested as potential treatments for nonpsychotic and psychotic illness in the puerperium, but the results of the clinical studies available so far are inconclusive to sustain their use.6
Jones et al conducted a genome-wide linkage study in families with bipolar disorder in which at least one woman had suffered a manic or psychotic episode within 6 weeks postpartum. They reported significant linkage signal on chromosome 16p13 and a suggestive linkage signal on chromosome 8q24, which suggests that chromosome 16 and chromosome 8 may contain genes potentially involved in the predisposition to puerperal psychosis.7
The other risk factors include being unmarried, first baby, Caesarian section, perinatal death, all this under the name of psychological stress. Also, women with a history of manic or depressive episodes have a higher risk than women with schizophrenia.8 Almost 10% of women hospitalized for psychiatric morbidity before delivery develop postpartum psychosis after their first birth.9 Of all women with PPP, 70% to 90% have bipolar disorder or schizoaffective disorder, while approximately 12% have schizophrenia.10,11 The risk of non-puerperal admission is higher for women with schizophrenia and PPP is a part of a lifelong recurrent psychiatric disorder.12
Generally, the prognosis for a singular episode is favorable, with symptoms remission and good social and occupational functioning in 75–86% of the cases. However, it is considered as belonging to the bipolar spectrum, with potential recurrences13 or as a part of schizophrenia with 50% recoveries, 33% recurrent episodes and 5% treatment-resistant schizophrenia (TRS) cases.14,15
Treatment for PPP is similar with non-puerperal episodes. The existing studies reveal that the treatment can include FGAs (first-generation antipsychotics), such as haloperidol, and SGAs (second-generation antipsychotics), such as olanzapine, quetiapine and risperidone. Olanzapine and quetiapine are preferred during breastfeeding, other antipsychotics are rarely mentioned.16,17
Regarding the association of gonadal hormones with antipsychotic use, there are still many aspects to be elucidated. While convincing evidence on their benefits is still missing, many factors should be taken into consideration. For instance, pharmacokinetic interactions of hormones with CYPP450 enzymes might change the plasma concentration of antipsychotics, thus influencing their effect on psychotic symptoms independent of the pharmacodynamics of estrogen. In this case, the outcome may depend on the antipsychotic agent; olanzapine and clozapine are metabolized by CYP1A2 liver enzyme, which is inhibited by estrogen; co-administration of estrogen will increase the antipsychotic level, while quetiapine is mainly metabolized by CYP3A4, which is induced by estrogens, so the antipsychotic level will decrease.6
The literature is very scarce in what resistant PPP is concerned and according to our knowledge no such cases treated with clozapine have been reported.
The present case report focuses on a female diagnosed with PPP who was treated with clozapine due to lack of response to adequate dosage of two SGAs. The Hospital Ethics’ Committee approval was not necessary for the publication of this case report. The patient provided written consent for the anonymous publication of her case.
Case Presentation
We present the case of a 30-year-old primiparous woman, brought by her husband on day 3 postpartum and admitted in the psychiatric emergency unit for agitation, intrusive thoughts with a content frequently related to the infant, ideas of reference, disorganized speech, bizarre behavior, verbal stereotypes, insomnia and anxiety.
From her history, we noticed a previous psychotic episode at the age of 24, successfully treated with olanzapine 10 mg/day for 6 months and then stopped at her physician’s recommendation. This episode was closely related to a stressful event. The patient had fully recovered without any residual symptoms. She got married and worked without any psychiatric problems. The biological investigations showed mild iron-deficiency anemia, mild hypercholesterolemia. The head computer tomography scan was normal. On admission, she was treated with injectable haloperidol 5 mg/day, diazepam 20mg/day and cabergoline 1mg/day for two days for ablactation. Due to extrapyramidal side effects (acute dystonia and rigidity), she was switched to olanzapine 20 mg/day, lorazepam 4 mg/day and trihexyphenidyl 4mg/day. Since no significant clinical response was registered after 2 weeks, the patient received add-on therapy with risperidone 4 mg/day. Despite the combination of two potent antipsychotics administered in proper doses, the patient remained intensely psychotic and 4 points mechanical restraint was often necessary. She started saying that she would kill herself to escape the terror caused by what was happening. She started being aggressive and presenting the Capgras delusion. Since she was non-responsive to adequate dosage of two second-generation antipsychotics, standard titration of clozapine was initiated up to 250 mg/day with ongoing monitoring in conformity with the current guidelines. Benzodiazepines were tapered off to discontinuation. The symptoms remitted in the next 5 days and the patient was discharged. After discharge, she continued the treatment for 6 months.
After 6 months the patient expressed the desire to switch from clozapine to olanzapine for several reasons: a) previous good outcome with olanzapine; b) less strict monitoring regimen; c) clozapine induced constipation. We chose the cross-tapering switch (6 weeks) in order to avoid rebound symptoms, based on our previous experience as well as the expert’s opinion on this topic.18 The cross-tapering switch is presented in Figure 1.Figure 1 Clozapine to olanzapine cross-tapering.
Visit at 1 year after discharge revealed full remission of symptoms and a good level of functioning on 10 mg/day olanzapine. We decided to gradually stop treatment with olanzapine during next 8 weeks. There were no signs of relapse at 6 months later. Family considered patient fully recovered.
Discussions and Conclusions
To our knowledge, PPP are very rarely treated with clozapine and data is limited on this topic. Most data are available from case reports and small studies. The term “resistant postpartum psychosis” is an analogy to the treatment-resistant schizophrenia, in which patients have persistent symptoms despite at least two adequate trials of neuroleptic drugs, over a prolonged period of time.18,19 In treatment-resistant schizophrenia clozapine is the gold standard.20
The risks for infants exposed to clozapine from breast milk are unknown. However, Imaz et al21 did not find any acute toxicological effect in the exposed newborns. Meanwhile, the majority of women stop breastfeeding during psychiatric hospitalization and therefore clozapine could be an alternative for the patients that are unresponsive to other antipsychotics. The treatment generally includes sequential administration of short-term benzodiazepines, antipsychotics, and lithium, with response monitoring.22
Insufficient response to an antipsychotic is most often followed by changing the antipsychotic, which is associated with an increased risk of side effects, prolonged hospitalization and major psychological consequences for the patient and family. Cases of long-term treatment-resistant psychoses with onset during the postpartum period have been reported and a few studies have explored the efficacy of electroconvulsive therapy, but data sustaining the best therapeutic attitude for these cases is lacking.22,23
The recognition of treatment-resistant postpartum psychosis as a rare but severe condition will probably make the clinicians weigh clozapine as an efficient and safe treatment.
In Romania clozapine is indicated for TRS and psychosis in Alzheimer’s Disease. According to our Hospital’s protocols, we are allowed to use clozapine in patients with another psychiatric diseases in cases with severe agitation, aggressiveness, recurrent suicidal or self-mutilation behavior. This experience resulted from the numerous cases that needed to be resolved quickly in order to prevent prolonged mechanical restraint, loaded therapeutic regimens, prolonged hospitalization, etc.24
An important aspect of our report was the duration of antipsychotic treatment after discharge. Due to the high risk of relapse after postpartum psychosis, we considered necessary to continue the treatment for at least 1 year.25 A recent meta-analysis shows that more than 40% of women were classified as having “isolated postpartum psychosis” which could be considered a distinct diagnostic category. The remaining 60% of women had severe non-puerperal psychotic episodes during longitudinal follow-up.26,27
Although data is extremely limited, clozapine has been shown to be effective and safe in this severe case of treatment-resistant PPP. Further studies will show whether clozapine might be an option for all patients with treatment-resistant postpartum psychosis.
Abbreviations
PPP, Postpartum psychosis; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, 5th edition; TRS, treatment-resistant schizophrenia; FGAs, First-generation antipsychotics; SGAs, Second-generation antipsychotics; CYPP450, Cytochrome P450; CYP1A2, Cytochrome P1A2; CYP3A4, Cytochrome P3A4.
Data Sharing Statement
Not applicable.
Ethics Approval
Not applicable.
Consent for Publication
The patient signed a voluntary written informed consent form authorizing the publication. A copy is available if requested.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Disclosure
All authors declare that they have no conflict of interests for this work. | CABERGOLINE, DIAZEPAM, HALOPERIDOL | DrugsGivenReaction | CC BY-NC | 33603521 | 19,741,679 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Extrapyramidal disorder'. | Clozapine Efficacy in a Case of Severe Treatment-Resistant Postpartum Psychosis.
The postpartum period is a difficult time for mother and family. Unfortunately, in some cases, two psychiatric complications may occur: postpartum psychoses (PPP) with a prevalence of 0.2% and a very low incidence of 0.25-0.50 per 1000 deliveries, and post-natal depressions with an incidence of 10 to 20% per 1000 deliveries. The onset of postpartum psychosis is in the first 4 weeks after childbirth with symptoms such as emotional lability, cognitive disorganization, delusional beliefs and hallucinations. It requires hospitalization due to the high risk of suicide and infanticide. The studies reveal that the treatment can include FGAs (first-generation antipsychotics), such as haloperidol, and SGAs (second-generation antipsychotics), such as olanzapine, quetiapine and risperidone. The literature is scarce in what resistant PPP is concerned and no such cases treated with clozapine have been reported, according to our knowledge. The present case report focuses on a female diagnosed with PPP who was treated with clozapine due to the lack of response to adequate dosage of 2 second-generation antipsychotics.
We present the case of a 30-year-old primiparous woman on her 3rd day after delivery, admitted in the psychiatric emergency unit for agitation, intrusive thoughts with a content frequently related to the infant, ideas of reference, disorganized speech, bizarre behavior, verbal stereotypes, insomnia and anxiety. Due to lack of response to adequate dosage of 2 second-generation antipsychotics, clozapine was initiated up to 250 mg/day. The symptoms remitted in the next 5 days and the patient was discharged. After discharge, at the patient's request, clozapine was replaced by olanzapine. Visit at 1 year revealed full remission of symptoms.
Although data is extremely limited, clozapine has been shown to be effective and safe in a severe case of treatment-resistant PPP.
Background
The postpartum period is a difficult time for mother and family. Unfortunately, in some cases, two psychiatric complications may occur: postpartum psychoses (PPP) with a prevalence of 0.2% and a very low incidence of 0.25–0.50 per 1000 deliveries and post-natal depressions with an incidence of 10 to 20% per 1000 deliveries. The postpartum psychosis is not only rare, but it is also not officially recognized as a distinct disorder in DSM-5.1,2
The onset of postpartum psychosis (a psychiatric emergency) is in the first 4 weeks after childbirth; it is marked by symptoms such as emotional lability, cognitive disorganization, delusional beliefs and hallucinations and it is most likely an overt presentation of bipolar disorder.3 It requires hospitalization due to the high risk of suicide and infanticide.4 Infanticide is associated with imperative hallucinations that command to kill the child or delusions that the child is possessed.5
The risk of developing psychosis is higher in the first 30 days after childbirth, especially in primiparous. Women who are already vulnerable as a result of genetics or stressful environmental exposure are susceptible to mental disease in this period and this was attributed to neuro-hormonal factors.6 The levels of estrogen and oxytocin gradually rise during the pregnancy and drop sharply after delivery, returning to normal within 3 weeks. Considering that the occurrence of psychosis is associated in time with the abrupt decline of the two hormones, an increased sensitivity of dopamine receptors due to the sudden decrease in estrogen levels has been involved. Given the putative role of estradiol and oxytocin in the pathophysiology, both estrogens (sometimes associated with progesterone) and oxytocin have been tested as potential treatments for nonpsychotic and psychotic illness in the puerperium, but the results of the clinical studies available so far are inconclusive to sustain their use.6
Jones et al conducted a genome-wide linkage study in families with bipolar disorder in which at least one woman had suffered a manic or psychotic episode within 6 weeks postpartum. They reported significant linkage signal on chromosome 16p13 and a suggestive linkage signal on chromosome 8q24, which suggests that chromosome 16 and chromosome 8 may contain genes potentially involved in the predisposition to puerperal psychosis.7
The other risk factors include being unmarried, first baby, Caesarian section, perinatal death, all this under the name of psychological stress. Also, women with a history of manic or depressive episodes have a higher risk than women with schizophrenia.8 Almost 10% of women hospitalized for psychiatric morbidity before delivery develop postpartum psychosis after their first birth.9 Of all women with PPP, 70% to 90% have bipolar disorder or schizoaffective disorder, while approximately 12% have schizophrenia.10,11 The risk of non-puerperal admission is higher for women with schizophrenia and PPP is a part of a lifelong recurrent psychiatric disorder.12
Generally, the prognosis for a singular episode is favorable, with symptoms remission and good social and occupational functioning in 75–86% of the cases. However, it is considered as belonging to the bipolar spectrum, with potential recurrences13 or as a part of schizophrenia with 50% recoveries, 33% recurrent episodes and 5% treatment-resistant schizophrenia (TRS) cases.14,15
Treatment for PPP is similar with non-puerperal episodes. The existing studies reveal that the treatment can include FGAs (first-generation antipsychotics), such as haloperidol, and SGAs (second-generation antipsychotics), such as olanzapine, quetiapine and risperidone. Olanzapine and quetiapine are preferred during breastfeeding, other antipsychotics are rarely mentioned.16,17
Regarding the association of gonadal hormones with antipsychotic use, there are still many aspects to be elucidated. While convincing evidence on their benefits is still missing, many factors should be taken into consideration. For instance, pharmacokinetic interactions of hormones with CYPP450 enzymes might change the plasma concentration of antipsychotics, thus influencing their effect on psychotic symptoms independent of the pharmacodynamics of estrogen. In this case, the outcome may depend on the antipsychotic agent; olanzapine and clozapine are metabolized by CYP1A2 liver enzyme, which is inhibited by estrogen; co-administration of estrogen will increase the antipsychotic level, while quetiapine is mainly metabolized by CYP3A4, which is induced by estrogens, so the antipsychotic level will decrease.6
The literature is very scarce in what resistant PPP is concerned and according to our knowledge no such cases treated with clozapine have been reported.
The present case report focuses on a female diagnosed with PPP who was treated with clozapine due to lack of response to adequate dosage of two SGAs. The Hospital Ethics’ Committee approval was not necessary for the publication of this case report. The patient provided written consent for the anonymous publication of her case.
Case Presentation
We present the case of a 30-year-old primiparous woman, brought by her husband on day 3 postpartum and admitted in the psychiatric emergency unit for agitation, intrusive thoughts with a content frequently related to the infant, ideas of reference, disorganized speech, bizarre behavior, verbal stereotypes, insomnia and anxiety.
From her history, we noticed a previous psychotic episode at the age of 24, successfully treated with olanzapine 10 mg/day for 6 months and then stopped at her physician’s recommendation. This episode was closely related to a stressful event. The patient had fully recovered without any residual symptoms. She got married and worked without any psychiatric problems. The biological investigations showed mild iron-deficiency anemia, mild hypercholesterolemia. The head computer tomography scan was normal. On admission, she was treated with injectable haloperidol 5 mg/day, diazepam 20mg/day and cabergoline 1mg/day for two days for ablactation. Due to extrapyramidal side effects (acute dystonia and rigidity), she was switched to olanzapine 20 mg/day, lorazepam 4 mg/day and trihexyphenidyl 4mg/day. Since no significant clinical response was registered after 2 weeks, the patient received add-on therapy with risperidone 4 mg/day. Despite the combination of two potent antipsychotics administered in proper doses, the patient remained intensely psychotic and 4 points mechanical restraint was often necessary. She started saying that she would kill herself to escape the terror caused by what was happening. She started being aggressive and presenting the Capgras delusion. Since she was non-responsive to adequate dosage of two second-generation antipsychotics, standard titration of clozapine was initiated up to 250 mg/day with ongoing monitoring in conformity with the current guidelines. Benzodiazepines were tapered off to discontinuation. The symptoms remitted in the next 5 days and the patient was discharged. After discharge, she continued the treatment for 6 months.
After 6 months the patient expressed the desire to switch from clozapine to olanzapine for several reasons: a) previous good outcome with olanzapine; b) less strict monitoring regimen; c) clozapine induced constipation. We chose the cross-tapering switch (6 weeks) in order to avoid rebound symptoms, based on our previous experience as well as the expert’s opinion on this topic.18 The cross-tapering switch is presented in Figure 1.Figure 1 Clozapine to olanzapine cross-tapering.
Visit at 1 year after discharge revealed full remission of symptoms and a good level of functioning on 10 mg/day olanzapine. We decided to gradually stop treatment with olanzapine during next 8 weeks. There were no signs of relapse at 6 months later. Family considered patient fully recovered.
Discussions and Conclusions
To our knowledge, PPP are very rarely treated with clozapine and data is limited on this topic. Most data are available from case reports and small studies. The term “resistant postpartum psychosis” is an analogy to the treatment-resistant schizophrenia, in which patients have persistent symptoms despite at least two adequate trials of neuroleptic drugs, over a prolonged period of time.18,19 In treatment-resistant schizophrenia clozapine is the gold standard.20
The risks for infants exposed to clozapine from breast milk are unknown. However, Imaz et al21 did not find any acute toxicological effect in the exposed newborns. Meanwhile, the majority of women stop breastfeeding during psychiatric hospitalization and therefore clozapine could be an alternative for the patients that are unresponsive to other antipsychotics. The treatment generally includes sequential administration of short-term benzodiazepines, antipsychotics, and lithium, with response monitoring.22
Insufficient response to an antipsychotic is most often followed by changing the antipsychotic, which is associated with an increased risk of side effects, prolonged hospitalization and major psychological consequences for the patient and family. Cases of long-term treatment-resistant psychoses with onset during the postpartum period have been reported and a few studies have explored the efficacy of electroconvulsive therapy, but data sustaining the best therapeutic attitude for these cases is lacking.22,23
The recognition of treatment-resistant postpartum psychosis as a rare but severe condition will probably make the clinicians weigh clozapine as an efficient and safe treatment.
In Romania clozapine is indicated for TRS and psychosis in Alzheimer’s Disease. According to our Hospital’s protocols, we are allowed to use clozapine in patients with another psychiatric diseases in cases with severe agitation, aggressiveness, recurrent suicidal or self-mutilation behavior. This experience resulted from the numerous cases that needed to be resolved quickly in order to prevent prolonged mechanical restraint, loaded therapeutic regimens, prolonged hospitalization, etc.24
An important aspect of our report was the duration of antipsychotic treatment after discharge. Due to the high risk of relapse after postpartum psychosis, we considered necessary to continue the treatment for at least 1 year.25 A recent meta-analysis shows that more than 40% of women were classified as having “isolated postpartum psychosis” which could be considered a distinct diagnostic category. The remaining 60% of women had severe non-puerperal psychotic episodes during longitudinal follow-up.26,27
Although data is extremely limited, clozapine has been shown to be effective and safe in this severe case of treatment-resistant PPP. Further studies will show whether clozapine might be an option for all patients with treatment-resistant postpartum psychosis.
Abbreviations
PPP, Postpartum psychosis; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, 5th edition; TRS, treatment-resistant schizophrenia; FGAs, First-generation antipsychotics; SGAs, Second-generation antipsychotics; CYPP450, Cytochrome P450; CYP1A2, Cytochrome P1A2; CYP3A4, Cytochrome P3A4.
Data Sharing Statement
Not applicable.
Ethics Approval
Not applicable.
Consent for Publication
The patient signed a voluntary written informed consent form authorizing the publication. A copy is available if requested.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Disclosure
All authors declare that they have no conflict of interests for this work. | CABERGOLINE, DIAZEPAM, HALOPERIDOL | DrugsGivenReaction | CC BY-NC | 33603521 | 19,741,679 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Muscle rigidity'. | Clozapine Efficacy in a Case of Severe Treatment-Resistant Postpartum Psychosis.
The postpartum period is a difficult time for mother and family. Unfortunately, in some cases, two psychiatric complications may occur: postpartum psychoses (PPP) with a prevalence of 0.2% and a very low incidence of 0.25-0.50 per 1000 deliveries, and post-natal depressions with an incidence of 10 to 20% per 1000 deliveries. The onset of postpartum psychosis is in the first 4 weeks after childbirth with symptoms such as emotional lability, cognitive disorganization, delusional beliefs and hallucinations. It requires hospitalization due to the high risk of suicide and infanticide. The studies reveal that the treatment can include FGAs (first-generation antipsychotics), such as haloperidol, and SGAs (second-generation antipsychotics), such as olanzapine, quetiapine and risperidone. The literature is scarce in what resistant PPP is concerned and no such cases treated with clozapine have been reported, according to our knowledge. The present case report focuses on a female diagnosed with PPP who was treated with clozapine due to the lack of response to adequate dosage of 2 second-generation antipsychotics.
We present the case of a 30-year-old primiparous woman on her 3rd day after delivery, admitted in the psychiatric emergency unit for agitation, intrusive thoughts with a content frequently related to the infant, ideas of reference, disorganized speech, bizarre behavior, verbal stereotypes, insomnia and anxiety. Due to lack of response to adequate dosage of 2 second-generation antipsychotics, clozapine was initiated up to 250 mg/day. The symptoms remitted in the next 5 days and the patient was discharged. After discharge, at the patient's request, clozapine was replaced by olanzapine. Visit at 1 year revealed full remission of symptoms.
Although data is extremely limited, clozapine has been shown to be effective and safe in a severe case of treatment-resistant PPP.
Background
The postpartum period is a difficult time for mother and family. Unfortunately, in some cases, two psychiatric complications may occur: postpartum psychoses (PPP) with a prevalence of 0.2% and a very low incidence of 0.25–0.50 per 1000 deliveries and post-natal depressions with an incidence of 10 to 20% per 1000 deliveries. The postpartum psychosis is not only rare, but it is also not officially recognized as a distinct disorder in DSM-5.1,2
The onset of postpartum psychosis (a psychiatric emergency) is in the first 4 weeks after childbirth; it is marked by symptoms such as emotional lability, cognitive disorganization, delusional beliefs and hallucinations and it is most likely an overt presentation of bipolar disorder.3 It requires hospitalization due to the high risk of suicide and infanticide.4 Infanticide is associated with imperative hallucinations that command to kill the child or delusions that the child is possessed.5
The risk of developing psychosis is higher in the first 30 days after childbirth, especially in primiparous. Women who are already vulnerable as a result of genetics or stressful environmental exposure are susceptible to mental disease in this period and this was attributed to neuro-hormonal factors.6 The levels of estrogen and oxytocin gradually rise during the pregnancy and drop sharply after delivery, returning to normal within 3 weeks. Considering that the occurrence of psychosis is associated in time with the abrupt decline of the two hormones, an increased sensitivity of dopamine receptors due to the sudden decrease in estrogen levels has been involved. Given the putative role of estradiol and oxytocin in the pathophysiology, both estrogens (sometimes associated with progesterone) and oxytocin have been tested as potential treatments for nonpsychotic and psychotic illness in the puerperium, but the results of the clinical studies available so far are inconclusive to sustain their use.6
Jones et al conducted a genome-wide linkage study in families with bipolar disorder in which at least one woman had suffered a manic or psychotic episode within 6 weeks postpartum. They reported significant linkage signal on chromosome 16p13 and a suggestive linkage signal on chromosome 8q24, which suggests that chromosome 16 and chromosome 8 may contain genes potentially involved in the predisposition to puerperal psychosis.7
The other risk factors include being unmarried, first baby, Caesarian section, perinatal death, all this under the name of psychological stress. Also, women with a history of manic or depressive episodes have a higher risk than women with schizophrenia.8 Almost 10% of women hospitalized for psychiatric morbidity before delivery develop postpartum psychosis after their first birth.9 Of all women with PPP, 70% to 90% have bipolar disorder or schizoaffective disorder, while approximately 12% have schizophrenia.10,11 The risk of non-puerperal admission is higher for women with schizophrenia and PPP is a part of a lifelong recurrent psychiatric disorder.12
Generally, the prognosis for a singular episode is favorable, with symptoms remission and good social and occupational functioning in 75–86% of the cases. However, it is considered as belonging to the bipolar spectrum, with potential recurrences13 or as a part of schizophrenia with 50% recoveries, 33% recurrent episodes and 5% treatment-resistant schizophrenia (TRS) cases.14,15
Treatment for PPP is similar with non-puerperal episodes. The existing studies reveal that the treatment can include FGAs (first-generation antipsychotics), such as haloperidol, and SGAs (second-generation antipsychotics), such as olanzapine, quetiapine and risperidone. Olanzapine and quetiapine are preferred during breastfeeding, other antipsychotics are rarely mentioned.16,17
Regarding the association of gonadal hormones with antipsychotic use, there are still many aspects to be elucidated. While convincing evidence on their benefits is still missing, many factors should be taken into consideration. For instance, pharmacokinetic interactions of hormones with CYPP450 enzymes might change the plasma concentration of antipsychotics, thus influencing their effect on psychotic symptoms independent of the pharmacodynamics of estrogen. In this case, the outcome may depend on the antipsychotic agent; olanzapine and clozapine are metabolized by CYP1A2 liver enzyme, which is inhibited by estrogen; co-administration of estrogen will increase the antipsychotic level, while quetiapine is mainly metabolized by CYP3A4, which is induced by estrogens, so the antipsychotic level will decrease.6
The literature is very scarce in what resistant PPP is concerned and according to our knowledge no such cases treated with clozapine have been reported.
The present case report focuses on a female diagnosed with PPP who was treated with clozapine due to lack of response to adequate dosage of two SGAs. The Hospital Ethics’ Committee approval was not necessary for the publication of this case report. The patient provided written consent for the anonymous publication of her case.
Case Presentation
We present the case of a 30-year-old primiparous woman, brought by her husband on day 3 postpartum and admitted in the psychiatric emergency unit for agitation, intrusive thoughts with a content frequently related to the infant, ideas of reference, disorganized speech, bizarre behavior, verbal stereotypes, insomnia and anxiety.
From her history, we noticed a previous psychotic episode at the age of 24, successfully treated with olanzapine 10 mg/day for 6 months and then stopped at her physician’s recommendation. This episode was closely related to a stressful event. The patient had fully recovered without any residual symptoms. She got married and worked without any psychiatric problems. The biological investigations showed mild iron-deficiency anemia, mild hypercholesterolemia. The head computer tomography scan was normal. On admission, she was treated with injectable haloperidol 5 mg/day, diazepam 20mg/day and cabergoline 1mg/day for two days for ablactation. Due to extrapyramidal side effects (acute dystonia and rigidity), she was switched to olanzapine 20 mg/day, lorazepam 4 mg/day and trihexyphenidyl 4mg/day. Since no significant clinical response was registered after 2 weeks, the patient received add-on therapy with risperidone 4 mg/day. Despite the combination of two potent antipsychotics administered in proper doses, the patient remained intensely psychotic and 4 points mechanical restraint was often necessary. She started saying that she would kill herself to escape the terror caused by what was happening. She started being aggressive and presenting the Capgras delusion. Since she was non-responsive to adequate dosage of two second-generation antipsychotics, standard titration of clozapine was initiated up to 250 mg/day with ongoing monitoring in conformity with the current guidelines. Benzodiazepines were tapered off to discontinuation. The symptoms remitted in the next 5 days and the patient was discharged. After discharge, she continued the treatment for 6 months.
After 6 months the patient expressed the desire to switch from clozapine to olanzapine for several reasons: a) previous good outcome with olanzapine; b) less strict monitoring regimen; c) clozapine induced constipation. We chose the cross-tapering switch (6 weeks) in order to avoid rebound symptoms, based on our previous experience as well as the expert’s opinion on this topic.18 The cross-tapering switch is presented in Figure 1.Figure 1 Clozapine to olanzapine cross-tapering.
Visit at 1 year after discharge revealed full remission of symptoms and a good level of functioning on 10 mg/day olanzapine. We decided to gradually stop treatment with olanzapine during next 8 weeks. There were no signs of relapse at 6 months later. Family considered patient fully recovered.
Discussions and Conclusions
To our knowledge, PPP are very rarely treated with clozapine and data is limited on this topic. Most data are available from case reports and small studies. The term “resistant postpartum psychosis” is an analogy to the treatment-resistant schizophrenia, in which patients have persistent symptoms despite at least two adequate trials of neuroleptic drugs, over a prolonged period of time.18,19 In treatment-resistant schizophrenia clozapine is the gold standard.20
The risks for infants exposed to clozapine from breast milk are unknown. However, Imaz et al21 did not find any acute toxicological effect in the exposed newborns. Meanwhile, the majority of women stop breastfeeding during psychiatric hospitalization and therefore clozapine could be an alternative for the patients that are unresponsive to other antipsychotics. The treatment generally includes sequential administration of short-term benzodiazepines, antipsychotics, and lithium, with response monitoring.22
Insufficient response to an antipsychotic is most often followed by changing the antipsychotic, which is associated with an increased risk of side effects, prolonged hospitalization and major psychological consequences for the patient and family. Cases of long-term treatment-resistant psychoses with onset during the postpartum period have been reported and a few studies have explored the efficacy of electroconvulsive therapy, but data sustaining the best therapeutic attitude for these cases is lacking.22,23
The recognition of treatment-resistant postpartum psychosis as a rare but severe condition will probably make the clinicians weigh clozapine as an efficient and safe treatment.
In Romania clozapine is indicated for TRS and psychosis in Alzheimer’s Disease. According to our Hospital’s protocols, we are allowed to use clozapine in patients with another psychiatric diseases in cases with severe agitation, aggressiveness, recurrent suicidal or self-mutilation behavior. This experience resulted from the numerous cases that needed to be resolved quickly in order to prevent prolonged mechanical restraint, loaded therapeutic regimens, prolonged hospitalization, etc.24
An important aspect of our report was the duration of antipsychotic treatment after discharge. Due to the high risk of relapse after postpartum psychosis, we considered necessary to continue the treatment for at least 1 year.25 A recent meta-analysis shows that more than 40% of women were classified as having “isolated postpartum psychosis” which could be considered a distinct diagnostic category. The remaining 60% of women had severe non-puerperal psychotic episodes during longitudinal follow-up.26,27
Although data is extremely limited, clozapine has been shown to be effective and safe in this severe case of treatment-resistant PPP. Further studies will show whether clozapine might be an option for all patients with treatment-resistant postpartum psychosis.
Abbreviations
PPP, Postpartum psychosis; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, 5th edition; TRS, treatment-resistant schizophrenia; FGAs, First-generation antipsychotics; SGAs, Second-generation antipsychotics; CYPP450, Cytochrome P450; CYP1A2, Cytochrome P1A2; CYP3A4, Cytochrome P3A4.
Data Sharing Statement
Not applicable.
Ethics Approval
Not applicable.
Consent for Publication
The patient signed a voluntary written informed consent form authorizing the publication. A copy is available if requested.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Disclosure
All authors declare that they have no conflict of interests for this work. | CABERGOLINE, DIAZEPAM, HALOPERIDOL | DrugsGivenReaction | CC BY-NC | 33603521 | 19,741,679 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood creatinine increased'. | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | ABEMACICLIB, AMLODIPINE BESYLATE, BROTIZOLAM, DOXAZOSIN MESYLATE, FULVESTRANT, GLIMEPIRIDE, INDOMETHACIN, LOPERAMIDE HYDROCHLORIDE, LOXOPROFEN SODIUM DIHYDRATE, PRAVASTATIN SODIUM, REBAMIPIDE, VALSARTAN | DrugsGivenReaction | CC BY-NC-ND | 33604051 | 19,837,038 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | BEVACIZUMAB, DENOSUMAB, FULVESTRANT, LETROZOLE, PACLITAXEL | DrugsGivenReaction | CC BY-NC-ND | 33604051 | 19,790,942 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypoglycaemia'. | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | ABEMACICLIB, AMLODIPINE BESYLATE, BROTIZOLAM, DOXAZOSIN MESYLATE, FULVESTRANT, GLIMEPIRIDE, INDOMETHACIN, LOPERAMIDE HYDROCHLORIDE, LOXOPROFEN SODIUM DIHYDRATE, PRAVASTATIN SODIUM, REBAMIPIDE, VALSARTAN | DrugsGivenReaction | CC BY-NC-ND | 33604051 | 19,837,038 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal impairment'. | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | ABEMACICLIB, AMLODIPINE BESYLATE, BROTIZOLAM, DOXAZOSIN MESYLATE, FULVESTRANT, GLIMEPIRIDE, INDOMETHACIN, LOPERAMIDE HYDROCHLORIDE, LOXOPROFEN SODIUM DIHYDRATE, PRAVASTATIN SODIUM, REBAMIPIDE, VALSARTAN | DrugsGivenReaction | CC BY-NC-ND | 33604051 | 19,837,038 | 2021-03 |
What was the administration route of drug 'ABEMACICLIB'? | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33604051 | 19,837,038 | 2021-03 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.