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Methods | PMC10436133 | |||
Trial Design | anxiety | RECRUITMENT | This randomized clinical trial was approved by the institutional review board at the University of Miami. All participants provided verbal informed consent or assent. This study followed the Consolidated Standards of Reporting Trials (Participants were recruited from the University of Miami and included patients who were indicated to have an elective, outpatient orthopedic surgery with the senior author (L.D.K.). Recruitment began in November 2021, and the follow-up for the final patient was completed in October 2022.To investigate the effect of a preoperative AR training experience on patient anxiety, we randomized 140 patients to receive either the AR experience or the standard set of preoperative instructions as a control. The interactive AR experience was a custom application developed in-house in collaboration with our institution’s Center for Computational Science by Xennial Digital Studios. The AR intervention visually walks patients through their trip to the operating room with narration from their surgeon while using an AR headset. The development was funded by an institutional grant of $10 000 that covered the costs of the application design and development. The AR experience takes approximately 3 minutes. Inclusion criteria consisted of all patients aged 12 years or older who were scheduled to have an ambulatory procedure with our senior author. Patients were excluded if they did not speak English (as the AR application was recorded only in English) or if they had circumstances that would prevent them from meeting or performing study requirements, such as canceling surgery or not completing the required surveys. After patients were indicated for surgery and given a surgical date, verbal informed consent was obtained. Patients were then randomized into 1 of 2 groups (AR or control) using a randomization table by whoever was performing the enrollment (M.G.R, J.P.C., or D.L.) ( | PMC10436133 |
Trial Flowchart and Survey Schedule | PMC10436133 | |||
Outcomes | Anxiety, anxiety | To quantify anxiety levels, we used the State-Trait Anxiety Inventory (STAI; range, 20-80; higher score indicates a higher level of anxiety), which is a validated and widely used survey to determine patients’ anxiety. | PMC10436133 | |
Statistical Analysis | pain | An a priori power analysis was conducted to determine the number of patients needed to detect a difference in STAI scores between the groups. To detect a clinically meaningful difference of a change of 5 points in the STAI with a power of 0.8, a significance level of 0.05, and an SD of 8.9, 51 patients were needed in each group. The SD used was based on a separate study involving patients undergoing procedures under general anesthesia.To determine whether we were appropriately powered to detect a clinically meaningful difference of 2 points in VAS, we conducted a post-hoc power analysis: with 80% power to detect α = .05, based on our VAS SD of 3.12, we required 40 patients in each group; as there were only 24 patients who completed the pain portion of the postoperative survey, we did not reach appropriate confidence for definitive conclusion for this comparison.Continuous variables are presented as mean and SD. Categorical variables are presented as count and percentage. Mann-Whitney | PMC10436133 | |
Results | psychiatric comorbidity | Of 140 eligible patients, 45 patients either declined or were excluded; therefore, 95 patients (63 [66.3%] male; mean [SD] age, 38 [16] years; range, 14-78 years) were recruited for the study and included in the final analysis, with 46 patients randomized to receive the AR intervention and 49 patients randomized to the standard instructions control group. There were no significant differences between AR and control groups with respect to age (mean [SD], 38 [16] years vs 38 [17] years), sex (30 [65.2%] male vs 33 [67.3%] male), ASA score (eg, ASA class 1: 23 patients [50.0%] vs 23 patients [46.9%]), smoking history (eg, never smoker: 40 patients vs 41 patients), psychiatric comorbidity (1 patient [2.2%] vs 6 patients [12.2%]), surgical location (eg, knee: 33 patients [71.7%] vs 31 patients [63.3%]), days between the preoperative appointment and date of surgery (mean [SD], 28 [32] days vs 26 [23] days), or screening STAI score (mean [SD], 35 [10] vs 35 [12]) ( | PMC10436133 | |
Basic Demographics and Clinical Factors Between Groups | Anxiety, anxiety | Abbreviations: AR, augmented reality; ASA, American Society of Anesthesiologists; STAI, State-Trait Anxiety Inventory.ASA score was not available for 1 patient in the AR group. There were no patients with ASA class 4 or higher included in the study.Range, 20 to 80; higher scores indicate greater levels of anxiety.To determine whether patients who received the AR experience had a change in their preoperative anxiety, we compared the differences in postintervention and preoperative STAI scores vs screening scores ( | PMC10436133 | |
Changes in State-Trait Anxiety Inventory Scores Between Groups at Different Survey Points | Abbreviation: AR, augmented reality.We additionally compared the changes from the screening and preoperative surveys to postoperative surveys ( | PMC10436133 | ||
Changes in State-Trait Anxiety Inventory Scores for the Augmented Reality Group Between Survey Points by Body Part | postoperative pain, pain | Analyses were performed using analysis of variance. .To determine whether the AR intervention influenced postoperative pain or narcotic use, patients were asked their pain levels as well as narcotic use both on postoperative day 1 and at the time of the postoperative appointment (7 to 10 days after surgery). There were no significant differences between groups with respect to postoperative pain or narcotic pill use on postoperative day 1 or at the time of the postoperative appointment (eTable in Among patients who underwent the AR intervention, 42 patients were additionally asked about their overall experience with the AR application. Most patients either agreed or strongly agreed that they enjoyed the AR experience (30 patients [71.4%]), would recommend the experience (29 patients [69.0%]), and would do it again (28 patients [66.7%]) ( | PMC10436133 | |
Augmented Reality (AR) Group Experiences With the AR Application | PMC10436133 | |||
Discussion | disorientation, postoperative pain, anxiety, pain | DISEASE, EVENTS, MOTION SICKNESS | Our randomized clinical trial focused on the effect of AR on the patient’s entire experience at our institution’s outpatient surgical center, from initial outpatient preoperative visit to completion of the scheduled surgery, and its effects on perceived anxiety and satisfaction. Our custom AR experience allowed a patient to visually walk through their day at the surgery center with narration from their surgeon, and it was designed to emulate what the patient would encounter on the day of surgery. This experience included a visual representation of the building, layout of the surgical center, progression from check-in to preoperative care, to the operating room, and finally postoperative care. Furthermore, a strength of our AR technology was that patients had the opportunity to revisit modules of the AR experience if they wanted to view them again. Users could also interact with the AR application by zooming in and out and rotating the model for a more personalized experience. The ultimate goal of our AR experience was to educate and prepare the patient for what to expect, potentially mitigating the cognitive and physiological burden of anxiety they perceived surrounding their surgery.We found that our AR experience significantly decreased patients’ preoperative anxiety even immediately from the time of screening to after intervention completion, with lasting effects until the time of surgery. This is contrasted with the control group, who had little significant change in their screening to postintervention surveys but did experience an increase in anxiety from screening to preoperative surveys. These changes subsided after surgery, with all patients showing a decrease in anxiety from their screening survey, with no significant difference between the groups. The focus of our AR application was on the day-of-surgery events and the immediate preoperative experience, which might explain the lack of observed postoperative differences. However, this study was underpowered, so this lack of statistical power increases the risk of type II error, potentially masking a significant effect.We also examined the AR experience’s effect on postoperative pain and narcotic use. There were no significant differences between groups on VAS pain scores or narcotic use. These results are limited by the fact that they were patient-reported at the time of their postoperative survey and could thus be influenced by recall bias. Our study could have been strengthened by contacting patients on postoperative day 1 to determine VAS and narcotic use at that time point. We conducted a post-hoc power analysis to assess whether this study was appropriately powered to detect a clinically meaningful difference in VAS, and we did not reach appropriate confidence for definitive conclusion for this comparison. Previous studies have suggested that pain scores might be improved with the assistance of VR.While most patients who completed the AR experience did enjoy it, some did not. Indeed, approximately 10% to 15% of patients disagreed or strongly disagreed that they enjoyed the experience, would recommend it, and would do it again. Specific factors cited for their criticism were disorientation associated with using the AR headset, as well as the quality of the animations present. Patients with glasses sometimes had difficulty with the headset and fitting their glasses inside it so that they could see it project across the room. Although visually induced motion sickness is a well-described phenomenon with VR and AR, no patients in our study experienced any.We additionally examined whether patient experience with AR had any association with their anxiety levels. Interestingly, not enjoying the AR experience was not associated with the intervention’s efficacy of decreasing preoperative anxiety, as there was no significant difference in STAI score from screening to the preoperative survey between patients who underwent the AR experience and were neutral, enjoyed, or strongly enjoyed the experience compared with those who did not enjoy or strongly did not enjoy it. This suggests that the mental exercise of experiencing the operative day walkthrough in AR has an anxiolytic effect and is not dependent on ultimate enjoyment.To our knowledge, limited randomized clinical trials have investigated the utility of an AR educational experience to prepare a patient for their day of surgery. A 2019 study by Eijlers et alOther studies have looked at VR and AR and patient education focusing on digital imaging and 3-dimensional models to educate the patient on the specifics of their involved anatomy and provide a detailed visual representation of the steps of the surgery, yet these were primarily interested in patient understanding of the disease process and not on the effect on perioperative anxiety. | PMC10436133 |
Future Directions | Future directions include the inclusion of multiple centers with multiple surgeons and expansion to other languages. Our current experience focused exclusively on the day-of-surgery experience and did not provide any postoperative instructions, such as wound care or physical therapy, so adding these components might also impact patient experience and potentially even outcomes. | PMC10436133 | ||
Limitations | anxiety | Our study has some limitations. First, this study was performed at a single institution with a single surgeon, and it was custom built to depict the exact process our patients experience. Generalizability is thus limited, since patients at other centers or with other surgeons may not experience a benefit. Additionally, we did not control for the presence of previous surgical procedures between the groups: a patient who has undergone surgery previously might not experience as much anxiety as someone who has never undergone surgery and is not as engaged in the experience. Furthermore, since participation was voluntary, our results may have been influenced by self-selection bias. Once enrolled, some patients no longer wished to complete the surveys, and this accounted for a small but noticeable attrition rate between patients who completed the preoperative surveys and those who did not complete either the entire or portions of the postoperative survey. Additionally, the study was underpowered in both groups, which increases the risk of type II error and reduces our confidence in the findings that were not statistically significant. | PMC10436133 | |
Conclusions | pain, anxiety, postoperative anxiety | In this randomized clinical trial, the administration of a preoperative AR experience decreased preoperative patient anxiety, and with most patient enjoying the experience, but there was no significant effect on postoperative anxiety, pain levels, or narcotic use. These findings suggest that the use of AR may serve as a means of decreasing preoperative patient anxiety. | PMC10436133 | |
Introduction | anxiety | perioperative anxiety in children may lead to psychological and physiological side effects. Clonidine is in increasing use in the pediatric population as an anxiolytic, sedative, and analgesic because of its central alpha2-adrenergic agonist effect. Our study aimed to evaluate the effect of clonidine in the prevention of perioperative children´s anxiety. | PMC10746874 | |
Methods | agitation, anxiety | ADVERSE EFFECTS, SEPARATION | we conducted a prospective controlled randomized double-blinded clinical trial including children aged between 2 and 15 years undergoing tonsillectomy surgery. The patients were randomly allocated to receive either an intranasal dose of clonidine (4 μg/kg) (clonidine group) or an equal volume dose of saline solution (control group) 30 minutes before entering the operating room. The level of anxiety assessed using the m-YPAS score was recorded before premedication, at the time of parent-child separation, and at the time of installation in the operating room. Acceptance of premedication, degree of sedation on entering the operating room as well as agitation on awakening, and sedation on arrival post-anesthesia care unit were noted. Adverse effects were recorded during the surgical procedure and in the postoperative recovery room. | PMC10746874 |
Results | anxiety | the number of patients analyzed was 78 with 39 patients in each group. There were no signification differences in demographic data and premedication acceptance between the two groups. Levels of anxiety before any premedication were similar in the two groups. However, the anxiety level 30 minutes after premedication and in the operating room was significantly lower in the clonidine group (p<0.001). Children who received clonidine showed better sedation on entering the operating room (p=0.002) as well as postoperatively on entering the post-anesthesia unit care (p=0.006). The hemodynamic and respiratory parameters recorded were statistically comparable. | PMC10746874 | |
Conclusion | anxiety | intranasal clonidine is an interesting premedication to prevent perioperative children´s anxiety with few side effects. | PMC10746874 | |
Introduction | anxiety | Up to 60% of children undergoing anesthesia and surgery can experience significant distress and anxiety during the perioperative period [ | PMC10746874 | |
Discussion | anxiety, disorientation, hyperactivity, agitation, postoperative shivering, hypersensitivity | HYPERSENSITIVITY | We conducted a prospective randomized clinical trial to evaluate the efficacity of clonidine in reducing perioperative children´s anxiety. Our study demonstrates that intranasal clonidine is effective in preoperative anxiety, preoperative and postoperative sedation, quality of induction and intubation, quality of awakening after anesthesia, and quality of immediate postoperative period compared to intranasal placebo when it is used as a premedication in children proposed for tonsillectomy.Clonidine is in increasing use in the pediatric population as an anxiolytic, sedative, and analgesic because of its central alpha2-adrenergic agonist effect [Clonidine is responsible for sedation close to physiological sleep from which the patient can be easily awakened and in possession of his cognitive faculties. It has even been shown that once awake, patients are quite capable of carrying out psychomotor tests [All these studies have shown that patients who received clonidine premedication accepted the face mask better than those who received another molecule, thanks to the anxiolytic effect provided by clonidine. Post-anesthetic agitation is a common problem in children who have undergone general anesthesia with sevoflurane. This agitation is characterized by a change in the child's perception of his environment with signs of disorientation, hypersensitivity to stimuli, and hyperactivity. Our study showed that intranasal clonidine reduced significantly postoperative agitation. Zhang In our study, we noted a single case of postoperative shivering in the clonidine group versus 16 children in the placebo group with a significant difference (p<0.001). A Cochrane meta-analysis [Our study has several limitations such as the choice of the sedation evaluation scale. We used it for the evaluation of the sedation on the WHO sedation scale. However, it is a scale applicable after the use of opioid products and whose validity in young patients is still limited. | PMC10746874 |
Conclusion | Intranasal clonidine administration is an interesting alternative as an anxiolytic premedication before pediatric surgery. It produces effective sedation with few side effects. | PMC10746874 | ||
Competing interests | The authors declare no competing interests. | PMC10746874 | ||
Authors' contributions | Conception and design: Mariem Keskes and Nouha Amouri; acquisition of data: Mariem Keskes and Nouha Amouri; analysis and interpretation of data: Mariem Keskes, Nouha Amouri, Salma Ketata, Rahma Derbel, Imen Zouche, and Maha Charfi; drafting the article or revising it critically for important intellectual content: Mariem Keskes, Nouha Amouri, Salma Ketata, Rahma Derbel, Imen Zouche, Hichem Chikhrouhou, Maha Charfi, Moez Elloumi, and Moncef Sallemi; final approval of the version to be published: Mariem Keskes, Nouha Amouri, Salma Ketata, Rahma Derbel, Imen Zouche, Maha Charfi, Moncef Sallemi, Moez Elloumi, and Hichem Chikhrouhou. All the authors read and approved the final version of this manuscript. | PMC10746874 | ||
Background | I have read the journal’s policy and the authors of this manuscript have the following competing interests: BV has a paid role as a member of the Therapeutic Goods Administration. BV, FA and KS own shares in respective IVF companies (Monash IVF, Virtus Health and Melbourne IVF).‡ These authors are joint senior authors on this work.In vitro fertilisation (IVF) is a common mode of conception. Understanding the long-term implications for these children is important. The aim of this study was to determine the causal effect of IVF conception on primary school-age childhood developmental and educational outcomes, compared with outcomes following spontaneous conception. | PMC9873192 | ||
Methods and findings | Causal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. The study cohort comprised statewide linked maternal and childhood administrative data. Participants included singleton infants conceived spontaneously or via IVF, born in Victoria, Australia between 2005 and 2014 and who had school-age developmental and educational outcomes assessed. The exposure examined was conception via IVF, with spontaneous conception the control condition. Two outcome measures were assessed. The first, childhood developmental vulnerability at school entry (age 4 to 6), was assessed using the Australian Early Developmental Census (AEDC) (The study included 412,713 children across the 2 outcome cohorts. Linked records were available for 4,697 IVF-conceived cases and 168,503 controls for AEDC, and 8,976 cases and 333,335 controls for NAPLAN. There was no causal effect of IVF-conception on the risk of developmental vulnerability at school-entry compared with spontaneously conceived children (AEDC metrics), with an adjusted risk difference of −0.3% (95% CI −3.7% to 3.1%) and an adjusted risk ratio of 0.97 (95% CI 0.77 to 1.25). At age 7 to 9 years, there was no causal effect of IVF-conception on the NAPLAN overall z-score, with an adjusted mean difference of 0.030 (95% CI −0.018 to 0.077) between IVF- and spontaneously conceived children. The models were adjusted for sex at birth, age at assessment, language background other than English, socioeconomic status, maternal age, parity, and education. Study limitations included the use of observational data, the potential for unmeasured confounding, the presence of missing data, and the necessary restriction of the cohort to children attending school. | PMC9873192 | ||
Conclusions | In this analysis, under the given causal assumptions, the school-age developmental and educational outcomes for children conceived by IVF are equivalent to those of spontaneously conceived children. These findings provide important reassurance for current and prospective parents and for clinicians.In a population-wide cohort study, Dr Anthea C Lindquist and colleagues, examine school-age outcomes among IVF-conceived children in Australia. | PMC9873192 | ||
Author summary | PMC9873192 | |||
Why was this study done? | congenital abnormalities, intellectual disability, autism spectrum disorder | More than 8 million children have been conceived globally with the assistance of in vitro fertilisation (IVF).Some studies suggest these children have an increased risk of congenital abnormalities, autism spectrum disorder, developmental delay, and intellectual disability.Educational and school-age developmental outcomes following IVF conception have not yet been adequately characterised. | PMC9873192 | |
What did the researchers do and find? | Using statewide, linked population data from Victoria, Australia, we investigated the school-age developmental and educational outcomes for children born following IVF-assisted conception.The study examined 2 separate assessments of school-age development and educational outcomes among 585,659 children, including 11,059 children who were conceived via IVF.This study was designed and performed within a causal framework, in order to produce the best possible estimate of exposure effect using observational data.We found no difference in school-age childhood developmental and educational outcomes between IVF- and spontaneously conceived children. | PMC9873192 | ||
What do these findings mean? | These findings provide reassurance for current and prospective parents, as well as clinicians who are involved in IVF.This information may be useful in providing informed consent and education to those considering IVF and those with children conceived via IVF. | PMC9873192 | ||
Data Availability | Data for this study was provided by various data custodians and linked by the Centre for Victorian Data linkage ( | PMC9873192 | ||
Introduction | COMPLICATIONS | In vitro fertilisation (IVF) is a common mode of conception worldwide [As the number of children born following IVF conception continues to rise, a deeper understanding of the long-term implications for these children is important. It is well established that there are increased risks of maternal and perinatal complications following IVF conception [Educational and cognitive outcomes following IVF conception have not yet been thoroughly investigated. Several small cohort studies [Parents of IVF- and spontaneously conceived children possess inherently different health and sociodemographic characteristics [Our study aimed to overcome some of the limitations of the analysis of observational (non-randomised) data by using a causal inference approach that seeks to emulate the results of a randomised comparison in a clinical trial ( | PMC9873192 | |
Target trial emulation. | SE | AEDC, Australian Early Development Census; ATE, average treatment effect; DAG, directed acyclic graph; IPW, inverse probability weight; IVF, in vitro fertilisation; NAPLAN, National Assessment Program for Literacy and Numeracy; RD, risk difference; RR, relative risk; SE, standard error. | PMC9873192 | |
Methods | PMC9873192 | |||
Study design | This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (Checklist in | PMC9873192 | ||
Population | The study population included all singleton livebirths in Victoria between 2005 and 2014. Twins and higher order multiple births were excluded. Perinatal information was collected from audited birth outcome data through the Victorian Perinatal Data Collection (VPDC) [ | PMC9873192 | ||
Exposure | The exposure was conception via IVF compared with spontaneous conception. The term “IVF” is used collectively to include both conventional IVF, IVF with ICSI, and associated laboratory techniques. IVF cases were identified through the IVF database. Victorian births not identified in the IVF database were allocated to the control group. Pregnancies recorded as “IVF conception” in the VPDC but not identified within the IVF database were excluded, ensuring the control group did not contain any IVF conceptions. These cases likely represent overseas or interstate IVF conceptions, Victorian IVF conceptions not captured by our database, or failed linkages between the IVF database and state birth records. | PMC9873192 | ||
Main outcome measures | Childhood educational and developmental outcomes were assessed using 2 standardised, national assessments. The Australian Early Development Census (AEDC) [ | PMC9873192 | ||
Australian Early Developmental Census (AEDC) | SECONDARY | The AEDC assesses broad childhood functional development at school entry (age 4 to 6) across 5 domains: physical health and wellbeing, social competence, emotional maturity, language and cognitive skills (school-based) and communication skills, and general knowledge. The primary AEDC outcome for this study was a global measure, developmental vulnerability, defined as scoring <10th percentile in ≥ 2 of the 5 developmental domains. The secondary outcomes included developmental vulnerability in each of the 5 domains. | PMC9873192 | |
The National Assessment Program–Literacy and Numeracy (NAPLAN) | NAPLAN is a school-based psychometric assessment, assessing 5 educational domains: grammar and punctuation, reading, writing, spelling, and numeracy [ | PMC9873192 | ||
Covariates | Covariates to be considered for inclusion in the statistical analysis models were decided a priori by the authorship team whose expertise included epidemiology, perinatology, reproductive endocrinology, and education. These covariates included child’s sex (as assigned at birth), child’s age in years at assessment, language background other than English (LBOTE), maternal age (at birth of the child), parity and both maternal and paternal highest obtained level of education, and socioeconomic status [ | PMC9873192 | ||
Linkage | Administrative record linkage techniques were employed to match cases with the exposure (conception via IVF) through to childhood outcome data. Data linkage was performed by the Centre for Victorian Data Linkage (CVDL), a third-party government-funded data linkage unit [Two separate, linked study populations were identified, children with a linked AEDC record and children with a linked NAPLAN record. These 2 cohorts were analysed and are reported separately. Some children were included in both cohorts. | PMC9873192 | ||
Causal assumptions | The ATE (average treatment effect) estimand used in this study is based upon the Potential Outcomes Framework. If a set of assumptions is met, then causal interpretation can be made. The causal assumptions are counterfactual consistency, ignorability (conditional exchangeability), and positivity. Counterfactual consistency means that the definition of exposure is consistent for all individuals. Ignorability states that treatment assignment can be considered random after controlling for, conditioning on, a set of covariates [To best emulate a target trial, it must be possible for all participants to potentially receive both treatments. To ensure the assumptions underlying our causal approach were as robust as possible, we considered our observational data in direct comparison with the conditions of a target trial ( | PMC9873192 | ||
Handling of missing data | The proportions of missing data are described in | PMC9873192 | ||
Statistical analysis | Descriptive statistics were calculated and are reported for each cohort by IVF exposure status, according to type and distribution of data. | PMC9873192 | ||
Treatment effect size modelling | REGRESSION | All multivariate models were adjusted for the listed covariates identified in the prespecified SAP, except for (1) maternal BMI; and (2) second parent education level, for AEDC outcome models only.For each of the imputed datasets, the predicted probability of exposure or PS and associated inverse probability weight (IPW = 1/PS) were estimated using a logistic regression model, conditional on all analysis model covariates [For each imputed dataset, a doubly robust inverse-probability-weighted regression adjustment (IPWRA) model [Finally, estimates for each imputed dataset were pooled to provide overall ATE with associated 95% confidence limits using Rubin’s method.Provided the assumptions outlined above are satisfied, the estimates generated from these analyses can be interpreted as the population average causal effect, that is, the mean effect on the outcome if the treatment was applied to the entire population and contrasted with the outcome if the entire population received the control condition. | PMC9873192 | |
Clustering | Clustering of data within mothers due to more than 1 singleton birth during the study period was accounted for in the imputation models, the calculation of inverse probability weights and estimation of the treatment effect by using robust SEs. | PMC9873192 | ||
Sensitivity analyses | MP | SENSITIVITY | Sensitivity analyses were also performed to address identified sources of potential bias. For both AEDC (special needs status) and NAPLAN (exempt status) cohorts, sensitivity analyses were performed: (1) by excluding these cases completely; and (2) by imputing their outcomes (Fig A in The analysis for this study was performed using STATA MP Version 17.0 [ | PMC9873192 |
Ethics/Governance | Ethical approval for the project was obtained from Mercy, Monash Health and Melbourne IVF Health Human Research Ethics Committees. Each data custodian provided contractual approval for data access and data linkage. The CVDL approved the project and performed the linkage. | PMC9873192 | ||
Results | The total cohort included 585,659 singleton births in Victoria between 2005 and 2014. Among this cohort, 173,200 children, including 4,697 IVF births, were linked to AEDC outcome data. Additionally, 342,331 children, including 8,976 IVF births, were linked to NAPLAN data ( | PMC9873192 | ||
Participant flow chart. | intrauterine insemination, Death | IVF, in vitro fertilisation; IVF cases, pregnancies and children identified with conception assisted by IVF; Controls, pregnancies and children not identified as IVF assisted conception; ART, assisted reproductive technology; non-IVF ART, ovulation induction and intrauterine insemination; VPDC, Victorian Perinatal Data Collection; BDM, Victorian Births Death Marriages Registry; IVF, combined Victorian IVF pregnancy record database.Baseline population characteristics differed considerably between the 2 exposure groups ( | PMC9873192 | |
Global developmental vulnerability at school entry (The Australian Early Development Census, AEDC) | PMC9873192 | |||
Primary outcome | Our findings suggest no causal effect of IVF conception on developmental vulnerability, with 13.6% of IVF-conceived children predicted to be developmentally vulnerable (<10th percentile in 2 or more domains of the 5 AEDC domains) compared with 13.9% of spontaneously conceived children. The adjusted RD was at −0.3%, indicating that 0.3% fewer children who were conceived by IVF were developmentally vulnerable compared with those conceived spontaneously. However, the 95% CI (−3.7% to 3.1%), indicates this result is indistinguishable from zero. Similarly, the adjusted relative risk showed no detectable difference in risk of developmental vulnerability, where IVF-conceived children were 3.0% less likely to be developmentally vulnerable than spontaneously conceived children (RR 0.97, 95% CI: 0.77 to 1.25) ( | PMC9873192 | ||
Secondary outcomes | SECONDARY | For secondary outcomes, we examined each of the 5 AEDC domains individually. The unadjusted observed results and causal model results for each individual domain are reported in | PMC9873192 | |
Missing data | Outcome data were missing for 5.6% of the AEDC-linked cohort. The vast majority (92%) of these missing cases were children with special needs (5.2% of overall cohort). There was no evidence of an association between the presence of missing outcome and exposure status (Chi | PMC9873192 | ||
Psychometric assessment of 5 educational domains at primary school (The National Assessment Program–Literacy and Numeracy, NAPLAN) | PMC9873192 | |||
Primary outcome | SE | Our findings indicate the causal effect of IVF conception on overall NAPLAN z-score was indistinguishable from zero. The predicted outcome mean z-score and was 0.013 (SE 0.024) for IVF-conceived children and −0.016 (SE 0.002) for spontaneously conceived controls, with an adjusted mean difference of 0.030 (95% CI −0.018 to 0.077) ( | PMC9873192 | |
Secondary outcomes | SECONDARY | For secondary outcomes, we examined individual NAPLAN domain z-scores (Additionally, for each domain, a binary outcome (domain scores above or below the national minimum standard) was examined. In 4 of 5 domains (numeracy, reading, spelling, and writing), IVF-conceived children were less likely to be below the national minimum standard compared with their spontaneously conceived peers ( | PMC9873192 | |
Missing data | Spontaneously conceived children were more likely to have missing NAPLAN data (7.6%) than IVF-conceived children (5.9%, Chi | PMC9873192 | ||
Sensitivity analyses | To validate our analysis model, we re-examined our AEDC primary outcome and the NAPLAN binary domain outcomes using TMLE modelling. Results from the TMLE model did not meaningfully differ from the findings of the primary analysis (Table A in An E-value was estimated for both primary outcomes and was found to be 1.90 and 1.77 for AEDC and NAPLAN outcomes, respectively, suggesting that an unknown bias of sufficient magnitude to change the study findings is unlikely (Figs A and B in | PMC9873192 | ||
Discussion | subfertility | REGRESSION | Using a causal inference approach, we found no effect of IVF conception on developmental vulnerability at school entry in Victorian children born between 2005 and 2014. Additionally, IVF-conceived children performed as well as their spontaneously conceived peers in school-based psychometric testing at age 7 to 9 years.For the first time, our study has estimated the causal effect of IVF conception on global childhood development at school entry and educational outcomes at primary school, under the assumptions of causal inference. Using an updated epidemiological approach [Two large Scandinavian studies have reported on childhood outcomes following IVF conception. Norrman and colleagues found that IVF-conceived children perform worse on school-based assessment in year 9 [These past studies are limited by examining historical birth cohorts dating back prior to the year 2001. Our study examines a more contemporary birth cohort (2005 to 2014), which is important given the advances in artificial reproductive techniques that have occurred since the turn of the century. IVF technologies that have evolved since this time include the introduction of blastocyst culture, vitrification, and single-embryo transfer [Given the use of observational data, there were missing data and inherent differences in the covariate profile of the exposure cohorts. An a priori SAP was developed to overcome these limitations. First, inverse probability weighting with regression adjustment was used to mimic exchangeable treatment and control comparison groups, similar to those that would be generated by randomisation in a controlled trial. The success of this procedure is demonstrated by achieving adequate covariate balance and thus sufficient overlap of covariate distributions between exposure groups after inverse probability weighting (Figs A–D in It is possible that unmeasured common cause confounders may have led to bias in estimating the ATEs. Many important factors (socioeconomic status, maternal age, and education) were identified a priori, measured, and included in the estimation procedure. Potential known but unmeasured sources of bias include subfertility and maternal BMI. Current evidence suggests that subfertility is likely to be associated with poorer childhood outcomes [Unmeasured variables may have had an impact on the outcome. Factors such as childcare attendance or grandparent involvement will be preceded on causal pathways by covariates that were measured and included in the model, such as maternal age and socioeconomic status [Generalisation of our findings to all IVF births is a potential study limitation. As described in our Methods, observations with non-overlapping PSs were excluded from analysis in order to meet the assumption of positivity, required for causal inference under the potential outcomes framework. Generalisation of our findings to all IVF births therefore requires the consideration that the baseline characteristics of the population of interest are comparable to the IVF cases analysed in our final cohort.Due to the use of school-based outcome assessments, our cohort was limited to children attending school. AEDC, as a triennial assessment, limited our sample to children captured during assessment years, and the later years of our birth cohort had not yet reached the assessment age for NAPLAN outcomes to be captured. However, our study included 70% of the relevant birth cohort for the study timeframe and in the years where both AEDC and NAPLAN data were available, over 95% of the Victorian birth cohort was sampled (Table A in Furthermore, through the examination of school-based outcomes, our study was inherently designed to examine outcomes for liveborn children. “Live birth bias” as it is known, is a recognised limitation of observational studies that investigate periconception and antenatal exposures [Under the specified assumptions, this analysis has demonstrated that there is no causal effect within the population studied of IVF conception on early childhood developmental vulnerability and school-age educational outcomes. Compared with spontaneously conceived children, children conceived by IVF were no more likely to be developmentally vulnerable at school entry and had equivalent numeracy and literacy performance by age 7 to 9 years. These findings provide important reassurance for current and prospective parents and their treating clinicians. | PMC9873192 |
Supporting information | PMC9873192 | |||
Direct acyclic graph. | (DOCX)Click here for additional data file. | PMC9873192 | ||
Methods: Description of outcome metrics. | (DOCX)Click here for additional data file. | PMC9873192 | ||
Study protocol. | (DOCX)Click here for additional data file.Tables A and B. Table A. Successful linkages by birth year. Table B. Annual cycle summaries from major Victorian IVF providers 2010–2014.(DOCX)Click here for additional data file.Fig A. Analysis flow chart (NAPLAN).(DOCX)Click here for additional data file. | PMC9873192 | ||
Methods: Multiple imputation model summary and model diagnostics. | REGRESSION, SENSITIVITY | Table A. Missing data summary (NAPLAN). Fig A. NAPLAN convergence. Fig B. NAPLAN density plots of observed and imputed data. Fig C. NAPLAN distribution of outcome and covariates after imputation in m = 1 dataset.(DOCX)Click here for additional data file.Figs A–D: Distribution and overlap of manually calculated stabilised weights. Fig A. AEDC imputation #1. Fig B. AEDC imputation #13. Fig C. NAPLAN imputation #1. Fig D. NAPLAN imputation #13.(DOCX)Click here for additional data file.Figs A–C: Variable standardised mean differences. Fig A. NAPLAN imputation #1 variable standardised mean differences. Fig B. NAPLAN imputation #13 variable standardised mean differences. Fig C. AEDC imputation #7 variable standardised mean differences.(DOCX)Click here for additional data file.Tables A and B. Table A. Sensitivity analysis–AEDC (special needs multiply imputed). Table B. Sensitivity analysis–AEDC (special needs excluded).(DOCX)Click here for additional data file.Tables A and B. Table A. Sensitivity analysis–NAPLAN (exempt multiply imputed). Table B. Sensitivity analysis–NAPLAN (exempt excluded).(DOCX)Click here for additional data file.Table A–Sensitivity analysis–binary outcomes TMLE.(DOCX)Click here for additional data file.Figs A and B. Fig A. Sensitivity analysis AEDC primary outcome–E-value estimation. Fig B. Sensitivity analysis NAPLAN primary outcome–E-value estimation.(DOCX)Click here for additional data file.Tables A and B. Table A. Traditional regression and treatment effect models (AEDC). Table B. Traditional regression and treatment effect models (NAPLAN).(DOCX)Click here for additional data file. | PMC9873192 | |
STROBE guideline checklist. | (DOCX)Click here for additional data file.This paper uses data from the Australian Early Development Census (AEDC). The AEDC is funded by the Australian Government Department of Education, Skills and Employment. The findings and views reported are those of the author(s) and should not be attributed to the Department or the Australian Government. We are grateful for the provision of data by the AEDC.We are grateful to CCOPMM for providing access to the data used for this project and for the assistance of the staff at Safer Care Victoria. The conclusions, findings, opinions and views, or recommendations expressed in this paper are strictly those of the author(s). They do not necessarily reflect those of CCOPMM.We are thankful for contribution of Victorian IVF providers, Melbourne IVF, Monash IVF, and City Fertility Centre to this research. We acknowledge the significant amount of work undertaken on behalf of this project and appreciate the opportunity to work with staff from each unit.Finally, we are grateful to the Australian Curriculum Assessment and Reporting Authority (ACARA) for their assistance, collaboration, and for providing the National Assessment Program for Literacy and Numeracy (NAPLAN) data. | PMC9873192 | ||
Abbreviations | REGRESSION | Australian Early Development Censusaverage treatment effectAboriginal and Torres Strait Islanderbody mass indexconfidence intervalCentre for Victorian Data Linkagedirected acyclic graphintracytoplasmic sperm injectioninverse probability weightinverse-probability-weighted regression adjustmentin vitro fertilisationmean differencesNational Assessment Program–Literacy and Numeracynational minimum standardpotential outcome meanspropensity scorerisk differencerelative riskstatistical analysis planstandard errorSocio-Economic Indexes for Areastargeted maximum likelihood estimationVictorian Perinatal Data Collection | PMC9873192 | |
References | birth defects, congenital abnormalities, Sarah Stock, congenital anomalies, primary schoolage, EPS, ALL, PhDSenior | PRETERM BIRTH, MINOR, SENSITIVITY, ADVERSE EFFECT, BEST, SAID, REGRESSION, EVENTS |
Dear Dr Lindquist, Thank you for submitting your manuscript entitled "School-age outcomes among IVF-conceived children: a causal inference analysis using linked population-wide data" for consideration by PLOS Medicine.Your manuscript has now been evaluated by the PLOS Medicine editorial staff as well as by an academic editor with relevant expertise and I am writing to let you know that we would like to send your submission out for external peer review.However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.Please re-submit your manuscript within two working days, i.e. by Jul 06 2022 11:59PM.Login to Editorial Manager here: Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review. Feel free to email us at Kind regards,PhilippaDr Philippa C Dodd, MBBS MRCP PhDSenior EditorPLOS Medicine
Dear Dr. Lindquist,Thank you very much for submitting your manuscript "School-age outcomes among IVF-conceived children: a causal inference analysis using linked population-wide data" (PMEDICINE-D-22-02257R1) for consideration at PLOS Medicine. Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:[LINK]In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers. In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: We expect to receive your revised manuscript by Sep 27 2022 11:59PM. Please email us (***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: Please use the following link to submit the revised manuscript:
Your article can be found in the "Submissions Needing Revision" folder. To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at Please ensure that the paper adheres to the PLOS Data Availability Policy (see We look forward to receiving your revised manuscript. Sincerely,Philippa Dodd, MBBS MRCP PhDPLOS Medicine
-----------------------------------------------------------Requests from the editors:ABSTRACTAbstract Methods and Findings: Please quantify the main results with 95% CIs and p values.Please include the important dependent variables that are adjusted for in the analyses.In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: INTRODUCTIONPlease conclude the Introduction with a clear description of the study question or hypothesis.METHODS and RESULTSPlease provide 95% CIs and p values where relevant When a p value is given, please specify the statistical test used to determine it.GENERALin the context of the reviewer comments below, it might be necessary to revise your titlePlease do so according to PLOS Medicine's style. Your title must be nondeclarative and not a question. It should begin with main concept if possible. "Effect of" should be used only if causality can be inferred, i.e., for an RCT. Please place the study design ("A randomized controlled trial," "A retrospective study," "A modelling study," etc.) in the subtitle (ie, after a colon) Please ensure that the study is reported according to the STROBE guideline and include the completed STROBE checklist as Supporting Information. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)." The STROBE guideline can be found here: Thank you for including a prospective analysis plan, please include any changes made to the analyses-- including those made in response to peer review comments-- in the Methods section of the paper, with rationale.In the manuscript text, please indicate: (1) the specific hypotheses you intended to test, (2) the analytical methods by which you planned to test them, (3) the analyses you actually performed, and (4) when reported analyses differ from those that were planned, transparent explanations for differences that affect the reliability of the study's results. If a reported analysis was performed based on an interesting but unanticipated pattern in the data, please be clear that the analysis was data-driven.DISCUSSIONPlease remove sub-headings such that the discussion is presented follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion.Comments from the academic editor:1. I do not buy the causal language. All observational studies have potential for unmeasured confounders. I think the use and emphasis of causal language could actually distract attention from the main message, which I think is important. In fact, the unadjusted data indicate an apparent protective effect of IVF which disappears on adjustment (Table 2). It would be good to add 95% CI to the unadjusted analysis to see if this was beyond the play of chance. But it is apparent that measured parental characteristics are associated with an increased chance of using IVF and a decreased risk of poor educational outcome. Hence, it follows that unmeasured parental characteristics associated with an increased chance of using IVF and a decreased risk of poor educational outcome could be masking an adverse effect of IVF and the use of causal language is wrong.2. It would be good to have a positive control, i.e. data on a factor which we know is associated with educational outcome. That way we know their methods can detect an association if there is one there. Preterm birth is an obvious one. Perhaps an easy way to do this is to provide coefficients for all the covariables that they included in adjustment.3. It would actually be quite interesting to see what the results are if they applied a more commonly used method of multivariate adjustment, such as logistic regression or propensity score analysis just to see how different (if at all) the results are with the method they employ. Comments 2 and 3 could be addressed by providing a supplementary table of unadjusted and adjusted ORs from logistic regression to allow comparison.4. I agree with the comments of the statistician. But it is reassuring that their overall assessment is positive.Comments from the reviewers:Reviewer #1 (methodological reviewer): This aim of this study was to determine the causal effect of in-vitro fertilization (IVF) conception on primary schoolage childhood developmental and educational outcomes, compared with outcomes following spontaneous conception.Comments:"Covariates to be considered for inclusion in the statistical analysis models were decided a priori by the authorship team whose expertise included epidemiology, perinatology, reproductive endocrinology and education"The authors have satisfactorily adjusted for potential confounding in the analysis."For the pre-specified statistical analysis plan (SAP) and the directed acyclic graph (DAG), see supplementary file (eFigure 1 in S3)."The authors have suitably provided the DAG in the supplementary material.Can the authors also please provide a copy of the SAP in the supplementary material (it is not currently clear if or where this is attached to the file)?"A doubly robust inverse-probability-weighted regression adjustment (IPWRA) model43,44 was used..."The authors have applied technically appropriate and rigorous statistical methods within the context of this research."Provided assumptions are satisfied, the estimates generated from these routines can be interpreted as the population average causal effect"Can the authors please include a transparent and thorough discussion on the assumptions that are required for causal inferences to be drawn?"Analysis involved detailed examination of missing data, consideration of missing outcome data, multiple imputation of missing covariate data, consideration of clustering within mothers and adjustments to effect size modelling. Finally, sensitivity analysis was also performed to address identified sources of potential bias."Can the authors please provide more detail on these important analyses within the main article here?"Overall, a total of 11,059 IVF-conceived children and 401,654 spontaneously conceived children were included in the study (2,614 IVF cases and 100,184 controls were in both study arms)."Whilst the authors have examined that "Analysis of the linked and nonlinked cases showed little evidence of association between linkage and exposure status (p = 0.80); that is, IVF cases were just as likely to be included in the final linked cohort as controls", can the authors please further comment on whether the final included samples analysed in this study can be considered to be representative of the wider populations of interest within the context of this research?"Outcome data were missing for 5.6% of the AEDC-linked cohort. The vast majority (92%) of these missing cases were children with special needs (5.2% of overall cohort). There was no evidence of an association between the presence of missing outcome and exposure status (p = 0.68). Sensitivity analysis was performed by 1) excluding children with special needs and 2) including these children, with multiple imputation of their missing outcomes (see supplementary file: eTable 4 and 5 - Sensitivity Analysis (AEDC) in S11 and s12). "and"Spontaneously conceived children were more likely to have missing NAPLAN data (7.6%) than IVF-conceived children (5.9%, p<0.001). During the primary analysis, missing outcomes related to a child being absent or withdrawing from the test, were imputed. The results presented include 7,222 children who were exempt from sitting the NAPLAN, with their results set to the lowest possible outcome score. Sensitivity analysis was performed by 1) excluding these children and 2) including the exempt cases, with multiple imputation of their missing outcomes. There was no meaningful difference in the results (see supplementary file: eTable 6 and 7 - Sensitivity Analysis (NAPLAN) in S13 and S14). "The authors have appropriately communicated and handled missing outcome data within the analysis."Maternal education level was missing for 30.5% and maternal post-school education was missing for 31.6%."and"Second parent school education level was missing in 13.8% of cases and post-school education missing in 15.4% of cases. "Whilst the authors discuss missing data in the discussion of the study limitations, can the authors please clarify and expand on how they dealt with missing covariate data in the Methods and Results sections?Overall, the results are presented clearly and the main study limitations have been thoroughly addressed.Reviewer #2: The authors report the lack of an association of IVF with later childhood educational outcomes using routinely collected data from Australia. This is an extremely well conducted and well written study, with robust and appropriate sensitivity analyses which adds substantially to the field and will reassures many parents. Minor comments:The authors make a big deal of the causal analysis, and I would suggest statistical review to confirm the appropriateness of the methodology and causal claims. I am conscious that the same used to be said regarding matching and that has now shown to be incorrect. I was not convicned that teh paper would materially suffer by removing the "casual anlaysis" claims in the title or intorudction etc. I wondered if graphical representation of the results would further enhance the paper. Reviewer #3: This study examined associations of ART conception with School-age outcomes using register data from Australia. The authors should be commended for trying to provide more reliable causal evidence from observational data, something we should all be doing. I have only a few minor commentseTable 1 should be brought into the main paper and / or a separate section in the methods should be added on the target trial emulation procedureWhere is the study protocol published / date it was published?In line with the glossary, the exposure of interest should be referred to as ART rather than IVFThe aim of the study was to emulate a target trial however, baseline characteristics differed considerably between the treatment groups. Can you describe the implications of this. Does it mean that trial emulation failed? Is there a way you can try to fix this?If data are available, it would be of interest to present results separately for fresh and frozen embryo transfers. Please consider this.Any attachments provided with reviews can be seen via the following link:[LINK]
Submitted filename: Click here for additional data file.
Dear Dr. Lindquist,Thank you very much for re-submitting your manuscript "School-age outcomes among IVF-conceived children: a causal inference analysis using linked population-wide data" (PMEDICINE-D-22-02257R2) for review by PLOS Medicine.I have discussed the paper with my colleagues and the academic editor and it was also seen again by 4 reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:[LINK]***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.Please also check the guidelines for revised papers at We expect to receive your revised manuscript within 1 week. Please email us (We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.Please ensure that the paper adheres to the PLOS Data Availability Policy (see To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at If you have any questions in the meantime, please contact me or the journal staff on We look forward to receiving the revised manuscript by Oct 25 2022 11:59PM. Sincerely,Philippa Dodd, MBBS MRCP PhDSenior Editor PLOS Medicine
------------------------------------------------------------Requests from Editors:GENERALPlease address all editor and reviewer comments detailed below, in fullPlease remove the funding/financial disclosure/DATA AVAILABILITY STATEMENTPlease provide a URL for The Centre for Victorian Data LinkageAUTHOR SUMMARYThank you for including an author summary. Line 74: Consider an alternative term to “defect” perhaps “congenital anomalies” in place of “…birth defects, congenital abnormalities…” to account for both structural and functional anomalies, or something similarREFERENCESFor in-text reference call-outs, citations should be placed within square brackets and preceding punctuation, as follows: “…asymptomatically [2,4].” Please check to ensure that the bibliography is listed in line with our guidance which can be found here: TABLE 1To improve accessibility to the reader, please adjust row width/text spacing to ensure IQRs are reported in a single row or place below the relevant data pointSUPPORTING INFORMATIONPlease ensure all figures and tables in the supporting files have abbreviations definedS2 TABLE 1 - Please define IVF, ITT, AEDC, NAPLANS4 TABLE 2b – please define “#" and "ICSI"S5 eMETHODS - please ensure referencing Is formatted as detailed above including in-text reference call-outsS6 FIGURE 2 - please define NAPLAN - please check and amend throughout all supplementary files S10 ALL FIGURES - please define the abbreviations - LBOTE, SEIFA, NAPLANS16 - please define AEDC, NAPLAN, DV2S17 TABLE 9 and 10 - please define AEDC and NAPLANSOCIAL MEDIATo help us extend the reach of your research, please provide any Twitter handle(s) that would be appropriate to tag, including your own, your coauthors’, your institution, funder, or lab. Please respond to this email with any handles you wish to be included when we tweet this paper.Comments from Reviewers:Reviewer #1: Many thanks to the authors for satisfactorily considering and responding to each comment in turn, suitably amending the manuscript as requested.Reviewer #2: I would stand by my comments that removal of the causal claim in the title would improve the paper, I am not a fan of playing different referees of each other several of us have highlighted that the causal language may be overstated. "School-age outcomes among IVF-conceived children" is snappier and cuts to the chase.Reviewer #4: I am grateful for the opportunity to review this interesting and innovative study that seeks to estimate the total causal effect of conception by assisted reproductive technology on educational outcomes in school-age children. I was approached to provide a methodological review of the appropriateness and accuracy of the causal inference methods as well as the reporting and use of language. My review will focus primarily on these points.Overall, I believe the study is has been well conducted and the research team should be commended for their hard work and diligence. I believe the research is scientifically sound but I believe the quality of the manuscript could be improved with some language and presentational changes as detailed below.1) TITLE: 'a causal inference analysis' is a vague term. I think it would be better for the study to be described more precisely as something like, 'a target trial emulation study using augmented inverse probability of treatment weighting'.2) INTRODUCTION, METHODS, AND RESULTS: A causal inference approach encourages a focus on interval estimation rather than (null) hypothesis testing. I therefore find it somewhat strange that the study states a null hypothesis at the end of the introduction and goes on to report null-distribution p-values. I think it would be less jarring if the authors instead described their aim/s as something more like 'to estimate the total causal effect of conception by IVF on the risk of developmental vulnerability'. Similar language would apply in the methods and results, e.g. rather than saying that 'The null hypothesis of no causal effect of IVF conception on developmental vulnerability was supported by our findings…' the study would simply report something like 'the estimated total causal effect of conception by IVF on the risk of developmental vulnerability was indistinguishable from zero (risk difference = -0.3%, 95% CI: -3.7% to 3.1%)'. 3) INTRODUCTION (lines 127-140): Although a target trial emulation study is indeed designed to 'mimic' a randomized controlled trial, I think this wording is likely to raise unfortunate associations among readers familiar with poorly-conducted propensity score analyses as 'mimicking randomised controlled trials'. I would therefore recommend toning down the language a little and simply stating that the study aimed to emulate a target trial by using the method introduced by Hernan et al with the augmented inverse probability of treatment weighting estimator. Similarly, I don't particularly like the language of achieving 'balance' in the distribution of baseline characteristic, in part because this is not what propensity score methods do (they aim to balance the outcome propensities, not the covariates). Comments about how this is 'similar to what occurs when participants are randomised' may be theoretically true, but this is unlikely to ever be achieved in practice. That said, I commend the authors for being clear about their causal aims. As outlined by Haber et al 2022 (Causal and Associational Language in Observational Health Research: A Systematic Evaluation) it is important for researchers to be clear where they seek to estimate a causal effect. It is just not necessary to 'over egg' this ambition or the methods used to achieve this aim. Thus, it is good to state an aim to 'estimate the total causal effect of conception by IVF on developmental vulnerability', and interpret the results as 'estimates of' this total causal effect, but perhaps not so good to start talking about 'mimicking randomised controlled trials'.4) METHODS: I would prefer the target trial emulation table to be presented in the main manuscript. I believe Plos Medicine is an online-only journal, so I see no reason why this should not be possible. 5) METHODS: There is a gap between the allocation and completion of the treatment because the conception must survive until live birth to be counted as belonging to either exposure group. In the target trial, what would happen to the pregnancies that don't result in live birth? I expect there will be an unequal chance of surviving to live birth between the in-vivo and in-vitro conceptions, creating the chance of selection bias. This ought to be acknowledged as a potential source of bias or, ideally, accounted for as competing events. 6) METHODS: In terms of exclusion criteria, what happened to the twins and other multiple pregnancies? I cannot see them described in the exclusion criteria. 7) METHODS: Regarding the target trial table, I think the authors could be more explicit in both the target trial and (in particular) the emulation study columns. I know it seems strange, but where the details of the emulation study are identical to the target trial, this really ought to be explicitly stated (either by repeating the details or simply saying 'same as for the target trial'). For example, if the inclusion criteria for the trial are 'all couples wanting to conceive and weight the ability to conceive' then the emulation column should repeat the same. In general, the emulation column does not really seem to state the expected criteria. E.g. the assignment procedures box should summarise your method for achieving conditional exchangeability and your causal contrasts box should start the target estimands. The recent paper by Matthews et al in the BMJ (Target trial emulation: applying principles of randomised trials to observational studies) offers a little help here about what should be mentioned in the table.8) METHODS: I think that the supplementary methods should be included in the main manuscript, which is currently rather light on details.9) METHODS, RESULTS, and throughout: Since this study uses a DAG, I believe it would benefit from following the reporting recommendations outlined in Tennant et al 2021 (Use of directed acyclic graphs (DAGs) to identify confounders in applied health research: review and recommendations). 10) METHODS and RESULTS: The authors present 'crude' associations in the non-weighted sample. I believe these results may have been added on the instruction of a previous reviewer, as per traditional. Alas, these associations should not be reported as they are likely to be extremely biased and prone to misinterpretation. Only the best estimate of the target estimands should be reported in the main manuscript. All sub-analyses involving alternative estimators (whether unweighted logistic regression, TLME, or - if absolutely necessary - the unweighted and unconditional analyses) should be reserved for the supplementary materials. 11) RESULTS: Null hypothesis significance testing is strongly discouraged in epidemiological analyses. The null-distribution p-values are therefore unnecessary and do not need to be reported. The authors may wish to present their E-values alongside the point estimates and confidence intervals instead.Any attachments provided with reviews can be seen via the following link:[LINK]
Submitted filename: Click here for additional data file.
Dear Dr. Lindquist,Thank you very much for re-submitting your manuscript "School-age outcomes among IVF-conceived children." (PMEDICINE-D-22-02257R3) for review by PLOS Medicine.I have discussed the paper with my colleagues and the academic editor and it was also seen again by 1 reviewer. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:[LINK]***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.Please also check the guidelines for revised papers at We expect to receive your revised manuscript within 1 week. Please email us (We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.Please ensure that the paper adheres to the PLOS Data Availability Policy (see To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at If you have any questions in the meantime, please contact me or the journal staff on We look forward to receiving the revised manuscript by Nov 17 2022 11:59PM. Sincerely,PippaPhilippa Dodd, MBBS MRCP PhDPLOS Medicine
------------------------------------------------------------Requests from Editors:1) Thank you for revising your title in context of previous reviewer comments. With these in mind, please revise your title according to PLOS Medicine's style. Your title must be nondeclarative and not a question. It should begin with main concept if possible. "Effect of" should be used only if causality can be inferred, i.e., for an RCT. Please place the study design ("A randomized controlled trial," "A retrospective study," "A modelling study," etc.) in the subtitle (ie, after a colon).2) Where you report adjusted analyses in data tables 3, 4 and 5 of the main manuscript, please also include the unadjusted analyses, either within an additional column in the existing tables or as additional supplementary files.3) Thank you for updating your data availability statement. Please ensure that the URL is placed in the manuscript submission form when you re-submit your manuscript.4) Thank you for including twitter handles. Please also ensure that these are placed in the manuscript submission form when you re-submit your manuscript.5) Please remove the COI and data availability statements from the end of the main manuscript and include only in the manuscript submission form6) Throughout, please replace "Fig" with "Figure", including in the supplementary files7) Please define DV2 in supplementary figures 13 and 14 - please check throughout and ensure all abbreviations are clearly defined within relevant capitions.Comments from the Academic Editor:The authors have done a nice job with revisions and happy to move to acceptAny attachments provided with reviews can be seen via the following link:[LINK]
Dear Dr Lindquist, On behalf of my colleagues and the Academic Editor, Dr Sarah Stock, I am pleased to inform you that we have agreed to publish your manuscript "School-age outcomes among IVF-conceived children: a population-wide cohort study" (PMEDICINE-D-22-02257R4) in PLOS Medicine.Before your manuscript can be published you will need to address the following which we asked for but could not locate:1) The completed STROBE checklist was not available in this version of your manuscript, please include AND2) Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)." When you re-submit please indicate where in the manuscript this sentence has been placed.3) In addition please remove spaces between in text reference callouts (e.g. line 99 "...conception [2, 3]." should read, "...conception [2,3]."4) Please define all abbreviations in figure 1 in an appropriate figure captionBefore your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.In the meantime, please log into Editorial Manager at PRESSWe frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper. Best wishes, PippaPhilippa Dodd, MBBS MRCP PhD PLOS Medicine | PMC9873192 |
Background | INFECTIOUS DISEASES, VIRUS, SEVERE ACUTE RESPIRATORY SYNDROME, CORONAVIRUS | Edited by: Ahmed Mostafa, National Research Centre, EgyptReviewed by: Abdullah Salah Alanazi, Al Jouf University, Saudi Arabia; Benjamin Florian Koch, Goethe University Frankfurt, GermanyThis article was submitted to Infectious Diseases: Epidemiology and Prevention, a section of the journal Frontiers in Public Health†These authors have contributed equally to this workRecent studies have shown that the infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is reduced under alkaline conditions. The purpose of this study is to assess the effect of nasal irrigation and oral rinse with sodium bicarbonate solution on virus clearance among COVID-19 patients. | PMC10053493 | |
Materials and methods | COVID-19 patients were recruited and randomly divided into two group, i.e., the experimental group and the control group. The experimental group received regular care plus nasal irrigation and oral rinse with 5% sodium bicarbonate solution, while the control group only received regular care. Nasopharyngeal and oropharyngeal swab samples were collected daily for reverse transcription-polymerase chain reaction (RT-PCR) assays. The negative conversion time and hospitalization time of the patients were recorded, and the results were statistically analyzed. | PMC10053493 | ||
Results | A total of 55 COVID-19 patients with mild or moderate symptoms were included in our study. There was no significant difference in gender, age and health status between the two groups. The average negative conversion time was 1.63 days after treatment with sodium bicarbonate, and the average hospitalization time of the control group and the experimental group were 12.53 and 7.7 days, respectively. | PMC10053493 | ||
Conclusions | VIRUS | Nasal irrigation and oral rinse with 5% sodium bicarbonate solution is effective in virus clearance for COVID-19 patients. | PMC10053493 | |
1. Introduction | coronavirus disease 2019 | CORONAVIRUS, CORONAVIRUS DISEASE 2019, SEVERE ACUTE RESPIRATORY SYNDROME, ACUTE INFECTION | The emergence and spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the global pandemic of coronavirus disease 2019 (COVID-19) (It has been demonstrated that nasal irrigation and oral rinse with physiological saline solution is a simple and effective way to reduce acute infection of the nasal and oral pharyngeal mucosa (Recent studies have shown that coronaviruses are unstable under alkaline conditions. Coronaviruses are rapidly and irreversibly inactivated by brief treatment at pH 8.0 and 37°C with a half-life of ~30 min ( | PMC10053493 |
2. Materials and methods | COVID-19 patients were recruited according to the following criteria. | PMC10053493 | ||
2.1. Inclusion criteria | POSITIVE | All admitted patients with age more than 18 years.COVID-19 patients with mild or moderate symptoms.Positive RT-PCR result at the time of admission. | PMC10053493 | |
2.2. Exclusion criteria | AIDS, immune deficiency | AIDS, IMMUNE DEFICIENCY, MALIGNANT TUMORS, CAVITY, CHRONIC SINUSITIS | Refusal to participate.Any severe cases of COVID-19.Patients with a history of nasal surgery, chronic sinusitis or drug intervention through nasal cavity.Women in the period of pregnancy or lactation.Patients with immune deficiency (such as patients with malignant tumors, organ or bone marrow transplants, AIDS, and those taking immunosuppressive drugs within 3 months).Other patients that were considered unsuitable to participate in this study. | PMC10053493 |
2.3. Study design | ≥24-h | This was a randomized, open-label, single-center pilot study. Patients were observed for 4–5 days after hospitalization to exclude any severe cases of COVID-19, and then randomly divided into two group, i.e., the experimental group and the control group. The experimental group received regular care plus nasal irrigation and oral rinse with 5% sodium bicarbonate solution, while the control group received regular care only. Regular care refers to the treatment according to the “Diagnosis and Treatment Protocol for COVID-19 (Trial Version 9).” Oral rinse with sodium bicarbonate solution was conducted three times every day. Nasal irrigation was conducted two times in total. The solution entered through one nostril and exited from the other one, and the order of nostrils was changed on the second day. 30–40 mL of solution was used every time and the irrigation was performed for at least 30 s. Nasopharyngeal and oropharyngeal swab samples were collected from patients every day for RT-PCR tests. The specimen was considered positive if Ct (cycle threshold) values for both E and RdRP genes were smaller than 40, and the specimen was negative when no Ct value was obtained. If the RT-PCR results were negative, the patient would receive a second test after 24 h. The presence of two negative RT-PCR results, at ≥24-h intervals, was defined as viral clearance ( | PMC10053493 | |
2.4. Data analysis | Statistical analysis was performed using the IBM SPSS Statistics (version 19). Categorical data were used for expressing frequency and percentage, and χ | PMC10053493 | ||
3. Results and discussion | infection, nose and mouth | CORONAVIRUS, INFECTION, DISEASES, INFLUENZA | A total of 55 patients (26 males and 29 females) were included in our study. These patients were hospitalized because of positive RT-PCR results. The patients were randomly divided into two groups, 32 cases in the control group and 23 cases in the experimental group. The minimum and maximum ages were 35 and 100 years old, respectively. Patients were treated according to the procedure shown in Flow chart of the clinical trial.Several important factors such as gender, age, and health status were studied. The mean ± SD of these factors are shown in Statistical analysis of difference between the two groups.Scatter plots of hospitalization time.We proposed three possible reasons for this: (1) the main infection area of coronavirus is the upper respiratory tract. Most coronaviruses were washed away during nasal irrigation and oral rinse (Nasal irrigation and oral rinse is very simple, which can be operated by the patient. In addition, sodium bicarbonate is a cheap and widely used alkaline reagent. COVID-19 patients can rinse nose and mouth with sodium bicarbonate solution to clear coronaviruses even at home, which is significant for areas lack of medical resources. We believe this method is not only effective for COVID-19, it might be useful for some other diseases such as influenza. | PMC10053493 |
4. Conclusions | The results of this pilot study demonstrated that nasal irrigation and oral rinse with 5% sodium bicarbonate solution was effective in reducing the viral load for COVID-19 patients. The sample size of this study was small. Some patients may already have symptoms before hospitalization, which might affect the total hospitalization time. Further studies with larger population are required to ascertain the benefits of nasal irrigation and oral rinse with sodium bicarbonate solution. Although this is only a preliminary study, the results are very promising. Nasal irrigation and oral rinse is simple and inexpensive. More importantly, this method can be performed at home, which might be an effective way to stop the spread of SARS-CoV-2. | PMC10053493 | ||
Data availability statement | The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author. | PMC10053493 | ||
Ethics statement | The studies involving human participants were reviewed and approved by Institutional Review Board of RuiJin Hospital LuWan Branch. The patients/participants provided their written informed consent to participate in this study. | PMC10053493 | ||
Author contributions | DISEASES | TW, YZ, RZ, YM, JY, YL, QC, XL, HW, SH, CZ, and BT: methodology, investigation, and data curation. XW: writing—original draft, review and editing, conceptualization, supervision, and funding acquisition. All authors contributed to the article and approved the submitted version.We thank Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases and Innovative Research Team of High-Level Local Universities in Shanghai. | PMC10053493 | |
Conflict of interest | XW is employed by company Nanning Jiuzhouyuan Biotechnology Co Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10053493 | ||
Publisher's note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10053493 | ||
References | PMC10053493 | |||
ABSTRACT | co-first author Tan et al. Apatinib plus exemestane for ER+/HER2- MBC. | PMC10578185 | ||
Purpose | MBC | METASTATIC BREAST CANCER | Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR)-2. This study was conducted to assess the efficacy and safety of apatinib combined with exemestane in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). | PMC10578185 |
Methods | toxicity | DISEASE, METASTATIC DISEASE | This single-center, single-arm phase II study enrolled patients with ER+/HER2- MBC progressed on previous letrozole or anastrozole. Stratified analysis was performed according to the number of chemotherapy regimens for metastatic disease. The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS) and toxicity. Patients received apatinib at a starting dose of 500 mg/d and exemestane 25 mg/d on days 1–28 of each 4-week cycle. | PMC10578185 |
Results | METASTATIC DISEASE | Thirty patients were enrolled with median four prior anticancer therapies. Eighty percent of patients received chemotherapy for metastatic disease. The median PFS (mPFS) and OS were 5.6 (95%CI: 4.3–6.9) months and 15.7 (95% CI: 9.7–21.7) months, respectively. The ORR, DCR, and CBR were 21.4%, 71.4%, and 46.4%, respectively. Patients with 0–1 line chemotherapy for MBC showed a slightly longer mPFS compared to those with ≥2 lines chemotherapy (mPFS: 6.4 months vs 4.8 months, | PMC10578185 | |
Conclusions | Apatinib plus exemestane exhibited objective efficacy in patients with ER+/HER2- MBC who have failed multiple lines of treatment. The AEs of apatinib required close monitoring and most of patients were well tolerated. | PMC10578185 | ||
KEYWORDS | PMC10578185 | |||
Introduction | gastric adenocarcinoma, breast cancer | GASTRIC ADENOCARCINOMA, BREAST CANCER | Nearly 70% of breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-).Much evidence supports a close interaction of the ER signaling with angiogenesis and its vascular endothelial growth factor receptor (VEGFR) signaling pathway.Apatinib, a small-molecule VEGFR-tyrosine kinase inhibitor, selectively acts on the intracellular ATP binding site of VEGFR-2, which plays a central role in the regulation of angiogenesis.At present,apatinib has been approved as third-line treatment for patients with advanced gastric adenocarcinoma in China, October 2014. | PMC10578185 |
Methods | PMC10578185 | |||
Patients | hematologic, hepatic, and renal function, cardiovascular disease, Cancer | UNCONTROLLED HYPERTENSION, RECURRENCE, METASTASIS, LIVER METASTASES, CARDIOVASCULAR DISEASE, BRAIN METASTASES, DISEASE, HER2 GENE AMPLIFICATION, ONCOLOGY, CANCER | The included patients aged 18–70 years and were pathologically diagnosed as MBC, with ER+ (+, >10%) and HER2–. HER2- was defined as no staining or scores of 1+ by immunohistochemistry (IHC), and cases with 2+ by IHC were confirmed absence of HER2 gene amplification by fluorescence in situ hybridization (FISH). Patients were either postmenopausal women or receiving ovarian suppressive therapy. All patients had experienced treatment failure with previous anastrozole or letrozole, defined as disease recurrence or metastasis during or within one year after the end of adjuvant endocrine therapy, or progression during endocrine therapy in MBC. Chemotherapy or other endocrine therapy (tamoxifen, fulvestrant, toremifene, progesterone) for advanced disease were also allowed before inclusion. Patients who had previously taken exemestane were excluded unless they had experienced disease recurrence or metastasis one year after the end of adjuvant therapy with exemstane. The included patients had to have at least one measurable lesion, a life expectancy of no less than 3 months, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. They also had to have adequate hematologic, hepatic, and renal function, as indicated by hemoglobin ≥8 g/dL, absolute neutrophil count (ANC) ≥1.5 × 109/L, platelet count ≥75 × 109/L, total serum bilirubin ≤1.5 × upper limit of normal (ULN), AST/ALT ≤2.5 × ULN (≤5× ULN in case of liver metastases), and serum creatinine ≤1.0 × ULN (calculated creatinine clearance ≥50 mL/min). Patients with symptomatic brain metastases, uncontrolled hypertension, serious cardiovascular disease or previous treatment with angiogenesis inhibitors were excluded. At last, a total of 30 patients were enrolled in this study. All of the enrolled patients signed the informed consent and could be cooperative with medical workers. The study was approved by the Medical Ethics Committee of Guangxi Medical University Cancer Hospital (KS2017(05)) and was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study protocol has been registered in the Chinese Clinical Trial Registry (Identifier: ChiCTR-OIC-17010440) | PMC10578185 |
Intervention measures | toxicity, proteinuria, hand and foot syndrome | ADVERSE EVENTS, DISEASE, HYPERTENSION | Eligible patients received apatinib at a starting dose of 500 mg/d and exemestane 25 mg/d on days 1–28 of each 4-week cycle. Apatinib could also be started with 250 mg/d, and then gradually increased to 500 mg/d in one week, as to improve tolerance for the old and infirm patients. A dose reduction of apatinib will be allowed to 250 mg/d. If grade 3/4 hematological toxicity or nonhematologic adverse events (AEs) such as hand and foot syndrome, hypertension, proteinuria, etc occur for the first time, it is recommended to stop the drug temporarily until the AEs relieve or disappear. If grade 3/4 of the above AE occurs again after resuming the drug, the drug can be continued after lowering the dose. If the AEs still persist, the drug will be stopped. The above regimen was performed until progressive disease, unacceptable toxicity, or consent withdrawal, whichever came first. | PMC10578185 |
Baseline and follow-up assessment | death | DISEASE PROGRESSION, ADVERSE EVENT | The pretreatment evaluation included detailed medical history, physical examination, routine laboratory tests, and computed tomography (CT) of measurable lesions at baseline. Laboratory tests included blood routine, liver function, renal function, electrolytes, and urinalysis. CT was conducted for efficacy evaluation every two cycles for the first 4–6 cycles, and then every 2–3 months until disease progression. Adverse events (AEs) were recorded at each cycle until 30 days after the last dose therapy. Subjects were observed until death, loss to follow-up, withdrawal from the trial, or the end of this study. | PMC10578185 |
Clinical efficacy | Tumors | TUMORS | Efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1), | PMC10578185 |
Statistical analysis | DISEASE | In sample size estimate, 24 months of accrual period and 6 months of follow-up period were assumed. The study was designed with two-sided, α = 0.05, 85% power to detect a null median PFS of 2.8 months and experimental median PFS of 5.6 months (All statistical analyses were conducted by using SPSS version 18 (SPSS Inc., Chicago, IL). The categorical data was described as frequency or percentage (%), and the chi-square test or Fisher exact probability method was used for comparison between groups. Kaplan–Meier method and log-rank test were used for survival analysis. The stratified analysis was performed according to the number of chemotherapy lines for advanced disease. | PMC10578185 |
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