Pravastatin for Prevention of Preeclampsia

Preeclampsia shares pathogenic similarities with adult cardiovascular diseases as well as
many risk factors. Endothelial dysfunction and inflammation are fundamental for the
initiation and progression of both. There is strong evidence that
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are beneficial
in primary and secondary prevention of cardiovascular mortality and other cardiovascular
events. Biological plausibility as well as animal data supports a similar role for statins in
preeclampsia.

Currently, there are no clinically available agents to prevent preeclampsia. However because
of the below properties of statins, this class of medications could substantially contribute
to preeclampsia prevention.

1. Statins pleiotropic actions on various mechanisms: reversing the angiogenic imbalance by
upregulating vascular endothelial growth factor (VEGF) and placental growth factor
(PlGF), and reducing the antiangiogenic factors such as soluble fms-like tyrosine
kinase-1 (sFlt-1) and soluble endoglin (sEng).

2. Statins up regulation of endothelial nitric oxide synthase, leading to improved nitric
oxide production in the vasculature and to activate the heme oxygenase-1/carbon monoxide
(HO-1/CO) pathway, protecting the endothelium and reducing the inflammatory and
oxidative insults.

The purpose of this pilot study is to evaluate the maternal-fetal safety and pharmacokinetic
(PK) profiles of pravastatin when used in pregnant women at high-risk of developing
preeclampsia.

Inclusion Criteria:

Documented history (review of chart or delivery note) of prior severe early onset PE in a
prior pregnancy and requiring delivery ≤340/7 weeks' gestation. If in the index pregnancy,
the woman was induced at the upper limit of 34 0/7 weeks of pregnancy and delivered within
48 hours in the same hospitalization, that woman could be enrolled. Women with severe PE in
a pregnancy remote (greater than 2 pregnancies removed) from the current pregnancy do not
qualify.

- 18 years or older with the ability to give informed consent

- Singleton pregnancy

- Normal serum transaminase (ALT and AST) concentrations in the last 6-months

- Gestational age (GA) between 12 weeks 0 days to 16 weeks 6 days based on clinical
information and confirmed by an ultrasound per study procedures.

- Willingness to participate in planned PK study visits

Exclusion Criteria:

Known chromosomal, genetic, or major fetal malformations, fetal demise, or planned
termination

- Patients with contraindications for statin therapy:

- Hypersensitivity to pravastatin or any component of the product

- Active liver disease (acute hepatitis, chronic active hepatitis, persistently abnormal
liver enzymes (2 x normal of serum transaminases)

- History of myopathy or rhabdomyolysis

- Patients with any of the following conditions:

- HIV positive

- Status post solid organ transplant

- Chronic renal disease/insufficiency with baseline serum creatinine ≥1.5 mg/dL

- Uterine malformations (didelphus, bicornuate, unicornate)

- Cancer

- Statin use in current pregnancy

- Current use of medications with potential drug interactions with statins, such as
cyclosporine, fibrates, gemfibrozil, niacin, erythromycin, fluconazole, itraconazole,
cholestyramine, digoxin, rifampin (patients will not be excluded if the drug has been
discontinued, or is prescribed for a short duration of time)

- Participating in another intervention study that influences the outcomes of this study

- Plans to deliver in a non-network site