Calcium supplementation for prevention of pre-eclampsia: a systematic review and individual participant data meta-analysis of randomised trials

Background Pre-eclampsia is a major cause of maternal and perinatal deaths globally, and calcium supplementation is recommended to reduce this risk in populations with low dietary calcium intake. However, the optimal timing, dose, and overall effectiveness across populations remain unclear. We aimed to assess the effects of calcium supplementation on pre-eclampsia and related outcomes using individual participant data (IPD) meta-analysis, and establish whether these vary by maternal or intervention characteristics, including dose and timing of supplementation. Methods In this systematic review and IPD meta-analysis, we searched Embase, CINAHL, MEDLINE, CENTRAL, PubMed, Scopus, AMED, LILACS, POPLINE, AIM, IMSEAR, ClinicalTrials.gov, and WHO ICTRP, from inception to Dec 16, 2025, using search terms related to pregnancy, calcium supplementation, and randomised trials, for randomised trials on calcium supplementation started before or during pregnancy. Authors were contacted to share IPD. Our primary outcomes were pre-eclampsia and early-onset pre-eclampsia. We performed a two-stage IPD random-effects meta-analysis to obtain summary estimates (odds ratios [ORs]) and 95% CIs for the intervention and subgroup effects, examined non-linear treatment–covariate interactions for continuous covariates using restricted cubic splines, and assessed heterogeneity with between-study variance (τ 2 ) with its associated 95% CI and small-study effects with contour-enhanced funnel plots for analyses containing ten or more trials. This study is registered with PROSPERO (CRD42021231276). Findings We screened 602 articles, with 46 trials (33 516 women) being identified as potentially eligible. Seven trials shared IPD (16 828/17 861 women, 94%) from Argentina, Egypt, The Gambia, India, Iran, Mexico, Peru, South Africa, the USA, and Zimbabwe. In a meta-analysis of the IPD trials, there was no clear evidence of a reduction in pre-eclampsia (OR 0·89, 95% CI 0·73–1·07, τ 2 =0·00, p=0·43; 5 trials, 14 763 women) or early-onset pre-eclampsia (OR 0·90, 95% CI 0·25–3·27, τ 2 =0·14, p=0·093; 3 trials, 13 413 women), with results consistent with no effects of calcium supplementation. Gestational age at start of supplementation showed a significant non-linear interaction with treatment effects in the IPD. When calcium supplementation was started at 10 weeks' gestation, the estimated OR for pre-eclampsia comparing calcium with control was 0·65 (95% CI 0·48–0·90). Effects did not vary by participant-level (maternal age, BMI, parity, or maternal risk factors) or trial-level characteristics (population dietary calcium intake, calcium dose, adherence, or population risk status). Interpretation In the IPD meta-analysis, calcium supplementation in pregnancy did not reduce the risk of pre-eclampsia. The observed risk reduction by the addition of aggregate data from smaller studies could be attributed to small-study effect bias. There is potential for calcium to prevent pre-eclampsia when started early in pregnancy, particularly in the first trimester as observed in the IPD meta-analysis. Future research should focus on earlier initiation of calcium supplementation and strategies to improve calcium intake early in pregnancy. Funding UK Research and Innovation Medical Research Council, UNDP–UN Population Fund–UNICEF–WHO–World Bank Special Programme of Research, Development and Research Training in Human Reproduction, US National Institute for Health and Care Research.