Delivery or expectant management for prevention of adverse maternal and neonatal outcomes in hypertensive disorders of pregnancy: an individual participant data meta-analysis.

OBJECTIVE: Hypertensive disorders affect 3-10% of pregnancies. Delayed delivery carries maternal risks, while early delivery increases fetal risk, so appropriate timing is important. The aim of this study was to compare immediate delivery with expectant management for prevention of adverse maternal and neonatal outcomes in women with hypertensive disease in pregnancy. METHODS: CENTRAL, PubMed, MEDLINE and ClinicalTrials.gov were searched for randomized controlled trials comparing immediate delivery to expectant management in women presenting with gestational hypertension or pre-eclampsia without severe features from 34 weeks of gestation. The primary neonatal outcome was respiratory distress syndrome (RDS) and the primary maternal outcome was a composite of HELLP syndrome and eclampsia. The PRISMA-IPD guideline was followed and a two-stage meta-analysis approach was used. Relative risks (RR) and numbers needed to treat or harm (NNT/NNH) with 95% CI were calculated to evaluate the effect of the intervention. RESULTS: Main outcomes were available for 1724 eligible women. Compared with expectant management, immediate delivery reduced the composite risk of HELLP syndrome and eclampsia in all women (0.8% vs 2.8%; RR, 0.33 (95% CI, 0.15-0.73); I2  = 0%; NNT, 51 (95% CI, 31.1-139.3)) as well as in the pre-eclampsia subgroup (1.1% vs 3.5%; RR, 0.39 (95% CI, 0.15-0.98); I2  = 0%). Immediate delivery increased RDS risk (3.4% vs 1.6%; RR, 1.94 (95% CI 1.05-3.6); I2  = 24%; NNH, 58 (95% CI, 31.1-363.1)), but depended upon gestational age. Immediate delivery in the 35th week of gestation increased RDS risk (5.1% vs 0.6%; RR, 5.5 (95% CI, 1.0-29.6); I2  = 0%), but immediate delivery in the 36th week did not (1.5% vs 0.4%; RR, 3.4 (95% CI, 0.4-30.3); I2 not applicable). CONCLUSION: In women with hypertension in pregnancy, immediate delivery reduces the risk of maternal complications, whilst the effect on the neonate depends on gestational age. Specifically, women with a-priori higher risk of progression to HELLP, such as those already presenting with pre-eclampsia instead of gestational hypertension, were shown to benefit from earlier delivery. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Prognostic model for chronic hypertension in women with a history of hypertensive pregnancy disorders at term.

INTRODUCTION: The association between hypertensive pregnancy disorders and cardiovascular disease later in life is well described. In this study we aim to develop a prognostic model from patients characteristics known before, early in, during and after pregnancy to identify women at increased risk of cardiovascular disease e.g. chronic hypertension years after pregnancy complicated by hypertension at term. METHODS: We included women with a history of singleton pregnancy complicated by hypertension at term. Women using antihypertensive medication before pregnancy were excluded. We measured hypertension in these women more than 2years postpartum. Different patients characteristics before, early in, during and after pregnancy were considered to develop a prognostic model of chronic hypertension at 2-years. These included amongst others maternal age, blood pressure at pregnancy intake and blood pressure six weeks post-partum. Univariable analyses followed by a multivariable logistic regression analysis was performed to determine which combination of predictors best predicted chronic hypertension. Model performance was assessed by calibration (graphical plot) and discrimination (area under the receiver operating characteristic (AUC)). RESULTS: Of the 305 women in who blood pressure 2.5years after pregnancy was assessed, 105 women (34%) had chronic hypertension. The following patient characteristics were significant associated with chronic hypertension: higher maternal age, lower education, negative family history on hypertensive pregnancy disorders, higher BMI at booking, higher diastolic blood pressure at pregnancy intake, higher systolic blood pressure during pregnancy and higher diastolic blood pressure at six weeks post-partum. These characteristics were included in the prognostic model for chronic hypertension. Model performance was good as indicated by good calibration and good discrimination (AUC; 0.83 (95% CI 0.75 - 0.92). CONCLUSION: Chronic hypertension can be expected from patient characteristics before, early in, during and after pregnancy. These data underline the importance and awareness of detectable risk factors both for increased risk of complicated pregnancy as well as increased risk of cardiovascular disease later in life.

Blood pressure patterns in women with gestational hypertension or mild preeclampsia at term.

OBJECTIVE: Gestational hypertension (GH) and mild preeclampsia (PE) represent the most common medical complications of pregnancy, with the majority of cases developing at or near term. There is little knowledge of the course of blood pressure over time in these women. We explored the pattern of systolic and diastolic blood pressure over time in women with GH or mild PE at term participating in the HYPITAT trial, and we attempted to identify clinical factors influencing these blood pressure patterns and the impact of severe hypertension on clinical management. STUDY DESIGN: We used data from the HYPITAT trial, that included women with a singleton pregnancy with a fetus in cephalic position between 36 and 41 weeks of gestation with the diagnosis of GH or mild PE. Blood pressure measurements were performed from randomization or admission until delivery or discharge from the hospital. We included the highest blood pressure of each day. We evaluated systolic and diastolic blood pressure change over time, as well as the influence of clinical characteristics and laboratory findings on the course of blood pressure. We used univariate and multivariate regression analysis with a backward stepwise algorithm for the selection of variables. The model with the best fit (lowest AIC) was selected as the final model. We also compared mode of delivery for women with and without severe hypertension. RESULTS: We studied 1076 women who had 4188 blood pressure measurements done. The systolic blood pressure showed a significant non-linear increase over time and for the diastolic blood pressure the pattern was also non-linear. In the multivariable model of systolic blood pressure change over time, nulliparity, ethnicity, systolic blood pressure (at baseline), BMI and LDH at randomization influenced the course of blood pressure. In the diastolic blood pressure model ALT and the baseline diastolic blood pressure had a significant influence. When we explored the association between blood pressure and mode of delivery, it appeared that development of severe hypertension was a risk factor for Caesarean section. CONCLUSION: The blood pressure in patients with GH or PE at term showed a non-linear increase with time, which was aggravated by clinical characteristics. Development of severe hypertension was a risk factor for Caesarean section, which may explain the elevated Caesarean section rates in the expectant monitoring group in the HYPITAT trial.

Caesarean 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. TWEETABLE ABSTRACT: Induction of labour at low Bishop scores does not increase caesarean section rate or poor neonatal outcome.

Prediction of neonatal outcome in women with gestational hypertension or mild preeclampsia after 36 weeks of gestation.

BACKGROUND: There is little knowledge about neonatal complications in GH and PE and induction at term, we aim to assess whether they can be predicted from clinical data. METHODS: We used data of the HYPITAT trial and evaluated whether adverse neonatal outcome (Apgar score < 7, pH < 7.05, NICU admission) could be predicted from clinical data. Logistic regression, ROC analysis and calibration were used to identify predictors and evaluate the predictive capacity in an antepartum and intrapartum model. RESULTS: We included 1153 pregnancies, of whom 76 (6.6%) had adverse neonatal outcome. Parity (primipara OR 2.75), BMI (OR 1.06), proteinuria (dipstick +++ OR 2.5), uric acid (OR 1.4) and creatinine (OR 1.02) were independent antepartum predictors; In the intrapartum model, meconium stained amniotic fluid (OR 2.2), temperature (OR 1.8), duration of first stage of labour (OR 1.15), proteinuria (dipstick +++ OR 2.7), creatinine (OR 1.02) and uric acid (OR 1.5) were predictors of adverse neonatal outcome. Both models showed good discrimination (AUC 0.75 and 0.78), but calibration was limited (Hosmer-Lemeshow p = 0.41, and p = 0.20). CONCLUSIONS: In women with GH or PE at term, it is difficult to predict neonatal complications, possibly since they are rare in the term pregnancy. However, the identified individual predictors may guide physicians to anticipate requirements for neonatal care.

High blood pressure six weeks postpartum after hypertensive pregnancy disorders at term is associated with chronic hypertension.

OBJECTIVES: Hypertension in pregnancy is associated with cardiovascular disease (CVD) later in life. Blood pressure monitoring in women who experienced hypertension in pregnancy after puerperium has been suggested to be important for early detection and prevention of CVD. The aim of this study is to evaluate if hypertension six weeks postpartum is associated with chronic hypertension in women with a history of term hypertensive pregnancy disorders. STUDY DESIGN: Women with a history of term gestational hypertension or preeclampsia were included in a follow up study of the HYPITAT trial. Blood pressures were measured six weeks and 2.5years postpartum according to the study protocol. MAIN OUTCOME MEASURES: Hypertension was defined as a diastolic blood pressure ⩾90mmHg and/or a systolic blood pressure ⩾140mmHg or use of antihypertensive medication. Differences in categorical variables between groups were analyzed by Chi-Square tests. Blood pressure was analyzed using unpaired t-tests and Wilcox ranked tests. RESULTS: Among 187 women who had term hypertensive pregnancy disorders, 75 (40%) had hypertension at six weeks postpartum. Of these 46 (61%) had hypertension 2.5years postpartum. In contrast, of 112 women without hypertension at six weeks postpartum, 36 (32%) had hypertension 2.5years (OR 3.3, 95% CI 1.8-6.2). CONCLUSION: Among 61% of women who had hypertensive pregnancy disorders at term, high blood pressure at six weeks postpartum indicated chronic hypertension. This warrants the importance of identification of hypertension 6weeks postpartum for women's future health.

Should cervical favourability play a role in the decision for labour induction in gestational hypertension or mild pre-eclampsia at term? An exploratory analysis of the HYPITAT trial.

OBJECTIVE: To examine whether cervical favourability (measured by cervical length and the Bishop score) should inform obstetricians' decision regarding labour induction for women with gestational hypertension or mild pre-eclampsia at term. DESIGN: A post hoc analysis of the Hypertension and Pre-eclampsia Intervention Trial At Term (HYPITAT). SETTING: Obstetric departments of six university and 32 teaching and district hospitals in the Netherlands. POPULATION: A total of 756 women diagnosed with gestational hypertension or pre-eclampsia between 36 + 0 and 41 + 0 weeks of gestation randomly allocated to induction of labour or expectant management. METHODS: Data were analysed using logistic regression modelling. MAIN OUTCOME MEASURES: The occurrence of a high-risk maternal situation defined as either maternal complications or progression to severe disease. Secondary outcomes were caesarean delivery and adverse neonatal outcomes. RESULTS: The superiority of labour induction in preventing high-risk situations in women with gestational hypertension or mild pre-eclampsia at term varied significantly according to cervical favourability. In women who were managed expectantly, the longer the cervix the higher the risk of developing maternal high-risk situations, whereas in women in whom labour was induced, cervical length was not associated with a higher probability of maternal high-risk situations (test of interaction P = 0.03). Similarly, the beneficial effect of labour induction on reducing the caesarean section rate was stronger in women with an unfavourable cervix. CONCLUSION: Against widely held opinion, our exploratory analysis showed that women with gestational hypertension or mild pre-eclampsia at term who have an unfavourable cervix benefited more from labour induction than other women. TRIAL REGISTRATION: The trial has been registered in the clinical trial register as ISRCTN08132825.

Impact of the HYPITAT trial on doctors' behaviour and prevalence of eclampsia in the Netherlands.

We questioned if participation in the HYPITAT trial (induction of labour versus expectant monitoring in women with gestational hypertension or pre-eclampsia at term) impacted implementation of its results and subsequently maternal health. We identified women with hypertensive disease from the Perinatal Registry, and distinguished the period before, during and after the trial. We included 43 641 women. Induction of labour increased from 58.3 to 67.1% (P < 0.001) and prevalence of eclampsia decreased from 0.85 to 0.19% (P < 0.001) before and after the trial. Concurrently, participation in the HYPITAT trial among others had immediate consequences for obstetric management and maternal health.

An economic analysis of induction of labour and expectant monitoring in women with gestational hypertension or pre-eclampsia at term (HYPITAT trial).

OBJECTIVE: To assess the economic consequences of labour induction compared with expectant monitoring in women with gestational hypertension or pre-eclampsia at term. DESIGN: An economic analysis alongside the Hypertension and Pre-eclampsia Intervention Trial At Term (HYPITAT). SETTING: Obstetric departments of six university and 32 teaching and district hospitals in the Netherlands. POPULATION: Women diagnosed with gestational hypertension or pre-eclampsia between 36(+0) and 41(+0) weeks of gestation, randomly allocated to either induction of labour or expectant monitoring. METHODS: A trial-based cost-effectiveness analysis was performed from a societal perspective during a 1-year time horizon. MAIN OUTCOME MEASURES: One-year costs were estimated and health outcomes were expressed as the prevalence of poor maternal outcome defined as either maternal complications or progression to severe disease. RESULTS: The average costs of induction of labour (n = 377) were €7077 versus €7908 for expectant monitoring (n = 379), with an average difference of -€831 (95% CI -€1561 to -€144). This 11% difference predominantly originated from the antepartum period: per woman costs were €1259 for induction versus €2700 for expectant monitoring. During delivery, more costs were generated following induction (€2190) compared with expectant monitoring (€1210). No substantial differences were found in the postpartum, follow-up and for non-medical costs. CONCLUSION: In women with gestational hypertension or mild pre-eclampsia at term, induction of labour is less costly than expectant monitoring because of differences in resource use in the antepartum period. As the trial already demonstrated that induction of labour results in less progression to severe disease without resulting in a higher caesarean section rate, both clinical and economic consequences are in favour of induction of labour in these women. TRIAL REGISTRATION: The trial has been registered in the clinical trial register as ISRCTN08132825.

Natural 15N abundance in two nitrogen saturated forest ecosystems.

Natural 15N abundance values were measured in needles, twigs, wood, soil, bulk precipitation, throughfall and soil water in a Douglas fir (Pseudotsuga menziesii (Mirb.) and a Scots pine (Pinus sylvestris L.) stand receiving high loads of nitrogen in throughfall (>50 kg N ha-1 year-1). In the Douglas fir stand δ15N values of the vegetation ranged between -5.7 and -4.2‰ with little variation between different compartments. The vegetation of the Scots pine stand was less depleted in 15N and varied from -3.3 to -1.2‰Î´15N. At both sites δ15N values increased with soil depth, from -5.7‰ and -1.2‰ in the organic layer to +4.1‰ and +4.7‰ at 70 cm soil depth in the Douglas fir and Scots pine stand, respectively. The δ15N values of inorganic nitrogen in bulk precipitation showed a seasonal variation with a mean in NH4+-N of -0.6‰ at the Douglas fir stand and +10.8‰ at the Scots pine stand. In soil water below the organic layer NH4+-N was enriched and NO3--N depleted in 15N, which was interpreted as being caused by isotope fractionation accompanying high nitrification rates in the organic layers. Mean δ15N values of NH4+ and NO3- were very similar in the drainage water at 90 cm soil depth at both sites (-7.1 to -3.8‰). A dynamic N cycling model was used to test the sensitivity of the natural abundance values for the amount of N deposition, the 15N ratio of atmospheric N deposited and for the intrinsic isotope discrimination factors associated with N transformation processes. Simulated δ15N values for the N saturated ecosystems appeared particularly sensitive to the 15N ratio of atmospheric N inputs and discrimination factors during nitrification and mineralization. The N-saturated coniferous forest ecosystems studied were not characterized by elevated natural 15N abundance values. The results indicated that the natural 15N abundance values can only be used as indicators for the stage of nitrogen saturation of an ecosystem if the δ15N values of the deposited N and isotope fractionation factors are taken into consideration. Combining dynamic isotope models and natural 15N abundance values seems a promising technique for interpreting natural 15N abundance values found in these forest ecosystems.