"Hypertension in Pregnancy Intervention Trial At Term" and "Disproportionate Intrauterine Growth Intervention Trial At Term" Studies.

In 2003, in the context of a national research funding program in which obstetric research was prioritized, several perinatal centers took the initiative to jointly submit a number of applications to the subsidy programs of Effectiveness Research and Prevention of ZonMw. This has led to the funding of the Obstetric Consortium with several projects, including the "Hypertension in Pregnancy Intervention Trial At Term" and the "Disproportionate Intrauterine Growth Intervention Trial At Term" studies. The studies showed that induction of labor for hypertension and growth restriction at term was the appropriate management. Subsequent implementation improved maternal and perinatal outcomes.

Morphine exposure and neurodevelopmental outcome in infants born extremely preterm.

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.

Planned delivery or expectant management in preeclampsia: an individual participant data meta-analysis.

OBJECTIVE: Pregnancy hypertension is a leading cause of maternal and perinatal mortality and morbidity. Between 34+0 and 36+6 weeks gestation, it is uncertain whether planned delivery could reduce maternal complications without serious neonatal consequences. In this individual participant data meta-analysis, we aimed to compare planned delivery to expectant management, focusing specifically on women with preeclampsia. DATA SOURCES: We performed an electronic database search using a prespecified search strategy, including trials published between January 1, 2000 and December 18, 2021. We sought individual participant-level data from all eligible trials. STUDY ELIGIBILITY CRITERIA: We included women with singleton or multifetal pregnancies with preeclampsia from 34 weeks gestation onward. METHODS: The primary maternal outcome was a composite of maternal mortality or morbidity. The primary perinatal outcome was a composite of perinatal mortality or morbidity. We analyzed all the available data for each prespecified outcome on an intention-to-treat basis. For primary individual patient data analyses, we used a 1-stage fixed effects model. RESULTS: We included 1790 participants from 6 trials in our analysis. Planned delivery from 34 weeks gestation onward significantly reduced the risk of maternal morbidity (2.6% vs 4.4%; adjusted risk ratio, 0.59; 95% confidence interval, 0.36-0.98) compared with expectant management. The primary composite perinatal outcome was increased by planned delivery (20.9% vs 17.1%; adjusted risk ratio, 1.22; 95% confidence interval, 1.01-1.47), driven by short-term neonatal respiratory morbidity. However, infants in the expectant management group were more likely to be born small for gestational age (7.8% vs 10.6%; risk ratio, 0.74; 95% confidence interval, 0.55-0.99). CONCLUSION: Planned early delivery in women with late preterm preeclampsia provides clear maternal benefits and may reduce the risk of the infant being born small for gestational age, with a possible increase in short-term neonatal respiratory morbidity. The potential benefits and risks of prolonging a pregnancy complicated by preeclampsia should be discussed with women as part of a shared decision-making process.

Reduced morbidity by using LigaSure compared to conventional inguinofemoral lymphadenectomy in vulvar cancer patients: A randomized controlled trial.

BACKGROUND: Inguinofemoral lymphadenectomy (IFL) is part of the surgical treatment of different malignancies of the genital tract and/or the lower limb including vulvar carcinoma, penile carcinoma and melanoma. IFL is associated with morbidity in up to 85% of the patients. The aims of this MAMBO-IC study (Morbidity And Measurement of the Body) are to study the feasibility of using LigaSure for IFL and to assess the differences in the incidence of short-term complications using LigaSure versus conventional IFL randomized within each individual patient. METHODS: In this multicenter randomized controlled trial (RCT), women diagnosed with squamous cell carcinoma of the vulva with an indication for bilateral IFL were included. It was randomly assigned for which groin the LigaSure was used; the other groin was treated with conventional IFL (sharp/diathermia). We estimated the incidence of ≥1 complication(s) per groin using logistic regression and compared this between the two surgical methods, adjusting for possible confounders. RESULTS: We included 40 groins of 20 patients. The estimated incidence of ≥1 complication(s) was 29% after LigaSure versus 70% after conventional IFL (risk difference 41% (95% CI 19-62), p < 0.001). Patients' reported restriction of daily living activities and maximum pain score were equal for both treatment methods. There were no differences in the surgeon reported workload scores. CONCLUSIONS: This RCT shows that LigaSure for IFL is feasible and associated with significantly less short-term surgical complications compared to conventional IFL. Further studies with a larger sample size are needed to validate our findings. ISRCTN15057626.

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 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.

Surgery for patients with newly diagnosed advanced ovarian cancer: which patient, when and extent?

PURPOSE OF REVIEW: Cytoreduction to no residual disease is the mainstay of primary treatment for advanced epithelial ovarian cancer (AdvEOC). This review addresses recent insights on optimal patient selection, timing, and extent of surgery, intended to optimize cytoreduction in patients with AdvEOC. RECENT FINDINGS: Clinical guidelines recommend primary cytoreductive surgery (PCS) for AdvEOC patients with a high likelihood of achieving complete cytoreduction with acceptable morbidity. In line with this, preoperative prediction markers such as cancer antigen-125, histologic and genomic factors, innovative imaging modalities, and the performance of a diagnostic laparoscopy have been suggested to improve clinical decision-making with regard to optimal timing of cytoreductive surgery. To determine whether these strategies should be incorporated into clinical practice validation in randomized clinical trials is essential. SUMMARY: The past decade has seen a paradigm shift in the number of AvdEOC patients that are being treated with upfront neoadjuvant chemotherapy instead of PCS. However, although neoadjuvant chemotherapy may reduce morbidity at the time of interval cytoreductive surgery, no favorable impact on survival has been demonstrated and it may induce resistance to chemotherapy. Therefore, optimizing patient selection for PCS is crucial. Furthermore, surgical innovations in patients diagnosed with AvdEOC should focus on improving survival outcomes.

Planned early delivery versus expectant management for hypertensive disorders from 34 weeks gestation to term.

BACKGROUND: Hypertensive disorders in pregnancy are significant contributors to maternal and perinatal morbidity and mortality. These disorders include well-controlled chronic hypertension, gestational hypertension (pregnancy-induced hypertension) and mild pre-eclampsia. The definitive treatment for these disorders is planned early delivery and the alternative is to manage the pregnancy expectantly if severe uncontrolled hypertension is not present, with close maternal and fetal monitoring. There are benefits and risks associated with both, so it is important to establish the safest option. OBJECTIVES: To assess the benefits and risks of a policy of planned early delivery versus a policy of expectant management in pregnant women with hypertensive disorders, at or near term (from 34 weeks onwards). SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth Trials Register (12 January 2016) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials of a policy of planned early delivery (by induction of labour or by caesarean section) compared with a policy of delayed delivery ("expectant management") for women with hypertensive disorders from 34 weeks' gestation. Cluster-randomised trials would have been eligible for inclusion in this review, but we found none.Studies using a quasi-randomised design are not eligible for inclusion in this review. Similarly, studies using a cross-over design are not eligible for inclusion, because they are not a suitable study design for investigating hypertensive disorders in pregnancy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and risks of bias. Two review authors independently extracted data. Data were checked for accuracy. MAIN RESULTS: We included five studies (involving 1819 women) in this review.There was a lower risk of composite maternal mortality and severe morbidity for women randomised to receive planned early delivery (risk ratio (RR) 0.69, 95% confidence interval (CI) 0.57 to 0.83, two studies, 1459 women (evidence graded high)). There were no clear differences between subgroups based on our subgroup analysis by gestational age, gestational week or condition. Planned early delivery was associated with lower risk of HELLP syndrome (RR 0.40, 95% CI 0.17 to 0.93, 1628 women; three studies) and severe renal impairment (RR 0.36, 95% CI 0.14 to 0.92, 100 women, one study).There was not enough information to draw any conclusions about the effects on composite infant mortality and severe morbidity. We observed a high level of heterogeneity between the two studies in this analysis (two studies, 1459 infants, I2 = 87%, Tau2 = 0.98), so we did not pool data in meta-analysis. There were no clear differences between subgroups based on our subgroup analysis by gestational age, gestational week or condition. Planned early delivery was associated with higher levels of respiratory distress syndrome (RR 2.24, 95% CI 1.20 to 4.18, three studies, 1511 infants), and NICU admission (RR 1.65, 95% CI 1.13 to 2.40, four studies, 1585 infants).There was no clear difference between groups for caesarean section (RR 0.91, 95% CI 0.78 to 1.07, 1728 women, four studies, evidence graded moderate), or in the duration of hospital stay for the mother after delivery of the baby (mean difference (MD) -0.16 days, 95% CI -0.46 to 0.15, two studies, 925 women, evidence graded moderate) or for the baby (MD -0.20 days, 95% CI -0.57 to 0.17, one study, 756 infants, evidence graded moderate).Two fairly large, well-designed trials with overall low risk of bias contributed the majority of the evidence. Other studies were at low or unclear risk of bias. No studies attempted to blind participants or clinicians to group allocation, potentially introducing bias as women and staff would have been aware of the intervention and this may have affected aspects of care and decision-making.The level of evidence was graded high (composite maternal mortality and morbidity), moderate (caesarean section, duration of hospital stay after delivery for mother, and duration of hospital stay after delivery for baby) or low (composite infant mortality and morbidity). Where the evidence was downgraded, it was mostly because the confidence intervals were wide, crossing both the line of no effect and appreciable benefit or harm. AUTHORS' CONCLUSIONS: For women suffering from hypertensive disorders of pregnancy after 34 weeks, planned early delivery is associated with less composite maternal morbidity and mortality. There is no clear difference in the composite outcome of infant mortality and severe morbidity; however, this is based on limited data (from two trials) assessing all hypertensive disorders as one group.Further studies are needed to look at the different types of hypertensive diseases and the optimal timing of delivery for these conditions. These studies should also include infant and maternal morbidity and mortality outcomes, caesarean section, duration of hospital stay after delivery for mother and duration of hospital stay after delivery for baby.An individual patient meta-analysis on the data currently available would provide further information on the outcomes of the different types of hypertensive disease encountered in pregnancy.

Homocysteinemia After Hypertensive Pregnancy Disorders at Term.

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.

Prediction of cesarean section risk in women with gestational hypertension or mild preeclampsia at term.

OBJECTIVE: In a recent randomized controlled trial we found that induction of labor in women with gestational hypertension (GH) or mild (preeclampsia) PE at term prevented high risk situations without increasing the cesarean section (CS) rate. We aimed to assess the predictability of the risk of CS. STUDY DESIGN: We used multivariable logistic regression analysis to identify predictive factors. Two models were created, one including antepartum and one including antepartum and intrapartum variables. The predictive capacity was assessed with ROC analysis and calibration. RESULTS: 126 (17%) of the 756 women delivered by CS. In multivariable analysis parity (OR 5.4), ethnicity (OR 2.4), previous miscarriage (OR 1.7), creatinine (OR 1.02), proteinuria (OR 2.4), cervical length (OR 1.02), engagement (OR 0.5) and dilatation (OR 0.7) were independent antepartum predictors. Intrapartum variables were parity (OR 3.6), ethnicity (OR 1.9), previous miscarriage (OR 1.5), gestational age at delivery (OR 1.2), antibiotic use (OR 8.0), disease progression (OR 2.4), uric acid (OR 1.4), proteinuria (OR 3.50) and dilatation (OR 0.76). Both models showed good discrimination (AUC 0.74 and 0.80) but calibration was moderate (Hosmer-Lemeshow P-value 0.42 and 0.70). CONCLUSION: In women with GH or mild PE at term, the risk of CS can be predicted.

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.

Determinants of health-related quality of life in the postpartum period after obstetric complications.

OBJECTIVE: To determine the influence of socio-demographic, clinical parameters and obstetric complications on postpartum health-related quality of life (HRQoL). STUDY DESIGN: We used data of three randomized controlled trials to investigate HRQoL determinants in women after an obstetric complication. The DIGITAT and HYPITAT trials compared induction of labor and expectant management in women with intra-uterine growth restriction (IUGR) and hypertensive disorders. The WOMB trial randomized anemic women after postpartum hemorrhage to red blood cell transfusion or expectant management. The HRQoL-measure Short-Form36 was completed at six weeks postpartum. Multivariable analyses were used to identify which parameters affected the Short-Form36 physical component score (PCS) and mental component score (MCS). RESULTS: HRQoL analyses included 1391 women (60%) of the 2310 trial participants. HYPITAT and DIGITAT participants had significantly lower MCS than WOMB participants. In multivariable analysis, PCS after elective and emergency cesarean section was 5-6 points lower than after vaginal delivery. Gestational hypertension, neonatal admission and delivery in an academic hospital had a small negative effect on PCS. No effect was found for randomization status, maternal age, BMI, country of birth, education, parity, induction of labor, analgesics, birth weight, perineal laceration, delivery of placenta, postpartum hemorrhage, congenital anomaly, urinary tract infection, thromboembolic event or endometritis. MCS was influenced only mildly by these parameters. CONCLUSIONS: IUGR and hypertensive disorders lead to lower HRQoL scores postpartum than PPH. In a heterogeneous obstetric population, only mode of delivery by cesarean section has a profound, negative impact, on physical HRQoL (PCS). No profound impacts on MCS were detected.

Prediction of postpartum hemorrhage in women with gestational hypertension or mild preeclampsia at term.

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.

Induction of labour or expectant monitoring in hypertensive pregnancy disorders at term: do women's postpartum cardiovascular risk factors differ between the two strategies?

OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of death in women in the western world. Several studies have described the association between hypertensive pregnancy disorders and CVD in later life. Our aim was to compare postpartum cardiovascular risk factors in women who had a shorter and women who had a longer exposure to endothelial activation during their term hypertensive pregnancy. STUDY DESIGN: We studied a subsample of women with pregnancy-induced hypertension or mild preeclampsia at term, who had participated in the randomized HYPITAT trial comparing induction of labour (IOL cohort) (n=110) or expectant monitoring (EM cohort) (n = 91). We assessed, 2.5 years postpartum, cardiovascular risk factors, i.e. blood pressure, anthropometrics, glucose, HbA1C, insulin, HOMA score, total cholesterol, HDL cholesterol, triglycerides, high sensitive CRP, micro-albumin and metabolic syndrome, and compared these risk factors between the induction and expectant groups. RESULTS: The mean time from randomization to delivery was 3.3 days in the induction group and 10.3 days in the expectant group (p<.001), generating a difference in exposure of 7 days. After a mean follow-up period of 2.5 years, the prevalence of hypertension (IOL 34%; EM 37%, p = .66) and metabolic syndrome (IOL 26%; EM 27%, p = 1.0) was similar in both groups. Furthermore, systolic and diastolic blood pressure, BMI, waist circumference, glucose, HbA1C, insulin, HOMA score, lipids, HsCRP-levels and micro-albumin were all comparable between women who had induction of labour and those who had expectant monitoring. CONCLUSION: In women with hypertensive disorders in pregnancy at term, induction of labour does not affect the clinical and biochemical cardiovascular profile at 2.5 years postpartum.

Prediction of progression to a high risk situation in women with gestational hypertension or mild pre-eclampsia at term.

OBJECTIVE: To evaluate whether progression to a high-risk situation is predictable in women with gestational hypertension (GH) or mild pre-eclampsia (PE) at term. METHODS: Women with a singleton pregnancy, a fetus in cephalic position, between 36 and 41 weeks of gestation, complicated by GH or mild PE that were managed expectantly, were selected from the HYPITAT trial. We evaluated the predictability of progression to a high-risk situation. Logistic regression was used to determine the predictive value of clinical characteristics or laboratory findings and to generate a prediction model for progression to a high-risk situation. The predictive value of this model was assessed with receiver-operating characteristic (ROC) analysis, calibration and internal validation. RESULTS: We included 703 women, of whom 244 (34.7%) had progression to a high-risk situation. After multivariable analysis, nulliparity (OR 1.87), maternal age (OR 1.05 per year), gestational age (OR 0.88 per week), previous abortion (OR 1.26), ethnicity (OR 2.05 for non-Caucasian ethnicity), diastolic (OR 1.04 per mmHg), systolic blood pressure (OR 1.02 per mmHg) and the laboratory parameters proteinuria, haemoglobin, platelets, uric acid and alanine aminotransferase were included in the final model. The area under the ROC curve of this model was 0.71 (95% CI, 0.67-0.74). Even though the goodness of fit was moderate (P=0.40), internal validation showed the model could hold in the overall population. CONCLUSION: In the prediction of progression to a high-risk situation, in women with GH or mild PE at term, a distinction can be made between women with a low risk and women with high risk.

Health-related quality of life after induction of labor versus expectant monitoring in gestational hypertension or preeclampsia at term.

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.

Accuracy of liver function tests for predicting adverse maternal and fetal outcomes in women with preeclampsia: a systematic review.

BACKGROUND: Liver function tests are routinely performed in women as part of a battery of investigations to assess severity at admission and later to guide appropriate management. OBJECTIVE: To determine the accuracy with which liver function tests predict complications in women with preeclampsia by a systematic review. DATA: We conducted electronic searches without language restrictions in (1951-2010), (1980-2010) and the Cochrane Library (2009). METHODS OF STUDY SELECTION: Primary articles that evaluated the accuracy of liver function tests in predicting complications in women with preeclampsia were chosen. Data was extracted by two reviewers independently. A bivariate model estimated area under the curve, sensitivity and specificity. RESULTS: There were 13 primary articles including a total of 3 497 women assessing maternal (30 2×2 tables) and fetal (19 2×2 tables) outcomes. For predicting adverse maternal outcome, the point estimates of specificity were >70% in 18 tables with 0.79 (95%CI 0.51, 0.93). For predicting adverse fetal outcomes the specificity of the test was >70% in 2×2 tables. Sensitivity of the test was poor for both maternal and fetal outcomes. CONCLUSION: In women with preeclampsia, function tests performed better in predicting adverse maternal than fetal outcomes. The presence of increased liver enzymes was associated with an increased probability of maternal and fetal complications, but normal liver enzyme levels did not rule out disease, as specificity was often higher than sensitivity.

Risk indicators for eclampsia in gestational hypertension or mild preeclampsia at term.

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.

Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks' gestation (HYPITAT): a multicentre, open-label randomised controlled trial.

BACKGROUND: Robust evidence to direct management of pregnant women with mild hypertensive disease at term is scarce. We investigated whether induction of labour in women with a singleton pregnancy complicated by gestational hypertension or mild pre-eclampsia reduces severe maternal morbidity. METHODS: We undertook a multicentre, parallel, open-label randomised controlled trial in six academic and 32 non-academic hospitals in the Netherlands between October, 2005, and March, 2008. We enrolled patients with a singleton pregnancy at 36-41 weeks' gestation, and who had gestational hypertension or mild pre-eclampsia. Participants were randomly allocated in a 1:1 ratio by block randomisation with a web-based application system to receive either induction of labour or expectant monitoring. Masking of intervention allocation was not possible. The primary outcome was a composite measure of poor maternal outcome--maternal mortality, maternal morbidity (eclampsia, HELLP syndrome, pulmonary oedema, thromboembolic disease, and placental abruption), progression to severe hypertension or proteinuria, and major post-partum haemorrhage (>1000 mL blood loss). Analysis was by intention to treat and treatment effect is presented as relative risk. This study is registered, number ISRCTN08132825. FINDINGS: 756 patients were allocated to receive induction of labour (n=377 patients) or expectant monitoring (n=379). 397 patients refused randomisation but authorised use of their medical records. Of women who were randomised, 117 (31%) allocated to induction of labour developed poor maternal outcome compared with 166 (44%) allocated to expectant monitoring (relative risk 0.71, 95% CI 0.59-0.86, p<0.0001). No cases of maternal or neonatal death or eclampsia were recorded. INTERPRETATION: Induction of labour is associated with improved maternal outcome and should be advised for women with mild hypertensive disease beyond 37 weeks' gestation. FUNDING: ZonMw.

Accuracy of serum uric acid as a predictive test for maternal complications in pre-eclampsia: bivariate meta-analysis and decision analysis.

The aim of this study is to determine the accuracy and clinical value of serum uric acid in predicting maternal complications in women with pre-eclampsia. An existing meta-analysis on the subject was updated. The accuracy of serum uric acid for the prediction of maternal complications was assessed with a bivariate model estimating a summary Receiver Operating Characteristic (sROC) curve. Subsequently, a clinical decision analysis was performed, in which three alternative strategies were modelled: (I) expectant management with monitoring until spontaneous labour; (II) induction of labour; (III) serum uric acid as test for predicting maternal complications. In the latter strategy, accuracy data of serum uric acid derived from the sROC curve were used to assess the value of serum uric acid in the management of women with pre-eclampsia. In this strategy, women with an increased serum uric acid were supposed to have labour induced, whereas women with serum uric acid levels below the threshold were managed expectantly. The decision whether to use the policy expectant management, to induce labour or to test serum uric acid levels, is based on the expected utility of each strategy. The expected utility depends on the probability of occurrence of severe maternal complications (i.e. severe hypertension, haemolysis, elevated liver enzymes and low platelet count (HELLP syndrome) or eclampsia) and the mode of delivery (caesarean section versus vaginal delivery). Valuation of the outcomes was performed using a distress ratio, which expresses how much worse a complication of pre-eclampsia is valued as compared to a caesarean section. Eight studies, testing 1565 women with pre-eclampsia, met the inclusion criteria. If the distress ratio was 10, the strategy regarding serum uric acid would be the preferred strategy when the probability of complications was between 2.9 and 6.3%. At higher complication rates induction of labour would be preferred, whereas at lower complication rates expectant management would be the best treatment option. These findings were stable in sensitivity analyses, using different distress ratios. Based on the decision analysis, serum uric acid seems to be a useful test in the management of pre-eclampsia under realistic assumptions.

Abnormal endothelium-dependent microvascular dilator reactivity in pregnancies complicated by normotensive intrauterine growth restriction.

OBJECTIVE: Normotensive intrauterine growth restriction and preeclampsia share a similar placenta pathophysiology, whereas maternal clinical manifestations differ. Clinical symptoms of preeclampsia are partly attributed to vascular endothelial dysfunction, but it is unclear whether this phenomenon plays a role in intrauterine growth restriction. Therefore, we investigated microvascular endothelial function in women with intrauterine growth restriction. STUDY DESIGN: Laser Doppler fluxmetry was used combined with iontophoresis of acetylcholine and sodium nitroprusside, namely, endothelium-dependent and endothelium-independent vasodilators. We studied 12 women with intrauterine growth restriction and 16 controls in the third trimester of pregnancy. All women had prepregnancy body mass indexes < 26. RESULTS: Acetylcholine-mediated vasodilatation was significantly increased in women with intrauterine growth restriction compared with controls (743% +/- 120% vs 390% +/- 67%, P = .01); sodium nitroprusside-mediated vasodilatation was not different (360% +/- 55% vs 363% +/- 65%, P > .99). CONCLUSION: Nonobese women with normotensive intrauterine growth restriction show abnormal endothelium-dependent microvascular vasodilatation, suggesting endothelial dysfunction as in preeclampsia. Obviously, for the clinical manifestation of preeclampsia additional factors are required, and a role of metabolic syndrome and obesity has been suggested.