Is it safe to give birth with an activated implantable cardioverter-defibrillator: A multicentre observational study.

OBJECTIVE: Data and guidelines are lacking, so implantable cardioverter-defibrillators (ICDs) are often deactivated during labour to prevent inappropriate shocks. This study aimed to ascertain the safety of an activated ICD during labour. DESIGN: An observational study was performed. SETTING: Dutch hospitals. POPULATION OR SAMPLE: A total of 41 childbirths were included of 26 patients who gave birth between February 2009 and November 2018 after receiving an ICD in our tertiary hospital. Five of these childbirths were attended by the research team between December 2018 and August 2020, during which the ICD remained active. METHODS: Groups were made based on ICD status during labour. Patients who gave birth with an activated ICD at least once were stratified to the activated ICD group. Patients' files were checked and patients received a questionnaire about childbirth perceptions and treatment preferences. The differences in ordinal data resulting from the questionnaire were calculated using a chi-square or Fisher's exact test. MAIN OUTCOME MEASURES: Primary outcome was inappropriate ICD therapy and occurrence of ventricular arrhythmias requiring treatment. RESULTS: During the 41 childbirths, no inappropriate shocks or ventricular arrhythmias occurred during labour. All patients in the activated ICD group (n = 13) preferred this setting, while 8 of the 13 patients in the deactivated ICD group preferred activation (p = 0.002). Reasons included avoiding hemodynamic monitoring, magnet placement, or labour induction to facilitate technician availability. CONCLUSIONS: This study shows no evidence that labour and birth in women with an activated ICD are unsafe, as there were no ventricular arrhythmias or inappropriate therapy. In addition, most patients prefer an activated ICD during labour.

Patient perspectives and preferences on cerclage and preterm birth: a focus group study.

AIM: This qualitative focus group study aims to asses cerclage-related symptoms, the impact of a cerclage on daily functioning and patient perspectives of their healthcare experience. This study extends beyond the current focus on surgical and obstetric outcomes of a cerclage, thereby contributing to a more comprehensive understanding of the challenges faced by individuals in the context of extreme preterm birth and fetal loss and the impact of a cerclage on multiple facets in life. METHODS: Participants were recruited from the Amsterdam University Medical Center, Amsterdam, the Netherlands or via the website of a Dutch patient organization for (extreme) preterm birth. Eligible participants were ≥ 18 years old with a previous vaginal and/or abdominal cerclage with a subsequent delivery at ≥ 34 weeks of gestation with neonatal survival. Two focus group discussions (FGD) were performed. A predefined format was used, which was identical for both the vaginal and abdominal cerclage group. The International Classification of Functioning, Disability and Health (ICF-DH) was used to provide structure. Outcomes were a broad range of participants reported perspectives on physical, emotional, and social-related quality of life. RESULTS: In the Vaginal Cerclage Group (VCG) and Abdominal Cerclage Group (ACG), respectively, 11 and 8 participants were included. Fear for a subsequent pregnancy loss was the most limiting factor to perform daily activities during pregnancy in all participants with a cerclage. Fear to conceive again because of prior second-trimester fetal loss was experienced by 27% in the VCG and 13% in the ACG. The majority of participants experienced a reduction in anxiety after placement of their cerclage (VCG = 64%, ACG = 75%). Decreased mobility/bedrest (VCG = 100%, ACG = 75%) and blood loss (VCG = 55%, ACG = 13%) were frequently mentioned complaints during pregnancy with cerclage. Other aspects mentioned in both groups were social isolation, the lack of societal participation, and the perceived need to quit work and sports. All participants in the abdominal cerclage group reported a lack of comprehensible and unambiguous information about obstetric management and expectations during pregnancy in secondary care hospitals. Clear communication between secondary and tertiary care hospitals about obstetric management following an abdominal cerclage, for example, about the need for cervical length measurements by ultrasound, the need for bedrest or advice concerning sexual activity was missing (63%). Psychologic support was desired in half of all participants, but was not offered to them. CONCLUSIONS: The fear of a subsequent pregnancy loss was reported as the most limiting factor in daily life by all participants. Cerclage placement resulted in the reduction of anxiety. Participants mentioned a significant impact of bedrest and activity restriction during pregnancy with cerclage on social participation and daily activities. Unfortunately, no high level evidence is available on this matter. Patients might even benefit from appropriate levels of physical activity throughout their pregnancy to promote their overall well-being. More evidence is needed to determine the optimal level of physical activity. There is a need for clear and unambiguous patient information about obstetric management.

Trends in preterm birth in the Netherlands in 2011-2019: A population-based study among singletons and multiples.

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.

The association between spontaneous preterm birth and maternal hypertension in the fifth decade of life: a retrospective case-control study.

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.

Progestogen maintenance therapy for prolongation of pregnancy after an episode of preterm labour: A systematic review and meta-analysis.

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.

Long-Term Maternal Mental Health after Spontaneous Preterm Birth.

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 220/7 and 366/7 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..

Evaluation of low-dose aspirin in the prevention of recurrent spontaneous preterm labour (the APRIL study): A multicentre, randomised, double-blinded, placebo-controlled trial.

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.

Tocolysis with nifedipine versus atosiban and perinatal outcome: an individual participant data meta-analysis.

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 240/7 and 340/7 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.

Temporizing management vs immediate delivery in early-onset severe preeclampsia between 28 and 34 weeks of gestation (TOTEM study): An open-label randomized controlled trial.

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.

Nationwide implementation of a decision aid on vaginal birth after cesarean: a before and after cohort study.

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.

TBX2, a Novel Regulator of Labour.

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.

Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses.

BACKGROUND: Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth. METHODS: We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134. FINDINGS: We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165 136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163 947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73-2·89]; I2=59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74-0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35-0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02-0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 µmol/L versus four (0·28%; 0·08-0·72) of 1412 cases with total bile acids of 40-99 µmol/L (hazard ratio [HR] 2·35 [95% CI 0·52-10·50]; p=0·26), and versus 18 (3·44%; 2·05-5·37) of 524 cases for bile acids of 100 µmol/L or more (HR 30·50 [8·83-105·30]; p<0·0001). INTERPRETATION: The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 µmol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery. FUNDING: Tommy's, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust.

Low-risk trials for children and pregnant women threatened by unnecessary strict regulations. Does the coming EU Clinical Trial Regulation offer a solution?

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.

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

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.

A qualitative study on stakeholders' views on the participation of pregnant women in the APOSTEL VI study: a low-risk obstetrical RCT.

BACKGROUND: Bioethicists argue that inclusion of pregnant women in clinical research should be more routine to increase the evidence-base for pregnant women and foetuses. Yet, it is unknown whether pregnant women and others directly involved are willing to be routinely included. Therefore, we first need to establish what these stakeholders think about research participation in regular pregnancy-related research. However, studies on their views are scarce. In our study, we piggy-backed on a relatively conventional RCT, the APOSTEL VI study, to identify the views of stakeholders on inclusion of pregnant women in this study. METHODS: We conducted a prospective qualitative study using 35 in-depth semi-structured interviews and one focus group. We interviewed pregnant women (n = 14) recruited for the APOSTEL VI study, in addition to healthcare professionals (n = 14), Research Ethics Committee members (RECs) (n = 5) and regulators (n = 7) involved in clinical research in pregnant women. RESULTS: Three themes characterise stakeholders' views on inclusion of pregnant women in the APOSTEL VI study. Additionally, one theme characterises stakeholders' interest in inclusion of pregnant women in clinical research in general. First, pregnant women participate in the APOSTEL VI study for potential individual benefit and secondarily for altruistic motives, contrary to hypothetical studies. Second, a gatekeeping tendency hampers recruitment of pregnant women who might be eligible and willing, and questions about pregnant women's decisional capacities surface. Third, healthcare professionals sometimes use the counselling conversation to steer pregnant women in a direction. Fourth, all stakeholders are hesitant about inclusion of pregnant women in clinical research in general due to a protective sentiment. CONCLUSIONS: Pregnant women are willing to participate in the APOSTEL VI study for potential individual benefit and altruistic motives. However, an underlying protective sentiment, resulting in gatekeeping and directive counselling, sometimes hampers recruitment in the APOSTEL VI study as well as in clinical research in general. While bioethicists claim that inclusion of pregnant women should be customary, our study indicates that healthcare professionals, regulators, RECs and pregnant women themselves are not necessarily interested in inclusion. Advancing the situation and increasing the evidence-base for pregnant women and foetuses may require additional measures such as investing in the recruitment and feasibility of RCTs and stimulating pregnant women's decisional capacities.

Balloon catheter for induction of labor in women with one previous cesarean and an unfavorable cervix.

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.

Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial.

BACKGROUND: In women with threatened preterm birth, delay of delivery by 48 h allows antenatal corticosteroids to improve neonatal outcomes. For this reason, tocolytics are often administered for 48 h; however, there is no consensus about which drug results in the best maternal and neonatal outcomes. In the APOSTEL III trial we aimed to compare the effectiveness and safety of the calcium-channel blocker nifedipine and the oxytocin inhibitor atosiban in women with threatened preterm birth. METHODS: We did this multicentre, randomised controlled trial in ten tertiary and nine teaching hospitals in the Netherlands and Belgium. Women with threatened preterm birth (gestational age 25-34 weeks) were randomly assigned (1:1) to either oral nifedipine or intravenous atosiban for 48 h. An independent data manager used a web-based computerised programme to randomly assign women in permuted block sizes of four, with groups stratified by centre. Clinicians, outcome assessors, and women were not masked to treatment group. The primary outcome was a composite of adverse perinatal outcomes, which included perinatal mortality, bronchopulmonary dysplasia, sepsis, intraventricular haemorrhage, periventricular leukomalacia, and necrotising enterocolitis. Analysis was done in all women and babies with follow-up data. The study is registered at the Dutch Clinical Trial Registry, number NTR2947. FINDINGS: Between July 6, 2011, and July 7, 2014, we randomly assigned 254 women to nifedipine and 256 to atosiban. Primary outcome data were available for 248 women and 297 babies in the nifedipine group and 255 women and 294 babies in the atosiban group. The primary outcome occurred in 42 babies (14%) in the nifedipine group and in 45 (15%) in the atosiban group (relative risk [RR] 0·91, 95% CI 0·61-1·37). 16 (5%) babies died in the nifedipine group and seven (2%) died in the atosiban group (RR 2·20, 95% CI 0·91-5·33); all deaths were deemed unlikely to be related to the study drug. Maternal adverse events did not differ between groups. INTERPRETATION: In women with threatened preterm birth, 48 h of tocolysis with nifedipine or atosiban results in similar perinatal outcomes. Future clinical research should focus on large placebo-controlled trials, powered for perinatal outcomes. FUNDING: ZonMw (the Netherlands Organisation for Health Research and Development).

Induction of labour at term with oral misoprostol versus a Foley catheter (PROBAAT-II): a multicentre randomised controlled non-inferiority trial.

BACKGROUND: Labour is induced in 20-30% of all pregnancies. In women with an unfavourable cervix, both oral misoprostol and Foley catheter are equally effective compared with dinoprostone in establishing vaginal birth, but each has a better safety profile. We did a trial to directly compare oral misoprostol with Foley catheter alone. METHODS: We did an open-label randomised non-inferiority trial in 29 hospitals in the Netherlands. Women with a term singleton pregnancy in cephalic presentation, an unfavourable cervix, intact membranes, and without a previous caesarean section who were scheduled for induction of labour were randomly allocated to cervical ripening with 50 µg oral misoprostol once every 4 h or to a 30 mL transcervical Foley catheter. The primary outcome was a composite of asphyxia (pH ≤7·05 or 5-min Apgar score <7) or post-partum haemorrhage (≥1000 mL). The non-inferiority margin was 5%. The trial is registered with the Netherlands Trial Register, NTR3466. FINDINGS: Between July, 2012, and October, 2013, we randomly assigned 932 women to oral misoprostol and 927 women to Foley catheter. The composite primary outcome occurred in 113 (12·2%) of 924 participants in the misoprostol group versus 106 (11·5%) of 921 in the Foley catheter group (adjusted relative risk 1·06, 90% CI 0·86-1·31). Caesarean section occurred in 155 (16·8%) women versus 185 (20·1%; relative risk 0·84, 95% CI 0·69-1·02, p=0·067). 27 adverse events were reported in the misoprostol group versus 25 in the Foley catheter group. None were directly related to the study procedure. INTERPRETATION: In women with an unfavourable cervix at term, induction of labour with oral misoprostol and Foley catheter has similar safety and effectiveness. FUNDING: FondsNutsOhra.

Low dose aspirin in the prevention of recurrent spontaneous preterm labour - the APRIL study: a multicenter randomized placebo controlled trial.

BACKGROUND: Preterm birth (birth before 37 weeks of gestation) is a major problem in obstetrics and affects an estimated 15 million pregnancies worldwide annually. A history of previous preterm birth is the strongest risk factor for preterm birth, and recurrent spontaneous preterm birth affects more than 2.5 million pregnancies each year. A recent meta-analysis showed possible benefits of the use of low dose aspirin in the prevention of recurrent spontaneous preterm birth. We will assess the (cost-)effectiveness of low dose aspirin in comparison with placebo in the prevention of recurrent spontaneous preterm birth in a randomized clinical trial. METHODS/DESIGN: Women with a singleton pregnancy and a history of spontaneous preterm birth in a singleton pregnancy (22-37 weeks of gestation) will be asked to participate in a multicenter, randomized, double blinded, placebo controlled trial. Women will be randomized to low dose aspirin (80 mg once daily) or placebo, initiated from 8 to 16 weeks up to maximal 36 weeks of gestation. The primary outcome measure will be preterm birth, defined as birth at a gestational age (GA) < 37 weeks. Secondary outcomes will be a composite of adverse neonatal outcome and maternal outcomes, including subgroups of prematurity, as well as intrauterine growth restriction (IUGR) and costs from a healthcare perspective. Preterm birth will be analyzed as a group, as well as separately for spontaneous or indicated onset. Analysis will be performed by intention to treat. In total, 406 pregnant women have to be randomized to show a reduction of 35% in preterm birth from 36 to 23%. If aspirin is effective in preventing preterm birth, we expect that there will be cost savings, because of the low costs of aspirin. To evaluate this, a cost-effectiveness analysis will be performed comparing preventive treatment with aspirin with placebo. DISCUSSION: This trial will provide evidence as to whether or not low dose aspirin is (cost-) effective in reducing recurrence of spontaneous preterm birth. TRIAL REGISTRATION: Clinical trial registration number of the Dutch Trial Register: NTR 5675 . EudraCT-registration number: 2015-003220-31.