Publications by authors named "Ben Willem J Mol"

268 Publications

Stillbirth and neonatal mortality in a subsequent pregnancy following stillbirth: a population-based cohort study.

BMC Pregnancy Childbirth 2022 Jan 4;22(1):11. Epub 2022 Jan 4.

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

Background: A history of stillbirth is a risk factor for recurrent fetal death in a subsequent pregnancy. Reported risks of recurrent fetal death are often not stratified by gestational age. In subsequent pregnancies increased rates of medical interventions are reported without evidence of perinatal benefit. The aim of this study was to estimate gestational-age specific risks of recurrent stillbirth and to evaluate the effect of obstetrical management on perinatal outcome after previous stillbirth.

Methods: A retrospective cohort study in the Netherlands was designed that included 252.827 women with two consecutive singleton pregnancies (1 and 2 delivery) between 1999 and 2007. Data was obtained from the national Perinatal Registry and analyzed for pregnancy outcomes. Fetal deaths associated with a congenital anomaly were excluded. The primary outcome was the occurrence of stillbirth in the second pregnancy stratified by gestational age. Secondary outcome was the influence of obstetrical management on perinatal outcome in a subsequent pregnancy.

Results: Of 252.827 first pregnancies, 2.058 pregnancies ended in a stillbirth (8.1 per 1000). After adjusting for confounding factors, women with a prior stillbirth have a two-fold higher risk of recurrence (aOR 1.96, 95% CI 1.07-3.60) compared to women with a live birth in their first pregnancy. The highest risk of recurrence occurred in the group of women with a stillbirth in early gestation between 22 and 28 weeks of gestation (a OR 2.25, 95% CI 0.62-8.15), while after 32 weeks the risk decreased. The risk of neonatal death after 34 weeks of gestation is higher in women with a history of stillbirth (aOR 6.48, 95% CI 2.61-16.1) and the risk of neonatal death increases with expectant obstetric management (aOR 10.0, 95% CI 2.43-41.1).

Conclusions: A history of stillbirth remains an important risk for recurrent stillbirth especially in early gestation (22-28 weeks). Women with a previous stillbirth should be counselled for elective induction in the subsequent pregnancy at 37-38 weeks of gestation to decrease the risk of perinatal death.
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http://dx.doi.org/10.1186/s12884-021-04355-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8725424PMC
January 2022

Uterine distension media for outpatient hysteroscopy.

Cochrane Database Syst Rev 2021 Nov 26;11:CD006604. Epub 2021 Nov 26.

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

Background: Hysteroscopy done in an outpatient setting is the 'gold standard' method for evaluating the uterine cavity. Media used to distend the uterine cavity include gas as carbon dioxide and liquid as saline that can be used at room temperature or warmed to body temperature. Both media offer advantages as well as disadvantages.

Objectives: The objective of this review is to compare the effectiveness, tolerability, and safety of gas (carbon dioxide) and liquid (normal saline) used for uterine distension during outpatient hysteroscopy.

Search Methods: We searched the Cochrane Gynaecology and Fertility (CGF) Group Specialised Register, CENTRAL, MEDLINE, Embase and PsycINFO on 28 April 2021. We checked references of relevant trials and contacted study authors and experts in the field to identify additional studies. CINAHL records and ongoing trials from the trial registries were included in the CENTRAL search.

Selection Criteria: We included randomised controlled trials (RCTs) comparing saline with carbon dioxide, as well as RCTs comparing saline at different temperatures, for uterine distension in outpatient hysteroscopy done for any indication.

Data Collection And Analysis: We used standard methodological procedures recommended by Cochrane. Primary review outcomes were patient tolerability and adverse events or complications related to the distending medium. Secondary outcomes were quality of the hysteroscopic view and duration of the procedure.

Main Results: We included 12 RCTs (1946 women). The quality of evidence ranged from very low to high: the main limitations were risk of bias due to absence of blinding due to the nature of the procedure, imprecision, and inconsistency. Saline versus carbon dioxide Analysis ruled out a clinically relevant difference in pain scores during the procedure between saline and carbon dioxide, but the quality of evidence was low (standardised mean difference (SMD) -0.07, 95% confidence interval (CI) -0.17 to 0.02; 9 RCTs, N = 1705; I² = 86%). This translates to differences of 0.39 cm (lower) and 0.05 cm (higher) on a 10-cm visual analogue scale (VAS). Evidence was insufficient to show differences between groups in the proportion of procedures abandoned due to intense pain (Peto odds ratio (OR) 0.48, 95% CI 0.09 to 2.42; 1 RCT, N = 189; very low-quality evidence). We are uncertain whether saline decreases the need for analgesia compared to carbon dioxide (Peto OR 0.34, 95% CI 0.12 to 0.99; 1 RCT, N = 189; very low-quality evidence). Saline compared to carbon dioxide is probably associated with fewer vasovagal reaction events (Peto OR 0.53, 95% CI 0.32 to 0.86; 6 RCTs, N = 1076; I² = 0%; moderate-quality evidence) and fewer shoulder-tip pain events (Peto OR 0.28, 95% CI 0.14 to 0.54; 4 RCTs, N = 623; I² = 0%, moderate-quality evidence). Evidence suggests that if 10% of women undergoing outpatient hysteroscopy experience a vasovagal reaction event with the use of carbon dioxide, this rate would be between 3% and 9% with the use of saline. Similarly, if the rate of shoulder-tip pain with carbon dioxide is 9%, it would be between 1% and 5% with saline. We are uncertain whether saline is similar to carbon dioxide in terms of endometrial bleeding (Peto OR 0.83, 95% CI 0.25 to 2.75; 2 RCTs, N = 349; I² = 0%; very low-quality evidence). Infection was not reported by any study in this comparison. Saline may result in fewer procedures with an unsatisfactory hysteroscopic view than carbon dioxide (Peto OR 0.51, 95% CI 0.32 to 0.82; 5 RCTs, N = 1082; I² = 67%; low-quality evidence). The duration of the procedure was shorter with saline in three of the four studies that reported this outcome, and duration was similar in both arms in the fourth study. Warm saline versus room temperature saline Use of warm saline for uterine distension during office hysteroscopy may reduce pain scores when compared with room temperature saline (mean difference (MD) -1.14, 95% CI -1.55 to -0.73; 3 RCTs, N = 241; I² = 77%; low-quality evidence). Evidence is insufficient to show differences between groups in either the proportion of procedures abandoned due to intense pain (Peto OR 0.97, 95% CI 0.06 to 15.87; 1 RCT, N = 77; very low-quality evidence) or the need for analgesia (Peto OR 1.00, 95% CI 0.14 to 7.32; 1 RCT, N = 100; very low-quality evidence). Analysis ruled out a clinically relevant difference in duration of the procedure between warm and room temperature saline, but the quality of evidence is low (MD 13.17 seconds, 95% CI -12.96 to 39.29; 2 RCTs, N = 141; I² = 21%). No cases of infection were reported in either group (1 RCT, N = 100). No other adverse events and no information on quality of the hysteroscopic view were reported by any study in this comparison.

Authors' Conclusions: Evidence was insufficient to show differences between different distension media used for uterine distension in outpatient hysteroscopy in terms of patient tolerability, operator satisfaction, or duration of the procedure. However, saline was superior to carbon dioxide in producing fewer adverse events (shoulder-tip pain and vasovagal reaction).
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http://dx.doi.org/10.1002/14651858.CD006604.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8623126PMC
November 2021

The Risk of Preterm Birth in Low Risk Pregnant Women with Urinary Tract Infections.

Am J Perinatol 2021 Nov 10. Epub 2021 Nov 10.

Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Objective:  Urinary tract infections are among the most common infections during pregnancy. The association between symptomatic lower urinary tract infections during pregnancy and fetal and maternal complications such as preterm birth and low birthweight remains unclear. The aim of this research is to evaluate the association between urinary tract infections during pregnancy and maternal and neonatal outcomes, especially preterm birth.

Study Design:  This study is a secondary analysis of a multicenter prospective cohort study, which included patients between October 2011 and June 2013. The population consists of women with low risk singleton pregnancies. We divided the cohort into women with and without a symptomatic lower urinary tract infection after 20 weeks of gestation. Baseline characteristics and maternal and neonatal outcomes were compared between the two groups. Multivariable logistic regression analysis was used to correct for confounders. The main outcome was spontaneous preterm birth at <37 weeks.

Results:  We identified 4,918 pregnant women eligible for enrollment, of whom 9.4% had a symptomatic lower urinary tract infection during their pregnancy. Women with symptomatic lower urinary tract infections were at increased risk for both preterm birth in general (12 vs. 5.1%, adjusted OR 2.5; 95% CI 1.7-3.5) as well as a spontaneous preterm birth at <37 weeks (8.2 vs. 3.7%, adjusted OR 2.3; 95% CI 1.5-3.5). This association was also present for early preterm birth at <34 weeks. Women with symptomatic lower urinary tract infections during pregnancy are also at increased risk of endometritis (8.9 vs. 1.8%, adjusted OR 5.3; 95% CI 1.4-20) and mastitis (7.8 vs. 1.8%, adjusted OR 4.0; 95% CI 1.6-10) postpartum.

Conclusion:  Low risk women with symptomatic lower urinary tract infections during pregnancy are at increased risk of spontaneous preterm birth. In addition, an increased risk for endometritis and mastitis postpartum was found in women with symptomatic lower urinary tract infection during pregnancy.

Key Points: · UTIs increase the risk of preterm birth.. · UTIs increase the risk of endometritis postpartum.. · UTIs increase the risk of mastitis postpartum..
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http://dx.doi.org/10.1055/s-0041-1739289DOI Listing
November 2021

A case of perinatal death after insertion of an intrauterine pressure catheter.

Eur J Obstet Gynecol Reprod Biol 2021 Oct 11;265:217-219. Epub 2021 Aug 11.

Department of Obstetrics and Gynaecology, Diakonessenhuis, Bosboomstraat 1, 3508 TG, Utrecht, the Netherlands.

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http://dx.doi.org/10.1016/j.ejogrb.2021.08.005DOI Listing
October 2021

Intrauterine insemination (IUI) with or without letrozole for unexplained or mild male factor infertility: A randomized pilot study.

Eur J Obstet Gynecol Reprod Biol 2021 Jul 15;262:216-220. Epub 2021 May 15.

Department of Obstetrics and Gynaecology, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia.

Objective: To study the feasibility of a randomized controlled trial (RCT) comparing intrauterine insemination (IUI) with and without letrozole in couples with unexplained or mild male factor infertility STUDY DESIGN: We performed a randomized pilot study including 100 couples with unexplained or mild male factor infertility in the Reproductive Medicine Centre of Peking University Third Hospital in China. The couples scheduled for IUI were randomized to IUI with or without ovarian stimulation (letrozole) for up to 3 cycles within a time horizon of 4 months. Women in the letrozole group received 5 mg oral letrozole daily starting from cycle day 3-5 for 5 days. Women in the natural cycle IUI group did not receive any ovarian stimulation before IUI. The primary outcome is ongoing pregnancy leading to live birth. The study was registered under trial number NCT03455426 RESULTS: Between March 2018 and January 2019, 158 couples were eligible to participate after initial screening and 100 (63.3 %) couples agreed to participate. Of the 100 recruited couples, 50 were randomly allocated to IUI with letrozole and 50 to natural cycle IUI. Live birth occurred in 12 women (24.0 %) in the letrozole group and 10 women (20.0 %) in the natural cycle group (RR 1.20 (95 % CI 0.57-2.52)). Clinical pregnancy rates were 28 % and 26 % in the letrozole group and natural cycle group respectively (RR 1.08 (95 % CI 0.56-2.05). There were no multiple pregnancies in both groups. Patients were willing to be randomized and useful information was gained to plan a definitive trial.

Conclusions: We showed that an RCT comparing IUI with letrozole versus natural cycle IUI in couples with unexplained or mild male factor infertility is feasible and acceptable.
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http://dx.doi.org/10.1016/j.ejogrb.2021.05.029DOI Listing
July 2021

Multi-professional simulation-based team training in obstetric emergencies for improving patient outcomes and trainees' performance.

Cochrane Database Syst Rev 2020 12 16;12:CD011545. Epub 2020 Dec 16.

Department of Obstetrics and Gynaecology; Department of Electrical Engineering (University of Technology, Eindhoven), Máxima Medical Centre, Veldhoven, Netherlands.

Background: Simulation-based obstetric team training focuses on building a system that will anticipate errors, improve patient outcomes and the performance of clinical care teams. Simulation-based obstetric team training has been proposed as a tool to improve the overall outcome of obstetric health care.

Objectives: To assess the effects of simulation-based obstetric team training on patient outcomes, performance of obstetric care teams in practice and educational settings, and trainees' experience.

Search Methods: The Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) were searched (14 April 2020), together with references checking and hand searching the available proceedings of 2 international conferences.

Selection Criteria: We included randomised controlled trials (RCTs) (including cluster-randomised trials) comparing simulation-based obstetric team training with no, or other type of training.

Data Collection And Analysis: We used standard methodological procedures expected by Cochrane, to identify articles, assess methodological quality and extract data. Data from three cluster-randomised trials could be used to perform generic inverse variance meta-analyses. The meta-analyses were based on risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs). We used the GRADE approach to rate the certainty of the evidence. We used Kirkpatrick's model of training evaluation to categorise the outcomes of interest; we chose Level 3 (behavioural change) and Level 4 (patient outcome) to categorise the primary outcomes.

Main Results: We included eight RCTs, six of which were cluster-randomised trials, involving more than 1000 training participants and more than 200,000 pregnancies/births. Four studies reported on outcome measures on Kirkpatrick level 4 (patient outcome), three studies on Kirkpatrick level 3 (performance in practice), two studies on Kitkpatrick level 2 (performance in educational settings), and none on Kirkpatrick level 1 (trainees' experience). The included studies were from Mexico, the Netherlands, the UK and the USA, all middle- and high-income countries. Kirkpatrick level 4 (patient outcome) Simulation-based obstetric team training may make little or no difference for composite outcomes of maternal and/or perinatal adverse events compared with no training (3 studies; n = 28,731, low-certainty evidence, data not pooled due to different composite outcome definitions). We are uncertain whether simulation-based obstetric team training affects maternal mortality compared with no training (2 studies; 79,246 women; very low-certainty evidence). However, it may reduce neonatal mortality (RR 0.70, 95% CI 0.48 to 1.01; 2 studies, 79,246 pregnancies/births, low-certainty evidence). Simulation-based obstetric team training may have little to no effect on low Apgar score compared with no training (RR 0.99, 95% 0.85 to 1.15; 2 studies; 115,171 infants; low-certainty evidence), but it probably reduces trauma after shoulder dystocia (RR 0.50, 95% CI 0.25 to 0.99; 1 study; moderate-certainty evidence) and probably slightly reduces the number of caesarean deliveries (RR 0.79, 95% CI 0.67 to 0.93; 1 study; n = 50,589; moderate-certainty evidence) Kirkpatrick level 3 (performance in practice) We found that simulation-based obstetric team training probably improves the performance of the obstetric teams in practice, compared with no training (3 studies; 2398 obstetric staff members, moderate-certainty evidence, data not pooled due to different outcome definitions).

Authors' Conclusions: Simulation-based obstetric team training may help to improve team performance of obstetric teams, and it might contribute to improvement of specific maternal and perinatal outcomes, compared with no training. However, high-certainty evidence is lacking due to serious risk of bias and imprecision, and the effect cannot be generalised for all outcomes. Future studies investigating simulation-based obstetric team training compared to training courses with a different instructional design should carefully consider how and when to measure outcomes. Particular attention should be paid to effect measurement at the level of patient outcome, taking into consideration the low incidence of adverse maternal and perinatal events.
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http://dx.doi.org/10.1002/14651858.CD011545.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094450PMC
December 2020

Uterine artery embolization versus surgical treatment in patients with symptomatic uterine fibroids: Protocol for a systematic review and meta-analysis of individual participant data.

Eur J Obstet Gynecol Reprod Biol 2021 Jan 11;256:179-183. Epub 2020 Nov 11.

Institute of Health and Wellbeing, University of Glasgow, 1 Lilybank Gardens, Glasgow, G12 8RZ, United Kingdom.

Objective: Uterine fibroids are the most common benign tumours in women of the reproductive age. Symptoms of heavy menstrual bleeding, abdominal discomfort and infertility may seriously affect a woman's quality of life. Uterine artery embolization is a safe and effective alternative treatment to hysterectomy or myomectomy for symptomatic uterine fibroids. Which treatment provides the highest quality of life, least complications, symptom reduction and least chance intervention, has not been established and might depend on strict patient selection. This study aims to identify which specific subgroups benefit most of each treatment by analyzing individual participant data derived from randomized controlled trials of women undergoing embolization or surgical treatment. This study will primarily assess the effectiveness of both treatment groups by evaluating the effect on quality of life of embolization in comparison to surgery on specific patient and fibroid characteristics and the possible need for re-intervention for fibroid-related symptoms.

Data Sources: PubMed/MEDLINE, Embase and The Cochrane Library were searched up to August 2020.

Study Eligibility Criteria: We will collect individual participant data from randomized controlled trials that studied clinical and procedural outcomes of premenopausal women with symptomatic uterine fibroids, who were randomized between uterine artery embolization and surgery.

Study Appraisal And Synthesis Methods: Individual participant data from all eligible trials will be sought and analysed according to intention-to-treat principle. Risk of Bias will be done by using version 2 of the Cochrane tool for Risk of Bias in randomized trials. Subgroup analyses to explore the effect of e.g. age, fibroid characteristics and fibroid complaints will be performed, if data is available. This individual patient data meta-analysis will be analysed according to a one-stage model.
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http://dx.doi.org/10.1016/j.ejogrb.2020.11.027DOI Listing
January 2021

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

Surgical treatment for tubal disease in women due to undergo in vitro fertilisation.

Cochrane Database Syst Rev 2020 10 22;10:CD002125. Epub 2020 Oct 22.

Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK.

Background: Tubal disease accounts for 20% of infertility cases. Hydrosalpinx, caused by distal tubal occlusion leading to fluid accumulation in the tube(s), is a particularly severe form of tubal disease negatively affecting the outcomes of assisted reproductive technology (ART). It is thought that tubal surgery may improve the outcome of ART in women with hydrosalpinges.

Objectives: To assess the effectiveness and safety of tubal surgery in women with hydrosalpinges prior to undergoing conventional in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI).

Search Methods: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, DARE, and two trial registers on 8 January 2020, together with reference checking and contact with study authors and experts in the field to identify additional trials.

Selection Criteria: Randomised controlled trials (RCTs) comparing surgical treatment versus no surgical treatment, or comparing surgical interventions head-to-head, in women with tubal disease prior to undergoing IVF.

Data Collection And Analysis: We used Cochrane's standard methodological procedures. The primary outcomes were live birth rate (LBR) and surgical complication rate per woman randomised. Secondary outcomes included clinical, multiple and ectopic pregnancy rates, miscarriage rates and mean numbers of oocytes retrieved and of embryos obtained.

Main Results: We included 11 parallel-design RCTs, involving a total of 1386 participants. The included trials compared different types of tubal surgery (salpingectomy, tubal occlusion or transvaginal aspiration of hydrosalpingeal fluid) to no tubal surgery, or individual interventions to one another. We assessed no studies as being at low risk of bias across all domains, with the main limitations being lack of blinding, wide confidence intervals and low event and sample sizes. We used GRADE methodology to rate the quality of the evidence. Apart from one moderate-quality result in one review comparison, the evidence provided by these 11 trials ranged between very low- to low-quality. Salpingectomy versus no tubal surgery No included study reported on LBR for this comparison. We are uncertain of the effect of salpingectomy on surgical complications such as the rate of conversion to laparotomy (Peto odds ratio (OR) 5.80, 95% confidence interval (CI) 0.11 to 303.69; one RCT; n = 204; very low-quality evidence) and pelvic infection (Peto OR 5.80, 95% CI 0.11 to 303.69; one RCT; n = 204; very low-quality evidence). Salpingectomy probably increases clinical pregnancy rate (CPR) versus no surgery (risk ratio (RR) 2.02, 95% CI 1.44 to 2.82; four RCTs; n = 455; I = 42.5%; moderate-quality evidence). This suggests that in women with a CPR of approximately 19% without tubal surgery, the rate with salpingectomy lies between 27% and 52%. Proximal tubal occlusion versus no surgery No study reported on LBR and surgical complication rate for this comparison. Tubal occlusion may increase CPR compared to no tubal surgery (RR 3.21, 95% CI 1.72 to 5.99; two RCTs; n = 209; I = 0%; low-quality evidence). This suggests that with a CPR of approximately 12% without tubal surgery, the rate with tubal occlusion lies between 21% and 74%. Transvaginal aspiration of hydrosalpingeal fluid versus no surgery No study reported on LBR for this comparison, and there was insufficient evidence to identify a difference in surgical complication rate between groups (Peto OR not estimable; one RCT; n = 176). We are uncertain whether transvaginal aspiration of hydrosalpingeal fluid increases CPR compared to no tubal surgery (RR 1.67, 95% CI 1.10 to 2.55; three RCTs; n = 311; I = 0%; very low-quality evidence). Laparoscopic proximal tubal occlusion versus laparoscopic salpingectomy We are uncertain of the effect of laparoscopic proximal tubal occlusion versus laparoscopic salpingectomy on LBR (RR 1.21, 95% CI 0.76 to 1.95; one RCT; n = 165; very low-quality evidence) and CPR (RR 0.81, 95% CI 0.62 to 1.07; three RCTs; n = 347; I = 77%; very low-quality evidence). No study reported on surgical complication rate for this comparison. Transvaginal aspiration of hydrosalpingeal fluid versus laparoscopic salpingectomy No study reported on LBR for this comparison, and there was insufficient evidence to identify a difference in surgical complication rate between groups (Peto OR not estimable; one RCT; n = 160). We are uncertain of the effect of transvaginal aspiration of hydrosalpingeal fluid versus laparoscopic salpingectomy on CPR (RR 0.69, 95% CI 0.44 to 1.07; one RCT; n = 160; very low-quality evidence).

Authors' Conclusions: We found moderate-quality evidence that salpingectomy prior to ART probably increases the CPR compared to no surgery in women with hydrosalpinges. When comparing tubal occlusion to no intervention, we found that tubal occlusion may increase CPR, although the evidence was of low quality. We found insufficient evidence of any effect on procedure- or pregnancy-related adverse events when comparing tubal surgery to no intervention. Importantly, none of the studies reported on long term fertility outcomes. Further high-quality trials are required to definitely determine the impact of tubal surgery on IVF and pregnancy outcomes of women with hydrosalpinges, particularly for LBR and surgical complications; and to investigate the relative efficacy and safety of the different surgical modalities in the treatment of hydrosalpinges prior to ART.
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http://dx.doi.org/10.1002/14651858.CD002125.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094448PMC
October 2020

The long-term costs and effects of tubal flushing with oil-based versus water-based contrast during hysterosalpingography.

Reprod Biomed Online 2021 Jan 17;42(1):150-157. Epub 2020 Sep 17.

Department of Obstetrics and Gynaecology, Monash University, Clayton, Australia; Aberdeen Centre for Women's Health Research, University of Aberdeen, Aberdeen, United Kingdom.

Research Question: What are the long-term costs and effects of oil- versus water-based contrast in infertile women undergoing hysterosalpingography (HSG)?

Design: This economic evaluation of a long-term follow-up of a multicentre randomized controlled trial involved 1119 infertile women randomized to HSG with oil- (n = 557) or water-based contrast (n = 562) in the Netherlands.

Results: In the oil-based contrast group, 39.8% of women needed no other treatment, 34.6% underwent intrauterine insemination (IUI) and 25.6% had IVF/intracytoplasmic sperm injection (ICSI) in the 5 years following HSG. In the water-based contrast group, 35.0% of women had no other treatment, 34.2% had IUI and 30.8% had IVF/ICSI in the 5 years following HSG (P = 0.113). After 5 years of follow-up, HSG using oil-based contrast resulted in equivalent costs (mean cost difference -€144; 95% confidence interval [CI] -€579 to +€290; P = 0.515) for a 5% increase in the cumulative ongoing pregnancy rate compared with HSG using water-based contrast (80% compared with 75%, Relative Risk (RR) 1.07; 95% CI 1.00-1.14). Similarly, HSG with oil-based contrast resulted in equivalent costs (mean cost difference -€50; 95% CI -€576 to +€475; P = 0.850) for a 7.5% increase in the cumulative live birth rate compared with HSG with water-based contrast (74.8% compared with 67.3%, RR 1.11; 95% CI 1.03-1.20), making it the dominant strategy. Scenario analyses suggest that the oil-based contrast medium is the dominant strategy up to a price difference of €300.

Conclusion: Over a 5-year follow-up, HSG with an oil-based contrast was associated with a 5% increase in ongoing pregnancy rate, a 7.5% increase in live birth rate and similar costs to HSG with water-based contrast.
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http://dx.doi.org/10.1016/j.rbmo.2020.09.015DOI Listing
January 2021

Tubal flushing for subfertility.

Cochrane Database Syst Rev 2020 10 15;10:CD003718. Epub 2020 Oct 15.

St Mary's Hospital, Manchester, UK.

Background: Establishing the subgroup analysis of the fallopian tubes (tubes) is a commonly undertaken diagnostic investigation for women with subfertility. This is usually achieved by flushing contrast medium through the tubes and visualising patency on radiographs, ultrasonography or laparoscopy. Many women were noted to conceive in the first three to six months after tubal flushing, raising the possibility that tubal flushing could also be a treatment for infertility. There has been debate about which contrast medium should be used (water-soluble or oil-soluble media) as this may influence pregnancy rates. An important adverse event during tubal flushing is intravasation (backflow of contrast medium into the blood or lymphatic vessels),which could lead to embolism although it is asymptomatic in most cases.

Objectives: To evaluate the effectiveness and safety of tubal flushing with oil-soluble contrast media (OSCM) and water-soluble contrast media (WSCM) on subsequent fertility outcomes in women with subfertility.

Search Methods: We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, MEDLINE, Embase, CENTRAL, PsycINFO, reference lists of identified articles and trial registries. The most recent search was conducted in April 2020.

Selection Criteria: Randomised controlled trials (RCTs) comparing tubal flushing with OSCM, WSCM with each other or with no treatment, in women with subfertility.

Data Collection And Analysis: Two review authors independently selected the trials, assessed risk of bias and extracted data. We contacted study authors for additional information. The overall quality of the evidence was assessed using GRADE methods.

Main Results: Fifteen trials involving 3864 women were included in this systematic review. Overall, the quality of evidence varied from very low to moderate: the main limitations were risk of bias, heterogeneity and imprecision. OSCM versus no treatment Four studies (506 women) were included in this comparison. Tubal flushing with OSCM may increase the odds of live birth (odds ratio (OR) 3.27, 95% confidence interval (CI) 1.57 to 6.85, 3 RCTs, 204 women, I = 0, low-quality evidence). This suggests that if the chance of live birth following no treatment is assumed to be 11%, the chance following tubal flushing with OSCM would be between 16% and 46%. Tubal flushing with OSCM may increase in the odds of clinical pregnancy (OR 3.54, 95% CI 2.08 to 6.02, 4 RCTs, 506 women, I = 18%, low-quality evidence). This suggests that if the chance of clinical pregnancy following no treatment is assumed to be 9%, the chance following tubal flushing with OSCM would be between 17% and 37%. No study measured intravasation or other adverse events such as infection, haemorrhage and congenital abnormalities. WSCM versus no treatment Only one study (334 women) was included in this comparison. We are uncertain whether tubal flushing with WSCM increase live birth compared to no treatment (OR 1.13, 95% CI 0.67 to 1.91, 1 RCT, 334 women, low-quality evidence). This suggests that if the chance of live birth following no treatment is assumed to be 21%, the chance following tubal flushing with WSCM would be between 15% and 33%. We are uncertain whether tubal flushing with WSCM increases clinical pregnancy compared to no treatment (OR 1.14, 95% CI 0.71 to 1.84, 1 RCT, 334 women, low-quality evidence). This suggests that if the chance of clinical pregnancy following no treatment is assumed to be 27%, the chance following tubal flushing with WSCM would be between 29% and 40%. One case with pelvic infection was reported in the WSCM group and no case with infection in the no treatment group in a one study (334 women). Meta-analysis was not performed due to the rare events. No study measured intravasation or other adverse events such as infection, haemorrhage and congenital abnormalities. OSCM versus WSCM Six studies (2598 women) were included in this comparison. Three studies reported live birth, including two with higher live birth in the OSCM group (OR 1.64, 95% CI 1.27 to 2.11, 1119 women; OR 3.45, 95% CI 1.97 to 6.03, 398 women); and one with insufficient evidence of a difference between groups (OR 0.92, 95% CI 0.60 to 1.40, 533 women). Given the substantial heterogeneity observed (I = 86%), meta-analysis was not performed. Tubal flushing with OSCM probably increased in the odds of intravasation (asymptomatic) compared to tubal flushing with WSCM (OR 5.00, 95% CI 2.25 to 11.12, 4 RCTs, 1912 women, I = 0, moderate-quality evidence). This suggests that if the chance of intravasation following tubal flushing with WSCM is assumed to be 1%, the chance following tubal flushing with OSCM would be between 2% and 9%. Tubal flushing with OSCM may increase the odds of clinical pregnancy (OR 1.42, 95% CI 1.10 to 1.85, 6 RCTs, 2598 women, I = 41%, low-quality evidence). This suggests that if the chance of clinical pregnancy following tubal flushing with WSCM is assumed to be 26%, the chance following tubal flushing with OSCM would be between 28% and 39%. We are uncertain whether tubal flushing with OSCM decreases the odds of infection (OR 0.22, 95% CI 0.04 to 1.22, 2 RCTs, 662 women, I = 0, very low-quality evidence) or haemorrhage (OR 0.65, 95% CI 0.40 to 1.06, 2 RCTs, 662 women, I = 0, very low-quality evidence). Three neonates with congenital abnormalities were reported in the OSCM group while no congenital abnormality was reported in the WSCM group in one study (1119 women). No meta-analysis was performed due to the rare events.

Authors' Conclusions: The evidence suggests that compared to no treatment, tubal flushing with OSCM may increase the chance of live birth and clinical pregnancy, while it is uncertain whether tubal flushing with WSCM improves those outcomes. Compared to tubal flushing with WSCM, OSCM may improve clinical pregnancy while meta-analysis was impossible for live birth due to heterogeneity. Evidence also suggests that OSCM is associated with an increased risk of asymptomatic intravasation. Overall, adverse events, especially long-term adverse events, are poorly reported across studies.
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http://dx.doi.org/10.1002/14651858.CD003718.pub5DOI Listing
October 2020

How long does the fertility-enhancing effect of hysterosalpingography with oil-based contrast last?

Reprod Biomed Online 2020 Dec 30;41(6):1038-1044. Epub 2020 Aug 30.

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

Research Question: Does the fertility-enhancing effect of tubal flushing during hysterosalpingography (HSG) with oil-based contrast change over time?

Design: This was a secondary analysis of the H2Oil (long-term follow-up) study, a multicentre randomized controlled trial evaluating the effectiveness of oil-based and water-based contrast during HSG. The main outcome was ongoing pregnancy. Cox proportional hazards models for time to ongoing pregnancy were fitted over 3 years of follow-up.

Results: Data on 1107 couples were available; 550 couples had oil-based contrast and 557 water-based contrast at HSG. Ongoing pregnancy rates after 3 years were 77% and 71%, respectively. Median follow-up was 9-10 months (5th-95th percentile: <1 to 36). The hazard ratio for ongoing pregnancy for oil versus water over 3 years of follow-up was 1.26 (95% confidence interval [CI] 1.10-1.45). The scaled Schoenfeld residual plots showed a decrease in hazard ratio that was linear with log-transformed time. After including an interaction with log-transformed time, the hazard ratio immediately after HSG was 1.71 (95% CI 1.27-2.31) and reduced to no effect (hazard ratio of 1) at approximately 2 years. There was no evidence for a change in hazard ratio over time in a subgroup of women who experienced pain during HSG.

Conclusions: The hazard ratio for ongoing pregnancy of oil-based versus water-based contrast was 1.71 immediately after HSG, gradually decreasing and plateauing towards a hazard ratio of 1 (indicating no effect) after approximately 2 years. This supports the hypothesis that oil-based contrast might dislodge debris or mucus plugs from the Fallopian tubes, but this has yet to be definitively proved.
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http://dx.doi.org/10.1016/j.rbmo.2020.08.038DOI Listing
December 2020

Efficacy and Safety of Triazavirin Therapy for Coronavirus Disease 2019: A Pilot Randomized Controlled Trial.

Engineering (Beijing) 2020 Oct 8;6(10):1185-1191. Epub 2020 Sep 8.

College of Pharmacology, Harbin Medical University, Harbin 150001, China.

No therapeutics have been proven effective yet for the treatment of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To assess the efficacy and safety of Triazavirin therapy for COVID-19, we conducted a randomized, double-blinded controlled trial involving hospitalized adult patients with COVID-19. Participants were enrolled from ten sites, and were randomized into two arms of the study with a ratio of 1:1. Patients were treated with Triazavirin 250 mg versus a placebo three or four times a day for 7 d. The primary outcome was set as the time to clinical improvement, defined as normalization of body temperature, respiratory rate, oxygen saturation, cough, and absorption of pulmonary infection by chest computed tomography (CT) until 28 d after randomization. Secondary outcomes included individual components of the primary outcome, the mean time and proportion of inflammatory absorption in the lung, and the conversion rate to a repeated negative SARS-CoV-2 nucleic acid test of throat swab sampling. Concomitant therapeutic treatments, adverse events, and serious adverse events were recorded. Our study was halted after the recruitment of 52 patients, since the number of new infections in the participating hospitals decreased greatly. We randomized 52 patients for treatment with Triazavirin ( = 26) or a placebo ( = 26). We found no differences in the time to clinical improvement (median, 7 d versus 12 d; risk ratio (RR), 2.0; 95% confidence interval (CI), 0.7-5.6;  = 0.2), with clinical improvement occurring in ten patients in the Triazavirin group and six patients in the placebo group (38.5% versus 23.1%; RR, 2.1; 95% CI, 0.6-7.0;  = 0.2). All components of the primary outcome normalized within 28 d, with the exception of absorption of pulmonary infection (Triazavirin 50.0%, placebo 26.1%). Patients in the Triazavirin group used less frequent concomitant therapies for respiratory, cardiac, renal, hepatic, or coagulation supports. Although no statistically significant evidence was found to indicate that Triazavirin benefits COVID-19 patients, our observations indicated possible benefits from its use to treat COVID-19 due to its antiviral effects. Further study is required for confirmation.
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http://dx.doi.org/10.1016/j.eng.2020.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476906PMC
October 2020

Design characteristics of studies on medical practice variation of caesarean section rates: a scoping review.

BMC Pregnancy Childbirth 2020 Aug 20;20(1):478. Epub 2020 Aug 20.

Department Health Sciences, Faculty of Science & Talma Institute, Vrije Universiteit, De Boelelaan 1085, 1081 HV, Amsterdam, the Netherlands.

Background: Medical practice variation in caesarean section rates is the most studied type of practice variation in the field of obstetrics and gynaecology. This has not resulted in increased homogeneity of treatment between geographic areas or healthcare providers. Our study aim was to evaluate whether current study designs on medical practice variation of caesarean section rates were optimized to identify the unwarranted share of practice variation and could contribute to the reduction of unwarranted practice variation by meeting criteria for audit and feedback.

Methods: We searched PubMed, Embase, EBSCO/CINAHL and Wiley/Cochrane Library from inception to March 24th, 2020. Studies that compared the rate of caesarean sections between individuals, institutions or geographic areas were included. Study design was assessed on: selection procedure of study population, data source, case-mix correction, patient preference, aggregation level of analysis, maternal and neonatal outcome, and determinants (professional and organizational characteristics).

Results: A total of 284 studies were included. Most studies (64%) measured the caesarean section rate in the entire study population instead of using a sample (30%). (National) databases were most often used as information source (57%). Case-mix correction was performed in 87 studies (31%). The Robson classification was used in 20% of the studies following its endorsement by the WHO in 2015. The most common levels of aggregation were hospital level (35%) and grouped hospitals (35%) e.g. private versus public. The percentage of studies that assessed the relationship between variation in caesarean section rates and maternal outcome was 9%, neonatal outcome 19%, determinants (professional and organizational characteristics) 21% and patient preference 2%.

Conclusions: Study designs of practice variation in caesarean sections varied considerably, raising questions about their appropriateness. Studies focused on measuring practice variation, rather than contributing to the reduction of unwarranted practice variation. Future studies should correct for differences in patient characteristics (case-mix) and patient preference to identify unwarranted practice variation. Practice variation studies could be used for audit and feedback if results are presented at lower levels of aggregation, and appeal to intrinsic motivation of physicians, for example by including the health effects on mother and child.
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http://dx.doi.org/10.1186/s12884-020-03169-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441547PMC
August 2020

Levonorgestrel-releasing intrauterine system versus endometrial ablation for heavy menstrual bleeding.

Am J Obstet Gynecol 2021 02 12;224(2):187.e1-187.e10. Epub 2020 Aug 12.

Department of Obstetrics and Gynaecology, Máxima MC, Veldhoven, Netherlands; Research School Grow, University of Maastricht, Maastricht, Netherlands.

Background: Heavy menstrual bleeding affects the physical functioning and social well-being of many women. The levonorgestrel-releasing intrauterine system and endometrial ablation are 2 frequently applied treatments in women with heavy menstrual bleeding.

Objective: This study aimed to compare the effectiveness of the levonorgestrel-releasing intrauterine system with endometrial ablation in women with heavy menstrual bleeding.

Study Design: This multicenter, randomized controlled, noninferiority trial was performed in 26 hospitals and in a network of general practices in the Netherlands. Women with heavy menstrual bleeding, aged 34 years and older, without a pregnancy wish or intracavitary pathology were randomly allocated to treatment with either the levonorgestrel-releasing intrauterine system (Mirena) or endometrial ablation, performed with a bipolar radiofrequency device (NovaSure). The primary outcome was blood loss at 24 months, measured with a Pictorial Blood Loss Assessment Chart score. Secondary outcomes included reintervention rates, patient satisfaction, quality of life, and sexual function.

Results: We registered 645 women as eligible, of whom 270 women provided informed consent. Of these, 132 women were allocated to the levonorgestrel-releasing intrauterine system (baseline Pictorial Blood Loss Assessment Chart score, 616) and 138 women to endometrial ablation (baseline Pictorial Blood Loss Assessment Chart score, 630). At 24 months, mean Pictorial Blood Loss Assessment Chart scores were 64.8 in the levonorgestrel-releasing intrauterine system group and 14.2 in the endometrial ablation group (difference, 50.5 points; 95% confidence interval, 4.3-96.7; noninferiority, P=.87 [25 Pictorial Blood Loss Assessment Chart point margin]). Compared with 14 women (10%) in the endometrial ablation group, 34 women (27%) underwent a surgical reintervention in the levonorgestrel-releasing intrauterine system group (relative risk, 2.64; 95% confidence interval, 1.49-4.68). There was no significant difference in patient satisfaction and quality of life between the groups.

Conclusion: Both the levonorgestrel-releasing intrauterine system and endometrial ablation strategies lead to a large decrease in menstrual blood loss in women with heavy menstrual bleeding, with comparable quality of life scores after treatment. Nevertheless, there was a significant difference in menstrual blood loss in favor of endometrial ablation, and we could not demonstrate noninferiority of starting with the levonorgestrel-releasing intrauterine system. Women who start with the levonorgestrel-releasing intrauterine system, a reversible and less invasive treatment, are at an increased risk of needing additional treatment compared with women who start with endometrial ablation. The results of this study will enable physicians to provide women with heavy menstrual bleeding with the evidence to make a well-informed decision between the 2 treatments.
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http://dx.doi.org/10.1016/j.ajog.2020.08.016DOI Listing
February 2021

Authors' reply re: Cerebroplacental ratio in predicting adverse perinatal outcome: a meta-analysis of individual participant data.

BJOG 2020 10 20;127(11):1439-1440. Epub 2020 Jul 20.

Department of Obstetrics and Gynecology, Reproduction and Development, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1111/1471-0528.16375DOI Listing
October 2020

Methodologic considerations in randomized clinical trials in reproductive medicine.

Fertil Steril 2020 06;113(6):1107-1112

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

Randomized controlled trials (RCTs) are the cornerstone of evidence-based medicine. In this series in Fertility and Sterility, several aspects of RCTs are discussed, with contributions on multicenter RCTs, different international settings, and integrity of RCTs. The present contribution deals with methodologic issues. We discuss different types of RCTs based on null hypothesis (superiority vs. noninferiority vs. equivalence) as well as frequentist versus Bayesian interpretation. We also discuss the use of RCTs in the era of personalized medicine and RCTs to address diagnostic and prognostic questions. Finally, we address the use of big data compared with the use of RCTs.
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http://dx.doi.org/10.1016/j.fertnstert.2020.04.038DOI Listing
June 2020

Coordination and planning of clinical research on a national and global level.

Fertil Steril 2020 06;113(6):1100-1106

Department of Obstetrics and Gynaecology, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

In reproductive medicine, the needs and desires of infertility patients drive future research, with the most important outcome being live birth of a baby. Large, multicenter, randomized clinical trials are considered the best research tool to evaluate the effectiveness of medical interventions, but they can often take a long time to find definitive answers. Advances in individual participant data (IPD) and network meta-analysis have enabled research questions to be answered more quickly, but better planning could streamline this process further. To harmonize research findings that are taking place globally in this way, it is crucial that the same outcomes are collected in clinical trials conducted in reproductive medicine. Furthermore, the conduct of clinical trials often requires collaboration on an international scale; however, individual countries have their own processes for research prioritization and delivery. We describe the perspective of high- and low-resourced settings and industry as well as the mechanisms of prioritization and coordination that are in place in different settings. In addition, we discuss the importance of the patient perspective, which can help shape the research question, clinical trial design, and the logistical operations of trial delivery. The need for increased global collaboration and coalitions within and between stakeholders is evident for the research community to accelerate advances and maximize benefits in reproductive medicine.
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http://dx.doi.org/10.1016/j.fertnstert.2020.04.032DOI Listing
June 2020

Fertility outcomes of IVF/ICSI after Caesarean section: a cohort study.

Reprod Biomed Online 2020 May 16;40(5):719-728. Epub 2019 Dec 16.

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

Research Question: The study objective was to evaluate the impact of a previous Caesarean section on fertility outcomes in women undergoing IVF/intracytoplasmic sperm injection (ICSI).

Design: A retrospective cohort study was designed that included 1793 women undergoing IVF/ICSI who had had a previous delivery from January 2015 to December 2016. The primary outcome was live birth. Secondary outcomes were implantation, clinical pregnancy, miscarriage, ectopic pregnancy, multiple pregnancy and perinatal complications.

Results: Of the 1793 women included, 796 had had a previous Caesarean section and 997 a previous vaginal delivery. Propensity score matching in a 1:1 ratio resulted in 538 women per group. Compared with women with a previous vaginal delivery, women with a previous Caesarean section had a lower live birth rate (30.1% versus 38.1%, odds ratio [OR] 0.70, 95% confidence interval [CI] 0.54-0.90) and a higher miscarriage rate (25.9% versus 17.5%, OR 1.65, 95% CI 1.06-2.56). Among other secondary outcomes, implantation rates were 32.9% and 37.1% (OR 0.83, 95% CI 0.69-1.01), and clinical pregnancy rates were 42.4% and 46.8% (OR 0.84, 95% CI 0.66-1.06), in the Caesarean section group and vaginal delivery group, respectively. There were no statistically significant differences in terms of ectopic pregnancy, multiple pregnancy or perinatal outcomes between the groups. Further adjustment for confounders did not change the result of the primary outcome (OR 0.64, 95% CI 0.49-0.84).

Conclusions: Women undergoing IVF/ICSI who have had a previous Caesarean section have a lower live birth rate and a higher miscarriage rate than those with a previous vaginal delivery.
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http://dx.doi.org/10.1016/j.rbmo.2019.12.004DOI Listing
May 2020

Is asymptomatic bacteriuria associated with short cervical length in women with a singleton pregnancy, a secondary analysis of two national cohort studies with small embedded randomized controlled trials.

Eur J Obstet Gynecol Reprod Biol 2020 May 12;248:172-176. Epub 2020 Mar 12.

Amsterdam University Medical Center, Department of Obstetrics and Gynecology, Amsterdam, the Netherlands.

Objective: To assess the association between asymptomatic bacteriuria (ASB) and short cervical length (CL), since they are both associated with preterm delivery.

Study Design: In two prospective multicentre cohort studies, pregnant women were screened for the presence of ASB and short CL (≤25 mm). We compared CL in women with and without ASB. Both studies had a small randomised clinical trial embedded.

Results: Our study population comprised 1 610 women, of whom 114 were ASB positive. Median cervical length was similar in women with and without ASB (44.0 vs 44.0 mm, P = 0.60). More women in the ASB positive group had a short CL compared to the ASB negative group (1.8 % versus 0.4 %, P = 0.047)). The gestational age at delivery did not differ between the groups (ranging from 38 + 3 in women with ASB and short CL to 39 + 5 in women without ASB with a short CL P = 0.52). No preterm births occurred in women with a short cervical length (regardless of ASB status). In the women without ASB and no short CL 4.8 % had a preterm birth, in the women with ASB but not a short CL 4.1 % had a preterm birth.

Conclusion: While ASB status did not influence median cervical length, we found a significant relationship between a short CL and ASB positive women. We found no statistical significant difference on the preterm birth rate and mean gestational age.
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http://dx.doi.org/10.1016/j.ejogrb.2020.03.015DOI Listing
May 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

Treatment of severe hypertension during pregnancy: we still do not know what the best option is.

Hypertens Pregnancy 2020 Feb 27;39(1):25-32. Epub 2019 Dec 27.

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

Intracranial hemorrhage and stroke are primary causes of maternal mortality in pregnancies affected by hypertensive disorders. As such antihypertensive therapy plays a crucial role in the management of severe hypertension. However, the target level to achieve the best outcome for both - mother and fetus - is still unclear. Moreover, given the lack of well-designed randomized controlled trials with standardized key outcomes, the current choice of antihypertensive medications depends rather on clinicians' preference. Furthermore, data on long-term outcomes of offspring is not available. Therefore, there is an urgent need for randomized trials comparing different anti-hypertensive options to address efficacy and safety questions.
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http://dx.doi.org/10.1080/10641955.2019.1708383DOI Listing
February 2020

Individualized ovarian stimulation in IVF/ICSI treatment: it is time to stop using high FSH doses in predicted low responders.

Hum Reprod 2020 09;35(9):1954-1963

Department of Reproductive Medicine and Gynaecology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.

In IVF/ICSI treatment, the FSH starting dose is often increased in predicted low responders from the belief that it improves the chance of having a baby by maximizing the number of retrieved oocytes. This intervention has been evaluated in several randomized controlled trials, and despite a slight increase in the number of oocytes-on average one to two more oocytes in the high versus standard dose group-no beneficial impact on the probability of a live birth has been demonstrated (risk difference, -0.02; 95% CI, -0.11 to 0.06). Still, many clinicians and researchers maintain a highly ingrained belief in 'the more oocytes, the better'. This is mainly based on cross-sectional studies, where the positive correlation between the number of retrieved oocytes and the probability of a live birth is interpreted as a direct causal relation. If the latter would be present, indeed, maximizing the oocyte number would benefit our patients. The current paper argues that the use of high FSH doses may not actually improve the probability of a live birth for predicted low responders undergoing IVF/ICSI treatment and exemplifies the flaws of directly using cross-sectional data to guide FSH dosing in clinical practice. Also, difficulties in the de-implementation of the increased FSH dosing strategy are discussed, which include the prioritization of intermediate outcomes (such as cycle cancellations) and the potential biases in the interpretation of study findings (such as confirmation or rescue bias).
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http://dx.doi.org/10.1093/humrep/dez184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485616PMC
September 2020

Mechanical methods for induction of labour.

Cochrane Database Syst Rev 2019 Oct 18;10:CD001233. Epub 2019 Oct 18.

Department of Obstetrics, Jeroen Bosch Hospital, Henri Dunantstraat 1, 's-Hertogenbosch, Netherlands, 5223 GZ.

Background: Mechanical methods were the first methods developed to ripen the cervix and induce labour. During recent decades they have been substituted by pharmacological methods. Potential advantages of mechanical methods, compared with pharmacological methods may include reduction in side effects that could improve neonatal outcomes. This is an update of a review first published in 2001, last updated in 2012.

Objectives: To determine the effectiveness and safety of mechanical methods for third trimester (> 24 weeks' gestation) induction of labour in comparison with prostaglandin E2 (PGE2) (vaginal and intracervical), low-dose misoprostol (oral and vaginal), amniotomy or oxytocin.

Search Methods: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies (9 January 2018). We updated the search in March 2019 and added the search results to the awaiting classification section of the review.

Selection Criteria: Clinical trials comparing mechanical methods used for third trimester cervical ripening or labour induction with pharmacological methods.Mechanical methods include: (1) the introduction of a catheter through the cervix into the extra-amniotic space with balloon insufflation; (2) introduction of laminaria tents, or their synthetic equivalent (Dilapan), into the cervical canal; (3) use of a catheter to inject fluid into the extra-amniotic space (EASI).This review includes the following comparisons: (1) specific mechanical methods (balloon catheter, laminaria tents or EASI) compared with prostaglandins (different types, different routes) or with oxytocin; (2) single balloon compared to a double balloon; (3) addition of prostaglandins or oxytocin to mechanical methods compared with prostaglandins or oxytocin alone.

Data Collection And Analysis: Two review authors independently assessed trials for inclusion and assessed risk of bias. Two review authors independently extracted data and assessed the quality of the evidence using the GRADE approach.

Main Results: This review update includes a total of 113 trials (22,373 women) contributing data to 21 comparisons. Risk of bias of trials varied. Overall, the evidence was graded from very-low to moderate quality. All evidence was downgraded for lack of blinding and, for many comparisons, the effect estimates were too imprecise to make a valid judgement.Balloon versus vaginal PGE2: there may be little or no difference in vaginal deliveries not achieved within 24 hours (average risk ratio (RR) 1.01, 95% confidence interval (CI) 0.82 to 1.26; 7 studies; 1685 women; I² = 79%; low-quality evidence) and there probably is little or no difference in caesarean sections (RR 1.00, 95% CI 0.92 to 1.09; 28 studies; 6619 women; moderate-quality evidence) between induction of labour with a balloon catheter and vaginal PGE2. A balloon catheter probably reduces the risk of uterine hyperstimulation with fetal heart rate (FHR) changes (RR 0.35, 95% CI 0.18 to 0.67; 6 studies; 1966 women; moderate-quality evidence), serious neonatal morbidity or perinatal death (RR 0.48, 95% CI 0.25 to 0.93; 8 studies; 2757 women; moderate-quality evidence) and may slightly reduce the risk of aneonatal intensive care unit (NICU) admission (RR 0.82, 95% CI 0.65 to 1.04; 3647 women; 12 studies; low-quality evidence). It is uncertain whether there is a difference in serious maternal morbidity or death (RR 0.20, 95% CI 0.01 to 4.12; 4 studies; 1481 women) or five-minute Apgar score < 7 (RR 0.74, 95% CI 0.49 to 1.14; 4271 women; 14 studies) because the quality of the evidence was found to be very low and low, respectively.Balloon versus low-dose vaginal misoprostol: it is uncertain whether there is a difference in vaginal deliveries not achieved within 24 hours between induction of labour with a balloon catheter and vaginal misoprostol (RR 1.09, 95% CI 0.85 to 1.39; 340 women; 2 studies; low-quality evidence). A balloon catheter probably reduces the risk of uterine hyperstimulation with FHR changes (RR 0.39, 95% CI 0.18 to 0.85; 1322 women; 8 studies; moderate-quality evidence) but may increase the risk of a caesarean section (average RR 1.28, 95% CI 1.02 to 1.60; 1756 women; 12 studies; I² = 45%; low-quality evidence). It is uncertain whether there is a difference in serious neonatal morbidity or perinatal death (RR 0.58, 95% CI 0.12 to 2.66; 381 women; 3 studies), serious maternal morbidity or death (no events; 4 studies, 464 women), both very low-quality evidence, and five-minute Apgar score < 7 (RR 1.00, 95% CI 0.50 to 1.97; 941 women; 7 studies) and NICU admissions (RR 1.00, 95% CI 0.61 to 1.63; 1302 women; 9 studies) both low-quality evidence.Balloon versus low-dose oral misoprostol: a balloon catheter probably increases the risk of a vaginal delivery not achieved within 24 hours (RR 1.28, 95% CI 1.13 to 1.46; 782 women, 2 studies, and probably slightly increases the risk of a caesarean section (RR 1.17, 95% CI 1.04 to 1.32; 3178 women; 7 studies; both moderate-quality evidence) when compared to oral misoprostol. It is uncertain whether there is a difference in uterine hyperstimulation with FHR changes (RR 0.81, 95% CI 0.48 to 1.38; 2033 women; 2 studies), serious neonatal morbidity or perinatal death (RR 1.11, 95% CI 0.60 to 2.06; 2627 women; 3 studies), both low-quality evidence, serious maternal morbidity or death (RR 0.50, 95% CI 0.05 to 5.52; 2627 women; 3 studies), very low-quality evidence, five-minute Apgar scores < 7 (RR 0.71, 95% CI 0.38 to 1.32; 2693 women; 4 studies) and NICU admissions (RR 0.82, 95% CI 0.58 to 1.17; 2873 women; 5 studies) both low-quality evidence.

Authors' Conclusions: Low- to moderate-quality evidence shows mechanical induction with a balloon is probably as effective as induction of labour with vaginal PGE2. However, a balloon seems to have a more favourable safety profile. More research on this comparison does not seem warranted.Moderate-quality evidence shows a balloon catheter may be slightly less effective as oral misoprostol, but it remains unclear if there is a difference in safety outcomes for the neonate. When compared to low-dose vaginal misoprostol, low-quality evidence shows a balloon may be less effective, but probably has a better safety profile.Future research could be focused more on safety aspects for the neonate and maternal satisfaction.
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http://dx.doi.org/10.1002/14651858.CD001233.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953206PMC
October 2019

Interventions for unexplained infertility: a systematic review and network meta-analysis.

Cochrane Database Syst Rev 2019 09 5;9:CD012692. Epub 2019 Sep 5.

Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia, 3168.

Background: Clinical management for unexplained infertility includes expectant management as well as active treatments, including ovarian stimulation (OS), intrauterine insemination (IUI), OS-IUI,  and in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI).Existing systematic reviews have conducted head-to-head comparisons of these interventions using pairwise meta-analyses. As this approach allows only the comparison of two interventions at a time and is contingent on the availability of appropriate primary evaluative studies, it is difficult to identify the best intervention in terms of effectiveness and safety. Network meta-analysis compares multiple treatments simultaneously by using both direct and indirect evidence and provides a hierarchy of these treatments, which can potentially better inform clinical decision-making.

Objectives: To evaluate the effectiveness and safety of different approaches to clinical management (expectant management, OS, IUI, OS-IUI, and IVF/ICSI) in couples with unexplained infertility.

Search Methods: We performed a systematic review and network meta-analysis of relevant randomised controlled trials (RCTs). We searched electronic databases including the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, the Cochrane Central Register of Studies Online, MEDLINE, Embase, PsycINFO and CINAHL, up to 6 September 2018, as well as reference lists, to identify eligible studies. We also searched trial registers for ongoing trials.

Selection Criteria: We included RCTs comparing at least two of the following clinical management options in couples with unexplained infertility: expectant management, OS, IUI, OS-IUI, and IVF (or combined with ICSI).

Data Collection And Analysis: Two review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardised forms. The primary effectiveness outcome was a composite of cumulative live birth or ongoing pregnancy, and the primary safety outcome was multiple pregnancy. We performed a network meta-analysis within a random-effects multi-variate meta-analysis model. We presented treatment effects by using odds ratios (ORs) and 95% confidence intervals (CIs). For the network meta-analysis, we used Confidence in Network Meta-analysis (CINeMA) to evaluate the overall certainty of evidence.

Main Results: We included 27 RCTs (4349 couples) in this systematic review and 24 RCTs (3983 couples) in a subsequent network meta-analysis. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity.Ten RCTs including 2725 couples reported on live birth. Evidence of differences between OS, IUI, OS-IUI, or IVF/ICSI versus expectant management was insufficient (OR 1.01, 95% CI 0.51 to 1.98; low-certainty evidence; OR 1.21, 95% CI 0.61 to 2.43; low-certainty evidence; OR 1.61, 95% CI 0.88 to 2.94; low-certainty evidence; OR 1.88, 95 CI 0.81 to 4.38; low-certainty evidence). This suggests that if the chance of live birth following expectant management is assumed to be 17%, the chance following OS, IUI, OS-IUI, and IVF would be 9% to 28%, 11% to 33%, 15% to 37%, and 14% to 47%, respectively. When only including couples with poor prognosis of natural conception (3 trials, 725 couples) we found OS-IUI and IVF/ICSI increased live birth rate compared to expectant management (OR 4.48, 95% CI 2.00 to 10.1; moderate-certainty evidence; OR 4.99, 95 CI 2.07 to 12.04; moderate-certainty evidence), while there was insufficient evidence of a difference between IVF/ICSI and OS-IUI (OR 1.11, 95% CI 0.78 to 1.60; low-certainty evidence).Eleven RCTs including 2564 couples reported on multiple pregnancy. Compared to expectant management/IUI, OS (OR 3.07, 95% CI 1.00 to 9.41; low-certainty evidence) and OS-IUI (OR 3.34 95% CI 1.09 to 10.29; moderate-certainty evidence) increased the odds of multiple pregnancy, and there was insufficient evidence of a difference between IVF/ICSI and expectant management/IUI (OR 2.66, 95% CI 0.68 to 10.43; low-certainty evidence). These findings suggest that if the chance of multiple pregnancy following expectant management or IUI is assumed to be 0.6%, the chance following OS, OS-IUI, and IVF/ICSI would be 0.6% to 5.0%, 0.6% to 5.4%, and 0.4% to 5.5%, respectively.Trial results show insufficient evidence of a difference between IVF/ICSI and OS-IUI for moderate/severe ovarian hyperstimulation syndrome (OHSS) (OR 2.50, 95% CI 0.92 to 6.76; 5 studies; 985 women; moderate-certainty evidence). This suggests that if the chance of moderate/severe OHSS following OS-IUI is assumed to be 1.1%, the chance following IVF/ICSI would be between 1.0% and 7.2%.

Authors' Conclusions: There is insufficient evidence of differences in live birth between expectant management and the other four interventions (OS, IUI, OS-IUI, and IVF/ICSI). Compared to expectant management/IUI, OS may increase the odds of multiple pregnancy, and OS-IUI probably increases the odds of multiple pregnancy. Evidence on differences between IVF/ICSI and expectant management for multiple pregnancy is insufficient, as is evidence of a difference for moderate or severe OHSS between IVF/ICSI and OS-IUI.
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http://dx.doi.org/10.1002/14651858.CD012692.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727181PMC
September 2019

Endocrine characteristics, body mass index and metabolic syndrome in women with polycystic ovary syndrome.

Reprod Biomed Online 2019 Nov 3;39(5):868-876. Epub 2019 Jul 3.

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

Research Question: The study aimed to evaluate the associations of endocrine and ultrasound characteristics with metabolic syndrome in women with polycystic ovary syndrome (PCOS), and whether these associations were modified by body mass index (BMI).

Design: The study was a secondary analysis of baseline data from a randomized controlled trial of induction of ovulation in women with PCOS.

Results: Among 947 Chinese women with PCOS, 153 (16.2%) were diagnosed with metabolic syndrome. The prevalence of metabolic syndrome in women with normal (<24 kg/m) and high (≥24 kg/m) BMI was 3.6% and 30.5%, respectively. In all women, a high free androgen index (FAI ≥5%) was positively associated with metabolic syndrome (adjusted odds ratio [OR] 2.06, 95% confidence interval [CI] 1.11-3.82). High FAI was positively associated with metabolic syndrome among women with high BMI (adjusted OR 3.37, 95% CI 1.78-6.37), but the association was not significant in women with normal BMI (adjusted OR 1.27, 95% CI 0.34-4.70). The presence of polycystic ovary morphology was negatively associated with metabolic syndrome (adjusted OR 0.52, 95% CI 0.26-1.03) in all women (normal BMI adjusted OR 0.42, 95% CI 0.11-1.67; high BMI adjusted OR 0.54, 95% CI 0.23-1.28). LH, sex hormone-binding globulin (SHBG) and anti-Müllerian hormone (AMH) were negatively associated with metabolic syndrome. The associations of FAI, SHBG and AMH in relation to metabolic syndrome were significantly modified by BMI.

Conclusion(s): The associations of endocrine characteristic with metabolic syndrome were modified by BMI in women with PCOS. Women with PCOS and normal BMI did not have an increased risk of metabolic syndrome.
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http://dx.doi.org/10.1016/j.rbmo.2019.06.014DOI Listing
November 2019

Publication bias may exist among prognostic accuracy studies of middle cerebral artery Doppler ultrasound.

J Clin Epidemiol 2019 12 30;116:1-8. Epub 2019 Jul 30.

Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Objectives: The objective of this study was to assess if there is evidence of publication bias in prognostic accuracy studies of middle cerebral artery (MCA) or cerebroplacental ratio (CPR) for adverse perinatal outcome.

Study Design And Setting: We queried PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov and searched abstract books of five perinatal conferences (1989-2017). We included prognostic accuracy studies on MCA and/or CPR. Highest reported accuracy estimates, sample size, study design, and conclusion positivity were extracted and compared.

Results: We included 127 full-text articles and 51 conference abstracts, 29 of which had not been reported as full-text article. In conference abstracts not reported in full, median negative predictive value was significantly lower compared to full-text articles (0.79 [interquartile range 0.67-0.97] vs. 0.95 [0.89-0.99]; P < 0.001). No significant difference was identified for positive predictive value (0.62 vs. 0.59; P = 0.827), sensitivity (0.67 vs. 0.71; P = 0.159), and specificity (0.86 vs. 0.86; P = 0.632). Study design differed significantly as well (P = 0.030), with fewer prospective studies in conference abstracts not reported in full compared to full-text articles (28% vs. 54%). We found no significant differences in sample size or conclusion positivity.

Conclusion: Possibly, a publication bias in previously published meta-analyses of MCA and CPR has led to overly generous estimates of prognostic performance.
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http://dx.doi.org/10.1016/j.jclinepi.2019.07.016DOI Listing
December 2019

Childhood adversity and women's cardiometabolic health in adulthood: associations with health behaviors, psychological distress, mood symptoms, and personality.

BMC Womens Health 2019 07 23;19(1):102. Epub 2019 Jul 23.

Departments of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC at the University of Amsterdam, Amsterdam, The Netherlands.

Background: We tested whether childhood adversity is associated with poor cardiometabolic health in adulthood among a sample of overweight or obese Dutch women of reproductive age. Health behaviors, psychological distress, mood symptoms, or personality traits were included as potential mediators.

Methods: Data came from a follow-up visit (N = 115), carried out in 2016/2017, of a randomized controlled lifestyle intervention trial in 577 obese infertile women. The associations between total adversity exposure score and cardiometabolic health were tested with regression models. Sleep, smoking and eating behavior, symptoms of depression, anxiety and stress, and personality traits were potential mediators.

Results: Childhood adversity scores were not associated with cardiometabolic outcomes but were associated with poorer sleep quality score (M = 7.2 (SD = 3.5) for those with ≥2 types of events versus 4.8 (2.9) for those with no events; p = 0.022), higher external eating score (26.4 (8.7) versus 21.8 (10.3); p = 0.038), higher perceived stress score (17.1 (6.8) versus 12.3 (4.5); p = 0.016), post-traumatic stress score (1.9 (1.5) versus 0.6 (1.1); p < 0.001), and lower agreeableness score (28.2 (4.2) versus 30.3 (3.1); p = 0.035).

Conclusion: Childhood adversity was associated with poorer health behaviors including sleep and eating behavior, and more stress-related symptoms, but not with women's cardiometabolic health.
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http://dx.doi.org/10.1186/s12905-019-0797-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652022PMC
July 2019

Medical treatment for early fetal death (less than 24 weeks).

Cochrane Database Syst Rev 2019 06 17;6:CD002253. Epub 2019 Jun 17.

Department of Obstetrics and Gynaecology, Academic Medical Center, Meibergdreef 9, Amsterdam, Netherlands, 1105 AZ.

Background: In most pregnancies that miscarry, arrest of embryonic or fetal development occurs some time (often weeks) before the miscarriage occurs. Ultrasound examination can reveal abnormal findings during this phase by demonstrating anembryonic pregnancies or embryonic or fetal death. Treatment has traditionally been surgical but medical treatments may be effective, safe, and acceptable, as may be waiting for spontaneous miscarriage. This is an update of a review first published in 2006.

Objectives: To assess, from clinical trials, the effectiveness and safety of different medical treatments for the termination of non-viable pregnancies.

Search Methods: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (24 October 2018) and reference lists of retrieved studies.

Selection Criteria: Randomised trials comparing medical treatment with another treatment (e.g. surgical evacuation), or placebo, or no treatment for early pregnancy failure. Quasi-randomised studies were excluded. Cluster-randomised trials were eligible for inclusion, as were studies reported in abstract form, if sufficient information was available to assess eligibility.

Data Collection And Analysis: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach.

Main Results: Forty-three studies (4966 women) were included. The main interventions examined were vaginal, sublingual, oral and buccal misoprostol, mifepristone and vaginal gemeprost. These were compared with surgical management, expectant management, placebo, or different types of medical interventions were compared with each other. The review includes a wide variety of different interventions which have been analysed across 23 different comparisons. Many of the comparisons consist of single studies. We limited the grading of the quality of evidence to two main comparisons: vaginal misoprostol versus placebo and vaginal misoprostol versus surgical evacuation of the uterus. Risk of bias varied widely among the included trials. The quality of the evidence varied between the different comparisons, but was mainly found to be very-low or low quality.Vaginal misoprostol versus placeboVaginal misoprostol may hasten miscarriage when compared with placebo: e.g. complete miscarriage (5 trials, 305 women, risk ratio (RR) 4.23, 95% confidence interval (CI) 3.01 to 5.94; low-quality evidence). No trial reported on pelvic infection rate for this comparison. Vaginal misoprostol made little difference to rates of nausea (2 trials, 88 women, RR 1.38, 95% CI 0.43 to 4.40; low-quality evidence), diarrhoea (2 trials, 88 women, RR 2.21, 95% CI 0.35 to 14.06; low-quality evidence) or to whether women were satisfied with the acceptability of the method (1 trial, 32 women, RR 1.17, 95% CI 0.83 to 1.64; low-quality evidence). It is uncertain whether vaginal misoprostol reduces blood loss (haemoglobin difference > 10 g/L) (1 trial, 50 women, RR 1.25, 95% CI 0.38 to 4.12; very-low quality) or pain (opiate use) (1 trial, 84 women, RR 5.00, 95% CI 0.25 to 101.11; very-low quality), because the quality of the evidence for these outcomes was found to be very low.Vaginal misoprostol versus surgical evacuation Vaginal misoprostol may be less effective in accomplishing a complete miscarriage compared to surgical management (6 trials, 943 women, average RR 0.40, 95% CI 0.32 to 0.50; Heterogeneity: Tau² = 0.03, I² = 46%; low-quality evidence) and may be associated with more nausea (1 trial, 154 women, RR 21.85, 95% CI 1.31 to 364.37; low-quality evidence) and diarrhoea (1 trial, 154 women, RR 40.85, 95% CI 2.52 to 662.57; low-quality evidence). There may be little or no difference between vaginal misoprostol and surgical evacuation for pelvic infection (1 trial, 618 women, RR 0.73, 95% CI 0.39 to 1.37; low-quality evidence), blood loss (post-treatment haematocrit (%) (1 trial, 50 women, mean difference (MD) 1.40%, 95% CI -3.51 to 0.71; low-quality evidence), pain relief (1 trial, 154 women, RR 1.42, 95% CI 0.82 to 2.46; low-quality evidence) or women's satisfaction/acceptability of method (1 trial, 45 women, RR 0.67, 95% CI 0.40 to 1.11; low-quality evidence).Other comparisonsBased on findings from a single trial, vaginal misoprostol was more effective at accomplishing complete miscarriage than expectant management (614 women, RR 1.25, 95% CI 1.09 to 1.45). There was little difference between vaginal misoprostol and sublingual misoprostol (5 trials, 513 women, average RR 0.84, 95% CI 0.61 to 1.16; Heterogeneity: Tau² = 0.10, I² = 871%; or between oral and vaginal misoprostol in terms of complete miscarriage at less than 13 weeks (4 trials, 418 women), average RR 0.68, 95% CI 0.45 to 1.03; Heterogeneity: Tau² = 0.13, I² = 90%). However, there was less abdominal pain with vaginal misoprostol in comparison to sublingual (3 trials, 392 women, RR 0.58, 95% CI 0.46 to 0.74). A single study (46 women) found mifepristone to be more effective than placebo: miscarriage complete by day five after treatment (46 women, RR 9.50, 95% CI 2.49 to 36.19). However the quality of this evidence is very low: there is a very serious risk of bias with signs of incomplete data and no proper intention-to-treat analysis in the included study; and serious imprecision with wide confidence intervals. Mifepristone did not appear to further hasten miscarriage when added to a misoprostol regimen (3 trials, 447 women, RR 1.18, 95% CI 0.95 to 1.47).

Authors' Conclusions: Available evidence from randomised trials suggests that medical treatment with vaginal misoprostol may be an acceptable alternative to surgical evacuation or expectant management. In general, side effects of medical treatment were minor, consisting mainly of nausea and diarrhoea. There were no major differences in effectiveness between different routes of administration. Treatment satisfaction was addressed in only a few studies, in which the majority of women were satisfied with the received intervention. Since the quality of evidence is low or very low for several comparisons, mainly because they included only one or two (small) trials; further research is necessary to assess the effectiveness, safety and side effects, optimal route of administration and dose of different medical treatments for early fetal death.
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http://dx.doi.org/10.1002/14651858.CD002253.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6574399PMC
June 2019

Do female age and body weight modify the effect of individualized FSH dosing in IVF/ICSI treatment? A secondary analysis of the OPTIMIST trial.

Acta Obstet Gynecol Scand 2019 10 21;98(10):1332-1340. Epub 2019 Jun 21.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Introduction: The OPTIMIST trial revealed that for women starting in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment, no substantial differences exist in first cycle and cumulative live birth rates between an antral follicle count (AFC)-based individualized follicle-stimulating hormone (FSH) dose and a standard dose. Female age and body weight have been suggested to cause heterogeneity in the effect of FSH dose individualization. The objective of the current study is to evaluate whether these patient characteristics modify the effect of AFC-based individualized FSH dosing in IVF/ICSI treatment.

Material And Methods: A secondary data-analysis of the OPTIMIST trial. Women initiating IVF/ICSI treatment were classified as predicted poor (AFC 0-7), suboptimal (AFC 8-10) or hyper responders (AFC >15), and randomly allocated to a standard FSH dose (150 IU/d) or an individualized FSH dose (450, 225 or 100 IU/d for predicted poor, suboptimal and hyper responders, respectively). In each predicted response category, logistic regression models with interaction terms were used to evaluate the presence of effect modification. The first cycle was analyzed, and the primary outcomes were first complete cycle live birth rate (including fresh plus frozen-thawed embryo transfers) and ovarian hyperstimulation syndrome (OHSS) risks.

Results: No effect modification was revealed in the predicted poor (n = 234) and suboptimal (n = 277) responders. In the predicted hyper responders (n = 521), the effect of the individualized FSH dose on the first cycle live birth rate was modified by female age (P = 0.02) and the effect on OHSS risks was modified by body weight (P = 0.02). A dose reduction from 150 to 100 IU/d generally decreased the OHSS risks in predicted hyper responders, but also reduced the chance of a live birth in young women, and had no beneficial impact on OHSS risks in women with a relatively low body weight.

Conclusions: In women with a predicted hyper response undergoing IVF/ICSI treatment, female age and body weight seem to modify the effect of FSH dose individualization. Although a reduced FSH starting dose generally decreases the OHSS risks, it may also reduce the chance of a live birth, specifically for young women. Future studies could consider these findings when investigating the optimal approach to reduce OHSS risks while maintaining the probability of a live birth for predicted hyper responders in IVF/ICSI treatment.
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October 2019
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