Preeclampsia remains a major cause of maternal and neonatal morbidity and mortality. Biological plausibility, compelling preliminary data, and a pilot clinical trial support the safety and utility of pravastatin to prevent preeclampsia.
We previously reported the results of a phase I clinical trial using a low dose (10 mg) of pravastatin in high-risk pregnant women. Here we report a follow up randomized trial of pravastatin 20 mg versus placebo in pregnant women with prior preeclampsia that required delivery before 34 weeks with the objective to evaluate of the safety and pharmacokinetic parameters of pravastatin.
Pilot, multicenter, blinded, placebo-controlled, randomized trial of women with singleton, non-anomalous pregnancies at high risk for preeclampsia. Women between 12 and 16 weeks of gestation were assigned to daily pravastatin 20 mg or placebo orally until delivery. In addition, steady-state pravastatin pharmacokinetic studies were conducted in the second and third trimesters of pregnancy as well as 4-6 months postpartum. Primary outcomes included maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included maternal and cord blood chemistries and maternal and neonatal outcomes including rates of preeclampsia and preterm delivery, gestational age at delivery, and birthweight (Clinicaltrials.gov Identifier NCT01717586).
Ten women assigned to pravastatin and ten assigned to placebo completed the trial. No significant differences were observed between the two groups in rates of adverse or serious adverse events, congenital anomalies, or maternal and cord blood chemistries. Headache, followed by heartburn and musculoskeletal pain were the most common side effects. We report pravastatin pharmacokinetic parameters including pravastatin area under the curve (total drug exposure over a dosing interval), apparent oral clearance, half-life and others in pregnancy compared with postpartum. In the majority of umbilical cord and maternal samples at the time of delivery, pravastatin concentrations were below the limit of quantification of the assay. Pregnancy and neonatal outcomes were more favorable in the pravastatin group. All newborns passed their brainstem auditory evoked response potential or similar hearing screening tests. The average maximum concentration and area under the curve values were more than two-fold higher following 20-mg dosing compared with the 10-mg pravastatin dose, but the apparent oral clearance, half-life, and time to reach maximum concentration were similar, which is consistent with the previously reported linear, dose-independent pharmacokinetics of pravastatin in non-pregnant subjects.
This study confirmed the overall safety and favorable pregnancy outcomes for pravastatin in women at high-risk for preeclampsia. This favorable risk-benefit analysis justifies a larger clinical trial to evaluate the efficacy of pravastatin in the prevention of preeclampsia. Until then, pravastatin use in pregnancy remains investigational.

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