Maria G. van Pampus

High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia

OBJECTIVE In patients with a history of severe preeclampsia, an increased frequency of hemostatic abnormalities has recently been suggested in small studies without control groups. Our purpose was to investigate the prevalence of such abnormalities in a large patient group with a history of severe hypertensive disorder in pregnancy, in comparison with an appropriate control group. STUDY DESIGN A total of 345 patients with a history of severe preeclampsia were investigated at a minimum of 10 weeks post partum for the presence of activated protein C resistance, the associated factor V mutation, hyperhomocysteinemia and anticardiolipin antibodies. The control group consisted of 67 healthy women with a history of uncomplicated pregnancies only. Blood was obtained during the second half of a normal menstrual cycle, and none of the patients or control subjects used oral contraceptives. RESULTS Of all patients, 11.3% had activated protein C resistance (control subjects 1.5%, P =.025). Only half of these patients had the factor V mutation. Hyperhomocysteinemia was present in 12.1% of all patients, in comparison with 4.5% in the control group (P =.115). Anticardiolipin antibodies were observed in 20.9% of the patients, whereas these antibodies were found in 7.5% of the control subjects (P =.016). In general, the prevalence of these abnormalities was 1.5 to 2 times higher in patients who were delivered before 28 weeks, in comparison with patients who were delivered after 28 weeks. CONCLUSIONS Hemostatic abnormalities, associated with an increased risk of thrombosis, are present in approximately 40% of patients with a history of severe preeclampsia, which is almost 4 times higher than in control subjects. These findings might suggest a cause of preeclampsia and could have implications in subsequent pregnancies and general health.

Foley catheter versus vaginal prostaglandin E2 gel for induction of labour at term (PROBAAT trial): an open-label, randomised controlled trial

BACKGROUND Induction of labour is a common obstetric procedure. Both mechanical (eg, Foley catheters) and pharmacological methods (eg, prostaglandins) are used for induction of labour in women with an unfavourable cervix. We aimed to compare the effectiveness and safety of induction of labour with a Foley catheter with induction with vaginal prostaglandin E2 gel. METHODS We did an open-label, randomised controlled trial in 12 hospitals in the Netherlands between Feb 10, 2009, and May 17, 2010. We enrolled women with a term singleton pregnancy in cephalic presentation, intact membranes, an unfavourable cervix, an indication for induction of labour, and no prior caesarean section. Participants were randomly allocated by an online randomisation system to induction of labour with a 30 mL Foley catheter or vaginal prostaglandin E2 gel (1:1 ratio). Because of the nature of the intervention this study was not blinded. The primary outcome was caesarean section rate. Secondary outcomes were maternal and neonatal morbidity and time from intervention to birth. All analyses were done on an intention-to-treat basis. We also did a meta-analysis that included our trial. The trial was registered with the Dutch trial registry, number NTR 1646. FINDINGS 824 women were allocated to induction of labour with a Foley catheter (n=412) or vaginal prostaglandin E2 gel (n=412). Caesarean section rates were much the same between the two groups (23%vs 20%, risk ratio [RR] 1·13, 95% CI 0·87-1·47). A meta-analysis including our trial data confirmed that a Foley catheter did not reduce caesarean section rates. We recorded two serious maternal adverse events, both in the prostaglandin group: one uterine perforation and one uterine rupture. INTERPRETATION In women with an unfavourable cervix at term, induction of labour with a Foley catheter is similar to induction of labour with prostaglandin E2 gel, with fewer maternal and neonatal side-effects. FUNDING None.

Long-term follow-up in patients with a history of (H)ELLP syndrome

OBJECTIVE To provide long-term follow-up data on women with a history of hemolysis, elevated liver enzymes, and low platelets [(H)ELLP] syndrome regarding the risk of recurrence in subsequent pregnancies and disease in later life. METHODS All women admitted to the Academic Medical Centre between January 1984 and January 1996 with (H)ELLP syndrome and a living singleton fetus in utero were included. Women with known preexisting diseases were excluded. The (H)ELLP syndrome was defined as elevated liver enzymes (serum aspartate aminotransferase or serum alanine aminotransferase >or= 50 U/L) and low platelet count (< 100 x 10(9)/L). Those patients with hemolysis (LDH >or= 600 U/L) were classified as HELLP, the remaining ones were classified as ELLP. The participants were asked to fill out a questionnaire regarding their general health and their own obstetric and medical history and that of their first-and second-degree relatives. RESULTS One hundred sixteen (94%) of 123 women responded; 4 women had died. The median age of the group was 36.0 years at completion of the questionnaire; the median interval after the index pregnancy was 5.7 years (3-12.9). The incidence of hypertension requiring medical treatment was three times higher than in a reference population of Dutch women between 20 and 40 years old. The need for psychological support was frequent. Thirty-nine patients (34%) refrained from further pregnancies. Twenty-nine percent of the first subsequent pregnancies were complicated by gestational hypertension (GH), but only 2% had (H)ELLP syndrome. Birth weight was, on average, 1385 g higher and gestational age at delivery 5 weeks later in the first subsequent pregnancy irrespective of a recurrence of GH. A family history of cardiovascular disease or preeclampsia was common in the total group; however, this did not influence the recurrence rate. Multiparity, gestational age at delivery <30 weeks, and birth weight <1000 g in the index pregnancy increased the risk of recurrence of GH in the first subsequent pregnancy significantly. CONCLUSIONS (H)ELLP syndrome is a severe complication of pregnancy that has not only short-term but also long-term sequelae.

Cardiovascular risk factors in women who had hypertensive disorders late in pregnancy: a cohort study

OBJECTIVE The purpose of this study was to determine cardiovascular risk factors in women with a history of hypertensive pregnancy disorders at term (HTP) 2.5 years after pregnancy. STUDY DESIGN In a multicenter cohort study in The Netherlands from June 2008 through November 2010, cardiovascular risk factors were compared between women with a history of HTP (HTP cohort, n = 306) and women with a history of normotensive pregnancies at term (NTP cohort, n = 99). HTP women had participated in a randomized, longitudinal trial assessing the effectiveness of induction of labor in women with hypertensive pregnancy disorders at term. All women were assessed 2.5 years after pregnancy for blood pressure, anthropometrics, glucose, glycosylated hemoglobin, insulin, homeostatic model assessment score, total cholesterol, high-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, and microalbumin and metabolic syndrome. RESULTS After a mean follow-up period of 2.5 years, hypertension (HTP, 34%; NTP, 1%; P < .001) and metabolic syndrome (HTP, 25%; NTP, 5%; P < .001) were more prevalent in HTP women compared with NTP women. HTP women had significantly higher systolic and diastolic blood pressure, higher body mass index, and higher waist circumference. Glucose, glycosylated hemoglobin, insulin, homeostatic model assessment score, total cholesterol, triglycerides, and high-sensitivity C-reactive protein levels were significantly higher and high-density lipoprotein cholesterol was significantly lower in HTP women. CONCLUSION In women with a history of HTP, hypertension and metabolic syndrome are more common, and they have higher levels of biochemical cardiovascular risk factors 2.5 years after pregnancy.

Increased Intima-Media Thickness After Early-Onset Preeclampsia

OBJECTIVE: Preeclampsia is associated with cardiovascular atherosclerotic events later in life. However, little is known about earlier subclinical signs of atherosclerosis. We aimed to investigate whether women who recently had preeclampsia show increased intima-media thickness (IMT), as marker of early atherosclerosis, compared with women with normal pregnancies or nulliparous women. METHODS: Intima-media thickness of carotid and femoral arteries measured by ultrasonography, and possible confounding risk factors as body mass index, blood pressure, serum lipids, smoking status, and family history of cardiovascular disease were compared among 22 nulliparous women, 22 primiparous women with normal pregnancy, and 22 primiparous women with early-onset preeclampsia at least 3 months postpartum and 6 weeks after ending lactation RESULTS: Except for slightly higher values for blood pressure, triglycerides, and homocysteine in the formerly preeclamptic women, no other clinical or biochemical differences were observed. The preeclampsia group showed an increased IMT (mean ± standard deviation, 0.63 ± 0.14 mm) of the common femoral artery compared with the normal pregnancy group (0.55 ± 0.06 mm, P = .005) and to the nulliparous group (0.52 ± 0.06 mm, P < .001). These differences remained significant after correction for possible confounders by multiple linear regression analyses. An increase in IMT of the common carotid artery between the normal pregnancy and the nulliparous group was observed, which became significant after adjustment for confounders. CONCLUSION: Preeclampsia and, to a lesser degree, normal pregnancy are associated with increased IMT. The association between increased IMT and (preeclamptic) pregnancy leads to the question of which comes first, which should be addressed in follow-up studies. LEVEL OF EVIDENCE: II-2

Abnormal endothelium-dependent microvascular reactivity in recently preeclamptic women

OBJECTIVE: To assess endothelial function at the level of skin microvasculature, using iontophoretic administration of acetylcholine (endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator), in women who recently had a preeclamptic pregnancy. METHODS: Microvascular skin reactivity was assessed by laser Doppler perfusion monitoring and iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) in 25 women with a history of early onset preeclampsia and 23 women with previous uncomplicated pregnancies, all of whom were between 3 and 11 months postpartum. RESULTS: Mean (± standard error of the mean) ACh-mediated vasodilatation, expressed as a percentage increase in flux, was higher in women who recently had a preeclampsia than in controls (535 ± 46% versus 314 ± 29%, P < .001). In contrast, SNP-mediated vasodilatation was not significantly different (560 ± 71% versus 483 ± 69%, P = .4) in both groups. Linear regression analysis revealed that the difference in ACh-mediated vasodilatation was explained by preeclampsia (P = .004), whereas vascular risk factors such as maternal age, diastolic blood pressure, and family history of premature cardiovascular diseases had no significant effect. CONCLUSION: The increased ACh-mediated vasodilatation in the microcirculation of recently preeclamptic women indicates abnormal endothelial function. Furthermore, it may represent a compensatory response to an impaired vasodilatory response of the macrocirculation, thereby supporting the hypothesis of an underlying (micro)angiopathy. LEVEL OF EVIDENCE: II-2

Pregnancy and preeclampsia affect monocyte subsets in humans and rats.

Introduction Both nonclassical and intermediate monocytes have been implicated in different inflammatory conditions. We hypothesized that these monocytes would increase during pregnancy, a condition associated with generalized activation of inflammatory responses and that they would increase even more during preeclampsia, in which inflammatory responses are further stimulated. In the present study we investigated changes in monocyte subsets during healthy pregnancy and preeclampsia in humans and rats. Methods Blood monocyte subsets of nonpregnant, preeclamptic and healthy pregnant women were identified with CD14 and CD16. In nonpregnant and pregnant rats, blood monocytes were identified with CD172a and CD43, as well as in rats infused with adenosine triphosphate (ATP), a pro-inflammatory stimulus known to induce preeclampsia-like symptoms. Total and CD206-positive macrophages were quantified in placentas of these animals. Results Lower percentages of classical monocytes were found in pregnant women (91%–[83–98%]) compared to nonpregnant women (94%–[90–98%]) and even less in preeclamptic patients (90%–[61–92%]). In contrast, the percentage of combined nonclassical/intermediate monocytes was higher in pregnant women (8.5%–[2.3–16.6%] vs. 5.6%–[1.9–9.5%]) and even higher in preeclamptic patients (9.9%–[7.8–38.7%]), which was caused by a selective increase of intermediate monocytes. In rats, we also found lower percentages of classical monocytes and higher percentages of nonclassical monocytes in pregnant versus nonpregnant rats. ATP infusion increased the percentage of nonclassical monocytes in pregnant rats even further but not in nonpregnant rats. These nonclassical monocytes showed a more activated phenotype in pregnant ATP-infused rats only. Mesometrial triangles of ATP-infused rats had less CD206-positive macrophages as compared to those of saline-infused rats. Conclusion The higher percentage of nonclassical/intermediate monocytes found in pregnancy and preeclampsia confirms their association with inflammatory responses. The observation that ATP stimulated numbers/activation of nonclassical monocytes in pregnant rats only, suggests that nonclassical monocytes are specifically altered in pregnancy and may play a role in the pathophysiology of preeclampsia.

Effects on (neuro)developmental and behavioral outcome at 2 years of age of induced labor compared with expectant management in intrauterine growth-restricted infants: long-term outcomes of the DIGITAT trial

OBJECTIVE We sought to study long-term (neuro)developmental and behavioral outcome of pregnancies complicated by intrauterine growth restriction at term in relation to induction of labor or an expectant management. STUDY DESIGN Parents of 2-year-old children included in the Disproportionate Intrauterine Growth Intervention Trial at Term (DIGITAT) answered the Ages and Stages Questionnaire (ASQ) and Child Behavior Checklist (CBCL). RESULTS We approached 582 (89.5%) of 650 parents. The response rate was 50%. Of these children, 27% had an abnormal score on the ASQ and 13% on the CBCL. Results of the ASQ and the CBCL for the 2 policies were comparable. Low birthweight, positive Morbidity Assessment Index score, and admission to intermediate care increased the risk of an abnormal outcome of the ASQ. This effect was not seen for the CBCL. CONCLUSION In women with intrauterine growth restriction at term, neither a policy of induction of labor nor expectant management affect developmental and behavioral outcome when compared to expectant management.

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.

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.