Publications by authors named "Ben W J Mol"

220 Publications

Dietary Intake, Eating Behavior, Physical Activity, and Quality of Life in Infertile Women with PCOS and Obesity Compared with Non-PCOS Obese Controls.

Nutrients 2021 Oct 8;13(10). Epub 2021 Oct 8.

Department of Obstetrics and Gynecology, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands.

To personalize lifestyle advice for women with polycystic ovary syndrome (PCOS) and obesity, detailed information regarding dietary intake, eating behavior, physical activity levels, and quality of life (QoL) may be useful. We aimed to investigate in a post-hoc cross-sectional analysis within a large multicenter randomized controlled trial in women with infertility whether there are significant differences in dietary intake (vegetables, fruits, sugary drinks, alcoholic beverages, savory snacks, and sweet snacks); eating behavior (emotional eating, external eating, and restricted eating); physical activity; and QoL between women with PCOS and obesity and non-PCOS obese controls. Participants were asked to complete the food frequency questionnaire (FFQ), the Dutch Eating Behavior Questionnaire (DEBQ), the Short QUestionnaire to ASsess Health-enhancing physical activity (SQUASH), and the 36-item Short Form Health Survey (SF-36) at study entry (PCOS: = 170; non-PCOS: = 321, mean BMI: 36). Linear and binary (multinomial) logistic regressions were used, and the analyses were adjusted for age, waist-hip circumference ratio, and homeostasis model assessment of insulin resistance (HOMA-IR). No statistically significant differences in dietary intake or physical activity were observed between the two groups. The overall score of emotional eating was 34.6 ± 11.2 in the PCOS group and 34.1 ± 11.3 in the non-PCOS group ( = 0.11). QoL scores (physical and mental) did not differ between PCOS and non-PCOS women. These findings suggest that infertile women with PCOS and obesity and infertile non-PCOS obese controls do not have different dietary habits and have similar mental and physical QoL.
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http://dx.doi.org/10.3390/nu13103526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538395PMC
October 2021

Effectiveness of a 6-Month Lifestyle Intervention on Diet, Physical Activity, Quality of Life, and Markers of Cardiometabolic Health in Women with PCOS and Obesity and Non-PCOS Obese Controls: One Size Fits All?

Nutrients 2021 Sep 28;13(10). Epub 2021 Sep 28.

Department of Obstetrics and Gynecology, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands.

Little is known about the difference in effectiveness of lifestyle intervention between women with PCOS and non-PCOS women. In a post hoc longitudinal analysis of a randomized, controlled trial, we aimed to investigate whether infertile women with PCOS and obesity ( = 87) responded differently to a 6-month lifestyle intervention program than infertile non-PCOS obese controls ( = 172). We evaluated several aspects of the intervention such as changes in diet, physical activity, and dropout rate, as well as the effect on weight, quality of life (QoL), and cardiometabolic outcomes. Multilevel analyses were used, and analyses were adjusted for baseline characteristics such as age, education, and smoking. Although BMI in both groups significantly decreased at 3 months and 6 months, there were no significant differences between the groups at 3 months (adjusted B: -0.3, 95% CI: -0.9 to 0.3, = 0.35) and 6 months (adjusted B: 0.5, 95% CI: -0.4 to 1.4, = 0.29). Women with PCOS and non-PCOS women had similar compliance with the lifestyle intervention in terms of actual change in diet and physical activity. Mental QoL scores were not different at either 3 or 6 months. Physical QoL scores were lower in women with PCOS compared with non-PCOS women at 3 months (adjusted B: -2.4, 95% CI: -4.8 to -0.06, = 0.045) but not at 6 months. Cardiometabolic parameters did not differ between the groups. Our results showed that infertile women with PCOS and obesity and non-PCOS obese controls responded largely similarly to our lifestyle intervention and achieved the same level of improvement in markers of cardiometabolic health.
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http://dx.doi.org/10.3390/nu13103425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538637PMC
September 2021

Preconception insulin resistance and neonatal birth weight in women with obesity: role of bile acids.

Reprod Biomed Online 2021 Nov 11;43(5):931-939. Epub 2021 Aug 11.

University of Groningen, University Medical Centre Groningen, Department of Obstetrics and Gynecology, Groningen, The Netherlands.

Research Question: Does maternal preconception insulin resistance affect neonatal birth weight among women with obesity? Is insulin resistance associated with circulating bile acids? Do bile acids influence the association between maternal preconception insulin resistance and neonatal birth weight?

Design: An exploratory post-hoc analysis of the LIFEstyle randomized controlled trial comparing lifestyle intervention with conventional infertility treatment in women with a BMI of ≥29 kg/m. Fasting blood samples were collected at randomization and after 3 and 6 months in 469 women. Insulin resistance was quantified using the homeostasis model assessment of insulin resistance (HOMA-IR). Bile acid sub-species were determined by liquid chromatography with tandem mass spectrometry. Singletons were included (n = 238). Birth weight Z-scores were adjusted for age, offspring gender and parity. Multilevel analysis and linear regressions were used.

Results: A total of 913 pairs of simultaneous preconception HOMA-IR (median [Q25; Q75]: 2.96 [2.07; 4.16]) and total bile acid measurements (1.79 [1.10; 2.94]) µmol/l were taken. Preconception HOMA-IR was positively associated with total bile acids (adjusted B 0.15; 95% CI 0.09 to 0.22; P < 0.001) and all bile acid sub-species. At the last measurement before pregnancy, HOMA-IR (2.71 [1.91; 3.74]) was positively related to birth weight Z-score (mean ± SD 0.4 ± 1.1; adjusted B 0.08; 95% CI 0.01 to 0.14; P = 0.03). None of the preconception bile acids measured were associated with birth weight.

Conclusion: Maternal preconception insulin resistance is an important determinant of neonatal birth weight in women with obesity, whereas preconception bile acids are not.
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http://dx.doi.org/10.1016/j.rbmo.2021.08.005DOI Listing
November 2021

The Effect of Lifestyle Intervention on Systemic Oxidative Stress in Women with Obesity and Infertility: A Post-Hoc Analysis of a Randomized Controlled Trial.

J Clin Med 2021 Sep 18;10(18). Epub 2021 Sep 18.

Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

We aimed to study whether lifestyle intervention could reduce systemic oxidative stress (OS) and the association between OS and cardiometabolic outcomes in women with obesity and infertility. From 2009 to 2012, infertile women with a BMI ≥ 29 kg/m were randomly assigned to a six-month lifestyle intervention followed by infertility treatment ( = 289) or to prompt infertility treatment ( = 285). Fasting serum free thiols (FT) concentrations were determined by colorimetry at baseline, at three and six months after randomization. Generalized estimating equations and restricted cubic spline regressions were used to estimate mean differences in serum FT levels between groups and to explore associations between serum FT levels and cardiometabolic outcomes. Baseline serum FT levels did not differ between the two groups ( = 203 in the intervention group vs = 226 in the control group, 222.1 ± 48.0 µM vs 229.9 ± 47.8 µM, = 0.09). Body weight decreased by 3.70 kg in the intervention group compared with the control group at six months (95% confidence interval [CI]: -7.61 to 0.21, = 0.06). No differences in serum FT levels were observed between groups at either three months ( = 142 vs = 150, mean differences: -1.03 µM, 95% CI: -8.37 to 6.32, = 0.78) or six months ( = 104 vs = 96, mean differences: 2.19 µM, 95% CI: -5.90 to 10.28, = 0.60). In a pooled analysis of all available measurements, triglycerides (crude B: 5.29, 95% CI: 1.08 to 9.50, = 0.01), insulin (crude B: 0.62, 95% CI: 0.26 to 0.98, = 0.001), and homeostasis model assessment of insulin resistance (crude B: 2.50, 95% CI: 1.16 to 3.38, < 0.001) were positively associated with serum FT levels. High-sensitivity C-reactive protein (hs-CRP) was negatively associated with serum FT levels (crude B: -0.60, 95% CI: -1.11 to -0.10, = 0.02). The change in hs-CRP during the lifestyle intervention was strongly and inversely associated with serum FT levels (crude B: -0.41, 95% CI: -0.70 to -0.13, = 0.005). No significant deviations from linear associations were observed between serum FT and hs-CRP. We do not observe an improvement in systemic OS in women with obesity and infertility with modest weight loss. There were potential associations between OS and biomarkers of cardiometabolic health. Trial registration: This trial was registered on 16 November 2008 at the Dutch trial register (NTR1530).
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http://dx.doi.org/10.3390/jcm10184243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467169PMC
September 2021

Risk Indicators for Urinary Tract Infections in Low Risk Pregnancy and the Subsequent Risk of Preterm Birth.

Antibiotics (Basel) 2021 Aug 31;10(9). Epub 2021 Aug 31.

Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Symptomatic urinary tract infections are associated with preterm birth. However, data on risk indicators for urinary tract infections are limited and outdated. The research is a secondary analysis. The study was a prospective multicenter cohort study of low-risk pregnant women. Logistic regression was used to identify risk indicators for urinary tract infections. The incidence of urinary tract infections was 9.4%. Multivariate logistic regression showed that a history of recurrent urinary tract infections and the presence of asymptomatic bacteriuria in the present pregnancy were associated with urinary tract infections (resp. OR 3.14, 95%CI 1.40-7.02 and OR 1.96 95%CI 1.27-3.03). Women with a urinary tract infection were at increased risk of preterm birth compared to women without a urinary tract infection (12 vs. 5.1%; adjusted HR 2.5 95%CI 1.8-3.5). This increased risk was not found in women with the identified risk indicators (resp. 5.3% vs. 5.1%, adjusted HR 0.35 95%CI 0.00-420 and adjusted HR 1.5 95CI% 0.59-3.9). In conclusion, in low-risk pregnant women, risk indicators for urinary tract infections are: a history of recurrent urinary tract infections and the presence of asymptomatic bacteriuria. The risk of preterm birth is increased in women with a urinary tract infection in this pregnancy. However, women with recurrent urinary tract infections and asymptomatic bacteriuria this pregnancy appear not to be at increased risk of preterm birth.
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http://dx.doi.org/10.3390/antibiotics10091055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468265PMC
August 2021

Lifestyle intervention prior to IVF does not improve embryo utilization rate and cumulative live birth rate in women with obesity: a nested cohort study.

Hum Reprod Open 2021 7;2021(4):hoab032. Epub 2021 Aug 7.

Department of Obstetrics and Gynecology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

Study Question: Does lifestyle intervention consisting of an energy-restricted diet, enhancement of physical activity and motivational counseling prior to IVF improve embryo utilization rate (EUR) and cumulative live birth rate (CLBR) in women with obesity?

Summary Answer: A 6-month lifestyle intervention preceding IVF improved neither EUR nor CLBR in women with obesity in the first IVF treatment cycle where at least one oocyte was retrieved.

What Is Known Already: A randomized controlled trial (RCT) evaluating the efficacy of a low caloric liquid formula diet (LCD) preceding IVF in women with obesity was unable to demonstrate an effect of LCD on embryo quality and live birth rate: in this study, only one fresh embryo transfer (ET) or, in case of freeze-all strategy, the first transfer with frozen-thawed embryos was reported. We hypothesized that any effect on embryo quality of a lifestyle intervention in women with obesity undergoing IVF treatment is better revealed by EUR and CLBR after transfer of all fresh and frozen-thawed embryos.

Study Design Size Duration: This is a nested cohort study within an RCT, the LIFEstyle study. The original study examined whether a 6-month lifestyle intervention prior to infertility treatment in women with obesity improved live birth rate, compared to prompt infertility treatment within 24 months after randomization. In the original study between 2009 and 2012, 577 (three women withdrew informed consent) women with obesity and infertility were assigned to a lifestyle intervention followed by infertility treatment (n = 289) or to prompt infertility treatment (n = 285).

Participants/materials Setting Methods: Only participants from the LIFEstyle study who received IVF treatment were eligible for the current analysis. In total, 137 participants (n = 58 in the intervention group and n = 79 in the control group) started the first cycle. In 25 participants, the first cycle was cancelled prior to oocyte retrieval mostly due to poor response. Sixteen participants started a second or third consecutive cycle. The first cycle with successful oocyte retrieval was used for this analysis, resulting in analysis of 51 participants in the intervention group and 72 participants in the control group. Considering differences in embryo scoring methods and ET day strategy between IVF centers, we used EUR as a proxy for embryo quality. EUR was defined as the proportion of inseminated/injected oocytes per cycle that was transferred or cryopreserved as an embryo. Analysis was performed per cycle and per oocyte/embryo. CLBR was defined as the percentage of participants with at least one live birth from the first fresh and subsequent frozen-thawed ET(s). In addition, we calculated the -score for singleton neonatal birthweight and compared these outcomes between the two groups.

Main Results And The Role Of Chance: The overall mean age was 31.6 years and the mean BMI was 35.4 ± 3.2 kg/m in the intervention group, and 34.9 ± 2.9 kg/m in the control group. The weight change at 6 months was in favor of the intervention group (mean difference in kg vs the control group: -3.14, 95% CI: -5.73 to -0.56). The median (Q25; Q75) number of oocytes retrieved was 4.00 (2.00; 8.00) in the intervention group versus 6.00 (4.00; 9.75) in the control group, and was not significantly different, as was the number of oocytes inseminated/injected (4.00 [2.00; 8.00] vs 6.00 [3.00; 8.75]), normal fertilized embryos (2.00 [0.50; 5.00] vs 3.00 [1.00; 5.00]) and the number of cryopreserved embryos (2.00 [1.25; 4.75] vs 2.00 [1.00; 4.00]). The median (Q25; Q75) EUR was 33.3% (12.5%; 60.0%) in the intervention group and 33.3% (16.7%; 50.0%) in the control group in the per cycle analysis (adjusted B: 2.7%, 95% CI: -8.6% to 14.0%). In the per oocyte/embryo analysis, in total, 280 oocytes were injected or inseminated in the intervention group, 113 were utilized (transferred or cryopreserved, EUR = 40.4%); in the control group, EUR was 30.8% (142/461). The lifestyle intervention did not significantly improve EUR (adjusted odds ratio [OR]: 1.36, 95% CI: 0.94-1.98) in the per oocyte/embryo analysis, taking into account the interdependency of the oocytes per participant. CLBR was not significantly different between the intervention group and the control group after adjusting for type of infertility (male factor and unexplained) and smoking (27.5% vs 22.2%, adjusted OR: 1.03, 95% CI: 0.43-2.47). Singleton neonatal birthweight and -score were not significantly different between the two groups.

Limitations Reasons For Caution: This study is a nested cohort study within an RCT, and no power calculation was performed. The randomization was not stratified for indicated treatment, and although we corrected our analyses for baseline differences, there may be residual confounding. The limited absolute weight loss and the short duration of the lifestyle intervention might be insufficient to affect EUR and CLBR.

Wider Implications Of The Findings: Our data do not support the hypothesis of a beneficial short-term effect of lifestyle intervention on EUR and CLBR after IVF in women with obesity, although more studies are needed as there may be a potential clinically relevant effect on EUR.

Study Funding/competing Interests: The study was supported by a grant from ZonMw, the Dutch Organization for Health Research and Development (50-50110-96-518). A.H. has received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands. B.W.J.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.J.M. reports consultancy for Guerbet, has been a member of the ObsEva advisory board and holds Stock options for ObsEva. B.W.J.M. has received research funding from Guerbet, Ferring and Merck. F.J.M.B. reports personal fees from membership of the external advisory board for Merck Serono and a research support grant from Merck Serono, outside the submitted work.

Trial Registration Number: The LIFEstyle RCT was registered at the Dutch trial registry (NTR 1530). https://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1530.
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http://dx.doi.org/10.1093/hropen/hoab032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452483PMC
August 2021

Ethnic differences in the impact of male fetal gender on the risk of spontaneous preterm birth.

J Perinatol 2021 09 9;41(9):2165-2172. Epub 2021 Mar 9.

Department of Obstetrics and Gynecology, Amsterdam UMC, 1105 AZ, Amsterdam, the Netherlands.

Objective: To study the impact of fetal gender on the risk of spontaneous preterm birth in various ethnicities.

Study Design: National cohort study in which all singleton live births from 25 weeks onwards without congenital anomalies were included of African, Asian, and Mediterranean women (1999-2010). Our primary outcome measure was preterm birth before 37 weeks. Per ethnic group, male and female neonates were compared.

Result: In each ethnic group, male fetuses were at increased risk of preterm birth (adjusted odds ratio (aOR) 1.63 for African, aOR 1.71 for Asian, and aOR 1.84 for Mediterranean males). The population-attributable risk of male gender on spontaneous preterm birth is lower in African women (3.9%) than in Asian (10.3%) and Mediterranean women (9.0%).

Conclusion: Male fetal gender is associated with spontaneous preterm birth in African, Asian, and Mediterranean women, but the total impact of ethnicity on spontaneous preterm birth rate is different.
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http://dx.doi.org/10.1038/s41372-021-01024-7DOI Listing
September 2021

Should we look for a low-grade threshold for blastocyst transfer? A scoping review.

Reprod Biomed Online 2021 Apr 30;42(4):709-716. Epub 2021 Jan 30.

Monash Women's, Monash Health, 246 Clayton Road Clayton 3168, Australia; Department of Obstetrics and Gynaecology, Monash University Clayton, Australia; Aberdeen Centre for Women's Health Research, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen Aberdeen, UK.

Embryo quality is a key determinant of the success of IVF. Although the focus has been on selecting the best embryo for transfer, the classification of low-grade blastocysts (LGB) in existing scoring systems has received less attention. This is worrisome; embryo freezing allows optimal use of all created embryos, thus maximizing the cumulative live birth rate, which is arguably the most important outcome for infertile couples. A PubMed search was conducted in August 2020, using '((('poor-quality' OR 'poor quality') OR ('low-grade' OR 'low grade')) AND ('embryo' OR 'blastocyst')) AND ('pregnancy' OR 'live birth')'. This scoping review shows that LGB have similar euploidy and pregnancy success rates after implantation and have no adverse effects on pregnancy or perinatal outcomes. Evidence for pregnancy outcomes is lacking for different grades of LGB, with most studies clustering all LQB as one to compare with optimal blastocysts.
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http://dx.doi.org/10.1016/j.rbmo.2021.01.019DOI Listing
April 2021

Perinatal death in a term fetal growth restriction randomized controlled trial: the paradox of prior risk and consent.

Am J Obstet Gynecol MFM 2020 11 24;2(4):100239. Epub 2020 Sep 24.

Leiden University Medical Center, Leiden, the Netherlands.

Background: The disproportionate intrauterine growth intervention trial at term was an intention to treat analysis and compared labor induction with expectant monitoring in pregnancies complicated by fetal growth restriction at term and showed equivalence for neonatal outcomes.

Objective: To evaluate trial participation bias and to examine the generalizability of the results of an obstetrical randomized trial.

Study Design: We used data from participants and nonparticipants of a randomized controlled trial-the disproportionate intrauterine growth intervention trial at term (n=1116) -to perform a secondary analysis. This study compared induction of labor and expectant management in women with term growth restriction. Data were collected in the same manner for both groups. Baseline characteristics and neonatal and maternal outcomes were compared. The primary outcome was a composite measure of adverse neonatal outcome. Secondary outcomes were delivery by cesarean delivery and instrumental vaginal delivery; length of stay in the neonatal intensive care, neonatal ward, and the maternal hospital; and maternal morbidity.

Results: Nonparticipants were older, had a lower body mass index, had a higher level of education, smoked less, and preferred expectant management. The time between study inclusion and labor onset was shorter in participants than in nonparticipants. Notably, 4 perinatal deaths occurred among nonparticipants and none among participants. Among nonparticipants, there were more children born with a birthweight below the third centile. The nonparticipants who had expectant management were monitored less frequently than the participants in both the intervention and the expectant arm.

Conclusion: We found less favorable outcomes and more perinatal deaths in nonparticipants. Protocol-driven management, differences between participants and nonparticipants, or the fact that nonparticipants had a preference for expectant management might explain the findings.
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http://dx.doi.org/10.1016/j.ajogmf.2020.100239DOI Listing
November 2020

How and Why to Define Unexplained Infertility?

Semin Reprod Med 2020 01 14;38(1):55-60. Epub 2020 Oct 14.

Department of Obstetrics and Gynecology, Kasr Al-Ainy Hospital, Faculty of Medicine, Cairo University, Cairo, Egypt.

Unexplained infertility represents up to 30% of all cases of infertility. It is a diagnosis of exclusion, where no cause for infertility may be identified in the investigation of the couple, be it anovulation, fallopian tube blockage, or severe male factor. Unexplained infertility therefore cannot be considered a diagnosis to which a specific treatment is directed, rather that it indicates a failure to reach a diagnosis of the true cause of infertility. In this review, we explore the evidence base and potential limitations of the current routine infertility assessment. We also aim to highlight the importance of considering the prognosis of each individual couple through the process of assessment and propose a reconsidered approach to treatment, targeted to the prognosis rather than the diagnosis. Ultimately, a better understanding of the mechanisms of infertility will reduce the number of couples diagnosed with "unexplained" infertility.
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http://dx.doi.org/10.1055/s-0040-1718709DOI Listing
January 2020

Reproducible research practices and transparency in reproductive endocrinology and infertility articles.

Fertil Steril 2020 12 6;114(6):1322-1329. Epub 2020 Aug 6.

Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California; Department of Medicine, Department of Health Research and Policy, and Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, California; Department of Statistics, Stanford University School of Humanities and Sciences, Stanford, California.

Objective: To analyse the published literature in reproductive endocrinology and infertility (REI) to examine the transparency and the use of reproducible research practices of the scientific literature and to identify possible avenues for improvement.

Design: Meta-epidemiologic study. We examined the first 20 consecutive full-text original articles presenting primary data from five REI-specific journals for 2013 and for 2018, and eligible REI articles published in 2013-2018 in five high-impact general journals. Eligible articles were required to be full-text original articles, presenting primary data.

Setting: Not applicable.

Patient(s): Not applicable.

Intervention(s): Not applicable.

Main Outcome Measure(s): Each article was assessed for study type, trial registration, protocol and raw data availability, funding and conflict of interest declarations, inclusion in subsequent systematic reviews and/or meta-analyses, sample size, and whether the work claimed to be novel or replication. Sample sizes and citation counts also were obtained.

Result(s): A total of 222 articles were deemed eligible; 98 from REI journals published in 2013, 90 from REI journals published in 2018, and 34 from high-impact journals. There were 37 studies registered, 15 contained a protocol, and two stated actively that they were willing to share data. Most studies provided a statement about funding and conflicts of interest. Two articles explicitly described themselves as replications. All randomized controlled trial published in REI journals were registered prospectively; many meta-analyses were not registered. High-impact journal articles had a greater median sample size and more citations and were more likely to be registered, to have a protocol, and to claim novelty explicitly when compared with REI 2013 and 2018 articles.

Conclusion(s): Research in REI can be improved in prospective registration, routine availability of protocols, wider sharing of raw data whenever feasible, and more emphasis on replication.
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http://dx.doi.org/10.1016/j.fertnstert.2020.05.020DOI Listing
December 2020

Tubal flushing with oil-based or water-based contrast at hysterosalpingography for infertility: long-term reproductive outcomes of a randomized trial.

Fertil Steril 2020 07 16;114(1):155-162. Epub 2020 Jun 16.

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

Objective: To determine the impact of oil-based versus water-based contrast on pregnancy and live birth rates ≤5 years after hysterosalpingography (HSG) in infertile women.

Design: A 5-year follow-up study of a multicenter randomized trial.

Setting: Hospitals.

Patient(s): Infertile women with an ovulatory cycle, 18-39 years of age, and having a low risk of tubal pathology.

Intervention(s): Use of oil-based versus water-based contrast during HSG.

Main Outcome Measure(s): Ongoing pregnancy, live births, time to ongoing pregnancy, second ongoing pregnancy.

Result(s): A total of 1,119 women were randomly assigned to HSG with oil-based contrast (n = 557) or water-based contrast (n = 562). After 5 years, 444 of 555 women in the oil group (80.0%) and 419 of 559 women in the water group (75.0%) had an ongoing pregnancy (relative risk [RR] 1.07; 95% confidence interval [CI] 1.00-1.14), and 415 of 555 women in the oil group (74.8%) and 376 of 559 women in the water group (67.3%) had live births (RR 1.11; 95% CI 1.03-1.20). In the oil group, 228 pregnancies (41.1%) were conceived naturally versus 194 (34.7%) pregnancies in the water group (RR 1.18; 95% CI 1.02-1.38). The time to ongoing pregnancy was significantly shorter in the oil group versus the water group (10.0 vs. 13.7 months; hazard ratio, 1.25; 95% CI 1.09-1.43). No difference was found in the occurrence of a second ongoing pregnancy.

Conclusion(s): During a 5-year time frame, ongoing pregnancy and live birth rates are higher after tubal flushing with oil-based contrast during HSG compared with water-based contrast. More pregnancies are naturally conceived and time to ongoing pregnancy is shorter after HSG with oil-based contrast.

Clinical Trial Registration Number: Netherlands Trial Register (NTR) 3270 and NTR6577(www.trialregister.nl).
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http://dx.doi.org/10.1016/j.fertnstert.2020.03.022DOI Listing
July 2020

The association between parity and spontaneous preterm birth: a population based study.

BMC Pregnancy Childbirth 2020 Apr 21;20(1):233. Epub 2020 Apr 21.

Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands.

Background: Preterm birth is the leading cause of perinatal mortality and neonatal morbidity worldwide. Many factors have been associated with preterm birth, including parity. The aim of the present study was to investigate associations between parity and risk of spontaneous preterm birth.

Methods: We conducted a retrospective study including live singleton births (≥22 weeks) of women with a first, second, third, fourth or fifth pregnancy in The Netherlands from 2010 through 2014. Our primary outcome was risk of spontaneous preterm birth < 37 weeks. Secondary outcomes were spontaneous preterm birth < 32 and < 28 weeks.

Results: We studied 802,119 pregnancies, including 30,237 pregnancies that ended spontaneously < 37 weeks. We identified an increased risk for spontaneous preterm birth < 37 weeks in nulliparous women (OR 1.95, 95% CI 1.89-2.00) and women in their fifth pregnancy (OR 1.26, 95% CI 1.13-1.41) compared to women in their second pregnancy. Similar results were seen for spontaneous preterm birth < 32 and < 28 weeks.

Conclusion: Our data show an independent association between nulliparity and spontaneous preterm birth < 37, < 32 and < 28 weeks. Furthermore, we observed an increased risk for spontaneous preterm birth in women in their fifth pregnancy, with highest risk for preterm birth at early gestational age.
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http://dx.doi.org/10.1186/s12884-020-02940-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175552PMC
April 2020

Trends in preterm birth in singleton and multiple gestations in the Netherlands 2008-2015: A population-based study.

Eur J Obstet Gynecol Reprod Biol 2020 Apr 14;247:111-115. Epub 2020 Feb 14.

Department of Obstetrics & Gynaecology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address:

Objective: Preterm birth is the most important cause of perinatal morbidity and mortality. Over the past years several preventive measures have been studied and implemented. Preterm birth percentage in 2015 in the Netherlands was 6.9 %, according to data from the European Peristat project, reporting on perinatal health in Europe. Various preventive measures might have influenced the incidence and outcome of preterm birth. Our aim was to give an overview of the trends in preterm births for both singleton and multiple gestations in the Netherlands in order to guide future research.

Study Design: We studied a nationwide cohort including both singleton and multiple gestations without congenital anomalies between 2008 and 2015. Outcomes were total preterm birth (defined as birth before 37 weeks of gestation), spontaneous and iatrogenic preterm birth < 37 weeks, spontaneous and iatrogenic preterm birth percentages between 34-36 weeks, 32-34 weeks, 28-31 weeks and ≤ 27 weeks using a moving average technique. Trend analysis was performed using the Cochran Armitage test. Singleton and multiple gestations were analyzed separately.

Results: Our final study population comprised 1,303.786 women with a singleton and 44,951 women with a multiple pregnancy. Preterm birth < 37 weeks in singletons decreased from 5.6 % in 2008 to 5.3 % in 2015 (P < 0.0001), in both spontaneous and iatrogenic preterm birth. Preterm birth ≤ 27 weeks increased from 0.40 % to 0.45 % (P for trend <0.0001). The number of multiple gestations decreased over the years, as well as the percentage of multiples conceived through IVF/ICSI. There was an increase in total and iatrogenic preterm birth < 37 weeks from 36.7-38.2% (P < 0.0001) in multiples. The number of multiples <32 decreased, in both the spontaneous and iatrogenic group.

Conclusion: In the Netherlands preterm birth risk in singletons decreased between 2008 and 2015 but an increase was noted in preterm birth ≤ 27 weeks. In multiples the total preterm birth risk increased, due to an increase in indicated preterm birth.
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http://dx.doi.org/10.1016/j.ejogrb.2020.02.021DOI Listing
April 2020

Neonatal developmental and behavioral outcomes of immediate delivery versus expectant monitoring in mild hypertensive disorders of pregnancy: 5-year outcomes of the HYPITAT II trial.

Eur J Obstet Gynecol Reprod Biol 2020 Jan 6;244:172-179. Epub 2019 Nov 6.

Epidemiology, University Medical Centre Groningen, Groningen, The Netherlands.

Objective: To compare effects of immediate delivery vs expectant monitoring on neurodevelopmental and behavioral outcomes at 5 years of age in offspring of women with mild late preterm hypertensive disorders.

Study Design: We studied children born during the HYPITAT-II trial, in which 704 women with a hypertensive disorder between 34 and 37 weeks of gestation were randomized to immediate delivery or expectant monitoring. Participating women were asked to complete the Ages and Stages Questionnaire (ASQ) for developmental outcome and the Child Behavior Checklist (CBCL) for behavioral problems when their child was 5 years old. Outcomes were dichotomized and analyzed by logistic regression analysis. We also assessed factors influencing development and behavior at both 2 and 5 years after a hypertensive pregnancy.

Results: Five years after the original study 322(46%) women were contacted for follow-up, of whom 148 (46%) responded. In the delivery group 22%(n = 14/65) of the children had an abnormal ASQ score compared to 21% (n = 13/62) in the expectant monitoring group (p = 0.9). Abnormal CBCL-scores were found in 19% (n = 14/72) of the children in the delivery group versus in 27% (n = 20/75) in the expectant monitoring group (p = 0.3). The main predictor of development and behavior at 2 and 5 years was fetal growth restriction (for abnormal development OR 2.1, CI 1.0-4.4; for behavior problems OR 2.2, CI 1.1-5.5). Higher maternal education decreased abnormal behavior outcomes (OR 0.5, CI 0.2-0.9) and a similar tendency was observed for developmental problems (OR 0.6, CI 0.3 - 1.1).

Conclusion: We did not find different developmental and behavior outcomes at 5 years of age between a management policy of immediate delivery and expectant management in preterm hypertensive disorders. The increased risk of developmental delay at 2 years of age after immediate delivery, we found in the 2 year follow up study, did not persist at 5 years of age.
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http://dx.doi.org/10.1016/j.ejogrb.2019.11.001DOI Listing
January 2020

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

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

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

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

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

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

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

Recurrence and prediction of abnormal uterine bleeding and re-intervention after initial hysteroscopic treatment: a retrospective cohort study.

Arch Gynecol Obstet 2019 12 15;300(6):1651-1657. Epub 2019 Nov 15.

Department of Obstetrics and Gynaecology, Zuyderland Medical Center, Henri Dunantstraat 5, 6419 PC, Heerlen, The Netherlands.

Purpose: To estimate the incidence of recurrence of complaints and repeated interventions after hysteroscopic treatment for abnormal uterine bleeding in premenopausal women and to determine potential predictors for re-intervention.

Methods: This is a retrospective cohort study in two secondary care centers in the Netherlands. We included 313 premenopausal women who underwent hysteroscopy for complaints of abnormal uterine bleeding and who had intrauterine pathology visualized at ultrasound. The intrauterine structure was hysteroscopically removed. These women were compared with women who had a hysteroscopy for abnormal uterine bleeding, but in whom hysteroscopy showed no abnormalities. We used Chi-squared test for categorical variables and independent-samples T test for continuous variables. p Values less than 0.05 were considered to indicate statistical significance.

Results: In total, 262 women had intrauterine pathology removed at hysteroscopy; 136 (52%) women had recurrence of complaints, while 101 women (39%) underwent re-intervention. Heavy menstrual bleeding at baseline and multiparity were predictive factors for recurrence of abnormal uterine bleeding and re-intervention. In the 51 women with abnormal uterine bleeding in whom hysteroscopy showed no intrauterine abnormality, 29 women (60%) had recurrence of complaints and 12 (24%) a re-intervention.

Conclusion: In premenopausal women with abnormal uterine bleeding, treatment of intrauterine pathology often does not reduce the complaints, thus questioning the effectiveness of hysteroscopic removal of these structures.
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http://dx.doi.org/10.1007/s00404-019-05380-wDOI Listing
December 2019

The predictive capacity of uterine artery Doppler for preterm birth-A cohort study.

Acta Obstet Gynecol Scand 2020 04 19;99(4):494-502. Epub 2020 Jan 19.

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

Introduction: Mid-trimester uterine artery resistance measured with Doppler sonography is predictive for iatrogenic preterm birth. In view of the emerging association between hypertensive disease in pregnancy and spontaneous preterm birth, we hypothesized that uterine artery resistance could also predict spontaneous preterm birth.

Material And Methods: We performed a cohort study of women with singleton pregnancies. Uterine artery resistance was routinely measured at the 18-22 weeks anomaly scan. Pregnancies complicated by congenital anomalies or intrauterine fetal death were excluded. We analyzed if the waveform of the uterine artery (no notch, unilateral notch or bilateral notch) was predictive for spontaneous and iatrogenic preterm birth, defined as delivery before 37 weeks of gestation. Furthermore, we assessed whether the uterine artery pulsatility index was associated with the risk of preterm birth.

Results: Between January 2009 and December 2016 we collected uterine Doppler indices and relevant outcome data in 4521 women. Mean gestational age at measurement was 19  weeks. There were 137 (3.0%) women with a bilateral and 213 (4.7%) with a unilateral notch. Mean gestational age at birth was 38  weeks. Spontaneous and iatrogenic preterm birth rates were 5.7% and 4.9%, respectively. Mean uterine artery resistance was 1.12 in the spontaneous preterm birth group compared with 1.04 in the term group (P = 0.004) The risk of preterm birth was increased with high uterine artery resistance (OR 2.9 per unit; 95% CI 2.4-3.9). Prevalence of spontaneous preterm birth increased from 5.5% in women without a notch in the uterine arteries to 8.0% in women with a unilateral notch and 8.0% in women with a bilateral notch. For iatrogenic preterm birth, these rates were 3.9%, 13.6% and 23.4%, respectively. Likelihood ratios for the prediction of spontaneous preterm birth were 1.6 (95% CI 1.0-2.6) and 1.9 (95% CI 1.0-3.5) for unilateral and bilateral notches, respectively, and for iatrogenic preterm birth they were 3.6 (95% CI 2.5-5.2) and 6.8 (95% CI 4.7-9.9) for unilateral and bilateral notches, respectively. Of all women with bilateral notching, 31.4% delivered preterm.

Conclusions: Mid-trimester uterine artery resistance measured at 18-22 weeks of gestation is a weak predictor of spontaneous preterm birth.
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http://dx.doi.org/10.1111/aogs.13770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155020PMC
April 2020

Medical and Surgical Treatment of Reproductive Outcomes in Polycystic Ovary Syndrome: An Overview of Systematic Reviews.

Int J Fertil Steril 2020 Jan 11;13(4):257-270. Epub 2019 Nov 11.

Robinson Research Institute, Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, Australia.

Polycystic ovary syndrome (PCOS) is a common, complex condition that affects up to 18% of reproductiveaged women, causing reproductive, metabolic and psychological dysfunctions. We performed an overview and appraisal of methodological quality of systematic reviews that assessed medical and surgical treatments for reproductive outcomes in women with PCOS. Databases (MEDLINE, EMBASE, CINAHL PLUS and PROSPERO) were searched on the 15th of September 2017. We included any systematic review that assessed the effect of medical or surgical management of PCOS on reproductive, pregnancy and neonatal outcomes. Eligibility assessment, data extraction and quality assessment by the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool were performed in duplicate. We identified 53 reviews comprising 44 reviews included in this overview; the majority were moderate to high quality. In unselected women with PCOS, letrozole was associated with a higher live birth rate than clomiphene citrate (CC), while CC was better than metformin or placebo. In women with CC-resistant PCOS, gonadotrophins were associated with a higher live birth rate than CC plus metformin, which was better than laparoscopic ovarian drilling (LOD). LOD was associated with lower multiple pregnancy rates than other medical treatments. In women with PCOS undergoing fertilization/intracytoplasmic sperm injection (IVF/ICSI), the addition of metformin to gonadotrophins resulted in less ovarian hyperstimulation syndrome (OHSS), and higher pregnancy and live birth rates than gonadotrophins alone. Gonadotrophin releasing hormone (GnRH) antagonist was associated with less OHSS, gonadotrophin units and shorter stimulation length than GnRH agonist. Letrozole appears to be a good first line treatment and gonadotrophins, as a second line treatment, for anovulatory women with PCOS. LOD results in lower multiple pregnancy rates. However, due to the heterogeneous nature of the included populations of women with PCOS, further larger scale trials are needed with more precise assessment of treatments according to heterogeneous variants of PCOS.
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http://dx.doi.org/10.22074/ijfs.2020.5608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875858PMC
January 2020

Gestational weight gain outside the Institute of Medicine recommendations and adverse pregnancy outcomes: analysis using individual participant data from randomised trials.

BMC Pregnancy Childbirth 2019 Sep 2;19(1):322. Epub 2019 Sep 2.

Women's Health Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Background: High Body Mass Index (BMI) and gestational weight gain (GWG) affect an increasing number of pregnancies. The Institute of Medicine (IOM) has issued recommendations on the optimal GWG for women according to their pre-pregnancy BMI (healthy, overweight or obese). It has been shown that pregnant women rarely met the recommendations; however, it is unclear by how much. Previous studies also adjusted the analyses for various women's characteristics making their comparison challenging.

Methods: We analysed individual participant data (IPD) of healthy women with a singleton pregnancy and a BMI of 18.5 kg/m or more from the control arms of 36 randomised trials (16 countries). Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were used to describe the association between GWG outside (above or below) the IOM recommendations (2009) and risks of caesarean section, preterm birth, and large or small for gestational age (LGA or SGA) infants. The association was examined overall, within the BMI categories and by quartile of GWG departure from the IOM recommendations. We obtained aOR using mixed-effects logistic regression, accounting for the within-study clustering and a priori identified characteristics.

Results: Out of 4429 women (from 33 trials) meeting the inclusion criteria, two thirds gained weight outside the IOM recommendations (1646 above; 1291 below). The median GWG outside the IOM recommendations was 3.1 kg above and 2.7 kg below. In comparison to GWG within the IOM recommendations, GWG above was associated with increased odds of caesarean section (aOR 1.50; 95%CI 1.25, 1.80), LGA (2.00; 1.58, 2.54), and reduced odds of SGA (0.66; 0.50, 0.87); no significant effect on preterm birth was detected. The relationship between GWG below the IOM recommendation and caesarean section or LGA was inconclusive; however, the odds of preterm birth (1.94; 1.31, 2.28) and SGA (1.52; 1.18, 1.96) were increased.

Conclusions: Consistently with previous findings, adherence to the IOM recommendations seem to help achieve better pregnancy outcomes. Nevertheless, even in the context of clinical trials, women find it difficult to adhere to them. Further research should focus on identifying ways of achieving a healthier GWG as defined by the IOM recommendations.
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http://dx.doi.org/10.1186/s12884-019-2472-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719382PMC
September 2019

Evidence-Based Prevention of Preeclampsia: Commonly Asked Questions in Clinical Practice.

J Pregnancy 2019 1;2019:2675101. Epub 2019 Aug 1.

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

In this review, we discuss the recent literature regarding the prevention of preeclampsia and aim to answer common questions that arise in the routine antenatal care of pregnant women. Prescription of low-dose aspirin for high-risk patients has been shown to reduce the risk of preeclampsia (PE). A daily dose between 100 and 150 mg taken in the evening should be initiated prior to 16 weeks of gestation and can be continued until delivery. Calcium supplementation seems to be advantageous but currently it is only considered for patients with poor dietary intake and high risk for PE. Recent data about heparin are still conflicting, and therefore, heparin can currently not be recommended in the prevention of PE.
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http://dx.doi.org/10.1155/2019/2675101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699262PMC
June 2020

Association between fetal sex, birthweight percentile and adverse pregnancy outcome.

Acta Obstet Gynecol Scand 2020 01 30;99(1):48-58. Epub 2019 Aug 30.

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

Introduction: The objective was to evaluate the association between fetal sex and adverse pregnancy outcome, while correcting for fetal growth and gestational age at delivery.

Material And Methods: Data from the Netherlands Perinatal Registry (1999-2010) were used. The study population comprised all white European women with a singleton delivery between 25 and 42  weeks of gestation. Fetuses with structural or chromosomal abnormalities were excluded. Outcomes were antepartum death, intrapartum/neonatal death (from onset of labor until 28 days after birth), perinatal death (antepartum death or intrapartum/neonatal death), a composite of neonatal morbidity (including infant respiratory distress syndrome, sepsis, necrotizing enterocolitis, meconium aspiration, persistent pulmonary hypertension of the newborn, periventricular leukomalacia, Apgar score <7 at 5 minutes, and intracranial hemorrhage) and a composite adverse neonatal outcome (perinatal death or neonatal morbidity). Outcomes were expressed stratified by birthweight percentile (p90 [large for gestation]) and gestational age at delivery (25 -27 , 28 -31 , 32 -36 , 37 -42 weeks). The association between fetal sex and outcome was assessed using the fetus at risk approach.

Results: We studied 1 742 831 pregnant women. We found no increased risk of antepartum, intrapartum/neonatal and perinatal death in normal weight and large-for-gestation males born after 28 weeks compared with females. We found an increased risk of antepartum death among small-for-gestation males born after 28 weeks (relative risk [RR] 1.16-1.40). All males born after 32  weeks of gestation suffered more neonatal morbidity than females regardless of birthweight percentile (RR 1.07-1.34). Infant respiratory distress syndrome, sepsis, persistent pulmonary hypertension of the newborn, Apgar score <7 at 5 minutes, and intracranial hemorrhage all occurred more often in males than in females.

Conclusions: Small-for-gestation males have an increased risk of antepartum death and all males born after 32  weeks of gestation have an increased risk of neonatal morbidity compared with females. In contrast to findings in previous studies we found no increased risk of antepartum, intrapartum/neonatal or perinatal death in normal weight and large-for-gestation males born after 28+0 weeks.
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http://dx.doi.org/10.1111/aogs.13709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973256PMC
January 2020

Tubal flushing with oil- or water-based contrast medium: can we identify markers that indicate treatment benefit?

Hum Reprod Open 2019 18;2019(3):hoz015. Epub 2019 Jul 18.

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

Study Question: Can we identify patient characteristics that distinguish which ovulatory infertile women undergoing hysterosalpingography (HSG) benefit more or less from flushing with oil-based contrast medium compared to water-based contrast medium?

Summary Answer: In ovulatory infertile women, HSG with oil-based contrast medium resulted in higher 6-month ongoing pregnancy and live birth rates as compared to HSG with water-based contrast medium and this treatment effect was independent of characteristics of the couple.

What Is Known Already: We recently showed that in infertile women undergoing HSG, flushing with oil-based contrast medium resulted in more ongoing pregnancies than flushing with water-based contrast medium.

Study Design Size Duration: We used data from our randomized clinical trial (RCT) in which 1,119 ovulatory infertile women undergoing HSG during fertility work-up were randomized for use of oil-based ( = 557) or water-based ( = 562) contrast medium.

Participants/materials Setting Methods: We built logistic regression models to predict ongoing pregnancy and live birth (secondary outcome) as a function of the specific contrast, the specific marker, and marker-by-contrast-interaction. Markers considered were female age, maternal ethnicity, female smoking, body mass index (BMI), duration of infertility, infertility being primary or secondary, sperm quality, and previous appendectomy.

Main Results And The Role Of Chance: The 6-month ongoing pregnancy rates in the overall population were 39.7% after use of oil-based contrast versus 29.1% after use of water-based contrast medium [relative risk (RR), 1.37; 95% confidence interval (CI), 1.16-1.61;  < 0.001]. Among the studied baseline characteristics, BMI ( = 0.002) and semen volume ( = 0.02) were statistically significant prognosticators. The treatment effect of oil-based contrast was stronger in women with a BMI ≤30 kg/m [RR, 1.54; 95% CI, 1.23-1.92;  = 0.002], and in women whose partner had a semen volume >3 ml [RR, 1.77; 95% CI, 1.28-2.46;  = 0.02]. Also, in women who smoked, the treatment effect of flushing with oil was stronger, but this interaction did not reach statistical significance ( = 0.066). We found no positive effect of oil-based contrast in obese women. We found similar but weaker associations for live birth, which was probably due to lower number of events resulting in less power.

Limitations Reasons For Caution: The RCT was restricted to infertile ovulatory women younger than 39 years of age without endocrinological disorders and at low risk for tubal pathology. Our results should not be generalized to infertile women who do not share these features.

Wider Implications Of The Findings: All infertile, ovulatory women younger than 39 years with a low risk for tubal pathology will benefit from an HSG with oil-based contrast; therefore, this should be offered to them after fertility work-up.

Study Funding/competing Interests: The original H2Oil RCT was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The study displayed in this paper was funded by an unconditional research grant from Guerbet. B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). K.D. reports consultancy for Guerbet, during the conduct of the study, and also reports research grants from Guerbet. C.B.L. reports grants from Guerbet, during the conduct of the study, and grants from Ferring, grants from Merck, and personal fees from Ferring, outside the submitted work. P.H. reports grants from Guerbet, during the conduct of the study, and grants from Ferring and Merck, outside the submitted work. V.M. reports receiving travel and speakers fee as well as research grants from Guerbet. B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA, and Guerbet, and research grants from Guerbet and Merck. The other authors have no conflict of interest to declare.

Trial Registration Number: NTR 3270 www.trialregister.nl.

Trial Registration Date: 1 February 2012.

Date Of First Patient’s Enrolment: 3 February 2012.
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http://dx.doi.org/10.1093/hropen/hoz015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6638263PMC
July 2019

Postnatal Catch-Up Growth After Suspected Fetal Growth Restriction at Term.

Front Endocrinol (Lausanne) 2019 20;10:274. Epub 2019 Jun 20.

Department of Obstetrics, University Medical Centre Groningen, Groningen, Netherlands.

The aim of this study was to study growth patterns of children born after suspected fetal growth restriction (FGR) at term and to compare the effect of induction of labor (IoL) and expectant management (EM), also in relation to neurodevelopmental and behavioral outcome at age 2. We performed a 2 years' follow-up of growth of children included in the Disproportionate Intrauterine Growth Restriction Trial at Term (DIGITAT) study, a Randomized Controlled Trial (RCT) comparing IoL with EM in pregnancies with suspected FGR at term. We collected data on child growth until the age of 2 years. Standard deviation scores (SDSs) for height and weight were calculated at different ages. We assessed the effects of IoL compared with EM and the effects of a birth weight below or above the 3rd or 10th centile on catch-up growth. Target height SDSs were calculated using the height of both parents. We found a significant increase in SDS in the first 2 years. Children born after EM showed more catch-up growth in the first month [height: mean difference -0.7 (95% CI: 0.2; 1.3)] and weight [mean difference -0.5 (95% CI: 0.3; 0.7)]. Children born with a birth weight below the 3rd and 10th centiles showed more catch-up growth after 1 year [mean difference -0.8 SDS (95% CI: -1.1; -0.5)] and after 2 years [mean difference -0.7 SDS (95% CI: -1.2; -0.2)] as compared to children with a birth weight above the 3rd and 10th centiles. SDS at birth had the strongest effect on adverse neurodevelopmental outcome at 2 years of age. After FGR at term, postnatal catch-up growth is generally present and associated with the degree of FGR. Obstetric management in FGR influences postnatal growth. Longer-term follow-up is therefore needed and should be directed at growth and physical health. www.ClinicalTrials.gov, identifier SRCTN10363217.
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http://dx.doi.org/10.3389/fendo.2019.00274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598620PMC
June 2019

Incidence and recurrence rate of postpartum hemorrhage and manual removal of the placenta: A longitudinal linked national cohort study in The Netherlands.

Eur J Obstet Gynecol Reprod Biol 2019 Jul 19;238:114-119. Epub 2019 May 19.

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

Objective: We studied the incidence of postpartum hemorrhage and manual removal of the placenta and their recurrence rate in a subsequent pregnancy. We hypothesized that the risk of recurrence was dependent on the gestational age at first birth and whether or not a manual removal of the placenta was necessary. Knowledge on this subject can potentially improve counselling, prevention and management in obstetric care for women at risk for PPH or identify women at low risk for recurrence.

Study Design: This was a retrospective national cohort study consisting of women with two consecutive singleton deliveries between 1999 and 2009 in the Netherlands. A longitudinal linked national cohort with information on subsequent singleton deliveries in the Netherlands was used. Main outcome measures were: postpartum hemorrhage (defined as ≥1000 mL after vaginal delivery or Caesarean section) and manual removal of the placenta. We calculated incidence and recurrence rates of postpartum hemorrhage and manual removal of the placenta for all women and stratified by gestational age.

Results: After application of in- and exclusion criteria 359 737 women were studied. A total of 5.4% women experienced postpartum hemorrhage in the first pregnancy and 2.7% of women had a manual removal of the placenta. The risk of postpartum hemorrhage in a subsequent pregnancy was significantly higher in women with a history of postpartum hemorrhage compared to women without a previous postpartum hemorrhage (18% vs 3.9%, adjusted odds ratio 4.5; 95% confidence interval 4.3-4.7). The risk of manual removal of the placenta in the second pregnancy was only 1.4% in women without a previous manual removal compared to 17% of women with a previous manual removal of the placenta. Women with a manual removal of the placenta in the first pregnancy between 32 and 37 weeks were most at risk for recurrence (adjusted odds ratio 8.9; 95% confidence interval 7.2-11).

Conclusion: Women with a previous delivery complicated by postpartum hemorrhage or manual removal of the placenta are at increased risk for recurrence. The magnitude of this risk is highest in women with deliveries beyond 32 weeks in the first pregnancy.
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http://dx.doi.org/10.1016/j.ejogrb.2019.05.022DOI Listing
July 2019

Prenatal screening for pre-eclampsia: Frequently asked questions.

Aust N Z J Obstet Gynaecol 2019 08 22;59(4):477-483. Epub 2019 May 22.

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

The current approach to screening for pre-eclampsia is based on guidelines that rely on medical and obstetric history in early pregnancy to select a high-risk group that might benefit from low-dose aspirin. However, combined screening tests with the addition of biophysical and biochemical measurements have shown significantly better detection rates for preterm pre-eclampsia. Furthermore, the administration of aspirin for the 10% screen-positive group can lead to a significant reduction in severe and preterm forms of pre-eclampsia. This review aims to answer frequently asked questions related to the clinical implementation of screening and the management of screening results.
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http://dx.doi.org/10.1111/ajo.12982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767595PMC
August 2019

Reply to: Cesarean scar defect-A rising concern or a physiological healing process?

Acta Obstet Gynecol Scand 2019 08 20;98(8):1078-1079. Epub 2019 May 20.

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

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http://dx.doi.org/10.1111/aogs.13634DOI Listing
August 2019

Child outcomes after placement of a cervical pessary in women with a multiple pregnancy: A 4-year follow-up of the ProTWIN trial.

Acta Obstet Gynecol Scand 2019 10 18;98(10):1292-1300. Epub 2019 Jun 18.

Department of Obstetrics and Gynecology, Amsterdam UMC - Location AMC, Amsterdam, The Netherlands.

Introduction: The ProTWIN trial previously showed no beneficial effect of treatment with a cervical pessary vs usual care to prevent preterm birth in women with a multiple pregnancy. However, in women with a midtrimester short cervix (<38 mm), pessary did reduce the composite outcome of neonatal morbidity and mortality. This follow-up study evaluates the long-term outcomes of all children born to mothers who participated in the ProTWIN trial at 4 years of age.

Material And Methods: Parents received the Ages and Stages Questionnaire, Strength and Difficulties Questionnaire and a health questionnaire. All questionnaires were reported separately and as a combined outcome (abnormal child outcome). A linear mixed effects model was used to adjust for correlated data in twins and correction for confounders was performed. In exploratory analysis, a composite outcome of death or survival with abnormal child outcome was used by combining extrapolated data on child outcome with survival data. All data were analyzed for the total group and the subgroup of women with midtrimester short cervix.

Results: Of the original 813 women of the ProTWIN trial, we approached 579, of whom 258 participated (45%) in follow-up. We received questionnaires of 514 children (281 pessary vs 233 control), with 119 children in the subgroup of women with midtrimester short cervix. An abnormal child outcome was found in 23% in the pessary group vs 16% in the control group (odds ratio 1.58; 95% confidence interval 0.94-2.65). In exploratory analysis with extrapolated data on child outcome (n = 815), no difference in abnormal child outcome was seen between the pessary and control group. In the subgroup of women with a short cervix (n = 268), this composite outcome indicated a favorable outcome for children born to mothers with pessary.

Conclusions: In women with a multiple pregnancy, the use of a cervical pessary did not improve development, behavior or physical outcomes of the surviving children at age 4.
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http://dx.doi.org/10.1111/aogs.13630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900136PMC
October 2019

Large-for-gestational-age fetuses have an increased risk for spontaneous preterm birth.

J Perinatol 2019 08 2;39(8):1050-1056. Epub 2019 Apr 2.

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

Objective: Our aim was to investigate the association between large-for-gestational-age and the risk of spontaneous preterm birth.

Study Design: We studied nulliparous women with a singleton gestation using data from the Dutch perinatal registry from 1999 to 2010. Neonates were categorized according to the Hadlock fetal weight standard, into 10th to 90th percentile, 90th to 97th percentile, or above 97th percentile. Outcomes were preterm birth <37 weeks and preterm birth between 25-27 weeks, 28-30 weeks, 31-33 weeks, and 34-36 weeks.

Results: We included 547,418 women. The number of spontaneous preterm births <37 weeks was significantly increased in the large-for-gestational-age group ( > p97) compared with fetuses with a normal growth (p10-p90) (11.3% vs. 7.3%, odds ratio (OR) 1.8; 95% CI 1.7-1.9). The same results were found when limiting analyses to women with certain pregnancy duration (after in vitro fertilization).

Conclusion: Large-for-gestational-age increases the risk of spontaneous preterm delivery from 25 weeks of gestation onwards.
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http://dx.doi.org/10.1038/s41372-019-0361-6DOI Listing
August 2019

Neonatal developmental and behavioral outcomes of immediate delivery versus expectant monitoring in mild hypertensive disorders of pregnancy: 2-year outcomes of the HYPITAT-II trial.

Am J Obstet Gynecol 2019 08 30;221(2):154.e1-154.e11. Epub 2019 Mar 30.

Epidemiology, University Medical Centre Groningen, Groningen, The Netherlands.

Background: Management of preterm hypertensive disorders remains a clinical dilemma. The maternal benefits of delivery need to be weighed against the adverse neonatal consequences of preterm birth. Long-term consequences of obstetric management in offspring of women with hypertensive disorders in preterm pregnancy are largely unknown. We report child neurodevelopmental and behavioral outcomes at 2 years after the Hypertension and Preeclampsia Intervention Trial at near Term (HYPITAT-II) trial, which compared immediate delivery versus expectant monitoring in mild late preterm hypertensive disorders of pregnancy.

Objective: To compare effects of immediate delivery vs expectant monitoring on neurodevelopmental and behavioral outcomes at 2 years of age in offspring of women with mild late preterm hypertensive disorders.

Materials And Methods: We studied children born in the HYPITAT-II trial, a study in which women (n = 704) with hypertensive disorders of pregnancy who were between 34 and 37 weeks' gestation were randomized to immediate delivery or expectant monitoring. Participating women were asked to complete the Ages and Stages Questionnaire for developmental outcome and the Child Behavior Checklist for behavioral problems when their toddlers were 2 years old.

Results: We approached 545 of 704 randomized women (77%); 330 of 545 (61%) returned the questionnaires. In the immediate delivery group, 45 of 162 infants (28%) had an abnormal Ages and Stages Questionnaire score compared to 27 of 148 (18%) in the expectant monitoring group (risk difference, 9.6%; 95% CI, 0.3-18.0%); P = .045. In the pregnancies (n = 94) that delivered before reaching 36 weeks, 27% (n = 25) had an abnormal Ages and Stages Questionnaire score compared to 22% (n = 47) when delivered after 36 weeks (odds ratio, 0.77; confidence interval, 0.44-1.34). An abnormal Child Behavior Checklist outcome was found in 31 of 175 (18%) in the delivery group vs 24 of 166 (15%) in the expectant monitoring group (risk difference, 3.2%; 95% CI, -4.6% to 11.0%). After correction for maternal education, management strategy remained an independent predictor of abnormal Ages and Stages Questionnaire score (odds ratio, 0.48; confidence interval, 0.24 to -0.96, P = .03). In multivariable analyses, low birth weight, low maternal education, and immediate delivery policy were all significantly associated with an abnormal Ages and Stages Questionnaire score.

Conclusion: In this study, we found that early delivery in women with late preterm hypertensive disorders is associated with poorer neurodevelopmental outcomes in their children at 2 years of age. These findings indicate an increased risk of developmental delay after early delivery compared to expectant monitoring. This follow-up study underlines the conclusion of the original HYPITAT-II study that, until the clinical situation deteriorates, expectant monitoring remains the most appropriate management strategy in the light of short- and long-term neonatal outcomes in women with preterm hypertensive disorders.
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http://dx.doi.org/10.1016/j.ajog.2019.03.024DOI Listing
August 2019
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