M.G. van Pampus

Induction versus expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT)

Objective To compare the effect of induction of labour with a policy of expectant monitoring for intrauterine growth restriction near term. Design Multicentre randomised equivalence trial (the Disproportionate Intrauterine Growth Intervention Trial At Term (DIGITAT)). Setting Eight academic and 44 non-academic hospitals in the Netherlands between November 2004 and November 2008. Participants Pregnant women who had a singleton pregnancy beyond 36+0 weeks’ gestation with suspected intrauterine growth restriction. Interventions Induction of labour or expectant monitoring. Main outcome measures The primary outcome was a composite measure of adverse neonatal outcome, defined as death before hospital discharge, five minute Apgar score of less than 7, umbilical artery pH of less than 7.05, or admission to the intensive care unit. Operative delivery (vaginal instrumental delivery or caesarean section) was a secondary outcome. Analysis was by intention to treat, with confidence intervals calculated for the differences in percentages or means. Results 321 pregnant women were randomly allocated to induction and 329 to expectant monitoring. Induction group infants were delivered 10 days earlier (mean difference −9.9 days, 95% CI −11.3 to −8.6) and weighed 130 g less (mean difference −130 g, 95% CI −188 g to −71 g) than babies in the expectant monitoring group. A total of 17 (5.3%) infants in the induction group experienced the composite adverse neonatal outcome, compared with 20 (6.1%) in the expectant monitoring group (difference −0.8%, 95% CI −4.3% to 3.2%). Caesarean sections were performed on 45 (14.0%) mothers in the induction group and 45 (13.7%) in the expectant monitoring group (difference 0.3%, 95% CI −5.0% to 5.6%). Conclusions In women with suspected intrauterine growth restriction at term, we found no important differences in adverse outcomes between induction of labour and expectant monitoring. Patients who are keen on non-intervention can safely choose expectant management with intensive maternal and fetal monitoring; however, it is rational to choose induction to prevent possible neonatal morbidity and stillbirth. Trial registration International Standard Randomised Controlled Trial number ISRCTN10363217.

Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-eclampsia in women with inheritable thrombophilia: the FRUIT-RCT

Summary.  Background: Early‐onset hypertensive disorders (HD) of pregnancy and small‐for‐gestational age infants (SGA) are associated with placental vascular thrombosis, these often recur and are also associated with inheritable thrombophilia. Aspirin reduces the recurrence risk. Objectives: Adding low‐molecular‐weight heparin (LMWH) to aspirin at < 12 weeks gestation reduces the recurrence of HD in women with previous early‐onset HD (pre‐eclampsia, hemolysis, elevated liver enzymes and low platelets [HELLP] syndrome and eclampsia) and/or SGA, in the context of inheritable thrombophilia without antiphospholipid antibodies. Patients/methods: In a multicenter randomized control trial (RCT), 139 women included were < 12 weeks gestation. Inclusion criteria: previous delivery < 34 weeks gestation with HD and/or SGA; inheritable thrombophilia (protein C deficiency, protein S deficiency, activated protein C resistance, factor V Leiden heterozygosity and prothrombin gene G20210A mutation heterozygosity); and no antiphospholipid antibodies detected. Intervention: either daily LMWH (dalteparin, 5000 IU weight‐adjusted dosage) with aspirin 80 mg or aspirin 80 mg alone. Main outcome measures: Primary outcomes: recurrent HD onset (i) < 34 weeks gestation and (ii) irrespective of gestational age. Secondary outcomes: recurrent SGA, preterm birth, maternal/neonatal hospitalization, spontaneous abortion and individual HD. Analysis by intention‐to‐treat. Results: Low‐molecular‐weight heparin with aspirin reduced recurrent HD onset < 34 weeks gestation (risk difference [RD] 8.7%: confidence interval [CI] of RD 1.9–15.5%; P = 0.012; number needed to treat [NNT] 12). Recurrent HD irrespective of gestational age was not different between the arms. No women withdrew as a result of adverse effects. Trial Registration: http://www.isrctn.org) (isrctn87325378). Conclusions: Adding LMWH to aspirin at < 12 weeks gestation reduces recurrent HD onset < 34 weeks gestation in women with inheritable thrombophilia and prior delivery for HD/SGA <34 weeks. However, close monitoring of the mother and fetus remains important throughout pregnancy.

Severe hypotension and fetal death due to tocolysis with nifedipine.

A 23 year old woman of African origin was referred from a peripheral unit at 26 weeks and five days of gestation in her second pregnancy because of preterm labour. She had previously had an uncomplicated pregnancy. On admission, we continued the tocolytic therapy with atosiban and the administration of steroids to mature the fetal lungs, which had already been started in the referring hospital. The uterine contractions continued and indomethacin was combined with atosiban for 24 hours. Finally, the contractions ceased. Ultrasound investigation showed one fetus with no obvious abnormalities. The estimated fetal weight was 800 g (10th– 25th centile). The membranes were intact and there were no signs of infection: no fever and the urine sample and vaginal swab showed no abnormalities. On admission, her blood pressure was 115/75 mmHg and remained stable. After 48 hours, the atosiban was discontinued and 5 hours later the uterine contractions started again. On examination per vaginam the cervix was fully effaced and the os uterine was 3 cm dilated. Because of severe prematurity, tocolytic therapy was restarted with orally administered nifedipine as outlined in the following regimen: first dose nifedipine 10 mg tablet chewed, followed by three further doses of nifedipine 10 mg every 15 minutes, followed by nifedipine slow release 20 mg every 3 or 4 hours depending on uterine activity. After the second dose, fetal cardiotocography became difficult to interpret due to a poor quality record and the blood pressure dropped without symptoms to 73/30 mmHg. Ultrasound examination showed severe bradycardia soon followed by fetal death. Tocolytic therapy was discontinued and colloid infusion started and after 6 hours the blood pressure reached its normal level again. The next day, labour was induced with vaginally administered misoprostol. A stillborn girl of 780 g was born (10th–25th centile). No obvious abnormalities were seen, apart from a marginal insertion of the umbilical cord to the placenta. The placenta weighted 150 g. The umbilical cord showed two arteries and one vein. On histopathology, 20% placental infarction was reported. Permission for autopsy was not obtained.

Posttraumatic stress disorder following preeclampsia and HELLP syndrome

Posttraumatic stress disorder (PTSD) in connection with pregnancy was first described in the 1990s - initially in relation to childbirth but later more specifically to the mode of delivery. Instrumental vaginal delivery carries the highest risk of PTSD followed by emergency caesarean section and normal spontaneous delivery. Loss of pregnancy, spontaneous abortion or intrauterine death for example can also lead to PTSD. Little systematic research has been performed regarding the psychological consequences of severe preeclampsia or HELLP syndrome, although it would seem obvious that these conditions may have a great effect. The combination of suffering a serious illness combined with an unexpected caesarean section or delivery, often of a premature child, is a heavy burden to bear both physically and psychologically. We describe here three patients who developed PTSD after pregnancies complicated by severe preeclampsia or HELLP syndrome. PTSD can develop after preeclampsia or HELLP syndrome.

Posttraumatic stress following childbirth in homelike- and hospital settings

Objective. To assess the prevalence of posttraumatic stress disorder (PTSD) following childbirth in homelike versus hospital settings and to determine risk factors for the development of posttraumatic stress symptoms. Methods. Multi-center cross-sectional study at midwifery practices, general hospitals and a tertiary (university) referral center. An unselected population of 907 women was invited to complete questionnaires on PTSD, demographic, psychosocial, and obstetric characteristics 2 to 6 months after delivery. Prevalence of PTSD was based on women who met all criteria of the diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV), whereas risk factors were determined using the severity (sum-score) of posttraumatic stress symptoms. Results. PTSD following childbirth was found in 1.2% of the respondents (5/428 women, response rate 47%), while 9.1% of women (39/428) had experienced the delivery as traumatic. Posttraumatic stress symptoms were associated with unplanned cesarean section, low sense of coherence (coping skills), and high intensity of pain. Initial differences in posttraumatic stress symptoms between home and hospital deliveries disappeared after taking into account the (by definition) uncomplicated nature of home births. Conclusion. In this Dutch study, 1 in 100 women had PTSD following childbirth, with no differences between home- and hospital deliveries after controlling for complications and interventions. Emergency cesarean section, severe labor pain, and poor coping skills were associated with more posttraumatic stress symptoms.

Hydrogen sulfide producing enzymes in pregnancy and preeclampsia

Preeclampsia, a human pregnancy specific disorder is characterized by an anti-angiogenic state. As hydrogen sulfide (H(2)S) has pro-angiogenic and anti-oxidative characteristics, we hypothesized that H(2)S levels could play a role in the pathogenesis of preeclampsia and studied the placental expression of the H(2)S-producing enzymes cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS). CBS and CSE protein are expressed in the fetal-placental endothelium and CBS only in Hofbauer cells. CBS mRNA expression is decreased (p = 0.002) in early-onset preeclampsia, while CSE mRNA is unchanged. Thus, down regulation of CBS during early-onset preeclampsia may result in less H(2)S-production and may aid in the anti-angiogenic state.

Posttraumatic Stress Disorder Following Preeclampsia and PPROM : A Prospective Study With 15 Months Follow-Up

Objective: A prospective longitudinal evaluation of the prevalence of and risk factors for posttraumatic stress disorder (PTSD) in women with preeclampsia (PE) or preterm premature rupture of membranes (PPROM) compared to uncomplicated pregnancies. Methods: Participating women completed PTSD and depression questionnaires during pregnancy, 6 weeks, and 15 months postpartum. Data regarding psychiatric history and indices of obstetric care were collected from patient charts. Results: We included 57 PE, 53 PPROM, and 65 healthy pregnant women, of whom 137 also participated in the 15-month follow-up (PE 70%, PPROM 48%, and controls 95%; P < .001). At 6 weeks postpartum, the prevalence of PTSD, but not depression, following childbirth was significantly higher in patients than in controls (14% vs 3%; P = .023). A history of depression, depressive symptoms during pregnancy, and infant death were significantly associated with symptoms of postpartum PTSD. The maternal condition seems to be of less decisive value, as there was no difference between the prevalence of PTSD after PE and PPROM (11% vs 17%; P = .324). At 15 months postpartum, 11% of women with PE had PTSD, some of which did not have PTSD 6 weeks postpartum. The low response rate in the PPROM group at 15 months postpartum does not allow for definite conclusions. Conclusion: Pregnancies complicated by PE or PPROM are associated with PTSD in a substantial number of women. Especially women with proven vulnerability for psychological problems are at risk of developing PTSD postpartum, as are women whose children died in the perinatal period.

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

Please cite this paper as: Tajik P, van der Tuuk K, Koopmans C, Groen H, van Pampus M, van der Berg P, van der Post J, van Loon A, de Groot C, Kwee A, Huisjes A, van Beek E, Papatsonis D, Bloemenkamp K, van Unnik G, Porath M, Rijnders R, Stigter R, de Boer K, Scheepers H, Zwinderman A, Bossuyt P, Mol B. 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. BJOG 2012;119:1123–1130.

Cost-effectiveness of induction of labour at term with a Foley catheter compared to vaginal prostaglandin E2 gel (PROBAAT trial)

To assess the economic consequences of labour induction with Foley catheter compared to prostaglandin E2 gel.

Plasma of pregnant and preeclamptic women activates monocytes in vitro

OBJECTIVE The objective of the study was to test the hypothesis that factors circulating in the plasma of pregnant women and women with preeclampsia activate monocytes. STUDY DESIGN Blood samples were taken from patients with early-onset severe preeclampsia (n = 9), healthy pregnant women (n = 9), and healthy nonpregnant women (n = 9). A monocytic cell line was incubated with the plasma for 4, 16, and 24 hours. After the incubation, reactive oxygen species (ROS) production and intercellular adhesion molecule (ICAM)-1 expression (protein and messenger ribonucleic acid) were measured. RESULTS Plasma of both pregnant women and women with preeclampsia, as compared with plasma from nonpregnant women, increased the mean channel brightness (MCB) of ROS after 4 hours of incubation, whereas only plasma of pregnant women increased the percentage of cells producing ROS (after 4 and 24 hours of incubation). Plasma of pregnant women and women with preeclampsia up-regulated the percentage of ICAM-1-expressing cells after 4 hours and down-regulated the percentage of ICAM-1-expressing cells and MCB after 24 hours. CONCLUSION Plasma of both pregnant women and women with preeclampsia activated monocytes in vitro.