Ben Willem J. Mol

Pessary for prevention of preterm birth in twin pregnancy with short cervix: 3‐year follow‐up study

A recent randomized clinical trial (ProTWIN) showed that a cervical pessary prevented preterm birth and improved neonatal outcome in women with multiple pregnancy and cervical length (CL)u2009<u200938u2009mm. In this follow‐up study, the long‐term developmental outcome of these children was evaluated at 3u2009years corrected age.

Perinatal outcomes according to the mode of delivery in women with a triplet pregnancy in The Netherlands

Abstract Objective: In women with a triplet pregnancy, there is debate on the preferred mode of delivery. We performed a nationwide cohort study to assess the impact of mode of delivery on perinatal outcome in women with a triplet pregnancy. Methods: Nationwide cohort study on women with a triplet pregnancy who delivered between 26u2009+u20090 and 40u2009+u20090 weeks of gestation in the years 1999–2008. We compared perinatal outcomes according to the intended mode of delivery and the actual mode of delivery. Outcome measures were perinatal mortality and neonatal morbidity. Perinatal outcomes were analyzed taking into account the dependency between the children of the same triplet pregnancy (“any mortality” and “any morbidity”) and were also analyzed separately per child. Results: We identified 386 women with a triplet pregnancy in the study period. Mean gestational age at delivery was 33.1 weeks (SD 2.5 weeks; range 26.0–40.0 weeks). Perinatal mortality was 2.3% for women with a planned caesarean section and 2.4% in women with a planned vaginal delivery (aOR 0.37; 95% confidence interval (CI) 0.09–1.5) and neonatal morbidity was 26.0% versus 36.0%, (aOR 0.88; 95% CI 0.51–1.4) respectively. In the subgroup analyses according to gestational age and in the analysis of perinatal outcomes per child separately, there were also no large differences in perinatal outcomes. The same applied for perinatal outcomes according to the actual mode of delivery. Conclusion: In this large cohort study among women with a triplet pregnancy, caesarean delivery is not associated with reduced perinatal mortality and morbidity.

Does AMH relate to timing of menopause? Results of an Individual Patient Data meta- analysis.

ContextnAnti-Müllerian hormone based (AMH) age at menopause predictions remain cumbersome due to predictive inaccuracy.nnnObjectivenTo perform an Individual Patient Data (IPD) meta-analysis, regarding AMH based menopause prediction.nnnData sourcesnA systematic literature search was performed using PubMed, Embase and Cochrane databases.nnnStudy selectionnProspective cohort studies regarding menopause prediction using serum AMH levels were selected by consensus discussion.nnnData selectionnIndividual cases were included if experiencing a regular cycle at baseline. Exclusion criteria were hormone use and gynecological surgery.nnnData synthesisn2596 women were included, 1077 experienced menopause. A multivariable Cox regression analysis assessed time to menopause (TTM) using age and AMH. AMH predicted TTM, however, added value on top of age was poor (age alone C-statistic 84%; age + AMH HR 0.66 95% CI 0.61-0.71, C-statistic 86%). Moreover, the capacity of AMH to predict early (≤45 years) and late menopause (≥55 years) was assessed. An added effect of AMH was demonstrated for early menopause (age alone C-statistic 52%; age + AMH HR 0.33, 95% CI 0.24-0.45, C-statistic 80%). A Weibull regression model calculating individual age at menopause revealed that predictive inaccuracy remained present and increased with decreasing age at menopause. Lastly, a check of non-proportionality of the predictive effect of AMH demonstrated a reduced predictive effect with increasing age.nnnConclusionnAMH was a significant predictor of TTM and especially of time to early menopause. However, individual predictions of age at menopause demonstrated a limited precision, particularly when concerning early age at menopause, making clinical application troublesome.

Successful weight loss interventions before in vitro fertilization: fat chance?

Most expert opinions and guidelines indicate the necessity for weight loss before inxa0vitro fertilization (IVF) in women who are overweight or obese. This is based on the documented impact of obesity on pregnancy rates and pregnancy complications and the long-term impact on the child in natural conceptions. Some clinicians and authorities refuse to treat patients unless they are below a certain body mass index. In the past this advice has been hindered by a lack of opportunity for patients to join lifestyle programs and the high dropout failure before treatment. However, the ideal has remained in the search for effective methods for weight loss. New clinical trials have evaluated a lifestyle program before IVF treatment and compared the results with those who were merely given advice and allowed to proceed directly to other fertility treatments or IVF. No compelling evidence of the value of lifestyle intervention for weight loss on live-birth rates was gained from these well-conducted studies. The research and medical and ethical opinions may now favor moving to fertility treatment earlier than originally recommended for patients who are overweight or obese.

Personalized ovarian stimulation for assisted reproductive technology: study design considerations to move from hype to added value for patients

Although most medical treatments are designed for the average patient with a one-size-fits-all-approach, they may not benefit all. Better understanding of the function of genes, proteins, and metabolite, and of personal and environmental factors has led to a call for personalized medicine. Personalized reproductive medicine is still in its infancy, without clear guidance on treatment aspects that could be personalized and on trial design to evaluate personalized treatment effect and benefit-harm balance. While the rationale for a personalized approach often relies on retrospective analyses of large observational studies or real-world data, solid evidence of superiority of a personalized approach will come from randomized trials comparing outcomes and safety between a personalized and one-size-fits-all strategy. A more efficient, targeted randomized trial design may recruit only patients or couples for which the personalized approach would differ from the previous, standard approach. Multiple monocenter studies using the same study protocol (allowing future meta-analysis) might reduce the major center effect associated with multicenter studies. In certain cases, single-arm observational studies can generate the necessary evidence for a personalized approach. This review describes each of the main segments of patient care in assisted reproductive technologies treatment, addressing which aspects could be personalized, emphasizing current evidence and relevant study design.

Ovulation induction and intrauterine insemination in infertile women with polycystic ovary syndrome: A comparison of drugs

OBJECTIVEnTo study the effectiveness of different ovulation induction protocols in infertile women with polycystic ovary syndrome (PCOS) undergoing intrauterine insemination (IUI).nnnDESIGNnRetrospective cohort study.nnnPATIENTSnInfertile women with PCOS undergoing IUI had ovulation induced with clomiphene citrate (CC), letrozole, or gonadotropins.nnnMAIN OUTCOME MEASUREnLive birth and multiple pregnancy rates.nnnRESULTSnWe performed 1068 IUI cycles in 765 couples. Live birth rates were comparable in CC-stimulated cycles (13.9%), letrozole-stimulated cycles (13.5%, OR 0.96 [95% CI, 0.63, 1.47]), and gonadotropins-stimulated cycles (13.2%, OR 0.94[95% CI, 0.62, 1.43]). Multiple pregnancy rates were 8.3%, 4.1% (OR 0.47 [95% CI, 0.09, 2.42]), and 3.3% (OR 0.34 [95% CI, 0.07, 1.95]) in CC, letrozole and gonadotropins stimulated cycles, respectively. Compared to CC, letrozole generated more often mono-follicular growth (75.9% versus 67.0%; OR 1.55 [95% CI, 1.11, 2.15]) but not more often after gonadotropins (72.9%, OR 1.17 [95% CI, 0.82, 1.66]. Cycles with multi-follicular growth did not result in statistically higher live birth rates than cycles with mono-follicular growth (15.8% vs. 12.7%, OR 1.29 [95% CI 0.89, 1.89]), but more often in multiple pregnancies (15.5% versus 0.8%, OR 22.4 [95% CI, 2.8, 181.6]).nnnCONCLUSIONnIn women with PCOS undergoing stimulated IUI, CC, letrozole and gonadotropins were equally effective and safe. Since multi-follicular growth increased the multiple pregnancy rates without increasing the overall live birth rate, ovulation induction would strictly aim for mono-follicular growth. Since letrozole had the highest mono-follicular growth rate, we recommend this drug as the treatment of first choice in infertile women undergoing ovulation induction and IUI.

Development and internal validation of a clinical prediction model for external cephalic version

OBJECTIVEnTo develop a prediction model for the chance of successful external cephalic version (ECV).nnnSTUDY DESIGNnThis is a secondary analysis of a multicenter, open-label randomized controlled trial that assessed the effectiveness of atosiban compared to fenoterol as uterine relaxant during ECV in women with a singleton fetus in breech presentation with a gestational age of 36 weeks or more. Potential predictors included maternal, pregnancy, fetal, and treatment characteristics and were recorded in all participants. Multivariable logistic regression analysis with a stepwise backward selection procedure was used to construct a prediction model for the occurrence of successful ECV. Model performance was assessed using calibration and discrimination.nnnRESULTSnWe included a total of 818 women with an overall ECV success rate of 37%. Ten predictive factors were identified with the stepwise selection procedure to be associated with a successful ECV: fenoterol as uterine relaxant, nulliparity, Caucasian ethnicity, gestational age at ECV, Amniotic Fluid Index, type of breech presentation, placental location, breech engagement, possibility to palpate the head and relaxation of the uterus. Our model showed good calibration and a good discriminative ability with a c-statistic of 0.78 (95% CI 0.75 to 0.81).nnnCONCLUSIONnPrediction of success of ECV seems feasible with a model showing good performance. This can be used in clinical practice after external validation.

Spontaneous and iatrogenic preterm birth rates among unselected women in three consecutive pregnancies

OBJECTIVEnTo assess the risk of sPTB and iPTB in women with three consecutive singleton pregnancies and the impact of the outcome of the 1st and 2nd pregnancy on the (recurrent) PTB risk in the 3rd pregnancy.nnnSTUDY DESIGNnA nationwide retrospective cohort study using the population based longitudinal linked dataset of the Netherlands. We included all nulliparous women with three consecutive singleton pregnancies ending between 22 and 44 weeks of gestation between 1999 and 2009. We excluded congenital abnormalities and stillbirths. We compared the incidence of sPTB and iPTB in the three pregnancies (<37, <34 and <30 weeks). Logistic regression analysis was performed to predict PTB in the 3rd pregnancy, adjusting for maternal age, fetal gender, socio-economic status, hypertension, interpregnancy interval, artificial reproductive technology, and small for gestational age. Analyses were also performed stratified by prior PTB subtype, gestational age and combined outcome of the 1st and 2nd pregnancy.nnnRESULTSnWe studied 52,978 women. PTB occurred in 7.0%, 3.7% and 3.4% in the 1st, 2nd and 3rd pregnancy, respectively. The outcome of the 2nd pregnancy is more predictive for PTB in the 3rd pregnancy then the outcome of the 1st pregnancy (sPTB aOR7.3 (95%CI 6.3-8.4) and iPTB (aOR 5.9 (95% CI 4.5-7.9) in 2nd pregnancy vs. sPTB aOR 3.0 (95% CI 2.6-3.4) and iPTB aOR 2.7 (95% CI 2.1-3.4) in the 1st pregnancy). In the prediction of sPTB in the 3rd pregnancy, sPTB in the 2nd pregnancy is most predictive (aOR8.2 (95% CI 7.1-9.6) and for prediction iPTB in the 3rd pregnancy, iPTB in the 2nd pregnancy is most predictive (aOR12.1 (95% CI 8.5-17.2).nnnCONCLUSIONnWe studied a population with three subsequent singleton deliveries within 10u202fyear. The incidence of PTB decreased with 50% from the 1st to the 2nd pregnancy, to then stay relative stable in the 3rd pregnancy. Compared to PTB in the 1st pregnancy, PTB in the 2nd pregnancy is more predictive for the occurrence of PTB in the 3rd pregnancy.

Correlation between neonatal outcomes of twins depends on the outcome: secondary analysis of twelve randomised controlled trials

To estimate the magnitude of the correlation between neonatal outcomes of twins and demonstrate how this information can be used in the design of randomised controlled trials (RCTs) in women with twin pregnancies.

Development of a core outcome set for trials on induction of labour: an international multistakeholder Delphi study

To develop a set of core outcomes to be minimally reported in trials on induction of labour.