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We describe vaginal microbiota, including Gardnerella species and sexually transmitted infections (STIs), during pregnancy and their associations with recurrent spontaneous preterm birth (sPTB). We performed a prospective cohort study in a tertiary referral centre in the Netherlands, among pregnant women with previous sPTB <34 weeks' gestation. Participants collected three vaginal swabs in the first and second trimester. Vaginal microbiota was profiled with 16S rDNA sequencing. Gardnerella species and STI's were tested with qPCR. Standard care was provided according to local protocol, including screening and treatment for bacterial vaginosis (BV), routine progesterone administration and screening for cervical length shortening. Of 154 participants, 26 (16.9 %) experienced recurrent sPTB <37 weeks' gestation. Microbiota composition was not associated with sPTB. During pregnancy, the share of Lactobacillus iners- dominated microbiota increased at the expense of diverse microbiota between the first and second trimester. This change coincided with treatment for BV, demonstrating a similar change in microbiota composition after treatment. In this cohort of high-risk women, we did not find an association between vaginal microbiota composition and recurrent sPTB. This should be interpreted with care, as these women were offered additional preventive therapies to reduce sPTB according to national guidelines including progesterone and BV treatment. The increase observed in L. iners dominated microbiota and the decrease in diverse microbiota mid-gestation was most likely mediated by BV treatment. Our findings suggest that in recurrent sPTB occurring despite several preventive therapies, the microbe-related etiologic contribution might be limited., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:R.C. Painter, P.H.M. Savelkoul reports financial support was provided by Amsterdam Reproduction and Development. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Introduction: Twin pregnancies have a high risk of extreme preterm birth (PTB) at less than 28 weeks of gestation, which is associated with increased risk of neonatal morbidity and mortality. Currently there is a lack of effective treatments for women with a twin pregnancy and a short cervix or cervical dilatation. A possible effective surgical method to reduce extreme PTB in twin pregnancies with an asymptomatic short cervix or dilatation at midpregnancy is the placement of a vaginal cerclage., Methods and Analysis: We designed two multicentre randomised trials involving eight hospitals in the Netherlands (sites in other countries may be added at a later date). Women older than 16 years with a twin pregnancy at <24 weeks of gestation and an asymptomatic short cervix of ≤25 mm or cervical dilatation will be randomly allocated (1:1) to both trials on vaginal cerclage and standard treatment according to the current Dutch Society of Obstetrics and Gynaecology guideline (no cerclage). Permuted blocks sized 2 and 4 will be used to minimise the risk of disbalance. The primary outcome measure is PTB of <28 weeks. Analyses will be by intention to treat. The first trial is to demonstrate a risk reduction from 25% to 10% in the short cervix group, for which 194 patients need to be recruited. The second trial is to demonstrate a risk reduction from 80% to 35% in the dilatation group and will recruit 44 women. A cost-effectiveness analysis will be performed from a societal perspective., Ethics and Dissemination: This study has been approved by the Research Ethics Committees in the Netherlands on 3/30/2023. Participants will be required to sign an informed consent form. The results will be presented at conferences and published in a peer-reviewed journal. Participants will be informed about the results., Trial Registration Number: ClinicalTrials.gov, NCT05968794., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The aim of this study is to investigate whether a history of spontaneous preterm birth (SPTB) is associated with maternal depressive and anxiety symptoms, or psychosocial distress in the fifth decade of life., Study Design: This is a secondary analysis of the PreCaris-study, a prospective observational study in which we included 350 women with a history of SPTB between 22 0/7 and 36 6/7 weeks of gestation and compared them to 115 women who had a term birth. Primary outcomes were the Depression and Anxiety scores measured using the Hospital Anxiety Depression Scale and Psychosocial distress assessed with the Distress Thermometer for Parents. Secondary outcomes were self-reported impact of the birth in daily life and psychosocial support after delivery., Results: After a median of 13 years after delivery, no significant differences were found in primary outcomes. Significantly more women with a history of SPTB reported that the birth still had impact in daily life; adjusted odds ratio: 2.46 (95% confidence interval: 1.35-4.48). A total of 57 (16.3%) women after SPTB reported to have needed professional psychosocial support after delivery but did not receive it. These women more often had a high Anxiety score ( p  = 0.030), psychosocial distress ( p  = 0.001), and influence of birth in daily life ( p  = 0.000)., Conclusion: There are no long-term effects on depressive and anxiety symptoms and psychosocial distress in women who experienced SPTB compared with women who had a full-term pregnancy. A significant part of the women who delivered preterm needed psychosocial support but did not receive it and were at higher risk of anxiety, psychosocial distress, and impact in daily life. We therefore recommend offering all women after SPTB psychosocial support after delivery., Key Points: · No long-term effects on depressive and anxiety symptoms and psychosocial distress after SPTB.. · A total of 16.3% of the cases needed professional psychosocial support after delivery but did not receive it.. · This subgroup was at higher risk of anxiety symptoms, psychosocial distress, and impact on daily life.., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Preterm birth presents a significant challenge in clinical obstetrics, requiring effective strategies to reduce associated mortality and morbidity risks. Tocolytic drugs, aimed at inhibiting uterine contractions, are a key aspect of addressing this challenge. Despite extensive research over many years, determining the most effective tocolytic agents remains a complex task, prompting better understanding of the underlying mechanisms of spontaneous preterm birth and recording meaningful outcome measures. This paper provides a comprehensive review of various obsolete and current tocolytic drug regimens that were instituted over the past century, examining both historical contexts and contemporary challenges in their development and adoption. The examination of historical debates and advancements highlights the complexity of introducing new therapies. While the search for effective tocolytics continues, questions arise regarding their actual benefits in obstetric care and the necessity for ongoing exploration. The presence of methodological limitations in current research emphasizes the importance of well-designed randomized controlled trials with robust endpoints and extended follow-up periods.In response to these complexities, the consideration of shifting towards prevention strategies aimed at addressing the root causes of preterm labor becomes more and more evident. This potential shift may offer a more effective approach than relying solely on tocolytics to delay labor initiation.Ultimately, effectively managing threatened preterm birth necessitates ongoing investigation, innovation, and a willingness to reassess strategies in pursuit of optimal outcomes for mothers, neonates, and long-term child health., Competing Interests: The authors have no conflicts of interest., (© 2024 The Authors.)

Objective: To compare the effectiveness of cervical pessary and vaginal progesterone in the prevention of adverse perinatal outcomes and preterm birth in pregnant women of singletons with no prior spontaneous preterm birth at less than 34 weeks' gestation and who have a short cervix of 35 mm or less., Design: Open label, multicentre, randomised, controlled trial., Setting: 20 hospitals and five obstetric ultrasound practices in the Netherlands., Participants: Women with a healthy singleton pregnancy and an asymptomatic short cervix of 35 mm or less between 18 and 22 weeks' gestation were eligible. Exclusion criteria were prior spontaneous preterm birth at less than 34 weeks, a cerclage in situ, maternal age of younger than 18 years, major congenital abnormalities, prior participation in this trial, vaginal blood loss, contractions, cervical length of less than 2 mm or cervical dilatation of 3 cm or more. Sample size was set at 628 participants., Interventions: 1:1 randomisation to an Arabin cervical pessary or vaginal progesterone 200 mg daily up to 36 weeks' of gestation or earlier in case of ruptured membranes, signs of infection, or preterm labour besides routine obstetric care., Main Outcome Measures: Primary outcome was a composite adverse perinatal outcome. Secondary outcomes were rates of (spontaneous) preterm birth at less than 28, 32, 34, and 37 weeks. A predefined subgroup analysis was planned for cervical length of 25 mm or less., Results: From 1 July 2014 to 31 March 2022, 635 participants were randomly assigned to pessary (n=315) or to progesterone (n=320). 612 were included in the intention to treat analysis. The composite adverse perinatal outcome occurred in 19 (6%) of 303 participants with a pessary versus 17 (6%) of 309 in the progesterone group (crude relative risk 1.1 (95% confidence interval (CI) 0.60 to 2.2)). The rates of spontaneous preterm birth were not significantly different between groups. In the subgroup of cervical length of 25 mm or less, spontaneous preterm birth at less than 28 weeks occurred more often after pessary than after progesterone (10/62 (16%) v 3/69 (4%), relative risk 3.7 (95% CI 1.1 to 12.9)) and adverse perinatal outcomes seemed more frequent in the pessary group (15/62 (24%) v 8/69 (12%), relative risk 2.1 (0.95 to 4.6))., Conclusions: In women with a singleton pregnancy with no prior spontaneous preterm birth at less than 34 weeks' gestation and with a midtrimester short cervix of 35 mm or less, pessary is not better than vaginal progesterone. In the subgroup of a cervical length of 25 mm or less, a pessary seemed less effective in preventing adverse outcomes. Overall, for women with single baby pregnancies, a short cervix, and no prior spontaneous preterm birth less than 34 weeks' gestation, superiority of a cervical pessary compared with vaginal progesterone to prevent preterm birth and consecutive adverse outcomes could not be proven., Trial Registration: International Clinical Trial Registry Platform (ICTRP, EUCTR2013-002884-24-NL)., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest and declare: BWJM declared support by a NHMRC Investigator grant (GNT1176437). BWM reports consultancy, research funding and travel support from Merck. EP and MAO declared participation on the board of the Research foundation ‘Stichting Stoptevroegbevallen’ that supported this study. EP, MAO and SJG received several grants with the purpose of scientific research in the field op preterm birth and fetal growth restriction. All other authors declare no support from any organisation for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Introduction: Preterm birth (PTB) is the leading cause of infant mortality and morbidity worldwide. Rates of PTB in the Netherlands are declining, possibly due to the implementation of preventive strategies. In this study we assessed the overall trend in PTB rates in the Netherlands in recent years, and in more detail in specific subgroups to investigate potential groups that require scrutiny in the near future., Material and Methods: Based on the national perinatal registry, we included all pregnancies without severe congenital abnormalities resulting in a birth from 24 to 42 completed weeks of gestation between 2011 and 2019 in the Netherlands. We assessed PTB rates in two different clinical subtypes (spontaneous vs. iatrogenic) and in five gestational age subgroups: 24-27 +6 weeks (extreme), 28-31 +6 weeks (very), 32-33 +6 weeks (moderate, 34-36 +6 weeks [late] and, in general, 24-36 +6 weeks [overall PTB]). Trend analysis was performed using the Cochran Armitage test. We also compared PTB rates in different subgroups in the first 2 years compared to the last 2 years. Singleton and multiple gestations were analyzed separately., Results: We included 1 447 689 singleton and 23 250 multiple pregnancies in our study. In singletons, we observed a significant decline in PTB from 5.5% to 5.0% (p < 0.0001), mainly due to a decrease in iatrogenic PTBs. When focusing on different gestational age subgroups, there was a decrease in all iatrogenic PTB and in moderate to late spontaneous PTB. However, in spontaneous extreme and very PTB there was an significant increase. When assessing overall PTB risk in different subgroups, the decline was only visible in women with age ≥25 years, nulliparous and primiparous women, women with a medium or high socioeconomic status and hypertensive women. In multiples, the rate of PTB remained fairly stable, from 52.3% in 2011 to 54.1% in 2019 (p = 0.57)., Conclusions: In the Netherlands, between 2011 and 2019, PTB decreased, mainly due to a reduction in late PTB, and more in iatrogenic than in spontaneous PTB. Focus for the near future should be on specific subgroups in which the decline was not visible, such as women with a low socioeconomic status or a young age., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. Maternal stress during pregnancy is an established risk factor for PTB. We aimed to review the effects of stress-reducing interventions during pregnancy on PTB. Studies reporting on stress-reducing interventions during pregnancy and PTB rates in general low-risk obstetric populations were included. PTB rates, low birth weight (LBW) rates, mean gestational age and birth weight, maternal anxiety and stress, and adverse perinatal outcomes were investigated. Data were extracted using a standardized extraction form, pooled effect sizes were calculated with the random effects model. Ten studies with a total of 4.816 women were included. The interventions included Pilates, yoga, a multidisciplinary stress reduction program, combination therapy (combining mindfulness, yoga, music, baby bonding, and education), and hypnosis. The incidence of PTB was significantly lower in the intervention group (RR 0.50, 95% CI 0.35 - 0.71). The overall quality of the included studies was low, and the risk of bias was high. In conclusion, this study provides evidence supporting the potential efficacy of stress-reducing interventions in reducing the incidence of PTB in low-risk women. We propose a RCT of high quality to determine the effectiveness of stress-reducing interventions in reducing PTB risk.

Introduction: Preterm birth (PTB) is among the leading causes of perinatal and childhood morbidity and mortality. Therefore, accurate identification of pregnant women at high risk of PTB is key to enable obstetric healthcare professionals to apply interventions that improve perinatal and childhood outcomes. Serial transvaginal cervical length measurement is used to screen asymptomatic pregnant women with a history of PTB and identify those at high risk for a recurrent PTB. Cervical length measurement, fetal fibronectin test or a combination of both can be used to identify women at high risk of PTB presenting with symptoms of threatened PTB. The predictive capacity of these methods can be improved. Cervical softening is a precursor of cervical shortening, effacement and dilatation and could be a new marker to identify women a high risk of PTB. However, the predictive value of cervical softening to predict spontaneous PTB still needs to be determined., Methods and Analysis: This is a single-centre, prospective cohort study, conducted at the Amsterdam University Medical Centers in the Netherlands. Cervical softening will be investigated with a non-invasive CE-marked device called the Pregnolia System. This device has been developed to evaluate consistency of the cervix based on tissue elasticity. Two different cohorts will be investigated. The first cohort includes women with a history of spontaneous PTB <34 weeks. These women undergo biweekly measurements between 14 and 24 weeks of gestation. The second cohort includes women with symptoms of threatened PTB. These women will receive the measurement once at presentation between 24 and 34 weeks of gestation. The primary outcome is spontaneous PTB before 34 weeks for women with a history of PTB and delivery within 7 days for women with threatened PTB. The minimum sample size required to analyse the primary outcome is 227 women in the cohort of women with a history of PTB and 163 women in the cohort of women with symptoms of threatened PTB. Once this number is achieved, the study will be continued to investigate secondary objectives., Ethics and Dissemination: The study is approved by the Medical Ethics Committee of Amsterdam UMC (METC2022.0226). All patients will give oral and written informed consent prior to study entry. Results will be disseminated via a peer-reviewed journal., Trial Registration Number: NCT05477381., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We operationalized a research usefulness tool identified through literature searches and consensus and examined if randomized controlled trials (RCTs) addressing preterm birth prevention met predefined criteria for usefulness., Study Design and Setting: The usefulness tool included eight criteria combining 13 items. RCTs were evaluated for compliance with each item by multiple assessors (reviewer agreement 95-98%). Proportions of compliances with 95% confidence interval (CI) were calculated and change over time was assessed using ≧ 2010 as a cutoff., Results: Among 347 selected RCTs, published within 56 preterm birth Cochrane reviews, only 36 (10%, 95% CI = 7-14%) met more than half of the usefulness criteria. Compared to trials before 2010, recent trials used composite or surrogate (less informative) outcomes more often (13% vs. 25%, relative risk 1.91, 95% CI = 1.21-3.00). Only 16 trials reflected real practice (pragmatism) in design (5%, 95% CI = 3-7%), with no improvements over time. No trials reported involvement of mothers to reflect patients' research priorities and outcomes selection. Recent trials were more transparent., Conclusion: Few preterm birth prevention RCTs met more than half of the usefulness criteria but most of usefulness criteria are improving after 2010. Use of informative outcomes, patient centeredness, pragmatism and transparency should be key targets for future research planning., Competing Interests: Declaration of competing interest Meta-Research Innovation Center at Stanford (METRICS), Stanford University is supported by a grant from the Laura and John Arnold Foundation. JvtH is supported by postdoctoral grant from the Netherlands Organization for Health Research and Development (Rubicon grand 452,182,306). C.A. is supported by postdoctoral grants from the Knut and Alice Wallenberg Foundation (K.A.W. 2019.0561), Uppsala University, and the Sweden-America Foundation. B.M. is supported by an NHMRC Investigator grant (GNT1176437). B.M. reports consultancy for Guerbet, has been a member of the ObsEva advisory board and holds Stock options for ObsEva. The work of J.I. has been supported by an unrestricted gift from Sue and Bob O'Donnell. J.I. is a team member of the editorial board of JCE. All the funders mentioned above had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Evidence for progestogen maintenance therapy after an episode of preterm labour (PTL) is contradictory., Objectives: To assess effectiveness of progestogen maintenance therapy after an episode of PTL., Search Strategy: An electronic search in Central Cochrane, Ovid Embase, Ovid Medline and clinical trial databases was performed., Selection Criteria: Randomised controlled trials (RCT) investigating women between 16 +0 and 37 +0  weeks of gestation with an episode of PTL who were treated with progestogen maintenance therapy compared with a control group., Data Collection and Analysis: Systematic review and meta-analysis were conducted. The primary outcome was latency time in days. Secondary neonatal and maternal outcomes are consistent with the core outcome set for preterm birth studies. Studies were extensively assessed for data trustworthiness (integrity) and risk of bias., Main Results: Thirteen RCT (1722 women) were included. Progestogen maintenance therapy demonstrated a longer latency time of 4.32 days compared with controls (mean difference [MD] 4.32, 95% CI 0.40-8.24) and neonates were born with a higher birthweight (MD 124.25 g, 95% CI 8.99-239.51). No differences were found for other perinatal outcomes. However, when analysing studies with low risk of bias only (five RCT, 591 women), a significantly longer latency time could not be shown (MD 2.44 days; 95% CI -4.55 to 9.42)., Conclusions: Progestogen maintenance therapy after PTL might have a modest effect on prolongation of latency time. When analysing low risk of bias studies only, this effect was not demonstrated. Validation through further research, preferably by an individual patient data meta-analysis is highly recommended., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Women with a history of spontaneous preterm birth (SPTB) have a mildly elevated cardiovascular risk (CVR) later in life and women with a history of preeclampsia have a highly elevated CVR. In placentas of women with preeclampsia pathological signs of maternal vascular malperfusion (MVM) are often seen. These signs of MVM are also seen in a substantial part of the placentas of women with SPTB. We therefore hypothesize that in women with a history of SPTB, the subgroup with placental MVM has an elevated CVR. This study is a secondary analysis of a cohort study including women 9-16 years after a SPTB. Women with pregnancy complications known to be associated with CVR were excluded. The primary outcome was hypertension defined as blood pressure ≥ 130/80 mmHg and/or treatment with antihypertensive medication. Secondary outcomes were mean blood pressure, anthropometrics, blood measurements including cholesterol and HbA1c, and creatinine in urine. Placental histology was available in 210 (60.0%) women. MVM was found in 91 (43.3%) of the placentas, most often diagnosed by the presence of accelerated villous maturation. Hypertension was diagnosed in 44 (48.4%) women with MVM and in 42 (35.3%) women without MVM (aOR 1.76, 95% CI 0.98 - 3.16). Women with a SPTB and placental MVM showed significantly higher mean diastolic blood pressure, mean arterial pressure and HbA1c approximately 13 years after delivery, compared to women with a SPTB without placental MVM. We therefore conclude that placental malperfusion in women with a SPTB might differentiate in CVR later in life., Competing Interests: Declaration of Competing Interest I have the following conflicts of interest: none., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Cardiovascular disease (CVD) is the number one cause of death in women and defining its risk factors is necessary to reduce its prevalence. A history of preeclampsia is shown to be associated with hypertension and alterations in left ventricular (LV) diastolic function parameters. Because of overlapping mechanisms between preeclampsia and spontaneous preterm birth (SPTB), our most recent study investigated the association between SPTB and hypertension, and found an almost 2 times higher prevalence of hypertension after SPTB. No previous studies have focused on the association between SPTB and LV diastolic function. The aim of this study is to investigate LV diastolic function as potential early parameter of CVD in women with a history of SPTB., Study Design: We included cases with a history of SPTB between 22 and 37 weeks and controls who had a term birth. Women with hypertensive disorders or gestational diabetes in any of their pregnancies, were excluded. Both groups underwent cardiovascular risk assessment and transthoracic echocardiography 9 to 16 years after pregnancy. Echocardiographic measures were adjusted using a linear regression analysis accounting for hypertension and other risk factors known to be associated with CVD. A subgroup analysis was performed based on hypertension at follow-up., Results: A total of 94 cases and 94 controls were included, on average 13 years after pregnancy. There were no significant differences in LV diastolic function parameters. Women with a history of SPTB and diagnosed hypertension at follow-up, showed significant higher late diastolic mitral flow velocity, lower e'septal velocity and higher E/e'ratio, compared to women with a history of SPTB without hypertension, although within normal ranges., Conclusions: When a history of SPTB is accompanied by hypertension at follow-up, significant changes in LV diastolic function were seen. Therefore, hypertension is the central factor in preventive screening methods, and transthoracic echocardiography has no additional value at this follow-up duration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

This study investigated whether sexual intercourse during pregnancy is associated with spontaneous preterm birth (SPTB). We included 77 women with SPTB and 145 women with a term birth. A total of 195 (87.8%) women had sexual intercourse during pregnancy, which was comparable between the groups. Primiparas with SPTB tended to report more often having sexual intercourse 3 - 4 times a week compared to primiparas with a term birth (8.8% vs. 0%, p =.082). We advise not to completely discourage sexual intercourse among pregnant women. Yet, high sexual intercourse frequency could be associated with SPTB., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To investigate whether a history of spontaneous preterm birth (SPTB) predisposes to maternal hypertension., Design: Retrospective case-control study., Setting: Two affiliated university medical hospitals in Amsterdam, the Netherlands., Population: We included 350 women with a history of SPTB between 22 and 36 +6  weeks and 166 women with a history of a term birth. Women with pregnancy complications that are known to be associated with cardiovascular disease were excluded., Methods: Both groups underwent cardiovascular risk assessment 9-16 years after pregnancy. We performed a subgroup analysis based upon the severity of SPTB., Main Outcome Measures: Hypertension. Secondary outcomes - metabolic syndrome, mean blood pressure, anthropometrics, blood and urine sampling, Framingham Risk Score and Systematic Coronary Risk Evaluation., Results: A history of SPTB was significantly associated with hypertension; adjusted odds ratio 1.60 (95% confidence interval 1.04-2.46, p = 0.033). Abdominal obesity was more often diagnosed after SPTB (n = 163, 46.6% versus n = 54, 32.5%, p = 0.003) and was more pronounced with more severe preterm birth (p = 0.002)., Conclusions: The presence of hypertension 9-16 years after pregnancy was statistically significantly higher among women with a history of SPTB than among women with a history of uncomplicated term birth. Women with a history of SPTB were more often diagnosed with abdominal obesity, especially those with a history of extreme preterm birth., (© 2022 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: Women of Black and other non-Western ethnicity and women who live in deprived neighborhoods are at increased risk for preterm birth (PTB). These women may live clustered in certain urban areas. If ethnicity reflects a biological rather than a socioeconomic risk factor, women should have a PTB risk independent of the urban area where they live. In this study we explored the association between urban living and the risk of PTB, combined with knowledge on ethnicity and neighborhood deprivation in these specific urban areas in the Netherlands., Study Design: National cohort study of 935,381 women (2014-2019) with a singleton pregnancy resulting in live birth between 24.0 and 42.6 weeks. Antepartum death and severe congenital anomalies were excluded. We performed logistic regression analysis and analyzed the impact of living in one of the four main urban areas on PTB. We adjusted for maternal age, parity and fetal gender. We tested for interaction between ethnicity, neighborhood deprivation index (NDI) and urban living., Results: Mean PTB rate among singleton pregnancies in The Netherlands is 5.1%. There was a strong ethnic difference in PTB risk, with the highest prevalence among South Asian women (7.9%) and African women (6.6%). In the most deprived neighborhoods the PTB risk was 5.7%. We found a significant interaction between ethnicity and urban living, and between NDI and urban living. South Asian and African women living in urban areas had the greatest risk of PTB, between 7.0% and 8.8%., Conclusion: Ethnicity remains a fixed biological risk for PTB that cannot be fully explained by socioeconomic status or neighborhood deprivation. Independent of ethnicity and neighborhood deprivation, urban living has a great influence on the risk of preterm birth. Future studies and policies should focus on population-based interventions in those urban areas where South Asian and African ethnic groups live and where the preterm birth risk is the highest., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To evaluate the effect of aspirin 80 mg compared to placebo on platelet function tests in the second and third trimester of pregnancy., Study Design: An explorative study was performed to assess laboratory platelet function in a subpopulation of the APRIL trial: a randomized double-blind trial comparing aspirin 80 mg once daily to placebo for the prevention of recurrent preterm birth. Platelet function was measured between 18 and 22, and between 28 and 32 weeks gestational age with three platelet function tests: VerifyNow®, Chronolog light transmission aggregometry (Chronolog LTA) and serum thromboxane B 2 (TxB 2 ). Medication adherence was evaluated by pill counts, self-reported diaries and structured interviews., Results: We included 11 women, six in the aspirin and five in the placebo group. In women receiving aspirin, platelet function was significantly lower compared to women receiving placebo for all three tests: VerifyNow® Aspirin Reaction Units (450.5 vs 648.0, p = 0.017); Chronolog LTA (9.5% vs 94.5%, p = 0.009); serum TxB 2 levels (11.9 ng/mL versus 175.9 ng/mL, p = 0.030). For all three tests, platelet function did not differ between the second and third trimester of pregnancy in the aspirin group. In the placebo group, serum TxB 2 levels were significantly higher in the third trimester. One non-adherent participant in the aspirin group showed results similar to the placebo group., Conclusion: Aspirin 80 mg has a clear inhibitory effect on laboratory platelet function during pregnancy compared to placebo. This effect is similar in the second and third trimester of pregnancy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Vaginal progesterone and a cervical pessary are both interventions that are investigated for the prevention of preterm birth (PTB). Thus far, beneficial or harmful effects of these interventions on long-term child health and development are described, but evidence is not robust enough to draw firm conclusions. With this follow-up study, we intent to investigate if progesterone or a pessary is superior for the prevention of PTB considering the child's health at 4-6 years of corrected age., Methods and Analysis: This study is a follow-up study of the Quadruple-P trial; a multicentre, randomised clinical trial (NL42926.018.13, Eudractnumber 2013-002884-24) which randomises women with an asymptomatic midtrimester short cervix to daily progesterone or a pessary for the prevention of PTB. All children born to mothers who participated in the Quadruple-P study (n=628 singletons and n=332 multiples) will be eligible for follow-up at 4-6 years of corrected age. Children will be assessed using parental questionnaires. Main outcomes are child (neuro)development and behaviour. Other outcomes include child mortality, growth and general health. A composite of adverse child outcomes will be compared between the progesterone and pessary groups reporting OR and the corresponding 95% CI. Analyses will be performed separately for singletons and multiples and using the intention-to-treat approach., Ethics and Dissemination: The Medical Research Ethics Committee from Amsterdam UMC confirmed that de Medical Research Involving Human Subjects Act (WMO) did not apply to our study (W20&#95;481 #20.531). Results will be published in a peer-reviewed journal and shared with stakeholders and participants. This protocol is published before analysis of the results., Trial Registration Number: Dutch Trial Register (NL9646)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The use of low-dose aspirin by pregnant women to prevent preterm pre-eclampsia is gradually increasing. The administration of aspirin during pregnancy improves perinatal outcome, which could translate into improved child outcome in the long term. However, antenatal exposure to aspirin could have adverse effects on child development that may manifest later in life. The aim of this follow-up study is to assess the long-term effects of antenatal exposure to low-dose aspirin compared with placebo on survival, (neuro)development, behaviour and general health at 4 years corrected age., Methods and Analysis: This is a follow-up study of the Dutch double-blind randomised controlled APRIL trial which assessed the effectiveness of treatment with aspirin (80 mg daily) compared with placebo for the prevention of preterm birth in women with a previous spontaneous preterm birth. Treatment was initiated before 16 weeks of gestation and continued until 36 weeks or birth. We aim to follow-up all 379 children born to women who participated in the APRIL trial and survived the neonatal period, at the corrected age of 4 years. The main outcomes are (neuro)development as assessed by the Ages and Stages Questionnaire, and behaviour as assessed by the Strength and Difficulties Questionnaire. Additional outcomes include mortality, growth and general health from birth up to 4 years, and a composite outcome including mortality, abnormal (neuro)development and problem behaviour. Analyses will be performed by intention-to-treat using a superiority design., Ethics and Dissemination: Institutional Review Board approval was obtained from the Medical Research Ethics Committee from Amsterdam Medical Center (no. W20 289#20.325). The results will be published in a peer-reviewed journal and presented at conferences., Trial Registration Number: The APRIL trial (NTR5675, NL5553; EudraCT number 2015-003220-31) and the APRIL follow-up study (NL8950) are registered in the Dutch trial register. The study is funded by the Amsterdam Reproduction & Development research institute., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Worldwide, nifedipine and atosiban are the two most commonly used tocolytic agents for the treatment of threatened preterm birth. The aim of this study was to evaluate the effectiveness of nifedipine and atosiban in an individual participant data meta-analysis (IPDMA)., Methods: We investigated the occurrence of adverse neonatal outcomes in women with threatened preterm birth by performing an IPDMA, and sought to identify possible subgroups in which one treatment may be preferred. We searched PubMed, Embase, and Cochrane for trials comparing nifedipine and atosiban for treatment of threatened preterm birth between 24 0/7 and 34 0/7 weeks' gestational age. Primary outcome was a composite of perinatal mortality and neonatal morbidities including respiratory distress syndrome, intraventricular haemorrhage, periventricular leucomalacia, necrotising enterocolitis, and sepsis. Secondary outcomes included NICU admission, prolongation of pregnancy and GA at delivery. For studies that did not have the original databases available, metadata was used. This led to a two-stage meta-analysis that combined individual participant data with aggregate metadata., Results: We detected four studies (N = 791 women), of which two provided individual participant data (N = 650 women). The composite neonatal outcome occurred in 58/364 (16%) after nifedipine versus 69/359 (19%) after atosiban (OR 0.76, 95%CI 0.47-1.23). Perinatal death occurred in 14/392 (3.6%) after nifedipine versus 7/380 (1.8%) after atosiban (OR 2.0, 95%CI 0.80-5.1). Nifedipine results in longer prolongation of pregnancy, with a 18 days to delivery compared with 10 days for atosiban (HR 0.83 (96% CI 0.69-0.99)). NICU admission occurred less often after nifedipine (46%) than after atosiban (59%), (OR 0.32, 95%CI 0.14-0.75). The sensitivity analysis revealed no difference in prolongation of pregnancy for 48 hours (OR 1.0, 95% CI 0.73-1.4) or 7 days (OR 1.3, 95% CI 0.85-5.8) between nifedipine and atosiban. There was a non-significant higher neonatal mortality in the nifedipine-exposed group (OR 1.4, 95% CI 0.60-3.4)., Conclusions: In this IPDMA, we found no differences in composite outcome between nifedipine and atosiban in the treatment of threatened preterm birth. However, the non-significant higher mortality after administering nifedipine warrants further investigation of the use of nifedipine as a tocolytic drug., Study Registration: We conducted this study according to a prospectively prepared protocol, registered with PROSPERO (the International Prospective Register of Systematic Reviews) under CRD42016024244., (© 2022. The Author(s).)

Objective: Spontaneous preterm birth is the leading cause of infant morbidity and mortality in the developed world. Environmental socio-economic factors, such as neighborhood deprivation, are known to negatively affect birth outcomes, including overall preterm birth. However, the role of neighborhood deprivation in spontaneous preterm birth (SPTB) is unclear. The aim of the study is to 1) to determine the effect of neighborhood deprivation on SPTB birth and 2) to investigate the trend in rates of SPTB between 2010 and 2019 for each quintile of neighborhood deprivation., Study Design: Based on the national perinatal registry, we included 1,584,225 singleton pregnancies resulting in a birth from 22 to 42 completed weeks of gestation between 2010 and 2019 in the Netherlands. Deprivation scores per neighborhood were derived from the Netherlands Institute of Social Research and were linked to the perinatal registry data, using the woman's home address. The scores were divided into quintiles (Q). Rates of SPTB were calculated, categorized into <37 weeks, <32 weeks and <28 weeks of gestation. We used logistic regression analysis to adjust for maternal age, parity and ethnicity., Results: Compared to the most affluent neighborhoods (Q1), women in all other quintiles had a statistically significant increased risk for SPTB. The largest effect was observed in the most deprived neighborhoods (Q5); adjusted odds ratio 1.16 (95% confidence interval 1.13 - 1.19). From 2010 to 2019, we observed an overall decrease of 0.21% in SPTB < 37 weeks (p < 0.0001). All quintiles showed a decrease in SPTBs < 37 weeks, but only in Q1, Q2 & Q5 this decline in SPTB was statistically significant., Conclusions: Pregnant women in deprived neighborhoods in the Netherlands are more at risk for spontaneous preterm birth. From 2010 to 2019, the rate of spontaneous preterm birth decreased. Efforts should be made by both governmental and medical professionals to develop intervention programs to reduce spontaneous preterm birth in more deprived neighborhoods., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Spontaneous preterm birth (SPTB) is a major cause of neonatal morbidity and mortality worldwide and defining its risk factors is necessary to reduce its prevalence. Recent studies have pointed out that bacterial vaginosis, a disturbance in the vaginal microbiome, is associated with SPTB. It is hypothesized that vaginal hygiene practices can alter the vaginal microbiome and are therefore associated with SPTB, but there are no studies investigating this matter., Methods and Findings: A case-control study was conducted between August 2018 and July 2021 in two affiliated university medical centers in Amsterdam, the Netherlands. We included a total of 79 women with a SPTB and compared them with 156 women with a term birth. Women with uterine anomalies, a history of cervical surgery or major congenital anomalies of the fetus were excluded. All participants filled in a questionnaire about vaginal washing with water, soap or gel, the use of intravaginal douches and vaginal steaming, both before and during pregnancy. Most women washed vaginally with water, 144 (61.3%) women before pregnancy and 135 (57.4%) women during pregnancy. A total of 43 (18.3%) washed with soap before and 36 (15.3%) during pregnancy. Before pregnancy, 40 (17.0%) women washed with vaginal gel and 27 (11.5%) during pregnancy. We found that the use of vaginal gel before pregnancy (aOR 2.29, 95% CI: 1.08-4.84) and even more during pregnancy, was associated with SPTB (aOR 3.45, 95% CI: 1.37-8.67). No association was found between washing with water or soap, intravaginal douching, or vaginal steaming and SPTB., Conclusions: Our findings suggest that the use of vaginal gel is associated with SPTB. Women should be informed that vaginal use of gels might not be safe., Competing Interests: The authors have declared that no competing interests exist.

Objective: To evaluate the implementation of low-dose aspirin in pregnancy for the prevention of utero-placental complications among gynecologists in the Netherlands between 2016 and 2021. In this timeframe, a national guideline about aspirin in pregnancy was introduced by the Dutch Society of Obstetrics and Gynecology., Materials and Methods: A national online survey among Dutch gynecologists and residents was performed. An online questionnaire was distributed among the members of the Dutch Society of Obstetrics and Gynecology in April 2016 and April 2021. Main outcome measure was the proportion of gynecologists indicating prescription of aspirin in pregnancy for high and moderate risk indications., Results: In 2016, 133 respondents completed the survey, and in 2021 231. For all indications mentioned in the guideline there was an increase in prescribing aspirin in 2021 in comparison to 2016. More specifically, the percentage of gynecologists prescribing aspirin for a history of preeclampsia before 34 weeks, between 34 and 37 weeks and at term increased from respectively 94% to 100%, 39% to 98%, and 15% to 97%. Consultant obstetricians and respondents working in an university hospital did not more often indicate the prescription of aspirin for tertiary care indications in 2021. Future use of a prediction model was suggested in the narrative comments., Conclusion: Implementation of aspirin in pregnancy among Dutch gynecologists substantially improved after a five year timeframe in which the national guideline on aspirin during pregnancy was introduced and trials confirming the effect of aspirin were published., Competing Interests: The authors have declared that no competing interests exist.

Background: Fibroids have been identified as a possible risk factor for preterm birth, however, the magnitude of this risk is unclear. Our objective was to determine the risk of total, spontaneous, and medically indicated preterm birth in women with fibroids., Methods: A literature search was performed on 9 June 2021. We selected studies reporting on preterm birth in women with and without fibroids. Fibroids had to be diagnosed by routine ultrasound before or during pregnancy. Main outcomes were total preterm birth <37, <34, <32, and <28 weeks of gestation, and spontaneous and medically indicated preterm birth. Two authors independently performed study selection, data extraction and quality assessment. We performed quality assessment with the Newcastle-Ottawa scale. Meta-analyses were presented as Odds Ratios (ORs) with 95% Confidence Intervals (95%CIs)., Main Results: The search yielded 2078 unique articles of which 11 were included. Meta-analysis for preterm birth <37 weeks of gestation included 256,650 singleton deliveries: 12,309 with fibroids and 244,341 without fibroids. Women with fibroids had a higher rate of preterm birth (11.6% versus 9.0%; OR 1.66, 95%CI 1.29-2.14). Fibroids were also associated with preterm birth <34 (OR 1.88, 95%CI 1.34-2.65), <32 (OR 2.03, 95%CI 1.40-2.95) and <28 (OR 2.24, 95%CI 1.45-3.47) weeks of gestation. Data on type of preterm birth was limited: one study showed a significant association of fibroids with spontaneous preterm birth and another with indicated preterm birth. The main limitations of the included studies were the lack of correction for confounders, the risk of ascertainment bias due to possible underreporting of fibroids, and the substantial heterogeneity between studies., Conclusions: Our results suggest fibroids are associated with an increased risk of preterm birth, with a stronger risk at earlier gestational ages. We encourage further research to clarify the association between fibroids and preterm birth by systematic myometrial assessment in pregnancy., Registration: Prospero database [CRD42020186976]., Competing Interests: The authors have declared that no competing interests exist.

Objective: To evaluate the effect of cervical pessary, as a strategy to prevent preterm birth (PTB), on the outcome of subsequent pregnancy and maternal quality of life 4 years after the index twin pregnancy., Methods: Between 2009 and 2012, the ProTWIN trial randomized women with a multiple pregnancy to pessary use vs standard care for the prevention of PTB. The trial showed no benefit in unselected women with a twin pregnancy, but showed a 60% reduction in poor perinatal outcomes in favor of the pessary group in the subgroup of women with a mid-trimester short cervix (cervical length < 38 mm). All women were invited to participate in a follow-up study 4 years after their participation in the ProTWIN trial. In this follow-up study, maternal quality of life was assessed using the EQ-5D-3L questionnaire and women were asked separate questions about subsequent pregnancies. Results were compared between women who were randomized to the pessary vs the control group in the ProTWIN trial by calculating relative risk (RR) and 95% CI. Subgroup analysis was performed for women with a mid-trimester short cervix (cervical length < 38 mm)., Results: Of the 813 women included in the ProTWIN trial, 408 (50.2%) participated in this follow-up study, comprising 228 randomized to the pessary group and 180 to the control group in the original trial. The median interval between participation in the ProTWIN trial and participation in this follow-up study was 4.1 (interquartile range (IQR), 3.9-7.1) years. Ninety-eight (24.0%) participants tried to conceive after their participation in the ProTWIN trial. Of those, 22 (22.4%) women did not have a subsequent pregnancy (no difference between pessary and control groups), seven (7.1%) women had at least one miscarriage but no live birth, and 67 (68.4%) women had at least one live birth (35 in the pessary vs 32 in the control group; RR, 0.93 (95% CI, 0.8-1.07)). In two women, the pregnancy outcome was unknown. Preterm delivery (< 37 weeks of gestation) of the first live birth occurred in three women in the pessary vs one woman in the control group (all singleton; RR, 2.57 (95% CI, 0.28-23.44)). No differences were found between the pessary and control groups in the subgroup of women with mid-trimester short cervix, but the numbers analyzed were small. The median health state index score was 0.95 (IQR, 0.82-0.95), with no difference between the pessary and control groups., Conclusion: Our findings suggest that there are no long-term effects of pessary use on the outcome of subsequent pregnancies and maternal quality of life. Data on obstetric outcome were limited due to the small numbers. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Background: Preterm birth is the leading cause of neonatal morbidity and mortality. The recurrence rate of spontaneous preterm birth is high, and additional preventive measures are required. Our objective was to assess the effectiveness of low-dose aspirin compared to placebo in the prevention of preterm birth in women with a previous spontaneous preterm birth., Methods and Findings: We performed a parallel multicentre, randomised, double-blinded, placebo-controlled trial (the APRIL study). The study was performed in 8 tertiary and 26 secondary care hospitals in the Netherlands. We included women with a singleton pregnancy and a history of spontaneous preterm birth of a singleton between 22 and 37 weeks. Participants were randomly assigned to aspirin 80 mg daily or placebo initiated between 8 and 16 weeks of gestation and continued until 36 weeks or delivery. Randomisation was computer generated, with allocation concealment by using sequentially numbered medication containers. Participants, their healthcare providers, and researchers were blinded for treatment allocation. The primary outcome was preterm birth <37 weeks of gestation. Secondary outcomes included a composite of poor neonatal outcome (bronchopulmonary dysplasia, periventricular leukomalacia > grade 1, intraventricular hemorrhage > grade 2, necrotising enterocolitis > stage 1, retinopathy of prematurity, culture proven sepsis, or perinatal death). Analyses were performed by intention to treat. From May 31, 2016 to June 13, 2019, 406 women were randomised to aspirin (n = 204) or placebo (n = 202). A total of 387 women (81.1% of white ethnic origin, mean age 32.5 ± SD 3.8) were included in the final analysis: 194 women were allocated to aspirin and 193 to placebo. Preterm birth <37 weeks occurred in 41 (21.2%) women in the aspirin group and 49 (25.4%) in the placebo group (relative risk (RR) 0.83, 95% confidence interval (CI) 0.58 to 1.20, p = 0.32). In women with ≥80% medication adherence, preterm birth occurred in 24 (19.2%) versus 30 (24.8%) women (RR 0.77, 95% CI 0.48 to 1.25, p = 0.29). The rate of the composite of poor neonatal outcome was 4.6% (n = 9) versus 2.6% (n = 5) (RR 1.79, 95% CI 0.61 to 5.25, p = 0.29). Among all randomised women, serious adverse events occurred in 11 out of 204 (5.4%) women allocated to aspirin and 11 out of 202 (5.4%) women allocated to placebo. None of these serious adverse events was considered to be associated with treatment allocation. The main study limitation is the underpowered sample size due to the lower than expected preterm birth rates., Conclusions: In this study, we observed that low-dose aspirin did not significantly reduce the preterm birth rate in women with a previous spontaneous preterm birth. However, a modest reduction of preterm birth with aspirin cannot be ruled out. Further research is required to determine a possible beneficial effect of low-dose aspirin for women with a previous spontaneous preterm birth., Trial Registration: Dutch Trial Register (NL5553, NTR5675) https://www.trialregister.nl/trial/5553., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: BM reported an Investigator grant from the National Health and Medical Research Council (NHMRC; grant no. GNT1176437); receipt of research funding from Guerbet; and is a former advisory board member at ObsEva. All other authors do not report any relevant financial activities outside the submitted work.

Liquid-based perinatal life support (PLS) technology will probably be applied in a first-in-human study within the next decade. Research and development of PLS technology should not only address technical issues, but also consider socio-ethical and legal aspects, its application area, and the corresponding design implications. This paper represents the consensus opinion of a group of healthcare professionals, designers, ethicists, researchers and patient representatives, who have expertise in tertiary obstetric and neonatal care, bio-ethics, experimental perinatal animal models for physiologic research, biomedical modeling, monitoring, and design. The aim of this paper is to provide a framework for research and development of PLS technology. These requirements are considering the possible respective user perspectives, with the aim to co-create a PLS system that facilitates physiological growth and development for extremely preterm born infants., Competing Interests: The work of MH, FD, LF, FN, MS, MV, SO, and FV has been funded by the European Union via the Horizon 2020: Future Emerging Topics call FET Open, grant EU863087, project PLS, https://cordis.europa.eu/project/id/863087. MH, MV, and SO are shareholders in Juno Perinatal Healthcare BV, Netherlands. AP is Chair of Scientific Advisory Board of Concord Neonatal BV, for which he receives no compensation, https://concordneonatal.com. He also consults for Fisher and Paykel Healthcare and receives compensation https://www.fphcare.com/en-gb. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 van der Hout-van der Jagt, Verweij, Andriessen, de Boode, Bos, Delbressine, Eggink, Erwich, Feijs, Groenendaal, Kramer, Lely, Loop, Neukamp, Onland, Oudijk, te Pas, Reiss, Schoberer, Scholten, Spaanderman, van der Ven, Vermeulen, van de Vosse and Oei.)

Objective: To evaluate the long-term effects of antenatal aspirin exposure on child health and neurodevelopmental outcome beyond the perinatal period., Study Design: PubMed, Embase.com, the Cochrane Library and Web of Science were systematically searched from inception through 5 November 2020. We performed a cited-reference search and ClinicalTrials.gov was searched on 20 October 2020 to identify trial results that were not reported elsewhere. We included randomized controlled trials reporting on health-related outcomes in children (aged > 28 days) exposed to aspirin versus placebo or no treatment during pregnancy. Studies with any dose or duration of aspirin use were included. We excluded studies evaluating other antiplatelet agents or non-steroidal inflammatory drugs. Two authors independently performed study selection, data extraction and quality assessment. Quality assessment was performed using the Cochrane RoB2 tool for the original randomized controlled trials and the QUIPS for the follow-up studies. Results are presented as relative risks (RR) with 95% confidence intervals (95%CI)., Results: The search yielded 6,907 unique records. Two studies were included, containing 4,168 children at age 12 months and 5,153 children at 18 months. Children were exposed to aspirin 50-60 mg versus placebo or no treatment. At 12 months, post-neonatal mortality was lower after allocation to aspirin (0.2% versus 0.5%; RR 0.28, 95%CI 0.08-0.99) in a single study. At 18 months, fewer children were found to have (gross and fine) motor problems (RR 0.49, 95%CI 0.26-0.91) after antenatal aspirin exposure in one study. No differences were found in mortality rate; the proportion of children with a short stature or low weight; or respiratory, hearing or visual problems at 18 months. Both included studies had a high risk of bias., Conclusion: The two included studies showed evidence of potential benefit of antenatal low-dose aspirin on mortality and neurodevelopment up to the age of 18 months. Our findings support the current application of low-dose aspirin in pregnant women at risk for preeclampsia and fetal growth restriction. However, further follow-up research of children who were exposed to low-dose aspirin during pregnancy is of utmost importance to exclude potential long-term harm., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The COVID-19 pandemic led to regional or nationwide lockdowns as part of risk mitigation measurements in many countries worldwide. Recent studies suggest an unexpected and unprecedented decrease in preterm births during the initial COVID-19 lockdowns in the first half of 2020. The objective of the current study was to assess the effects of the two months of the initial national COVID-19 lockdown period on the incidence of very and extremely preterm birth in the Netherlands, stratified by either spontaneous or iatrogenic onset of delivery, in both singleton and multiple pregnancies., Methods: Retrospective cohort study using data from all 10 perinatal centers in the Netherlands on very and extremely preterm births during the initial COVID-19 lockdown from March 15 to May 15, 2020. Incidences of very and extremely preterm birth were calculated using an estimate of the total number of births in the Netherlands in this period. As reference, we used data from the corresponding calendar period in 2015-2018 from the national perinatal registry (Perined). We differentiated between spontaneous versus iatrogenic onset of delivery and between singleton versus multiple pregnancies., Results: The incidence of total preterm birth < 32 weeks in singleton pregnancies was 6.1‰ in the study period in 2020 versus 6.5‰ in the corresponding period in 2015-2018. The decrease in preterm births in singletons was solely due to a significant decrease in iatrogenic preterm births, both < 32 weeks (OR 0.71; 95%CI 0.53 to 0.95) and < 28 weeks (OR 0.53; 95%CI 0.29 to 0.97). For multiple pregnancies, an increase in preterm births < 28 weeks was observed (OR 2.43; 95%CI 1.35 to 4.39)., Conclusion: This study shows a decrease in iatrogenic preterm births during the initial COVID-19-related lockdown in the Netherlands in singletons. Future studies should focus on the mechanism of action of lockdown measures and reduction of preterm birth and the effects of perinatal outcome., (© 2021. The Author(s).)

The precautionary principle is often invoked in relation to pregnant women and may be one of the underlying reasons for their continuous underrepresentation in clinical research. The principle is appealing, because potential fetal harm as a result of research participation is considered to be serious and irreversible. In our paper, we explore through conceptual analysis whether and if so how the precautionary principle should apply to pregnant women. We argue that the principle is a decision-making strategy underlying risk-benefit decisions in clinical research, which can be applied to pregnant women. However, the current application is a strong one, leading to the promotion of absolute exclusion or, less often, absolute inclusion of pregnant women. In order to change this paralyzing situation, a shift toward weak precautionary thinking is necessary. Instead of automatic extreme precaution, a balance will be found between harms and potential benefits of including pregnant women in clinical research., (© The Author(s) 2021. Published by Oxford University Press, on behalf of the Journal of Medicine and Philosophy Inc. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Preterm birth is one of the main problems in obstetrics, and the most important cause of neonatal mortality, morbidity and neurodevelopmental impairment. Multiple gestation is an important risk factor for preterm birth, with up to 50% delivering before 37 weeks. Progesterone has a role in maintaining pregnancy and is frequently prescribed to prevent (recurrent) preterm birth and improve pregnancy outcomes in high-risk patients. However, little is known about its long-term effects in multiple gestations. The objective of this follow-up study is to assess long-term benefits and harms of prenatal exposure to progesterone treatment in multiple gestations on child development., Methods and Analysis: This is a follow-up study of a multicentre, double-blind, placebo-controlled randomised trial (AMPHIA trial, ISRCTN40512715). Between 2006 and 2009 women with a multiple gestation were randomised at 16-20 weeks of gestation to weekly injections 250 mg 17α-hydroxyprogesterone caproate or placebo, until 36 weeks of gestation or delivery. The current long-term follow-up will assess all children (n=1355) born to mothers who participated in the AMPHIA trial, at 11-14 years of age, with internationally validated questionnaires, completed by themselves, their parents and their teachers., Main Outcomes Are Child Cognition and Behaviour: Additional outcomes are death (perinatal and up to age 14), gender identity, educational performance and health-related problems. We will use intention-to-treat analyses comparing experimental and placebo group. To adjust for the correlation between twins, general linear mixed-effects models will be used., Ethics and Dissemination: Amsterdam UMC MEC provided a waiver for the Medical Research Involving Human Subjects Act (W20&#95;234#20.268). Results will be disseminated through peer-reviewed journals and summaries shared with stakeholders, patients and participants. This protocol is published before analysis of the results., Trial Registration Number: NL8933., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes., Methods: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 μmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495., Findings: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35-3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04-2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86-1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39-0·91; p=0·016)., Interpretation: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment., Funding: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research., Competing Interests: Declaration of interests CO and H-UM are consultants for Mirum Pharmaceuticals. CW is a consultant for Mirum Pharmaceuticals and GlaxoSmithKline. KK is an unpaid consultant for Myriad Pharmaceuticals. WMH reports non-financial support from the Falk Foundation, during the conduct of the study, and is co-author of the Cochrane review on pharmacological interventions for treating intrahepatic cholestasis of pregnancy.(14) RMT reports grants from Tommy's and the Lauren Page Trust during the conduct of the study. All other authors declare no competing interests., (Copyright © 2021 The Authors(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Woman with a history of a previous cesarean section (CS) can choose between an elective repeat CS (ERCS) and a trial of labor (TOL), which can end in a vaginal birth after cesarean (VBAC) or an unplanned CS. Guidelines describe women's rights to make an informed decision between an ERCS or a TOL. However, the rates of TOL and vaginal birth after CS varies greatly between and within countries. The objective of this study is to asses nation-wide implementation of counselling with a decision aid (DA) including a prediction model, on intended delivery compared to care as usual. We hypothesize that this may result in a reduction in practice variation without an increase in cesarean rates or complications., Methods: In a multicenter controlled before and after cohort study we evaluate the effect of nation-wide implementation of a DA. Practice variation was defined as the standard deviation (SD) of TOL percentages., Results: A total of 27 hospitals and 1,364 women were included. A significant decrease was found in practice variation (SD TOL rates: 0.17 control group vs. 0.10 intervention group following decision aid implementation, p=0.011). There was no significant difference in the ERCS rate or overall CS rates. A 21% reduction in the combined maternal and perinatal adverse outcomes was seen., Conclusions: Nationwide implementation of the DA showed a significant reduction in practice variation without an increase in the rate of cesarean section or complications, suggesting an improvement in equality of care., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Background and Objectives : Therapeutic interventions targeting molecular factors involved in the transition from uterine quiescence to overt labour are not substantially reducing the rate of spontaneous preterm labour. The identification of novel rational therapeutic targets are essential to prevent the most common cause of neonatal mortality. Based on our previous work showing that Tbx2 (T-Box transcription factor 2) is a putative upstream regulator preceding progesterone withdrawal in mouse myometrium, we now investigate the role of TBX2 in human myometrium. Materials and Methods : RNA microarray analysis of (A) preterm human myometrium samples and (B) myometrial cells overexpressing TBX2 in vitro, combined with subsequent analysis of the two publicly available datasets of (C) Chan et al. and (D) Sharp et al. The effect of TBX2 overexpression on cytokines/chemokines secreted to the myometrium cell culture medium were determined by Luminex assay. Results : Analysis shows that overexpression of TBX2 in myometrial cells results in downregulation of TNFα- and interferon signalling. This downregulation is consistent with the decreased expression of cytokines and chemokines of which a subset has been previously associated with the inflammatory pathways relevant for human labour. In contrast, CXCL5 (C-X-C motif chemokine ligand 5), CCL21 and IL-6 (Interleukin 6), previously reported in relation to parturition, do not seem to be under TBX2 control. The combined bioinformatical analysis of the four mRNA datasets identifies a subset of upstream regulators common to both preterm and term labour under control of TBX2. Surprisingly, TBX2 mRNA levels are increased in preterm contractile myometrium. Conclusions : We identified a subset of upstream regulators common to both preterm and term labour that are activated in labour and repressed by TBX2. The increased TBX2 mRNA expression in myometrium collected during a preterm caesarean section while in spontaneous preterm labour compared to tissue harvested during iatrogenic preterm delivery does not fit the bioinformatical model. We can only explain this by speculating that the in vivo activity of TBX2 in human myometrium depends not only on the TBX2 expression levels but also on levels of the accessory proteins necessary for TBX2 activity.

Background: Progesterone is widely used in prenatal care. However, long-term effects of prenatal progesterone treatment on child development are unclear., Objectives: To evaluate long-term outcomes in children after prenatal progesterone treatment., Search Strategy: MEDLINE, Embase and Cochrane Central Register of Controlled Trials from inception to 24 May 2020., Selection Criteria: Randomised controlled trials (RCTs) reporting outcomes in children born to women who received progesterone treatment (compared with placebo or another intervention) during any trimester in pregnancy., Data Collection and Analysis: Two authors independently selected and extracted data. We used the Cochrane Risk of Bias tool for randomised trials and Quality In Prognosis Studies., Main Results: Of 388 papers, we included seven articles based on five RCTs, comprising 4222 measurements of children aged 6 months to 8 years. All studies compared progesterone to placebo in second and/or third trimester for the prevention of preterm birth. Meta-analysis (two studies, n = 890 children) showed no difference in neurodevelopment as assessed by the Bayley-III Cognitive Composite score at 2 years between children exposed to progesterone versus placebo (Standardised Mean Difference -0.04, 95% Confidence Interval -0.26 to 0.19), I 2  = 22%. Heterogeneity prohibited additional meta-analyses. Other long-term outcomes showed no differences., Conclusions: Our systematic review comprising a multitude of developmental measurements with a broad age range did not find evidence of benefit or harm in offspring prenatally exposed to progesterone treatment for the prevention of preterm birth. We identified an urgent need for follow-up studies of prenatal progesterone administration in early pregnancy and effects in offspring beyond early childhood., Tweetable Abstract: Progesterone to prevent preterm birth: no effect on child development. Outcomes after first trimester progesterone are unclear., (© 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: To evaluate the rate of preterm birth (PTB) in a subsequent pregnancy in women who had undergone term induction using a Foley catheter compared with prostaglandins., Methods: This was a follow-up study of two large randomized controlled trials (PROBAAT-1 and PROBAAT-2). In the original trials, women with a term singleton pregnancy with the fetus in cephalic presentation and with an indication for labor induction were randomized to receive either a 30-mL Foley catheter or prostaglandins (vaginal prostaglandin E2 in PROBAAT-1 and oral misoprostol in PROBAAT-2). Data on subsequent ongoing pregnancies > 16 weeks' gestation were collected from hospital charts from clinics participating in this follow-up study. The main outcome measure was preterm birth < 37 weeks' gestation in a subsequent pregnancy., Results: Fourteen hospitals agreed to participate in this follow-up study. Of the 1142 eligible women, 572 had been allocated to induction of labor using a Foley catheter and 570 to induction of labor using prostaglandins. Of these, 162 (14%) were lost to follow-up. In total, 251 and 258 women had a known subsequent pregnancy > 16 weeks' gestation in the Foley catheter and prostaglandin groups, respectively. There were no differences in baseline characteristics between the groups. The overall rate of PTB in a subsequent pregnancy was 9/251 (3.6%) in the Foley catheter group vs 10/258 (3.9%) in the prostaglandin group (relative risk (RR), 0.93; 95% CI, 0.38-2.24), and the rate of spontaneous PTB was 5/251 (2.0%) vs 5/258 (1.9%) (RR, 1.03; 95% CI, 0.30-3.51)., Conclusion: In women with term singleton pregnancy, induction of labor using a 30-mL Foley catheter is not associated with an increased risk of PTB in a subsequent pregnancy, as compared to induction of labor using prostaglandins. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Introduction: There is little evidence to guide the timing of delivery of women with early-onset severe preeclampsia. We hypothesize that immediate delivery is not inferior for neonatal outcome but reduces maternal complications compared with temporizing management., Material and Methods: This Dutch multicenter open-label randomized clinical trial investigated non-inferiority for neonatal outcome of temporizing management as compared with immediate delivery (TOTEM NTR 2986) in women between 27 +5 and 33 +5  weeks of gestation admitted for early-onset severe preeclampsia with or without HELLP syndrome. In participants allocated to receive immediate delivery, either induction of labor or cesarean section was initiated at least 48 hours after admission. Primary outcomes were adverse perinatal outcome, defined as a composite of severe respiratory distress syndrome, bronchopulmonary dysplasia, culture proven sepsis, intraventricular hemorrhage grade 3 or worse, periventricular leukomalacia grade 2 or worse, necrotizing enterocolitis stage 2 or worse, and perinatal death. Major maternal complications were secondary outcomes. It was estimated 1130 women needed to be enrolled. Analysis was by intention-to-treat., Results: The trial was halted after 35 months because of slow recruitment. Between February 2011 and December 2013, a total of 56 women were randomized to immediate delivery (n = 26) or temporizing management (n = 30). Median gestational age at randomization was 30 weeks. Median prolongation of pregnancy was 2 days (interquartile range 1-3 days) in the temporizing management group. Mean birthweight was 1435 g after immediate delivery vs 1294 g after temporizing management (P = .14). The adverse perinatal outcome rate was 55% in the immediate delivery group vs 52% in the temporizing management group (relative risk 1.06; 95% confidence interval 0.67-1.70). In both groups there was one neonatal death and no maternal deaths. In the temporizing treatment group, one woman experienced pulmonary edema and one placental abruption. Analyses of only the singleton pregnancies did not result in other outcomes., Conclusions: Early termination of the trial precluded any conclusions for the main outcomes. We observed that temporizing management resulted in a modest prolongation of pregnancy without changes in perinatal and maternal outcome. Conducting a randomized study for this important research question did not prove feasible., (© 2020 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Introduction: In women with preterm ruptured membranes and contractions, the administration of tocolysis is controversial. This study compares tocolysis with no tocolysis in women with threatened preterm birth and ruptured membranes., Objective: To compare tocolysis with no tocolysis in women with threatened preterm birth and ruptured membranes., Study Design: Data from the APOSTEL III RCT was combined with data from the National Maternity Hospital, Dublin. In the APOSTEL III trial, women with threatened preterm birth were randomized to atosiban or nifedipine. Patient data from Ireland were obtained from a cohort of women with threatened preterm birth with ruptured membranes. The Irish women received no tocolytic treatment. Only women with ruptured membranes and contractions were selected. We studied women with singleton or twin pregnancies and a gestational age between 25 +0 and 33 +6 weeks. Propensity score matching was performed to create comparable groups. Primary outcome was a composite adverse neonatal outcome. Secondary outcomes were individual components of the primary outcome, as well as neonatal intensive care unit (NICU) admission, gestational age at delivery, prolongation of pregnancy and mode of delivery., Results: 153 women from the Apostel III trial were compared with 51 eligible women of the Irish cohort. We could match 46 women who received tocolysis and 46 women who received no tocolysis. All women had ruptured membranes. Maternal age, BMI, parity and gestational age at study entry were comparable between the groups after matching. There were no statistically significant differences in neonatal composite outcome (9.6 % in the tocolysis group versus 18 % in the control group, OR 0.46, 95 % CI 0.13-1.63). We found a lower incidence of NICU admission in the tocolysis group (63 %) than in the control group (94 %; OR 0.11, 95 % CI 0.03-0.41), which could be explained by differences in national admission policies. There were no statistically significant differences between tocolysis and no tocolysis in any of the other outcomes including sepsis, gestational age at delivery and time to delivery., Conclusion: In this propensity score analysis of women with threatened preterm birth and ruptured membranes, tocolytic therapy did not alter composite adverse neonatal outcome or time to delivery., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To compare the long-term effects of tocolysis with nifedipine or atosiban on child outcome at age 2.5-5.5 years., Design: The APOSTEL III trial was a multicentre randomised controlled trial that compared tocolysis with nifedipine or atosiban in 503 women with threatened preterm birth. Neonatal outcomes did not differ between both treatment arms, except for a higher incidence of intubation in the atosiban group., Methods: Parents were asked to complete four questionnaires regarding neurodevelopment, executive function, behaviour problems and general health., Main Outcome Measures: The main long-term outcome measure was a composite of abnormal development at the age of 2.5-5.5 years., Results: Of the 426 women eligible for follow-up, 196 (46%) parents returned the questionnaires for 115 children in the nifedipine group and 110 children in the atosiban group. Abnormal development occurred in 32 children (30%) in the nifedipine group and in 38 children (38%) in the atosiban group (OR 0.74, 95% CI 0.41-1.34). The separate outcomes for neurodevelopment, executive function, behaviour, and general health showed no significant differences between the groups. Sensitivity analysis for all children of the APOSTEL III trial, including a comparison of deceased children, resulted in a higher rate of healthy survival in the nifedipine group (64 versus 54%), but there was no significant difference in the overall mortality rate (5.4 versus 2.7%). There were no significant subgroup effects., Conclusion: Outcomes on broad child neurodevelopment, executive function, behaviour and general health were comparable in both groups. Neither nifedipine nor atosiban can be considered as the preferred treatment for women with threatened preterm birth., Tweetable Abstract: Nifedipine- and atosiban-exposed children had comparable long-term outcomes, including neurodevelopment, executive function and behaviour., (© 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Investigator-initiated clinical trials are crucial for improving quality of care for children and pregnant women as they are often excluded from industry-initiated trials. However, trials have become increasingly time-consuming and costly since the EU Clinical Trial Directive entered into force in 2001. This directive made compliance with ICH-Good Clinical Practice Guidelines (ethical and quality standard for conducting human subject research) mandatory for all clinical trials, regardless of its risk-classification. By discussing two investigator-initiated, 'low-risk' drug trials, we aim to illustrate that compliance with all GCP requirements makes trials very laborious and expensive, while a clear rationale is missing. This discourages clinical researchers to start and carry out investigator-initiated research. However, the forthcoming EU Clinical Trial Regulation (No 536/2014) seems to provide a solution as it allows for less stringent rules for low-risk trials. We want to raise awareness for these developments in both the clinical research community and the European and national regulatory authorities. Implementation of this forthcoming Regulation regulatory policies should be done in such a way that investigator-initiated trials evaluating standard care interventions will become more feasible. This will allow us to obtain evidence on optimal and safe treatments, especially for groups that are underrepresented in medical research. What is Known • Investigator-initiated trials are indispensable for improving care for children and pregnant women as they are often excluded from industry-initiated trials • Trials have become increasingly time-consuming and costly because of mandatory compliance with ICH-GCP guidelines What is New • The forthcoming EU Clinical Trial Regulation allows less stringent rules for low-risk trials • The national legislator and regulatory authorities should recognize the importance of this opportunity and implement the Regulation in such a way that investigator-initiated trials will become more feasible.

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.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Objective: To determine the risk of overall preterm birth (PTB) and spontaneous PTB in a pregnancy after a caesarean section (CS) at term., Design: Longitudinal linked national cohort study., Setting: The Dutch Perinatal Registry (1999-2009)., Population: 268 495 women with two subsequent singleton pregnancies were identified., Methods: A cohort study based on linked registered data from two subsequent pregnancies in the Netherlands., Main Outcome Measures: The incidence of overall PTB and spontaneous PTB with subgroup analysis on gestational age at first delivery and type of CS (planned or unplanned)., Results: Of 268 495 women with a singleton first pregnancy who delivered at term, 15.76% (n = 42 328) had a CS. The incidence of PTB in the second pregnancy was 2.79% (n = 1182) in women with a previous CS versus 2.46% (n = 5570) in women with a previous vaginal delivery (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 1.07-1.21). This increased risk is mainly driven by an increased risk of spontaneous PTB after previous CS at term (aOR 1.50, 95% CI 1.38-1.70). Analysis for type of CS compared with vaginal delivery showed an aOR on spontaneous PTB of 1.86 (95% CI 1.58-2.18) for planned CS and an aOR of 1.40 (95% CI 1.24-1.58) for unplanned CS., Conclusions: CS at term is associated with a marginally increased risk of spontaneous PTB in a subsequent pregnancy., Tweetable Abstract: Caesarean section at term is associated with a marginally increased risk of spontaneous PTB in a subsequent pregnancy., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Introduction: Preterm birth complicates >15 million pregnancies annually worldwide. In many countries, women who present with signs of preterm labour are treated with tocolytics for 48 hours. Although this delays birth, it has never been shown to improve neonatal outcome. In 2015, the WHO stated that the use of tocolytics should be reconsidered and that large placebo-controlled studies to evaluate the effectiveness of tocolytics are urgently needed., Methods and Analysis: We designed an international, multicentre, randomised, double-blinded, placebo-controlled clinical trial. Women with threatened preterm birth (gestational age 30-34 weeks), defined as uterine contractions with (1) a cervical length of < 15 mm or (2) a cervical length of 15-30 mm and a positive fibronectin test or (3) in centres where cervical length measurement is not part of the local protocol: a positive fibronectin test or insulin-like growth factor binding protein-1 (Actim-Partus test) or (4) ruptured membranes, will be randomly allocated to treatment with atosiban or placebo for 48 hours. The primary outcome is a composite of perinatal mortality and severe neonatal morbidity. Analysis will be by intention to treat. A sample size of 1514 participants (757 per group) will detect a reduction in adverse neonatal outcome from 10% to 6% (alpha 0.05, beta 0.2). A cost-effectiveness analysis will be performed from a societal perspective., Ethics and Dissemination: This study has been approved by the Research Ethics Committee (REC) of the Amsterdam University Medical Centres, location AMC, as well as the REC's in Dublin and the UK. The results will be presented at conferences and published in a peer-reviewed journal. Participants will be informed about the results., Trial Registration Number: Nederlands Trial Register (Trial NL6469)., Competing Interests: Competing interests: JT received a number of lectures and medical advisory fees from Ferring pharmaceuticals between 2000 and 2016., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Objective: Pregnant women with congenital heart disease (CHD) have an increased risk of abnormal uteroplacental flow, measured from the second trimester onwards, which is associated with pregnancy complications affecting the mother and the fetus. Maternal right ventricular (RV) dysfunction has been suggested as a predisposing factor for impaired uteroplacental flow in these women. The aim of this study was to investigate the association of first-trimester uteroplacental flow measurements with prepregnancy maternal cardiac function and pregnancy complications in women with CHD, with particular focus on the potential role of RV (dys)function., Methods: This study included 138 pregnant women with CHD from the prospective ZAHARA III study (Zwangerschap bij Aangeboren HARtAfwijkingen; Pregnancy and CHD). Prepregnancy clinical and echocardiographic data were collected. Clinical evaluation, echocardiography (focused on RV function, as assessed by tricuspid annular plane systolic excursion (TAPSE)) and uterine artery (UtA) pulsatility index (PI) measurements were performed at 12, 20 and 32 weeks of gestation. Univariable and multivariable regression analyses were performed to assess the association between prepregnancy variables and UtA-PI during pregnancy. The association between UtA-PI at 12 weeks and cardiovascular, obstetric and neonatal complications was also assessed., Results: On multivariable regression analysis, prepregnancy TAPSE was associated negatively with UtA-PI at 12 weeks of gestation (β = -0.026; P = 0.036). Women with lower prepregnancy TAPSE (≤ 20 mm vs > 20 mm) had higher UtA-PI at 12 weeks (1.5 ± 0.5 vs 1.2 ± 0.6; P = 0.047). Increased UtA-PI at 12 weeks was associated with obstetric complications (P = 0.003), particularly hypertensive disorders (pregnancy-induced hypertension and pre-eclampsia, P = 0.019 and P = 0.026, respectively)., Conclusions: In women with CHD, RV dysfunction before pregnancy seems to impact placentation, resulting in increased resistance in UtA flow, which is detectable as early as in the first trimester. This, in turn, is associated with pregnancy complications. Early monitoring of uteroplacental flow might be of value in women with CHD with pre-existing subclinical RV dysfunction to identify pregnancies that would benefit from close obstetric surveillance. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.)

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 +0 weeks and preterm birth between 25 +0 -27 +6 weeks, 28 +0 -30 +6 weeks, 31 +0 -33 +6 weeks, and 34 +0 -36 +6 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.

Competing Interests: Competing interests: None declared.

Introduction: When women with a previous cesarean section and an unfavorable cervix have an indication for delivery, the choice is to induce labor or to perform a cesarean section. This study aims to assess the effectiveness and safety of a balloon catheter as a method of induction of labor in women with one previous cesarean section and an unfavorable cervix compared with an elective repeat cesarean section., Material and Methods: We performed a prospective cohort study in 51 hospitals in the Netherlands on term women with one previous cesarean section, a live singleton fetus in cephalic position, an unfavorable cervix and an indication for delivery. We recorded obstetric, maternal and neonatal characteristics. We compared the outcome of women who were induced with a balloon catheter with the outcome of women who delivered by elective repeat cesarean section. Main outcomes were maternal and neonatal morbidity. Mode of delivery was a secondary outcome for women who were induced. Adjusted odds ratios (aOR) were calculated using logistic regression, adjusted for potential confounders., Results: Analysis was performed on 993 women who were induced and 321 women who had a repeat cesarean section (August 2011 until September 2012). Among the women who were induced, 560 (56.4%) delivered vaginally and 11 (1.1%) sustained a uterine rupture. Composite adverse maternal outcome (uterine rupture, severe postpartum hemorrhage or postpartum infection) occurred in 73 (7.4%) in the balloon and 14 (4.5%) women in the repeat cesarean section group (aOR 1.58, 95% confidence interval [CI] 0.85-2.96). Composite adverse neonatal outcome (Apgar score <7 at 5 minutes or umbilical pH <7.10) occurred in 57 (5.7%) and 10 (3.2%) neonates, respectively (aOR 1.40, 95% CI 0.87-3.48). Women who were induced had a shorter postpartum admission time (2.0 vs 3.0 days (P < 0.0001))., Conclusions: In women with a previous cesarean section and a need for delivery, induction of labor with a balloon catheter does not result in a significant increase in adverse maternal and neonatal outcomes as compared with planned cesarean section., (© 2019 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)