Studies looking at pravastatin for preeclampsia prevention

A promising pilot

Daily pravastatin use in pregnancy, starting in the second trimester, got its first major test of safety and pharmacokinetics in a pilot randomized, controlled trial undertaken by the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s (NICHD’s) Obstetric-Fetal Pharmacology Research Units Network. Women with singleton pregnancies and a history of severe preeclampsia requiring delivery prior to 34 weeks’ gestation were randomized between 12 and 16 weeks’ gestation to receive pravastatin or placebo until delivery.

This pilot is the first of three cohorts of women who were or will be randomized in separate pilot trials to escalating doses of pravastatin: 10 mg, 20 mg, and 40 mg (the last of which is the usual dose for lipid lowering in adults). Results of the first cohort, in which 20 patients were randomized to 10 mg pravastatin or placebo, were reported in 2016, and those from the second cohort will be reported soon. The third pilot is currently enrolling women.

In this first pilot we found no differences in rates of congenital anomalies or other identifiable maternal or fetal/neonatal safety risks, no differences in adverse events, and no maternal, fetal, or neonatal deaths. There were also no reports of myopathy/rhabdomyolysis or liver injury; the most common adverse events were heartburn (reported by four patients in the pravastatin group and three in the placebo group) and musculoskeletal pain (reported by four patients and one patient, respectively).

Although not statistically significant, a 10-mg dose of pravastatin was associated with favorable outcomes. None of the women receiving pravastatin developed preeclampsia, while four in the placebo group developed the disorder (with three of these four having severe preeclampsia).

Women in the pravastatin group also were less likely to have an indicated preterm delivery (one vs. five in the placebo group), and their neonates were less likely to be admitted to intermediate nurseries or the neonatal ICU. In addition, their angiogenic profiles were improved (higher placental growth factor and lower FMS-like tyrosine kinase 1 and soluble endoglin).

Importantly, while pravastatin reduced maternal cholesterol concentrations, there were no differences in birth weight or umbilical cord cholesterol concentrations (total cholesterol or LDL) between the two groups (Am J Obstet Gynecol. 2016;214[6]:720.e1-17).

That cholesterol concentrations were not reduced in fetuses exposed to pravastatin is reassuring and aligns with findings from other studies showing that fetal cholesterol concentrations are largely independent from maternal cholesterol concentrations or diet. For instance, we know from studies of Smith-Lemli-Opitz syndrome, a multiple congenital anomaly/intellectual disability syndrome caused by a defect in cholesterol synthesis, that there is not any significant interaction between cholesterol concentrations of the mother and fetus. Only about 10% of the fetal absolute cholesterol requirement comes from the mother, research has demonstrated.

The future

Infant follow-up in the NICHD study is planned, and a large, randomized clinical trial powered to look at the efficacy of pravastatin for preventing preeclampsia in high-risk women has been approved by the NICHD. Once funded, the study is expected to enroll approximately 1,700 pregnant women who have a history of severe preeclampsia and delivery before 36 weeks’ gestation and who are between 10 and 16 weeks’ gestation.

With continued research, we face the question of whether pravastatin may potentiate the benefit of aspirin in pregnant women. In cardiovascular medicine, there is evidence for additive or synergistic effects of the combined use of aspirin and statins.

Interestingly, a recent prospective cohort study of women with antiphospholipid syndrome and poor outcomes in prior pregnancies showed dramatic improvement in both maternal and fetal/neonatal outcomes when pravastatin was administered after the onset of preeclampsia or intrauterine growth restriction. All 21 women in the cohort were treated with low-dose aspirin and low-molecular-weight heparin; after the development of preeclampsia or intrauterine growth restriction, 10 patients were maintained on aspirin and LMWH, and 11 were started on 20 mg daily pravastatin along with the aspirin and LMWH (J Clin Invest. 2016 Aug;126[8]:2933-40; and J Clin Invest. 2016 Aug;126[8]:2792-4).

Those who received the statin had improved uterine artery Doppler velocimetry, lower systemic blood pressure, and delivered infants with higher birth weights and at a more advanced gestational age (median, 36 weeks’ vs. 26.5 weeks’ gestation). The study did not randomly allocate the women and did not include a placebo arm. Still, it is another impressive proof-of-concept study.

Dr. Costantine is an associate professor of obstetrics and gynecology at the University of Texas Medical Branch in Galveston. He reported that he has no financial disclosures.