Abstract
RATIONALE: Calcium supplementation may reduce the risk of developing pre-eclampsia, a common cause of serious maternal and neonatal morbidity and death. However, its effectiveness in preventing hypertensive disorders of pregnancy is uncertain. This updates a review last published in 2018. OBJECTIVES: To assess the effects of calcium supplementation during pregnancy on hypertensive disorders of pregnancy and related maternal and child outcomes. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, four other databases and two trials registries to 7 January 2025, and screened reference lists of retrieved studies and relevant systematic reviews. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) that compared calcium supplementation during pregnancy with placebo or standard care only. We compared low and high doses. Trials conducted after 2010 had to be prospectively registered. We assessed trustworthiness. OUTCOMES: Critical outcomes were pre-eclampsia for women and perinatal loss for children. Important outcomes for women included maternal death, maternal death or severe morbidity, adverse effects and preterm delivery before 37 weeks. Important outcomes for children were neonatal death or severe morbidity, stillbirth, and neonatal death. RISK OF BIAS: We assessed risk of bias in RCTs using version 2 of the Cochrane tool (RoB 2). SYNTHESIS METHODS: Two review authors independently selected trials, extracted data, and assessed bias and trustworthiness. We pooled data using random-effects meta-analysis. We assessed certainty of evidence using GRADE. INCLUDED STUDIES: We included 10 RCTs with 37,504 participants. All trials provided standard care. Eight compared calcium supplementation to placebo, and two compared low- to high-dose calcium supplementation. We excluded 20 previously included trials; 11 because eligibility criteria changed and nine because they are awaiting classification due to trustworthiness issues. SYNTHESIS OF RESULTS: Calcium supplementation versus placebo Calcium may result in little to no difference in pre-eclampsia (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.67 to 1.04; 6 RCTs, 15,364 women; risk difference (RD) 9/1000 fewer, 95% CI 17 fewer to 2 more; low-certainty evidence). Sensitivity analysis excluding small studies (fewer than 500 participants) indicates little to no difference in pre-eclampsia (RR 0.92, 95% CI 0.79 to 1.05; 4 RCTs, 14,730 women; high-certainty evidence). The evidence is very uncertain about the effect of calcium on maternal death (RR 0.33, 95% CI 0.06 to 1.83; 3 RCTs, 9430 women; very low-certainty evidence) and on adverse effects (RR 2.16, 95% CI 0.43 to 10.78; 2 RCTs, 714 women; very low-certainty evidence). Calcium probably results in little to no difference in the composite outcome maternal death or severe morbidity (RR 0.80, 95% CI 0.54 to 1.19; 1 RCT, 8312 women; moderate-certainty evidence), and may result in little to no difference in perinatal loss (RR 0.93, 95% CI 0.64 to 1.35; 4 RCTs, 6832 women; RD 1/1000 fewer, 95% CI 6 fewer to 6 more; low-certainty evidence). The evidence is very uncertain about the effect of calcium on preterm delivery before 37 weeks (RR 0.83, 95% CI 0.65 to 1.05; 6 RCTs, 15,074 women; very low-certainty evidence). Sensitivity analysis excluding small studies indicates little to no difference in preterm delivery before 37 weeks (RR 0.97, 95% CI 0.85 to 1.11; 4 RCTs, 14,429 women; high-certainty evidence). Calcium probably results in little to no difference in stillbirth (RR 0.91, 95% CI 0.72 to 1.15; 4 RCTs, 14,085 women; moderate-certainty evidence) but the evidence is very uncertain about its effect on neonatal death (RR 1.09, 95% CI 0.50 to 2.38; 4 RCTs, 13,300 women; very low-certainty evidence). No trials measured neonatal death or severe morbidity. Low- versus high-dose calcium There may be little to no difference between low- and high-dose calcium in pre-eclampsia (RR 0.96, 95% CI 0.73 to 1.25; 2 RCTs, 22,000 women; low-certainty evidence). The evidence is very uncertain about the effect of low- versus high-dose calcium on maternal death (RR 1.20, 95% CI 0.36 to 3.94; 2 RCTs, 22,000 women; very low-certainty evidence). There is little to no difference between low- and high-dose calcium in perinatal loss (RR 1.02, 95% CI 0.91 to 1.16; 2 RCTs, 21,412 women; high-certainty evidence), and stillbirth (RR 0.99, 95% CI 0.84 to 1.16; 2 RCTs, 21,131 women; high-certainty evidence). There is probably little to no difference between low- and high-dose calcium in preterm delivery before 37 weeks (RR 0.98, 95% CI 0.81 to 1.17; 2 RCTs, 20,578 women; moderate-certainty evidence). No trials measured maternal death or severe morbidity, adverse effects, neonatal death or severe morbidity, or neonatal death. AUTHORS' CONCLUSIONS: Calcium supplementation versus placebo Meta-analyses showed that calcium supplementation compared to placebo may result in little to no difference in pre-eclampsia, but we are very uncertain about its effect on preterm delivery before 37 weeks. However, high-certainty evidence from sensitivity analyses with only large trials (> 95% of participants in the main analyses), showed little to no difference in both pre-eclampsia and preterm delivery before 37 weeks. Maternal death was rare, so evidence about it is very uncertain. Calcium supplementation probably results in little to no difference in the composite outcome maternal death or severe morbidity, may result in little to no difference in perinatal loss, and probably results in little to no difference in stillbirth. Evidence about adverse effects and neonatal death is very uncertain. No trials measured neonatal death or severe morbidity. Baseline calcium intake level and pre-eclampsia risk status did not impact our findings. Low- versus high-dose calcium supplementation Low- compared to high-dose calcium supplementation made no difference to outcomes in women at high risk for pre-eclampsia in low calcium-intake populations. Low-dose calcium supplementation may result in little to no difference in pre-eclampsia. Maternal death (5 per 10,000 women) was rare; the evidence is very uncertain. Low-dose calcium results in little to no difference in perinatal loss and stillbirth, and probably results in little to no difference in preterm delivery before 37 weeks. No trials measured severe maternal morbidity, neonatal death, severe neonatal morbidity, or adverse effects. FUNDING: This review was part-funded by the World Health Organization. REGISTRATION: Updated protocol (2024) PROSPERO: CRD42024623889 Review update (2018) DOI: 10.1002/14651858.CD001059.pub5 Original review (2002) DOI: 10.1002/14651858.CD001059.