title: 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 3-5% 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.
  
  
  METHODS
  We conducted a pilot, multicenter, double-blind, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12(0/7) and 16(6/7) 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.
  
  
  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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX. Electronic address: mmcostan@utmb.edu.
authors.forename: Maged M
authors.initials: MM
authors.lastname: Costantine
authors.affiliation: Columbia University, New York, NY.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Cleary
authors.affiliation: Department of Pharmacy and Obstetrics and Gynecology, University of Washington, Seattle, WA.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Hebert
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
authors.forename: Mahmoud S
authors.initials: MS
authors.lastname: Ahmed
authors.affiliation: Department of Obstetrics and Gynecology and Pediatrics, RTI International, Rockville, MD.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Brown
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Ren
authors.affiliation: Department of Pharmacy and Obstetrics and Gynecology, University of Washington, Seattle, WA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Easterling
authors.affiliation: Department of Obstetrics and Gynecology and Pediatrics, Indiana University, Indianapolis, IN.
authors.forename: David M
authors.initials: DM
authors.lastname: Haas
authors.affiliation: Department of Obstetrics and Gynecology and Pediatrics, Indiana University, Indianapolis, IN.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Haneline
authors.affiliation: Department of Pharmacy and Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Steve N
authors.initials: SN
authors.lastname: Caritis
authors.affiliation: Department of Pharmacy and Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
authors.forename: Holly
authors.initials: H
authors.lastname: West
authors.affiliation: Columbia University, New York, NY.
authors.forename: Mary
authors.initials: M
authors.lastname: D'Alton
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
authors.forename: Gary
authors.initials: G
authors.lastname: Hankins
mesh_terms: D000328:Adult; D001724:Birth Weight; D002784:Cholesterol / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007231:Infant, Newborn; D010865:Pilot Projects; D017035:Pravastatin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011225:Pre-Eclampsia / Q000517:prevention & control*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011262:Pregnancy Trimester, Second; D018566:Pregnancy, High-Risk
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D017035:Pravastatin
keywords: angiogenic; pharmacokinetics; pravastatin; preeclampsia; safety