A Randomized Controlled Trial of Pravastatin to Prevent Preeclampsia in High Risk Women
Phase: PHASE3
Conditions: Preeclampsia, Obstetric Labor Complications, Hypertension in Pregnancy
Sponsor: The George Washington University Biostatistics Center

 
A Randomized Controlled Trial of Pravastatin to 
Prevent Preeclampsia in High Risk Women 
 
 
 
 
Protocol 
 
 
 
 
Eunice Kennedy Shriver  
National Institute of Child Health and Human Development (NICHD) 
Maternal-Fetal Medicine Units (MFMU) Network  
 
IND # 114205 
 
Prepared by the 
 
Biostatistical Coordinating Center for the NICHD MFMU Network 
 
The Biostatistics Center 
George Washington University 
6110 Executive Boulevard, Suite 750 
Rockville, MD 20852 
(301) 881-9260 
 
 
 
March 8, 2022 

Table of Contents 
1 
Introduction ...................................................................................................................................... 1 
1.1 
Study Abstract ........................................................................................................................... 1 
1.2 
Primary Hypothesis ................................................................................................................... 1 
1.3 
Purpose of the Study Protocol.................................................................................................... 1 
2 
Background....................................................................................................................................... 2 
2.1 
Introduction ............................................................................................................................... 2 
2.2 
Etiology of Preeclampsia ........................................................................................................... 2 
2.2.1 
Angiogenic Imbalance ......................................................................................................... 2 
2.2.2 
Endothelial Dysfunction, Oxidative Injury, and Inflammation ............................................ 2 
2.3 
Preeclampsia and Cardiovascular Disease ................................................................................. 3 
2.4 
Prevention of Preeclampsia ....................................................................................................... 3 
2.4.1 
Low-dose Aspirin to Prevent Preeclampsia ......................................................................... 3 
2.4.2 
Biologic Plausibility of Statins to Prevent Preeclampsia ..................................................... 4 
2.5 
Safety of Pravastatin in Pregnancy ............................................................................................ 5 
2.5.1 
Congenital Anomalies ......................................................................................................... 5 
2.5.2 
Cholesterol Synthesis in the Fetus ....................................................................................... 7 
2.5.3 
Fetal Brain Development..................................................................................................... 8 
2.5.4 
Maternal Safety ................................................................................................................... 9 
2.5.5 
Interactions with Other Medications ................................................................................. 10 
2.6 
Preliminary Studies of Pravastatin as a Modifier of Outcomes Associated with Preeclampsia 11 
2.6.1 
Animal Models .................................................................................................................. 11 
2.6.2 
NICHD OPRC Pilot Study ................................................................................................ 11 
2.6.3 
Other Studies of Pravastatin in Pregnancy ........................................................................ 13 
2.7 
Rationale for a Randomized Trial ............................................................................................ 13 
3 
Study Design ................................................................................................................................... 15 
3.1 
Primary Research Question ..................................................................................................... 15 
3.2 
Secondary Research Questions ................................................................................................ 15 
3.3 
Design Summary ..................................................................................................................... 15 
3.4 
Eligibility Criteria .................................................................................................................... 16 
3.4.1 
Inclusion Criteria ............................................................................................................... 16 
3.4.2 
Gestational Age Determination ......................................................................................... 16 
3.4.3 
Exclusion Criteria.............................................................................................................. 17 
3.5 
Informed Consent Criteria ....................................................................................................... 17 
3.6 
Randomization Method and Masking ...................................................................................... 18 
4 
Study Procedures ........................................................................................................................... 19 
4.1 
Screening for Eligibility and Consent ...................................................................................... 19 
4.2 
Randomization ......................................................................................................................... 19 
4.3 
Baseline Procedures ................................................................................................................. 19 
4.4 
Study Procedures ..................................................................................................................... 20 
4.4.1 
Child 2-year Follow-up ..................................................................................................... 21 
4.4.2 
Child 5-year Follow-up ..................................................................................................... 21 
4.5 
Patient Management ................................................................................................................ 22 
4.6 
Study Outcome Measures and Ascertainment.......................................................................... 23 
4.6.1 
Primary Outcome .............................................................................................................. 23 
4.6.2 
Maternal Secondary Outcomes .......................................................................................... 25 
4.6.3 
Fetal and Neonatal secondary outcomes ............................................................................ 25 
4.6.4 
Child Secondary Outcomes ............................................................................................... 26 
4.7 
Adverse Event Reporting ......................................................................................................... 27 
4.8 
Emergency Unblinding ............................................................................................................ 27 
5 
Data and Safety Monitoring Plan .................................................................................................. 28 

5.1 
Data and Safety Monitoring Committee .................................................................................. 28 
5.1.1 
DSMC Membership Qualifications ................................................................................... 28 
5.1.2 
Conflict of Interest and Confidentiality ............................................................................. 28 
5.1.3 
Responsibilities of the DSMC ........................................................................................... 28 
5.2 
Protocol Review ...................................................................................................................... 29 
5.3 
Ongoing Safety Monitoring ..................................................................................................... 29 
5.4 
Data and Safety Monitoring Committee Meetings ................................................................... 30 
5.4.1 
Study Report to the DSMC ............................................................................................... 30 
5.4.2 
Interim Analysis ................................................................................................................ 31 
5.4.3 
Trial Stopping Rules.......................................................................................................... 31 
5.5 
Reporting from the DSMC ...................................................................................................... 32 
6 
Statistical Considerations .............................................................................................................. 33 
6.1 
Data Relevant to the Primary Outcome ................................................................................... 33 
6.2 
Sample Size and Power ........................................................................................................... 33 
6.3 
Analysis Plan ........................................................................................................................... 34 
6.3.1 
Subgroup Analyses ............................................................................................................ 35 
7 
Data Collection ............................................................................................................................... 36 
7.1 
Data Collection Forms ............................................................................................................. 36 
7.2 
Web Data Entry System ........................................................................................................... 37 
7.3 
Centralized Data Management System .................................................................................... 37 
7.4 
Performance Monitoring .......................................................................................................... 37 
8 
Study Administration ..................................................................................................................... 38 
8.1 
Organization and Funding ....................................................................................................... 38 
8.1.1 
MFMU Clinical Centers .................................................................................................... 38 
8.1.2 
Biostatistical Coordinating Center (BCC) ......................................................................... 38 
8.1.3 
Clinical Coordinating Center (CCC) ................................................................................. 38 
8.1.4 
NHLBI/NICHD ................................................................................................................. 38 
8.1.5 
Network External Advisory Committee ............................................................................ 38 
8.2 
Committees .............................................................................................................................. 38 
8.2.1 
Steering Committee ........................................................................................................... 38 
8.2.2 
Protocol Subcommittee ..................................................................................................... 39 
8.2.3 
Publications Committee .................................................................................................... 39 
9 
Study Timetable ............................................................................................................................. 40 
9.1 
Training and Certification ........................................................................................................ 40 
9.2 
Recruitment and Data Collection Period .................................................................................. 40 
9.2.1 
Estimate of the Prevalence of Previous Preeclampsia ....................................................... 40 
9.2.2 
Estimate of Recruitment Rate ............................................................................................ 41 
9.3 
Final Analysis .......................................................................................................................... 41 
Appendix A 
Design Summary ......................................................................................................... 42 
References................................................................................................................................................ 43 
 
Tables 
Table 1. Summary of studies assessing the use of statins in pregnancy ...................................................... 7 
Table 2. Results of the OPRC pilot trial using pravastatin versus placebo to prevent preeclampsia ......... 12 
Table 3. Cutoffs for Using LMP to Determine Gestational Age for Sure LMP ........................................ 17 
Table 4. Study visit procedures ................................................................................................................. 20 
Table 5. Sample Sizes for Different, Levels of Power and Effect Sizes .................................................... 34 
Table 6. Probability of Previous Preeclampsia in the MFMU Network Population .................................. 41 
 
Figures 
Figure 1. Timetable ................................................................................................................................... 40 

March 8, 2022 
 
1 
1 
Introduction 
1.1 
Study Abstract 
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 HMG-CoA reductase inhibitors (statins) may prevent the development of 
preeclampsia by reversing various pathophysiological pathways associated with preeclampsia. Pravastatin 
has a favorable safety profile and pharmacokinetic properties. The beneficial effects of pravastatin are 
likely to contribute substantially to preventing preeclampsia, and provide biological plausibility for its use 
in this setting.   
This protocol describes 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 
preeclampsia in high-risk women. 
1.2 
Primary Hypothesis 
In women who have a prior history of preeclampsia and were delivered by 34 weeks 0 days of gestation, 
prophylactic treatment of pravastatin prevents a composite outcome of preeclampsia, fetal loss, and 
maternal death.  
1.3 
Purpose of the Study Protocol 
This protocol describes the background, design and organization of the randomized clinical trial and may 
be viewed as a written agreement among the study investigators.  The Data and Safety Monitoring 
Committee (DSMC) and the External Advisory Committee review the protocol.  Before recruitment 
begins, the protocol is approved by the Eunice Kennedy Shriver National Institute of Child Health and 
Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network Steering Committee, 
and the single Institutional Review Board (IRB) of record.  Other study materials must also be approved 
by the IRB before study start. Any changes to the protocol during the study period require the approval of 
the Steering Committee and the single IRB of record.  The protocol and any subsequent changes will also 
be submitted as IND amendments to the FDA.  A manual of operations supplements the protocol with 
detailed specifications of the study procedures. 

March 8, 2022 
 
2 
2 
Background 
2.1 
Introduction 
Preeclampsia is a pregnancy-specific syndrome characterized by widespread endothelial damage in 
multiple organ systems in the second half of pregnancy. Clinical presentation includes hypertension, 
proteinuria, and end organ dysfunction.1 For the mother, preeclampsia may lead to seizure, stroke, 
intracranial bleeding, uncontrolled hypertension, renal failure, pulmonary edema, and death. For the fetus, 
it may lead to intrauterine growth restriction, death, and complications of prematurity.1 Apart from the use 
of low dose aspirin, which remains controversial, there is no effective prophylactic therapy, and delivery 
remains the main approach to preventing maternal morbidity and mortality. However, this is frequently 
achieved at the expense of premature delivery and the associated neonatal morbidities and mortality. 
Women with underlying hypertension, pregestational diabetes, multifetal gestation, renal or autoimmune 
disease are at increased risk. Women with a previous history of preeclampsia, especially if early and 
severe, are at a substantially high risk (up to 65%) for the disease.1,2  
2.2 
Etiology of Preeclampsia 
The pathogenesis of preeclampsia is not completely understood, but the origin of the disease is thought to 
be related to impaired early placental development mainly through defective trophoblast invasion and 
remodeling of the spiral arterioles.3 Many mechanisms have been proposed for the pathogenesis, but 
abnormalities in the following processes have generally been well accepted: angiogenesis, endothelial 
injury, oxidative stress, and inflammation.4-7  
2.2.1 Angiogenic Imbalance 
Imbalances in pro- and anti-angiogenic factors are thought to play a role in preeclampsia.5-7 Two anti-
angiogenic factors, soluble Fms-like tyrosine kinase (sFlt-1) and soluble endoglin (sEng), have been 
shown to bind vascular endothelium growth factor (VEGF) and placental growth factor (PlGF) in the 
circulation and suppress their effects. Over expression of these anti-angiogenic factors results in a 
preeclampsia-like condition in animal models.8,9 The concentration of sFlt-1 in the maternal circulation 
correlates with the severity of the preeclampsia-like condition.8 In the case of over expression of sFlt-1, 
lowering the circulating levels of free sFlt-1 below a critical threshold reverses some of the pathological 
findings of preeclampsia and lowers the blood pressure.10 In humans, both sFlt-1 and sEng are known to 
increase dramatically weeks prior to the onset of clinical manifestations of preeclampsia.5,6  
Findings in the animal models strongly support a role for sFlt-1 in the temporal relation between elevated 
sFlt-1 levels and later development of preeclampsia.5,6,8,9,11 This angiogenic imbalance may represent a 
“common pathway” responsible for the expression of the clinical features of preeclampsia. The trigger for 
the cascade of events leading to preeclampsia remains unknown, but may include immunologic, 
inflammatory, and/or genetic susceptibilities, and may be related to a mismatch between placental 
metabolic demands versus supply.3,4 The end result is excessive release of vasoactive factors, cytokines, 
and maternal endothelial dysfunction, which then triggers the clinically apparent maternal syndrome 
characterized by hypertension, proteinuria, and other systemic manifestations of end-stage organ 
damage.3  
2.2.2 Endothelial Dysfunction, Oxidative Injury, and Inflammation 
Preeclampsia is accompanied by endothelial dysfunction. This dysfunction results in abnormal vascular 
relaxation and platelet activation and is associated with inflammation and oxidative imbalance.4,12 The 
activation of the inflammatory cascade that occurs in normal pregnancy is further exaggerated in 
preeclampsia.13 Markers of inflammation, such as the C-reactive protein (CRP) or its high-sensitivity 

March 8, 2022 
 
3 
form (hs-CRP), are elevated in patients who later develop preeclampsia; this association no longer 
persists when body mass index is added to the multivariable model implying that inflammation might be 
part of a causal pathway between obesity and preeclampsia.14 The risk of developing preeclampsia in 
patients with elevated hs-CRP increases by 10% for every 5 unit increases in hs-CRP level.15  In addition, 
preeclampsia is associated with elevated cytokines such as tumor necrosis factor-α (TNF-α), TNF 
receptor, interleukin-6 (IL-6), and IL-12. Some of these cytokines are known to activate the inflammatory 
cascade and increase free radical generation and oxidative stress, thus contributing to generalized 
endothelial injury.16-18 
In addition to the dyslipidemia associated with preeclampsia, studies have shown increased antibodies for 
the oxidized form of LDL (ox-LDL)19 in patients with preeclampsia, a finding that is consistent with 
oxidative stress and similar to changes noted in atherosclerotic disease.20 Preeclampsia may also be 
associated with suppression of the heme oxygenase-1/carbon monoxide pathway. Heme oxygenase-1 
(HO-1) is an inducible anti-oxidant enzyme essential for the degradation of heme into biliverdin in a 
three-step process that liberates carbon monoxide (CO). HO-1 has anti-inflammatory properties and is 
known to have a protective effect against oxidative stress in the vascular system.21 HO-1 messenger 
ribonucleic acid (mRNA) is down-regulated in placental samples obtained at chorionic villous sampling 
(CVS) from women who subsequently developed preeclampsia.22 In addition, patients with preeclampsia 
have significantly decreased CO concentrations in their exhaled breath, signifying either decreased levels 
or activity of HO-1.23 
2.3 
Preeclampsia and Cardiovascular Disease 
Although preeclampsia is unique to human pregnancy, it shares biological and pathological similarities as 
well as many risk factors (e.g., obesity, diabetes, dyslipidemia, hypertension, metabolic syndrome, 
prothrombotic state, and family history) with adult cardiovascular diseases.24-26  Endothelial dysfunction 
and inflammation are fundamental mechanisms for the initiation and progression of both 
atherosclerosis27,28 and preeclampsia.3,26 Preeclampsia is considered by many as either an early 
manifestation of cardiovascular disorders unmasked by the challenges and characteristics of pregnancy or 
a risk factor for future cardiovascular disease. This association is demonstrated in studies that showed that 
a diagnosis of preeclampsia increases the patient’s risk of hypertension, ischemic heart disease, and 
ischemic stroke later in life by two- to three- fold.29-31  Moreover, the severity and gestational age at 
diagnosis of preeclampsia are important determinants of the risk of cardiovascular disease later in life. 
When compared with patients who did not develop preeclampsia, the relative risk (RR) of developing 
cardiovascular disease later in life was 2.0 (95% confidence interval [CI] 1.8-2.2) for patients who had 
mild preeclampsia and 5.4 (95% CI 4-7.3) for patients who had severe preeclampsia.32 Similarly, the RR 
of death from cardiovascular disease later in life is 2.1 (95% CI 1.3-3.6) for patients who had 
preeclampsia at term and 9.5 (95% CI 4.5–20.3) if the preeclampsia resulted in delivery at less than 34 
weeks.33 
2.4 
Prevention of Preeclampsia  
Numerous attempts at primary and secondary prevention of preeclampsia, using various supplements and 
medications, have failed. Use of antihypertensive medications in women with chronic hypertension, who 
are at higher risk of preeclampsia, was found to control severe hypertension, without decreasing the risk 
of preeclampsia.2,34  Supplementation with fish oil, calcium, or antioxidant vitamins C and E did not show 
any benefit in reducing the rate of recurrence or severity of preeclampsia.2,35-40 
2.4.1 Low-dose Aspirin to Prevent Preeclampsia 
Low-dose aspirin, by selectively inhibiting the production of the vasocontractile thromboxane A2 without 
affecting the production of the vasorelaxant prostacyclin, was thought to protect the vasculature and thus 

March 8, 2022 
 
4 
theoretically prevent preeclampsia. However, the benefits of low-dose aspirin in preeclampsia prevention 
were not supported by large randomized studies that included high- and low-risk women in the USA.41,42 
The Perinatal Antiplatelet Review of International Studies (PARIS) Collaborative Group performed an 
individual patient meta-analysis of the effectiveness of antiplatelet agents (predominantly aspirin) for the 
prevention of preeclampsia. This meta-analysis, which included 31 randomized trials involving 32,217 
women, found a small benefit in reducing the occurrence of preeclampsia:  0.90 (95% CI 0.84-0.96).43  In 
the pre-specified subgroup analyses, including early versus late gestation, no interaction term was 
positive. Therefore the analysis did not identify a particular group of women that would benefit more or 
less.  
The authors of another meta-analysis reported that low-dose aspirin reduces the risk of preeclampsia 
when started before 16 weeks gestational age (RR = 0.47; 95% CI 0.36-0.62), with no benefit if aspirin 
was started after that point.44  This meta-analysis, which included data from 34 studies, has been heavily 
criticized. Unlike the PARIS collaboration, the meta-analysis was not comprehensive (for example, it did 
not include the MFMU Network Low Risk Trial, which was large and well-conducted in comparison with 
many of those included). The authors did not conduct an interaction test to determine whether there was 
heterogeneity before concluding that the aspirin effect was different by gestational age category. The 
analysis was also subject to publication bias, wherein smaller, negative trials are not published and 
therefore unavailable for inclusion in meta-analyses.45 This meta-analysis was particularly susceptible to 
bias.  The trials designated as recruiting women at ≤ 16 weeks were all small with sample size between 33 
and 255 women. Because it was not based on individual patient data, the authors were unable to separate 
the results by less than 16 weeks versus greater in many trials where the gestational age range spanned 16 
weeks. This included two of the largest trials, the High Risk trial conducted by the MFMU Network and 
the Collaborative Low-dose Aspirin Study in Pregnancy (CLASP)46 where the lower limit of eligibility 
was 12-13 weeks. These trials were placed in the greater than 16 weeks category although they would 
have contributed a substantial number of women randomized by 16 weeks.  The limitations and biases of 
misclassification, inclusion of small studies and inappropriate subgroup analyses were confirmed in a 
recent IPD meta-analysis by the same authors, which included 3,293 women, from larger clinical trials, 
who were started on aspirin before 17 weeks. In this meta-analysis, low dose aspirin started before 17 
weeks did not reduce risk of preeclampsia (RR 0.93; 95% CI 0.75-1.15), or small for gestational age (RR 
0.84, 95% CI 0.56-1.26).47  
Despite the limitations of the aspirin data, and the fact that the majority of the large aspirin trials 
regarding prevention of preeclampsia have been negative or contradictory, the United States Preventive 
Services Task Force (USPSTF) recommended the use of low dose aspirin in high-risk women including 
those with previous history of preeclampsia. The American College of Obstetricians and Gynecologists 
(ACOG) initially recommended that low dose aspirin be considered for women with preeclampsia in a 
prior pregnancy that resulted in delivery before 34 weeks gestation, but updated their guidelines in 2016 
and now currently recommends the use of low dose aspirin in all women with prior preeclampsia, 
irrespective of gestational age at delivery in the index pregnancy, and this practice is currently part of the 
standard of care in the U.S.1,48 This practice is also supported by patient advocacy groups such as the 
Preeclampsia Foundation.49 
2.4.2 Biologic Plausibility of Statins to Prevent Preeclampsia 
The properties and mechanisms of action of statins make them highly promising candidates for the 
prevention and/or treatment of preeclampsia due to their ability to improve vascular health broadly. 
Statins up regulate endothelial nitric oxide synthase (NOS3), which in turn increases nitric oxide (NO) 
production in the vasculature.50 They also promote VEGF and PlGF release, which may moderate the 
effects of sFlt-1, and also upregulate the transcription and expression of HO-1 which in turn suppresses 
the production of sFlt-1 and s-Eng in the placenta and endothelium.51  Furthermore, using various rodent 
models of preeclampsia, daily pravastatin administration was found to prevent the hypertensive vascular 
phenotype, attenuate kidney injury, restore trophoblast invasiveness and placental blood flow, upregulate 

March 8, 2022 
 
5 
NOS3 in the vasculature, reverse the angiogenic imbalance (reduce circulating sFlt-1 and sEng levels, and 
upregulate VEGF and PlGF), and prevent growth restriction without any deleterious effects on the pups, 
and without affecting maternal cholesterol levels.52-56 
Statins are also known to have anti-inflammatory properties and have been shown to decrease hs-CRP 
(37%) in parallel with the decrease in cardiovascular mortality and morbidities even in patients with 
normal cholesterol levels.57 Preeclampsia is associated with reversal of the Th1 and Th2 responses 
(increase in Th1 proinflammatory cytokines, such as TNF-α, IL-1, IL-2, IFN-γ, and decrease in Th2 anti-
inflammatory cytokines such as IL-4, IL 10).58 Statins are known to up regulate Th2 cell cytokine 
production and down regulate Th1 cell differentiation.59 These and other pleiotropic actions on free 
oxygen radical formation and smooth muscle cell proliferation, as well as immunomodulatory and anti-
inflammatory effects,60 make statins highly promising candidates for the prevention and/or treatment of 
preeclampsia.  
In conclusion, it appears that statins are capable of 1) reversing the pregnancy-specific angiogenic 
imbalance associated with preeclampsia, 2) restoring global endothelial health, and 3) preventing 
oxidative and inflammatory injury, actions that provide biological plausibility for the use of statins in the 
prevention of preeclampsia. 
2.5 
Safety of Pravastatin in Pregnancy  
Pravastatin was previously labeled as a U.S. Food and Drug Administration (FDA) category X drug, 
signifying that “studies in animals or humans have demonstrated fetal abnormalities and/or there is 
positive evidence of human fetal risk based on adverse reaction data from investigational or marketing 
experience and the risks involved in use of the drug in pregnant women clearly outweigh potential 
benefits”. The FDA recently changed the designation of drugs in pregnancy and discontinued 
categorization of medications. The new rule requires that the pregnancy subsection in the package insert 
provides information relevant to the use of the drug in pregnant women, such as dosing and potential risks 
to the developing fetus, and requires information about whether there is a registry that collects and 
maintains data on how pregnant women are affected when they use the drug or biological product. The 
package insert for Pravachol (pravastatin) was updated in 2016 and still reports pravastatin as 
contraindicated for use in pregnant women.  This is predominantly due to the limited published safety 
data and no known benefit to therapy with pravastatin during pregnancy.61  Potential concerns are 
addressed in the subsections below. 
2.5.1 Congenital Anomalies 
Pravastatin was neither embryolethal nor teratogenic in rats at doses up to 1000 mg/kg daily or in rabbits 
at doses of up to 50 mg/kg daily. These doses resulted in 10 times (rabbit) or 120 times (rat) the human 
exposure at 80 mg/day maximum recommended human dose based on surface area (mg/m2).62 
In humans (Table 1), an increased risk of congenital malformations has not been seen with pravastatin. 
The Medical Genetics branch of the National Institutes of Health reviewed 214 ascertained pregnancy 
exposures to statins that were reported to the FDA from 1987 to 2001. Of the 70 evaluable cases reviewed 
in the final report, 20 cases of pravastatin exposure were included. No congenital malformations or 
adverse pregnancy outcomes occurred in the pravastatin exposed group compared with 22 cases of 
structural defects, 4 cases of growth restriction, and 5 cases of fetal demise with exposure to lipophilic 
statins (cerivastatin, lovastatin, atorvastatin, or simvastatin).63   
Recent epidemiologic data from two large case-control studies of birth defects, the National Birth Defects 
Prevention Study and the Slone Epidemiology Center Birth Defects Study failed to show any link 
between pravastatin exposure and a pattern of birth defects. In this database analysis, the authors 
identified preconception statin exposure in 22 cases of birth defects. Three of these defects were reported 

March 8, 2022 
 
6 
with exposure to pravastatin; however, two patients were diabetic and the third infant had Down 
syndrome.64   
A Canadian population based pregnancy registry that collected data on women exposed to statins and 
other cholesterol-lowering agents prior to and in the first trimester of pregnancy showed no pattern or 
increased rate of congenital abnormalities in 288 women with live births.65  The rate of congenital 
anomalies was 3/64 (4.69%; 95% CI 1.00, 13.69) in women exposed to statins prior to and in the first 
trimester, and 7/67 (10.45%; 95% CI 4.19, 21.53) in women exposed to statins between 1 year and 1 
month before conception, but not during pregnancy. The adjusted odds ratio for congenital anomalies in 
women exposed to statin prior to and in the first trimester of pregnancy compared with those exposed to 
statin prior to conception was 0.36 (95% CI 0.06, 2.18). Of note, no cases of congenital anomalies were 
found in women exposed to pravastatin. In addition, a prospective observational cohort study by the 
Motherisk program in Toronto did not find any malformation patterns or increased malformations in 
infants of 64 women with first trimester exposure to statins (atorvastatin [n = 46], simvastatin [n = 9], 
pravastatin [n = 6], and rosuvastatin [n = 3]) compared with women without exposure to known 
teratogens.66  The rate of major congenital malformations was not significantly different between the 
statin-exposed and control groups (2.2% vs. 1.9%; p=0.93). In addition, the rates of live birth (71.9% vs. 
81.2%), spontaneous abortions (21.9% vs. 17.2%), therapeutic abortions (4.7% vs. 0%), and stillbirths 
(1.5% vs. 1.6%) were similar between the two study groups.  
A multicenter observational prospective controlled study from the European Network of Teratology 
Information Services followed 249 pregnant women who were exposed to statins in the first trimester (32 
were exposed to pravastatin), and another 249 pregnant women who were not exposed to any teratogenic 
drugs as a matched control group.  There was not a significant association between exposure and 
congenital malformations (4.1% vs. 2.7%; OR 1.5 95% CI 0.5 – 4.5) or miscarriage (hazard ratio 1.36, 
95% CI 0.63–2.93, P = 0.43) compared with the control group.67   
Lastly, using data from more than 800,000 pregnant women enrolled in the Medicaid program, Bateman 
et al. compared the outcomes of 1,152 women exposed to statins during the first trimester with those not 
exposed. Using propensity score analysis and after controlling for confounders, particularly pre-existing 
diabetes, there was no increased risk of congenital malformation (aOR 1.07; 95% CI 0.85 - 1.37) or organ 
specific malformations.68  
The findings from these studies, and various systematic reviews and meta-analyses,69-71 support the lack 
of teratogenicity of pravastatin. One limitation is that most of the statin-exposed patients discontinued 
statin use as soon as pregnancy was confirmed.  
The reassuring findings from these studies are to be expected because of pravastatin’s unique 
pharmacokinetic properties.72  Pravastatin is one of the most hydrophilic (polar) statins and a substrate of 
the efflux pump P-glycoprotein and thus is expected to have limited transplacental transfer. This was 
confirmed in recent placental transfer studies, which demonstrated, using an ex-vivo placental perfusion 
model, that pravastatin transfer across the placenta appears to be limited and slow,73 and its clearance is 
higher from the fetal-to-maternal direction than the maternal-to fetal direction.74  This is secondary to 
pravastatin being a substrate of placental efflux transporters such as P-glycoprotein and multidrug 
resistance-associated protein 2.74  Moreover, pravastatin is one of the least potent inhibitors of HMG-CoA 
reductase compared with other statins and its inhibitory activity is specific to hepatocytes.75  This 
hepatoselectivity is also a result of pravastatin being actively and preferentially taken up into hepatocytes 
via a Na+-independent multispecific anion transporter. In addition, pravastatin is cleared through both 
hepatic and renal routes, which reduces the need for dose reduction in case of liver/renal impairment; and 
CYP3A-dependent metabolism represents only a minor pathway in pravastatin elimination with no 
clinically important pharmacokinetic interaction between pravastatin and CYP3A inhibitors.72   
 
 
 

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7 
Table 1. Summary of studies assessing the use of statins in pregnancy 
 
Study 
Population 
Statin (n) 
Control (n) 
Congenital 
anomalies 
Edison et al 63 
2004 case series 
Reports of maternal 
statin exposure 
spontaneously reported
to the FDA from 1987 
to 2001 
Atorvastatin, ceriva-
statin, lovastatin, 
pravastatin, simva-
statin (n=70; prava-
statin n=20) 
None 
22 reports of 
congenital 
anomalies, none 
with pravastatin 
Ofori et al 65  
2007 cohort 
Women (15-45 years) 
prescribed statins in 
the year before and/or 
during pregnancy from 
1997-2003 
Atorvastatin, fluva-
statin, lovastatin, 
pravastatin, simva-
statin (n=64; prava-
statin n=12) 
Use of statins only 
before conception (1 
year – 1 month) 
(n=67) 
Exposed vs non-
exposed: 4.7% 
vs.10.5%  aOR 0.36 
(95% CI 0.06-2.18) 
No anomalies with 
pravastatin 
Taguchi et al 66 
2008 cohort 
Hypercholesterolemic 
women using statins 
during pregnancy and 
contacting the 
teratogen information 
service from 1998 to 
2005 
Atorvastatin, prava-
statin, simvastatin, 
rosuvastatin (n=64; 
pravastatin n=6) 
No exposure to 
known teratogens 
(n=64) matched with 
women who 
contacted the 
Motherisk program 
with ordinary 
therapeutic uses of 
nonteratogens 
Exposed vs non-
exposed: 2.2% vs 
1.9%; p = 0.93 
McGrogan et al76 
2017 cohort 
Women (aged 10–49 
years) using statins 3 
months before or 
during the 1st trimester 
1992 - 2009  
(n = 281, pravastatin 
n=8)  
No statin use (n = 
2,643) matched on 
maternal age, year of 
pregnancy, and 
hypertension & 
diabetes diagnosis 
Exposed vs non-
exposed: 3.2% vs. 
2.8%, OR* 1.6 (95% 
CI 0.72-3.64) 
Winterfeld et al67 
2013 cohort 
Women with statin 
exposure in first 
trimester, who 
contacted European 
teratology information 
services between 
1990-2009. 
(n=249; pravastatin 
n=32) 
Exposure to agents 
known to be non-
teratogenic (n=249) 
Exposed vs non-
exposed.: 4.1% vs. 
2.7%, OR 1.5 (95% 
CI 0.5 – 4.5) 
Bateman et al68 
2015 cohort 
Women (12-52 years) 
with live birth, from US 
Medicaid data 2000-07;
used statin in the 1st 
trimester  
Simvastatin, 
lovastatin, pravastatin, 
uvastatin, atorvastatin, 
ceriva-statin, and 
rosuvastatin (n=1152) 
(pravastatin n=75) 
No statin use in the 
first trimester (n=3327 
in propensity score 
matched cohort; 
885,844 in overall 
cohort) 
Exposed vs non-
exposed: 6.3% vs. 
3.6%, aOR 1.04 
(95% CI 0.85-1.37) 
*Unadjusted OR calculated from data in report. 
 
2.5.2 Cholesterol Synthesis in the Fetus 
Cholesterol is an essential component of fetal development because it is an integral part of the cell 
membrane and is also the precursor of other steroid hormones such as progesterone.77  The majority of 
fetal cholesterol originates from de novo synthesis (fetus or placenta) rather than from maternal sources. 
Defects in cholesterol synthesis pathways in the fetus lead to congenital malformations. Six are extremely 
rare and often lethal. A seventh (Δ7 reductase) is more common and leads to Smith-Lemli-Optiz 
syndrome. Fetuses with null mutations in Δ7 reductase (i.e., they do not synthesize cholesterol) have only 

March 8, 2022 
 
8 
very low amounts of cholesterol in their tissues and blood, confirming the minor role of maternal 
exogenous sources.77  In the presence of normal fetal sterol synthesis, maternal cholesterol supply is of 
minimal importance.77  Additionally, women with abetalipoproteinemia or hypobetalipoproteinemia and 
those consuming low-cholesterol diets have low plasma cholesterol concentrations during gestation and 
yet there are no adverse effects on pregnancy or the fetus.77   
In a group of women with diets different in cholesterol content (from cholesterol-free to high cholesterol) 
during pregnancy, maternal serum total cholesterol at term ranged from 188 to 291 mg/dL. Switching to a 
cholesterol-free diet decreased total serum cholesterol from 234 to 187 mg/dL, a 20% drop without any 
adverse fetal or pregnancy effects.78  Similarly, the Tarahumara Indians of Mexico are known to consume 
little cholesterol/fat and have a low plasma lipid profile. The average total cholesterol and LDL 
cholesterol are 141 and 89 mg/dL in non-pregnant females and 193 and 122 mg/dL during pregnancy. 
Although the degree of increase in cholesterol during pregnancy is similar to that observed in women 
consuming normal diets in other populations, cholesterol levels during pregnancy are still lower in the 
Tarahumara Indians compared with American women (193 vs. 250–300 mg/dL during pregnancy).  Yet 
no increased rates of congenital malformations or pregnancy complications are observed in this Indian 
group.79  The lower cholesterol levels during pregnancy in these populations are in accordance with the 
reduction in total cholesterol levels observed with a 40 mg dose of pravastatin.80,81   Lower doses of 
pravastatin would be expected to have a smaller reduction in cholesterol levels.  In summary, concerns 
regarding the effect of maternal intake of pravastatin during pregnancy on fetal cholesterol are not 
supported.   
2.5.3 Fetal Brain Development  
Pravastatin is unlikely to cross to the fetal brain as it has limited ability to cross the blood-brain barrier.  
No traces of pravastatin have been found in the cerebrospinal fluid of adult patients taking pravastatin. 
Pravastatin is a substrate of P-glycoprotein, an efflux pump in the endothelial cells of the blood-brain 
barrier.72  This supports the previously reported cohort studies that did not find any association between 
pravastatin exposure during early pregnancy and risk of congenital (especially central nervous system) 
malformations.   
2.5.3.1 
Preclinical Studies 
In pregnant rats given oral gavage doses of 10, 100, and 1000 mg/kg/day from gestation day 17 through 
lactation day 21 (weaning), increased mortality of offspring and developmental delays were observed at 
100 mg/kg/day systemic exposure, twelve  times the human exposure at 80 mg/day (maximum 
recommended human dose, MRHD) based on body surface area (mg/m2).82  
The approval package for Pravachol83 reports that when administered to juvenile rats on postnatal days 4 
through 80 at 5-45 mg/kg/day, no drug related changes were observed at 5 mg/kg/day. At 15 and 45 
mg/kg/day, slight thinning of the corpus callosum at the end of the recovery period was observed. This 
finding was not evident in rats at the completion of the dosing period, and was not associated with any 
inflammatory or degenerative changes in the brain. The biologic relevance of the corpus callosum finding 
was noted to be uncertain.  Neurobehavioral changes (enhanced acoustic startle responses and increased 
errors in water-maze learning) combined with evidence of generalized toxicity were noted at 45 
mg/kg/day during the later part of the recovery period.  
It was also reported that studies performed since the marketing approval in 1991 consisted of direct 
dosing neonatal rats at postnatal days 4 to 80 to address neurodevelopmental events specifically  (such as 
myelination) which occur prenatally in humans but postnatally in the rat. Decreased thickness of the 
corpus callosum was observed at 20X systemic exposure following an 80 mg clinical dose. At higher 
exposures (40X) this finding in conjunction with decreased relative brain weights and functional 
alterations in reflex response (acoustical startle) and learning (water-maze) were observed.  

March 8, 2022 
 
9 
Together these studies were deemed to indicate a perturbation in myelination. The No Observed Adverse 
Effect Level (NOAEL) of 5 mg/kg/day or 5X systemic exposure following an 80 mg human dose was 
established in the rat neonatal neurodevelopmental study.” 
Data from a preeclampsia-like rodent model in which dams were treated with pravastatin at a dose of 5 
mg/kg/day, demonstrated that 6-month old mice offspring born to preeclamptic dams, and who were 
exposed in-utero to pravastatin from embryo day 9 till birth performed similarly on assays testing 
vestibular function, balance, and coordination (righting reflex, negative geotaxis, balance beam, and 
climbing) compared with control offspring born to non-preeclamptic dams. In fact, pravastatin corrected 
some of the findings observed in offspring from preeclamptic dams in the placebo group.84 Additionally, 
whole brains from these offspring underwent magnetic resonance imaging (MRI) to evaluate the volumes 
of 28 regions of interest, including areas involved in adaptation and motor, spatial and sensory function. 
Offspring born to preeclamptic dams and who were exposed to pravastatin in utero had similar brain 
volumes compared with those born to non-preeclamptic dams. Similar to the functional data, pravastatin 
prevented the changes seen in mice offspring born to preeclamptic dams in the placebo group (changes 
seen in the fimbria, periaquaductal gray, stria medullaris, ventricles, lateral globus pallidus, neocortex, 
fasciculus retroflexus, inferior colliculus, thalamus, and lateral globus pallidus).85 Neuronal quantification 
exhibited decreased cell counts in the neocortex of offspring born to preeclamptic dams, and prenatal 
pravastatin treatment prevented these changes.  
Data from another murine model of preeclampsia (C1q KO model) in which mice destined to develop 
preeclampsia were treated with pravastatin 10 microgram i.p., a human equivalent dose of 20 mg, showed 
that pravastatin treatment in pregnancy prevented the microglial activation seen in the brains of 30 day 
old (P30) offspring born to preeclamptic dams assigned to placebo.86 
Other studies using other statins showed that simvastatin attenuates the hypomyelination induced by 
hypoxia-ischemia injury in PND 7 rats, through its anti-inflammatory properties via suppression of 
microglial activation.87 Simvastatin also improves functional outcomes in neonatal rat stroke models 
through reduced cytokine induction and dampening of the inflammatory response.88 
2.5.3.2 
Clinical Studies 
Data from the NICHD Obstetrics Fetal Pharmacology Research Centers (OPRC) Network pilot studies in 
which pravastatin 10 mg and 20 mg were used (described in section 2.6.2), showed the following: 1) the 
only central nervous system anomaly observed was ventriculomegaly and was seen in a patient who 
received placebo, 2) there were no cases of holoprosencephaly or agenesis (or hypogenesis) of the corpus 
callosum on prenatal ultrasound examination, 3) neurologic injury markers in the cord blood (NSE and 
S100-B) were not different between the pravastatin or placebo arms of either cohort, 4) all newborns in 
both cohorts who were exposed to pravastatin passed either the Auditory Brain Stem Response (ABR) or 
Otoacoustic Emissions (OAE) tests before discharge from the hospital after birth, 5) neither the 10 mg 
dose nor the 20 mg dose of pravastatin resulted in a difference in neonatal head circumference compared 
with placebo  (34 ± 1.8 cm vs. 34.2 ± 0.6 cm, p=0.6 and 31.1 ± 4.7 vs. 32.4 ± 3.1, p=0.5), and 6) 
pravastatin drug concentrations in the cord blood were undetectable for the majority of newborns born to 
mothers on active treatment for both the 10 mg cohort (5 out of 7 available cord blood concentrations 
were less than the lower limits of quantification (LLOQ) and the 20 mg cohort (6 out of 7 available cord 
blood concentrations were less than LLOQ).  
 
2.5.4 Maternal Safety 
A thorough evaluation of the safety profile for a therapeutic intervention for preeclampsia prevention 
must also focus on potential maternal risks. Pooled data from the large-scale placebo-controlled 
randomized clinical trials in non-pregnant patients have provided significant information on the risks and 
side effects associated with use of pravastatin and have reassured clinicians that serious side effects (e.g., 

March 8, 2022 
 
10 
liver injury and rhabdomyolysis) are extremely rare. In general, pravastatin is considered to be safe and 
tolerable. Three long-term (4.8- to 5.9-year) placebo-controlled trials of pravastatin (the West of Scotland 
Coronary Prevention Study, the Cholesterol and Recurrent Events Study, and the Long-term Intervention 
with Pravastatin in Ischemic Disease Study) collectively included 19,592 patients randomized to 
pravastatin (40 mg daily) or placebo and accumulated more than 112,000 person-years of exposure.80,81,89   
During five years of exposure, the rates of marked elevations of aminotransferases were low and similar 
between the two groups (<1.2%). In addition, experience with pravastatin in these trials suggests that liver 
function test abnormalities observed during pravastatin therapy were usually asymptomatic, not 
associated with cholestasis, and did not appear to be related to treatment duration. On the other hand, the 
rate of myopathy, defined as muscle aching or muscle weakness with elevated creatine phosphokinase 
(CPK) serum levels greater than 10 times the upper limit of normal, was rare (<0.1%) in pravastatin 
clinical trials.61,90    
Adverse events were assessed in an indirect comparison meta-analysis of all statins including pravastatin 
(higher doses than proposed in this trial). In pravastatin exposed patients, rhabdomyolysis occurred in 120 
(0.6%; data available from 10 randomized trials; 40,394 individuals), increased AST (3xULN) occurred 
in 244 (1.4%; data available from seven randomized trials; 35,350 individuals), increased ALT (3xULN) 
occurred in 134 (1.8%; data available from four randomized trials; 15,200 individuals), and 10 fold 
increase in creatine kinase (CK) without muscle symptoms occurred in 156 (1.2%; data available from 
seven randomized trials; 26,407 individuals).91  
Regarding side effects, pravastatin is generally considered safe, and side effects associated with its use are 
usually mild and transient. In short-term (4-month) placebo-controlled trials, the rate of study drug 
discontinuation was similar between pravastatin- and placebo-treated patients (1.7% vs. 1.2%).61  Of 
patients on pravastatin (any dose) or placebo, 10.1% and 10.2% reported localized muscle pain; however, 
only 1.4% and 1.5% of these events were attributed to study medication. The rate of myalgia, regardless 
of causality, was 2.3%; however, that attributed to pravastatin use was 0.6%.61 On the other hand, data 
from 21,483 patients from seven long-term (1.9- to 5.1-year) placebo-controlled pravastatin (40 mg) trials 
showed similar safety and tolerability profiles for pravastatin compared with placebo (47,613 patient-
years of exposure to pravastatin). In these long-term trials, the most common reasons for discontinuation 
were mild, nonspecific gastrointestinal side effects.61  Finally in the PRIMO observational study, the rate 
of muscle related symptoms with pravastatin 40 mg was 10.9%.92  Findings from the OPRC pilot trials 
are similar to data from non-pregnant subjects and are summarized in section 2.6.2. 
2.5.5 Interactions with Other Medications 
Studies regarding the interaction of pravastatin and other medications did not include pregnant women. 
The effects of pregnancy on such interactions are unknown.  
The concurrent use of erythromycin, niacin, cyclosporine, or fibrates with HMG-CoA reductase inhibitors 
other than pravastatin has been thought to be associated with increased risk of myopathy. However, 
except for fibrates, the risk has not been proven with concurrent use of these medications and pravastatin. 
Therefore, it is recommended not to co-administer pravastatin with fibrates and colchicines; and to reduce 
the pravastatin dose when given together with niacin.61  
On the other hand, inhibitors of cytochrome P450 3A4- such as diltiazem, itraconazole, ketoconazole, 
mibefradil, and erythromycin- were not found to significantly affect the pharmacokinetic properties of 
pravastatin when used concurrently. That may be explained by the fact that pravastatin is a weak substrate 
of cytochrome P450 3A4.72  
The concurrent use of bile acid resins (cholestyramine, colestipol) and pravastatin resulted in 
approximately 40-50% decrease in the mean area under the curve (AUC) of pravastatin. Therefore, it is 
recommended to administer pravastatin at least 1 hour before or 4 hours after the administration of the 
resin. For pravastatin and cimetidine (H2-receptor antagonist), there was 30% increase in the AUC of 

March 8, 2022 
 
11 
pravastatin compared with when pravastatin was taken alone. On the other hand, when it was taken 
concomitantly with digoxin, there were no differences in digoxin bioavailability, but the AUC of 
pravastatin increased by 23%. Concomitant use with clarithromycin resulted in increase in pravastatin 
AUC by 110%, therefore it is recommended to limit pravastatin to 40 mg daily when used concomitantly 
with clarithromycin. Regarding cyclosporin, studies in transplant patients taking both medications 
concurrently did not show any significant effect on cyclosporine levels, however, pravastatin AUC was 
increased by 282% and Cmax by 327%; and it is recommended to limit pravastatin dosage to 20 mg once 
daily for concomitant use with cyclosporine.61,72 
2.6 
Preliminary Studies of Pravastatin as a Modifier of Outcomes Associated 
with Preeclampsia 
2.6.1 Animal Models 
The ability of pravastatin to reverse pathophysiological pathways associated with preeclampsia and to 
ameliorate the preeclampsia phenotype was evaluated in several studies using different rodent models of 
preeclampsia (adenoviral overexpression of sFlt-1;52,54,93  CBA/J x DBA/2 model of immunologically-
mediated preeclampsia55; C1q-deficient (C1q-/-) mice56; and lentiviral vector-mediated placenta-specific 
sFlt-1 overexpression53). These models are based on various pathophysiological pathways thought to be 
associated with preeclampsia. Findings from these studies support the benefit of pravastatin in preventing 
preeclampsia and did not raise any safety concerns regarding pravastatin use in pregnant dams. 
Pravastatin was demonstrated to 1) improve angiogenic balance by reducing sFlt-1 and sEng serum 
concentrations, increasing PlGF serum concentration, and increasing the expression of PlGF and VEGF in 
the placenta; 2) lower blood pressure, likely through improvement in vasculature reactivity and up-
regulation of endothelial nitric oxide synthase in the vasculature; 3) prevent kidney damage (decrease 
albuminuria, improve glomerular blood flow, prevent glomerular endotheliosis, and reduce fibrin 
deposition); 4) improve placental blood flow, restore trophoblast invasiveness, up-regulate a pro-
survival/anti-apoptotic MAPK pathway in the placenta, restored placental weight; and 5) prevent pup 
growth restriction.51-55,93 These findings were observed without any increase in pup resorption or 
deformations.  
Long-term follow-up of offspring was reassuring and showed prevention of metabolic, cardiovascular, 
and neuromotor dysfunction, and normalization of postnatal growth in offspring of dams treated with 
pravastatin, as compared with the altered fetal programming in the offspring of the preeclampsia-like 
syndrome dams that were not treated with pravastatin.52-54,56,86  
2.6.2 NICHD OPRC Pilot Study  
The NICHD Obstetrics Fetal Pharmacology Research Centers (OPRC) network conducted a phase I/II 
pilot study (Clinicaltrials.gov Identifier NCT01717586, IND # 114205) to assess the safety and 
pharmacokinetic properties of pravastatin in women at high-risk for preeclampsia (due to history of 
severe preeclampsia that required delivery prior to 34 completed weeks). The initial study consisted of   
two double-blind placebo-controlled trials conducted in sequence, the first with a pravastatin dose of 10 
mg and the second with a dose of 20 mg.  The FDA requested the dosing schedule and sample size. Each 
trial consisted of 20 patients (10 randomized to pravastatin and 10 to placebo) with singleton non-
anomalous pregnancies and a history of prior severe preeclampsia that required delivery before 34 
completed weeks. A third cohort was added later using 40 mg (in order to complete the pharmacokinetic 
profile of pravastatin in pregnancy).  
Results of the first two trials are summarized in Table 2.94  Combining data from the two cohorts, there 
were no differences in rates of maternal demographic characteristics. Low dose aspirin was also used by 
25% of patients in the 10 mg cohort and 70% in the 20 mg cohort with no differences in aspirin use 
between the pravastatin and placebo groups. The rates of adverse and serious adverse events were similar 

March 8, 2022 
 
12 
between the two groups with the most common side effect among patients who received pravastatin being 
heartburn and musculoskeletal pain. There were no reports of rhabdomyolysis or liver injury, but one 
patient in the 20 mg cohort assigned to pravastatin developed muscle weakness and pain without increase 
in creatine kinase, and study medication was discontinued followed by complete reversal of symptoms. In 
addition, there was no maternal, fetal or infant death in either group. The rate of any congenital anomaly 
was not different between the two groups (20% in the placebo group compared with 10% in the 
pravastatin group). Congenital anomalies in the pravastatin group included hypospadias (infant’s father 
also had hypospadias) and coarctation of aorta. Congenital anomalies in the placebo group included 
polydactyly, ventriculomegaly, hypospadias and atrial septal defect.  
Overall maternal and neonatal outcomes were more favorable in women randomized to pravastatin 
compared with placebo, with reduced rates of preeclampsia, preeclampsia with severe features and 
indicated preterm delivery before 37 weeks. Infants of women assigned to pravastatin were born at a later 
gestational age (mean difference 1 week, 95% CI -0.5 – 2.5 weeks for the 10 mg cohort and 1.9 weeks, 
95% CI -1.6 – 5.4 weeks for the 20 mg cohort) and were heavier at birth (mean difference 141 grams, 
95% CI -309.3 – 591.3, for the 10 mg cohort and 456.4 grams, 95% CI -502.1 – 1414.8 grams, for the 20 
mg cohort compared with those assigned to placebo, but these differences were not statistically 
significant. The concentrations of PLGF were higher and those of sFlt-1 and sEng were lower among 
women assigned to pravastatin compared with placebo, but the differences were not statistically 
significant. Maternal cholesterol and LDL concentrations were marginally decreased in patients receiving 
pravastatin (consistent with pravastatin’s weak cholesterol lowering properties). Cord blood cholesterol 
concentrations were not significantly different.   
Table 2. Results of the OPRC pilot trial using pravastatin versus placebo to prevent preeclampsia 
 
10 mg cohort 
20 mg cohort 
Overall  
Variable 
Placebo 
(N= 10) 
Pravastatin 
(N= 10) 
Placebo 
(N=10) 
Pravastatin 
(N= 10) 
Placebo 
(N=20) 
Pravastatin 
(N=20) 
Use of low-dose 
aspirin 
3 (30) 
2 (20) 
6 (60) 
8 (80) 
9 (45) 
10 (50) 
Heartburn 
3 (30) 
4 (40) 
1 (10) 
4 (40) 
4 (20) 
8 (40) 
Musculoskeletal pain 1 (10) 
4 (40) 
4 (40) 
4 (40) 
5 (25) 
8 (40) 
Maternal, fetal, or 
infant death 
0 
0 
0 
0 
0 
0 
Rhabdomyolysis 
0 
0 
0 
0 
0 
0 
Liver injury 
0 
0 
0 
0 
0 
0 
Myopathy (weakness 
without increase in 
CK) 
0 
0 
0 
1 
0 
1 
Congenital anomalies 2 
2 
2 
0 
4 (20) 
2 (10) 
Preeclampsia (any) 
4 (40) 
0 
5 (50) 
2 (20) 
9 (45) 
2 (10) 
RR 0.22 (0.05-0.90) 
p=0.03 
Preeclampsia with 
severe features 
3 (30) 
0 
5 (50) 
0 
8 (40) 
0 (0) 
p=0.003 
(continued next page) 
 
 
 
 
 

March 8, 2022 
 
13 
 
Table 2. Results of the OPRC pilot trial using pravastatin versus placebo to prevent preeclampsia (continued) 
 
 
10 mg cohort 
20 mg cohort  
Overall 
Variable 
Placebo 
(N= 10) 
Pravastatin 
(N= 10) 
Placebo 
(N=10) 
Pravastatin 
(N= 10) 
Placebo 
(N=20) 
Pravastatin 
(N=20) 
Gestational age at 
delivery (wks) 
36.7± 2.1 
37.7± 0.9 
34.5 ± 4.1 
36.4 ± 3.2 
Mean difference    
1.5 (-0.4, 3.3), p=0.11 
Indicated preterm 
delivery < 37 weeks 
5 (50) 
1 (10)  
6 (60) 
3 (30) 
11 (55) 
4 (20) 
 
 
RR 0.36 (0.14-0.95) 
p=0.048 
Indicated preterm 
delivery < 34 weeks 
1(10) 
0 (0) 
3 (30) 
1 (10) 
4 (20) 
1 (5) 
RR 0.25 (0.03-2.0) 
p=0.34 
Total cholesterol at 
34- 37 weeks (mg/dl) 252 ± 27 
207 ± 31 
209 ± 40 
197±44 
Mean diff -26.7 
(-55.3, 1.9), p=0.07 
LDL cholesterol at 34-
37 weeks (mg/dl) 
130.8 ± 46.7 90.4 ± 21.9 
97.5 ± 29.3 
91.2 ± 40.8 
Mean diff -22.1  
(-48.6, 4.4), p=0.10 
Birth weight (g) 
2,877±630 
3,018± 260 
2356 ± 1024 2812 ± 1016 Mean diff 299  
(-215, 812), p=0.2 
Highest level of care 
routine nursery 
 
5 (50) 
 
 
8 (80) 
 
4 (40) 
6 (60) 
9 (45) 
14 (70) 
NICU length of stay ≥ 
48 hours 
3 (30) 
0 
5 (50) 
4 (40) 
8 (40) 
4 (20) 
 
2.6.3 Other Studies of Pravastatin in Pregnancy  
The use of pravastatin to prevent adverse pregnancy outcomes in women with antiphospholipid syndrome 
and prior poor obstetrical history was recently investigated in a prospective cohort study of 21 patients. 
All patients received low dose aspirin and low molecular weight heparin, which was continued when they 
all developed preeclampsia and/or intrauterine growth restriction. In 11 patients, 20 mg pravastatin daily 
was added. Compared with patients in the control cohort, those who received pravastatin had improved 
uterine artery Doppler velocimetry, lower blood pressure, and delivered infants with higher birth weight 
(2390 grams, IQR [2065-2770] vs. 900 grams, IQR [580-1100]), at a more advanced gestational age (36 
weeks, IQR [35-36] weeks vs. 26.5 weeks, IQR [26-32]).95  
Another proof of concept randomized trial conducted in the United Kingdom (Statins to Ameliorate early 
onset Preeclampsia (StAmP) trial) and designed to examine the utility of pravastatin 40 mg to improve 
angiogenic imbalance in women with early-onset preeclampsia before 32 weeks (www.controlled-
trials.com; ISRCTN23410175) has not yet reported results. 
2.7 
Rationale for a Randomized Trial 
Multiple clinical trials, using various supplements and medications, have failed to find a satisfactory 
preventative approach to preeclampsia or its complications. Preeclampsia and adult cardiovascular 
diseases have biological and pathological similarities and share many risk factors. Endothelial 
dysfunction and inflammation are fundamental for the initiation and progression of both atherosclerosis 
and preeclampsia. Primary and secondary prevention of cardiovascular mortality and other cardiovascular 
events in non-pregnant patients using 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase 
inhibitors, or statins, through their pleiotropic and lipid-lowering actions is widely accepted.96,97  
Data presented as mean±SD, median [IQR], n (%), statistics as RR (95% CI) or mean difference (95% CI) 

March 8, 2022 
 
14 
Pravastatin has been shown in various preclinical and clinical studies to reverse various 
pathophysiological pathways associated with preeclampsia. The data on degree of intrauterine exposure 
and fetal cholesterol synthesis presented above, combined with pravastatin’s low potency for inhibition of 
HMG-CoA reductase, and limited ability to cross the placenta are reassuring and add support to the use of 
pravastatin in pregnancy.72,75,98 In animal studies, a possible signal of disrupted myelination based on 
thinning of the corpus callosum is reported in the pravastatin sodium labeling. While the potential for 
myelination disruption or risk of neurodevelopmental insults from any medication is of concern, it is 
worth noting that children born to preeclamptic mothers especially if born prematurely are also at 
increased risk of neurodevelopmental adverse outcomes.99-101 Pravastatin has not been shown to be 
teratogenic in animal or human cohort studies, and data from the cardiovascular trials in non-pregnant 
women and men suggest a favorable maternal safety and tolerability profiles.  
Data from the Eunice Kennedy Shriver NICHD-OPRC Network pilot study also support the favorable 
maternal and fetal safety profiles of pravastatin and its effectiveness to prevent preeclampsia. All of the 
above provide the rationale for the use of pravastatin in the prevention of preeclampsia in high-risk 
women. 

March 8, 2022 
 
15 
3 
Study Design 
3.1 
Primary Research Question 
The randomized trial will address the primary research question:  
In women with a prior history of preeclampsia with preterm delivery less than 34 weeks, does early 
treatment with pravastatin in a subsequent pregnancy reduce the rate of a composite outcome of 
preeclampsia, fetal loss and maternal death, when compared with placebo? 
3.2 
Secondary Research Questions 
Secondary research questions this study will address are:  
• 
Does treatment with pravastatin alter the risk of:  
o pregnancy associated hypertensive disorders, 
o indicated and spontaneous preterm delivery,  
o fetal/neonatal mortality or neonatal morbidity including small for gestational age 
o severe maternal and perinatal morbidity? 
• 
Does pravastatin increase neonatal birth weight? 
• 
Does pravastatin prolong the gestational age at delivery? 
• 
Does pravastatin improve the maternal angiogenic profile by decreasing sFlt-1 and sEng, and 
increasing PlGF? 
• 
Are there specific subgroups in which treatment with pravastatin is more efficacious (see Section 
6.3.1 for a discussion of subgroup analyses)?  
• 
Does treatment with pravastatin affect child neurodevelopment, behavior, hearing or vision at 2 
and 5 years of age? 
3.3 
Design Summary 
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 34 weeks gestation, randomized to one of two arms at 
participating MFMU Network clinical centers.  
• 
20 mg pravastatin daily 
• 
Identical appearing daily placebo 
20 mg was chosen as a dose, since it showed a significant effect in the pilot study, is the same as the 
pediatric dose and assumed to be safer than 40 mg.  The dose proposed is significantly lower than the 
reported no-observed-adverse-effect-level in rats.  The Data and Safety Monitoring Committee will 
evaluate maternal and neonatal safety data after the first 50 and 310 patients have delivered and will make 
the recommendation to continue the 20mg dose or lower the dose to 10mg. 
An initial cohort of 50 women will be randomized to evaluate the safety profile through delivery and to 
assess long-term follow-up of the children through 5 years.  Recruitment beyond the first 50 will continue 
after obtaining approval from the FDA.  

March 8, 2022 
 
16 
3.4 
Eligibility Criteria 
3.4.1 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 (see below). 
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 as described in Gestational Age 
Determination in Section 3.4.2 below. 
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. Severe gestational hypertension 
managed as preeclampsia and reported as an indication for delivery also qualifies.   
5. Normal serum transaminase (AST/ALT) concentrations documented in the last 6 months. 
3.4.2 Gestational Age Determination 
Gestational age is determined using criteria proposed by the American Congress of Obstetricians and 
Gynecologists, the American Institute of Ultrasound in Medicine and the Society for Maternal-Fetal 
Medicine and is denoted “project gestational age”.102  The project EDD (estimated date of delivery), 
which is based on the project gestational age, cannot be revised once a determination has been made.  If 
the pregnancy is conceived by in-vitro fertilization, project gestational age is calculated from the date of 
embryo transfer and the embryo age at transfer.  If the pregnancy is conceived spontaneously (including 
ovulation induction and artificial insemination) information from the earliest dating ultrasound and the 
last menstrual period are used to determine project gestational age.  If no dating ultrasound has been 
performed previously, one must be performed before the patient can be randomized.   
The following algorithm is used:   
• 
The first day of the last menstrual period (LMP) is determined, and a judgment made as to 
whether or not the patient has a “sure” LMP date. 
• 
If the LMP date is unsure, ultrasound measurement(s) of the single fetus or larger twin obtained 
at the patient’s first dating ultrasound examination is used to determine the project gestational 
age. If the first dating ultrasound was conducted before 14 weeks 0 days, the measurement must 
be based on crown rump length (CRL). 
• 
If the LMP date is sure, project gestational age is determined by a comparison between the 
gestational age by LMP and by ultrasound measurement of the single fetus or larger twin based 
on the earliest dating ultrasound.  If the ultrasound confirms the gestational age by LMP as in the 
table below, the LMP-derived gestational age is used to determine the project gestational age.  
Otherwise, project gestational age will be determined based upon the ultrasound measurement of 
the larger twin (if applicable). 
 
 
 

March 8, 2022 
 
17 
Table 3. Cutoffs for Using LMP to Determine Gestational Age for Sure LMP 
 
3.4.3 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:  
a. Hypersensitivity to pravastatin or any component of the product  
b. Active liver disease: acute hepatitis or chronic active hepatitis  
5. Statin use in current pregnancy 
6. Patients with any of the following medical conditions: 
a. Uncontrolled hypothyroidism with a TSH level above 10 mIU/L, because of increased 
risk of myopathy 
b. HIV positive, because of increased risk of myopathy with use of protease inhibitors 
c. 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. 
3.5 
Informed Consent Criteria 
Written informed consent must be obtained from patients before they can be randomized into the study. 
Full disclosure of the nature and potential risks of participating in the trial is to be made. Patients will be 
given a document summarizing the safety and side effects of pravastatin. This will also be discussed with 
the patient in detail. A copy of the signed consent form will be provided to the patient. 
Gestational age at first ultrasound by 
LMP 
Ultrasound method of 
measurement 
Ultrasound agreement with 
LMP 
Up to 8 weeks 6 days 
CRL 
± 5 days 
9 weeks 0 days to 13 weeks 6 days 
CRL 
± 7 days 
14 weeks 0 days to 15 weeks 6 days 
Per institution 
± 7 days 
16 weeks 0 days to 21 weeks 6 days 
Per institution 
± 10 days 

March 8, 2022 
 
18 
Women who are not fluent in English will be enrolled by a person fluent in their language, if possible.  
Both verbal and written informed consent and authorization will be obtained in that language; if this is not 
possible the patient will be excluded. 
3.6 
Randomization Method and Masking 
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 Biostatistical Coordinating Center (BCC). 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.  
The simple urn method will be used to generate the randomization sequences because it provides a high 
probability of balance in treatment assignments, it is unpredictable, and it allows an explicit 
randomization analysis to be conducted with relative ease.103  Randomization will be stratified by clinical 
site to assure balance between the two treatment groups with respect to anticipated differences among the 
clinic population and possible differences in patient management.

March 8, 2022 
 
19 
4 
Study Procedures 
4.1 
Screening for Eligibility and Consent 
Women who present for prenatal care before 17 weeks 0 days are potentially eligible for screening.  
Women may also be contacted using an approved phone script. The inclusion/exclusion criteria will be 
reviewed in the patient’s medical records and documented on the screening log. If an ultrasound 
examination has not been performed, one must be arranged prior to randomization to confirm gestational 
age and check for exclusion criteria.  
If a patient meets all the inclusion criteria for enrollment, does not have any of the exclusion criteria, and 
expresses interest in the study, she will be approached by research personnel and fully informed in detail 
about the study, the medication, and its potential effects on her and her fetus, and she will be asked to sign 
the informed consent form if she is willing to participate. Eligibility will be confirmed by reviewing the 
delivery note/ record, admission note, discharge summary or other parts of the medical record of the 
qualifying delivery. Patients will be asked for permission to maintain/update their contact information for 
future contacts, and to sign a release of medical records form in the event that they deliver at different 
hospital. A copy of the signed consent form will be provided to the patient and another one kept in the 
medical record. 
After consent is obtained and before randomization, the patient’s liver enzymes (AST, ALT) will be 
assayed, if these results are not available in the past 6 months in the patient medical record. If the results 
are normal, the patient will be scheduled as soon as possible for the randomization visit. 
4.2 
Randomization   
If the patient is eligible and willing to participate, study-certified research staff will make an entry on the 
next line of the randomization log.  This assigns a study drug code to the patient and defines the point of 
randomization. The study drug code corresponds to a blinded study medication kit packaged according to 
the randomization sequence that consists of a sufficient number of bottles to last the remainder of her 
pregnancy.     
4.3 
Baseline Procedures 
In addition to information collected for eligibility, project gestational age, and project EDD 
determination, the following information will be obtained at randomization from a patient interview 
followed by a review of her chart: 
• 
Demographic information: age, race, ethnicity, insurance status 
• 
Medical history:  pre-pregnancy weight, height, medication use (e.g., aspirin, calcium, vitamins, 
anti-platelet agents, prior statins, antihypertensives), blood pressure, and thyroid and chronic 
disease history. 
• 
Obstetrical history including outcomes of all prior pregnancies and which pregnancy(ies) was 
complicated by preeclampsia.  
• 
Social history including marital status, years of education, alcohol and tobacco use. 
During the randomization visit, blood pressure, height and weight will be recorded. Blood (27 ml) will be 
collected for Creatine Kinase (CK) and run in real-time at the local laboratory to serve as a reference in 
the event the patient develops a condition that suggests the possibility of myopathy and a repeat CK is 
warranted (Section 4.5).  The remainder of the sample will be stored for analysis of DNA, lipids and 

March 8, 2022 
 
20 
angiogenic markers.  Proteinuria status at baseline is required for assessment of the primary outcome.  
Proteinuria will be evaluated by dipstick if not available from a recent prenatal visit. Dipstick values of 
1+ or higher will require a protein:creatinine ratio or 24-hour urine collection for confirmation if not done 
clinically. 
Treatment will be initiated at the randomization visit between 12 weeks 0 days and 16 weeks 6 days, in 
order to 1) avoid the period of organogenesis, and 2) start as early in pregnancy as possible. Treatment 
will start the same day as randomization, and the patient will be asked to take one capsule daily orally, 
with or without food. Treatment will continue until delivery or until a condition develops requiring 
discontinuation of the study drug. 
4.4 
Study Procedures 
All patients will have monthly assessments (in-person or virtual) with a research nurse to assess drug side 
effects and the occurrence of adverse events, and compliance by pill count.  Patients will receive a 35 day 
supply of study drug to last until their next visit (in case it is slightly more than 4 weeks).  Specifically, at 
each study visit, the following procedures will be performed: 
• 
Assess drug side effects and adverse events  
• 
Record weight 
• 
Record blood pressure  
• 
Perform pill count and dispense new supply 
• 
Record current medication list 
Treatment will continue until delivery or until a condition develops requiring discontinuation of the study 
drug (see Section 4.5).  Blood will be collected and stored for retrospective analysis at two time periods, 
1) 23-286/7 weeks gestation and 2) at 33-376/7 weeks gestation to measure lipids, angiogenic markers and 
pravastatin concentration (20 ml).  Cord blood will be collected at delivery for the first 50 women 
randomized to measure pravastatin concentration (6 ml). 
Table 4. Study visit procedures 
 
Timing 
Procedures 
Screening 
< 166/7 weeks 
Consent, AST/ALT (if not available), verify eligibility criteria 
Randomization  
120/7–166/7 
weeks 
Baseline data, record blood pressure and weight  
Blood collected for:  
• 
Creatine Kinase (to be run immediately) 
• 
lipid profile(to be run at the end of study) 
• 
angiogenic markers (to be run during study) 
• 
maternal DNA (may be run in future)  
Study visits 
Monthly 
Assessment of side effects, pill count, record BP and weight 
230–286/7 
weeks 
Blood collected for: 
• 
lipid profile (to be run at the end of study) 
• 
angiogenic markers (to be run during study) 
• 
maternal pravastatin concentration (may be run in future) 
330-376/7 weeks 
Blood collected for: 
• 
lipid profile (to be run at the end of study) 
• 
angiogenic markers (to be run during study) 
• 
maternal pravastatin concentration (may be run in future) 

March 8, 2022 
 
21 
 
Information on interventions during the pregnancy such as receipt of antenatal corticosteroids, tocolytics, 
or antihypertensive medications, pregnancy complications, and delivery outcomes will be collected by 
trained research personnel from chart review. Blood pressure measurements made during labor will be 
abstracted from the patient’s chart. For the neonate, birth weight, length, head circumference, and 
ABR/OAE testing, will be obtained from the infant’s chart. Neonatal data on all infants will be collected 
through discharge or 120 days after birth, whichever occurs first. 
All patients will be followed up at 6 weeks postpartum, and information on any postpartum 
complications, including readmissions for blood pressure control, postpartum preeclampsia, infection or 
other morbidities, will be recorded.   
The children will be followed for five years with study visits performed at 2 years and 5 years of age, 
including neonates who fail both the ABR and OAE testing at birth. To keep in touch with the family, 
follow-up coordinators will use a variety of methods, including contacting the family by telephone/e-
mail/text every six months.  Comprehensive pediatric neurodevelopmental testing will be performed at 
these two time points by study examiners that are trained and certified for the study.  At the time of the 2-
year child visit, maternal assessments will also be performed.  
4.4.1 Child 2-year Follow-up  
The following assessments will be performed at the child 2-year visit: 
• 
Medical history including hearing loss and need of hearing aids 
• 
Height and weight   
• 
Cognitive, Motor and Language Scores from the Bayley Scales of Infant and Toddler  
Development 4 
• 
The Gross Motor Function Classification System (GMFCS) and the Manual Abilities 
Classification System (MACS) 
• 
Visual and hearing assessment 
• 
Child Behavior Checklist (CBCL)  
4.4.2 Maternal 2-year Follow-up 
The following assessments will be performed at the same time as the child 2-year visit: 
• 
Medical history 
• 
Blood pressure 
Delivery 
 
Clinical outcomes (maternal and neonatal) 
Cord blood collected for pravastatin concentration (first 50 only) 
 
Postpartum  
6 weeks 
postpartum 
Assessment of adverse events, postpartum complications, record 
blood pressure and weight 
Child Two-year 
Follow-up 
2 years of age 
Medical history, height and weight 
Cognitive, behavior, motor, visual and hearing assessment 
Maternal Two-
year Follow-up 
2 years of 
child’s age 
Medical history 
Blood pressure & anthropometric (height, weight, waist, hip) 
assessments 
Blood collection for lipid profile and additional analytes 
Child Five-year 
Follow-up 
5 years of age 
Medical history, height and weight  
Cognitive, behavior, and vision test 

March 8, 2022 
 
22 
• 
Anthropometrics including height, weight, waist and hip circumferences   
• 
Blood collection  
Maternal blood will be processed for lipids, HbA1c, fasting glucose and insulin, hs-CRP, Lipoprotein A 
and other analytes.  
 
4.4.3 Child 5-year Follow-up  
The following assessments will be performed at the child 5-year visit: 
• 
Medical history including hearing loss and need of hearing aids 
• 
Height and weight   
• 
Differential Ability Scales-II (DAS-II) cognitive assessment.  The DAS II general conceptual 
ability score correlates well with full scale IQ as measured by the Wechsler Preschool and 
Primary Scale of Intelligence (0.89). 
• 
Behavior Rating Inventory of Executive Function (BRIEF 2nd Edition) 
• 
Vineland Adaptive Behavior Scales, 3rd Edition 
• 
The Gross Motor Function Classification System (GMFCS) and the Manual Abilities 
Classification System (MACS) 
• 
Child Behavior Checklist (CBCL) 
• 
Opthalmologic exam including visual acuity/refraction and cover test (evaluate strabismus) 
4.5 
Patient Management 
Use of low dose aspirin is recommended, as it is currently standard of care in the U.S. for women with 
prior preeclampsia according to the ACOG guidelines.  
Patients’ pregnancy management (including antenatal testing, ultrasounds, control of hypertension, 
inpatient vs. outpatient management, and mode and timing of delivery) will be performed as 
recommended by standard prenatal care as defined by the respective participating institution. Inpatient vs. 
outpatient management of patients with preeclampsia (without severe features), single vs. double courses 
of antenatal corticosteroids in the setting of preterm labor, and other obstetric interventions will be left to 
the discretion of the treating physician. 
Although chronic use of the drugs that may have potential significant interactions with pravastatin are 
listed as an exclusion criteria, the occasion may arise that a pregnant woman in the study may require one 
or more of these medications. Therefore, and to avoid any potential (or unknown) interactions; patients 
and providers in this study will be advised of the following: 
• 
Study drug should be taken at least 1 hour before or 4 hours after the administration of 
cholestyramine. 
• 
Cimetidine (H2-receptor antagonists) should be taken at least 1 hour before study drug. 
• 
There is no need to change the timing or stop study drug if also taking aspirin, digoxin, or 
diltiazem. 
• 
In the event that a patient requires erythromycin (e.g., rupture of membranes), an alternative 
antibiotic will be recommended if available. If not, the study drug will be stopped for the duration 
of erythromycin intake (usually 7 days). The study drug will be resumed at the end of that period. 

March 8, 2022 
 
23 
In this study, the following events that could be related to pravastatin use will be defined and monitored 
as Adverse Events of Special Interest (AESI).   
• 
Myalgia: diffuse muscle pain, cramps, or soreness without elevation in CK  
• 
Muscle weakness: muscle weakness documented on physical exam without elevation in CK  
• 
Myositis: muscle symptoms (myalgia or weakness) with CK elevations between 3 and 10 times 
upper limit of normal (ULN) in pregnancy or between 3 and 10 times the baseline CK value, 
whichever is higher 
• 
Myopathy: muscle symptoms (myalgia or weakness) plus CK ≥ 10x ULN or 10x baseline CK 
• 
Rhabdomyolysis: muscle symptoms (myalgia or weakness) plus CK ≥ 10x ULN or 10x baseline 
CK plus an elevation in serum creatinine (usually with brown urine and myoglobinuria) or need 
for medical interventions such as hospitalization and intravenous hydration.104-109 
• 
Serious liver injury defined as persistent AST or ALT of 3 x ULN or increased AST or ALT 
levels with clinical symptoms and  hyperbilirubinemia or jaundice, in the absence of severe 
preeclampsia or other hepatic disease   
Severe Adverse Events of Special Interest will be defined as maternal myositis, myopathy, 
rhabdomyolysis, or serious liver injury.  Patients will be advised throughout the study to report promptly 
unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. If 
myositis, myopathy, rhabdomyolysis, or serious liver injury occurs, the study drug (regardless of actual 
treatment assignment) will be discontinued permanently. If a patient develops myalgia or muscle 
weakness (documented on physical exam) with CK elevation <3 x ULN (or baseline CK), then the 
following will take place, 1) study drug will be stopped temporarily, 2) a workup will be done to ensure 
the patient does not have any of the other more serious muscle related serious adverse events, and 3) risk 
and precipitating factors will be evaluated. The patient will be monitored until complete resolution of 
symptoms and the CK values are back to normal (if applicable). The CK values will be checked weekly if 
above the ULN or baseline CK. Upon resolution, the patient will be re-challenged with pravastatin to be 
used every day or every other day.   
Any woman who withdraws from taking study medication for any reason, including discontinuation for 
side effects, will be encouraged to continue study visits as planned, including the postpartum contact and 
follow-up of the child through 5 years of age.   
4.6 
Study Outcome Measures and Ascertainment 
4.6.1 Primary Outcome 
The primary outcome of the study is a composite of fetal loss, maternal death, and preeclampsia 
diagnosed prior to 48 hours postpartum as follows: 
1. In previously normotensive women, preeclampsia is diagnosed based on  
a) Severe hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110 
mmHg) at ≥ 20 weeks in gestation on two occasions with measurements taken at least 4 hours 
apart, or 1 occasion with subsequent anti-hypertensive therapy, or  
b) Mild hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg) 
at ≥ 20 weeks in gestation on two occasions with measurements taken at least 4 hours apart, with 
any of the following: 
i. 
New-onset proteinuria ≥300 mg in a 24-hour period, protein to creatinine ratio ≥ 0.3, or 
1+ protein on maternal urine dipstick (only if 24-hour urine collection or protein to 

March 8, 2022 
 
24 
creatinine ratio is not possible) or a doubling in protein in women with baseline 
proteinuria 
ii. 
Thrombocytopenia (platelet count <100,000 per microliter) 
iii. 
Progressive renal insufficiency (serum creatinine >1.1 mg/dl or doubling of the serum 
creatinine in women with abnormal baseline values (>1.1 mg/dl) and in the absence of 
other renal disease) 
iv. 
Impaired liver function (elevated transaminases ≥ 70 U/L , or severe persistent right 
upper quadrant or epigastric pain unresponsive to medication) 
v. 
Pulmonary edema diagnosed clinically by exam or chest x-ray 
vi. 
New-onset and persistent (non-responsive to supportive treatment) cerebral or visual 
symptoms. 
2. In women with baseline chronic hypertension, preeclampsia is diagnosed based on any of the 
following (not accounted for by alternative diagnoses): 
a) Severe hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110 
mmHg) ≥ 20 weeks in gestation on two occasions with measurements taken at least 4 hours apart, 
or 1 occasion with subsequent anti-hypertensive therapy, or an escalation of antihypertensive 
medications to control blood pressure  
b) New onset of proteinuria or a doubling in protein in women with baseline proteinuria  
a) Thrombocytopenia (platelet count <100,000 per microliter) 
b) Progressive renal insufficiency (serum creatinine >1.1 mg/dl or doubling of the serum creatinine 
in the absence of other renal disease) 
c) Impaired liver function (elevated transaminases ≥ 70 U/L , or severe persistent right upper 
quadrant or epigastric pain unresponsive to medication) 
d) Pulmonary edema diagnosed clinically by exam or chest x-ray 
e) New-onset and persistent (non-responsive to supportive treatment) cerebral or visual symptoms. 
3. HELLP [hemolysis, elevated liver enzymes and low platelet count] syndrome defined as the 
occurrence of all of the following (not accounted for by alternative diagnoses): 
a) Hemolysis: evidenced by (1) serum total bilirubin ≥ 1.2 mg/dL (20 µmol/L), (2) serum lactate 
dehydrogenase (LDH) ≥ 600 IU/L, or (3) hemolysis on peripheral smear  
b) Thrombocytopenia (platelet count < 100,000 / microliter) 
c) Serum aspartate aminotransferase (AST) or alanine transaminase (ALT) ≥ 70 IU/L 
4. Atypical HELLP defined as the occurrence of 2 of the 3 following (not accounted for by alternative 
diagnoses) 
a) Hemolysis: evidenced by (1) serum total bilirubin ≥ 1.2 mg/dL (20 µmol/L), (2) serum lactate 
dehydrogenase (LDH) ≥ 600 IU/L, or (3) hemolysis on peripheral smear  
b) Thrombocytopenia (platelet count < 100,000 / microliter) 
c) Serum aspartate aminotransferase (AST) or alanine transaminase (ALT) ≥ 70 IU/L 
5. Eclampsia defined as an occurrence of a seizure without any known cause 
6. Competing outcomes also qualify as the primary outcome 

March 8, 2022 
 
25 
a) Maternal death before delivery 
b) Fetal loss less than 20 weeks, 0 days 
All charts of women who have any elevated BP ≥ 140/90 mmHg or a diagnosis of proteinuria, will be 
centrally reviewed by teams of three Protocol Subcommittee members (three investigators/nurse 
coordinators) blinded to assignment to ensure integrity of the primary and key secondary outcomes. 
4.6.2 Maternal Secondary Outcomes 
1. Preterm birth < 37 weeks (major secondary outcome) 
2. Indicated preterm birth < 37 weeks 
3. Preterm birth < 34 weeks 
4. Preeclampsia with severe features as defined by the ACOG diagnostic criteria (i.e., severe 
hypertension, thrombocytopenia, impaired liver function, progressive renal insufficiency, 
pulmonary edema, new-onset and persistent cerebral or visual symptoms) 
5. Postpartum preeclampsia diagnosed after 48 hours  
6. Gestational hypertension defined as new onset hypertension in the absence of accompanying 
proteinuria or other features of preeclampsia 
7. Pregnancy associated hypertension (gestational hypertension or preeclampsia) 
8. Gestational diabetes  
9. Adherence to study medication 
10. Adverse Events of Special Interest (AESI) defined as myalgia and muscle weakness, and serious 
AESI defined as maternal myositis, myopathy, rhabdomyolysis, and serious liver injury  
11. Gestational age at delivery  
12. Length of hospital stay for the delivery admission and number and length of maternal 
hypertension related and overall hospitalizations during the pregnancy  
13. Concentrations of angiogenic factors (sFlt-1, sEng, and PlGF) 
14. Concentrations of cholesterol (total, low density lipoprotein, high density lipoprotein) and 
triglycerides 
15. 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 
4.6.3 Fetal and Neonatal secondary outcomes 
1. Fetal and neonatal death  
2. Birth weight and rate of “small for gestational age” as measured by birth weight: a) < 5th 
percentile and b) < 10th percentile for gestational age, assessed specifically by sex and race of the 
infant based on United States birth certificate data 110,111  
3. Admission to neonatal intensive care unit/intermediate nursery and total length of stay in that unit 
4. Complications of prematurity including: 
a. Mechanical ventilation in the first 72 hours of life and duration 
b. Oxygen support and duration 

March 8, 2022 
 
26 
c. 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 
d. Bronchopulmonary dysplasia (BPD), defined as oxygen requirement at 28 days of life 
and at 36 weeks corrected gestational age 
e. 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) 
f. Intraventricular hemorrhage (IVH) grade III-IV 
g. Periventricular leukomalacia (PVL), diagnosed by neuroimaging  
h. Retinopathy of prematurity (ROP) stage III or higher 
i. 
Neonatal sepsis (within 72 hours and > 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, CSF, or catheterized/suprapubic urine culture; or, in the absence of 
positive cultures, clinical evidence of cardiovascular collapse or an unequivocal 
radiograph confirming infection. 
j. 
Composite outcome of: 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 
k. Seizures 
5. Congenital anomaly / birth defect (excluding any conditions that must have been present before 
randomization) 
6. Neonatal auditory brain stem response (ABR)/ Otoacoustic Emissions (OAE)  
4.6.4 Child Secondary Outcomes 
1. Body mass index for age at 24 corrected months and 5 years of age using CDC pediatric growth 
charts 
2. Cognitive, Language and Motor Scale Scores from the Bayley Certified Scales of Infant 
Development 4 at 24 months age 
3. Level from the Gross Motor Function Classification System at 24 months of age 
4. Hearing loss or vision problems (severe nearsightedness or farsightedness, and eye movement 
problems) at 24 months of age 
5. Total problems score and syndrome scale (emotionally reactive, anxious/depressed, somatic 
complaints, withdrawn, attention problems, aggressive behavior) scores from the Child Behavior 
Checklist at 24 months and 5 years of age 
6. General Conceptual Ability score and subscale (verbal ability, non-verbal reasoning ability, and 
spatial ability) scores from the Differential Ability Scales at 5 years of age 
7. Global Executive Composite score and index (behavioral, emotion, and cognitive regulation) 
scores from the Behavior Rating Inventory of Executive Function at 5 years of age  
8. Adaptive Behavior Composite score and domain (communication, daily living skills, socialization 
and motor skills) scores from the Vineland Adaptive Behavior Scale at 5 years of age 
9. Visual acuity and strabismus from visual assessment at 5 years of age 

March 8, 2022 
 
27 
4.7 
Adverse Event Reporting 
Detailed information concerning adverse events will be collected and evaluated throughout the conduct of 
the protocol.  
Any maternal death, neonatal death, life threatening maternal event or Serious Adverse Event of Special 
Interest  as defined in Section 4.5 must be entered into the adverse events database within twenty-four 
hours of being notified.  If a death is reported, a copy of the patient’s de-identified medical record will be 
uploaded to the adverse events database. 
Adverse events which do not qualify under the above definition must be entered into the database within 
7 days of being notified.   
4.8 
Emergency Unblinding 
The only indication for breaking the randomization code is when it is medically necessary to unmask the 
study drug assignment to be able to treat the patient, i.e. when treatment options would differ based on the 
knowledge of the medication.  In such a situation, the center should try to contact the BCC before 
unmasking but in an emergency situation, the PI of the center, the Nurse Coordinator, the alternate PI or 
the site PI may authorize the unmasking.  

March 8, 2022 
 
28 
5 
Data and Safety Monitoring Plan 
5.1 
Data and Safety Monitoring Committee 
The Data and Safety and Monitoring Committee (DSMC) for the Eunice Kennedy Shriver National 
Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) 
Network is an independent group appointed by the NICHD to oversee MFMU Network trials. The 
primary objective of the DSMC is to ensure the safety of study subjects and to provide NICHD, and for 
this study, NHLBI with advice on the ethical and safe progression of the trial.  The DSMC also advises 
the Institutes on research design issues, data quality and analysis, as well as ethical and human subject 
aspects of studies.  Recommendations will be made to the NICHD and NHLBI and disseminated to the 
Steering Committee. 
5.1.1 DSMC Membership Qualifications 
The DSMC members are appointed by the Director of NICHD in accordance with established NIH 
policies governing the use of advisors.  DSMC members are chosen for their expertise in one or more of 
the following fields: 
• 
Maternal-fetal medicine or obstetrics 
• 
Neonatology 
• 
Ethics 
• 
Biostatistics/epidemiology  
• 
Clinical trial methods 
One of the members with expertise in obstetrics or maternal-fetal medicine is appointed as Chairperson.  
In addition, a layperson or member of the public is appointed as a patient advocate. 
In addition to the members of the DSMC, an NICHD representative who is not part of the MFMU 
Network is appointed as a liaison between the Institute and the committee.  NHLBI may also appoint a 
representative.  The NIH representatives participate in the deliberations, but do not vote.   
5.1.2 Conflict of Interest and Confidentiality 
Members of the DSMC may not be affiliated with any of the clinical centers or the BCC and must be 
financially and intellectually independent of the trial investigators.  As part of their service on the 
Committee, members must sign an annual conflict of interest and confidentiality declaration. If a new 
conflict arises for a member, it must be disclosed in a timely manner (within 30 days) to the NICHD.  The 
NICHD will determine whether the conflict limits the ability of the DSMC member to participate in the 
committee.   
All data and information remain confidential.  Interim data analysis reports and any other reports provided 
to DSMC by the BCC must be returned or destroyed.  Investigators from the MFMU Network will not 
communicate directly with DSMC members about the study except when making presentations or 
responding to questions regarding review of a protocol during a DSMC meeting or scheduled conference 
call. 
5.1.3 Responsibilities of the DSMC 
Specifically, the responsibilities of the DSMC members are as follows: 
Before the start of the trial:   

March 8, 2022 
 
29 
• 
To review the research protocol and informed consent document(s) with respect to ethical and 
safety standards.  The study design should be evaluated to determine whether it is adequate to 
answer the research question(s). 
While the trial is ongoing:  
• 
To evaluate whether the study design assumptions are valid and the impact of the assumptions on 
how well the research question(s) will be answered. 
• 
To monitor the safety of the participants including review of serious adverse events as they arise. 
• 
To monitor recruitment, losses to follow-up, compliance with the protocol by investigators and 
participants, and data quality. 
• 
To monitor the evidence for treatment harm or benefit and to evaluate evidence for treatment 
differences in the main efficacy outcome measures. 
• 
To assess the impact and relevance of external evidence on the advisability of trial continuation 
as well as on the need for design modification including the necessity for modification of the 
informed consent material.  
• 
To make recommendations for changes to the study design, if necessary, to ensure that the 
research question(s) will be answered. 
• 
To recommend continuation or termination of a trial for all participants, certain treatment groups, 
or certain participant subgroups. 
5.2 
Protocol Review 
Before the start of the trial, the DSMC reviews the final protocol and provides comments.  The Chair of 
the Protocol Subcommittee or designee may present the protocol, and be available to answer questions.  
The subcommittee Chair will report the DSMC’s comments to the Steering Committee for consideration 
and possible modification of the protocol.  The trial cannot start until the DSMC approves the protocol.  
Approval is by consensus. 
If the Steering Committee proposes major changes to the protocol during the course of the trial (e.g. 
eligibility criteria), the DSMC must review and approve the changes before they can go into effect, 
provided that the DSMC has not already been unblinded to study treatment in an interim analysis.   
5.3 
Ongoing Safety Monitoring  
As described in Section 4.7 any maternal death, neonatal death, life threatening maternal event or serious 
Adverse Event of Special Interest (myositis, myopathy, rhabdomyolysis or serious liver injury as defined 
in Section 4.5) is reported electronically within twenty-four hours of notification.  Other adverse events 
are reported within seven days of notification. The BCC is automatically notified by the adverse event 
system of the addition of a new adverse event. BCC staff review each report for completeness before 
passing it on to the NICHD – approved medical monitor.  The medical monitor reviews the adverse event 
reports including the accuracy of the classification of seriousness, unexpectedness and relatedness to the 
study interventions.  The medical monitor is masked to treatment assignment.   
The adverse events reports are then forwarded electronically to the DSMC Chair, the NIH 
representative(s) to the DSMC, and any other DSMC member who requests notification.  Deaths, life 
threatening events, serious Adverse Events of Special Interest and SUSARS (see below) are reported 
immediately.  Other adverse events are forwarded on a monthly basis.  The DSMC Chair decides whether 
the adverse event reports should be disseminated to the rest of the committee, whether a follow-up call or 
meeting is required, and whether the treatment assignment should be unmasked.  If NIH or the Steering 

March 8, 2022 
 
30 
Committee is concerned about a pattern of events, they may request that the DSMC consider their 
concern.   
An FDA Investigational New Drug (IND) safety report will be completed and forwarded to the FDA for 
any serious unexpected suspected adverse reaction (SUSAR) to the study medication that is fatal or life 
threatening (whether active or placebo) within 7 days after the event was entered into the database. For 
other adverse events classified as SUSAR, notification will be reported to the FDA within 15 days. All 
cumulative adverse events will be reported in the annual IND report. 
Finally, cumulative adverse events are reported to the DSMC at each meeting and will be considered 
along with other interim safety data in the DSMC deliberations. 
5.4 
Data and Safety Monitoring Committee Meetings 
For this study the DSMC will meet at least every six months, once in person and once most likely by 
conference call.  The committee may meet more often as needed.   DSMC meetings and conference calls 
are organized into open and closed sessions, and if requested, an executive session.  Definitions for each 
of the session types are included below.   
• 
Open session – Open sessions are attended by the NICHD Project Scientist, the NHLBI Project 
Scientist if desired and may be attended by Steering Committee member(s), or the Steering 
Committee Chairperson as requested by NICHD Project Scientist.   
• 
Closed session – Closed sessions are attended only by the NICHD (and NHLBI representative if 
desired), the BCC PI, and BCC personnel involved in the trials being monitored.  The Project 
Scientist(s) do not attend the closed session.  For closed session conference calls, the BCC will 
provide participants with the dial-in information shortly before the call.    
• 
Executive session – An executive session may be requested at any time by the committee.  Only 
the full voting members, appropriate ad hoc members of the DSMC, and NICHD/other Institute 
DSMC representatives attend. BCC staff do not attend the executive session.   
Meetings will always be scheduled to include the DSMC Chair and a biostatistician.  A quorum of this 
DSMC is considered to be two-thirds of the full members (i.e. not including the NIH representatives).  
Agreement is reached by consensus.    
5.4.1 Study Report to the DSMC 
For the bi-annual meeting, and any other meeting called by the DSMC to review data, a report will be 
generated by the BCC in advance.  Data are presented by treatment group and by center.  For security 
purposes, the treatment groups will be coded in the report (e.g. A or B).  The decision to unmask the 
treatment group at the meeting is at the discretion of the DSMC.  A full report on a study that has accrued 
sufficient patients to evaluate outcome will include the following:  
• 
Enrollment data  
• 
Baseline data 
• 
Compliance and side effects 
• 
Adverse events  
• 
Protocol adherence, including data quality, data completeness, and timeliness 
• 
Primary outcome  
• 
Secondary outcomes 

March 8, 2022 
 
31 
• 
Additional study specific information as requested by the DSMC  
However, the main emphasis is on the primary outcome as well as maternal safety outcomes (including 
maternal myositis, myopathy, rhabdomyolysis and serious liver injury).   
5.4.2 Interim Analysis 
Two special interim analyses will be performed to review the maternal and neonatal safety outcomes by 
treatment group. The first after the first 50 women randomized have delivered and the second after the 
first 310 women randomized (20%) have delivered. After each of these special interim analyses, the 
DSMC will make the recommendation to continue the 20mg dose or lower the dose to 10mg. 
Given that the sample size estimates involve a number of assumptions, it is planned that the assumptions 
and the resulting primary outcome rate in the placebo group be examined after the first 310 women 
randomized have delivered. The DSMC would be charged with making a recommendation regarding 
potential revision of the sample size.   
Once the first 50% of the patients have been accrued into the trial and delivered, the report also will 
include a formal interim analysis evaluating the primary outcome by treatment group on this cohort of 
patients. A second interim analysis will be performed after 75% of the patients have been accrued and 
delivered. Each cohort consists of all patients randomized before a certain date so that the analysis cohort 
does not depend on gestational age at delivery. Additional interim analyses of the primary outcome will 
be at the discretion of the DSMC. 
 
5.4.3 Trial Stopping Rules 
For the primary outcome, the group sequential method of Lan and DeMets will be used to characterize the 
rate at which the type I error is spent.112  This method is flexible with regard to the timing of the interim 
analyses.  Asymmetric stopping boundaries will be used.  The upper boundary which describes the 
stopping rule for benefit will be based on 1-sided type I error of .025 and the Lan-DeMets generalization 
of the O’Brien-Fleming boundary.  The lower boundary will be based on a less stringent stopping rule: 1-
sided type I error of .05 and the Lan-DeMets generalization of the Pocock type boundary.   
It also planned to calculate conditional power given the observed data to date, and conditional on the 
future data showing the originally assumed design effect.  If this conditional power is low (under 10 
percent) the DSMC may consider termination for futility if the accrual rate is slow, with confidence that 
the Type II error is not greatly inflated.113 
Specific stopping rules for the trial will be established for monitoring maternal, neonatal and child events 
relevant to pravastatin risk.  For the maternal stopping rule, an occurrence of one of the following events 
will qualify: 
• 
Serious Adverse Event of Special Interest (serious AESI; myositis, myopathy, rhabdomyolysis or 
serious liver injury as defined in Section 4.5).  
• 
Non-serious AESI (myalgia or muscle weakness as defined in Section 4.5) that required repeat 
discontinuation of study medication (initial discontinuation, rechallenge, discontinuation again) 
For the neonatal stopping rule the following event will qualify:  
• 
Failed newborn ABR/OAE test   
The BCC will continuously monitor these maternal and neonatal events and if there is an excess of 
women in the pravastatin group who have experienced one or more of the events such that the one sided 
nominal p-value of a Fisher’s exact test is less than 0.05 or such that the lower 90% confidence bound of 
the relative risk exceeds 1.0 for larger sample sizes of 50 or more, will request that the DSMC review the 

March 8, 2022 
 
32 
data immediately and make a determination on stopping or pausing the trial, or modifying the dose.  
Likewise if there is an excess of neonates who have failed their hearing tests, the same stopping criteria 
will apply. 
For the child stopping rule, the following events will qualify: 
• 
Cognitive or Motor Scale Score < 70 (2.5th percentile) from the Bayley Certified Scales of Infant 
Development 4 at 24 months age 
• 
Total problems or syndrome scale score > 97th percentile (clinical range) from the Child Behavior 
Checklist at 24 months 
• 
Hearing loss at 24 months of age 
These childhood events will be monitored by the DSMC at their regular meetings or more frequently 
upon request once any children reach two years of age. The 1-sided Lan-DeMets generalization of the 
Pocock type with type I error of .05 will be used as a stopping rule.  
It is recognized that any decision to terminate the study would not be reached solely on statistical grounds 
but on a number of complex clinical and statistical considerations. 
5.5 
Reporting from the DSMC  
At the conclusion of each call or meeting, an open session will be held to report the recommendations of 
the DSMC to the NICHD MFMU Network Project Scientist (and the NHLBI Project Scientist if desired). 
If the recommendations are complex and/or if requested by the Project Scientist, the BCC will collaborate 
with the DSMC Chair and the NICHD representative to write a brief summary of the discussion and 
recommendations for presentation to the NICHD Director.  
In addition the BCC will prepare  
1) Within 2 weeks, a brief summary of trial status and DSMC recommendations for NIH and the clinical 
centers including whether the trial should proceed or not, and whether modifications are required.   
2) Within 4 weeks, detailed formal minutes of the DSMC’s discussion and recommendations to the 
NICHD within 30 days of the meeting.  The minutes are initially reviewed by the DSMC Chair, and then 
distributed to the members for final review and approval.  
3) Within 4 weeks, a summary report for the IRB which will include a brief accounting of all adverse 
event reports since the previous meeting and cumulatively.  If there are no safety or other protocol-related 
concerns, the report will state that the DSMC recommended that the study continue without modification.  
If concerns are identified, the report will outline the concerns and recommendations, as well as any 
decisions of the NICHD Director.  
 

March 8, 2022 
 
33 
6 
Statistical Considerations 
6.1 
Data Relevant to the Primary Outcome 
To determine the recurrence rate of preeclampsia based on the gestational age at delivery of the previous 
preeclampsia, several sources of information were considered.   
First, the NICHD MFMU Network conducted a randomized controlled trial to evaluate the efficacy of 
low dose aspirin compared with placebo in preventing preeclampsia in high-risk women. The trial, which 
was negative, included four independently powered arms, with one being in women who had prior 
preeclampsia, without other risk factors.42 One hundred sixty nine women who had a prior pregnancy 
complicated by preeclampsia that required preterm delivery were assigned to low dose aspirin, and had a 
rate of preeclampsia recurrence of 16% (27/169 women, 95% confidence interval 10%-22%).  
The second source was a large cohort study in the US that included 6,157 women who had preeclampsia 
at the time of their first birth.  In this study, the rates of recurrence of preeclampsia at their second 
delivery were 38.6%, 29.1% and 21.9% if the delivery for preeclampsia in the prior pregnancy occurred at 
20-28 weeks, 29-32 weeks and 33-36 weeks, respectively.114 Assuming the same distribution of 
gestational ages at the index pregnancy as in the MFMU Network High Risk Aspirin trial the rate of 
recurrent preeclampsia before 34 weeks would be close to 31%.   
An individual patient meta-analysis showed that the rate of recurrence of preeclampsia was 16.0% for 
women with prior preeclampsia (at any gestational age).115   
In the VIP trial, women with prior history of preeclampsia with delivery < 37 weeks had a 23% 
recurrence rate of preeclampsia.116  In another study 25% of primiparous women who experienced 
preeclampsia and were delivered before 34 weeks, were diagnosed with preeclampsia in their next 
pregnancy.117     
In a prospective cohort study using data from the Swedish medical birth register (763,795 women), 
Hernandez-Diaz and colleagues reported that for patients who had severe preeclampsia in their first 
pregnancy that required delivery before 34 weeks’ gestation, the rate of preeclampsia recurrence was 29% 
in the subsequent pregnancy.118 Moreover, in the NICHD-OPRC pilot trials, which included women with 
history of preeclampsia that required delivery < 34 weeks, the rate of recurrence of preeclampsia in the 
placebo groups was 45%.94 
6.2 
Sample Size and Power 
In all of the older studies, except the High Risk Aspirin study, aspirin was not being used routinely.  In 
the High Risk Aspirin trial, the dose was lower than is generally used today and was started later in 
gestation.  Therefore, for the purposes of sample size estimation, it is conservatively assumed that all 
women will be receiving low dose aspirin, and that the rate of preeclampsia (primary outcome) in the 
placebo group is 20%.  It is estimated that a sample size of 1,550 women is required to demonstrate at 
least a 30% reduction in preeclampsia with the use of pravastatin (from 20% to 14%), with a power of 
85%, and type I error of 5% 2-sided.  The sample size is adjusted for a drop-out rate of 5% (i.e. that 5% of 
the women on pravastatin discontinued their study drug and had the same primary outcome rate as the 
placebo group) and for the interim ‘looks’ at 50% and 75% information.   
 
 

March 8, 2022 
 
34 
Table 5. Sample Sizes for Different, Levels of Power and Effect Sizes 
 
Reduction in Primary 
Outcome Rate 
Power % 
Estimated Sample Size 
25%  
80 
2000 
85 
2280 
90 
2660 
30%   
80 
1360 
85 
1550 
90 
1810 
35%  
80 
980 
85 
1120 
90 
1290 
 
Trials evaluating cardiovascular disease event rates have reported that the combination of pravastatin and 
aspirin consistently has greater efficacy than pravastatin or aspirin alone indicating at least an additive 
and possibly a synergistic effect.119 Therefore, there is minimal concern that concomitant aspirin use 
would reduce the effect size. 
Preterm birth < 37 weeks of gestation is considered to be the major secondary outcome.  With a sample 
size of 1550, there is more than 80% power to detect an effect as small a 20% reduction in preterm birth.   
The sample size for this study is also sufficient to detect with at least 80% power a 40% reduction in 
preterm delivery < 34 weeks and a 30% reduction in NICU/special care admission. 
6.3 
Analysis Plan 
All statistical analyses will be based upon the total cohort of patients randomized into the trial.  Although 
data on some patients may be missing, all relevant data available from each patient will be employed in 
the analyses.  Patients will be included in the treatment group to which they were randomly assigned 
regardless of compliance. 
The primary analysis will consist of a simple comparison of binomial proportions.  The relative risks and 
confidence intervals will be reported.  If the treatment groups are found to differ on a pre-treatment factor 
known to be a risk factor for the outcome, the statistical analysis will adjust for these differences, using a 
log binomial regression (or log-Poisson when relevant).  An evaluation of treatment by center interaction 
will be included, using the Breslow-Day test.  An analysis adjusting by center also will be performed to 
ensure that center differences do not change the conclusion.   
If the primary outcome is significant or the trial is stopped early for benefit, the methods of Maurer and 
Bretz will be used to test formally the major secondary endpoint of preterm delivery < 37 weeks, while 
controlling the familywise error rate.120 
Loss to follow-up will be defined as the inability to ascertain whether a woman has preeclampsia.  Those 
defined as lost to follow-up will not be included in the primary analysis.  It is expected that the loss to 
follow-up rate will be very low.  However, a sensitivity analysis will be performed including patients lost 
to follow-up with different assumptions regarding their outcome, to determine whether the results are 

March 8, 2022 
 
35 
robust.  Multiple imputation techniques (or a Bayesian bootstrap technique if the ‘missingness’ is non-
ignorable) will be evaluated if required.121 
Since many of the secondary endpoints are dichotomous variables like the primary outcome, standard 
statistical methods for rates and proportions will be appropriate.  For normally distributed continuous 
outcomes, least squares means general linear regression will be used to estimate means and 95% 
confidence intervals.  The Wilcoxon test and the Hodges-Lehmann estimators will be used to compare 
non-normal continuous variables that cannot be transformed to approximate normality. For time-to-event 
variables, the log-rank test and Cox proportional hazards model will be used (model assumptions tested 
by Lin’s test).  
6.3.1 Subgroup Analyses 
If the two groups show a difference in the incidence of the primary outcome or major secondary outcome, 
interactions will be evaluated and subgroup analyses conducted to determine whether the effect prevails 
throughout particular subgroups of patients.  Indeed, NIH guidelines require investigators to evaluate 
consistency between the genders and across racial subgroups.  It should be noted, however, that subgroup 
analyses have been greatly abused, particularly when there is no overall treatment difference.122  There is 
a strong temptation to search for a specific subpopulation in which the therapy is nevertheless effective.  
Yusuf et al. concluded “the overall ‘average’ result of a randomized clinical trial is usually a more 
reliable estimate of the treatment effect in the various subgroups examined than are the observed effects 
in individual subgroups.”123  Thus subgroup analyses will be interpreted with care.   
It is generally acknowledged that subgroup analysis that is pre-specified in the protocol has more validity 
than ad-hoc comparisons.  The following factors will be considered for subgroup analysis, if there is a 
significant interaction between the factor of interest and the treatment effect: 
• 
Race/ethnicity 
• 
Baseline BMI category 
• 
Gestational age at randomization 
• 
Actual or prescribed aspirin use at baseline 
• 
Pregestational diabetes 
• 
Chronic hypertension at baseline 
• 
Singleton pregnancy  
For subgroup analyses, there will be more limited power. However, if an interaction test were positive for 
the primary outcome, indicating the presence of heterogeneity between subgroups, and 1) the subgroups 
were each 50% of the sample size and 2) the placebo outcome rate in the subgroup were the same as 
assumed overall (20%), then there would be more than 85% power to detect a 40% difference between 
treatment groups within one of the subgroups.  
The racial/ethnic composition of women recruited into the MFMU Network trials varies.  Assuming for 
this trial that the composition is 31% African-American and 24% Hispanic (estimates based on site 
specific rates reported among preeclamptics in the RCT of Antioxidants to Prevent Preeclampsia CAPPS 
trial) there is more than 85% power to detect a 50% reduction in the primary outcome in African 
American women and 77% power to detect a 50% reduction in the primary outcome in Hispanic women 
within these separate subgroups. 
 
 

March 8, 2022 
 
36 
7 
Data Collection 
7.1 
Data Collection Forms 
Data will be collected on standardized forms on which nearly all responses have been pre-coded.  Each 
form is briefly described below: 
• 
Screening Log 
• 
Eligibility and Randomization Form is completed for all patients eligible for the study. 
• 
Study Drug Randomization Log: lists patients randomized to pravastatin or placebo, and provides 
the drug code number. 
• 
Baseline Form is completed for all randomized patients.  This form includes detailed 
demographic and social data, medical and obstetrical history, and current pregnancy 
complications. 
• 
Previous Pregnancy Outcome Form 
• 
Study Visit Form documents monthly study visits, possible side effects and compliance 
• 
Creatine Kinase Log documents CK values reported for the participant. 
• 
Study Drug Dispensing and Compliance Log documents the dispensing of study medication and 
the return of any unused study medication. 
• 
Study Drug Alteration Log for Side Effects documents the modification of study medication due 
to side effects. 
• 
Unscheduled Visit or Hospitalization Form is completed for all patients who had an unscheduled 
emergency room, Labor & Delivery, clinic visit or hospitalization between the scheduled monthly 
visits, including the delivery admission. 
• 
Maternal Delivery and Outcome Form documents specific pregnancy complications since 
randomization, in addition to labor, delivery and postpartum information.  
• 
Neonatal Baseline Form records date and time of birth, delivery data and status at delivery, for 
each fetus/infant. 
• 
Neonatal Outcome Form records outcome data for all infants admitted to the NICU or special 
care nursery. 
• 
Patient Status Form documents loss to follow up/withdrawal status, last date of contact for lost to 
follow-up patients, side effects since the last dose. 
• 
Follow-up Visit Form documents maternal complications since discharge and the 6-week 
postpartum study visit. 
• 
Postpartum Readmissions Log is completed for all patients who are readmitted to the hospital 
after discharge following delivery.   
• 
Adverse Event Form records serious and non-serious adverse events. 
• 
Outcome Diagnosis Form records outcome data for hypertension and preeclampsia 
• 
Two Year Study Visit Form for infants and proprietary forms for neurodevelopmental and 
behavior testing  

March 8, 2022 
 
37 
• 
Five Year Study Visit Form for infants and proprietary forms for neurodevelopmental and 
behavior testing 
7.2 
Web Data Entry System 
For this protocol, web data entry screens corresponding to the study forms listed above will be developed 
and maintained by the staff of the BCC.  Clinical center staff will enter data into the MySQL database 
located at the BCC through a web data management system (MIDAS).  The data are edited on-line for 
missing, out of range and inconsistent values.  A Users’ Manual documenting this system is provided to 
the centers by the BCC.  
7.3 
Centralized Data Management System 
Daily data conversions from the MySQL database create up-to-date SAS datasets.  Data are reviewed 
weekly using edit routines similar to those implemented on-line during data entry, as well as additional 
checks for data consistency within or across forms.  A database of resulting potential data problems is 
generated in MIDAS for initial review by BCC staff who then evaluate the comments keyed in 
association with edits on missing or unusual values.  Valid edits will be flagged in MIDAS for resolution 
at the clinical centers.   
At regular intervals, specialized data reviews comparing data availability and consistency across forms 
are run by the BCC staff on the entire database or on a specific subset of data.  These reports are also 
submitted to the centers for correction or clarification. 
An audit trail, consisting of all prior versions of each data form as entered in the computer for each 
patient, is maintained so that the succession of corrections can be monitored. 
7.4 
Performance Monitoring 
The BCC will present regular reports to the Protocol Subcommittee, the Steering Committee, and the 
Data and Safety Monitoring Committee.  These include: 
• 
Monthly Recruitment Reports - reports of the number of women screened and enrolled by month 
and by clinical center are provided monthly to the subcommittee and all other members of the 
Steering Committee.  Weekly or bi-weekly reports are provided electronically as decided by the 
Protocol Subcommittee. 
• 
Quarterly Steering Committee Reports - reports detailing recruitment, baseline patient 
characteristics, data quality, incidence of missing data and adherence to study protocol by clinical 
center, are provided quarterly to the subcommittee and all other members of the Steering 
Committee. 
 

March 8, 2022 
 
38 
8 
Study Administration 
8.1 
Organization and Funding 
The study is funded by the National Heart Lung and Blood Institute (NHLBI) and by the Eunice Kennedy 
Shriver National Institute of Child Health and Human Development (NICHD).  The study is conducted by 
the NICHD Maternal-Fetal Medicine Units (MFMU) Network, consisting of twelve clinical centers, the 
Biostatistical Coordinating Center (BCC) and the NICHD.     
8.1.1 MFMU Clinical Centers 
Each of the funded institutions is represented by a Principal Investigator.  A complete description of the 
organization of the MFMU Network is provided in the MFMU Network Policy Manual. The participating 
Principal Investigators of the clinical centers have agreed to abide by the study protocol, to have 
comparable staff, facilities and equipment and to ensure the proper conduct of the study at each of their 
centers including: recruitment and treatment of patients as specified in the protocol, accurate data 
collection and the transmission of information to the Steering Committee. 
8.1.2 Biostatistical Coordinating Center (BCC) 
The BCC is responsible for all aspects of biostatistical design, data management, interim and final 
statistical analyses, and preparation of publications based on the study results.  The Principal Investigator 
of the BCC reports to the Steering Committee and the Data and Safety Monitoring Committee. 
8.1.3 Clinical Coordinating Center (CCC) 
For this study, the University of Texas Medical Branch and Columbia University together will serve the 
role of Clinical Coordinating Center. 
8.1.4 NHLBI/NICHD 
In addition to their role as funding agency, the NICHD and NHLBI participate in the activities of the 
Network, including the development of the protocol, administration and conduct of the study and 
preparation of publications. 
8.1.5 Network External Advisory Committee 
Appointed by the NICHD, the members of the Network External Advisory Committee (EAC) consist of a 
group of experts who are not affiliated with research being conducted by the Network and represent the 
disciplines of maternal-fetal medicine, neonatology and biostatistics/epidemiology.  The role of the EAC 
includes the review and prioritization of proposed studies, in addition to the identification of scientifically 
and clinically important questions and ideas that might be conducted by the Network.  The NICHD 
Program Scientist convenes and attends the meetings. 
8.2 
Committees 
8.2.1 Steering Committee 
This committee consists of fifteen members.  The Principal Investigator from each of the twelve clinical 
centers, the BCC, and the NICHD MFMU Network Project Scientist are all voting members. The Chair of 
the Steering Committee may vote to break a tie.  The Chair, a person independent of the participating 
institutions, is appointed by NICHD.  The Steering Committee has the responsibility for identifying topics 
for Network studies, designing and conducting study protocols and monitoring study implementation, 
recruitment and protocol adherence.  The committee receives recommendations from the Data and Safety 
Monitoring Committee and the Network External Advisory Committee. 

March 8, 2022 
 
39 
8.2.2 Protocol Subcommittee 
The subcommittee consists of the multiple PIs named in the Clinical Coordinating Center and Data 
Coordinating Center NHLBI grants,  investigators from one or more other clinical centers, , nurse 
coordinators, outside consultants (if appropriate), the NICHD Network Program Scientist and the NHLBI 
Project Scientist.  The Protocol Subcommittee is responsible for the preparation and conduct of the study, 
and reporting the progress of the study to the Steering Committee. 
8.2.3 Publications Committee 
The Publications Committee is a standing committee of the Steering Committee.  The functions of this 
committee are to develop publication policies and to review all manuscripts and abstracts prior to 
submission.  The goals of this committee are fair and appropriate authorship credit and high quality 
publications. 

March 8, 2022 
 
40 
9 
Study Timetable 
 
 
Figure 1. Timetable  
 
Finalize Study Documents / Training / 
Certification
 
Recruitment
 
Primary Follow-up
 
Primary Closeout/    
Data Analysis
 
2018
2027
2019
2020
2021
2022
2023
2024
2025
2026
Child Follow-up
 
2032
// ------------- I
Child Follow-up Closeout/ 
Data Analysis 
 
 
 
9.1 
Training and Certification 
Training will be held with the nurse coordinators in July 2018.  Each participating center must be certified 
to start the trial before recruitment at that center can begin.  The certification requirements are designed to 
ensure that personnel involved in the trial are committed to the study and proficient in study procedures, 
and that the center has satisfied regulatory requirements. The trial is expected to start in June 2019. 
9.2 
Recruitment and Data Collection Period  
9.2.1 Estimate of the Prevalence of Previous Preeclampsia  
Using the Swedish Medical Birth Registry, Hernandez-Diaz identified a cohort of 763,795 nulliparous 
women. At the first pregnancy the cohort was subdivided into those who had preeclampsia and those who 
did not, and women within each subcohort followed forward to their next pregnancy if they had one.  The 
process was reported until the fourth pregnancy.118  This can be used to calculate the probability of 
previous preeclampsia in a general population at the second, third and fourth pregnancies as shown, and 
naturally takes into account that women who have had a bad experience in one pregnancy may avoid 
another one.  For the grouped category of 5 or more pregnancies it was assumed that 5.5% would have 
had previous preeclampsia in a previous pregnancy.  From the MFMU Network APEX study of a random 
sample of all deliveries in the MFMU Network over a 3-year period, it is possible to estimate the 

March 8, 2022 
 
41 
prevalence of previous preeclampsia in the MFMU Network population by multiplying the probability of 
previous preeclampsia at each pregnancy number (1-4, 5+). 
Overall it is estimated that 2.58% of the MFMU population would have prior preeclampsia (Table 6). 
This is likely an underestimate since the MFMU Network incorporates tertiary care centers and the rate of 
preeclampsia is higher in the US than in Sweden.   
Table 6. Probability of Previous Preeclampsia in the MFMU Network Population 
Gravida  
Estimated probability of 
previous preeclampsia 
from Hernandez-Diaz et al. 
Percent of women in 
MFMU population  
Percent of MFMU 
population with 
previous preeclampsia  
1 
0 
 40.5 
0 
2 
0.0387 
 31.4 
1.22 
3 
0.0455 
 16.4 
0.75 
4 
0.0517 
  6.9 
0.35 
5 or more 
0.0550 
  4.8 
0.26 
Overall  
 
100.0 
2.58 
 
To determine the percentage of women with previous preeclampsia that would have delivered before 34 
weeks the High Risk Aspirin trial was examined.  In the High Risk Aspirin trial 28.2% of those who 
enrolled had prior preeclampsia before 36 weeks which yields a prevalence of 0.73% (2.58% x 28.2%). 
This may be an overestimate of the prevalence in the population since women who had a worse 
experience previously may have been more likely to enroll. 
Hernandez-Diaz et al. also examined severe preeclampsia, defined as preeclampsia associated with 
delivery < 34 weeks.  Using the same calculations for this outcome as for the overall prevalence, the 
prevalence of previous preeclampsia <34 weeks is 0.25% .  This is probably too low, since the MFMU 
Network incorporates tertiary care centers and the rate of preeclampsia is higher in the US than in 
Sweden.  Also the cohort represented women who had their first deliveries between 1987-2004 and the 
rate of preeclampsia has risen over time.   
The average of these two rates (0.5%) is used as the estimate of the prevalence of previous preeclampsia 
with delivery before 34 weeks.  
9.2.2 Estimate of Recruitment Rate 
There are more than 160,000 deliveries per year in the MFMU network which would result in 800 
potentially eligible women (160,000 x 0.5%). Assuming that 80% of the women delivering at MFMU 
network centers would be available for screening (i.e. that they present for care early enough in gestation, 
at clinics that are accessible and do not meet exclusion criteria), and that 50% of these women consent (a 
conservative consent rate for studies involving high risk patients in the Network) it is estimated that 
approximately 320 patients per year or 26-27 patients will be enrolled per month.  The first 50 women 
will be enrolled over 6 months.  Recruitment of the remaining 1500 women will take approximately 4.8 
years.    
9.3 
Final Analysis 
After a three-month period for completion of data entry for the trial and close-out of the delivery and 
primary outcome, the data set will be locked and available for the primary and other main analysis.  After 
completion of the 5 year infant follow-up, a two-month period will be dedicated to complete data entry, 
close-out this follow-up, and lock the follow-up dataset.   

March 8, 2022 
 
42 
Appendix A 
Design Summary 
OBJECTIVE:  To determine whether treatment with pravastatin among women with a prior history of preeclampsia with preterm delivery by 34 weeks reduce the rate of 
preeclampsia. 
 
ORGANIZATION 
 
SCHEDULED EVALUATIONS / DATA COLLECTION 
Clinical Centers: 
Magee, UAB, Ohio State, Utah, Brown, Columbia, 
Case Western, UT-Houston, UNC, Northwestern, 
UTMB-Galveston, U Penn 
Pre-Randomization: 
 History 
 
 Dating ultrasound  and AST/ALT if not done 
Randomization: 
 BP, height, weight 
Subcommittee: 
Maged Costantine, MD (Chair) 
 
 Blood collection 
 
 
Post-randomization 
(monthly): 
 Blood collection at 230 to 286 and 330 to 376 
 
 
 Study visits monthly to assess side effects and 
AEs, record weight and BP, pill count and 
dispense study medication, review current 
medications 
DESIGN 
 
Delivery:  
 Delivery and neonatal data  
 Cord blood (first 50 participants) 
Major Eligibility Criteria: 
 Prior preeclampsia with delivery ≤ 340 
 Gestational age 120 to 166  wks at randomization 
 Contraindications for statin therapy, use in current 
pregnancy 
Postpartum (6 wks): 
 
Maternal Follow-up at 2 yrs: 
Child Follow-up at 2 yrs: 
 
Child Follow-up at 5 yrs: 
 Assess AEs and postpartum complications, 
record weight and BP 
 Medical history, BP, height, weight, waist and 
hip circumferences, blood collection 
 Medical history, height, weight, vision & hearing 
assessment, neurodevelopment & behavior 
testing 
 Medical history, height, weight, vision, 
neurodevelopment & behavior testing 
Groups: 
 Pravastatin 20mg 
 Matching placebo 
 
 
MANAGEMENT PROTOCOL 
Level of Masking: 
 Double masked 
Masked medication: 
 Daily dose of pravastatin 20mg or placebo until 
delivery 
Stratification: 
 Clinical site 
OUTCOME MEASURES 
 
Sample Size: 
 1550 
Primary: 
 Preeclampsia, mat death, or fetal loss < 20 wks 
Assumptions: 
 Outcome = Incidence of preeclampsia 
 Placebo group event rate = 20% 
 Pravastatin group event rate = 14% (30% 
reduction) 
 Type 1 error = 5% 2-sided 
 Power =85% 
 Adjustment for 5% loss to follow-up and scheduled 
interim analysis 
Secondary: 
 Preterm birth < 37 weeks (major secondary)  
 Preterm birth < 34 weeks, gest age at delivery  
 Preeclampsia with severe features  
 Gestational hypertension  
 Gestational diabetes  
 Concentrations of angiogenic factors and lipids  
 Fetal and neonatal death  
 Birth weight and small for gestational age  
 Complications of prematurity 
 Child BMI for age at 2 and 5 years  
 Cognitive, Language and Motor Scale Scores 
from the Bayley 4 at 2 years 
 General Conceptual Ability score and subscale 
scores from the Differential Ability Scales at 5 
years of age 
Interim Analysis: 
 Lan-DeMets group sequential method 
TIMETABLE  
Enrollment: 
Data collection: 
Primary analysis: 
Child data collection: 
 
Closeout/final analysis: 
 
 Jun 2019 – Jul 2025 
 Jun 2019 – Mar 2026 (primary) 
 Apr 2026 – Jun 2026 (primary) 
 Jun 2019 – Mar 2028 (child 2 yr follow-up) 
 Jun 2019 – Mar 2031 (child 5 yr follow-up) 
 Apr 2031 – Jun 2031 

March 8, 2022 
 
43 
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