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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. [ABSTRACT FROM AUTHOR]

Background: Preterm birth is a major cause of neonatal mortality and morbidity. As preventive strategies are largely ineffective, threatened preterm labor is a frequent problem that affects approximately 10 % of pregnancies. In recent years, risk assessment in these women has incorporated cervical length measurement and fetal fibronectin testing, and this has improved the capacity to identify women at increased risk for delivery within 14 days. Despite these improvements, risk for preterm birth continues to be increased in women who did not deliver after an episode of threatened preterm labor, as indicated by a preterm birth rate between 30 to 60 % in this group of women. Currently no effective treatment is available. Studies on maintenance tocolysis and progesterone have shown ambiguous results. The pessary has not been evaluated in women with threatened preterm labor, however studies in asymptomatic women with a short cervix show reduced rates of preterm birth rates as well as perinatal complications. The APOSTEL VI trial aims to assess the effectiveness of a cervical pessary in women who did not deliver within 48 h after an episode of threatened preterm labor.Methods/design: This is a nationwide multicenter open-label randomized clinical trial. Women with a singleton or twin gestation with intact membranes, who were admitted for threatened preterm labor, at a gestational age between 24 and 34 weeks, a cervical length between 15 and 30 mm and a positive fibronectin test or a cervical length below 15 mm, who did not deliver after 48 h will be eligible for inclusion. Women will be allocated to a pessary or no intervention (usual care). Primary outcome is preterm delivery < 37 weeks. Secondary outcomes are amongst others a composite of perinatal morbidity and mortality. Sample size is based on an expected 50 % reduction of preterm birth before 37 weeks (two-sided test, α 0.05 and β 0.2). Two hundred women with a singleton pregnancy need to be randomized. Analysis will be done by intention to treat.Discussion: The APOSTEL VI trial will provide evidence whether a pessary is effective in preventing preterm birth in women who did not deliver 48 h after admission for threatened preterm labor and who remain at high risk for preterm birth.Trial Registration: Trial is registered at the Dutch Trial Register: http://www.trialregister.nl , NTR4210, date of registration: October 16th 2013. [ABSTRACT FROM AUTHOR]

Background: Hyperemesis gravidarum (HG), or intractable vomiting during pregnancy, is the single most frequent cause of hospital admission in early pregnancy. HG has a major impact on maternal quality of life and has repeatedly been associated with poor pregnancy outcome such as low birth weight. Currently, women with HG are admitted to hospital for intravenous fluid replacement, without receiving specific nutritional attention. Nasogastric tube feeding is sometimes used as last resort treatment. At present no randomised trials on dietary or rehydration interventions have been performed. Small observational studies indicate that enteral tube feeding may have the ability to effectively treat dehydration and malnutrition and alleviate nausea and vomiting symptoms. We aim to evaluate the effectiveness of early enteral tube feeding in addition to standard care on nausea and vomiting symptoms and pregnancy outcomes in HG patients.Methods/design: The MOTHER trial is a multicentre open label randomised controlled trial ( www.studies-obsgyn.nl/mother ). Women ≥ 18 years hospitalised for HG between 5 + 0 and 19 + 6 weeks gestation are eligible for participation. After informed consent participants are randomly allocated to standard care with intravenous rehydration or early enteral tube feeding in addition to standard care. All women keep a weekly diary to record symptoms and dietary intake until 20 weeks gestation. The primary outcome will be neonatal birth weight. Secondary outcomes will be the 24-h Pregnancy Unique Quantification of Emesis and nausea score (PUQE-24), maternal weight gain, dietary intake, duration of hospital stay, number of readmissions, quality of life and side-effects. Also gestational age at birth, placental weight, umbilical cord plasma lipid concentration and neonatal morbidity will be evaluated. Analysis will be according to the intention to treat principle.Discussion: With this trial we aim to clarify whether early enteral tube feeding is more effective in treating HG than intravenous rehydration alone and improves pregnancy outcome.Trial Registration: Trial Registration Number: NTR4197 . Date of registration: October 2(nd) 2013. [ABSTRACT FROM AUTHOR]

Objective To evaluate whether tocolysis with nifedipine can be omitted in women with symptoms of preterm labor, a shortened cervix, and negative fetal fibronectin test. Study Design A randomized noninferiority trial was performed in all Dutch perinatal centers. Women with symptoms of preterm labor between 24 and 34 weeks, intact membranes, cervical length between 10 and 30 mm, and negative fibronectin test were randomly allocated to nifedipine (80 mg/day) or placebo. The primary outcome was delivery within 7 days. Secondary outcomes were severe neonatal morbidity and mortality. We also followed all eligible nonrandomized women. Results We allocated 37 women to nifedipine and 36 women to placebo. In the nifedipine group, three women (8.1%) delivered within 7 days, compared with one woman (2.8%) in the placebo group (difference -5.3%; one-sided 95% confidence limit 4.5%). Median gestational age at delivery were respectively 37 + 0 (interquartile range [IQR] 34 + 6 to 38 + 5) and 38 + 2 (IQR 37 + 0 to 39 + 6) weeks (p = 0.008). In the nifedipine group, three pregnancies (8.1%) had a poor outcome; there were no poor outcomes in the placebo group. We observed similar trends in eligible nonrandomized women. Conclusion In symptomatic women with preterm labor, a shortened cervix, and negative fibronectin test, placebo treatment is not inferior to tocolysis with nifedipine. [ABSTRACT FROM AUTHOR]

Objective: To assess the effectiveness of amnioinfusion in women with second-trimester preterm prelabor rupture of membranes.Methods: We performed a nationwide, multicenter, open-label, randomized controlled trial, the PPROM: Expectant Management versus Induction of Labor-III (PPROMEXIL-III) trial, in women with singleton pregnancies and preterm prelabor rupture of membranes at 16 0/7 to 24 0/7 weeks of gestation with oligohydramnios (single deepest pocket less than 20 mm). Participants were allocated to transabdominal amnioinfusion or no intervention in a one-to-one ratio by a web-based system. If the single deepest pocket was less than 20 mm on follow-up visits, amnioinfusion was repeated weekly until 28 0/7 weeks of gestation. The primary outcome was perinatal mortality. We needed 56 women to show a reduction in perinatal mortality from 70% to 35% (β error 0.20, two-sided α error 0.05).Results: Between June 15, 2012, and January 13, 2016, we randomized 28 women to amnioinfusion and 28 to no intervention. One woman was enrolled before the trial registration date (June 19, 2012). Perinatal mortality rates were 18 of 28 (64%) in the amnioinfusion group vs 21 of 28 (75%) in the no intervention group (relative risk 0.86, 95% CI 0.60-1.22, P=.39).Conclusion: In women with second-trimester preterm prelabor rupture of membranes and oligohydramnios, we found no reduction in perinatal mortality after amnioinfusion.Clinical Trial Registration: NTR Dutch Trial Register, NTR3492. [ABSTRACT FROM AUTHOR]

Objective: Preterm birth is the most common cause of neonatal morbidity and mortality. Around one third of preterm deliveries starts with preterm prelabor rupture of membranes (PPROM). The aim of this trial was to study the effect of prolonged tocolysis with nifedipine versus placebo in women with PPROM on perinatal outcome and prolongation of pregnancy.Study Design: The Apostel IV was a nationwide multicenter randomized placebo controlled trial. We included women with PPROM without contractions between 24(+0) and 33(+6) weeks of gestation. Participants were randomly allocated to daily 80mg nifedipine or placebo, until the start of labor, with a maximum of 18 days. The primary outcome measure was a composite of poor neonatal outcome, including perinatal death, bronchopulmonary dysplasia, periventricular leukomalacia>grade 1, intraventricular hemorrhage>grade 2, necrotizing enterocolitis>stage 1 and culture proven sepsis. Secondary outcomes were gestational age at delivery and prolongation of pregnancy. Analysis was by intention to treat. To detect a reduction of poor neonatal outcome from 30% to 10%, 120 women needed to be randomized.Trial Registry: NTR 3363.Results: Between October 2012 and December 2014 we randomized 25 women to nifedipine and 25 women to placebo. Due to slow recruitment the study was stopped prematurely. The median gestational age at randomization was 29.9 weeks (IQR 27.7-31.3) in the nifedipine group and 27.0 weeks (IQR 24.7-29.9) in the placebo group. Other baseline characteristics were comparable. The adverse perinatal outcome occurred in 9 neonates (33.3%) in the nifedipine group and 9 neonates (32.1%) in the placebo group (RR 1.04, 95% CI 0.49-2.2). Two perinatal deaths occurred, both in the nifedipine group. Bronchopulmonary dysplasia was seen less frequently in the nifedipine group (0% versus 17.9%; p=0.03). Prolongation of pregnancy did not differ between the nifedipine and placebo group (median 11 versus 8 days, HR 1.02; 95% CI 0.58-1.79).Conclusion: This randomized trial did not show a beneficial effect of prolonged tocolysis on neonatal outcomes or prolongation of pregnancy in women with PPROM without contractions. However, since results are based on a small sample size, a difference in effectiveness cannot be excluded. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]