Pravastatin to Ameliorate Early Onset Preeclampsia: Promising but not there yet

In this issue, Ahmed at al. (BJOG 2019;https://doi.org/10.1111/1471-0528.16013) reported the results of the Statins to Ameliorate early onset Preeclampsia (StAmP) trial that was conducted in the UK between 2011-2014, and randomized women with preeclampsia between 24⁰ and 31⁶ weeks to either pravastatin (40 mg; n=30) or placebo (n=32). The primary outcome was the mean concentration of soluble FMS-like Tyrosine Kinase (sFlt-1) during the first three days post randomization. While it did not show any significant reductions in sFlt-1, or improvement in clinical outcomes, the StAmP had some limitations. These included slow recruitment (average of 1.4 participants per hospital per year), low compliance with study medication, timing of the primary outcome, and overoptimistic sample size assumptions. In addition, with the large variance in sFlt-1 concentrations, the trial was underpowered. Despite the negative results and limitations, the trial confirmed several findings that support the safety of pravastatin use in high-risk pregnancies. These included the following: 1) pravastatin was not associated with reduction in birthweight or head circumference, 2) adverse neonatal outcomes appeared to be less common in women who received pravastatin, with no perinatal death in the pravastatin group compared with 3 (9%) in the placebo group, and lower rates of necrotizing enterocolitis and retinopathy of prematurity, 3) no maternal serious adverse events, typically associated with statin use, such as myopathies or liver injury, were reported, and 4) the mean drug concentration in cord blood was 0.84±1.05 ng/ml (lowest level of quantification of the assay, (LLOQ) = 0.88 ng/ml) and 14/18 fetuses exposed to pravastatin (with cord blood samples available) had drug concentrations <LLOQ in their cord blood. This supports the limited transplacental transfer of pravastatin and that the drug is not being concentrated in the fetus, and is similar to what was demonstrated in a pilot U.S. randomized prevention trial by Costantine et al. (AJOG,2016;214:720e.1-7) in which the majority of fetuses born to high-risk women who received pravastatin 10 mg during pregnancy, had drug concentrations in the cord blood below the LLOQ of the assay.

In contrast to the StAmP trial, a study by Lefkou et al. (J Clin Invest,2016;126:2933-40) in a cohort of women with antiphospholipid syndrome showed that the addition of pravastatin 20 mg daily to the standard of care, in women who developed preeclampsia or fetal growth restriction, improved pregnancy and neonatal outcomes. The StAmp trial results are also different from the U.S. pilot prevention trial that demonstrated improved pregnancy outcomes and a favorable angiogenic profile with the use of pravastatin.

We have come a long way from the time when giving statins to pregnant women was considered a taboo. The accumulating evidence regarding safety of pravastatin is reassuring, and undermines the old concerns on its teratogenicity or safety in pregnancy. This may be one of the reasons for the recent proliferation of trials of pravastatin for prevention of preeclampsia. While the lack of efficacy in the StAmP trial may be secondary to the study limitations, this should not impact the prevention trials since a medication may still be effective as a prevention strategy when it is not as effective as a treatment (e.g. aspirin for preeclampsia and progesterone for preterm birth). The data from the StAmP trial are encouraging in that they did not raise any safety concerns. While there is no evidence for clinical use at this point, it supports the ongoing research of using pravastatin to prevent preeclampsia.