Background Preeclampsia complicates approximately 3% to 5% of pregnancies and remains a major cause of maternal and neonatal morbidity and mortality. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Pravastatin, a hydrophilic, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, has been shown in preclinical studies to reverse various pathophysiological pathways associated with preeclampsia, providing biological plausibility for its use for preeclampsia prevention. However, human trials are lacking. Objective As an initial step in evaluating the utility of pravastatin in preventing preeclampsia, and after consultation with the U.S. Food and Drug Administration, we undertook a pilot randomized controlled trial with the objective to determine pravastatin safety and pharmacokinetic parameters when used in pregnant women at high risk of preeclampsia. Study Design We conducted a pilot, multicenter, double-blind, placebo-controlled, randomized trial of women with singleton, non-anomalous pregnancies at high risk for preeclampsia. Women between 120/7 and 166/7 weeks gestation were assigned to daily pravastatin 10 mg or placebo orally until delivery. Primary outcomes were maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included rates of preeclampsia and preterm delivery, gestational age at delivery, birthweight, and maternal and cord blood lipid profile (Clinicaltrials.gov Identifier NCT01717586). Results Ten women assigned to pravastatin and ten to placebo completed the trial. There were no differences between the two groups in rates of study drug side effects, congenital anomalies, or other adverse or serious adverse events. There was no maternal, fetal, or neonatal death. Pravastatin renal clearance was significantly higher in pregnancy compared to postpartum. Four subjects in the placebo group developed preeclampsia compared to none in the pravastatin group. Although pravastatin reduced maternal cholesterol concentrations, umbilical cord cholesterol concentrations and infant birthweight were not different between the groups. The majority of umbilical cord and maternal pravastatin plasma concentrations at time of delivery were below the lower limit of quantification of the assay. Conclusions This study provides preliminary safety and pharmacokinetic data regarding the use of pravastatin for preventing preeclampsia in high-risk pregnant women. Although the data are preliminary, no identifiable safety risks were associated with pravastatin use in this cohort. This favorable risk-benefit analysis justifies using pravastatin in a larger clinical trial with dose escalation.

BACKGROUND The addition of azithromycin to standard regimens for antibiotic prophylaxis before cesarean delivery may further reduce the rate of postoperative infection. We evaluated the benefits and safety of azithromycin-based extended-spectrum prophylaxis in women undergoing nonelective cesarean section. METHODS In this trial conducted at 14 centers in the United States, we studied 2013 women who had a singleton pregnancy with a gestation of 24 weeks or more and who were undergoing cesarean delivery during labor or after membrane rupture. We randomly assigned 1019 to receive 500 mg of intravenous azithromycin and 994 to receive placebo. All the women were also scheduled to receive standard antibiotic prophylaxis. The primary outcome was a composite of endometritis, wound infection, or other infection occurring within 6 weeks. RESULTS The primary outcome occurred in 62 women (6.1%) who received azithromycin and in 119 (12.0%) who received placebo (relative risk, 0.51; 95% confidence interval [CI], 0.38 to 0.68; P<0.001). There were significant differences between the azithromycin group and the placebo group in rates of endometritis (3.8% vs. 6.1%, P = 0.02), wound infection (2.4% vs. 6.6%, P<0.001), and serious maternal adverse events (1.5% vs. 2.9%, P = 0.03). There was no significant between-group difference in a secondary neonatal composite outcome that included neonatal death and serious neonatal complications (14.3% vs. 13.6%, P = 0.63). CONCLUSIONS Among women undergoing nonelective cesarean delivery who were all receiving standard antibiotic prophylaxis, extended-spectrum prophylaxis with adjunctive azithromycin was more effective than placebo in reducing the risk of postoperative infection. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; C/SOAP ClinicalTrials.gov number, NCT01235546.)

BackgroundIdentifying pregnancy‐associated risk factors before the development of major cardiovascular disease events could provide opportunities for prevention. The objective of this study was to determine the association between outcomes in first pregnancies and subsequent cardiovascular health.Methods and ResultsThe Nulliparous Pregnancy Outcomes Study Monitoring Mothers‐to‐be Heart Health Study is a prospective observational cohort that followed 4484 women 2 to 7 years (mean 3.2 years) after their first pregnancy. Adverse pregnancy outcomes (defined as hypertensive disorders of pregnancy, small‐for‐gestational‐age birth, preterm birth, and stillbirth) were identified prospectively in 1017 of the women (22.7%) during this pregnancy. The primary outcome was incident hypertension (HTN). Women without adverse pregnancy outcomes served as controls. Risk ratios (RR) and 95% CIs were adjusted for age, smoking, body mass index, insurance type, and race/ethnicity at enrollment during pregnancy. The overall incidence of HTN was 5.4% (95% CI 4.7% to 6.1%). Women with adverse pregnancy outcomes had higher adjusted risk of HTN at follow‐up compared with controls (RR 2.4, 95% CI 1.8‐3.1). The association held for individual adverse pregnancy outcomes: any hypertensive disorders of pregnancy (RR 2.7, 95% CI 2.0‐3.6), preeclampsia (RR 2.8, 95% CI 2.0‐4.0), and preterm birth (RR 2.7, 95% CI 1.9‐3.8). Women who had an indicated preterm birth and hypertensive disorders of pregnancy had the highest risk of HTN (RR 4.3, 95% CI 2.7‐6.7).ConclusionsSeveral pregnancy complications in the first pregnancy are associated with development of HTN 2 to 7 years later. Preventive care for women should include a detailed pregnancy history to aid in counseling about HTN risk.Clinical Trial Registration URL: http://www.clinicaltrials.gov Unique identifier: NCT02231398.

Preeclampsia complicates approximately 3-5% of pregnancies and remains one of the major causes of maternal and neonatal morbidity. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Attempts at prevention of preeclampsia using various supplements and classes of medications have failed or had limited success, and were not convincing enough to lead to widespread adoption of any particular strategy. Contrary to the experience with preeclampsia, prevention of cardiovascular mortality and other cardiovascular events in non-pregnant patients using 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, or statins, is widely accepted. Pravastatin, and other statins, have been shown to reverse various pathophysiological pathways associated with preeclampsia, such as angiogenic imbalance, endothelial injury, inflammation, and oxidative stress. These beneficial effects are likely to contribute substantially to preventing preeclampsia, and provide biological plausibility for the use of pravastatin in this setting. Pravastatin has favorable safety and pharmacokinetic profiles. In addition, animal studies and pregnancy human exposure data do not support teratogenicity claims for pravastatin. Therefore, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric-Fetal Pharmacology Research Units Network started a pilot trial to collect maternal-fetal safety data and evaluate pravastatin pharmacokinetics when used as a prophylactic daily treatment in high-risk pregnant women (ClinicalTrials.gov identifier NCT01717586).