Risk of Preeclampsia, Preterm Birth Prevented as Well by Low-dose Calcium as by Recommended High-Dose, Study Finds

Dietary supplementation during pregnancy with 500 mg of low-dose calcium may be equally as effective as the high-dose supplementation of 1500 mg daily currently recommended by the World Health Organization (WHO) in reducing risk for preterm births and preeclampsia, according to research led by the Harvard TH Chan School of Public Health and collaborators in India and Tanzania.¹

Findings were published in the New England Journal of Medicine this month.¹

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In 2 studies of 11 000 nulliparous pregnant women, 1 in each country, investigators found that the cumulative incidence of preeclampsia in the Indian arm for the 500 mg group was 3% and percentage of live preterm births (before 37 weeks of gestation) was 11.4%.¹In this study preeclampsia incidence among women in the 1500 mg group was 3.6% and proportion of live preterm births, 12.8%, demonstrating noninferiority of the lower vs the higher dose for both outcomes.¹

In Tanzania, the researchers reported a cumulative risk of preeclampsia among women taking 500 mg of low-dose calcium of 3.0% and among those on the higher dose, 2.7%, findings also consistent with noninferiority, authors wrote.¹ The percentage of live preterm births in this trial, however, exceeded the noninferiority margin, at 10.4% for the 500-mg dose and 9.7% for the 1500-mg dose.¹

When they pooled the data from both trials, however, the authors found no significantly different effect of the low-dose supplementation compared with high-dose supplementation.¹

The WHO recommendation for calcium supplementation of 1500 to 2000 mg daily, established in 2011, is based on findings from placebo-controlled trials conducted in populations consuming low-calcium diets, predominantly in low- and middle-income countries, wrote lead study author Wafaie Fawzi, MBBS, MPH, MS, DrPH, Richard Saltonstall Professor of Population Sciences and professor of nutrition, epidemiology, and global health, and colleagues.¹ They cite data showing that the risk of preeclampsia was reduced by half in those studies and risk of live preterm birth by 24%.¹ WHO guidance recommends a complex perigestational dosing schedule that has proven a barrier to widespread implementation, added researchers, and, among other negative downstream effects, threatens the United Nations Sustainable Development Goals to reduce maternal and child mortality by 2030.¹

“The current recommendation for pregnant women to take three calcium pills per day presents feasibility concerns for women and cost concerns for governments and public health programs,” said Fawzi in a news release.2 “As such, most middle- and low-income countries have not implemented calcium supplementation in pregnancy, leaving women and infants unnecessarily vulnerable.”²

Participants enrolled in both studies were aged 18 years or older, pregnant for the first time and at less than 20 weeks’ gestation, according to the study.¹ All received a 35-day supply of daily calcium supplements and were randomized to receive either three 500 mg pills or one 500 mg pill plus 2 placebo pills. Research teams monitored participant’s health during monthly clinic visits during pregnancy, at delivery, and at 6 weeks postpartum.¹

FINDINGS¹

The majority of participants in both trials were between 18 and 24 years of age and were free of hypertension at study baseline, according to the results. In India, the baseline daily dietary calcium intake of less than 800 mg was approximately 87% and in Tanzania, 67%.

In both trials, the findings for preeclampsia were consistent with the investigators’ 1.54 noninferiority margin.

The percentage of live preterm births differed between the 2 countries, with the Indian findings falling within the established 1.16 noninferiority margin but the Tanzanian results exceeding that.

The investigators’ review of secondary outcomes as well as safety outcomes revealed no evidence to favor the 1500-mg group over the 500-mg group in either trial, they wrote.¹

Among the study’s limitations the investigators noted the possibility for measurement error and misclassification of preterm birth, given their reliance on patient self-report of last menstrual period. Self-report of dietary intake via the 24-hour diet recall method also may have introduced error. Also, enrollment of nulliparous participants skewed the study population age younger and so findings should be generalized with caution.¹

“Overall, our findings show that a single pill per day can be as effective as three,” said joint first author Christopher Sudfeld, ScD, associate professor of global health and nutrition, in the statement.² “With a reduced pill burden for women and lower costs for governments and programs that buy calcium pills, calcium supplementation should be considered widely implementable in the places it’s needed most—and should start saving thousands of maternal and newborn lives.”²

References

1. Dwarkanath P, Muhihi A, Sudfeld CR, et al. Two randomized trials of low-dose calcium supplementation in pregnancy. N Engl J Med. 2024; 390:143-153. doi:10.1056/NEJMoa2307212
2. Preeclampsia and preterm birth risk may be reduced by calcium dose lower than current WHO standard. News release. Harvard TH Chan School of Public Health. January 11, 2024. Accessed January 30, 2024. https://www.hsph.harvard.edu/news/press-releases/preeclampsia-and-preterm-birth-risk-may-be-reduced-by-calcium-dose-lower-than-current-who-standard/