Background
Preeclampsia complicates approximately 3–5% 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 US 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, nonanomalous 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 10 to placebo completed the trial. There were no differences between the 2 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 with postpartum. Four subjects in the placebo group developed preeclampsia compared with 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 the time of delivery were below the lower limit of quantification of the assay. Pravastatin use was associated with a more favorable pregnancy angiogenic profile.
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 using pravastatin in a larger clinical trial with dose escalation.
Preeclampsia is a multisystem disorder that complicates 3-5% of pregnancies and remains a major cause of maternal, fetal, and neonatal morbidity and mortality. 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.
Preeclampsia is associated with serious short- and long-term maternal and neonatal morbidities, and its recurrence in subsequent pregnancies depends on the presence of risk factors (eg, diabetes, hypertension, and multifetal gestation) and the severity and time of onset of preeclampsia in a prior pregnancy.
Despite being unique to pregnancy, preeclampsia shares pathogenic similarities and many risk factors with adult cardiovascular disease. Endothelial dysfunction and inflammation are fundamental for the initiation and progression of both atherosclerosis and preeclampsia. Numerous attempts at primary and secondary prevention of preeclampsia, using various supplements and medications, have had limited success. Only low-dose aspirin was found to have a modest benefit in reducing the rate of preeclampsia in an individual patient metaanalysis, and that benefit was achieved only 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. Moreover, statins have been used 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.
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 US Food and Drug Administration (FDA), we undertook a pilot randomized controlled trial 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. 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 old or older, with singleton, nonanomalous 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 (eg, hypersensitivity to pravastatin, recent or active liver disease); concomitant therapy with fibrates, niacin, cyclosporine, clarithromycin, or erythromycin; pregestational diabetes mellitus; human immunodeficiency virus 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 Network at 5 clinical center sites as an FDA-approved investigational new drug study (IND; number 114205). 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 number NCT01717586 ).
Study design and intervention
Before randomization, all participants were documented to have normal liver transaminases (aminotransferase [AST] and aspartate aminotransferase [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 (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 up 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 data coordinating center, 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 after the 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 1-10th to 1-40th as potent as parent drug in inhibiting HMG-CoA reductase) concentrations in plasma at times: before the 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 before the dose, and then all urine over 1 dosing interval was collected as follows: 0–4, 4–8, 8–12, and 12–24 hours following the 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 supplemental materials ).
Outcome variables
The primary outcomes were the maternal-fetal safety and the 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 ( supplemental 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 antiangiogenic 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 (see supplemental material ), and the diagnosis (or absence) was confirmed by a panel of 3 maternal-fetal medicine physicians, blinded to treatment assignment, who reviewed the deidentified 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 antiangiogenic markers, steroidogenic hormones (thyrotropin, follicle-stimulating hormone, luteinizing hormone, estradiol, and total testosterone), and S100B and neuron specific enolase, 2 nonspecific markers of neurological 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 χ 2 or Fisher exact test as appropriate. Biomarker concentrations were analyzed as continuous variables. Steady-state pravastatin PK parameters were estimated using standard noncompartmental techniques and normalized using actual body weights (see supplemental material ). PK parameters during pregnancy were compared with those postpartum using a 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 the FDA as part of the IND approval process and was not intended to achieve power to detect hypothetical differences in primary or secondary clinical outcomes or other laboratory values. A value of P < .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 ( Supplemental 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% vs 95.9%).
At study entry, there were no differences in baseline characteristics such as gestational age at delivery in prior qualifying pregnancy and the percentage of subjects receiving low-dose aspirin. Although statistically nonsignificant, more subjects in the pravastatin group were obese ( Table 1 and Supplemental Figure 2 ).
| Characteristic | Placebo group a (n = 10) | Pravastatin group a (n = 11) |
|---|---|---|
| Race b | ||
| White | 9 | 10 |
| African American | 1 | 0 |
| Asian | 0 | 0 |
| American Indian | 0 | 1 |
| Ethnicity b | ||
| Hispanic | 7 | 5 |
| Non-Hispanic | 3 | 6 |
| Age, y | 30 [27, 34] | 27 [21, 34] |
| Body mass index, kg/m 2 | 29.6 [27, 32.3] | 36 [26, 38.2] |
| Obesity c | 4 (40) | 8 (72.7) |
| Systolic blood pressure at entry to care, mm Hg d | 115 [110, 122] | 109 [107, 131] |
| Diastolic blood pressure at entry to care, mm Hg d | 68 [64, 72] | 64 [55, 77] |
| Parity e | 2 [2, 3] | 1 [1, 2] |
| Gestational age at randomization, wks | 14.9 [13.4, 16.4] | 13.9 [13.3, 16.1] |
| Gestational age at delivery in prior pregnancy, wks | 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) |
a None of the comparisons between the 2 groups is statistically significant ( P > .05)
b Race and ethnicity were self-reported by patients
c Obesity is defined as body mass index of ≥ 30 kg/m 2 using prepregnancy weight
d Blood 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
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 Supplemental Table 1 ). None of the participants discontinued their study medication.
| Condition | Placebo group a (n = 10) | Pravastatin group a (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 |
| Rhabdomyolysis b | 0 | 0 |
| Liver injury b | 0 | 0 |
| Congenital anomalies | Polydactyly c Ventriculomegaly | Hypospadias c Coarctation of aorta |
| Hospitalization > 24 h | ||
| 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) |
a None of the comparisons between the 2 groups is statistically significant ( P > .05)
b Rhabdomyolysis was defined as muscle pain or muscle weakness in conjunction with increase in 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 3 times the upper limit of normal. Data on maternal AST, ALT, and CK concentrations are in Supplemental Table 1
c Family history of polydactyly and hypospadias in the father of each child, respectively.
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.
Pravastatin C max , T max , AUC, T 1/2 , percentage of the dose excreted unchanged as parent drug, and CL/F were not significantly different between the 3 time periods ( Table 3 ). The average steady-state concentration-time profiles are depicted graphically in Supplemental Figure 3 .
| Parameter | 18–24 wks gestation (n = 11) | 30–34 wks gestation (n = 10) | 4–6 mo postpartum (n = 9) |
|---|---|---|---|
| C max , ng/mL | 14.9 ± 11.3 | 11.1 ± 6.2 | 17.2 ± 11.5 |
| T max , h | 1.6 ± 0.6 | 1.5 ± 0.4 | 1.6 ± 1.0 |
| Half-life apparent , h | 2.1 ± 0.9 | 3.0 ± 1.6 | 2.4 ± 1.3 |
| CL/F, L/h | 396 ± 190 | 389 ± 215 | 289 ± 142 |
| CL/F, L/h/kg | 4.6 ± 2.4 | 4.2 ± 2.0 | 3.2 ± 1.5 |
| AUC (0-24) , ng/h/mL | 31 ± 16 | 32 ± 16 | 43 ± 20 |
| Amount excreted (0-24 h) , mg | 0.98 ± 0.60 | 1.04 ± 0.57 | 0.93 ± 0.60 |
| Percent excreted unchanged | 10 ± 6 | 10 ± 6 | 9 ± 6 |
| CL renal , L/h | 34 ± 16 a | 34 ± 11 a | 23 ± 4 |
| CL secretion , mL/min | 480 ± 273 a | 471 ± 151 a | 325 ± 65 |
a P < .05, second and third trimester compared with postpartum.
For subjects in whom we were able to quantify the 24 hour postdose concentration, pravastatin appears to exhibit a 2-compartment PK model. The apparent half-life of pravastatin based on concentration data until 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 postdose 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 an 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 the time of delivery, pravastatin concentrations were below the limit of quantification of the assay ( Supplemental Table 2 ).
Four subjects in the placebo group developed preeclampsia (with 3 of 4 having severe disease) compared with none in the pravastatin group. There were 5 indicated preterm deliveries before 37 weeks in the placebo group compared with 1 in the pravastatin group. ( Table 4 ) Other obstetric outcomes were similar between the 2 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 4 women in the placebo arm who developed preeclampsia had the highest sFlt-1 concentrations near term ( Figure and Supplemental Table 1 ).
| Outcomes | Placebo group a (n = 10) | Pravastatin group a (n = 10) |
|---|---|---|
| Maternal outcomes | ||
| Preeclampsia | 4 (40) | 0 (0) |
| Severe features | 3 | 0 |
| Postpartum preeclampsia | 1 (10) b | 0 (0) |
| Gestational hypertension | 1 (10) | 1 (10) |
| Gestational age at delivery, wks | 36.7 ± 2.1 | 37.7 ± 0.9 |
| Indicated preterm delivery less than 37 wks | 5 (50) c | 1 (10) d |
| Indicated preterm delivery less than 34 wks | 1 (10) | 0 (0) |
| Blood transfusion | 1 (10) | 1 (10) |
| Length of hospital stay, d e | 4 [3–7]; range, 2–43 | 3 [3–4]; range, 1–6 |
| Neonatal outcomes | ||
| Birthweight, g | 2877 ± 630 | 3018 ± 260 |
| Highest level of care | ||
| Well-baby/routine | 5 (50) | 8 (80) |
| Intermediate (level 2) | 2 (20) | 1 (10) |
| NICU | 3 (30) | 1 (10) |
| NICU length of stay ≥ 48 h | 3 (30) | 0 |
| Respiratory distress syndrome | 2 (20) | 1 (10) |
a None of the comparisons between the 2 groups is statistically significant ( P > .05)
b This subject developed preeclampsia and was delivered at 35 3/7 weeks because of spontaneous preterm labor and a 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
c Three patients were delivered at 33 6/7 , 34 3/7 , and 35 2/7 for preeclampsia with severe features, 1 patient was delivered at 36 1/7 for worsening gestational hypertension and history of classical cesarean delivery, and 1 patient was delivered at 35 4/7 for placenta previa
d One patient was delivered at 35 5/7 weeks for worsening chronic hypertension
e Length of hospital stay was for the hospitalization resulting in delivery.
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