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Aim: To investigate the association between morphine exposure in the neonatal period and neurodevelopment at 2 and 5 years of age while controlling for potential confounders. Method: We performed a retrospective, single‐centre cohort study on 106 infants (60 males, 46 females; mean gestational age 26 weeks [SD 1]) born extremely preterm (gestational age < 28 weeks). Morphine administration was expressed as cumulative dose (mg/kg) until term‐equivalent age. Neurodevelopmental outcome was assessed at 2 years with the Bayley Scales of Infant and Toddler Development, Third Edition, Dutch version and at 5 years with the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, Dutch version. Multiple linear regression analysis was used to assess the association between morphine exposure and outcome. Results: Sixty‐four out of 106 (60.4%) infants included in the study received morphine. Morphine exposure was not associated with poorer motor, cognitive, and language subscores of the Bayley Scales of Infant and Toddler Development, Third Edition, Dutch version at 2 years. Morphine exposure was associated with lower Full‐Scale IQ scores (p = 0.008, B = −9.3, 95% confidence interval [CI] = −15.6 to −3.1) and Performance IQ scores (p = 0.005, B = −17.5, 95% CI = −27.9 to −7) at 5 years of age. Interpretation: Morphine exposure in infants born preterm is associated with poorer Full‐Scale IQ and Performance IQ at 5 years. Individualized morphine administration is advised in infants born extremely preterm. What this paper adds: A significant association between morphine exposure and neurodevelopmental impairment at 5 years was observed.Higher exposure to painful and stressful procedures during the neonatal period was associated with poorer abilities at 5 years of age.Differently from previous studies on morphine, this association was also considered in the statistical analysis.A more individualized morphine administration is advised in infants born extremely preterm to counteract the negative effects of high stress without affecting neurodevelopment. [ABSTRACT FROM AUTHOR]

Abstract Background Hypertensive disorders, i.e. pregnancy induced hypertension and preeclampsia, complicate 10 to15% of all pregnancies at term and are a major cause of maternal and perinatal morbidity and mortality. The only causal treatment is delivery. In case of preterm pregnancies conservative management is advocated if the risks for mother and child remain acceptable. In contrast, there is no consensus on how to manage mild hypertensive disease in pregnancies at term. Induction of labour might prevent maternal and neonatal complications at the expense of increased instrumental vaginal delivery rates and caesarean section rates. Methods/Design Women with a pregnancy complicated by pregnancy induced hypertension or mild preeclampsia at a gestational age between 36+0 and 41+0 weeks will be asked to participate in a multi-centre randomised controlled trial. Women will be randomised to either induction of labour or expectant management for spontaneous delivery. The primary outcome of this study is severe maternal morbidity, which can be complicated by maternal mortality in rare cases. Secondary outcome measures are neonatal mortality and morbidity, caesarean and vaginal instrumental delivery rates, maternal quality of life and costs. Analysis will be by intention to treat. In total, 720 pregnant women have to be randomised to show a reduction in severe maternal complications of hypertensive disease from 12 to 6%. Discussion This trial will provide evidence as to whether or not induction of labour in women with pregnancy induced hypertension or mild preeclampsia (nearly) at term is an effective treatment to prevent severe maternal complications. Trial Registration The protocol is registered in the clinical trial register number ISRCTN08132825.

Biomarkers that predict treatment effects may be used to guide treatment decisions, thus improving patient outcomes. A meta-analysis of individual participant data (IPD) is potentially more powerful than a single-study data analysis in evaluating markers for treatment selection. Our study was motivated by the IPD that were collected from 2 randomized controlled trials of hypertension and preeclampsia among pregnant women to evaluate the effect of labor induction over expectant management of the pregnancy in preventing progression to severe maternal disease. The existing literature on statistical methods for biomarker evaluation in IPD meta-analysis have evaluated a marker's performance in terms of its ability to predict risk of disease outcome, which do not directly apply to the treatment selection problem. In this study, we propose a statistical framework for evaluating a marker for treatment selection given IPD from a small number of individual clinical trials. We derive marker-based treatment rules by minimizing the average expected outcome across studies. The application of the proposed methods to the IPD from 2 studies in women with hypertension in pregnancy is presented. [ABSTRACT FROM AUTHOR]

Background: Results from a number of long-term follow-up studies have suggested that hypertensive disorders in pregnancy are associated with increased risk of cardiovascular disease later in life. More recently, this putative relationship has been substantiated with findings of elevated cardiovascular risk factors, such as lipid profiles and glucose, in women with a history of hypertensive pregnancy disorders. Homocysteine is a sensitive indicator of increased risk but data on homocysteine levels in women with a history of hypertensive pregnancy disorders are inconsistent. Design: This cohort study included 279 women with a history of hypertensive pregnancy disorders at term and 85 women with a history of uncomplicated pregnancies who participated in the Hypitat Risk Assessment Study (HyRAS). Methods: Blood samples for total homocysteine determination were taken 2.5 years postpartum. Homocysteine levels were determined in plasma using an immunoassay. Results: Women with a history of hypertensive pregnancy disorders had significant higher median homocysteine levels (10.66 μmol/L) 2.5 years postpartum compared with women with a history uncomplicated pregnancies (9.82 μmol/L; p=0.002). Women with a history of hypertensive pregnancy disorders had a higher risk of having a homocysteine level in the highest quartile (odds ratio 3.4, 95% confidence interval 1.5-7.6). Conclusion: At 2.5 years postpartum, women with a history hypertensive pregnancy disorders had higher homocysteine levels than women who had uncomplicated pregnancies. Although higher homocysteine levels might be a potential link between a history of hypertensive pregnancy disorders and increased cardiovascular disease risk later in life, the clinical implications remain an area for future research. [ABSTRACT FROM AUTHOR]

Objective To assess whether postpartum hemorrhage can be predicted in women with gestational hypertension or mild preeclampsia at term. Design A cohort study in which we used data from our multicentre randomized controlled trial ( HYPITAT trial). Setting The study was conducted in 38 hospitals in the Netherlands between 2005 and 2008. Population Women with gestational hypertension or mild preeclampsia at term ( n = 1132). Methods An antepartum model (model A) and an antepartum/intrapartum model (model B) were created using logistic regression. The predictive capacity of the models was assessed with receiver operating characteristic analysis and calibration. Main outcome measure Postpartum hemorrhage, defined as blood loss >1000 mL within 24 h after delivery. Results Postpartum hemorrhage occurred in 118 (10.4%) women. Maternal age (odds ratio 1.03), prepregnancy body mass index (odds ratio 0.96), and women with preeclampsia (odds ratio 1.5) were independent antepartum prognostic variables of postpartum hemorrhage. Intrapartum variables incorporated in the model were gestational age at delivery (odds ratio 1.2), duration of dilatation stage (odds ratio 1.1), and episiotomy (odds ratio 1.5). Model A and model B showed moderate discrimination, with areas under the receiver operating characteristic curve of 0.59 (95% confidence interval 0.53-0.64) and 0.64 (95% confidence interval 0.59-0.70), respectively. Calibration was moderate for model A (Hosmer-Lemeshow p = 0.26) but better for model B (Hosmer-Lemeshow p = 0.36). The rates of postpartum hemorrhage ranged from 4% (lowest 10%) to 22% (highest 10%). Conclusion In the assessment of performance of a prediction model, calibration is more important than discriminative capacity. Our prediction model shows that for women with gestational hypertension or mild preeclampsia at term, distinction between low and high risk of developing postpartum hemorrhage is possible when antepartum and intrapartum variables are combined. [ABSTRACT FROM AUTHOR]

Objective. To evaluate whether eclampsia can be predicted in gestational hypertension or mild preeclampsia at term. Methods. For this case-control study we selected 76 cases with eclampsia from the LEMMoN study and 1149 controls with mild hypertensive disease of pregnancy, who did not develop eclampsia, from the HYPITAT study. Risk indicators for eclampsia, identified in multivariable logistic regression, were used to assess the predictive capacity of our model with receiver-operating characteristic (ROC) curve analysis. Model optimism was assessed with bootstrapping. Results. Maternal age, non-Caucasian ethnicity, systolic blood pressure >155 mmHg, ≥2++ protein on dipstick, elevated uric acid, creatinin >74 μmol//L, aspartate aminotransferase >30 U//L, and lactate dehydrogenase >400 U//L were significantly associated with eclampsia. Other factors included in the model were previous fetal loss, previous miscarriage, gestational age, and low platelet count. The area under the ROC curve was 0.92. Bootstrapping showed minimal overfitting of the model. Conclusion. In women with gestational hypertension or mild preeclampsia at term eclampsia can be predicted. [ABSTRACT FROM AUTHOR]

Objective. Gestational hypertension (GH) and preeclampsia (PE) are major contributors to maternal and neonatal morbidity and mortality. In GH or PE, labor may be either induced or monitored expectantly. We studied maternal health-related quality of life (HR-QoL) after induction of labor versus expectant monitoring in GH or PE at term. We performed the HR-QoL study alongside a multicenter randomized controlled trial comparing induction of labor to expectant monitoring in women with GH or PE after 36 weeks. Methods. We used written questionnaires, covering background characteristics, condition-specific issues, and validated measures: the Short-Form (SF-36), European Quality of Life (EuroQoL 6D3L), Hospital Anxiety and Depression Scale (HADS), and Symptom Checklist (SCL-90). Measurements were at the following time points: baseline, 6 weeks postpartum, and 6 months postpartum. A multivariate mixed model with repeated measures was defined to assess the effect of the treatments on the physical component score (PCS) and mental component score (MCS) of the SF-36. Analysis was by intention to treat. Results. We analyzed the data of 491 randomized and 220 nonrandomized women. We did not find treatment effect on long-term HR-QoL (PCS: p  ==  0.09; MCS: p  ==  0.82). The PCS improved over time ( p  <  0.001) and was better in nonrandomized patients ( p  ==  0.02). Conclusion. Despite a clinical benefit of induction of labor, long-term HR-QoL is equal after the induction of labor and expectant management in women with GH or PE beyond 36 weeks of gestation. [ABSTRACT FROM AUTHOR]

Background: Hypertensive disorders, i.e. pregnancy induced hypertension and preeclampsia, complicate 10 to15% of all pregnancies at term and are a major cause of maternal and perinatal morbidity and mortality. The only causal treatment is delivery. In case of preterm pregnancies conservative management is advocated if the risks for mother and child remain acceptable. In contrast, there is no consensus on how to manage mild hypertensive disease in pregnancies at term. Induction of labour might prevent maternal and neonatal complications at the expense of increased instrumental vaginal delivery rates and caesarean section rates. Methods/Design: Women with a pregnancy complicated by pregnancy induced hypertension or mild preeclampsia at a gestational age between 36+0 and 41+0 weeks will be asked to participate in a multi-centre randomised controlled trial. Women will be randomised to either induction of labour or expectant management for spontaneous delivery. The primary outcome of this study is severe maternal morbidity, which can be complicated by maternal mortality in rare cases. Secondary outcome measures are neonatal mortality and morbidity, caesarean and vaginal instrumental delivery rates, maternal quality of life and costs. Analysis will be by intention to treat. In total, 720 pregnant women have to be randomised to show a reduction in severe maternal complications of hypertensive disease from 12 to 6%. Discussion: This trial will provide evidence as to whether or not induction of labour in women with pregnancy induced hypertension or mild preeclampsia (nearly) at term is an effective treatment to prevent severe maternal complications. [ABSTRACT FROM AUTHOR]

Introduction Hypertensive disorders affect about 10% of pregnancies. Delivery is the definitive treatment. Delay carries maternal risks, but early delivery increases fetal risk so appropriate timing is difficult. Objective To compare immediate delivery and expectant management for prevention of adverse maternal and neonatal outcomes in hypertensive disease of pregnancy. Study Design A systematic review and meta-analysis of individual patient data of randomized controlled trials including pregnant women from 34 gestational weeks with hypertensive disease allocated to immediate delivery or expectant management. Main outcomes were respiratory distress syndrome (RDS) and a composite of HELLP syndrome and eclampsia. Five datasets (GRIT, HYPITAT I and II, DIGITAT, and "Deliver or Deliberate") were merged and analyzed using a 2-stage meta-analysis approach. We calculated relative risks (RR) and numbers needed to treat or harm (NNT/NNH) with 95% confidence intervals (CI). Results Main outcomes were available for 1,724 eligible women. Immediate delivery reduced overall HELLP syndrome and eclampsia risk (0.8% vs. 2.8%; RR 0.33, CI [0.15–0.73]; I[b] = 0%; NNT 51, CI [31.1–139.3]) as well as in the subgroup with preeclampsia (1.1% vs. 3.5%; RR 0.39, CI [0.15-0.98]; I[b] = 0%). The risk of RDS increased after immediate delivery (3.4% vs. 1.6%; RR 1.9, CI [1.05–3.6]; I[b] = 24%; NNH 58, CI [31.1-363.1]), but this effect was dependent on gestational age. Increased risk was present in the 35th week (5.1% vs. 0.6%; RR 5.5, CI [1.0–29.6]; I[b] = 0%), but this risk was lower in the 36th week, and did not reach statistical significance. (1.5% vs. 0.4%; RR 3.4, 95% CI [0.4–30.3]; I[b] = 0%). We found no evidence of difference in NICU admissions, 5-min Apgar score <7, umbilical cord arterial pH < 7.05, severe post-partum hemorrhage and cesarean sections. Conclusion In women with hypertension in pregnancy, immediate delivery reduces the risk of maternal complications, while the effect on the baby is dependent on gestational age. [ABSTRACT FROM AUTHOR]