Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial

Abstract

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.

Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy

“…Another recent study has shown that pravastatin stabilized clinical and biochemical features of PE in 4 women (32). Statins have been shown not to be teratogenic as demonstrated by several studies (33,34). A study by Costantine et al reported no identifiable safety risks associated with pravastatin use in a pilot randomized trial designed to determine pravastatin safety and pharmacokinetic parameters in pregnant women at high risk of PE (33).…”

Pravastatin to prevent obstetrical complications in women with antiphospholipid syndrome

“…Consistent with these characteristics, recent transplacental studies have shown that the drug's ability to cross the placenta was limited and clearance was higher in the fetal-to-maternal direction than the maternal-to-fetal direction (18). The US randomized controlled trial additionally showed that renal clearance of pravastatin is higher in pregnancy compared with in the nonpregnant state, adding uncertainty to the ideal dose with the safest profile to be used in high-risk pregnant women (15). Data from pregnancy exposure cohorts do not support the teratogenicity claims of pravastatin (6, 19).…”

“…Importantly, the US trial demonstrated an improved angiogenic profile with the use of pravastatin and no difference in the rate of adverse events (based on clinical and laboratory observations) or congenital anomalies. Although pravastatin reduced maternal cholesterol concentrations, umbilical cord cholesterol concentrations and infant birth weight were not different between the treatment and control groups (15).…”

“…These beneficial effects were demonstrated without any harmful effects on dams or any increase in the rates of anomalies in offspring (6,(9)(10)(11)(12). The growing evidence from preclinical work that pravastatin improves pregnancy outcome, its biological plausibility, and the lack of agents effective at preventing placental disease led to several pilot clinical studies (13)(14)(15), including one by Lefkou et al in this issue (16).…”

“…However, a recently completed pilot, multicenter, double-blind, placebo-controlled trial in the US randomized women at high risk for preeclampsia. Those with prior pregnancy that required delivery at less than 34 weeks' gestation for severe preeclampsia and were between 12 0/7 and 16 6/7 weeks' gestation were given daily pravastatin or placebo orally until delivery (www.clinicaltrials.gov NCT01717586) (15). Findings from the Eunice Kennedy Shriver National Institute of Child Health and Human Development -Obstetric Fetal Pharmacology Research Unit trial also support the beneficial role of pravastatin, as women who received pravastatin had lower rates of preeclampsia and indicated preterm delivery and better neonatal outcomes compared with those who received placebo, although the results of this trial were not as dramatic as the results of Lefkou et al (16).…”