Kim Broekhuijsen

Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-II): an open-label, randomised controlled trial

BACKGROUND There is little evidence to guide the management of women with hypertensive disorders in late preterm pregnancy. We investigated the effect of immediate delivery versus expectant monitoring on maternal and neonatal outcomes in such women. METHODS We did an open-label, randomised controlled trial, in seven academic hospitals and 44 non-academic hospitals in the Netherlands. Women with non-severe hypertensive disorders of pregnancy between 34 and 37 weeks of gestation were randomly allocated to either induction of labour or caesarean section within 24 h (immediate delivery) or a strategy aimed at prolonging pregnancy until 37 weeks of gestation (expectant monitoring). The primary outcomes were a composite of adverse maternal outcomes (thromboembolic disease, pulmonary oedema, eclampsia, HELLP syndrome, placental abruption, or maternal death), and neonatal respiratory distress syndrome, both analysed by intention-to-treat. This study is registered with the Netherlands Trial Register (NTR1792). FINDINGS Between March 1, 2009, and Feb 21, 2013, 897 women were invited to participate, of whom 703 were enrolled and randomly assigned to immediate delivery (n=352) or expectant monitoring (n=351). The composite adverse maternal outcome occurred in four (1·1%) of 352 women allocated to immediate delivery versus 11 (3·1%) of 351 women allocated to expectant monitoring (relative risk [RR] 0·36, 95% CI 0·12-1·11; p=0·069). Respiratory distress syndrome was diagnosed in 20 (5·7%) of 352 neonates in the immediate delivery group versus six (1·7%) of 351 neonates in the expectant monitoring group (RR 3·3, 95% CI 1·4-8·2; p=0·005). No maternal or perinatal deaths occurred. INTERPRETATION For women with non-severe hypertensive disorders at 34-37 weeks of gestation, immediate delivery might reduce the already small risk of adverse maternal outcomes. However, it significantly increases the risk of neonatal respiratory distress syndrome, therefore, routine immediate delivery does not seem justified and a strategy of expectant monitoring until the clinical situation deteriorates can be considered. FUNDING ZonMw.

Relevance of individual participant data meta-analysis for studies in obstetrics: delivery versus expectant monitoring for hypertensive disorders of pregnancy

Like many other research subjects in obstetrics, research on immediate delivery versus expectant monitoring for women with hypertensive disorders of pregnancy faces certain challenges when it comes to interpretation and generalisation of the results; relatively rare outcomes are studied, in a clinically heterogeneous population, while the clinical practice in some countries has dictated that studies in term pregnancy were completed before earlier gestational ages could be studied. This has resulted in multiple smaller studies, some studying surrogate outcome measures, with different in- and exclusion criteria, and without enough power for reliable subgroup analyses. All this complicates the generation of definitive answers and implementation of the results into clinical practice. Performing multiple studies and subsequently pooling their results in a meta-analysis can be a way to overcome the difficulties of studying relatively rare outcomes and subgroups with enough power, as well as a solution to reach a final answer on questions involving an uncertain and possibly harmful intervention. However, in the case of the current studies on delivery versus expectant monitoring in women with hypertensive disorders of pregnancy, differences regarding eligibility criteria, outcome measures and subgroup definitions make it difficult to pool their results in an aggregate meta-analysis. Individual patient data meta-analysis (IPDMA) has the potential to overcome these challenges, because it allows for flexibility regarding the choice of endpoints and standardisation of inclusion and exclusion criteria across studies. In addition, it has more statistical power for informative subgroup analyses. We therefore propose an IPDMA on immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy, and advocate the use of IPDMA for research questions in obstetrics that face similar challenges.

Adjuvanted vaccines in pregnancy: no evidence for effect of the adjuvanted H1N1/09 vaccination on occurrence of preeclampsia or intra-uterine growth restriction.

OBJECTIVE During the H1N1/09 pandemic, pregnant women in the Netherlands were vaccinated with an adjuvanted vaccine. During pregnancy, the maternal immune system changes to enable placental development and growth and acceptance of the semi-allogeneic fetus. As an adjuvant is a pro-inflammatory substance, it may interfere with these immunological changes, resulting in poor placentation or placental growth, which may result in preeclampsia (PE) and fetal intra-uterine growth restriction (IUGR). This study investigated a possible association between adjuvanted H1N1/09 vaccination and the development of PE and/or IUGR. STUDY DESIGN Case-control study. Cases were Dutch women with PE and/or IUGR occurring during H1N1/09 vaccination program. Controls had uncomplicated pregnancies during the same period. Maternal characteristics, pregnancy and neonatal outcomes were collected from medical files. Participants were contacted by telephone to enquire about vaccination. Data were analyzed using t-tests, Chi-square tests or Fishers exact tests. Multivariate analysis was conducted to control for confounders. RESULTS We included 254 cases and 247 controls. Of the cases, 90 (35.4%) were vaccinated, compared to 87 (35.2%) of the controls (OR:1.009, 95% CI:0.70-1.46, p:0.961). The majority (73.5%) had been vaccinated in second and third trimester. In multivariate analysis, there were no confounders influencing these results. Exploratory subgroup analysis did not show an association between vaccination status in subgroups of women with either PE or IUGR. CONCLUSION Our study showed no association between adjuvanted H1N1/09 vaccination and PE and/or IUGR.

Maternal and neonatal outcomes of pregnancy in women with chronic hypertension: a retrospective analysis of a national register.

Pregnancies complicated by chronic hypertension are at increased risk of adverse pregnancy outcomes. To assess whether planned early delivery might prevent some of these adverse outcomes, we studied maternal and neonatal outcomes of pregnancy in women with chronic hypertension, including gestational‐age‐specific outcomes.

Correction : Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia between 34 and 37 weeks' gestation (HYPITAT-II) : a multicentre, open-label randomised controlled trial (vol 13, pg 232, 2013)

The earliest draft versions of the protocol for our study described the composite adverse maternal outcome as one or more of progression to severe disease, pulmonary edema, thrombo-embolic disease, HELLP syndrome, eclampsia, placental abruption or maternal death. However, there is ongoing debate as to whether progression to severe disease should be considered an adverse maternal outcome [1,2]. Therefore, after obtaining funding which enabled us to increase our sample size to the current sample size of 680, we decided to study a composite adverse maternal outcome excluding progression to severe disease. These changes were incorporated in the protocol as submitted to and approved by the instutional review board;* the current protocol is available from our website (http://www.studies-obsgyn.nl/hypitat2/ page.asp?page_id=642). Unfortunately, the change to the maternal outcome definition was not incorporated into the published protocol, which incorrectly includes progression to severe disease in the composite adverse maternal outcome [3]. We also discovered minor differences between the published protocol and the IRB approved protocol. The definition for neonatal morbidity should have contained meconium aspiration syndrome, pneumothorax and/or pneumomediastinum, periventricular leucomalacia, convulsions and other neurological abnormalities. Finally, low 5-minute Apgar score should have been defined as below 7 (as opposed to below 3), and low umbilical artery pH as below 7.05 (as opposed to below 7.0).

Prediction of progression to severe disease in women with late preterm hypertensive disorders of pregnancy

If hypertensive disorders of pregnancy are diagnosed before term, the benefits of immediate delivery need to be weighed against the neonatal consequences of preterm delivery. If we are able to predict which women are at high risk of progression to severe disease, they could be targeted for delivery and maternal complications might be reduced. In addition, this may prevent unnecessary preterm births in women at low risk.

Evaluation of biomarkers for treatment selection using individual participant data from multiple clinical trials

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 markers 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.

Cesarean Section Rates and Adverse Neonatal Outcomes After Induction of Labour Versus Expectant Management in Women With an Unripe Cervix: A Secondary Analysis of the HYPITAT and DIGITAT Trials

Objective To evaluate caesarean section and adverse neonatal outcome rates after induction of labour or expectant management in women with an unripe cervix at or near term. Design Secondary analysis of data from two randomised clinical trials. Setting Data were collected in two nationwide Dutch trials. Population Women with hypertensive disease (HYPITAT trial) or suspected fetal growth restriction (DIGITAT trial) and a Bishop score ≤ 6. Methods Comparison of outcomes after induction of labour and expectant management. Main outcome measures Rates of caesarean section and adverse neonatal outcome, defined as 5-minute Apgar score ≤ 6 and/or arterial umbilical cord pH < 7.05 and/or neonatal intensive care unit admission and/or seizures and/or perinatal death. Results Of 1172 included women with an unripe cervix, 572 had induction of labour and 600 had expectant management. We found no significant difference in the overall caesarean rate (difference -1.1%, 95% CI -5.4 to 3.2). Induction of labour did not increase caesarean rates in women with Bishop scores from 3 to 6 (difference -2.7%, 95% CI -7.6 to 2.2) or adverse neonatal outcome rates (difference -1.5%, 95% CI -4.3 to 1.3). However, there was a significant difference in the rates of arterial umbilical cord pH < 7.05 favouring induction (difference -3.2%, 95% CI -5.6 to -0.9). The number needed to treat to prevent one case of umbilical arterial pH < 7.05 was 32. Conclusions We found no evidence that induction of labour increases the caesarean rate or compromises neonatal outcome as compared with expectant management. Concerns over increased risk of failed induction in women with a Bishop score from 3 to 6 seem unwarranted. This article is commented on by WM Gilbert. To view this mini commentary visit http://dx.doi.org/10.1111/1471-0528.14025.