A Proof of Principle Randomised Placebo-Controlled Trial for Use of Statins to Ameliorate Early Onset Preeclampsia

Preeclampsia (PE) is a potentially dangerous condition of pregnancy in which the mother?s blood pressure is higher than normal and there is protein in the urine. About 1 in 100 women experience preeclampsia before 32 weeks of pregnancy. The only effective treatment is to deliver the baby prematurely, but this has serious consequences for the baby. Watchful waiting, often employed clinically to allow the baby?s lungs to mature, risks progression of disease severity in the mother. A cheap and effective therapy for prevention of preeclampsia complications is urgently needed.

It is not known what causes preeclampsia but recently some blood molecules (called anti-angiogenic factors) known to affect blood flow are higher in women with PE. These anti-angiogenic factors when given to pregnant animals mimic preeclampsia. Drugs called statins, which lower cholesterol, reduce the levels of these molecules. It is not known whether statins can reduce the severity and complications of preeclampsia.

We will test the idea that statins can reduce these molecules in preeclamptic women before 32 weeks of pregnancy and decrease the severity of preeclampsia. Doctors from six hospitals will seek consent from these women. Those who are suitable and agree, will be randomly divided into two groups. One group will get a daily dose of statin. The other will get a dummy sugar pill (placebo). We hope to recruit 128 women. Neither the women nor their doctors will know what group they are in. In this way, we can be confident that any differences between the two groups are due to treatment. Women will stay in hospital and be closely monitored, and if the preeclampsia gets worse, their baby will be delivered.

This trial is unique because it is the first to test whether statins can reduce the severity of preeclampsia and because statins are not prescribed normally to pregnant women. There is some concern that statins may cause congenital defects in the baby, but we have found no convincing evidence to support this. Furthermore, we believe it is safe to give statins later in pregnancy once the baby?s organs have already developed. However, all side effects and complications will be closely monitored.

If this small trial shows that the severity of preeclampsia is reduced, and there are few side effects, a bigger trial will be organised to determine if statins can increase the length of pregnancy and reduce the number of premature deliveries.

Preeclampsia (PE) is a systemic endothelial disease characterised by hypertension, proteinuria, exacerbated inflammation, dysregulated angiogenesis and can lead to morbidity and mortality in both mother and baby. Currently the only effective treatment for PE is delivery of the baby. However, early delivery, especially before 32 weeks gestation, often has serious consequences for the health of the baby. A cheap and effective therapy for prevention of PE complications is urgently needed. Increasing evidence shows that excess circulating soluble Flt-1 (sFlt-1) plays a role in the pathogenesis of PE. We showed that statins (HMG-CoA reductase inhibitors), a class of lipid-lowering drugs, inhibit cytokine-mediated release of sFlt-1 in ex vivo human placental model. This IES platform will test the hypothesis that statin use during early onset PE would lead to a significant reduction of sFlt-1 and alleviate the severity of PE. We will undertake a proof of principle randomised placebo-controlled multi-centre RCT trial for use of statins to ameliorate early onset PE. A minimum of 128 pregnancies will be randomised from six maternity units in the UK. Minimum inclusion clinical criteria will be gestational age range of 24-32 weeks with new onset hypertension; systolic 140mmHg and diastolic 90mmHg; Protein/creatinine ratio 30mg/mmol or 300mg proteinuria/24 hours. Consenting mothers will be randomised to receive either 40mg pravastatin capsules once a day or identical placebo until delivery with conservative management of their PE. The primary outcome measures will be changes in plasma levels of biomarkers (sFlt-1/sEng/PlGF). Secondary outcomes measures will be severity of PE, prolongation of pregnancy post treatment, maternal and neonatal outcomes and adverse effects. We will also formally assess the feasibility of a definitive trial by examining recruitment rates, compliance and physcian and patient readiness for randomisaiton to statins. This study will identify a novel intervention based on strong scientific rationale, which will inform a future large-scale multi-centre randomised trial.