What calcium supplementation dose and timing is recommended to prevent pre‑eclampsia in pregnant women according to the Cochrane meta‑analysis?

Calcium Supplementation for Preeclampsia Prevention: Cochrane Meta-Analysis Recommendations

Direct Answer

Prescribe 1.0–1.5 g of elemental calcium daily, divided into 2–3 doses of ≤500 mg each, starting at the first antenatal contact and continuing until delivery, particularly in populations with low dietary calcium intake (<900 mg/day). 1

Target Population

• Implement calcium supplementation when habitual dietary calcium intake is unknown or likely <900 mg/day, which applies to most low- and middle-income populations across Asia, Africa, and Latin America. 1
• Women at high risk for hypertensive disorders of pregnancy benefit most substantially, with preeclampsia risk reduction of approximately 78% (RR 0.22) in this subgroup. 2

Dosing Protocol

Optimal Dose Range

• The WHO recommends 1.5–2.0 g elemental calcium daily, though implementation data support 1.0–1.5 g as effective and more feasible with better adherence. 1, 3
• Cochrane meta-analyses demonstrate consistent preeclampsia reduction with ≥1 g daily (12 trials, 15,206 women: RR 0.48,95% CI 0.33–0.69), with the greatest effect in low-calcium populations (RR 0.36). 4
• Low-dose calcium (<1 g/day) also shows promise (9 trials, 2,234 women: RR 0.38,95% CI 0.28–0.52), though this represents lower-quality evidence. 5

Formulation and Administration

• Use calcium carbonate as the preferred formulation due to 40% elemental calcium content by weight, lower cost, and high bioavailability compared to calcium citrate (21% elemental calcium). 1, 6
• Divide the total daily dose into 2–3 administrations of ≤500 mg elemental calcium each to maximize fractional absorption, which declines with larger single doses. 1, 6
• Administer calcium carbonate with meals because gastric acid is required for optimal absorption. 6

Timing of Initiation

• Start calcium supplementation at the earliest antenatal contact (regardless of gestational age) and continue through delivery. 1, 3
• The WHO specifies starting from 20 weeks gestation, though earlier initiation is encouraged for ease of prescribing and adherence. 1
• One trial testing prepregnancy supplementation until 20 weeks showed no significant benefit (RR 0.80, p=0.121), though compliant women had reduced risk (RR 0.66, p=0.037), suggesting continuous supplementation throughout pregnancy is necessary. 7

Co-Administration with Iron-Folic Acid

A critical practice point: Instruct patients to take calcium and iron-folic acid supplements together at the same time. 1, 3

• The WHO explicitly states that calcium and iron-folic acid supplements can and should be taken together, as clinical effects of calcium on iron absorption are minimal in real-world settings. 1
• Counseling patients to separate calcium from iron creates an unnecessarily complex regimen that reduces adherence without meaningful clinical benefit. 1
• This recommendation contradicts older theoretical concerns about calcium-iron interactions that have not materialized in clinical outcomes. 6

Evidence Quality and Magnitude of Benefit

Preeclampsia Prevention

• Calcium supplementation prevents approximately 50% of preeclampsia cases in populations with low dietary calcium intake (moderate-quality evidence from >15,000 women). 1
• The effect is most pronounced in high-risk women (5 trials, 587 women: RR 0.22,95% CI 0.12–0.42) and those with low baseline calcium intake (7 trials, 10,154 women: RR 0.36,95% CI 0.18–0.70). 4
• High blood pressure is reduced (11 trials, 14,946 women: RR 0.70,95% CI 0.57–0.86). 4

Additional Maternal-Fetal Benefits

• The composite outcome of maternal death or serious morbidity is reduced (4 trials, 9,732 women: RR 0.80,95% CI 0.65–0.97). 4
• Fewer babies with birthweight <2,500 g (RR 0.83,95% CI 0.71–0.98). 2
• Childhood systolic blood pressure >95th percentile is reduced in one long-term follow-up study (RR 0.59,95% CI 0.39–0.91). 2

Safety Considerations

• The benefits of calcium supplementation substantially outweigh the risks, considering the magnitude and severity of preeclampsia-related maternal and perinatal mortality. 1
• Do not exceed 2,000–2,500 mg elemental calcium daily from all sources, as excessive supplementation may increase risk of kidney stones and potentially cardiovascular events. 1, 6
• HELLP syndrome showed a rare increase in meta-analysis (2 trials, 12,901 women: RR 2.67,95% CI 1.05–6.82), though absolute risk remains very low. 4
• Common side effects include constipation and abdominal bloating; counsel patients and offer stool softeners if needed. 6

Special Populations

Reserve calcium citrate for women with achlorhydria, those on proton-pump inhibitors, or those unable to take supplements with meals. 6

• When using calcium citrate, prescribe approximately 7.1 g of the salt daily to deliver 1.5 g elemental calcium, divided into 3–4 doses. 6
• Calcium citrate can be taken with or without food, which is its principal advantage. 6

Critical Implementation Pitfalls to Avoid

• Do not wait for dietary intake assessment data; limited data on habitual calcium intake should not impede implementation. 1
• Do not administer the entire daily calcium dose as a single tablet; this leads to poor absorption and diminishes clinical benefit. 6
• Do not recommend separation from iron supplements, which creates unnecessary complexity and reduces adherence. 1
• Despite WHO endorsement, only 29 of 92 countries with published antenatal-care guidelines include calcium supplementation recommendations, representing a critical implementation gap. 1