Pravastatin for early-onset pre-eclampsia: a randomised, blinded, placebo-controlled trial

Abstract

Objective: Women with pre-eclampsia have elevated circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1). Statins can reduce sFlt-1 from cultured cells and improve pregnancy outcome in animals with a pre-eclampsia-like syndrome. We investigated the effect of pravastatin on plasma sFlt-1 levels during pre-eclampsia.

Design: Blinded (clinician and participant), proof of principle, placebo-controlled trial.

Setting: Fifteen UK maternity units.

Population: We used a minimisation algorithm to assign 62 women with early-onset pre-eclampsia (24⁺⁰ -31⁺⁶ weeks of gestation) to receive pravastatin 40 mg daily (n = 30) or matched placebo (n = 32), from randomisation to childbirth.

Primary outcome: Difference in mean plasma sFlt-1 levels over the first 3 days following randomisation.

Results: The difference in the mean maternal plasma sFlt-1 levels over the first 3 days after randomisation between the pravastatin (n = 27) and placebo (n = 29) groups was 292 pg/ml (95% CI -1175 to 592; P = 0.5), and over days 1-14 was 48 pg/ml (95% CI -1009 to 913; P = 0.9). Women who received pravastatin had a similar length of pregnancy following randomisation compared with those who received placebo (hazard ratio 0.84; 95% CI 0.50-1.40; P = 0.6). The median time from randomisation to childbirth was 9 days (interquartile range [IQR] 5-14 days) for the pravastatin group and 7 days (IQR 4-11 days) for the placebo group. There were three perinatal deaths in the placebo-treated group and no deaths or serious adverse events attributable to pravastatin.

Conclusions: We found no evidence that pravastatin lowered maternal plasma sFlt-1 levels once early-onset pre-eclampsia had developed. Pravastatin appears to have no adverse perinatal effects.

Tweetable abstract: Pravastatin does not improve maternal plasma sFlt-1 or placental growth factor levels following a diagnosis of early preterm pre-eclampsia #clinicaltrial finds.

Keywords: Anti-angiogenic factor; double-blind; perinatal mortality; placebo-controlled; pravastatin; pre-eclampsia; randomised trial; statin.

Figure 1

Patient flow through the StAmP Trial. Compliance categorisation: Complete: took study drug all days before delivery or ceased on day of delivery. Partial: stopped taking study drug before delivery, or took study drug intermittently, but took study drug on days 1–3 from randomisation. Poor: took study drug for 0–2 days but pregnancy maintained ≥3days. Rapid delivery: took study drug for 0–2 days, pregnancy ended by day 3.

Figure 2

Repeated measures analysis of s‐FLT‐1, PlGF and sFLT‐1:PlGF during pregnancy and post‐randomisation, intention‐to‐treat analysis: (A) soluble FMS‐like tyrosine kinase‐1 (sFlt‐1); (B) placental‐derived growth factor (PlGF); (C) sFlt‐1:PlGF ratio. A mean is taken for each patient with any daily value within 1–3 days, 4–7 days and 8–14 days.