Pravastatin to Prevent Preeclampsia (Pravastatin)

A Randomized Controlled Trial of Pravastatin to Prevent Preeclampsia in High Risk Women

This study is a double-blind randomized placebo-controlled trial of 1,550 high-risk women to assess whether daily treatment with pravastatin administered early in pregnancy reduces the rate of a composite outcome of preeclampsia, fetal loss and maternal death. Women with a prior history of preeclampsia with preterm delivery less than 34 weeks will be randomized to pravastatin or placebo daily until delivery. Women will have monthly study visits during pregnancy, a follow-up visit at 6 weeks postpartum and children will have follow-up visits at 2 and 5 years of age.

Study Overview

• Status: Terminated
• Conditions: Obstetric Labor Complications; Preeclampsia; Hypertension in Pregnancy
• Intervention / Treatment: Drug: Pravastatin; Other: Placebo

Detailed Description

Preeclampsia complicates approximately 3% to 5% of pregnancies and remains a major cause of maternal and neonatal morbidities and mortality. Women who experience preeclampsia in one pregnancy are at higher risk of developing preeclampsia in a subsequent pregnancy than those who have never experienced the condition. There is evidence from laboratory studies and clinical trials, as well as biological plausibility, to suggest that statins may prevent the development of preeclampsia by reversing various pathways associated with preeclampsia. Pravastatin has a favorable safety profile and pharmacokinetic properties.

The study is a randomized placebo-controlled multi-center clinical trial of 1,550 women with a prior history of preeclampsia that required delivery at less than 34 weeks, randomized to either 20mg pravastatin or an identical appearing placebo daily until delivery. Women with a singleton or twin gestation will be randomized between 12 weeks 0 days and 16 weeks 6 days will be followed monthly during pregnancy and then at 6 weeks postpartum. Children will have follow-up visits at 2 and 5 years of age to assess growth, cognition, behavior, motor skills, vision and hearing.

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama - Birmingham
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina - Chapel Hill
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • Case Western Reserve-Metro Health
    • Columbus, Ohio, United States, 43210
      • Ohio State University Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of The University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee Women's Hospital of UPMC
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University
  • Texas
    • Galveston, Texas, United States, 77555
      • University of Texas Medical Branch
    • Houston, Texas, United States, 77030
      • University of Texas - Houston
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 16 years or older at time of consent with ability to give informed consent
2. Single or twin gestation with cardiac activity in one or both fetuses. Higher order multifetal gestations reduced to twins, either spontaneously or therapeutically, are not eligible unless the reduction occurred by 13 weeks 6 days project gestational age.
3. Gestational age at randomization between 12 weeks 0 days and 16 weeks 6 days based on clinical information and evaluation of the earliest ultrasound.
4. Documented history (by chart or delivery/operative note review) of prior preeclampsia with delivery less than or equal to 34 weeks 0 days gestation in any previous pregnancy. If in the index pregnancy, the woman was induced by 34 weeks 0 days gestation and delivered within 48 hours in the same hospitalization, that woman would be eligible.
5. Normal serum transaminase (AST/ALT) concentrations documented in the last 6 months.

Exclusion Criteria:

1. Monoamniotic gestation because of the risk of fetal demise
2. Known chromosomal, genetic or major malformations
3. Fetal demise or planned termination of pregnancy. Selective reduction by 13 weeks 6 days gestation, from triplets to twins or twins to singleton is not an exclusion.

4. Contraindications for statin therapy:

   1. Hypersensitivity to pravastatin or any component of the product
   2. Active liver disease: acute hepatitis or chronic active hepatitis
5. Statin use in current pregnancy

6. Patients with any of the following medical conditions:

   1. Uncontrolled hypothyroidism with a TSH level above 10 mIU/L, because of increased risk of myopathy
   2. HIV positive, because of increased risk of myopathy with use of protease inhibitors
   3. Chronic renal disease with baseline serum creatinine ≥1.5 mg/dL, because of association with adverse pregnancy outcomes
7. Current use of concomitant medication with potential for drug interaction with statins (i.e.,, cyclosporine, fibrates, niacin, erythromycin). Patients will not be excluded if the drug is discontinued (at least one week) prior to randomization.
8. Participating in another intervention study that influences the primary outcome in this study
9. Plan to deliver in a non-network site
10. Participation in this trial in a previous pregnancy. Patients who were screened in a previous pregnancy, but not randomized, do not have to be excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pravastatin; 20 mg pravastatin daily	Drug: Pravastatin; 20 mg Pravastatin taken daily
Placebo Comparator: Placebo; Identical appearing daily placebo	Other: Placebo; Identical appearing placebo pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants With Composite of Preeclampsia, Fetal Loss and Maternal Death	Proportion of participants demonstrating a composite of preeclampsia, fetal loss, or maternal death.; Baseline Normotensive: a) Severe hypertension (HTN) or b) Mild HTN w/ any of the following: i.) New-onset proteinuria or doubling in protein w/ baseline proteinuria ii.) Thrombocytopenia iii.) Progressive renal insufficiency iv). Impaired liver function v.) Pulmonary edema vi.) New-onset & persistent cerebral or visual symptoms; Baseline chronic HTN: any of the following a)Severe HTN b) New onset proteinuria or doubling in protein from baseline proteinuria c)Thrombocytopenia d) Progressive renal insufficiency e) Impaired liver function f) Pulmonary edema g) New-onset & persistent cerebral or visual symptoms.; HELLP a) Hemolysis AND b)Thrombocytopenia AND c) AST/ALT ≥ 70 IU/L; Atypical HELLP an occurrence of 2 of the 3: a) Hemolysis, b)Thrombocytopenia, OR c) AST/ALT ≥ 70 IU/L; Eclampsia; Competing outcomes: maternal death before delivery or fetal loss < 20wks, 0 days	48 hours postpartum

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants With Preeclampsia With Severe Features	Preeclampsia with severe features as defined by the American College of Obstetricians and Gynecologists (ACOG) diagnostic criteria (i.e., severe hypertension, thrombocytopenia, impaired liver function, progressive renal insufficiency, pulmonary edema, new-onset and persistent cerebral or visual symptoms)	48 hours postpartum
Proportion of Participants With Gestational Hypertension	Defined as new onset hypertension in the absence of accompanying proteinuria or other features of preeclampsia	48 hours postpartum
Proportion of Participants With Pregnancy Associated Hypertension	Defined as gestational hypertension or preeclampsia	48 hours postpartum
Proportion of Participants With Postpartum Preeclampsia	Preeclampsia that occurs more than 48 hours after birth	48 hours postpartum through 6 weeks post partum
Proportion of Participants With Gestational Diabetes	Gestational diabetes mellitus	At any time during pregnancy through delivery (up to approximately 30 weeks)
Rate of Adherence to Study Medication	Adherence to the medication regimen for the study (daily pill) defined as the time from randomization to delivery. The earliest gestational age at randomization is 12 weeks and most women deliver by 42 weeks gestation which is why the time frame is up to a maximum of approximately 30 weeks. Given the earlier gestational age of delivery in this cohort, the time period is shorter than 30 weeks.	Randomization to delivery (up to approximately 30 weeks)
Proportion of Participants With Severe Maternal Morbidity Composite	A composite of severe maternal morbidity of either maternal death, eclampsia, HELLP syndrome, cerebral vascular accident, heart failure, myocardial infarction, acute respiratory distress syndrome requiring mechanical ventilation, disseminated intravascular coagulopathy, pulmonary edema, renal failure, liver rupture, or placental abruption	Randomization through 6 weeks postpartum
Length of Maternal Hospital Stay	Length of maternal hospital stay for the delivery admission (admission to discharge)	Delivery admission through discharge from the hospital (a median of 3 days)
Rate of Adverse Events of Special Interest (AESI) or Serious AESI	Adverse events of Special Interest (AESI) including myalgia and muscle weakness, and serious AESI include maternal myositis, myopathy, rhabdomyolysis, or serious liver injury	Randomization through 48 hours postpartum
Gestational Age at Delivery	Gestational age at the time of delivery	Delivery
Proportion of Participants With Preterm Birth < 37 Weeks	Preterm birth before 37 weeks gestation	Delivery before 37 weeks
Proportion of Participants With Indicated Preterm Birth < 37 Weeks	Indicated preterm birth less than 37 weeks	Delivery before 37 weeks
Proportion of Participants With Preterm Birth < 34 Weeks	Preterm birth before 34 weeks gestation	Delivery before 34 weeks
Proportion of Fetal or Neonatal Deaths	Death of the fetus or neonate	randomization (mother) through 28 days of life (neonate)
Birth Weight	Birth weight	Birth
Proportion of Small for Gestational Age < 5th Percentile	Birthweight < 5th percentile	Birth
Proportion of Small for Gestational Age < 10th Percentile	Birthweight < 10th percentile	Birth
Proportion of NICU/Intermediate Nursery Admission	Admission to the neonatal intensive care unit (NICU) or intermediate nursery	Birth through hospital discharge (an average of 4 days)
NICU/Intermediate Nursery Length of Stay	Length of stay in the neonatal intensive care unit (NICU) and/or intermediate nursery.	Birth through hospital discharge (an average of 4 days)
Proportion of Neonates Needing Mechanical Ventilation or Continuous Positive Airway Pressure (CPAP)	Mechanical ventilation or CPAP support	Birth through hospital discharge (an average of 4 days)
Proportion of Neonates Needing Oxygen Support	Provision of oxygen support for the neonate	Birth through hospital discharge (an average of 4 days)
Proportion of Neonates With Respiratory Distress Syndrome	Respiratory distress syndrome (RDS), defined as the presence of clinical signs of respiratory distress (tachypnea, retractions, flaring, grunting, or cyanosis), with an oxygen requirement and confirmed by a chest x-ray	Birth through hospital discharge (an average of 4 days)
Proportion of Neonates With Bronchopulmonary Dysplasia	Bronchopulmonary dysplasia (BPD), defined as oxygen requirement at 28 days of life and at 36 weeks corrected gestational age	28 days of life and 36 weeks corrected gestational age
Proportion of Neonates With Necrotizing Enterocolitis	Necrotizing enterocolitis (NEC), defined as modified Bell Stage 2 (clinical signs and symptoms with pneumatosis intestinalis on radiographs) or Stage 3 (advanced clinical signs and symptoms, pneumatosis, impending or proven intestinal perforation)	Birth through hospital discharge (an average of 4 days)
Proportion of Neonates With Intraventricular Hemorrhage	Intraventricular hemorrhage (IVH) grade III-IV	Birth through hospital discharge (an average of 4 days)
Proportion of Neonates With Periventricular Leukomalacia (PVL)	Periventricular leukomalacia (PVL), diagnosed by neuroimaging	Birth through hospital discharge (an average of 4 days)
Proportion of Neonates Experiencing Early Onset Sepsis	Neonatal sepsis (within first 72 hours after birth). The diagnosis of sepsis will require the presence of a clinically ill infant in whom systemic infection is suspected with a positive blood, cerebral spinal fluid (CSF), or catheterized/suprapubic urine culture; or, in the absence of positive cultures, clinical evidence of cardiovascular collapse or an unequivocal radiograph confirming infection.	Birth to 72 hours from birth
Proportion of Neonates Experiencing Late Onset Sepsis	Neonatal sepsis (>72 hours after birth). The diagnosis of sepsis will require the presence of a clinically ill infant in whom systemic infection is suspected with a positive blood, cerebral spinal fluid (CSF), or catheterized/suprapubic urine culture; or, in the absence of positive cultures, clinical evidence of cardiovascular collapse or an unequivocal radiograph confirming infection.	Birth through hospital discharge (an average of 4 days)
Proportion of Neonates With Retinopathy of Prematurity	Retinopathy of prematurity (ROP) stage III or higher	Birth through hospital discharge (an average of 4 days)
Proportion of Neonates With Composite Neonatal Outcome	Fetal or neonatal death, RDS, Grade III-IV IVH, PVL, Stage 2 or 3 NEC, BPD, Stage III or higher ROP, or early onset sepsis	Birth through hospital discharge (an average of 4 days)
Proportion of Neonates Experiencing Seizures	Neonatal seizure activity	Birth through hospital discharge (an average of 4 days)
Proportion of Neonates With a Congenital Anomaly / Birth Defect	Congenital anomaly or birth defect excluding any conditions that must have been present before randomization	Randomization through delivery (up to approximately 30 weeks)
Neonatal Auditory Brain Stem Response (ABR)/Otoacoustic Emissions (OAE)	Neonatal auditory brain stem response (ABR)/Otoacoustic Emissions (OAE) test results of fail/refer.	Birth through hospital discharge (an average of 4 days)
BMI for Age at 24 Corrected Months	Body mass index for age percentile at 24 corrected months using Centers for Disease Control (CDC) pediatric growth charts	24 months of age
Cognitive Standard Score From the Bayley Certified Scales of Infant Development III Edition at 24 Months of Age	Bayley Certified Scales of Infant Development III Edition standard score for cognitive abilities at 24 months of age. Composite standard scores are derived for cognitive, language, and motor development and scaled to a metric, with a mean of 100, standard deviation of 15, and range of 40 to 160. Higher scores mean better outcome.	24 months of age
Motor Standard Score From the Bayley Certified Scales of Infant Development III Edition at 24 Months of Age	Bayley Certified Scales of Infant Development III Edition standard score for motor abilities at 24 months of age. Composite standard scores are derived for cognitive, language, and motor development and scaled to a metric, with a mean of 100, standard deviation of 15, and range of 40 to 160. Higher scores mean better outcome.	24 months of age
Language Standard Score From the Bayley Certified Scales of Infant Development III Edition at 24 Months of Age	Bayley Certified Scales of Infant Development III Edition standard score for language abilities at 24 months of age. Composite standard scores are derived for cognitive, language, and motor development and scaled to a metric, with a mean of 100, standard deviation of 15, and range of 40 to 160. Higher scores mean better outcome.	24 months of age
Gross Motor Function Classification System at 24 Months of Age	Level from the Gross Motor Function Classification System at 24 months of age Level I (Handles objects easily and successfully) Level II (Handles most objects, but with somewhat reduced quality and/or speed of achievement) Level III (Handles objects with difficulty) Level IV (Handles a limited selection of easily managed objects in simple actions) Level V (Does not handle objects and has severely limited ability to perform even simple actions)	24 months of age
Proportion of Children With Hearing Loss at 24 Months of Age	Hearing loss at 24 months of age	24 months of age
Child Behavior Checklist Total Problems T-Score at 24 Months	Total problems T score from the Child Behavior Checklist (CBCL) at 24 months. The Child Behavior Checklist (CBCL) is a survey used to detect behavioral and emotional problems in children. The CBCL is filled out by the caregiver. Each of the 100 questions indicates a behavior for which the caregiver scores as Not True (0), Sometimes True (1), or Often True (2). The scores for all the questions are then summed and evaluated against the normative data/T-scores. The raw total scores are converted to norm-referenced T-scores (mean 50, standard deviation of 10). Lower scores represent better outcomes. A T-score of 64 or higher indicates a clinically significant elevation. Lower scores represent better outcomes.	24 months of age
Proportion of Children With Vision Problems at 24 Months of Age	Vision problems (severe nearsightedness or farsightedness, and eye movement problems) at 24 months of age	24 months of age

Collaborators and Investigators

• Sponsor: The George Washington University Biostatistics Center
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Maged Costantine, MD, Ohio State University; Study Director: Monica Longo, MD, PHD, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Study Director: Victoria Pemberton, RNC, MS, CCRC, National Heart, Lung, and Blood Institute (NHLBI); Principal Investigator: Rebecca Clifton, PhD, The George Washington University Biostatistics Center

Publications and helpful links

General Publications

• Costantine MM, Cleary K, Hebert MF, Ahmed MS, Brown LM, Ren Z, Easterling TR, Haas DM, Haneline LS, Caritis SN, Venkataramanan R, West H, D'Alton M, Hankins G; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric-Fetal Pharmacology Research Units Network. 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 Jun;214(6):720.e1-720.e17. doi: 10.1016/j.ajog.2015.12.038. Epub 2015 Dec 23.

Study record dates

Study Major Dates

• Study Start (Actual): July 17, 2019
• Primary Completion (Actual): June 6, 2021
• Study Completion (Actual): June 20, 2024

Study Registration Dates

• First Submitted: May 7, 2019
• First Submitted That Met QC Criteria: May 8, 2019
• First Posted (Actual): May 9, 2019

Study Record Updates

• Last Update Posted (Estimated): December 23, 2025
• Last Update Submitted That Met QC Criteria: December 9, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Pregnancy; Preeclampsia
• Additional Relevant MeSH Terms: Urogenital Diseases; Vascular Diseases; Cardiovascular Diseases; Female Urogenital Diseases and Pregnancy Complications; Pregnancy Complications; Hypertension; Pre-Eclampsia; Hypertension, Pregnancy-Induced; Obstetric Labor Complications; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Pravastatin
• Other Study ID Numbers: HD036801-Pravastatin; 5U10HD036801-20 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Given enrollment was limited to 50 participants, the dataset will not be shared.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No