RATIONALE: Hypertensive disorders of pregnancy are a leading cause of maternal and perinatal morbidity and mortality. Calcium supplementation commenced before pregnancy may prevent the development of these disorders. This is an update of a review last published in 2019.
OBJECTIVES: To assess the effects of calcium supplementation commenced before pregnancy on hypertensive disorders of pregnancy and related maternal and neonatal outcomes.
SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, Portal Regional BVS-Lilacs, Scopus, Web of Science, WHO ICTRP and ClinicalTrials.gov on 7 January 2025 and searched reference lists of retrieved trials and relevant systematic reviews.
ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) that compared calcium supplementation commenced before pregnancy with placebo or standard care. Trials conducted after 2010 needed to be prospectively registered. We applied a trustworthiness checklist.
OUTCOMES: Critical outcomes for women were pre-eclampsia or pregnancy loss, and pre-eclampsia. The critical outcome for children was perinatal loss. Our main important outcomes for women were pregnancy loss at any gestational age, maternal death, maternal death or severe morbidity, and adverse effects. Our main important outcomes for children were preterm delivery before 37 weeks, neonatal death or severe morbidity, stillbirth, neonatal death, and early neonatal death.
RISK OF BIAS: We used version 2 of the Cochrane tool for assessing risk of bias in randomised trials (RoB 2).
SYNTHESIS METHODS: Two review authors independently selected trials, extracted data, and assessed risk of bias and trustworthiness. We pooled data using random-effects meta-analysis. We assessed the certainty of the evidence using GRADE. Because conception and pregnancy loss are intermediate outcomes potentially on the causal pathway to pre-eclampsia, we chose the composite outcome 'pre-eclampsia or pregnancy loss' as the first critical outcome (and most relevant to pregnant women), and included sensitivity analyses including only women who conceived during the trial.
INCLUDED STUDIES: We included one multicentre, double-blind, randomised, placebo-controlled trial. It included 1355 parous women, whose most recent planned pregnancy had been complicated by pre-eclampsia or eclampsia.
SYNTHESIS OF RESULTS: Pre-eclampsia or pregnancy loss at any gestational age Compared to placebo, calcium may result in little to no difference in pre-eclampsia or pregnancy loss at any gestational age (risk ratio (RR) 0.85, 95% confidence interval (CI) 0.67 to 1.07; 1 RCT, 1355 women; risk difference (RD) 28/1000 fewer, 95% CI 61 fewer to 13 more; low-certainty evidence). Sensitivity analysis including only women who conceived during the trial yielded a risk ratio of 0.82 (95% CI 0.66 to 1.00; 1 RCT, 633 women). Pre-eclampsia Compared to placebo, calcium may result in little to no difference in pre-eclampsia (RR 0.84, 95% CI 0.62 to 1.14; 1 RCT, 1355 women; RD 19/1000 fewer, 95% CI 46 fewer to 17 more; low-certainty evidence). Sensitivity analysis including only women who conceived during the trial yielded a risk ratio of 0.81 (95% CI 0.61 to 1.07; 1 RCT, 633 women). Pregnancy loss at any gestational age Compared to placebo, calcium may result in little to no difference in pregnancy loss at any gestational age (RR 0.92, 95% CI 0.69 to 1.24; 1 RCT, 1355 women; RD 9/1000 fewer, 95% CI 37 fewer to 28 more; low-certainty evidence). Sensitivity analysis including only women who conceived during the trial yielded a risk ratio of 0.89 (95% CI 0.67 to 1.17; 1 RCT, 633 women). Maternal death The evidence is very uncertain about the effect of calcium compared to placebo on maternal death (RR 1.00, 95% CI 0.14 to 7.07; 1 RCT, 1355 women; RD 0/10,000 fewer, 95% CI 25 fewer to 179 more; very low-certainty evidence). Sensitivity analysis including only women who conceived during the trial yielded a risk ratio of 0.96 (95% CI 0.14 to 6.77; 1 RCT, 633 women). Maternal death or severe morbidity The evidence is very uncertain about the effect of calcium, compared to placebo, on maternal death or severe morbidity (RR 0.97, 95% CI 0.70 to 1.35; 1 RCT, 1355 women; RD 3/1000 fewer, 95% CI 29 fewer to 34 more; very low-certainty evidence). Sensitivity analysis including only women who conceived during the trial yielded a risk ratio of 0.93 (95% CI 0.68 to 1.27; 1 RCT, 633 women). Preterm delivery before 37 weeks Compared to placebo, calcium may result in little to no difference in preterm delivery before 37 weeks (RR 0.94, 95% CI 0.74 to 1.19; 1 RCT, 1355 women; RD 11/1000 fewer, 95% CI 46 fewer to 33 more; low-certainty evidence). Sensitivity analysis including only women who conceived during the trial yielded a risk ratio of 0.90 (95% CI 0.74 to 1.11; 1 RCT, 633 women). Stillbirth The evidence is very uncertain about the effect of calcium compared to placebo on stillbirth (RR 0.82, 95% CI 0.50 to 1.34; 1 RCT, 1355 women; RD 9/1000 fewer, 95% CI 24 fewer to 17 more; very low-certainty evidence). Sensitivity analysis including only women who conceived during the trial yielded a risk ratio of 0.79 (95% CI 0.48 to 1.27; 1 RCT, 633 women). The included trial did not measure perinatal loss, maternal adverse effects, neonatal death or severe morbidity, neonatal death, or early neonatal death.
AUTHORS' CONCLUSIONS: When all randomised women are considered, calcium commenced before pregnancy may result in little to no difference in pre-eclampsia or pregnancy loss, and pre-eclampsia. When only pregnant women are considered, calcium may result in little to no difference in pre-eclampsia but may result in a slight reduction in pre-eclampsia or pregnancy loss. No trials measured perinatal loss. The evidence is drawn from one trial of calcium supplementation that commenced before and continued into the first half of pregnancy. Current evidence neither supports nor refutes the routine use of calcium supplementation commencing before conception.
FUNDING: This review was funded in part by the World Health Organization.
REGISTRATION: Updated protocol (2025): PROSPERO: CRD420250649571 Review update (2019): DOI: 10.1002/14651858.CD011192.pub3 Original review (2017): DOI: 10.1002/14651858.CD011192.pub2.
