Publications by authors named "Madelon van Wely"

122 Publications

Methods to assess research misconduct in health-related research: A scoping review.

J Clin Epidemiol 2021 May 22. Epub 2021 May 22.

Centre for Reproductive Medicine, Amsterdam UMC, Amsterdam, The Netherlands.

Objective: To give an overview of the available methods to investigate research misconduct in health-related research.

Study Design And Setting: In this scoping review, we conducted a literature search in MEDLINE, Embase, The Cochrane CENTRAL Register of Studies Online (CRSO), and The Virtual Health Library portal up to July 2020. We included papers that mentioned and/or described methods for screening or assessing research misconduct in health-related research. We categorised identified methods into the following four groups according to their scopes: overall concern, textual concern, image concern, and data concern.

Results: We included 57 papers reporting on 27 methods: two on overall concern, four on textual concern, three on image concern, and 18 on data concern. Apart from the methods to locate textual plagiarism and image manipulation, all other methods, be it theoretical or empirical, are based on examples, are not standardized and lack formal validation.

Conclusion: Existing methods cover a wide range of issues regarding research misconduct. While measures to counteract textual plagiarism are well implemented, tools to investigate other forms of research misconduct are rudimentary and labour-intensive. To cope with the rising challenge of research misconduct, further development of automatic tools and routine validation of these methods is needed.

Trial Registration Number: Center for Open Science (OSF) (https://osf.io/mq89w).
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http://dx.doi.org/10.1016/j.jclinepi.2021.05.012DOI Listing
May 2021

Concerns about Data Integrity of 22 Randomized Controlled Trials in Women's Health.

Am J Perinatol 2021 May 18. Epub 2021 May 18.

Department of Obstetrics and Gynecology, Monash University, Clayton, Australia.

Objective:  During a review on postpartum hemorrhage, we identified randomized controlled trials (RCTs) of one author conducted at the same time and place for the same condition, with large differences in baseline characteristics. We assessed the data integrity of the RCTs of this author.

Study Design:  We undertook a focused analysis of the data integrity of all RCTs published by Dr. Ahmed M. Maged. We examined the studies for clinical logic and made pairwise comparisons of baseline characteristics and outcomes between trials. We used mathematical methods to assess whether the distribution of baseline characteristics was compatible with chance.

Results:  Between March 2015 and December 2019, Dr. Maged published 22 RCTs ( = 3,722). The median number of participants randomized per center per month was 32 (range = 1-89). Fifteen studies were either not or retrospectively registered, with one study registered 1 year after publication. One study was submitted for publication prior to the completion of the described study period. There were many unusual findings in the studies, including biologically implausible occurrences such as the absence of an association between gestational age and birthweight in seven studies and very different body mass index between three trials, which ran at the same time in the same hospital on the same topic as well as unlikely occurrences such as limited participant drop outs. One paper contained considerable text duplication and identical data to that in a paper published by a different author group from a different hospital, with both papers submitted at the same time. Mathematical analysis of the baseline characteristics of all 22 trials indicated that at least some of the reported baseline characteristics were unlikely to be the result of proper randomization.

Conclusion:  Our analyses of the 22 RCTs of Dr. Maged suggest potential data integrity issues in at least some of them. We suggest that journals investigate according to the Committee on Publication Ethics guidelines. The procedures demonstrated in this paper may help to assess data integrity in future attempts to verify the authenticity of published RCTs.

Key Points: · We identified a number of findings biologically implausible in RCTs by Maged.. · Monte Carlo simulation found pooled data of Maged RCTs were unlikely result of proper randomization.. · Textual overlap and almost identical data were found between a Maged paper and another paper.. · The methods we described may be useful for future efforts in validating scientific data integrity..
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http://dx.doi.org/10.1055/s-0041-1727280DOI Listing
May 2021

Reply: Freeze-all vs conventional IVF: a valid and valuable RCT.

Hum Reprod 2021 May 16. Epub 2021 May 16.

Amsterdam UMC, University of Amsterdam, Center for Reproductive Medicine, Amsterdam Reproduction & Development Research Institute, Amsterdam, Netherlands.

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http://dx.doi.org/10.1093/humrep/deab113DOI Listing
May 2021

An investigation of seven other publications by the first author of a retracted paper due to doubts about data integrity.

Eur J Obstet Gynecol Reprod Biol 2021 Jun 18;261:236-241. Epub 2021 Apr 18.

Department of Obstetrics and Gynecology, Monash University, Clayton, Australia. Electronic address:

Background: In 2019, a randomized controlled trial (RCT) authored by Dr. Ismail was retracted due to concerns about data integrity. Since there are no policies in place to investigate other publications of authors of retracted studies, we investigated Dr. Ismail's other trials.

Methods: We searched for RCTs authored by Dr. Ismail. We made pairwise comparisons of values in baseline and outcome tables between trials. We assessed whether the distributions of baseline characteristics were compatible with properly conducted randomization, using Monte Carlo simulations and the Kolmogorov-Smirnov test. We read the publications carefully for unusual features.

Results: Dr. Ismail was author in eight published and one unpublished trial. In three of his first author studies we found multiple identical values in the baseline and/or outcome tables from different trials. At least some of the trials were unlikely to have followed a proper randomization process. There were a number of other unusual features in the papers we reviewed.

Conclusions: It is probable that other trials published by Dr. Ismail contain questionable data. We call for a thorough investigation of the original trial data and related official documents. Our exercise suggests that the practice to assess research integrity should include all publications of authors with retracted fabricated articles.
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http://dx.doi.org/10.1016/j.ejogrb.2021.04.018DOI Listing
June 2021

Pharmacological and non-pharmacological strategies for obese women with subfertility.

Cochrane Database Syst Rev 2021 Mar 25;3:CD012650. Epub 2021 Mar 25.

Social Determinants of Health Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

Background: Clinicians primarily recommend weight loss for obese women seeking pregnancy. The effectiveness of interventions aimed at weight loss in obese women with subfertility is unclear.

Objectives: To assess the effectiveness and safety of pharmacological and non-pharmacological strategies compared with each other, placebo, or no treatment for achieving weight loss in obese women with subfertility.

Search Methods: We searched the CGF Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and AMED from inception to 18 August 2020. We also checked reference lists and contacted experts in the field for additional relevant papers.

Selection Criteria: We included published and unpublished randomised controlled trials in which weight loss was the main goal of the intervention. Our primary effectiveness outcomes were live birth or ongoing pregnancy and primary safety outcomes were miscarriage and adverse events. Secondary outcomes included clinical pregnancy, weight change, quality of life, and mental health outcome.

Data Collection And Analysis: Review authors followed standard Cochrane methodology.

Main Results: This review includes 10 trials. Evidence was of very low to low quality: the main limitations were due to lack of studies and poor reporting of study methods. The main reasons for downgrading evidence were lack of details by which to judge risk of bias (randomisation and allocation concealment), lack of blinding, and imprecision. Non-pharmacological intervention versus no intervention or placebo Evidence is insufficient to determine whether a diet or lifestyle intervention compared to no intervention affects live birth (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.65 to 1.11; 918 women, 3 studies; I² = 78%; low-quality evidence). This suggests that if the chance of live birth following no intervention is assumed to be 43%, the chance following diet or lifestyle changes would be 33% to 46%. We are uncertain if lifestyle change compared with no intervention affects miscarriage rate (OR 1.54, 95% CI 0.99 to 2.39; 917 women, 3 studies; I² = 0%; very low-quality evidence). Evidence is insufficient to determine whether lifestyle change compared with no intervention affects clinical pregnancy (OR 1.06, 95% CI 0.81 to 1.40; 917 women, 3 studies; I² = 73%; low-quality evidence). Lifestyle intervention resulted in a decrease in body mass index (BMI), but data were not pooled due to heterogeneity in effect (mean difference (MD) -3.70, 95% CI -4.10 to -3.30; 305 women, 1 study; low-quality evidence; and MD -1.80, 95% CI -2.67 to -0.93; 43 women, 1 study; very low-quality evidence). Non-pharmacological versus non-pharmacological intervention We are uncertain whether intensive weight loss interventions compared to standard care nutrition counselling affects live birth (OR 11.00, 95% CI 0.43 to 284; 11 women, 1 study; very low-quality evidence), clinical pregnancy (OR 11.00, 95% CI 0.43 to 284; 11 women, 1 study; very low-quality evidence), BMI (MD -3.00, 95% CI -5.37 to -0.63; 11 women, 1 study; very low-quality evidence), weight change (MD -9.00, 95% CI -15.50 to -2.50; 11 women, 1 study; very low-quality evidence), quality of life (MD 0.06, 95% CI -0.03 to 0.15; 11 women, 1 study; very low-quality evidence), or mental health (MD -7.00, 95% CI -13.92 to -0.08; 11 women, 1 study; very low-quality evidence). No study reported on adverse events . Pharmacological versus pharmacological intervention For metformin plus liraglutide compared to metformin we are uncertain of an effect on the adverse events nausea (OR 7.22, 95% CI 0.72 to 72.7; 28 women, 1 study; very low-quality evidence), diarrhoea (OR 0.31, 95% CI 0.01 to 8.3; 28 women, 1 study; very low-quality evidence), and headache (OR 5.80, 95% CI 0.25 to 133; 28 women, 1 study; very low-quality evidence). We are uncertain if a combination of metformin plus liraglutide vs metformin affects BMI (MD 2.1, 95% CI -0.42 to 2.62; 28 women, 1 study; very low-quality evidence) and total body fat (MD -0.50, 95% CI -4.65 to 3.65; 28 women, 1 study; very low-quality evidence). For metformin, clomiphene, and L-carnitine versus metformin, clomiphene, and placebo, we are uncertain of an effect on miscarriage (OR 3.58, 95% CI 0.73 to 17.55; 274 women, 1 study; very low-quality evidence), clinical pregnancy (OR 5.56, 95% CI 2.57 to 12.02; 274 women, 1 study; very low-quality evidence) or BMI (MD -0.3, 95% CI 1.17 to 0.57, 274 women, 1 study, very low-quality evidence). We are uncertain if dexfenfluramine versus placebo affects weight loss in kilograms (MD -0.10, 95% CI -2.77 to 2.57; 21 women, 1 study; very low-quality evidence). No study reported on live birth, quality of life, or mental health outcomes. Pharmacological intervention versus no intervention or placebo We are uncertain if metformin compared with placebo affects live birth (OR 1.57, 95% CI 0.44 to 5.57; 65 women, 1 study; very low-quality evidence). This suggests that if the chance of live birth following placebo is assumed to be 15%, the chance following metformin would be 7% to 50%. We are uncertain if metformin compared with placebo affects gastrointestinal adverse events (OR 0.91, 95% CI 0.32 to 2.57; 65 women, 1 study; very low-quality evidence) or miscarriage (OR 0.50, 95% CI 0.04 to 5.80; 65 women, 1 study; very low-quality evidence) or clinical pregnancy (OR 2.67, 95% CI 0.90 to 7.93; 96 women, 2 studies; I² = 48%; very low-quality evidence). We are also uncertain if diet combined with metformin versus diet and placebo affects BMI (MD -0.30, 95% CI -2.16 to 1.56; 143 women, 1 study; very low-quality evidence) or waist-to-hip ratio (WHR) (MD 2.00, 95% CI -2.21 to 6.21; 143 women, 1 study; very low-quality evidence). Pharmacological versus non-pharmacological intervention No study undertook this comparison.

Authors' Conclusions: Evidence is insufficient to support the use of pharmacological and non-pharmacological strategies for obese women with subfertility. No data are available for the comparison of pharmacological versus non-pharmacological strategies. We are uncertain whether pharmacological or non-pharmacological strategies effect live birth, ongoing pregnancy, adverse events, clinical pregnancy, quality of life, or mental heath outcomes. However, for obese women with subfertility, a lifestyle intervention may reduce BMI. Future studies should compare a combination of pharmacological and lifestyle interventions for obese women with subfertility.
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http://dx.doi.org/10.1002/14651858.CD012650.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094444PMC
March 2021

Increased obstetric and neonatal risks in artificial cycles for frozen embryo transfers?

Reprod Biomed Online 2021 May 1;42(5):919-929. Epub 2021 Feb 1.

Amsterdam UMC, University of Amsterdam, Center for Reproductive Medicine, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9 Amsterdam, the Netherlands. Electronic address:

Research Question: What are the obstetric and neonatal risks for women conceiving via frozen-thawed embryo transfer (FET) during a modified natural cycle compared with an artificial cycle method.

Design: A follow-up study to the ANTARCTICA randomized controlled trial (RCT) (NTR 1586) conducted in the Netherlands, which showed that modified natural cycle FET (NC-FET) was non-inferior to artificial cycle FET (AC-FET) in terms of live birth rates. The current study collected data on obstetric and neonatal outcomes of 98 women who had a singleton live birth. The main outcome was birthweight; additional outcomes included hypertensive disorder of pregnancy, premature birth, gestational diabetes, obstetric haemorrhage and neonatal outcomes including Apgar scores and admission to the neonatal ward or the neonatal intensive care unit and congenital anomalies.

Results: Data from 82 out of 98 women were analysed according to the per protocol principle. There was no significant difference in the birthweights of children born between groups (mean difference -124 g [-363 g to 114 g]; P = 0.30). Women who conceived by modified NC-FET have a decreased risk of hypertensive disorders of pregnancy compared with AC-FET (relative risk 0.27; 95% CI 0.08-0.94; P = 0.031). Other outcomes, such as rates of premature birth, gestational diabetes or obstetric haemorrhage and neonatal outcomes, were not significantly different.

Conclusions: The interpretation is that modified NC-FET is the preferred treatment in women with ovulatory cycles undergoing FET when the increased risk of obstetrical complications and potential neonatal complications in AC-FET are considered.
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http://dx.doi.org/10.1016/j.rbmo.2021.01.015DOI Listing
May 2021

Fresh versus frozen embryo transfers in assisted reproduction.

Cochrane Database Syst Rev 2021 02 4;2:CD011184. Epub 2021 Feb 4.

Amsterdam UMC, University of Amsterdam, Center for Reproductive Medicine, Amsterdam Reproduction & Development Research Institute, Amsterdam, Netherlands.

Background: In vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatments conventionally consist of a fresh embryo transfer, possibly followed by one or more cryopreserved embryo transfers in subsequent cycles. An alternative option is to freeze all suitable embryos and transfer cryopreserved embryos in subsequent cycles only, which is known as the 'freeze all' strategy. This is the first update of the Cochrane Review on this comparison.

Objectives: To evaluate the effectiveness and safety of the freeze all strategy compared to the conventional IVF/ICSI strategy in women undergoing assisted reproductive technology.

Search Methods: We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two registers of ongoing trials from inception until 23 September 2020 for relevant studies, checked references of publications found, and contacted study authors to obtain additional data.

Selection Criteria: Two review authors (TZ and MZ) independently selected studies for inclusion, assessed risk of bias, and extracted study data. We included randomised controlled trials comparing a 'freeze all' strategy with a conventional IVF/ICSI strategy including a fresh embryo transfer in women undergoing IVF or ICSI treatment.

Data Collection And Analysis: The primary outcomes were cumulative live birth rate and ovarian hyperstimulation syndrome (OHSS). Secondary outcomes included effectiveness outcomes (including ongoing pregnancy rate and clinical pregnancy rate), time to pregnancy and obstetric, perinatal and neonatal outcomes.

Main Results: We included 15 studies in the systematic review and eight studies with a total of 4712 women in the meta-analysis. The overall evidence was of moderate to low quality. We graded all the outcomes and downgraded due to serious risk of bias, serious imprecision and serious unexplained heterogeneity. Risk of bias was associated with unclear blinding of investigators for preliminary outcomes of the study during the interim analysis, unit of analysis error, and absence of adequate study termination rules. There was an absence of high-quality evidence according to GRADE assessments for our primary outcomes, which is reflected in the cautious language below. There is probably little or no difference in cumulative live birth rate between the 'freeze all' strategy and the conventional IVF/ICSI strategy (odds ratio (OR) 1.08, 95% CI 0.95 to 1.22; I = 0%; 8 RCTs, 4712 women; moderate-quality evidence). This suggests that for a cumulative live birth rate of 58% following the conventional strategy, the cumulative live birth rate following the 'freeze all' strategy would be between 57% and 63%. Women might develop less OHSS after the 'freeze all' strategy compared to the conventional IVF/ICSI strategy (OR 0.26, 95% CI 0.17 to 0.39; I = 0%; 6 RCTs, 4478 women; low-quality evidence). These data suggest that for an OHSS rate of 3% following the conventional strategy, the rate following the 'freeze all' strategy would be 1%. There is probably little or no difference between the two strategies in the cumulative ongoing pregnancy rate (OR 0.95, 95% CI 0.75 to 1.19; I = 31%; 4 RCTs, 1245 women; moderate-quality evidence).  We could not analyse time to pregnancy; by design, time to pregnancy is shorter in the conventional strategy than in the 'freeze all' strategy when the cumulative live birth rate is comparable, as embryo transfer is delayed in a 'freeze all' strategy. We are uncertain whether the two strategies differ in cumulative miscarriage rate because the evidence is very low quality (Peto OR 1.06, 95% CI 0.72 to 1.55; I = 55%; 2 RCTs, 986 women; very low-quality evidence) and cumulative multiple-pregnancy rate (Peto OR 0.88, 95% CI 0.61 to 1.25; I = 63%; 2 RCTs, 986 women; very low-quality evidence). The risk of hypertensive disorders of pregnancy (Peto OR 2.15, 95% CI 1.42 to 3.25; I = 29%; 3 RCTs, 3940 women; low-quality evidence), having a large-for-gestational-age baby (Peto OR 1.96, 95% CI 1.51 to 2.55; I = 0%; 3 RCTs, 3940 women; low-quality evidence) and a higher birth weight of the children born (mean difference (MD) 127 g, 95% CI 77.1 to 177.8; I = 0%; 5 RCTs, 1607 singletons; moderate-quality evidence) may be increased following the 'freeze all' strategy. We are uncertain whether the two strategies differ in the risk of having a small-for-gestational-age baby because the evidence is low quality (Peto OR 0.82, 95% CI 0.65 to 1.05; I = 64%; 3 RCTs, 3940 women; low-quality evidence).

Authors' Conclusions: We found moderate-quality evidence showing that one strategy is probably not superior to the other in terms of cumulative live birth rate and ongoing pregnancy rate. The risk of OHSS may be decreased in the 'freeze all' strategy. Based on the results of the included studies, we could not analyse time to pregnancy. It is likely to be shorter using a conventional IVF/ICSI strategy with fresh embryo transfer in the case of similar cumulative live birth rate, as embryo transfer is delayed in a 'freeze all' strategy. The risk of maternal hypertensive disorders of pregnancy, of having a large-for-gestational-age baby and a higher birth weight of the children born may be increased following the 'freeze all' strategy. We are uncertain if 'freeze all' strategy reduces the risk of miscarriage, multiple pregnancy rate or having a small-for-gestational-age baby compared to conventional IVF/ICSI.
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http://dx.doi.org/10.1002/14651858.CD011184.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095009PMC
February 2021

Comparing the cumulative live birth rate of cleavage-stage versus blastocyst-stage embryo transfers between IVF cycles: a study protocol for a multicentre randomised controlled superiority trial (the ToF trial).

BMJ Open 2021 01 13;11(1):e042395. Epub 2021 Jan 13.

Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, The Netherlands.

Introduction: In vitro fertilisation (IVF) has evolved as an intervention of choice to help couples with infertility to conceive. In the last decade, a strategy change in the day of embryo transfer has been developed. Many IVF centres choose nowadays to transfer at later stages of embryo development, for example, transferring embryos at blastocyst stage instead of cleavage stage. However, it still is not known which embryo transfer policy in IVF is more efficient in terms of cumulative live birth rate (cLBR), following a fresh and the subsequent frozen-thawed transfers after one oocyte retrieval. Furthermore, studies reporting on obstetric and neonatal outcomes from both transfer policies are limited.

Methods And Analysis: We have set up a multicentre randomised superiority trial in the Netherlands, named the Three or Fivetrial. We plan to include 1200 women with an indication for IVF with at least four embryos available on day 2 after the oocyte retrieval. Women are randomly allocated to either (1) control group: embryo transfer on day 3 and cryopreservation of supernumerary good-quality embryos on day 3 or 4, or (2) intervention group: embryo transfer on day 5 and cryopreservation of supernumerary good-quality embryos on day 5 or 6. The primary outcome is the cLBR per oocyte retrieval. Secondary outcomes include LBR following fresh transfer, multiple pregnancy rate and time until pregnancy leading a live birth. We will also assess the obstetric and neonatal outcomes, costs and patients' treatment burden.

Ethics And Dissemination: The study protocol has been approved by the Central Committee on Research involving Human Subjects in the Netherlands in June 2018 (CCMO NL 64060.000.18). The results of this trial will be submitted for publication in international peer-reviewed and in open access journals.

Trial Registration Number: Netherlands Trial Register (NL 6857).
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http://dx.doi.org/10.1136/bmjopen-2020-042395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812106PMC
January 2021

Clinical manifestations, prevalence, risk factors, outcomes, transmission, diagnosis and treatment of COVID-19 in pregnancy and postpartum: a living systematic review protocol.

BMJ Open 2020 12 2;10(12):e041868. Epub 2020 Dec 2.

Department of Sexual and Reproductive Health and Research, UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), World Health Organization, Geneva, Switzerland.

Introduction: Rapid, robust and continually updated evidence synthesis is required to inform management of COVID-19 in pregnant and postpartum women and to keep pace with the emerging evidence during the pandemic.

Methods And Analysis: We plan to undertake a living systematic review to assess the prevalence, clinical manifestations, risk factors, rates of maternal and perinatal complications, potential for mother-to-child transmission, accuracy of diagnostic tests and effectiveness of treatment for COVID-19 in pregnant and postpartum women (including after miscarriage or abortion). We will search Medline, Embase, WHO COVID-19 database, preprint servers, the China National Knowledge Infrastructure system and Wanfang databases from 1 December 2019. We will supplement our search with studies mapped by Cochrane Fertility and Gynaecology group, Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-Centre), COVID-19 study repositories, reference lists and social media blogs. The search will be updated every week and not be restricted by language. We will include observational cohort (≥10 participants) and randomised studies reporting on prevalence of COVID-19 in pregnant and postpartum women, the rates of clinical manifestations and outcomes, risk factors in pregnant and postpartum women alone or in comparison with non-pregnant women with COVID-19 or pregnant women without COVID-19 and studies on tests and treatments for COVID-19. We will additionally include case reports and series with evidence on mother-to-child transmission of SARS-CoV-2 in utero, intrapartum or postpartum. We will appraise the quality of the included studies using appropriate tools to assess the risk of bias. At least two independent reviewers will undertake study selection, quality assessment and data extraction every 2 weeks. We will synthesise the findings using quantitative random effects meta-analysis and report OR or proportions with 95% CIs and prediction intervals. Case reports and series will be reported as qualitative narrative synthesis. Heterogeneity will be reported as I and τ statistics.

Ethics And Dissemination: Ethical approval is not required as this is a synthesis of primary data. Regular updates of the results will be published on a dedicated website (https://www.birmingham.ac.uk/research/who-collaborating-centre/pregcov/index.aspx) and disseminated through publications, social media and webinars.

Prospero Registration Number: CRD42020178076.
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http://dx.doi.org/10.1136/bmjopen-2020-041868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712931PMC
December 2020

In-vitro maturation versus IVF: a cost-effectiveness analysis.

Reprod Biomed Online 2021 Jan 28;42(1):143-149. Epub 2020 Sep 28.

Department of Obstetrics and Gynaecology, University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam; HOPE Research Center, My Duc Hospital, Ho Chi Minh City, Vietnam. Electronic address:

Research Question: How do costs and effects of in-vitro maturation (IVM) compare to IVF in women with a high antral follicle count (AFC)?

Design: This cost-effectiveness analysis (CEA) was based on data of a previous retrospective cohort study at IVFMD, My Duc Hospital, Ho Chi Minh City, Vietnam. Between July 2015 and December 2017, 608 women underwent IVM and 311 women IVF. The effectiveness measure for the CEA was cumulative live birth rate (LBR) after one completed cycle including subsequent cryo-cycles within 12 months of inclusion. Data were collected on resource use related to treatment, medication and pregnancy from the case report forms. The mean costs and effects, average cost differences and incremental cost-effectiveness ratios (ICER) were calculated using non-parametric bootstrap resampling to assess the effect of uncertainty in the estimates.

Results: Cumulative LBR after one completed cycle were 239/608 (39.3%) in the IVM group versus 155/311 (49.8%) in the IVF group (adjusted odds ratio 0.52, 95% confidence interval [CI] 0.30-0.89). Ovarian hyperstimulation syndrome (OHSS) did not occur in the IVM group versus 11/311 (3.5%) in the IVF group. The mean costs per couple were €4300 (95% CI €1371-18,798) for IVM and €6493 (95% CI €2204-20,136) for IVF. The ICER per additional live birth with IVF was €20,144 (95% CI €9116-50,418). Results were robust over a wide range of assumptions.

Conclusions: IVM is less expensive than IVF in women with a high AFC undergoing treatment with assisted reproductive technology, while leading to a slightly lower effectiveness in terms of cumulative LBR.
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http://dx.doi.org/10.1016/j.rbmo.2020.09.022DOI Listing
January 2021

Treatment Strategies for Unexplained Infertility.

Semin Reprod Med 2020 Jan 29;38(1):48-54. Epub 2020 Oct 29.

Centre for Reproductive Medicine, Amsterdam UMC, Amsterdam, The Netherlands.

Unexplained infertility is a common diagnosis among couples with infertility. Pragmatic treatment options in these couples are directed at trying to improve chances to conceive, and consequently intrauterine insemination (IUI) with ovarian stimulation and in vitro fertilization (IVF) are standard clinical practice, while expectant management remains an important alternative. While evidence on IVF or IUI with ovarian stimulation versus expectant management was inconclusive, these interventions seem more effective in couples with a poor prognosis of natural conception. Strategies such as strict cancellation criteria and single-embryo transfer aim to reduce multiple pregnancies without compromising cumulative live birth. We propose a prognosis-based approach to manage couples with unexplained infertility so as to expose less couples to unnecessary interventions and less mothers and children to the potential adverse effects of ovarian stimulation or laboratory procedures.
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http://dx.doi.org/10.1055/s-0040-1719074DOI Listing
January 2020

Iodine contrast prior to or during pregnancy and neonatal thyroid function: a systematic review.

Eur J Endocrinol 2021 Jan;184(1):189-198

Department of Paediatric Endocrinology, Amsterdam UMC, Vrije Universiteit Amsterdam, Emma Children's Hospital, Amsterdam, the Netherlands.

Objective: Thyroid dysfunction is a known side effect of iodinated contrast media. There is some evidence to suggest that iodinated contrast media administered to pregnant women may cause thyroid dysfunction not only in themselves but also in their offspring. Here, we systematically evaluated literature on the use of iodinated contrast media prior to or during pregnancy on the offspring's thyroid function.

Design: Systematic review of published literature.

Materials And Methods: Relevant studies were identified by PubMed, EMBASE and The Cochrane Library up to June 5, 2020. All study designs, reporting on the foetal or neonatal thyroid function after exposure to iodinated contrast media prior to or during pregnancy, were included. We undertook random effects meta-analysis and pooled the estimates as proportions with 95% CIs.

Results: We identified 402 articles, of which 26 were included. Six studies reported (n = 369) on exposure to iodinated contrast media prior to pregnancy by hysterosalpingography and 20 studies (n = 670) on exposure to these media during pregnancy by amniofetography, urography or CT. There was low to high risk of bias. The proportion of (transient) neonatal thyroid dysfunction was 0.0% (95% CI: 0.0-2.9% based on 3 studies) for hysterosalpingography, 2.25% (95% CI: 0.03-6.55% based on 2 studies) for amniofetography and 0.0% (95% CI: 0.0-0.02% based on 5 studies) for CT. There was a tendency towards an increased risk of thyroid dysfunction with higher amounts of contrast used.

Conclusions: Exposure to iodinated contrast media prior to or during pregnancy may increase the risk of thyroid dysfunction in offspring. We recommend keeping the amount of contrast used as low as possible.
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http://dx.doi.org/10.1530/EJE-20-0627DOI Listing
January 2021

Comments on the methodology of an endometrial receptivity array trial.

Reprod Biomed Online 2021 01 3;42(1):283. Epub 2020 Oct 3.

Department of Obstetrics and Gynecology, University of Auckland, New Zealand.

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http://dx.doi.org/10.1016/j.rbmo.2020.09.027DOI Listing
January 2021

Letter of response (2) - Data integrity of 35 randomised controlled trials in women' health.

Eur J Obstet Gynecol Reprod Biol 2020 12 30;255:261-262. Epub 2020 Aug 30.

Department of Obstetrics and Gynecology, Monash University, Clayton, Australia.

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http://dx.doi.org/10.1016/j.ejogrb.2020.08.050DOI Listing
December 2020

To share or not to share data: how valid are trials evaluating first-line ovulation induction for polycystic ovary syndrome?

Hum Reprod Update 2020 11;26(6):929-941

Department of Obstetrics and Gynecology, Monash University, Clayton, Australia.

Background: In our recent individual participant data (IPD) meta-analysis evaluating the effectiveness of first-line ovulation induction for polycystic ovary syndrome (PCOS), IPD were only available from 20 studies of 53 randomized controlled trials (RCTs). We noticed that the summary effect sizes of meta-analyses of RCTs without IPD sharing were different from those of RCTs with IPD sharing. Granting access to IPD for secondary analysis has implications for promoting fair and transparent conduct of RCTs. It is, however, still common for authors to choose to withhold IPD, limiting the impact of and confidence in the results of RCTs and systematic reviews based on aggregate data.

Objective And Rationale: We performed a meta-epidemiologic study to elucidate if RCTs without IPD sharing have lower quality and more methodological issues than those with IPD sharing in an IPD meta-analysis evaluating first-line ovulation induction for PCOS.

Search Methods: We included RCTs identified for the IPD meta-analysis. We dichotomized RCTs according to whether they provided IPD (shared group) or not (non-shared group) in the IPD meta-analysis. We restricted RCTs to full-text published trials written in English.We assessed and compared RCTs in the shared and non-shared groups on the following criteria: Risk of Bias (RoB 2.0), GRADE approach, adequacy of trial registration; description of statistical methods and reproducibility of univariable statistical analysis; excessive similarity or difference in baseline characteristics that is not compatible with chance; and other miscellaneous methodological issues.

Outcomes: In total, 45 trials (8697 women) were included in this study. IPD were available from 17 RCTs and 28 trials were categorized as the non-shared IPD group. Pooled risk rates obtained from the shared and non-shared groups were different. Overall low risk of bias was associated with 13/17 (76%) of shared RCTs versus 7/28 (25%) of non-shared RCTs. For RCTs that started recruitment after 1 July 2005, adequate trial registration was found in 3/9 (33%) of shared IPD RCTs versus 0/16 (0%) in non-shared RCTs. In total, 7/17 (41%) of shared RCTs and 19/28 (68%) of non-shared RCTs had issues with the statistical methods described. The median (range) of inconsistency rate per study, between reported and reproduced analyses for baseline variables, was 0% (0-92%) (6 RCTs applicable) in the shared group and 54% (0-100%) (13 RCTs applicable) in the non-shared group. The median (range) of inconsistency rate of univariable statistical results for the outcome(s) per study was 0% (0-63%) (14 RCTs applicable) in the shared group and 44% (0-100%) (24 RCTs applicable) in the non-shared group. The distributions of simulation-generated P-values from comparisons of baseline continuous variables between intervention and control arms suggested that RCTs in the shared group are likely to be consistent with properly conducted randomization (P = 0.163), whereas this was not the case for the RCTs in the non-shared group (P = 4.535 × 10-8).

Wider Implications: IPD meta-analysis on evaluating first-line ovulation induction for PCOS preserves validity and generates more accurate estimates of risk than meta-analyses using aggregate data, which enables more transparent assessments of benefits and risks. The availability of IPD and the willingness to share these data may be a good indicator of quality, methodological soundness and integrity of RCTs when they are being considered for inclusion in systematic reviews and meta-analyses.
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November 2020

Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilisation.

Cochrane Database Syst Rev 2020 09 8;9:CD005291. Epub 2020 Sep 8.

Center for Reproductive Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Background: In in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI), selection of the most competent embryo(s) for transfer is based on morphological criteria. However, many women do not achieve a pregnancy even after 'good quality' embryo transfer. One of the presumed causes is that such morphologically normal embryos have an abnormal number of chromosomes (aneuploidies). Preimplantation genetic testing for aneuploidies (PGT-A), formerly known as preimplantation genetic screening (PGS), was therefore developed as an alternative method to select embryos for transfer in IVF. In PGT-A, the polar body or one or a few cells of the embryo are obtained by biopsy and tested. Only polar bodies and embryos that show a normal number of chromosomes are transferred. The first generation of PGT-A, using cleavage-stage biopsy and fluorescence in situ hybridisation (FISH) for the genetic analysis, was demonstrated to be ineffective in improving live birth rates. Since then, new PGT-A methodologies have been developed that perform the biopsy procedure at other stages of development and use different methods for genetic analysis. Whether or not PGT-A improves IVF outcomes and is beneficial to patients has remained controversial.

Objectives: To evaluate the effectiveness and safety of PGT-A in women undergoing an IVF treatment.

Search Methods: We searched the Cochrane Gynaecology and Fertility (CGF) Group Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers in September 2019 and checked the references of appropriate papers.

Selection Criteria: All randomised controlled trials (RCTs) reporting data on clinical outcomes in participants undergoing IVF with PGT-A versus IVF without PGT-A were eligible for inclusion.

Data Collection And Analysis: Two review authors independently selected studies for inclusion, assessed risk of bias, and extracted study data. The primary outcome was the cumulative live birth rate (cLBR). Secondary outcomes were live birth rate (LBR) after the first embryo transfer, miscarriage rate, ongoing pregnancy rate, clinical pregnancy rate, multiple pregnancy rate, proportion of women reaching an embryo transfer, and mean number of embryos per transfer.

Main Results: We included 13 trials involving 2794 women. The quality of the evidence ranged from low to moderate. The main limitations were imprecision, inconsistency, and risk of publication bias. IVF with PGT-A versus IVF without PGT-A with the use of genome-wide analyses Polar body biopsy One trial used polar body biopsy with array comparative genomic hybridisation (aCGH). It is uncertain whether the addition of PGT-A by polar body biopsy increases the cLBR compared to IVF without PGT-A (odds ratio (OR) 1.05, 95% confidence interval (CI) 0.66 to 1.66, 1 RCT, N = 396, low-quality evidence). The evidence suggests that for the observed cLBR of 24% in the control group, the chance of live birth following the results of one IVF cycle with PGT-A is between 17% and 34%. It is uncertain whether the LBR after the first embryo transfer improves with PGT-A by polar body biopsy (OR 1.10, 95% CI 0.68 to 1.79, 1 RCT, N = 396, low-quality evidence). PGT-A with polar body biopsy may reduce miscarriage rate (OR 0.45, 95% CI 0.23 to 0.88, 1 RCT, N = 396, low-quality evidence). No data on ongoing pregnancy rate were available. The effect of PGT-A by polar body biopsy on improving clinical pregnancy rate is uncertain (OR 0.77, 95% CI 0.50 to 1.16, 1 RCT, N = 396, low-quality evidence). Blastocyst stage biopsy One trial used blastocyst stage biopsy with next-generation sequencing. It is uncertain whether IVF with the addition of PGT-A by blastocyst stage biopsy increases cLBR compared to IVF without PGT-A, since no data were available. It is uncertain if LBR after the first embryo transfer improves with PGT-A with blastocyst stage biopsy (OR 0.93, 95% CI 0.69 to 1.27, 1 RCT, N = 661, low-quality evidence). It is uncertain whether PGT-A with blastocyst stage biopsy reduces miscarriage rate (OR 0.89, 95% CI 0.52 to 1.54, 1 RCT, N = 661, low-quality evidence). No data on ongoing pregnancy rate or clinical pregnancy rate were available. IVF with PGT-A versus IVF without PGT-A with the use of FISH for the genetic analysis Eleven trials were included in this comparison. It is uncertain whether IVF with addition of PGT-A increases cLBR (OR 0.59, 95% CI 0.35 to 1.01, 1 RCT, N = 408, low-quality evidence). The evidence suggests that for the observed average cLBR of 29% in the control group, the chance of live birth following the results of one IVF cycle with PGT-A is between 12% and 29%. PGT-A performed with FISH probably reduces live births after the first transfer compared to the control group (OR 0.62, 95% CI 0.43 to 0.91, 10 RCTs, N = 1680, I² = 54%, moderate-quality evidence). The evidence suggests that for the observed average LBR per first transfer of 31% in the control group, the chance of live birth after the first embryo transfer with PGT-A is between 16% and 29%. There is probably little or no difference in miscarriage rate between PGT-A and the control group (OR 1.03, 95%, CI 0.75 to 1.41; 10 RCTs, N = 1680, I² = 16%; moderate-quality evidence). The addition of PGT-A may reduce ongoing pregnancy rate (OR 0.68, 95% CI 0.51 to 0.90, 5 RCTs, N = 1121, I² = 60%, low-quality evidence) and probably reduces clinical pregnancies (OR 0.60, 95% CI 0.45 to 0.81, 5 RCTs, N = 1131; I² = 0%, moderate-quality evidence).

Authors' Conclusions: There is insufficient good-quality evidence of a difference in cumulative live birth rate, live birth rate after the first embryo transfer, or miscarriage rate between IVF with and IVF without PGT-A as currently performed. No data were available on ongoing pregnancy rates. The effect of PGT-A on clinical pregnancy rate is uncertain. Women need to be aware that it is uncertain whether PGT-A with the use of genome-wide analyses is an effective addition to IVF, especially in view of the invasiveness and costs involved in PGT-A. PGT-A using FISH for the genetic analysis is probably harmful. The currently available evidence is insufficient to support PGT-A in routine clinical practice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094272PMC
September 2020

Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.

BMJ 2020 09 1;370:m3320. Epub 2020 Sep 1.

UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Sexual and Reproductive Health and Research, World Health Organization, Geneva, Switzerland.

Objective: To determine the clinical manifestations, risk factors, and maternal and perinatal outcomes in pregnant and recently pregnant women with suspected or confirmed coronavirus disease 2019 (covid-19).

Design: Living systematic review and meta-analysis.

Data Sources: Medline, Embase, Cochrane database, WHO COVID-19 database, China National Knowledge Infrastructure (CNKI), and Wanfang databases from 1 December 2019 to 6 October 2020, along with preprint servers, social media, and reference lists.

Study Selection: Cohort studies reporting the rates, clinical manifestations (symptoms, laboratory and radiological findings), risk factors, and maternal and perinatal outcomes in pregnant and recently pregnant women with suspected or confirmed covid-19.

Data Extraction: At least two researchers independently extracted the data and assessed study quality. Random effects meta-analysis was performed, with estimates pooled as odds ratios and proportions with 95% confidence intervals. All analyses will be updated regularly.

Results: 192 studies were included. Overall, 10% (95% confidence interval 7% to 12%; 73 studies, 67 271 women) of pregnant and recently pregnant women attending or admitted to hospital for any reason were diagnosed as having suspected or confirmed covid-19. The most common clinical manifestations of covid-19 in pregnancy were fever (40%) and cough (41%). Compared with non-pregnant women of reproductive age, pregnant and recently pregnant women with covid-19 were less likely to have symptoms (odds ratio 0.28, 95% confidence interval 0.13 to 0.62; I2=42.9%) or report symptoms of fever (0.49, 0.38 to 0.63; I2=40.8%), dyspnoea (0.76, 0.67 to 0.85; I2=4.4%) and myalgia (0.53, 0.36 to 0.78; I2=59.4%). The odds of admission to an intensive care unit (odds ratio 2.13, 1.53 to 2.95; I2=71.2%), invasive ventilation (2.59, 2.28 to 2.94; I2=0%) and need for extra corporeal membrane oxygenation (2.02, 1.22 to 3.34; I2=0%) were higher in pregnant and recently pregnant than non-pregnant reproductive aged women. Overall, 339 pregnant women (0.02%, 59 studies, 41 664 women) with confirmed covid-19 died from any cause. Increased maternal age (odds ratio 1.83, 1.27 to 2.63; I2=43.4%), high body mass index (2.37, 1.83 to 3.07; I2=0%), any pre-existing maternal comorbidity (1.81, 1.49 to 2.20; I2=0%), chronic hypertension (2.0, 1.14 to 3.48; I2=0%), pre-existing diabetes (2.12, 1.62 to 2.78; I2=0%), and pre-eclampsia (4.21, 1.27 to 14.0; I2=0%) were associated with severe covid-19 in pregnancy. In pregnant women with covid-19, increased maternal age, high body mass index, non-white ethnicity, any pre-existing maternal comorbidity including chronic hypertension and diabetes, and pre-eclampsia were associated with serious complications such as admission to an intensive care unit, invasive ventilation and maternal death. Compared to pregnant women without covid-19, those with the disease had increased odds of maternal death (odds ratio 2.85, 1.08 to 7.52; I2=0%), of needing admission to the intensive care unit (18.58, 7.53 to 45.82; I2=0%), and of preterm birth (1.47, 1.14 to 1.91; I2=18.6%). The odds of admission to the neonatal intensive care unit (4.89, 1.87 to 12.81, I2=96.2%) were higher in babies born to mothers with covid-19 versus those without covid-19.

Conclusion: Pregnant and recently pregnant women with covid-19 attending or admitted to the hospitals for any reason are less likely to manifest symptoms such as fever, dyspnoea, and myalgia, and are more likely to be admitted to the intensive care unit or needing invasive ventilation than non-pregnant women of reproductive age. Pre-existing comorbidities, non-white ethnicity, chronic hypertension, pre-existing diabetes, high maternal age, and high body mass index are risk factors for severe covid-19 in pregnancy. Pregnant women with covid-19 versus without covid-19 are more likely to deliver preterm and could have an increased risk of maternal death and of being admitted to the intensive care unit. Their babies are more likely to be admitted to the neonatal unit.

Systematic Review Registration: PROSPERO CRD42020178076.

Readers' Note: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This version is update 1 of the original article published on 1 September 2020 (BMJ 2020;370:m3320), and previous updates can be found as data supplements (https://www.bmj.com/content/370/bmj.m3320/related#datasupp). When citing this paper please consider adding the update number and date of access for clarity.
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http://dx.doi.org/10.1136/bmj.m3320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459193PMC
September 2020

Network meta-analyses in reproductive medicine: challenges and opportunities.

Hum Reprod 2020 08;35(8):1723-1731

Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia.

Network meta-analysis allows researchers to synthesise both direct and indirect evidence, thus enabling simultaneous comparisons of multiple treatments. A relatively recent addition to evidence synthesis in reproductive medicine, this approach has become increasingly popular. Yet, the underlying assumptions of network meta-analyses, which drive the validity of their findings, have been frequently ignored. In this article, we discuss the strengths and limitations of network meta-analyses. In addition, we present an overview of published network meta-analyses in reproductive medicine, summarize their challenges and provide insights into future research opportunities.
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http://dx.doi.org/10.1093/humrep/deaa126DOI Listing
August 2020

Letter of response - Data integrity of 35 randomised controlled trials in women' health.

Eur J Obstet Gynecol Reprod Biol 2020 12 13;255:260. Epub 2020 Jun 13.

Department of Obstetrics and Gynecology, Monash University, Clayton, Australia.

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December 2020

Cytogenetic testing of pregnancy loss tissue: a meta-analysis.

Reprod Biomed Online 2020 Jun 15;40(6):867-879. Epub 2020 Feb 15.

Amsterdam UMC, University of Amsterdam, Center for Reproductive Medicine, Amsterdam Reproduction and Development Research Institute Amsterdam, the Netherlands. Electronic address:

Many clinics offer routine genetic testing of pregnancy loss tissue. This review presents a comprehensive literature search and meta-analysis on chromosomal abnormality rates of pregnancy loss tissue from women with a single or recurrent pregnancy loss. A total of 55 studies published since 2000 were included, analysed on the prevalence of test failure rates, abnormality detection rates and percentages of trisomy, monosomy X, structural abnormalities and other clinically (ir)relevant abnormalities detected by conventional karyotyping, array-comparative genomic hybridization (aCGH), single nucleotide polymorphism (SNP) array, fluorescence in-situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA). The detected prevalence of chromosomal abnormalities was 48% (95% confidence interval [CI] 39-57) using aCGH, 38% (95% CI 28-49) with FISH, 25% (95% CI 12-42) using MLPA, 60% (95% CI 58-63) using SNP array and 47% (95% CI 43-51) with conventional karyotyping. The percentage of detected abnormalities did not differ between women that suffered sporadic (46%; 95% CI 39-53) or recurrent (46%; 95% CI 39-52) pregnancy loss. In view of the high prevalence of chromosomal abnormalities in pregnancy loss tissue, and the low chance of recurrence of the same chromosomal aberration, it was concluded that detection of specific chromosomal abnormalities in pregnancy loss tissue has no clinical benefit. Therefore, routine testing of pregnancy loss tissue for chromosomal abnormalities is not recommended.
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http://dx.doi.org/10.1016/j.rbmo.2020.02.001DOI Listing
June 2020

Integrity of randomized controlled trials: challenges and solutions.

Fertil Steril 2020 06 6;113(6):1113-1119. Epub 2020 May 6.

Department of Obstetrics and Gynaecology, Monash University, Clayton, Australia.

There has been increasing concern about compromised integrity in randomized controlled trials (RCTs) because it undermines the authority of this top-level evidence-generating method and puts patients at risk. Compromised RCTs also jeopardize the validity of systematic reviews and meta-analyses when they are included. The publication-driven research environment is responsible for the emergence of integrity issues in RCTs, which has been facilitated by insufficient efforts to prevent, identify, and disclose research misconduct. The ability to assess integrity in RCTs is important to deter research misconduct. Data integrity in RCTs can be assessed in three domains: general assessment, analysis with summary data, and individual participant data check. Statistical methods play an important role in finding evidence against data fabrication or falsification in RCTs. It is important to strictly implement the prospective registration policy and the Consolidated Standards of Reporting Trials (CONSORT) statement for RCT publication, but more effort needs to be devoted to developing and validating statistical methods that identify different patterns of data manipulation. Ideally the system of submission, review, and publication would be reformed in a way that allows the timely investigation and retraction of compromised RCTs. Authors of systematic reviews should be aware of the uncertainty posed by compromised RCTs to the quality of synthesized evidence, and they should participate in the campaign to fight compromised integrity.
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http://dx.doi.org/10.1016/j.fertnstert.2020.04.018DOI Listing
June 2020

Data integrity of 35 randomised controlled trials in women' health.

Eur J Obstet Gynecol Reprod Biol 2020 Jun 11;249:72-83. Epub 2020 Apr 11.

Department of Obstetrics and Gynecology, Monash University, Clayton, Australia.

While updating a systematic review on the topic of ovulation of induction, we observed unusual similarities in a number of randomised controlled trials (RCTs) published by two authors from the same institute in the same disease spectrum in a short period of time. We therefore undertook a focused analysis of the data integrity of all RCTs published by the two authors. We made pairwise comparisons to find identical or similar values in baseline characteristics and outcome tables between trials. We also assessed whether baseline characteristics were compatible with chance, using Monte Carlo simulations and Kolmogorov-Smirnov test. For 35 trials published between September 2006 and January 2016, we found a large number of similarities in both the baseline characteristics and outcomes of 26. Analysis of the baseline characteristics of the trials indicated that their distribution was unlikely to be the result of proper randomisation. The procedures demonstrated in this paper may help to assess data integrity in future attempts to verify the authenticity of published RCTs.
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http://dx.doi.org/10.1016/j.ejogrb.2020.04.016DOI Listing
June 2020

Recurrent pregnancy loss: diagnostic workup after two or three pregnancy losses? A systematic review of the literature and meta-analysis.

Hum Reprod Update 2020 04;26(3):356-367

Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Recurrent pregnancy loss (RPL) occurs in 1-3% of all couples trying to conceive. No consensus exists regarding when to perform testing for risk factors in couples with RPL. Some guidelines recommend testing if a patient has had two pregnancy losses whereas others advise to test after three losses.

Objective And Rationale: The aim of this systematic review was to evaluate the current evidence on the prevalence of abnormal test results for RPL amongst patients with two versus three or more pregnancy losses. We also aimed to contribute to the debate regarding whether the investigations for RPL should take place after two or three or more pregnancy losses.

Search Methods: Relevant studies were identified by a systematic search in OVID Medline and EMBASE from inception to March 2019. A search for RPL was combined with a broad search for terms indicative of number of pregnancy losses, screening/testing for pregnancy loss or the prevalence of known risk factors. Meta-analyses were performed in case of adequate clinical and statistical homogeneity. The quality of the studies was assessed using the Newcastle-Ottawa scale.

Outcomes: From a total of 1985 identified publications, 21 were included in this systematic review and 19 were suitable for meta-analyses. For uterine abnormalities (seven studies, odds ratio (OR) 1.00, 95% CI 0.79-1.27, I2 = 0%) and for antiphospholipid syndrome (three studies, OR 1.04, 95% CI 0.86-1.25, I2 = 0%) we found low quality evidence for a lack of a difference in prevalence of abnormal test results between couples with two versus three or more pregnancy losses. We found insufficient evidence of a difference in prevalence of abnormal test results between couples with two versus three or more pregnancy losses for chromosomal abnormalities (10 studies, OR 0.78, 95% CI 0.55-1.10), inherited thrombophilia (five studies) and thyroid disorders (two studies, OR 0.52, 95% CI: 0.06-4.56).

Wider Implications: A difference in prevalence in uterine abnormalities and antiphospholipid syndrome is unlikely in women with two versus three pregnancy losses. We cannot exclude a difference in prevalence of chromosomal abnormalities, inherited thrombophilia and thyroid disorders following testing after two versus three pregnancy losses. The results of this systematic review may support investigations after two pregnancy losses in couples with RPL, but it should be stressed that additional studies of the prognostic value of test results used in the RPL population are urgently needed. An evidenced-based treatment is not currently available in the majority of cases when abnormal test results are present.
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http://dx.doi.org/10.1093/humupd/dmz048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161667PMC
April 2020

Laparoscopic ovarian drilling for ovulation induction in women with anovulatory polycystic ovary syndrome.

Cochrane Database Syst Rev 2020 02 11;2:CD001122. Epub 2020 Feb 11.

Amsterdam UMC, University of Amsterdam, Center for Reproductive Medicine, Amsterdam, Netherlands, 1105 AZ.

Background: Polycystic ovary syndrome (PCOS) is a common condition affecting 8% to 13% of reproductive-aged women. In the past clomiphene citrate (CC) used to be the first-line treatment in women with PCOS. Ovulation induction with letrozole should be the first-line treatment according to new guidelines, but the use of letrozole is off-label. Consequently, CC is still commonly used. Approximately 20% of women on CC do not ovulate. Women who are CC-resistant can be treated with gonadotrophins or other medical ovulation-induction agents. These medications are not always successful, can be time-consuming and can cause adverse events like multiple pregnancies and cycle cancellation due to an excessive response. Laparoscopic ovarian drilling (LOD) is a surgical alternative to medical treatment. There are risks associated with surgery, such as complications from anaesthesia, infection, and adhesions.

Objectives: To evaluate the effectiveness and safety of LOD with or without medical ovulation induction compared with medical ovulation induction alone for women with anovulatory polycystic PCOS and CC-resistance.

Search Methods: We searched the Cochrane Gynaecology and Fertility Group (CGFG) trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers up to 8 October 2019, together with reference checking and contact with study authors and experts in the field to identify additional studies.

Selection Criteria: We included randomised controlled trials (RCTs) of women with anovulatory PCOS and CC resistance who underwent LOD with or without medical ovulation induction versus medical ovulation induction alone, LOD with assisted reproductive technologies (ART) versus ART, LOD with second-look laparoscopy versus expectant management, or different techniques of LOD.

Data Collection And Analysis: Two review authors independently selected studies, assessed risks of bias, extracted data and evaluated the quality of the evidence using the GRADE method. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. Pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS), ovulation, costs, and quality of life were secondary outcomes.

Main Results: This updated review includes 38 trials (3326 women). The evidence was very low- to moderate-quality; the main limitations were due to poor reporting of study methods, with downgrading for risks of bias (randomisation and allocation concealment) and lack of blinding. Laparoscopic ovarian drilling with or without medical ovulation induction versus medical ovulation induction alone Pooled results suggest LOD may decrease live birth slightly when compared with medical ovulation induction alone (odds ratio (OR) 0.71, 95% confidence interval (CI) 0.54 to 0.92; 9 studies, 1015 women; I = 0%; low-quality evidence). The evidence suggest that if the chance of live birth following medical ovulation induction alone is 42%, the chance following LOD would be between 28% and 40%. The sensitivity analysis restricted to only RCTs with low risk of selection bias suggested there is uncertainty whether there is a difference between the treatments (OR 0.90, 95% CI 0.59 to 1.36; 4 studies, 415 women; I = 0%, low-quality evidence). LOD probably reduces multiple pregnancy rates (Peto OR 0.34, 95% CI 0.18 to 0.66; 14 studies, 1161 women; I = 2%; moderate-quality evidence). This suggests that if we assume the risk of multiple pregnancy following medical ovulation induction is 5.0%, the risk following LOD would be between 0.9% and 3.4%. Restricting to RCTs that followed women for six months after LOD and six cycles of ovulation induction only, the results for live birth were consistent with the main analysis. There may be little or no difference between the treatments for the likelihood of a clinical pregnancy (OR 0.86, 95% CI 0.72 to 1.03; 21 studies, 2016 women; I = 19%; low-quality evidence). There is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage (OR 1.11, 95% CI 0.78 to 1.59; 19 studies, 1909 women; I = 0%; low-quality evidence). OHSS was a very rare event. LOD may reduce OHSS (Peto OR 0.25, 95% CI 0.07 to 0.91; 8 studies, 722 women; I = 0%; low-quality evidence). Unilateral LOD versus bilateral LOD Due to the small sample size, the quality of evidence is insufficient to justify a conclusion on live birth (OR 0.83, 95% CI 0.24 to 2.78; 1 study, 44 women; very low-quality evidence). There were no data available on multiple pregnancy. The likelihood of a clinical pregnancy is uncertain between the treatments, due to the quality of the evidence and the large heterogeneity between the studies (OR 0.57, 95% CI 0.39 to 0.84; 7 studies, 470 women; I = 60%, very low-quality evidence). Due to the small sample size, the quality of evidence is not sufficient to justify a conclusion on miscarriage (OR 1.02, 95% CI 0.31 to 3.33; 2 studies, 131 women; I = 0%; very low-quality evidence). Other comparisons Due to lack of evidence and very low-quality data there is uncertainty whether there is a difference for any of the following comparisons: LOD with IVF versus IVF, LOD with second-look laparoscopy versus expectant management, monopolar versus bipolar LOD, and adjusted thermal dose versus fixed thermal dose.

Authors' Conclusions: Laparoscopic ovarian drilling with and without medical ovulation induction may decrease the live birth rate in women with anovulatory PCOS and CC resistance compared with medical ovulation induction alone. But the sensitivity analysis restricted to only RCTs at low risk of selection bias suggests there is uncertainty whether there is a difference between the treatments, due to uncertainty around the estimate. Moderate-quality evidence shows that LOD probably reduces the number of multiple pregnancy. Low-quality evidence suggests that there may be little or no difference between the treatments for the likelihood of a clinical pregnancy, and there is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage. LOD may result in less OHSS. The quality of evidence is insufficient to justify a conclusion on live birth, clinical pregnancy or miscarriage rate for the analysis of unilateral LOD versus bilateral LOD. There were no data available on multiple pregnancy.
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http://dx.doi.org/10.1002/14651858.CD001122.pub5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013239PMC
February 2020

Understand low-quality evidence: learn from food chains.

Fertil Steril 2020 01;113(1):93-94

Centre for Reproductive Medicine, UMC Amsterdam, University of Amsterdam, Amsterdam, the Netherlands.

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January 2020

Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence.

Am J Obstet Gynecol 2020 08 31;223(2):167-176. Epub 2020 Jan 31.

Tommy's National Centre for Miscarriage Research, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, United Kingdom.

Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE [PROgesterone in recurrent MIScarriagE] trial) and the other targeting women with early pregnancy bleeding (the PRISM [PRogesterone In Spontaneous Miscarriage] trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03-1.15; P=.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (rate difference 15%; risk ratio, 1.28, 95% confidence interval, 1.08-1.51; P=.004). No short-term safety concerns were identified from the PROMISE and PRISM trials. Therefore, women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg twice daily. Women and their care providers should use the findings for shared decision-making.
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http://dx.doi.org/10.1016/j.ajog.2019.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408486PMC
August 2020

Endometrial scratching and the tales of the randomised studies.

Authors:
Madelon van Wely

Hum Reprod 2019 12;34(12):2317-2318

Deputy Editor, Center for Reproductive Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1093/humrep/dez244DOI Listing
December 2019

Gonadotrophins or clomiphene citrate in couples with unexplained infertility undergoing intrauterine insemination: a cost-effectiveness analysis.

Reprod Biomed Online 2020 Jan 16;40(1):99-104. Epub 2019 Sep 16.

Centre for Reproductive Medicine, Academic Medical Centre, Amsterdam, the Netherlands. Electronic address:

Research Question: What is the cost-effectiveness of gonadotrophins compared with clomiphene citrate in couples with unexplained subfertility undergoing intrauterine insemination (IUI) with ovarian stimulation under strict cancellation criteria?

Design: A cost-effectiveness analysis alongside a randomized controlled trial (RCT). Between July 2013 and March 2016, 738 couples were randomized to gonadotrophins (369) or clomiphene citrate (369) in a multicentre RCT in the Netherlands. The direct medical costs of both strategies were compared. Direct medical costs included costs of medication, cycle monitoring, insemination and, if applicable, pregnancy monitoring. Non-parametric bootstrap resampling was used to investigate the effect of uncertainty in estimates. The cost-effectiveness analysis was performed according to intention-to-treat. The incremental cost-effectiveness ratio (ICER) between gonadotrophins and clomiphene citrate for ongoing pregnancy and live birth was assessed.

Results: The mean costs per couple were €1534 for gonadotrophins and €1067 for clomiphene citrate (mean difference of €468; 95% confidence interval [CI] €464-472). As ongoing pregnancy rates were 31% in women allocated to gonadotrophins and 26% in women allocated to clomiphene citrate (relative risk 1.16, 95% CI 0.93-1.47), the ICER was €21,804 (95% CI €11,628-31,980) per additional ongoing pregnancy with gonadotrophins and €17,044 (95% CI €8998-25,090) per additional live birth with gonadotrophins.

Conclusions: Gonadotrophins are more expensive compared with clomiphene citrate in couples with unexplained subfertility undergoing IUI with adherence to strict cancellation criteria, without being significantly more effective.
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http://dx.doi.org/10.1016/j.rbmo.2019.09.004DOI Listing
January 2020