Studies looking at pravastatin for preeclampsia prevention

In the United States, preeclampsia affects 3%-5% of all pregnancies and 10%-20% of pregnancies complicated by diabetes. Up to 20% of maternal deaths in the United States – and a much larger percentage of maternal deaths worldwide – occur in women with the condition, as do numerous maternal and fetal comorbidities. These include severe hypertension, pulmonary edema, stroke, and kidney and liver injury in the mother, and stillbirth, placental abruption, growth restriction, and premature delivery of the fetus.

Longer-term complications for the offspring include chronic lung disease, hearing and vision disorders, cerebral palsy and other neurodevelopmental disorders, and – as shown by more recent research – poor cardiovascular and metabolic outcomes.

Preeclampsia predisposes the mother to at least a twofold increased risk of future heart disease, compared with a woman who does not have the condition. In addition, women with preeclampsia who deliver at term are approximately two times more likely to die prematurely from heart disease than women without a history of preeclampsia, and those who deliver before 34 weeks’ gestation have been shown to have a ninefold greater risk of premature death. The American Heart Association, in fact, now includes preeclampsia in its list of heart disease risk factors.

Dr. Maged Costantine

Much attention now is focused on statins (inhibitors of HMG-CoA reductase), which have been used for more than 30 years for the primary and secondary prevention of heart disease. The properties and mechanisms of this class of drugs – and the similarities in the pathophysiology of cardiovascular disease and preeclampsia – make statins a plausible candidate for preeclampsia prevention. Thus far, data from preclinical work and subsequent pilot studies have been encouraging.

The commonalities

Preeclampsia is unique to pregnancy, but its pathophysiology and risk factors largely overlap with those of adult atherosclerotic cardiovascular disease. The exact pathophysiology of preeclampsia is unknown, but it is generally agreed that angiogenic imbalance and endothelial dysfunction play key roles, as do associated inflammation and oxidative stress.

Women with preeclampsia have been shown, for instance, to have had increased levels of antiangiogenic factors (soluble FMS-like tyrosine kinase 1 and soluble endoglin) and decreased levels of angiogenic factors (vascular endothelial growth factor and placental growth factor) prior to developing the condition clinically. Risk factors common to both preeclampsia and heart disease include chronic hypertension, dyslipidemia, diabetes or insulin resistance, obesity, and a family history of the condition.

Statins, meanwhile, have been shown to prevent or reverse angiogenic imbalance by promoting the release of vascular endothelial growth factor and placental growth factor and by suppressing the production of soluble FMS-like tyrosine kinase 1 and soluble endoglin. The drugs also improve vascular relaxation and exhibit anti-inflammatory and antioxidative effects, thereby broadly improving endovascular health. In the cardiovascular arena, notably, men and women who have elevated inflammatory markers even without hypercholesterolemia have been shown to have improved cardiovascular outcomes with statin treatment.

In various mouse models of preeclampsia studied in the past decade, pravastatin, a hydrophilic statin, has had beneficial effects. Mice with the angiogenic imbalance characteristic of preeclampsia that received this statin have shown a reversal of the imbalance, as well as reduced blood pressure, increased levels of nitric oxide synthase production, decreased oxidative stress, improved vascular reactivity, decreased kidney damage and proteinuria, and other positive effects. These effects occurred without detrimental outcomes to the mice or any increase in the rates of anomalies or resorption in offspring (Clin Obstet Gynecol. 2017 Mar;60:161-8).

Moreover, in addition to ameliorating the preeclampsia phenotype, pravastatin use in these animal models has improved pregnancy outcomes and reduced rates of pregnancy losses.

Safety issues

So, can we use statins in pregnancy? When statins were originally marketed in the 1980s, they were labeled pregnancy category X, which means 1) that there is evidence of fetal abnormalities or risk and 2) that these risks clearly outweigh potential benefits.

This designation for statins was based largely on the second half of the definition (no benefit to outweigh any risk). In addition, there were theoretical concerns about the inhibition of cholesterol synthesis during embryologic development and about a small case series of the original lipophilic statins suggesting an increased risk of malformations. While pregnancy category X does not exist anymore, statins are still labeled as contraindicated in pregnancy.

Pravastatin is one of the safest statins to consider in pregnancy for several reasons: It is one of the most hydrophilic statins and is a substrate of the placental efflux transporters, such as P-glycoprotein; both of those properties limit its ability to cross the placenta. It also has a short-elimination half-life, is cleared through both hepatic and renal routes, and is among the most hepatoselective statins available (one of the weakest inhibitors of HMG-CoA reductase). Indeed, in vitro placental transfer studies suggest that pravastatin transfer is limited and slow and that clearance is significantly higher in the fetal-to-maternal direction than in the maternal-to-fetal direction.

Animal studies have demonstrated that pravastatin is not teratogenic and has no effect on placental weight, pup birth weight, and pup adult weight. Moreover, at least six published cohort studies of women with first-trimester exposure to statins (women who had been prescribed the drugs before becoming pregnant and who received the drugs in the first trimester before realizing they were pregnant) showed no patterns or increased rates of congenital anomalies, compared with women without exposure to known teratogens. Additionally, these cohorts did not show any associations with miscarriage or fetal growth restriction (Obstet Gynecol. 2013 Feb;121:349-53).

A more recent cohort study of close to 900,000 women – of which 1,152 women used a statin (pravastatin or other statins) during their first trimester – similarly found no significant increases in any type of congenital malformation, compared with other completed pregnancies in the larger cohort. Notably, the analysis of this cohort was done using propensity score–based methods to control for potential confounders, including prepregnancy conditions that prompted use of a statin (BMJ. 2015;350:h1035).

A drawback to this body of research is that, with the exception of the BMJ study, the cohorts have been generally small; furthermore, in keeping with current recommendations, most of the statin-exposed patients discontinued use of the drugs upon confirmation of their pregnancies, thereby leaving the effects of long-term use unknown.