Calcium supplementation for prevention of pre-eclampsia in high-risk women: study protocol for a randomised triple-blind placebo-controlled trial (CaPE)

Abstract Background Pre-eclampsia is a multisystem disorder affecting 2.8% of pregnancies in the UK. It usually presents after 20-week gestation with new-onset high blood pressure and proteinuria. Complications include eclampsia, stroke, and HELLP syndrome for the mother and preterm birth, fetal growth restriction, and stillbirth for the baby. Delivery is the only definitive cure, with antenatal care focusing on early detection and management of complications and optimising timing of delivery. Previous studies have shown calcium supplementation may reduce the risk of pre-eclampsia, but findings are driven by large effects seen in small trials that have not been replicated in larger trials. Subgroup analysis suggests benefits may only be seen in women with low dietary calcium intake, so findings may not be applicable to populations with adequate dietary calcium. Although the largest benefits appear to be in high-risk women, data are very limited, with no large trials conducted. Methods CaPE is a two-arm parallel triple-blinded, placebo-controlled, multicentre, superiority randomised controlled trial testing the hypothesis that in pregnant women at increased risk, calcium supplementation is effective in reducing the occurrence of pre-eclampsia. The study will recruit 7756 women from approximately 60 obstetric units in hospitals across the UK. Women with a confirmed viable pregnancy, with gestation 22 + 0 weeks or less and deemed eligible for aspirin therapy based on either NICE guideline criteria (at least one high-risk factor or two or more moderate risk factors) or the Fetal Medicine Foundation (FMF) algorithm will be eligible to be randomised in a 1:1 ratio to receive either 2 g per day of calcium supplementation or placebo taken from 12 to 22 weeks, up to birth. The primary outcome is clinician diagnosis of pre-eclampsia, based on the ISSHP definition. Key secondary outcomes are severe pre-eclampsia index and preterm birth < 37 weeks; other secondary outcomes include the Pre-eclampsia Core Outcome Set (COS). Discussion Calcium supplementation in high-risk women is an attractive intervention due to its potential efficacy, low cost, and safety profile, but a definitive trial is required to confirm benefits. Trial registration ISRCTN 12033893. Registered on 25 May 2021.