Calcium supplementation to prevent pre-eclampsia: protocol for an individual participant data meta- analysis, network meta-analysis and health economic evaluation

The UKRI Medical Research Council supports this work—Global Maternal and Neonatal Health grant number MR/T010185/1. This work is also funded by the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Sexual and Reproductive Health and Research (SRH), WHO. JPV is supported by the NHMRC Investigator grant.IntroductionLow dietary calcium intake is a risk factor for pre-eclampsia, a major contributor to maternal and perinatal mortality and morbidity worldwide. Calcium supplementation can prevent pre-eclampsia in women with low dietary calcium. However, the optimal dose and timing of calcium supplementation are not known. We plan to undertake an individual participant data (IPD) meta-analysis of randomised trials to determine the effects of various calcium supplementation regimens in preventing pre-eclampsia and its complications and rank these by effectiveness. We also aim to evaluate the cost-effectiveness of calcium supplementation to prevent pre-eclampsia.Methods and analysisWe will identify randomised trials on calcium supplementation before and during pregnancy by searching major electronic databases including Embase, CINAHL, MEDLINE, CENTRAL, PubMed, Scopus, AMED, LILACS, POPLINE, AIM, IMSEAR, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, without language restrictions, from inception to February 2022. Primary researchers of the identified trials will be invited to join the International Calcium in Pregnancy Collaborative Network and share their IPD. We will check each study's IPD for consistency with the original authors before standardising and harmonising the data. We will perform a series of one-stage and two-stage IPD random-effect meta-analyses to obtain the summary intervention effects on pre-eclampsia with 95% CIs and summary treatment-covariate interactions (maternal risk status, dietary intake, timing of intervention, daily dose of calcium prescribed and total intake of calcium). Heterogeneity will be summarised using tau(2), I-2 and 95% prediction intervals for effect in a new study. Sensitivity analysis to explore robustness of statistical and clinical assumptions will be carried out. Minor study effects (potential publication bias) will be investigated using funnel plots. A decision analytical model for use in low-income and middle-income countries will assess the cost-effectiveness of calcium supplementation to prevent pre-eclampsia.Ethics and disseminationNo ethical approvals are required. We will store the data in a secure repository in an anonymised format. The results will be published in peer-reviewed journals.PROSPERO registration numberCRD42021231276.UKRI Medical Research Council MR/T010185/1UNDP/UNFPA/UNICEF/WHO/World BankNHMRC Investigato