Safety and Pharmacokinetics of Pravastatin Used for the Prevention of Preeclampsia in High-Risk Pregnant Women: A Pilot Randomized Controlled Trial

Abstract

Background

Preeclampsia complicates approximately 3% to 5% of pregnancies and remains a major cause of maternal and neonatal morbidity and mortality. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Pravastatin, a hydrophilic, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, has been shown in preclinical studies to reverse various pathophysiological pathways associated with preeclampsia, providing biological plausibility for its use for preeclampsia prevention. However, human trials are lacking.

Objective

As an initial step in evaluating the utility of pravastatin in preventing preeclampsia, and after consultation with the U.S. Food and Drug Administration, we undertook a pilot randomized controlled trial with the objective to determine pravastatin safety and pharmacokinetic parameters when used in pregnant women at high risk of preeclampsia.

Study Design

We conducted a pilot, multicenter, double-blind, placebo-controlled, randomized trial of women with singleton, non-anomalous pregnancies at high risk for preeclampsia. Women between 12^0/7 and 16^6/7 weeks gestation were assigned to daily pravastatin 10 mg or placebo orally until delivery. Primary outcomes were maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included rates of preeclampsia and preterm delivery, gestational age at delivery, birthweight, and maternal and cord blood lipid profile (Clinicaltrials.gov Identifier NCT01717586).

Results

Ten women assigned to pravastatin and ten to placebo completed the trial. There were no differences between the two groups in rates of study drug side effects, congenital anomalies, or other adverse or serious adverse events. There was no maternal, fetal, or neonatal death. Pravastatin renal clearance was significantly higher in pregnancy compared to postpartum. Four subjects in the placebo group developed preeclampsia compared to none in the pravastatin group. Although pravastatin reduced maternal cholesterol concentrations, umbilical cord cholesterol concentrations and infant birthweight were not different between the groups. The majority of umbilical cord and maternal pravastatin plasma concentrations at time of delivery were below the lower limit of quantification of the assay.

Conclusions

This study provides preliminary safety and pharmacokinetic data regarding the use of pravastatin for preventing preeclampsia in high-risk pregnant women. Although the data are preliminary, no identifiable safety risks were associated with pravastatin use in this cohort. This favorable risk-benefit analysis justifies using pravastatin in a larger clinical trial with dose escalation.

Introduction

Preeclampsia is a multisystem disorder that complicates 3%–5% of pregnancies and remains a major cause of maternal, fetal, and neonatal morbidity and mortality (1). It is characterized by angiogenic imbalance, exaggerated inflammation, and endothelial dysfunction, which ultimately lead to the clinical manifestations of hypertension, proteinuria, and end organ damage (1,2). Preeclampsia is associated with serious short- and long-term maternal and neonatal morbidities (1,3), and its recurrence in subsequent pregnancies depends on the presence of risk factors (e.g., diabetes, hypertension, and multifetal gestation) and the severity and time of onset of preeclampsia in a prior pregnancy (4, 5).

Despite being unique to pregnancy, preeclampsia shares pathogenic similarities and many risk factors with adult cardiovascular disease (4). Endothelial dysfunction and inflammation are fundamental for the initiation and progression of both atherosclerosis and preeclampsia (2,6,7,8). Numerous attempts at primary and secondary prevention of preeclampsia, using various supplements and medications, have had limited success. (4) Only low-dose aspirin was found to have a modest benefit in reducing the rate of preeclampsia in an individual patient meta-analysis, (9) and that benefit was only achieved if the drug was started before 16 weeks gestational age. On the contrary, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase (statins) are effective in primary and secondary prevention of cardiovascular mortality and morbidity (10,11). Moreover, statins have been in animal models of preeclampsia to revert the angiogenic imbalance, a hallmark of preeclampsia, and restore endothelial dysfunction. This biological plausibility and data from preclinical animal studies support a role for statins in preeclampsia prevention (12–19).

Our long-term goal is to evaluate the utility of pravastatin (a hydrophilic statin) to reduce the recurrence of preeclampsia in high-risk pregnant women. As an initial step in this process, and after consultation with the U.S. Food and Drug Administration (FDA), we undertook a pilot randomized controlled trial (RCT) with an objective to evaluate the maternal-fetal safety and pharmacokinetic (PK) parameters of pravastatin when used in pregnant women at high risk for preeclampsia (19). In this publication, we are reporting the first phase of a series of planned studies using a low dose (10 mg) of pravastatin.

Materials and Methods

Study population

We conducted a multicenter, double-blind, placebo-controlled randomized trial involving pregnant women at high risk for preeclampsia. Eligible women were 18 years or older, with singleton, non-anomalous pregnancy between 12^0/7 weeks and 16^6/7 weeks gestation (confirmed with an ultrasound examination), and with a history of severe preeclampsia in a prior pregnancy that required delivery prior to 34 weeks gestation (documented by chart review). We excluded women with known fetal genetic or major malformations; fetal demise; multifetal gestation; contraindications for statin therapy (e.g., hypersensitivity to pravastatin, recent or active liver disease); concomitant therapy with fibrates, niacin, cyclosporine, clarithromycin, or erythromycin; pre-gestational diabetes mellitus; HIV infection; history of solid organ transplant; chronic renal disease; epilepsy; uterine malformations; cancer; familial hypercholesterolemia; or inability to tolerate oral medications secondary to severe nausea and vomiting of pregnancy.

The trial was conducted from August 2012 through February 2014 by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Obstetric-Fetal Pharmacology Research Units (OPRU) Network at five clinical center sites as an FDA-approved investigational new drug study (IND #114205) (19). The institutional review boards at all the participating sites approved the study protocol. All women provided written informed consent. The study was registered on Clinicaltrials.gov (Identifier NCT01717586).

Study Design and Intervention

Before randomization, all participants were documented to have normal liver transaminases (AST and ALT). Women were randomized to pravastatin 10 mg or placebo and were assigned a prepackaged supply of study medication corresponding to the appropriate study drug code. Randomization was performed through a central process that was prepared and maintained by the data coordinating center (DCC; RTI International, Research Triangle Park, NC). Initial stratification was by clinical site. Pravastatin and placebo capsules were manufactured by University of Iowa Pharmaceuticals and packaged in identical capsules. Subjects were asked to take 1 capsule orally daily, and treatment continued until delivery or until a condition developed that required discontinuation of the study drug.

After randomization, research personnel followed subjects at scheduled intervals. Subjects’ care and that of their infants was according to standard practice. At each study visit, medication’s side effects were assessed using a checklist, adverse events (AEs) were determined and assessed, and pill count performed. Subjects’ pregnancy management (including antenatal testing, ultrasounds, management of preeclampsia, use of low dose aspirin, and others) was left to the discretion of the treating physician and performed as recommended by standard prenatal care as defined by the respective participating institution. All data were collected or abstracted by research coordinators at the clinical centers and uploaded to a central database that was managed by the DCC, which was responsible for data analysis.

Pharmacokinetic studies

Steady-state pravastatin PK studies were conducted in the second trimester (18–24 weeks gestation) and third trimester (30–34 weeks gestation) of pregnancy as well as postpartum (4–6 months post-delivery). Each subject served as her own control. Subjects recorded the time of pravastatin dosing for the 4 days prior to each study day and pill counts were conducted to determine adherence. Women were asked to fast (except for water) for 5 hours prior to each study visit until 1 hour after dosing. Serial blood samples (6 mL each) were collected for measurement of pravastatin and 3’α-isopravastatin (a major metabolite of pravastatin, that is only 1/10^th to 1/40^th as potent as parent drug in inhibiting HMG-CoA reductase) concentrations in plasma at times: pre-dose, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the dose on each pharmacokinetic study day. Urine was collected pre-dose and then all urine over one dosing interval was collected as follows: 0–4, 4–8, 8–12 and 12–24 hours following dosing on each study day. Urine from each interval was combined, mixed and total volume measured. An aliquot from each interval was assayed for pravastatin and 3’α-isopravastatin concentrations. Maternal, umbilical cord venous and umbilical cord arterial blood samples were collected at the time of delivery for measurement of pravastatin and 3’α-isopravastatin concentrations in plasma. All samples were stored at −70° C until analysis (More details on PK studies and analysis will be found in the supplementary materials).

Outcome variables

The primary outcomes were (1) maternal-fetal safety and (2) pravastatin PK parameters during pregnancy.

Safety outcomes included evaluation of medication side effects (checklist), maternal AEs and serious AEs, as well as fetal or perinatal death, and congenital malformations. Pravastatin PK parameters included maximum concentration (C_max) and time to maximum concentration (T_max), area under the concentration time curve (AUC), apparent oral clearance (CL/F), half-life, renal clearance, and others (supplementary material).

In addition, the study collected secondary maternal and fetal/neonatal outcomes including rate and severity of preeclampsia, gestational age at delivery, rate of preterm delivery, maternal lipid profile, and the concentrations of angiogenic (placental growth factor, PlGF) and anti-angiogenic factors (soluble fms-like tyrosine kinase-1, sFlt-1; and soluble endoglin, sEng) in the maternal circulation. Preeclampsia was diagnosed according to criteria set by the American College of Obstetricians and Gynecologists (20) (see supplementary material), and the diagnosis (or absence) was confirmed by a panel of three maternal-fetal medicine physicians, blinded to treatment assignment, who reviewed the de-identified medical records of all enrolled subjects.

Fetal and neonatal secondary outcomes included birthweight, rates of small for gestational age, failure of auditory brainstem response evoked potential, admission to the neonatal intensive care unit (NICU) and other neonatal complications, and cord blood analytes (concentrations of pravastatin and 3’α-isopravastatin, liver enzymes, lipid profile, creatine kinase, angiogenic and anti-angiogenic markers, steroidogenic hormones (TSH, FSH, LH, estradiol, and total testosterone), and S100B and neuron specific enolase, two non-specific markers of neurologic injury).

Statistical Analysis

Statistical analyses were performed using SAS statistical software (SAS Institute, Cary, NC). Maternal and neonatal continuous variables were compared using Wilcoxon rank-sum and categorical variables with the chi-square or Fisher’s exact test as appropriate. Biomarker concentrations were analyzed as continuous variables. Steady-state pravastatin PK parameters were estimated using standard non-compartmental techniques and normalized using actual body weights (see supplementary material). PK parameters during pregnancy were compared to those postpartum using paired Wilcoxon signed-rank test.

Our sample size was 20 subjects (10 assigned to pravastatin and 10 to placebo) for which the primary outcomes were available. This was determined a priori by FDA as part of the IND approval process (19) and was not intended to achieve power to detect hypothetical differences in primary or secondary clinical outcomes or other laboratory values. P-value less than 0.05 was considered statistically significant.

Results

Of 22 subjects who consented for the study, 21 were randomized, with 11 assigned to the pravastatin group and 10 to the placebo group. One subject from the pravastatin group withdrew from the study after randomization for social reasons (Supplementary Figure 1). Ten subjects in each group completed the trial, as requested by the FDA. No subjects were lost to follow-up. There was no significant difference in estimated adherence to study medication between the pravastatin group and placebo group (94.6 percent vs. 95.9 percent). At study entry, there were no differences in baseline characteristics such as gestational age at delivery in prior qualifying pregnancy and the percent of subjects receiving low dose aspirin. Although statistically non significant, more subjects in the pravastatin group were obese (Table 1, Supplementary Figure 2).

Table 1.

Baseline characteristics of subjects who participated in the study. Data are reported as median [interquartile range], or n (%).

Characteristic	Placebo Group # (N= 10)	Pravastatin Group# (N=11)
aRace:
White	9	10
African American	1	0
Asian	0	0
American Indian	0	1
aEthnicity:
Hispanic	7	5
Non-Hispanic	3	6
Age—years	30 [27,34]	27 [21, 34]
Body mass index—Kg/m2	29.6 [27, 32.3]	36 [26, 38.2]
bObesity	4 (40)	8 (72.7)
cSystolic blood pressure at entry to care, mm Hg	115 [110, 122]	109 [107, 131]
cDiastolic blood pressure at entry to care, mm Hg	68 [64, 72]	64 [55, 77]
dParity	2 [2, 3]	1 [1, 2]
Gestational age at randomization—weeks	14.9 [13.4, 16.4]	13.9 [13.3, 16.1]
Gestational age at delivery in prior pregnancy—weeks	30.7 [29.4, 32.0]	32.0 [30.7, 33.0]
Chronic hypertension	3(30)	5(50)
Use of low-dose aspirin	3 (30)	2 (18)

^#None of the comparisons between the two groups is statistically significant (P > 0.05)

^aRace and ethnicity were self-reported by patients.

^bObesity is defined as BMI≥30 Kg/m² using pre-pregnancy weight.

^cBlood pressure at entry to care, measured in clinic after a 10-minute rest period, in seating position with the right arm in a roughly horizontal position at heart level, supported on a desk.

^dParity is any pregnancy that lasted >20 weeks.

The rates and types of side effects and AEs, irrespective of relation to study medication, were not different between the 2 groups (Table 2). The most common side effects reported by subjects who received pravastatin were musculoskeletal pain and heartburn. There were no reports of myopathy/rhabdomyolysis or liver injury (data on maternal concentrations of creatine kinase, AST, and ALT are in Supplementary Table 1). None of the participants discontinued their study medication. In addition, there were no maternal, fetal, or infant deaths in either group. One fetus in the pravastatin group had hypospadias and another had coarctation of the aorta (diagnosed postnatally), whereas in the placebo group one fetus had polydactyly and another had ventriculomegaly. One subject in the placebo group underwent postpartum hysterectomy secondary to hemorrhage from placenta previa and uterine atony.

Table 2.

Adverse and serious adverse events experienced by subjects, irrespective of association with study medications. Data are reported as n (%).

Condition		Placebo Group# (N=10)	Pravastatin Group# (N=11)
Adverse events
Heartburn		3 (30)	4 (36)
Musculoskeletal pain		1 (10)	4 (36)
Dizziness		2 (20)	3 (27)
Chest Pain		0	2 (18)
Diarrhea		1 (10)	2 (18)
Headache		3 (30)	2 (18)
Cough		1 (10)	2 (18)
Swelling		0	2 (18)
Nausea		1 (10)	1 (9)
Fever		2 (20)	1 (9)
Flatulence		0	1 (9)
Fatigue		0	1 (9)
Wheezing		0	1 (9)
Vomiting		1 (10)	0
Influenza-like symptoms		2 (20)	0
Serious Adverse Events
Maternal, fetal, or infant death		0	0
aRhabdomyolysis		0	0
aLiver injury		0	0
Congenital anomalies		Polydactylyb Ventriculomegaly	Hypospadiasb Coarctation of aorta
Hospitalization >24 hours:
HTN/BP exacerbation,		3 (30)	2 (18)
Preeclampsia workup		1 (10)	0
Vaginal bleeding		1 (10)	0
Influenza infection		1 (10)	0
Migraine		1 (10)	0
Syncope		0	1 (9)

^#None of the comparisons between the two groups is statistically significant (P > 0.05)

^aRhabdomyolysis was defined as muscle pain or muscle weakness in conjunction with increase in creatinine kinase (CK) values to greater than 10 times the upper limit of normal. Liver injury was diagnosed with elevation of transaminases (AST or ALT) values greater than three times the upper limit of normal. Data on maternal AST, ALT and CK concentrations are in Supplementary Table 1.

^bFamily history of polydactyly and hypospadias in the father of each child respectively.

Pravastatin C_max, T_max, AUC, T_1/2, percent of the dose excreted unchanged as parent drug, and CL/F were not significantly different between the three time periods (Table 3). The average steady-state concentration-time profiles are depicted graphically in Supplementary Figure 3. For subjects in whom we were able to quantify the 24-hour post-dose concentration, pravastatin appears to exhibit a 2-compartment PK model. The apparent half-life of pravastatin based on concentration data till 12 hours was estimated to be 2.1±0.9 hours in the second trimester (n=11), 3.0±1.6 hours in the third trimester (n=10), and 2.4±1.3 hours postpartum (n=9). However, in the small subset of subjects (n=1–3 per PK study day) in whom we were able to quantify the 24-hour post-dose concentration, the estimated terminal half-life was much longer. Renal clearance and net renal secretion clearance of pravastatin were significantly higher during pregnancy compared with postpartum (Table 3). We had adequate sample to assay for pravastatin concentrations in 6 umbilical cord arterial and 7 umbilical cord venous samples. In the majority of umbilical cord and maternal samples at time of delivery, pravastatin concentrations were below the limit of quantification of the assay (Supplementary Table 2).

Table 3.

Estimated steady-state pravastatin pharmacokinetics in subjects during the 2^nd and 3^rd trimesters of pregnancy compared with postpartum. Data are reported as mean±SD.

Parameter	18–24 weeks Gestation (n=11)	30–34 weeks Gestation (n=10)	4–6 months Postpartum (n=9)
Cmax (ng/mL)	14.9± 11.3	11.1± 6.2	17.2± 11.5
Tmax (hr)	1.6±0.6	1.5±0.4	1.6±1.0
Half-lifeapparent (hr)	2.1±0.9	3.0±1.6	2.4 ±1.3
CL/F (L/hr)	396±190	389±215	289± 142
CL/F (L/hr/kg)	4.6±2.4	4.2±2.0	3.2±1.5
AUC(0–24) (ng· hr/mL)	31±16	32±16	43±20
Amount excreted(0–24hr) (mg)	0.98±0.60	1.04±0.57	0.93±0.60
Percent excreted unchanged	10±6	10±6	9±6
CLRenal (L/hr)	34±16a	34±1 1a	23±4
CLSecretion (mL/min)	480±273a	471± 151a	325 ±65

^aP<0.05; second and third trimester compared with postpartum

C_max=maximum concentration; T_max=time to maximum concentration; CL/F=apparent oral clearance; AUC_(0–24)=area under the concentration time curve; CL_Renal=renal clearance; CL_Secretion=net renal secretion clearance

Four subjects in the placebo group developed preeclampsia (with 3 of 4 having severe disease) compared to none in the pravastatin group. There were five indicated preterm deliveries before 37 weeks in the placebo group compared with one in the pravastatin group. (Table 4) Other obstetric outcomes were similar between the two groups. The concentrations of PlGF were increased in subjects receiving pravastatin, and those of sFlt-1 and sEng were decreased; however the differences for these markers did not reach statistical significance. Of note, the four women in the placebo arm who developed preeclampsia had the highest sFlt-1 concentrations near term (Figure 1, Supplementary Table 1).

Table 4.

Maternal and neonatal outcomes of participants in the study. Data are reported as n (%) mean±SD, or median [IQR].

Outcomes	Placebo Group# (N=10)	Pravastatin Group# (N=10)
Maternal Outcomes
Preeclampsia Severe features	4 (40) 3	0 (0) 0
Postpartum preeclampsia	1 (10)a	0 (0)
Gestational hypertension	1(10)	1 (10)
Gestational age at delivery, weeks	36.7±2.1	37.7±0.9
Indicated preterm delivery less than 37 weeks	5 (50)b	1 (10) c
Indicated preterm delivery less than 34 weeks	1(10)	0 (0)
Blood transfusion	1 (10)	1 (10)
dLength of hospital stay (days)	4 [3–7], range 2–43	3 [3–4], range 1–6
Neonatal Outcomes
Birth weight, grams	2,877±630	3,018± 260
Highest level of care Well baby/routine Intermediate (Level 2) NICU	5 (50) 2 (20) 3 (30)	8 (80) 1 (10) 1 (10)
NICU length of stay ≥ 48 hours	3 (30)	0
Respiratory Distress Syndrome	2 (20)	1 (10)

^#None of the comparisons between the two groups is statistically significant (P > 0.05)

^aThis subject developed preeclampsia and was delivered at 35^3/7 weeks because of spontaneous preterm labor and history of prior classical cesarean delivery. She received magnesium sulfate and on discharge had normal blood pressure. She then presented 7 days after delivery with elevated blood pressure and was diagnosed with postpartum preeclampsia.

^bThree patients were delivered at 33^6/7, 34^3/7, and 35^2/7 for preeclampsia with severe features, one patient was delivered at 36^1/7 for worsening gestational hypertension and history of classical cesarean delivery, and one patient was delivered at 35^4/7 for placenta previa.

^cOne patient was delivered at 35^5/7 weeks for worsening chronic hypertension

^dLength of hospital stay was for the hospitalization resulting in delivery.

NICU=neonatal intensive care unit

Figure 1.

Longitudinal plots of serum concentrations of soluble fms-like tyrosine kinase (Panel A; sFlt-1), soluble endoglin (Panel B; sEng), and placental growth factor (Panel C; PlGF) within individual subjects who received pravastatin (n=10, red) or placebo (n=10, blue) according to the gestational age window at time of collection: 12^0/7–16^6/7 weeks (baseline and before treatment), 24^0/7–27^6/7, and 34^0/7–36^6/7.

Δ designates the subjects who developed preeclampsia.

Birthweight was similar between the 2 groups. One infant in the placebo group was diagnosed as small for gestational age. Five infants born to women in the placebo group were admitted either to an intermediate nursery (n=2) or NICU (n=3) compared with two in the pravastatin group (intermediate nursery [n=1] and NICU [n=1]; Table 4). None of the newborns in either group failed their auditory brainstem response evoked potential or similar hearing screening tests. Of note, eight of 10 women in both groups breast fed or provided breast milk to their newborns.

Maternal total cholesterol (TC) and low density lipoproteins (LDL) were similar at baseline, but lower in subjects receiving pravastatin compared with placebo in the second trimester (TC 188.6±31 vs 230±48.3 mg/dL and LDL 81.1±20.9 vs 124.1±42 mg/dL) and in the third trimester (TC 201.7±33.5 vs 250±25.3 mg/dL, P=0.02, and LDL 85.6±25.7 vs 126.1±44.4 mg/dL; Supplementary Table 1). Despite the decrease in maternal TC and LDL, cord blood concentrations of TC and LDL were similar between the pravastatin- and placebo-exposed fetuses (TC: 56.2±11.5 vs 63.9±18.8 mg/dL and LDL 28.2±10.2 vs 31.8±13.3 mg/dL). There were no differences in other cord blood parameters assayed (Supplementary Table 3).

Comment

This pilot RCT provides preliminary safety and PK data regarding the use of pravastatin, a drug traditionally avoided in pregnancy, for preventing preeclampsia, a pregnancy complication with serious morbidity. Initiation and completion of this trial was a direct result of collaboration between the NICHD–OPRU network and FDA. Although the data are preliminary, no identifiable safety risks were associated with the use of pravastatin at a dose of 10 mg in this cohort of high-risk pregnant women, with strong signals for possible efficacy (lower rates of preeclampsia and indicated preterm delivery and a maternal pro-angiogenic profile). The lack of a reduction in cholesterol concentration in the fetuses exposed to pravastatin is reassuring. This favorable risk-benefit analysis justifies continued research using pravastatin in a larger clinical trial with dose escalation.

Pravastatin classification as a Category X medication was due to a lack of indications that warranted its use during pregnancy rather than for observed risk. An increased risk of congenital malformations has not been demonstrated in multiple cohorts of subjects exposed to pravastatin during pregnancy (21–26). In this trial, pravastatin was started in the second trimester (i.e., after completion of organ formation), and the rate of anomalies was similar between subjects receiving pravastatin or placebo. Additionally, despite maternal concentrations of TC and LDL being reduced in the second and third trimesters with pravastatin use, neither cord blood TC and LDL concentrations nor infant birthweight differed between the 2 groups. These findings support prior studies that showed independence of fetal cholesterol concentrations from maternal cholesterol levels or diet (27, 28). The pattern and rates of AEs and serious AEs in our study are consistent with data from prior large pravastatin trials in nonpregnant women and men (29), suggesting that pregnancy does not adversely affect the occurrence of these AEs.

Although not statistically significant, a 10-mg dose of pravastatin was associated with favorable pregnancy outcomes including lower rates of preeclampsia, indicated preterm delivery, and neonatal admissions to intermediate nurseries or NICU, as well as improved pro-angiogenic profile (lower sFlt-1, sEng, and higher PlGF). The high rate of preeclampsia recurrence in the placebo group is consistent with prior studies (4,5). The exact mechanism of how pravastatin may prevent preeclampsia is unknown but is thought to be associated with pravastatin’s ability to reverse the pregnancy-specific angiogenic imbalance and oxidative and inflammatory stress and to restore global endothelial health (19). The ability of pravastatin to restore the angiogenic balance is also being tested in a proof of concept “StAmP trial” in the UK (Statins to Ameliorate early onset Preeclampsia; www.controlled-trials.com; ISRCTN23410175)

Pravastatin’s reassuring data with its use in human pregnancy and in animal models were not unexpected. Pravastatin is one of the most hydrophilic statins and is a substrate for the efflux transporters P-glycoprotein and multidrug resistance-associated protein 2 (MRP2), which would potentially limit its transplacental transfer (30–32). Consistent with these characteristics, recent transplacental studies have shown that the clearance of pravastatin in third-trimester placentas was higher in the fetal-to-maternal than the maternal-to-fetal direction (32). In this study, the majority of umbilical cord and maternal pravastatin concentrations at delivery were below the lower limit of quantification of the assay (<0.1 ng/mL). Only 2 subjects had measurable concentrations in the umbilical cord plasma (Supplementary Table 2), which may also be related to the low dose of pravastatin used in this study and its short apparent half-life.

Postpartum values for pravastatin CL/F, renal clearance, AUC, half-life_initial, C_max, T_max, and fraction of dose excreted unchanged in the urine are consistent with those previously reported in nonpregnant subjects (33,34). Although significance was not reached because of the small sample size, there is a strong trend toward an increase in CL/F and a decrease in pravastatin AUC in pregnancy compared with postpartum. As expected, the renal clearance of pravastatin was significantly increased during pregnancy consistent with the increased glomerular filtration as measured by creatinine clearance, accounting for some of the variability. In addition, the net renal secretion clearance was also increased in pregnancy, likely because of changes in active transport by renal excretory transporters such as P-glycoprotein, MRP2, BCRP or renal uptake transporters such as OAT3 and OAT1 (31, 32, 35). The PK parameters of 3’α-isopravastatin, a major metabolite of pravastatin with only 1/10^th to 1/40^th of its HMG-CoA reductase inhibition (30), are reported in Supplementary Table 4.

Because to our knowledge this is the first preeclampsia prevention trial using statins, it was designed to have multiple layers of safety including being conducted under an IND, use of an independent medical monitor who reviewed all serious AEs in real time, oversight by a data safety monitoring board that reviewed all AEs and serious AEs quarterly, and use of well-defined criteria to withdraw subjects or stop the study. Maternal, fetal, and neonatal safety was determined using clinical and laboratory outcomes at multiple time points. An independent panel, blinded to study drug allocation, reviewed the preeclampsia outcomes. At the recommendation of FDA, we were limited by our sample size, which prevented us from conducting subgroup and other more detailed analyses. In addition, our study does not have the power to detect differences in individual outcomes such as congenital anomalies or other clinical or safety outcomes of low prevalence. Other limitations include the use of a low dose of pravastatin (10 mg/day) and the short-term follow-up for subjects and infants included in this report. Infant follow-up is planned at 5 years of age, and subjects’ contact information is updated regularly to facilitate long-term follow-up.

Conclusion

This study provides preliminary safety and pharmacokinetic data regarding the use of pravastatin for preventing preeclampsia in high-risk pregnant women. Although the data are preliminary, no identifiable safety risks were associated with pravastatin use in this cohort. This favorable risk-benefit analysis justifies continued research with dose escalation in a future larger clinical trial to evaluate pravastatin’s effectiveness in preventing preeclampsia. Finally, collaboration between NICHD and FDA was essential for the success of this trial.