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

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Background

Preeclampsia complicates approximately 3–5% 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 US 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, nonanomalous 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 10 to placebo completed the trial. There were no differences between the 2 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 with postpartum. Four subjects in the placebo group developed preeclampsia compared with 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 the time of delivery were below the lower limit of quantification of the assay. Pravastatin use was associated with a more favorable pregnancy angiogenic profile.

Conclusion

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.

Section snippets

Study population

We conducted a multicenter, double-blind, placebo-controlled randomized trial involving pregnant women at high risk for preeclampsia. Eligible women were 18 years old or older, with singleton, nonanomalous pregnancy between 120/7 weeks and 166/7 weeks’ gestation (confirmed with an ultrasound examination), and with a history of severe preeclampsia in a prior pregnancy that required delivery prior to 34 weeks’ gestation (documented by chart review).

We excluded women with known fetal genetic or

Results

Of 22 subjects who consented for the study, 21 were randomized, with 11 assigned to the pravastatin group and 10 to the placebo group. One subject from the pravastatin group withdrew from the study after randomization for social reasons (Supplemental Figure 1). Ten subjects in each group completed the trial, as requested by the FDA. No subjects were lost to follow-up. There was no significant difference in estimated adherence to study medication between the pravastatin group and placebo group

Comment

This pilot randomized controlled trial provides preliminary safety and PK data regarding the use of pravastatin, a drug traditionally avoided in pregnancy, for preventing preeclampsia, a pregnancy complication with serious morbidity. Initiation and completion of this trial was a direct result of collaboration between the NICHD–Obstetric-Fetal Pharmacology Research Units network and the FDA. Although the data are preliminary, no identifiable safety risks were associated with the use of

Acknowledgments

We thank Ms Charlene Williamson and members of the FDA Division of Reproductive and Urologic Products who reviewed our Investigational New Drug application for their thoughtful study design comments. In addition, we thank the following members who participated in protocol development, oversight, data management, and coordination between the clinical research centers: Katrina Burson, RN, and Julie Croxford, RN, MPH. They also thank the following collaborators and study research personnel:

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    The views expressed herein are those of the authors and do not necessarily represent the official views of Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health.

    This study was supported by grants U10HD047891, U10HD063094, U10HD047892, U10HD047905, and U10HD057753 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and grants UL1TR000423 and UL1TR001439 from National Institutes of Health and National Center for Advancing Translational Sciences through the Clinical and Translational Science Awards Program.

    The authors report no conflict of interest.

    Cite this article as: Costantine MM, Cleary K, Hebert MF, et al. Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial. Am J Obstet Gynecol 2016;214:720.e1-17.

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