Hypertension in Pregnancy, Obstetric Labor Complications, Preeclampsia
Conditions
Keywords
Pregnancy, Preeclampsia
Brief summary
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.
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.
Interventions
DRUGPravastatin
20 mg Pravastatin taken daily
OTHERPlacebo
Identical appearing placebo pill
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Heart, Lung, and Blood Institute (NHLBI)
The George Washington University Biostatistics Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Masking description
Consenting women will be assigned to pravastatin or placebo in a 1:1 ratio according to a randomization sequence prepared and maintained centrally by the Data Coordinating Center (DCC). The two study medication arms of the study (pravastatin or placebo) are double masked; neither the patient nor the clinical staff will be aware of the treatment assignment.
Intervention model description
The study is a randomized controlled multi-center clinical trial of 1,550 women with a prior history of preeclampsia that required delivery at less than or equal to 34 weeks 0 days gestation, randomized to one of two arms at participating Maternal Fetal Medicine Units Network clinical centers. * 20 mg pravastatin daily * Identical appearing daily placebo
Eligibility
Sex/Gender
FEMALE
Age
16 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Composite of Preeclampsia, Fetal Loss and Maternal Death | 48 hours postpartum | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Gestational Hypertension | 48 hours postpartum | Defined as new onset hypertension in the absence of accompanying proteinuria or other features of preeclampsia |
| Proportion of Participants With Pregnancy Associated Hypertension | 48 hours postpartum | Defined as gestational hypertension or preeclampsia |
| Proportion of Participants With Postpartum Preeclampsia | 48 hours postpartum through 6 weeks post partum | Preeclampsia that occurs more than 48 hours after birth |
| Proportion of Participants With Gestational Diabetes | At any time during pregnancy through delivery (up to approximately 30 weeks) | Gestational diabetes mellitus |
| Rate of Adherence to Study Medication | Randomization to delivery (up to approximately 30 weeks) | 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. |
| Proportion of Participants With Severe Maternal Morbidity Composite | Randomization through 6 weeks postpartum | 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 |
| Length of Maternal Hospital Stay | Delivery admission through discharge from the hospital (a median of 3 days) | Length of maternal hospital stay for the delivery admission (admission to discharge) |
| Rate of Adverse Events of Special Interest (AESI) or Serious AESI | Randomization through 48 hours postpartum | Adverse events of Special Interest (AESI) including myalgia and muscle weakness, and serious AESI include maternal myositis, myopathy, rhabdomyolysis, or serious liver injury |
| Gestational Age at Delivery | Delivery | Gestational age at the time of delivery |
| Proportion of Participants With Preterm Birth < 37 Weeks | Delivery before 37 weeks | Preterm birth before 37 weeks gestation |
| Proportion of Participants With Indicated Preterm Birth < 37 Weeks | Delivery before 37 weeks | Indicated preterm birth less than 37 weeks |
| Proportion of Participants With Preterm Birth < 34 Weeks | Delivery before 34 weeks | Preterm birth before 34 weeks gestation |
| Proportion of Fetal or Neonatal Deaths | randomization (mother) through 28 days of life (neonate) | Death of the fetus or neonate |
| Birth Weight | Birth | Birth weight |
| Proportion of Small for Gestational Age < 5th Percentile | Birth | Birthweight \< 5th percentile |
| Proportion of Small for Gestational Age < 10th Percentile | Birth | Birthweight \< 10th percentile |
| Proportion of NICU/Intermediate Nursery Admission | Birth through hospital discharge (an average of 4 days) | Admission to the neonatal intensive care unit (NICU) or intermediate nursery |
| NICU/Intermediate Nursery Length of Stay | Birth through hospital discharge (an average of 4 days) | Length of stay in the neonatal intensive care unit (NICU) and/or intermediate nursery. |
| Proportion of Neonates Needing Mechanical Ventilation or Continuous Positive Airway Pressure (CPAP) | Birth through hospital discharge (an average of 4 days) | Mechanical ventilation or CPAP support |
| Proportion of Neonates Needing Oxygen Support | Birth through hospital discharge (an average of 4 days) | Provision of oxygen support for the neonate |
| Proportion of Neonates With Respiratory Distress Syndrome | Birth through hospital discharge (an average of 4 days) | 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 |
| Proportion of Neonates With Bronchopulmonary Dysplasia | 28 days of life and 36 weeks corrected gestational age | Bronchopulmonary dysplasia (BPD), defined as oxygen requirement at 28 days of life and at 36 weeks corrected gestational age |
| Proportion of Neonates With Necrotizing Enterocolitis | Birth through hospital discharge (an average of 4 days) | 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) |
| Proportion of Neonates With Intraventricular Hemorrhage | Birth through hospital discharge (an average of 4 days) | Intraventricular hemorrhage (IVH) grade III-IV |
| Proportion of Neonates With Periventricular Leukomalacia (PVL) | Birth through hospital discharge (an average of 4 days) | Periventricular leukomalacia (PVL), diagnosed by neuroimaging |
| Proportion of Neonates Experiencing Early Onset Sepsis | Birth to 72 hours from birth | 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. |
| Proportion of Neonates Experiencing Late Onset Sepsis | Birth through hospital discharge (an average of 4 days) | 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. |
| Proportion of Neonates With Retinopathy of Prematurity | Birth through hospital discharge (an average of 4 days) | Retinopathy of prematurity (ROP) stage III or higher |
| Proportion of Neonates With Composite Neonatal Outcome | Birth through hospital discharge (an average of 4 days) | 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 |
| Proportion of Neonates Experiencing Seizures | Birth through hospital discharge (an average of 4 days) | Neonatal seizure activity |
| Proportion of Neonates With a Congenital Anomaly / Birth Defect | Randomization through delivery (up to approximately 30 weeks) | Congenital anomaly or birth defect excluding any conditions that must have been present before randomization |
| Neonatal Auditory Brain Stem Response (ABR)/Otoacoustic Emissions (OAE) | Birth through hospital discharge (an average of 4 days) | Neonatal auditory brain stem response (ABR)/Otoacoustic Emissions (OAE) test results of fail/refer. |
| BMI for Age at 24 Corrected Months | 24 months of age | Body mass index for age percentile at 24 corrected months using Centers for Disease Control (CDC) pediatric growth charts |
| Cognitive Standard Score From the Bayley Certified Scales of Infant Development III Edition at 24 Months of Age | 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. |
| Motor Standard Score From the Bayley Certified Scales of Infant Development III Edition at 24 Months of Age | 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. |
| Proportion of Participants With Preeclampsia With Severe Features | 48 hours postpartum | 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) |
| Gross Motor Function Classification System at 24 Months of Age | 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) |
| Proportion of Children With Hearing Loss at 24 Months of Age | 24 months of age | Hearing loss at 24 months of age |
| Child Behavior Checklist Total Problems T-Score at 24 Months | 24 months of age | 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. |
| Proportion of Children With Vision Problems at 24 Months of Age | 24 months of age | Vision problems (severe nearsightedness or farsightedness, and eye movement problems) at 24 months of age |
| Language Standard Score From the Bayley Certified Scales of Infant Development III Edition at 24 Months of Age | 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. |
Countries
United States
Participant flow
Recruitment details
This trial began under an FDA clinical hold that limited recruitment to 50 participants of the planned 1,550. The hold was not lifted and the trial was terminated after enrollment of the first 50 participants. We conducted the trial at 13 hospitals. Mothers were enrolled in pregnancy and their offspring followed for 2 years. Recruitment period was Jul 2019 to Dec 2020. Infants were enrolled but were not consented. Two mothers delivered twins resulting in 52 fetus/neonates (26 in each arm).
Participants by arm
| Arm | Count |
|---|---|
| Pravastatin 20 mg pravastatin daily
Pravastatin: 20 mg Pravastatin taken daily | 25 |
| Placebo Identical appearing daily placebo
Placebo: Identical appearing placebo pill | 25 |
| Pravastatin - Fetus/ Neonates /Infants Fetus/Neonates/Infants of participants in the 20 mg Pravastatin group | 0 |
| Placebo - Fetus/ Neonates /Infants Fetus/Neonates /Infants of participants in the placebo group | 0 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 1 | 2 |
| Overall Study | Lost to Follow-up | 0 | 0 | 4 | 4 |
| Overall Study | refused follow-up | 0 | 0 | 2 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Pravastatin |
|---|---|---|---|
| Age, Continuous | 31.6 years STANDARD_DEVIATION 6.8 | 31.6 years STANDARD_DEVIATION 5.8 | 31.6 years STANDARD_DEVIATION 4.7 |
| Chronic Hypertension | 10 Participants | 23 Participants | 13 Participants |
| Gestational age at randomization | 15.4 weeks | 14.9 weeks | 14.1 weeks |
| Race/Ethnicity, Customized American Indian/Alaskan Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic | 8 Participants | 17 Participants | 9 Participants |
| Race/Ethnicity, Customized More than 1 self-reported race | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian / Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Non-Hispanic Black | 6 Participants | 10 Participants | 4 Participants |
| Race/Ethnicity, Customized Non-Hispanic White | 9 Participants | 20 Participants | 11 Participants |
| Sex: Female, Male Female | 25 Participants | 50 Participants | 25 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Twin pregnancy | 1 Participants | 2 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 25 | 0 / 25 | 1 / 26 | 2 / 26 |
| other Total, other adverse events | 12 / 25 | 11 / 24 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 4 / 25 | 5 / 25 | 5 / 26 | 5 / 26 |
Outcome results
Primary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Participants With Composite of Preeclampsia, Fetal Loss and Maternal Death | 10 Participants |
| Placebo | Proportion of Participants With Composite of Preeclampsia, Fetal Loss and Maternal Death | 15 Participants |
95% CI: [0.37, 1.19]
Secondary
Birth Weight
Birth weight
Time frame: Birth
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pravastatin | Birth Weight | 2626 grams | Standard Deviation 668 |
| Placebo | Birth Weight | 2543 grams | Standard Deviation 884 |
p-value: 0.72t-test, 2 sided
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pravastatin | BMI for Age at 24 Corrected Months | 83.8 percentile |
| Placebo | BMI for Age at 24 Corrected Months | 50.6 percentile |
p-value: 0.08Wilcoxon (Mann-Whitney)
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pravastatin | Child Behavior Checklist Total Problems T-Score at 24 Months | 45 T-score |
| Placebo | Child Behavior Checklist Total Problems T-Score at 24 Months | 44.5 T-score |
p-value: 0.84Wilcoxon (Mann-Whitney)
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pravastatin | Cognitive Standard Score From the Bayley Certified Scales of Infant Development III Edition at 24 Months of Age | 93.8 score on a scale | Standard Deviation 10.2 |
| Placebo | Cognitive Standard Score From the Bayley Certified Scales of Infant Development III Edition at 24 Months of Age | 87.9 score on a scale | Standard Deviation 14.6 |
p-value: 0.21t-test, 2 sided
Secondary
Gestational Age at Delivery
Gestational age at the time of delivery
Time frame: Delivery
Population: For twin gestation, the worst outcome for the twin pair is analyzed/reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pravastatin | Gestational Age at Delivery | 36.7 weeks |
| Placebo | Gestational Age at Delivery | 37.0 weeks |
p-value: 0.68Wilcoxon (Mann-Whitney)
Secondary
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
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pravastatin | Gross Motor Function Classification System at 24 Months of Age | Level I | 18 Participants |
| Pravastatin | Gross Motor Function Classification System at 24 Months of Age | Level II | 1 Participants |
| Placebo | Gross Motor Function Classification System at 24 Months of Age | Level I | 16 Participants |
| Placebo | Gross Motor Function Classification System at 24 Months of Age | Level II | 1 Participants |
p-value: 1Fisher Exact
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pravastatin | Language Standard Score From the Bayley Certified Scales of Infant Development III Edition at 24 Months of Age | 88.9 score on a scale | Standard Deviation 16.7 |
| Placebo | Language Standard Score From the Bayley Certified Scales of Infant Development III Edition at 24 Months of Age | 87.8 score on a scale | Standard Deviation 20.1 |
p-value: 0.88t-test, 2 sided
Secondary
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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pravastatin | Length of Maternal Hospital Stay | 3 days |
| Placebo | Length of Maternal Hospital Stay | 3 days |
p-value: 1Wilcoxon (Mann-Whitney)
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pravastatin | Motor Standard Score From the Bayley Certified Scales of Infant Development III Edition at 24 Months of Age | 90.5 score on a scale | Standard Deviation 9.2 |
| Placebo | Motor Standard Score From the Bayley Certified Scales of Infant Development III Edition at 24 Months of Age | 88.2 score on a scale | Standard Deviation 11.9 |
p-value: 0.58t-test, 2 sided
Secondary
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)
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported. Data missing for 1 pravastatin and 1 placebo participant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Neonatal Auditory Brain Stem Response (ABR)/Otoacoustic Emissions (OAE) | 0 Participants |
| Placebo | Neonatal Auditory Brain Stem Response (ABR)/Otoacoustic Emissions (OAE) | 0 Participants |
Secondary
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)
Population: Neonates admitted to the NICU. For twin gestation, the worst outcome for the twin pair is analyzed/reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pravastatin | NICU/Intermediate Nursery Length of Stay | 13 days |
| Placebo | NICU/Intermediate Nursery Length of Stay | 42 days |
p-value: 0.12Wilcoxon (Mann-Whitney)
Secondary
Proportion of Children With Hearing Loss at 24 Months of Age
Hearing loss at 24 months of age
Time frame: 24 months of age
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Children With Hearing Loss at 24 Months of Age | 0 Participants |
| Placebo | Proportion of Children With Hearing Loss at 24 Months of Age | 2 Participants |
p-value: 0.22Fisher Exact
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Children With Vision Problems at 24 Months of Age | 0 Participants |
| Placebo | Proportion of Children With Vision Problems at 24 Months of Age | 1 Participants |
p-value: 0.47Fisher Exact
Secondary
Proportion of Fetal or Neonatal Deaths
Death of the fetus or neonate
Time frame: randomization (mother) through 28 days of life (neonate)
Population: For twin gestation, the worst outcome for the twin pair is analyzed/reported.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Fetal or Neonatal Deaths | 1 Participants |
| Placebo | Proportion of Fetal or Neonatal Deaths | 2 Participants |
95% CI: [0.02, 5.35]
Secondary
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
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported. Data missing for 1 pravastatin and 1 placebo participant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Neonates Experiencing Early Onset Sepsis | 0 Participants |
| Placebo | Proportion of Neonates Experiencing Early Onset Sepsis | 0 Participants |
Secondary
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)
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported. Data missing for 1 pravastatin and 1 placebo participant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Neonates Experiencing Late Onset Sepsis | 0 Participants |
| Placebo | Proportion of Neonates Experiencing Late Onset Sepsis | 1 Participants |
Secondary
Proportion of Neonates Experiencing Seizures
Neonatal seizure activity
Time frame: Birth through hospital discharge (an average of 4 days)
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported. Data missing for 1 pravastatin and 1 placebo participant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Neonates Experiencing Seizures | 0 Participants |
| Placebo | Proportion of Neonates Experiencing Seizures | 0 Participants |
Secondary
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)
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported. Data missing for 1 pravastatin and 2 placebo participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Neonates Needing Mechanical Ventilation or Continuous Positive Airway Pressure (CPAP) | 7 Participants |
| Placebo | Proportion of Neonates Needing Mechanical Ventilation or Continuous Positive Airway Pressure (CPAP) | 4 Participants |
95% CI: [0.52, 4.51]
Secondary
Proportion of Neonates Needing Oxygen Support
Provision of oxygen support for the neonate
Time frame: Birth through hospital discharge (an average of 4 days)
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported. Data missing for 1 pravastatin and 2 placebo participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Neonates Needing Oxygen Support | 6 Participants |
| Placebo | Proportion of Neonates Needing Oxygen Support | 4 Participants |
95% CI: [0.42, 5]
Secondary
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)
Population: For twin gestation, the worst outcome for the twin pair is analyzed/reported. Data missing for 1 placebo participant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Neonates With a Congenital Anomaly / Birth Defect | 1 Participants |
| Placebo | Proportion of Neonates With a Congenital Anomaly / Birth Defect | 1 Participants |
95% CI: [0.03, 31.79]
Secondary
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
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported. Data missing for 1 pravastatin and 1 placebo participant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Neonates With Bronchopulmonary Dysplasia | 0 Participants |
| Placebo | Proportion of Neonates With Bronchopulmonary Dysplasia | 0 Participants |
Secondary
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)
Population: For twin gestation, the worst outcome for the twin pair is analyzed/reported. Data missing for 1 placebo participant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Neonates With Composite Neonatal Outcome | 4 Participants |
| Placebo | Proportion of Neonates With Composite Neonatal Outcome | 6 Participants |
95% CI: [0.17, 2.04]
Secondary
Proportion of Neonates With Intraventricular Hemorrhage
Intraventricular hemorrhage (IVH) grade III-IV
Time frame: Birth through hospital discharge (an average of 4 days)
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported. Data missing for 1 pravastatin and 1 placebo participant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Neonates With Intraventricular Hemorrhage | 0 Participants |
| Placebo | Proportion of Neonates With Intraventricular Hemorrhage | 0 Participants |
Secondary
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)
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported. Data missing for 1 pravastatin and 1 placebo participant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Neonates With Necrotizing Enterocolitis | 0 Participants |
| Placebo | Proportion of Neonates With Necrotizing Enterocolitis | 1 Participants |
Secondary
Proportion of Neonates With Periventricular Leukomalacia (PVL)
Periventricular leukomalacia (PVL), diagnosed by neuroimaging
Time frame: Birth through hospital discharge (an average of 4 days)
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported. Data missing for 1 pravastatin and 1 placebo participant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Neonates With Periventricular Leukomalacia (PVL) | 0 Participants |
| Placebo | Proportion of Neonates With Periventricular Leukomalacia (PVL) | 0 Participants |
Secondary
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)
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported. Data missing for 1 pravastatin and 1 placebo participant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Neonates With Respiratory Distress Syndrome | 3 Participants |
| Placebo | Proportion of Neonates With Respiratory Distress Syndrome | 4 Participants |
95% CI: [0.11, 2.95]
Secondary
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)
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported. Data missing for 1 pravastatin and 1 placebo participant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Neonates With Retinopathy of Prematurity | 0 Participants |
| Placebo | Proportion of Neonates With Retinopathy of Prematurity | 0 Participants |
Secondary
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)
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported. Data missing for 1 pravastatin and 1 placebo participant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of NICU/Intermediate Nursery Admission | 11 Participants |
| Placebo | Proportion of NICU/Intermediate Nursery Admission | 9 Participants |
95% CI: [0.58, 2.18]
Secondary
Proportion of Participants With Gestational Diabetes
Gestational diabetes mellitus
Time frame: At any time during pregnancy through delivery (up to approximately 30 weeks)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Participants With Gestational Diabetes | 7 Participants |
| Placebo | Proportion of Participants With Gestational Diabetes | 4 Participants |
95% CI: [0.58, 5.24]
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Participants With Gestational Hypertension | 3 Participants |
| Placebo | Proportion of Participants With Gestational Hypertension | 1 Participants |
95% CI: [0.32, 77.16]
Secondary
Proportion of Participants With Indicated Preterm Birth < 37 Weeks
Indicated preterm birth less than 37 weeks
Time frame: Delivery before 37 weeks
Population: For twin gestation, the worst outcome for the twin pair is analyzed/reported.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Participants With Indicated Preterm Birth < 37 Weeks | 9 Participants |
| Placebo | Proportion of Participants With Indicated Preterm Birth < 37 Weeks | 7 Participants |
95% CI: [0.57, 2.91]
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Participants With Postpartum Preeclampsia | 1 Participants |
| Placebo | Proportion of Participants With Postpartum Preeclampsia | 0 Participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Participants With Preeclampsia With Severe Features | 2 Participants |
| Placebo | Proportion of Participants With Preeclampsia With Severe Features | 4 Participants |
95% CI: [0.07, 2.67]
Secondary
Proportion of Participants With Pregnancy Associated Hypertension
Defined as gestational hypertension or preeclampsia
Time frame: 48 hours postpartum
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Participants With Pregnancy Associated Hypertension | 5 Participants |
| Placebo | Proportion of Participants With Pregnancy Associated Hypertension | 9 Participants |
95% CI: [0.22, 1.43]
Secondary
Proportion of Participants With Preterm Birth < 34 Weeks
Preterm birth before 34 weeks gestation
Time frame: Delivery before 34 weeks
Population: For twin gestation, the worst outcome for the twin pair is analyzed/reported.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Participants With Preterm Birth < 34 Weeks | 4 Participants |
| Placebo | Proportion of Participants With Preterm Birth < 34 Weeks | 7 Participants |
95% CI: [0.19, 1.71]
Secondary
Proportion of Participants With Preterm Birth < 37 Weeks
Preterm birth before 37 weeks gestation
Time frame: Delivery before 37 weeks
Population: For twin gestation, the worst outcome for the twin pair is analyzed/reported.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Participants With Preterm Birth < 37 Weeks | 14 Participants |
| Placebo | Proportion of Participants With Preterm Birth < 37 Weeks | 11 Participants |
95% CI: [0.73, 2.23]
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Participants With Severe Maternal Morbidity Composite | 0 Participants |
| Placebo | Proportion of Participants With Severe Maternal Morbidity Composite | 0 Participants |
Secondary
Proportion of Small for Gestational Age < 10th Percentile
Birthweight \< 10th percentile
Time frame: Birth
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Small for Gestational Age < 10th Percentile | 7 Participants |
| Placebo | Proportion of Small for Gestational Age < 10th Percentile | 6 Participants |
95% CI: [0.42, 2.73]
Secondary
Proportion of Small for Gestational Age < 5th Percentile
Birthweight \< 5th percentile
Time frame: Birth
Population: Liveborn neonates only. For twin gestation, the worst outcome for the twin pair is analyzed/reported.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Proportion of Small for Gestational Age < 5th Percentile | 3 Participants |
| Placebo | Proportion of Small for Gestational Age < 5th Percentile | 2 Participants |
95% CI: [0.24, 13.59]
Secondary
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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pravastatin | Rate of Adherence to Study Medication | 88.8 percentage of compliance |
| Placebo | Rate of Adherence to Study Medication | 90.3 percentage of compliance |
p-value: 0.92Wilcoxon (Mann-Whitney)
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pravastatin | Rate of Adverse Events of Special Interest (AESI) or Serious AESI | 1 Participants |
| Placebo | Rate of Adverse Events of Special Interest (AESI) or Serious AESI | 0 Participants |