Calcium Supplementation for Prevention of Pre-eclampsia in High Risk Women: CaPE Trial

Research question: HTA commissioned call to investigate the clinical and cost-effectiveness of calcium supplementation plus usual care compared with usual care alone in women at high risk of pre-eclampsia. Background: epidemiological studies and RCTs suggest calcium may reduce risk of pre-eclampsia. However, most studies have been conducted in populations with low dietary calcium intake, so findings have not been viewed as applicable to a population with adequate calcium intake, such as in the UK. Moreover, little research has focused on impact of calcium on women at high risk of pre-eclampsia. Primary objective: (1) to determine whether calcium during pregnancy plus usual care (including aspirin) is more effective than usual care alone in reducing risk of pre-eclampsia in high risk women. Secondary objectives: to assess (1) impact on other important outcomes for mother and baby; (2) cost-effectiveness (3) adherence (4) which subgroups would benefit most. Design: randomised, triple-masked, placebo-controlled multi-centre trial in 40 maternity units across the UK, with a 12 month internal pilot and a health economic evaluation. Central randomisation in 1:1 ratio, with minimisation. Participants: women at high risk of pre-eclampsia, deemed eligible for aspirin based on NICE guideline criteria (single high risk factor or two or more moderate risk factors). Exclusions: contraindications to regular calcium intake, or any medication with potential severe interactions with calcium, use of calcium supplements or regular high dose Vitamin D. Intervention: Calcium 2 g/day commenced from 12 to 22 weeks’ gestation, taken until delivery, plus usual care (including aspirin) compared with placebo tablets plus usual care. Outcomes: based on Core Outcome Set and the commissioning brief. Primary: pre-eclampsia. Secondary: for the woman: death, eclampsia, stroke, cortical blindness, pulmonary oedema, acute kidney injury, liver capsule haematoma, abruption, postpartum haemorrhage, raised liver enzymes, low platelets, ITU admission, intubation, mechanical ventilation, gestational and severe hypertension, early onset pre-eclampsia <34 weeks, need for elective delivery, mode of delivery, composite morbidity, adverse effects. For the baby: death before hospital discharge, gestational age at delivery, birthweight, small for gestational age, admission to neonatal unit and level of care, number of admission days, neonatal brain injury syndromes, respiratory support, preterm birth <34 and <37 weeks, chronic lung disease, necrotising enterocolitis, intraventricular haemorrhage, retinopathy of prematurity, and composite neonatal morbidity/mortality. Follow up to hospital discharge or 40 weeks gestation plus four weeks, whichever is sooner. Health economic outcomes and consent for data linkage studies for long term outcomes. Sample size: 7756 women, to detect a 20% reduction in the occurrence of pre-eclampsia from 11.5% to 9.2% with 90% power (p=0.05), allowing for 5% loss to follow up. Timelines: 6 month set up, with 12 month pilot; site opening at 3/month through the pilot to around 34 sites. Main trial: further 22 months of recruitment from 40 sites; 8 months closing down for data collection, 6 months of analysis and reporting (total 4.5 years). Impact/dissemination: findings will have direct application to clinical practice. Results will be presented at conferences, published in a journal and made available via open source methods.