Mifepristone followed by misoprostol compared with placebo followed by misoprostol as medical treatment for early pregnancy loss (the Triple M trial): A double-blind placebo-controlled randomised trial.

BACKGROUND: Worldwide, millions of women seek treatment for early pregnancy loss (EPL) annually. Medical management with misoprostol is widely used, but only effective 60% of the time. Pre-treatment with mifepristone prior to misoprostol might improve the success rate of medical management. METHODS: This was a multi-centre, double-blind, placebo-controlled randomised trial in 17 Dutch hospitals. Women with a non-viable pregnancy between 6 and 14 weeks of gestation were eligible for inclusion after at least one week of expectant management. Participants were randomised (1:1) between oral mifepristone 600 mg or an oral placebo tablet. Participants took 400 µg misoprostol orally, repeated after four hours on day two and, if necessary, day three. Primary outcome was expulsion of gestational sac and endometrial thickness <15 mm after 6-8 weeks. Analyses were done according to intention-to-treat principles. This trial is registered with ClinicalTrials.gov, NCT03212352. FINDINGS: Between June 28th 2018 and January 8th 2020, 175 women were randomised to mifepristone and 176 to placebo, including 344 in the intention-to-treat analysis. In the mifepristone group 136 (79•1%) of 172 participants reached complete evacuation compared to 101 (58•7%) of 172 participants in the placebo group (p<0•0001, RR 1•35, 95% CI 1•16-1•56). Incidence of serious adverse events was significantly lower in the mifepristone group with 24 (14%) patients affected versus 55 (32%) in the placebo group (p = 0•0005) (Table 3). INTERPRETATION: Pre-treatment with mifepristone prior to misoprostol was more effective than misoprostol alone in managing EPL. FUNDING: Healthcare Insurers Innovation Foundation, Radboud University Medical Centre, Canisius Wilhelmina Hospital.

Balloon catheter for induction of labor in women with one previous cesarean and an unfavorable cervix.

INTRODUCTION: When women with a previous cesarean section and an unfavorable cervix have an indication for delivery, the choice is to induce labor or to perform a cesarean section. This study aims to assess the effectiveness and safety of a balloon catheter as a method of induction of labor in women with one previous cesarean section and an unfavorable cervix compared with an elective repeat cesarean section. MATERIAL AND METHODS: We performed a prospective cohort study in 51 hospitals in the Netherlands on term women with one previous cesarean section, a live singleton fetus in cephalic position, an unfavorable cervix and an indication for delivery. We recorded obstetric, maternal and neonatal characteristics. We compared the outcome of women who were induced with a balloon catheter with the outcome of women who delivered by elective repeat cesarean section. Main outcomes were maternal and neonatal morbidity. Mode of delivery was a secondary outcome for women who were induced. Adjusted odds ratios (aOR) were calculated using logistic regression, adjusted for potential confounders. RESULTS: Analysis was performed on 993 women who were induced and 321 women who had a repeat cesarean section (August 2011 until September 2012). Among the women who were induced, 560 (56.4%) delivered vaginally and 11 (1.1%) sustained a uterine rupture. Composite adverse maternal outcome (uterine rupture, severe postpartum hemorrhage or postpartum infection) occurred in 73 (7.4%) in the balloon and 14 (4.5%) women in the repeat cesarean section group (aOR 1.58, 95% confidence interval [CI] 0.85-2.96). Composite adverse neonatal outcome (Apgar score <7 at 5 minutes or umbilical pH <7.10) occurred in 57 (5.7%) and 10 (3.2%) neonates, respectively (aOR 1.40, 95% CI 0.87-3.48). Women who were induced had a shorter postpartum admission time (2.0 vs 3.0 days (P < 0.0001)). CONCLUSIONS: In women with a previous cesarean section and a need for delivery, induction of labor with a balloon catheter does not result in a significant increase in adverse maternal and neonatal outcomes as compared with planned cesarean section.

Mode of Delivery in Severe Preeclampsia Before 28 Weeks' Gestation: A Systematic Review.

IMPORTANCE: Preeclampsia with an onset before 28 weeks' gestation poses dilemmas for the obstetrician with regard to the mode of delivery. OBJECTIVE: The aim of this study was to analyze the success rate of attempted vaginal delivery and the maternal and neonatal outcome according to the mode of delivery in women with preeclampsia and an indicated delivery before 28 weeks' gestation. EVIDENCE ACQUISITION: A comprehensive search was performed in the bibliographic databases PubMed, Embase.com, and Wiley Cochrane Library. The main outcome was success rate of attempted vaginal delivery. Secondary outcomes were maternal and neonatal outcomes. RESULTS: Eight studies describing a total of 800 women were included. Success rates of vaginal delivery varied from 1.8% to 80%, and rates for cesarean delivery after induction of labor varied from 13% to 51%. The rates for planned cesarean delivery varied from 0% to 73%. Two studies (n = 53) described no statistical significant differences in maternal outcomes. Two other studies (n = 107) report no statistical difference in neonatal outcome. CONCLUSIONS: Studies that report the success rate of attempted vaginal delivery are limited in size. However, giving the available evidence in the reported studies a trial of labor is a considerable option in counseling women with a pregnancy complicated by preeclampsia before 28 weeks' gestation due to the similar maternal and neonatal outcome. No differences in maternal or neonatal outcome were attributed to the mode of delivery, however, numbers are small.

Recurrence of hypertensive disorders of pregnancy: an individual patient data metaanalysis.

OBJECTIVE: We performed an individual participant data (IPD) metaanalysis to calculate the recurrence risk of hypertensive disorders of pregnancy (HDP) and recurrence of individual hypertensive syndromes. STUDY DESIGN: We performed an electronic literature search for cohort studies that reported on women experiencing HDP and who had a subsequent pregnancy. The principal investigators were contacted and informed of our study; we requested their original study data. The data were merged to form one combined database. The results will be presented as percentages with 95% confidence interval (CI) and odds ratios with 95% CI. RESULTS: Of 94 eligible cohort studies, we obtained IPD of 22 studies, including a total of 99,415 women. Pooled data of 64 studies that used published data (IPD where available) showed a recurrence rate of 18.1% (n=152,213; 95% CI, 17.9-18.3%). In the 22 studies that are included in our IPD, the recurrence rate of a HDP was 20.7% (95% CI, 20.4-20.9%). Recurrence manifested as preeclampsia in 13.8% of the studies (95% CI,13.6-14.1%), gestational hypertension in 8.6% of the studies (95% CI, 8.4-8.8%) and hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome in 0.2% of the studies (95% CI, 0.16-0.25%). The delivery of a small-for-gestational-age child accompanied the recurrent HDP in 3.4% of the studies (95% CI, 3.2-3.6%). Concomitant HELLP syndrome or delivery of a small-for-gestational-age child increased the risk of recurrence of HDP. Recurrence increased with decreasing gestational age at delivery in the index pregnancy. If the HDP recurred, in general it was milder, regarding maximum diastolic blood pressure, proteinuria, the use of oral antihypertensive and anticonvulsive medication, the delivery of a small-for-gestational-age child, premature delivery, and perinatal death. Normotensive women experienced chronic hypertension after pregnancy more often after experiencing recurrence (odds ratio, 3.7; 95% CI, 2.3-6.1). CONCLUSION: Among women that experience hypertension in pregnancy, the recurrence rate in a next pregnancy is relatively low, and the course of disease is milder for most women with recurrent disease. These reassuring data should be used for shared decision-making in women who consider a new pregnancy after a pregnancy that was complicated by hypertension.

Angiogenic factors in women ten years after severe very early onset preeclampsia.

BACKGROUND: Women with a history of mainly severe and early onset preeclampsia have an increased risk of future cardiovascular disease. During these complicated pregnancies increased levels of anti-angiogenic factors can be found. We hypothesize that women with a history of severe very early onset preeclampsia still have increased levels of these biomarkers years after this pregnancy, resulting in increased risk for cardiovascular disease. METHODS: Twenty women with severe early onset preeclampsia before 24 weeks' gestation, who delivered between 1993-2003 in a tertiary referral centre and twenty matched controls with uncomplicated pregnancies and healthy term infants, were addressed for participation in the study. Venous plasma samples were analyzed for basic fibroblast growth factor (bFGF), placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFlt-1), vascular endothelial growth factor (VEGF), E- and P-selectin, soluble intercellular adhesion molecule-3 (sICAM-3) and thrombomodulin by ELISA. RESULTS: Sixteen case subjects and 18 control subjects consented participation. The median time interval index pregnancy to study was 9.4 and 9.7 years for cases and controls, respectively. Median levels for cases-controls (p-value) were not different; bFGF: 17.43-11.11 pg/mL (0.33), sFlt-1: 102.98-101.92 pg/ml (0.84), PLGF: 3.57-4.20 pg/mL (0.38), VEGF: 64.05-45.72 pg/mL (0.73), E-selectin: 5.11-4.68 ng/mL (0.20), P-selectin: 85.35-71.69 ng/mL (0.69), sICAM-3: 0.42-0.63 ng/mL (0.41) and Thrombomodulin: 0.92-0.93 ng/mL (0.59). CONCLUSION: There were no differences in angiogenic biomarkers between women with a history of severe early onset preeclampsia versus uncomplicated pregnancy almost 10 years later, suggesting that these angiogenic factors will not contribute to the early detection of women at risk for future cardiovascular disease.

Maternal psychosocial outcome after early onset preeclampsia and preterm birth.

OBJECTIVE: To evaluate the impact of severe, early onset preeclampsia on long-term maternal psychosocial outcome after preterm birth. METHODS: Women with severe, early onset preeclampsia before 32 weeks' gestation (cases) admitted in a tertiary university referral center between 1993 and 2004, and women with preterm delivery without preeclampsia (controls), matched for age, parity, gestational age at delivery, ethnicity, and year of delivery. Women who consented to participation received three questionnaires in 2008 concerning depression (Zung Depression Scale: score range 0-20; 20 items with 2-point frequency scale: no = 0 and yes = 1), posttraumatic stress symptoms (Impact of Event Scale: score range 0-75; 15 items with 4-point frequency scale: not at all = 0, rarely = 1, sometimes = 3 and often = 5. Scores > 19 are regarded as high symptom levels), and social aspects (Social Readjustment Rating Scale: selection of six items concerning relational aspects with husband/partner, employer, or future family planning). RESULTS: Included in the study were 104 cases and 78 controls (response rate 79% and 58%, respectively). There was no difference in depression scores between cases (5.4 ± 4.0) and controls (5.4 ± 4.3). Patients with severe, early onset preeclampsia had significantly higher scores of posttraumatic stress symptoms (28.7 ± 8.6 vs. 25.7 ± 7.9). The majority of women among both cases and controls had high-posttraumatic stress symptom levels (88% vs. 79%). No differences could be found in relational aspects. CONCLUSION: Women with preterm birth due to severe, early onset preeclampsia experience more often posttraumatic stress symptoms on average 7 years after the pregnancy compared to women with preterm birth without preeclampsia.

Severe, very early onset preeclampsia: subsequent pregnancies and future parental cardiovascular health.

OBJECTIVE: To study subsequent pregnancy outcome in women with severe, very early onset preeclampsia (onset before 24 weeks' gestation) and to analyze cardiovascular risk profiles of these women and their partners. STUDY DESIGN: Twenty women with preeclampsia with an onset before 24 weeks' gestation, admitted between 1 January 1993 and 31 December 2002 at a tertiary university referral center, were enrolled in the study. Data on subsequent pregnancies were obtained from medical records. Their cardiovascular risk profiles and those of their partners (n=15) were compared with those of 20 control women after uncomplicated pregnancies only, matched for age and parity, and those of their partners (n=13). Body weight, height, waist and hip circumference, blood pressure and intima media thickness (IMT) of the common carotid artery were measured. Fasted blood samples were drawn for detection of metabolic cardiovascular risk factors. RESULTS: Of the 20 case women 17 women had 24 subsequent pregnancies, of which 12 (50%) were complicated by preeclampsia. Severe preeclampsia developed in five (21%) pregnancies. No perinatal deaths occurred. Case women had significantly more often chronic hypertension as compared to controls (55% vs. 10%, P=0.002). IMT of the common carotid artery was increased in a subset of case women using antihypertensive medication (P=0.03). Case women showed increased microalbuminuria (P<0.05). No differences were found in cardiovascular risk profiles between partners of cases and controls. CONCLUSIONS: Women with severe, very early onset preeclampsia have an increased risk of preeclampsia in future pregnancies, yet neonatal outcome is, in general, favourable. Regarding cardiovascular health, women after severe, very early onset preeclampsia exhibit more risk factors compared to controls whereas men who fathered these pregnancies do not.

Outcome after transabdominal cervicoisthmic cerclage.

OBJECTIVE: To estimate benefits and risks of transabdominal cervicoisthmic cerclage in women with cervical insufficiency in whom transvaginal cerclage is considered surgically unfeasible. METHODS: This was an observational cohort study with historical controls of 101 pregnancies after transabdominal cervicoisthmic cerclage in 101 women with a classic history of cervical insufficiency and severe cervical defects precluding transvaginal cerclage. RESULTS: Median gestational age at elective transabdominal cerclage (n = 95) was 14 (range 12-16) weeks and at emergency cerclage (n = 6) was 18 (range 17-22) weeks. Perioperative complications were blood loss 500 mL or more (n = 3) and rupture of membranes (n = 2). Patients were delivered by cesarean. Before cerclage 76% (95% confidence interval [CI] 70.2-81.1%) of births occurred before 32 weeks of gestation; total neonatal survival was 27.5% (95% CI 22.5-33.8%). After transabdominal cervicoisthmic cerclage 7% (95% CI 2.9-13.9%) of births took place before 32 weeks of gestation, and total neonatal survival was 93.5% (95% CI 85.5-96.6%). CONCLUSION: In women with a classic history of cervical insufficiency and a traumatized cervix that precludes transvaginal cerclage, transabdominal cervicoisthmic cerclage is associated with successful outcome in the absence of procedure-related major complications. LEVEL OF EVIDENCE: II-2.

Maternal and perinatal outcome of preeclampsia with an onset before 24 weeks' gestation. Audit in a tertiary referral center.

OBJECTIVE: Preeclampsia, with an onset before 24 weeks' gestation is a rare but severe condition in pregnancy with little data of maternal and perinatal outcome, particularly after expectant management. We therefore, evaluated pregnancy outcome in these women at our department where temporising management was introduced as the standard policy in early onset preeclampsia. STUDY DESIGN: We analysed retrospectively all consecutive women with preeclampsia, with an onset before 24 weeks' gestation, between 1 January 1993 and 31 December 2002 at a tertiary university referral center. RESULTS: Twenty-six pregnancies, of which two were twin pregnancies, resulted in 65% of the women in at least one major maternal complication: maternal death (n=1), HELLP syndrome (n=16), eclampsia (n=5) and pulmonary edema (n=4). Thirty percent of these women presented already with serious morbidity at admission. The median prolongation of the pregnancy was 24 days (range 3-46 days). The overall perinatal mortality was 82%: 19 fetal deaths and 4 neonatal deaths. CONCLUSION: Early onset preeclampsia, with an onset before 24 weeks' gestation, results in considerable maternal and perinatal morbidity and mortality. Therefore, expectant management should not be considered as a routine treatment option in these patients.