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BACKGROUND: Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy. METHODS: We performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m2) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930. FINDINGS: Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference -0·01, 95% CI -0·10 to 0·09; p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95% CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group. INTERPRETATION: In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions. FUNDING: National Institute of Health Research.

BACKGROUND Several GnRH antagonist protocols are currently used during COS in the context of ART treatments; however, questions remain regarding whether these protocols are comparable in terms of efficacy and safety. OBJECTIVE AND RATIONALE A systematic review followed by a pairwise and network meta-analyses were performed. The systematic review and pairwise meta-analysis of direct comparative data according to the PRISMA guidelines evaluated the effectiveness of different GnRH antagonist protocols (fixed Day 5/6 versus flexible, ganirelix versus cetrorelix, with or without hormonal pretreatment) on the probability of live birth and ongoing pregnancy after COS during ART treatment. A frequentist network meta-analysis combining direct and indirect comparisons (using the long GnRH agonist protocol as the comparator) was also performed to enhance the precision of the estimates. SEARCH METHODS The systematic literature search was performed using Embase (Ovid), MEDLINE (Ovid), Cochrane Central Register of Trials (CENTRAL), SCOPUS and Web of Science (WOS), from inception until 23 November 2021. The search terms comprised three different MeSH terms that should be present in the identified studies: GnRH antagonist; assisted reproduction treatment; randomized controlled trial (RCT). Only studies published in English were included. OUTCOMES The search strategy resulted in 6738 individual publications, of which 102 were included in the systematic review (corresponding to 75 unique studies) and 73 were included in the meta-analysis. Most studies were of low quality. One study compared a flexible protocol with a fixed Day 5 protocol and the remaining RCTs with a fixed Day 6 protocol. There was a lack of data regarding live birth when comparing the flexible and fixed GnRH antagonist protocols or cetrorelix and ganirelix. No significant difference in live birth rate was observed between the different pretreatment regimens versus no pretreatment or between the different pretreatment protocols. A flexible GnRH antagonist protocol resulted in a significantly lower OPR compared with a fixed Day 5/6 protocol (relative risk (RR) 0.76, 95% CI 0.62 to 0.94, I2 = 0%; 6 RCTs; n = 907 participants; low certainty evidence). There were insufficient data for a comparison of cetrorelix and ganirelix for OPR. OCP pretreatment was associated with a lower OPR compared with no pretreatment intervention (RR 0.79, 95% CI 0.69 to 0.92; I2 = 0%; 5 RCTs, n = 1318 participants; low certainty evidence). Furthermore, in the network meta-analysis, a fixed protocol with OCP resulted in a significantly lower OPR than a fixed protocol with no pretreatment (RR 0.84, 95% CI 0.71 to 0.99; moderate quality evidence). The surface under the cumulative ranking (SUCRA) scores suggested that the fixed protocol with no pretreatment is the antagonist protocol most likely (84%) to result in the highest OPR. There was insufficient evidence of a difference between fixed/flexible or OCP pretreatment/no pretreatment interventions regarding other outcomes, such as ovarian hyperstimulation syndrome and miscarriage rates. WIDER IMPLICATIONS Available evidence, mostly of low quality and certainty, suggests that different antagonist protocols should not be considered as equivalent for clinical decision-making. More trials are required to assess the comparative effectiveness of ganirelix versus cetrorelix, the effect of different pretreatment interventions (e.g. progestins or oestradiol) or the effect of different criteria for initiation of the antagonist in the flexible protocol. Furthermore, more studies are required examining the optimal GnRH antagonist protocol in women with high or low response to ovarian stimulation.

To verify the accuracy of an online algorithm using Bayes' theorem for diagnosing ectopic pregnancy (EP) using human chorionic gonadotropin (hCG), ultrasound, and clinical data in a real cohort.A retrospective cohort study.Gynecologic emergency unit in a tertiary teaching hospital.First-trimester pregnant women who attended the gynecologic emergency unit for any reason. Those who had13 weeks of pregnancy confirmed by a recent positive pregnancy test; a digital image or electronic report of transvaginal ultrasound (TVUS) obtained from hospital database; and a follow-up with a pathology report or a clinical resolution of a confirmed pregnancy were included in the study. Clinical signs and symptoms, the presence of risk factors for EP, the TVUS findings in each consultation, and the hCG levels were independent variables obtained from the electronic medical records. From these data, the pretest probability, based on the clinical presentation and risk factors, and the likelihood ratio for each variable were calculated for their use in the algorithm, yielding a posttest probability.Not applicable.The accuracy of the online algorithm to identify cases of EP using clinical signs and symptoms, the presence of risk factors for EP, the TVUS findings in each consultation, and the hCG levels. The main outcome was EP, confirmed either by pathology report or by the presence of fetal heartbeat or gestational sac outside the uterine cavity.Between January 1, 2009 and December 27, 2016, 2,495 women were analyzed, and the algorithm was applied to 2,185 of them. The incidence of EP was 8.5% (212/2,495); 310 women were excluded because they were submitted to surgery with decision thresholds95%. The algorithm was applied to 2,185 women. Just one case remained inconclusive after 3 consultations, and it was considered as an error in prediction. The sensitivity, specificity, and accuracy values (95% confidence interval) of the algorithm were 98.9% (96.1%-99.8%), 98.9% (98.3%-99.2%), and 98.9% (98.3%-99.2%), respectively.The accuracy of the Bayesian algorithm to confirm or rule out EP is excellent. Online Nomogram https://docs.google.com/spreadsheets/d/1jStXlMBjbPyDf6_W0deKGKQLZHU5EFAe8rLhNVPuJuY/edit?usp=sharing.

As the burden of misconduct in medical research is increasingly recognised, questions have been raised about how best to address this problem. Whilst there are existing mechanisms for the investigation and management of misconduct in medical literature, they are inadequate to deal with the magnitude of the problem. Journal editors and publishers play an essential role in protecting the veracity of the medical literature. Whilst ethical guidance for journal editors and publishers is important, it is not as readily enforceable as legal obligations might be. This article questions the legal obligations that might exist for journal editors and publishing companies with respect to ensuring the veracity of the published literature. Ultimately, there is no enforceable legal obligation in Australia, the United Kingdom, or the United States. In light of this, more robust mechanisms are needed to deliver greater confidence and transparency in the investigative process, the management of concerns or findings of misconduct and the need to cleanse the literature. We show that the law disincentivises journals and publishers from ensuring truth in their publications. There are harmful consequences for medical care and public confidence in the medical profession and health care system when the foundations of medical science are questionable.

To investigate the relationship between the embryo frozen time and live birth rate (LBR) in women having a freeze-all cycle.Retrospective cohort study.Academic hospital.Women who underwent their first vitrified-warmed cycles from January 2013 to December 2019.Embryo storage time.The primary outcome was the LBR.A total of 14,928 women were eligible for the analysis. Women with the frozen time of transferred embryos for 2-5 months were associated with a higher LBR compared with other groups. The results were confirmed by an inverted U curve in the restricted cubic splines before as well as after adjustment for covariables, which suggested that an embryo storage time of 3-4 months was associated with the highest LBR. Subgroup analyses demonstrated that the inverted U curve relationship between embryo storage time and LBR was only observed in women with the high response. Sensitivity analyses in women with at least one good-quality embryo for transfer, in women aged36 years at embryo transfer, or in women with double cleavage embryo transfer showed that the association remained valid. The association was weakened in women with single blastocyst transfer probably because of the small sample size in these women.An inverted U-shaped relationship was found between embryo storage time and treatment success in women with high ovarian response in freeze-all embryo transfer cycles. Prolonged storage time of6 months was associated with reduced pregnancy rates.

Worldwide reports have produced conflicting data on perinatal outcomes during the COVID-19 pandemic. This systematic review and meta-analysis addressed the effect of mitigation measures against COVID-19 on preterm birth, stillbirth, low birth weight, and NICU admission during the first nine months of the pandemic. A search was performed using MEDLINE, Embase and SCOPUS for manuscripts published up until 24th May 2021. Studies that reported perinatal outcomes (preterm birth, stillbirth, low birth weight, NICU admission) during the COVID-19 pandemic with a pre-pandemic control period were included. Risk of bias assessment was performed using ROBINS-I tool. RevMan5 was used to perform meta-analysis with random-effects models. A score of the stringency of mitigation measures was calculated from the Oxford COVID-19 Government Response Tracker. Thirty-eight studies of moderate to serious risk of bias were included, with varied methodology, analysis and regional mitigation measures, using stringency index scores. There was no overall effect on preterm birth at less than 37 weeks (OR 0.96, 95% CI 0.92-1.00). However, there was a reduction in preterm birth at less than 37 weeks (OR 0.89, 95% CI 0.81-0.98) and 34 weeks (OR 0.56, 95% CI 0.37-0.83) for iatrogenic births and in singleton pregnancies. There was also a significant reduction in preterm births at less than 34 weeks in studies with above median stringency index scores (OR 0.71, 95% CI 0.58-0.88). There was no effect on risk of stillbirth (OR 1.04, 95% CI 0.90-1.19) or birth weight. NICU admission rates were significantly reduced in studies with above median stringency index scores (OR 0.87, 95% CI 0.78-0.97). The reduction in preterm births in regions with high mitigation measures against SARS-CoV-2 infection is likely driven by a reduction in iatrogenic births. Variability in study design and cohort characteristics need to be considered for future studies to allow further investigation of population level health measures of perinatal outcomes.

BackgroundMelbourne, Australia, recorded one of the longest and most stringent pandemic lockdowns in 2020, which was associated with an increase in preterm stillbirths among singleton pregnancies. Twin pregnancies may be particularly susceptible to the impacts of pandemic disruptions to maternity care due to their higher background risk of adverse perinatal outcomes.ObjectiveTo compare the rates of adverse perinatal outcomes in twin pregnancies exposed and unexposed to lockdown restrictions in Melbourne.Study DesignMulticenter retrospective cohort study of all twin pregnancies birthing in public maternity hospitals in Melbourne. We compared perinatal outcomes between a pre- pandemic group (‘unexposed’) and two lockdown-exposed groups: exposure 1 from 22 March 2020 to 21 March 2021 and exposure 2 from 22 March 2021 to 27 March 2022. We analyzed routinely-collected maternity data on all twin births≥20 weeks where outcomes were available for both infants. The primary outcomes were rates of preterm birth+0to 40+0of their pregnancy occurred entirely during each lockdown-exposure period. Perinatal outcomes were calculated per infant; maternal outcomes were calculated per pregnancy.ResultsWe included 2267 women birthing twins. Total preterm birthsrdcentile (5.7% vs 6.0%; aRR 1.00, 95%CI 0.98-1.02 p=0.74) or neonatal intensive care unit admissions in the exposure 1 group compared to the pre-pandemic group. In contrast, when comparing the pre-pandemic group with exposure 2 group, there was no significant difference in the rates of preterm birthConclusionsMelbourne’s first lockdown-exposure period was associated with fewer twin preterm births

Contains fulltext : 287686.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To determine the prevalence of depression, anxiety, and posttraumatic stress disorder (PTSD) years after hyperemesis gravidarum (HG) and its association with HG severity. MATERIAL AND METHODS: This prospective cohort study consisted of a follow-up of 215 women admitted for HG, who were eligible to participate in a randomized controlled trial and either declined or agreed to be randomized between 2013 and 2016 in 19 hospitals in the Netherlands. Participants completed the Hospital Anxiety and Depression Scale (HADS) six weeks postpartum and during follow-up and the PTSD checklist for DSM-5 (PCL-5) during follow-up. An anxiety or depression score ≥8 is indicative of an anxiety or depression disorder and a PCL-5 ≥ 31 indicative of PTSD. Measures of HG severity were symptom severity (PUQE-24: Pregnancy Unique Quantification of Emesis), weight change, duration of admissions, readmissions, and admissions after the first trimester. RESULTS: About 54/215 participants completed the HADS six weeks postpartum and 73/215 participants completed the follow-up questionnaire, on average 4.5 years later. Six weeks postpartum, 13 participants (24.1%) had an anxiety score ≥8 and 11 participants (20.4%) a depression score ≥8. During follow-up, 29 participants (39.7%) had an anxiety score ≥8, 20 participants (27.4%) a depression score ≥8, and 16 participants (21.9%) a PCL-5 ≥ 31.Multivariable logistic regression analysis showed that for every additional point of the mean PUQE-24 three weeks after inclusion, the likelihood of having an anxiety score ≥8 and PCL-5 ≥ 31 at follow-up increased with OR 1.41 (95% CI: 1.10;1.79) and OR 1.49 (95% CI: 1.06;2.10) respectively. CONCLUSION: Depression, anxiety, and PTSD symptoms are common years after HG occurred.

To assess the performance of placental, fetal and maternal cardiovascular markers in the prediction of adverse perinatal and maternal outcomes in women with suspected or confirmed pre-eclampsia.This was a prospective prognostic accuracy study of women with suspected or confirmed pre-eclampsia who underwent a series of investigations to measure maternal hemodynamic indices, mean arterial pressure, augmentation index, ophthalmic artery peak systolic velocity (PSV) ratio, uterine artery pulsatility index (UtA-PI), fetal biometric and Doppler parameters, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF). The performance of these markers, individually or in combination, in predicting adverse perinatal and maternal outcomes was then assessed using receiver-operating-characteristics (ROC)-curve analysis. Adverse maternal outcome was defined as one or more of severe hypertension, admission to the intensive care unit, eclampsia, placental abruption, HELLP syndrome, disseminated intravascular coagulation, platelets 100 × 10We recruited 126 women with suspected (n = 31) or confirmed (n = 95) pre-eclampsia at a median gestational age of 33.9 weeks (interquartile range, 30.9-36.3 weeks). Pregnancies with adverse perinatal outcome compared to those without had a higher median UtA-PI (1.3 vs 0.8; P 0.001), ophthalmic artery PSV ratio (0.8 vs 0.7; P = 0.01) and umbilical artery PI percentile (82.0 vs 68.5; P 0.01) and lower median estimated fetal weight percentile (4.0 vs 43.0; P 0.001), abdominal circumference percentile (4.0 vs 63.0; P 0.001), middle cerebral artery PI percentile (28.0 vs 58.5; P 0.001) and cerebroplacental ratio percentile (18.0 vs 46.5; P 0.001). Pregnancies with adverse perinatal outcome also had a higher median sFlt-1 (8208.0 pg/mL vs 4508.0 pg/mL; P 0.001), lower PlGF (27.2 pg/mL vs 76.3 pg/mL; P 0.001) and a higher sFlt-1/PlGF ratio (445.4 vs 74.4; P 0.001). The best performing individual marker for predicting adverse perinatal outcome was the sFlt-1/PlGF ratio (area under the ROC curve (AUC), 0.87 (95% CI, 0.81-0.93)), followed by estimated fetal weight (AUC, 0.81 (95% CI, 0.73-0.89)). Women who experienced adverse maternal outcome had a higher median sFlt-1 level (7471.0 pg/mL vs 5131.0 pg/mL; P 0.001) and sFlt-1/PlGF ratio (204.3 vs 93.3; P 0.001) and a lower PlGF level (37.0 pg/mL vs 66.1 pg/mL; P = 0.01) and estimated fetal weight percentile (16.5 vs 37.0; P = 0.04). All markers performed poorly in predicting adverse maternal outcome, with sFlt-1 (AUC, 0.69 (95% CI, 0.60-0.79)) and sFlt-1/PlGF ratio (AUC, 0.69 (95% CI, 0.59-0.78)) demonstrating the best individual performance. The addition of cardiovascular, fetal or other placental indices to the sFlt-1/PlGF ratio did not improve the prediction of adverse maternal or perinatal outcomes.The sFlt-1/PlGF ratio performs well in predicting adverse perinatal outcomes but is a poor predictor of adverse maternal outcomes in women with suspected or diagnosed pre-eclampsia. The addition of cardiovascular or fetal indices to the model is unlikely to improve the prognostic performance of the sFlt-1/PlGF ratio. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

STUDY QUESTION What is the impact of uterine malformations on reproductive and neonatal outcomes of IVF/ICSI–frozen embryo transfer? SUMMARY ANSWER Unification defective uteri are associated with poorer neonatal outcomes including higher preterm delivery rate and lower birthweight, and septate uteri are associated with worse fertility outcomes including higher miscarriage and lower live birth rates (LBRs). WHAT IS KNOWN ALREADY Several studies have investigated the negative effects of uterine malformations on pregnancy outcomes. However, an all-round and definitive conclusion has not been reached yet owing to the relatively low incidence of the disease and the heterogeneity of study populations, especially among women undergoing ART. STUDY DESIGN, SIZE, DURATION This was a retrospective cohort study including 411 women with congenital uterine anomalies and 14 936 women with a normal uterus who underwent first frozen-thawed embryo transfer cycles of IVF/ICSI from July 2008 to August 2019. We compared reproductive outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS Reproductive outcomes of women with uterine malformations were studied through three propensity score-matched comparisons (patients with bicorporeal uterus, septate uterus and hemi-uterus [bicorporeal, septate and hemi-uterus groups, respectively] along with corresponding control groups without uterine malformations). We also compared pregnancy and neonatal outcomes, and performed subgroup analysis addressing didelphus, bicornuate uteri and septate uteri before and after surgery independently. MAIN RESULTS AND THE ROLE OF CHANCE Compared to the matched control group, women with a bicorporeal uterus had a significantly lower LBR (24.4% versus 34.8%, odds ratio (OR) 0.61 [95% CI: 0.37, 1.00], P = 0.048). The incidence of miscarriage and preterm delivery was higher but not statistically significant (29.0% versus 18.1%, OR 1.85 [95% CI: 0.82, 4.19], P = 0.135; 22.6% versus 9.9%, OR 2.64 [95% CI: 1.07, 6.52], P = 0.063, respectively). In addition, the bicorporeal group had a significantly lower gestational age, higher caesarean rate and lower birthweight than bicorporeal control. Women with a septate uterus had comparable clinical pregnancy rates to controls (43.3% versus 49.9%, OR 0.77 [95% CI: 0.57, 1.04], P = 0.091), increased miscarriage rates (23.5% versus 13.0%, OR 2.05 [95% CI: 1.18, 3.58], P = 0.010) and lower LBRs (29.4% versus 42.2%, OR 0.57 [95% CI: 0.41, 0.79], P = 0.001). In both singleton and twins pregnancies, pregnancy and neonatal outcomes were comparable between women with a septate uterus and control. Women with a hemi-uterus had a tendency for lower clinical pregnancy rate (36.8% versus 42.3%, OR 0.80 [95% CI: 0.52, 1.21], P = 0.287) and LBR (29.8% versus 33.1%, OR 0.86 [95% CI: 0.55, 1.34], P = 0.502), compared to women without malformations. The incidences of miscarriage and preterm delivery, respectively, were 16.7% versus 16.6% (OR 1.01 [95% CI: 0.41, 2.47], P = 0.989), and 9.5% versus 11.4% (OR 0.82 [95% CI: 0.27, 2.51], P = 1) in women with a hemi-uterus as compared to control. LIMITATIONS, REASONS FOR CAUTION This was a single-centre, retrospective study in which neonatal data were extracted from parental questionnaires. The information on uteri septum type and surgery methods was poorly presented, with limited detail. In patients with uterine malformations, the number of babies with birth defects and twin pregnancies was relatively small, limiting the power of the study. WIDER IMPLICATIONS OF THE FINDINGS Compared to patients with a normal uterus, women with uterine malformation have poorer reproductive outcomes. Pregnant women with a uterine anomaly need to be managed as high-risk pregnancies and followed with appropriate obstetric review. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Ministry of Technology (2018YFC1003000), the Elite Team Project of Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine (JY201801), Shanghai Sailing Program (21YF1423200) and the Fundamental Research Program Funding of Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine (JYZZ117). B.W.M. is supported by an NHMRC Investigatorgrant (GNT1176437). B.W.M. reports consultancy (with stock options) for ObsEva. B.W.M. has received research funding from Ferring and Merck. The authors declare no other competing interests. TRIAL REGISTRATION NUMBER N/A.

PDF file - 139K, Extracted labels.

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There is an increasing interest in the evaluation of prognostic and predictive biomarkers for personalizing cancer care. The literature on the trial designs for evaluation of these markers is diverse and there is no consensus in the classification or nomenclature. We set this study to review the literature systematically, to identify the proposed trial designs, and to develop a classification scheme. We searched MEDLINE, EMBASE, Cochrane Methodology Register, and MathSciNet up to January 2013 for articles describing these trial designs. In each eligible article, we identified the trial designs presented and extracted the term used for labeling the design, components of patient flow (marker status of eligible participants, intervention, and comparator), study questions, and analysis plan. Our search strategy resulted in 88 eligible articles, wherein 315 labels had been used by authors in presenting trial designs; 134 of these were unique. By analyzing patient flow components, we could classify the 134 unique design labels into four basic patient flow categories, which we labeled with the most frequently used term: single-arm, enrichment, randomize-all, and biomarker-strategy designs. A fifth category consists of combinations of the other four patient flow categories. Our review showed that a considerable number of labels has been proposed for trial designs evaluating prognostic and predictive biomarkers which, based on patient flow elements, can be classified into five basic categories. The classification system proposed here could help clinicians and researchers in designing and interpreting trials evaluating predictive biomarkers, and could reduce confusion in labeling and reporting. Clin Cancer Res; 19(17); 4578–88. ©2013 AACR.

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IntroductionIn 2021, we learnt about the problems in studies on ivermectin and hydrocholoroquine in COVID-19. We noticed an appreciable number of unfunded randomised clinical trials (RCTs) on the treatment of COVID-19 conducted across three centres in Egypt (Tanta University, Assiut University, Ain-shams University) on COVID-19 patients with similar inclusion criteria and overlapping time frames. Dr Sherief M Abd-Elsalam ran seven such RCTs across these three centres; four of these RCTs have since been retracted. We therefore set out to systematically analyse the integrity of all RCTs (co-)authored by Dr Abd-Elsalam, in particular 23 RCTs on Gastroenterology and Hepatology. MethodsWe searched PubMed, Google Scholar, Scopus and clinical trial registries for RCTs published by Dr Sherief M Abd-Elsalam, affiliated with the Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt. We assessed trial registration, tables for identical data values, statistical errors, and improbable data trends. We assessed the probability of true randomization by assessing baseline characteristics through a Monte Carlo Analysis. ResultsWe report on 30 published randomized control trials (RCTs) of Dr. Sherief Abd-Elsalam, in particular 23 RCTs on Gastroenterology and Hepatology. We found important issues in all RCTs examined. Of these 23 RCTs, 10 RCTs had substantial trial registration inconsistencies. Only one of these 10 RCTs has been retracted to date. We found nine RCTs with substantial statistical mistakes, five RCTs with similarities between tables unlikely to happen by chance, four RCTs with implausible Gaussian distributions, three RCTs in which almost all dichotomous variables had even values, while part of at least one study was plagiarized. Monte Carlo analysis indicated that the probability that distribution of baseline characteristics due to randomisation was 0.0000228. According to the trial registration, Dr. Abd-Elsalam is coordinating 76 clinical trials with 45 trials currently marked as ‘Recruiting’ and 17 trials marked as ‘Unknown Status’ as of November 2022.InterpretationWe strongly recommend a thorough investigation of the data integrity of all RCTs by Dr Sherief M Abd-Elsalam by journal editors. Until the completion of such an investigation, we suggest that none of these studies are used to inform clinical practice.

Objectives: To develop a checklist to screen, for trustworthiness, papers reporting the results of randomised controlled trials (RCTs). Design: A screening tool was developed using the four-stage approach proposed by Moher et al. This included defining the scope, reviewing the evidence base, suggesting a list of items from piloting, and holding a consensus meeting as part of a Delphi method. The initial checklist was set-up by a core group who had been involved in the assessment of dubious RCTs for several years. We piloted this in a Delphi panel of several stakeholders, including health professionals, reviewers, journal editors, policymakers, researchers and evidence-synthesis specialists. Each member was asked to score three articles with the checklist and the the results were then discussed in two Delphi sessions. Results: The Trustworthiness in RAndomised Clinical Trials (TRACT) checklist includes seven domains that are applicable to every RCT: governance, author group, plausibility of intervention usage, timeframe, drop-out rates, baseline characteristics and outcomes. Each domain contains two or three signalling questions that can be answered as either no concerns, some concerns/no information, or major concerns. If a study is assessed and found to have significant concerns, then editors or reviewers should consider a more thorough investigation, including assessment of original individual participant data. Conclusions: The TRACT checklist is the first checklist developed in a formal process to detect trustworthiness issues in RCTs. It might help editors, publishers and researchers to screen for such issues in submitted or published RCTs in a transparent and replicable manner.

Research indicates that soluble fms-like tyrosine kinase 1 (sFLT-1) and placental growth factor (PLGF) have diagnostic and prognostic significance for women with preeclampsia. However, sparse research has studied these biomarkers in women with preexisting comorbidities such as chronic hypertension, diabetes mellitus, systemic lupus erythematosus and chronic kidney disease. We undertook a prospective longitudinal cohort study to compare the sFLT-1: PlGF ratio between women with and without comorbidities who did and did not go on to develop preeclampsia. We found that women with comorbidities may develop preeclampsia with a milder elevation in sFLT-1: PlGF than do women without comorbidities. This has clinical and research implications.

Detailed analyses of published trials conducted as part of a Cochrane review led to concerns over two trials conducted by a single author. The Cochrane team therefore requested a forensic analysis of all his published papers. Eleven papers were found. Where appropriate, pairwise comparisons were made of values in baseline and outcome tables, and p-values recalculated. The distributions of baseline characteristics were assessed for compatibility with properly conducted randomization using Monte Carlo analysis and unusual features noted. The analyses brought up several areas of concern; for instance, a high degree of identical or highly similar values in some baseline and outcome tables between studies; all recalculated p-values, save for one, are different from the p-values given; for all eleven studies, the probability that participants have been grouped according to properly randomised processes is very low. In correspondence with the author, he agreed that the sample we sent him showed that published p-values were incorrect, but was unable to provide original data to conduct further checks. We conclude that analyses of papers published by this author suggest considerable data concerns and that they should not be used to inform clinical practice until further investigation is completed.

Biosimilars of follitropin alfa have been introduced in many countries as more affordable alternatives to the reference product for patients undergoing ovarian stimulation for assisted reproductive technology cycles. A recent meta-analysis, by reviewing available evidence originating from randomised controlled trials, has shown that based on the best available evidence, biosimilars of follitropin alfa are associated with lower live birth, ongoing and clinical pregnancy rates compared to the reference product. A subsequently published opinion paper challenges the methodology and results of this meta-analysis and suggests that these data should be ignored. In the present paper, it is clearly demonstrated why this criticism is largely unfounded and in stark contradiction with basic principles of evidence-based medicine. Furthermore, it is presented why the results of this meta-analysis provide the best available evidence to date and therefore the base that should inform clinical practice and, importantly, stimulate further research.

This study aimed to compare the prognostic accuracy of intrapartum transperineal ultrasound measures of fetal descent before operative vaginal birth in predicting complicated or failed procedures.We performed a predefined systematic search in Medline, Embase, CINAHL, and Scopus from inception to June 10, 2022.We included studies assessing the following intrapartum transperineal ultrasound measures before operative vaginal birth to predict procedure outcome: angle of progression, head direction, head-perineum distance, head-symphysis distance, midline angle, and/or progression distance.Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Bivariate meta-analysis was used to pool sensitivities and specificities into summary receiver operating characteristic curves for each intrapartum transperineal ultrasound measure. Subgroup analyses were performed for measures taken at rest vs with pushing and prediction of failed vs complicated operative vaginal birth.Overall, 16 studies involving 2848 women undergoing attempted operative vaginal birth were included. The prognostic accuracy of intrapartum transperineal ultrasound measures taken at rest to predict failed or complicated operative vaginal birth was high for angle of progression (area under the receiver operating characteristic curve, 0.891; 9 studies) and progression distance (area under the receiver operating characteristic curve, 0.901; 3 studies), moderate for head direction (area under the receiver operating characteristic curve, 0.791; 6 studies) and head-perineum distance (area under the receiver operating characteristic curve, 0.747; 8 studies), and fair for midline angle (area under the receiver operating characteristic curve, 0.642; 4 studies). There was no study with sufficient data to assess head-symphysis distance. Subgroup analysis showed that measures taken with pushing tended to have a higher area under the receiver operating characteristic curve for angle of progression (0.927; 4 studies), progression distance (0.930; 2 studies), and midline angle (0.903; 3 studies), with a similar area under the receiver operating characteristic curve for head direction (0.802; 4 studies). The prediction of failed vs complicated operative vaginal birth tended to be less accurate for angle of progression (0.837 [4 studies] vs 0.907 [6 studies]) and head direction (0.745 [3 studies] vs 0.810 [5 studies]), predominantly because of lower specificity, and was more accurate for head-perineum distance (0.812 [6 studies] vs 0.687 [2 studies]).Angle of progression, progression distance, and midline angle measured with pushing demonstrated the highest prognostic accuracy in predicting complicated or failed operative vaginal birth. Overall, the measurements seem to perform better with pushing than at rest.

To assess the outcomes of pregnancies at high-risk for rare autosomal trisomies (RATs) and segmental imbalances (SIs) on cell-free DNA (cfDNA) screening.A retrospective study of women who underwent cfDNA screening between September 2019 and July 2021 at three ultrasound services in Australia. Positive predictive values (PPVs) were calculated using fetal chromosomal analysis.Among 23,857 women screened, there were 93 high-risk results for RATs (0.39%) and 82 for SIs (0.34%). The PPVs were 3.8% (3/78, 95% CI 0.8%-10.8%) for RATs and 19.1% (13/68, 95% CI 10.6%-30.5%) for SIs. If fetuses with structural anomalies were also counted as true-positive cases, the PPV for RATS increased to 8.5% (7/82, 95% CI 3.5%-16.8%). Among 85 discordant cases with birth outcomes available (65.4%), discordant positive RATs had a significantly higher proportion of infants born below the 10th and 3rd birthweight percentiles than expected (19.6% (p = 0.022) and 9.8% (p = 0.004), respectively), which was not observed in the SI group (2.9% 10th (p = 0.168) and 0.0%3rd (p = 0.305)).The PPVs for SI and RAT results are low, except when a structural abnormality is also present. Discordant positive RATs are associated with growth restriction.

Obstetric and gynaecological conditions represent a significant burden of disease, requiring clinical research. We aimed to study trends in the publication of randomised controlled trials (RCTs) in women's health over the last two decades. The primary objective was to describe longitudinal trends in the geographical distribution of RCTs in obstetrics and gynaecology. We also described trends in trial funding, publication sources and separately published trial protocols.RCTs were identified by searching the Web of Science alone, due to the large number of results and descriptive nature of analyses. Using the filter tool, only studies labelled as "Clinical trial" or "Article" were included; all other document types were excluded. Trial protocols were identified and analysed separately. Indexing data were extracted using the Web of Science selection tools. As we aimed simply to describe research trends using a single platform, we did not check for duplicates. No process for data pooling was necessary. Correlation of GDP, funding and number of RCTs was calculated using Pearson's r test.We identified 39,071 RCTs. The number of annual publications globally increased from 1,406 in 2001 to 1,979 in 2020. The US (n = 12,479) and the UK (n = 3,745) were responsible for the most RCTs, followed by Italy (n = 2,676) and China (n = 2,338). The largest percentage increase in annual publications was seen in Iran (n = 5 to n = 113, +2,160 %) and the Western Pacific Region (n = 16 to n = 171, +968.8 %). GDP was significantly correlated with the number of published RCTs in 2019 for the 25 most prolific countries (p 0.001), but not with the proportion of RCTs funded.Despite growing contributions from the Western Pacific and Eastern Mediterranean regions, most RCTs are still produced in a small nucleus of high-income countries. Increased international collaboration may benefit both high- and low-income countries.

Individual participant data meta-analyses enable detailed checking of data quality and more complex analyses than standard study-level synthesis of summary data based on publications. However, there is limited existing guidance on the specific systematic checks that should be undertaken to confirm and enhance data quality for individual participant data meta-analyses and how to conduct these checks. We aim to address this gap by developing a checklist of items for data quality checking and cleaning to be applied to individual participant data meta-analyses of randomised trials. This study will comprise three phases: 1) a scoping review to identify potential checklist items; 2) two e-Delphi survey rounds among an invited panel of experts followed by a consensus meeting; and 3) pilot testing and refinement of the checklist, including development of an accompanying R-markdown program to facilitate its uptake.

BackgroundCOVID-19 infection in pregnancy is associated with a higher risk of progression to severe disease, but vaccine uptake by pregnant women is hindered by persistent safety concerns. COVID-19 vaccination in pregnancy has been shown to reduce stillbirth, but its relationship with preterm birth is uncertain.ObjectiveThe aim of this study was to investigate the sociodemographic characteristics associated with vaccine uptake in Melbourne, Australia, and to compare perinatal outcomes by vaccination status.Study designRetrospective multicenter cohort study in Melbourne following the national recommendations for mRNA COVID-19 vaccination during pregnancy in June 2021. Routinely collected data from all 12 public maternity hospitals in Melbourne were extracted on births ≥ 20 weeks’ gestation from 1st July 2021 to 31 March 2022. Maternal sociodemographic characteristics were analyzed from the total birth cohort. Perinatal outcomes were compared between vaccinated and unvaccinated women for whom weeks 20-43 of gestation fell entirely within the 9-month data collection period. The primary outcome was the rate of congenital anomaly in singleton infants ≥ 20 weeks’ gestation among women vaccinated during pregnancy. Secondary perinatal outcomes including stillbirth, preterm birth (spontaneous and iatrogenic), birthweight ≤ 3rd centile, and newborn intensive care unit admissions were examined for singleton infants ≥ 24 weeks’ gestation without congenital anomalies. We calculated the adjusted odds ratio of congenital anomalies and perinatal outcomes among vaccinated versus unvaccinated women using inverse propensity score weighting regression adjustment with multiple covariates; p< 0.05 was considered statistically significant.ResultsBirths from 32,536 women were analyzed: 17,365 (53.4%) were vaccinated and 15,171 (47.6%) were unvaccinated. Vaccinated women were significantly more likely to be older, nulliparous, non-smoking, not requiring an interpreter, of higher socioeconomic status, and vaccinated against pertussis and influenza. Vaccination status also varied by region of birth: compared with women born in Australia, women born in South and Eastern Europe, the Middle East, Africa and Oceania had lower adjusted odds of vaccination. There was no significant increase in the rate of congenital anomalies or birth weight ≤ 3rd centile in vaccinated women. Vaccinated women were significantly less like to have an infant with a major congenital anomaly compared with the unvaccinated group (2.4% vs 3.0%, aOR 0.72, 95%CI 0.56-0.94, p=0.02). This finding remained significant even when the analysis was restricted to women vaccinated before 20 weeks’ gestation. Vaccinated women had a significantly lower rate of stillbirth (0.2% vs 0.8%, aOR 0.18, 95%CI 0.09-0.37, P < 0.001. Vaccination was associated with a significant reduction in total preterm births < 37 weeks (5.1% vs 9.2%, aOR 0.60, 95% CI 0.51-0.71, p< 0.001), spontaneous preterm birth (2.4% vs 4.0%, aOR 0.73 95% CI 0.56-0.96, p=0.02) and iatrogenic preterm birth (2.7% vs 5.2%, aOR 0.52, 95%CI 0.41-0.65, p< 0.001).ConclusionsCOVID-19 Vaccine coverage was significantly influenced by known social determinants of health, which is likely to influence the strong association between COVID-19 vaccination and lower risks of stillbirth and preterm birth. We did not observe any adverse impacts of vaccination on fetal growth or development.AT A GLANCEWhy was this study conducted?⍰COVID-19 infection in pregnancy is associated with a higher risk of progression to severe disease, but vaccine uptake by pregnant women is hindered by persistent safety concerns. COVID-19 vaccination in pregnancy has been shown to reduce stillbirth, but its relationship with preterm birth is uncertain.⍰Most of the published literature on COVID-19 vaccination in pregnancy have methodological limitations including fixed cohort bias and time-varying exposure.⍰We conducted this multicenter study to provide robust evidence on mRNA COVID-19 vaccination and perinatal outcomes including congenital anomalies, stillbirth, and preterm birth.What are the key findings?⍰The adjusted odds of stillbirth, preterm birth, and neonatal intensive care admission were significantly reduced among infants born to COVID-19 vaccinated women compared with unvaccinated women. COVID-19 vaccination during pregnancy was not associated with an increase in congenital anomalies.⍰Our results conclusively demonstrate a significant reduction in both spontaneous and iatrogenic preterm birth for vaccinated women⍰Vaccinated women were significantly more likely to be older, nulliparous, non-smoking, not requiring an interpreter, residing in a higher socioeconomic postcode, and vaccinated against pertussis and influenza. There were also significant differences in vaccination rates by region of birth.What does this study add to what is already known?⍰Our analysis confirmed a strong relationship between the COVID-19 mRNA vaccine and lower preterm births and stillbirths⍰In addition to its impact on reducing severe COVID-19 illness, vaccination may be a proxy for other biological and social determinants of health among our pregnant population.

One unique character of reproductive medicine is the involvement of multiple individuals. Apart from individual(s) who want to become parents, also the interests offspring that is created by reproductive medicine treatments should be considered. This unique character brings unique ethical challenges, as the principle ‘Primum non nocere’ should be applied on all involved, including the children born form fertility treatments. I will present a framework that involves three dimensions, the risks for the mother, risks for the offspring and consequences for society and the public system. First, treatment can be refused as there is uncertainty about the quality of life of the future offspring. I will argue that before the treatment is started, the new individual is not there and cannot claim any rights. The care provider has a responsibility towards the future individual, not only in terms of health, but also from a social perspective. If the future child going to live an abusive family, it might be better of not existing. Second, treatment can be refused because of an unhealthy lifestyle or a health risk for the future mother. Treatment might be refused because a mother has an underlying disease that could severely exacerbate during pregnancy, or because she smokes or is obese. I will argue that in these situations decisions should be made in the context of absolute health risks for the mother and the offspring, as well as success rates of treatments. I will demonstrate that the bar to refuse treatments based on these grounds is high and that in most cases risks are acceptable while success rates are sufficiently high to justify treatment. Third, the risks of treatments should be balanced against the expected success rates of treatments. Risks of treatment are more acceptable if the success rates are higher. This obviously does not count for risks that only occur if the treatment is successful, for example pregnancy risks or risks for the offspring. Finally, treatments without proven effectiveness should preferably be offered in the context of research. Uncertainty about their effectiveness should be shared with the individual(s) who undergo the treatment. While in a private context, where patients pay their own treatment, the issue of cost-effectiveness is less relevant, efficiency is important in a public system, where society pays for treatment. In the latter case, ineffective treatments (for example IVF for older women with success rates of 1 or 2%) can be delayed in favour of less expensive treatments, or even denied. Koning A, Mol BW, Dondorp W. It is not justified to reject fertility treatment based on obesity. Hum Reprod Open. 2017 Jul 28;2017(2):hox009. Braakhekke M, Kamphuis EI, Mol F, Norman RJ, Bhattacharya S, van der Veen F, Mol BW. Hum Reprod. Effectiveness and safety as outcome measures in reproductive medicine. 2015 Oct;30(10):2249-51.

Study question Does transfer of low grade blastocysts results in acceptable live birth rates the birth of healthy babies? Summary answer While BC/CB/CC blastocysts have a reduced chance of live birth compared with AA/AB/BA/BB blastocysts, the absolute chances are still reasonable. What is known already Transfer of poorer quality embryos and blastocysts result in lower live birth rates, though to what extent is unclear, nor if there is an absolute threshold below which live births are very rare or even do not occur. Further, the developmental competence of the inner cell mass (ICM) or trophectoderm (TE) could at least theoretically impact the pregnancy and/or the health of the baby. Many clinics do not transfer or freeze poor quality embryos and blastocysts, and prefer to submit the patient to a further stimulation cycle. Study design, size, duration We performed a retrospective analysis of 10,978 couples undergoing singleton blastocyst transfers between 2009 and March 2020. We included all single blastocyst transfers for which there was complete data on blastocyst quality, singleton or twin births, birthweight and gestation at delivery, irrespective of blastocyst grading, female age, cause of infertility, ovarian response or endometrial thickness. We recorded live birth rates, birth weight and gestational age. Participants/materials, setting, methods Data from 14 clinics in 3 countries, 8 from China, 5 from New Zealand, and 1 from Australia were included in the final dataset. We compared the impact of blastocyst grading using multiple logistic regression. Blastocyst grading was based on the Gardner classification, in which the first letter denotes the grade of the inner cell mass (A is best), and the second letter the grade of the trophectoderm. Main results and the role of chance Overall, 10,978 single blastocyst cycles resulted in 4,261 live births (38.8%) (4195 singletons and 132 twins). Live birth rates were 47% after transfer of AA blastocysts (n = 2306); 42% after AB/BA (n = 2088); 33% after BC (n = 1973); 25% after CB (n = 715) and 14% after CC (n = 117). There were too few AC (n = 27) or CA (n = 12) blastocysts to include in the analysis. The odds of live birth for BC/CB/CC blastocysts compared with AA/AB/BA blastocysts, vary between 0.8 and 0.9. The live birth rate appears to be more dependent on ICM quality (C grade, n = 844, 23.2%) rather than TE quality (C grade, n = 2117, 32.1%), with the odds of live birth 0.43 and 0.57 respectively compared to A grade ICM or TE. The average birth weight (singleton only) was 3336.9+/-570.3 g (range 3323 to 3386 g), and the average gestation at delivery (singleton only) was 38+6+/-2.0 weeks (range 38+2 to 39+1). There was no significant difference for birth weight or gestational age at delivery between blastocysts of different grades. Limitations, reasons for caution This was a retrospective study. Grading was based on inner cell mass and trophectoderm and not on degree of expansion, or on day of transfer. It is likely that higher quality blastocysts were transferred first, in a fresh cycle, and poorer quality blastocysts frozen for later transfer. Wider implications of the findings The most important finding is that reasonable live birth rates are obtained in CC-blastocysts. We therefore advocate that CC-blastocysts should be replaced or frozen for later transfer. It is reassuring that there was no impact of blastocyst quality on birth weights or gestational age at the time of delivery. Trial registration number Not applicable

Recurrent pregnancy loss negatively affects the reproductive outcomes of natural conception. Preimplantation genetic testing for aneuploidies has been the focus of interventions in women with recurrent pregnancy loss. However, the risk of no embryos being available, high costs, and uncertainties surrounding its effectiveness limit its use. Factors beyond euploidy, such as an appropriate intrauterine environment, are also important for improving the reproductive outcomes in women with recurrent pregnancy loss. It remains unknown whether a history of recurrent pregnancy loss can affect reproductive outcomes after fertility treatment.This study aimed to investigate the impact of history of recurrent pregnancy loss on the reproductive outcomes of women undergoing fertility treatment.This was a retrospective cohort study of women who underwent their first frozen embryo transfer cycle or intrauterine insemination cycle between January 2014 and July 2020 in Shanghai, China. We excluded couples with known karyotypic abnormalities (eg, balanced translocation) or uterine malformation. We performed multivariate binary logistic regressions for biochemical pregnancy, miscarriage, and live birth rates to investigate the associations between recurrent pregnancy loss history and reproductive outcomes.A total of 29,825 women who underwent frozen embryo transfer cycles and 5476 women who underwent intrauterine insemination cycles were included in this study. In those who underwent frozen embryo transfer, history of recurrent pregnancy loss was not significantly associated with biochemical pregnancy (adjusted odds ratio, 1.19; 95% confidence interval, 0.87-1.63), miscarriage (adjusted odds ratio, 0.99; 95% confidence interval, 0.78-1.26), or live birth rates (adjusted odds ratio, 0.91; 95% confidence interval, 0.79-1.06). Similarly, in frozen embryo transfer cycles that led to clinical pregnancy, recurrent pregnancy loss history was not significantly associated with live birth (adjusted odds ratio, 0.99; 95% confidence interval, 0.76-1.28) or miscarriage rates (adjusted odds ratio, 1.04; 95% confidence interval, 0.81-1.35). In women with intrauterine insemination, history of recurrent pregnancy loss showed no significant associations with fertility outcomes in all cycles ([adjusted odds ratio, 1.36; 95% confidence interval, 0.88-2.10] for live birth rate and [adjusted odds ratio, 1.74; 95% confidence interval, 0.75-4.01], for miscarriage rate) and in cycles that led to clinical pregnancy ([adjusted odds ratio, 0.70; 95% confidence interval, 0.31-1.63] for live birth rate and [adjusted odds ratio, 1.45; 95% confidence interval, 0.58-3.63] for miscarriage rate).In women without obvious chromosome abnormality and uterine malformation who undergo fertility treatment, recurrent pregnancy loss history was not significantly associated with miscarriage and live birth rates, suggesting that it has little or no prognostic value in predicting the reproductive outcomes of frozen embryo transfer or intrauterine insemination cycles.