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.
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
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
DOUBLE
Enrollment
102
20 mg Pravastatin taken daily
Identical appearing placebo pill
University of Alabama - Birmingham
Birmingham, Alabama, United States
Northwestern University
Chicago, Illinois, United States
Columbia University
New York, New York, United States
University of North Carolina - Chapel Hill
Chapel Hill, North Carolina, United States
Case Western Reserve-Metro Health
Cleveland, Ohio, United States
Ohio State University Hospital
Columbus, Ohio, United States
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States
Magee Women's Hospital of UPMC
Pittsburgh, Pennsylvania, United States
Brown University
Providence, Rhode Island, United States
University of Texas Medical Branch
Galveston, Texas, United States
...and 2 more locations
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. 1. 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 2. 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. 3. HELLP a) Hemolysis AND b)Thrombocytopenia AND c) AST/ALT ≥ 70 IU/L 4. Atypical HELLP an occurrence of 2 of the 3: a) Hemolysis, b)Thrombocytopenia, OR c) AST/ALT ≥ 70 IU/L 5. Eclampsia 6. Competing outcomes: maternal death before delivery or fetal loss \< 20wks, 0 days
Time frame: 48 hours postpartum
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)
Time frame: 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
Time frame: 48 hours postpartum
Proportion of Participants With Pregnancy Associated Hypertension
Defined as gestational hypertension or preeclampsia
Time frame: 48 hours postpartum
Proportion of Participants With Postpartum Preeclampsia
Preeclampsia that occurs more than 48 hours after birth
Time frame: 48 hours postpartum through 6 weeks post partum
Proportion of Participants With Gestational Diabetes
Gestational diabetes mellitus
Time frame: 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.
Time frame: 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
Time frame: Randomization through 6 weeks postpartum
Length of Maternal Hospital Stay
Length of maternal hospital stay for the delivery admission (admission to discharge)
Time frame: 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
Time frame: Randomization through 48 hours postpartum
Gestational Age at Delivery
Gestational age at the time of delivery
Time frame: Delivery
Proportion of Participants With Preterm Birth < 37 Weeks
Preterm birth before 37 weeks gestation
Time frame: Delivery before 37 weeks
Proportion of Participants With Indicated Preterm Birth < 37 Weeks
Indicated preterm birth less than 37 weeks
Time frame: Delivery before 37 weeks
Proportion of Participants With Preterm Birth < 34 Weeks
Preterm birth before 34 weeks gestation
Time frame: Delivery before 34 weeks
Proportion of Fetal or Neonatal Deaths
Death of the fetus or neonate
Time frame: randomization (mother) through 28 days of life (neonate)
Birth Weight
Birth weight
Time frame: Birth
Proportion of Small for Gestational Age < 5th Percentile
Birthweight \< 5th percentile
Time frame: Birth
Proportion of Small for Gestational Age < 10th Percentile
Birthweight \< 10th percentile
Time frame: Birth
Proportion of NICU/Intermediate Nursery Admission
Admission to the neonatal intensive care unit (NICU) or intermediate nursery
Time frame: 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.
Time frame: 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
Time frame: Birth through hospital discharge (an average of 4 days)
Proportion of Neonates Needing Oxygen Support
Provision of oxygen support for the neonate
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: Birth through hospital discharge (an average of 4 days)
Proportion of Neonates With Intraventricular Hemorrhage
Intraventricular hemorrhage (IVH) grade III-IV
Time frame: Birth through hospital discharge (an average of 4 days)
Proportion of Neonates With Periventricular Leukomalacia (PVL)
Periventricular leukomalacia (PVL), diagnosed by neuroimaging
Time frame: 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.
Time frame: 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.
Time frame: Birth through hospital discharge (an average of 4 days)
Proportion of Neonates With Retinopathy of Prematurity
Retinopathy of prematurity (ROP) stage III or higher
Time frame: 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
Time frame: Birth through hospital discharge (an average of 4 days)
Proportion of Neonates Experiencing Seizures
Neonatal seizure activity
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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)
Time frame: 24 months of age
Proportion of Children With Hearing Loss at 24 Months of Age
Hearing loss at 24 months of age
Time frame: 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.
Time frame: 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
Time frame: 24 months of age
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.