Study finds low-dose calcium as effective as the WHO's recommended high-dose in preventing preeclampsia and preterm births

By Vijay Kumar MalesuJan 16 2024Reviewed by Danielle Ellis, B.Sc.

In a recent study published in The New England Journal of Medicine, a group of researchers assessed the noninferiority of a 500-mg daily dose of calcium supplementation compared to a 1500-mg dose in preventing preeclampsia and preterm birth in pregnant women in India and Tanzania.

Background 

Hypertensive disorders, including preeclampsia, affect 2-8% of pregnancies globally and contribute to significant maternal and neonatal mortality. These conditions, closely linked to preterm birth, are critical targets in achieving the United Nations Sustainable Development Goals for reducing maternal and child deaths by 2030. Since 2011, the World Health Organization (WHO) has advocated for calcium supplementation in pregnancy, especially in areas with low dietary calcium, to mitigate the risk of preeclampsia.

High-dose calcium supplementation (at least 1000 mg daily) has been shown to substantially decrease the risks of preeclampsia and preterm birth, with even greater efficacy in low-calcium diet populations. Despite these findings, routine implementation of high-dose calcium supplementation has been limited due to adherence issues and logistical challenges. In contrast, low-dose supplementation (below 1000 mg daily), mostly involving 500 mg daily, has demonstrated similar benefits in smaller studies.

Further research is required to explore optimal dosing, adherence strategies, and the long-term maternal and neonatal outcomes of varied calcium supplementation levels in pregnancy.

About the study

Two independent, double-blind, parallel-group, noninferiority trials were conducted in India and Tanzania, comparing low-dose and high-dose calcium supplementation in nulliparous pregnant women. These trials, designed with similar interventions, methods, and outcome definitions, were independently powered and analyzed. The trials aimed to test the efficacy of a 500-mg daily dose against a 1500-mg dose in reducing risks of preeclampsia and preterm birth. 

In both India and Tanzania, adult nulliparous pregnant women under 20 weeks’ gestation were enrolled. The women were required to commit to remaining in the trial area until six weeks postpartum and provide written informed consent. Exclusion criteria included a history of kidney stones, parathyroid disorders, thyroidectomy, or need for specific medications. 

Participants were randomized to receive either 500 mg or 1500 mg of elemental calcium daily until delivery. The 500-mg group received one calcium tablet and two placebos daily, while the 1500-mg group received three 500-mg calcium tablets daily. Additionally, in India, participants received 250 IU of vitamin D3 daily, unlike in Tanzania. The tablets were manufactured by Influx Healthcare and distributed in blister packs for daily dosing, with adherence monitored through pill counts.

Randomization was done using a computer-generated list with block randomization, stratified by clinic. All tablets, calcium or placebo, were identical in appearance, taste, and smell, ensuring blinding. 

Data were collected through monthly clinic visits, delivery, and a postpartum visit at six weeks. Baseline dietary intake was assessed, and blood samples were taken for hemoglobin concentration. Primary outcomes were preeclampsia and preterm birth, with specific criteria for each defined. Secondary outcomes included gestational hypertension, severe preeclampsia, pregnancy-related death, and several neonatal outcomes.

Standard antenatal and postpartum care was provided in both countries, with guidelines-specific supplements administered. The trials adhered to ethical standards, with oversight from a data and safety monitoring board.

Statistical analysis was conducted independently for each trial, using intention-to-treat principles. Log-binomial models estimated relative risks, with per-protocol analyses for primary outcomes and various sensitivity analyses. Secondary maternal and infant outcomes were assessed using appropriate statistical models. Meta-analyses provided pooled effect estimates, and Statistical Analysis System (SAS) software was used for all analyses.

Study results 

In comprehensive trials conducted in India and Tanzania, researchers investigated the efficacy of low-dose versus high-dose calcium supplementation in preventing preeclampsia and preterm birth among nulliparous pregnant women. The India trial, running from November 2018 to February 2022, screened 33,449 women and enrolled 11,000 participants. Concurrently, the Tanzania trial, from March 2019 to March 2022, screened 45,186 women, enrolling the same number of participants. Both trials achieved high follow-up rates for pregnancy outcomes and demonstrated notable adherence to calcium supplementation, with median adherence rates of 97.7% in India and 92.3% in Tanzania.

The participant demographics at baseline were similar across both groups in each trial, predominantly featuring young women with normal blood pressure and low dietary calcium intake. In the India trial, the cumulative incidence of preeclampsia was slightly lower in the 500-mg group compared to the 1500-mg group. Conversely, in Tanzania, the incidence was marginally higher in the 500-mg group. Despite these differences, the 500-mg dose was found to be noninferior to the 1500-mg dose for the risk of preeclampsia in both trials.

Regarding preterm birth, the India trial showed a lower incidence in the 500-mg group, while the Tanzania trial reported a slightly higher incidence in the same group. However, the findings in India supported the noninferiority of the lower dose, which was not the case in Tanzania. The per-protocol analyses, sensitivity analyses, and adjustments for potential baseline imbalances yielded results similar to the primary analyses in both trials. No significant differences were noted in the incidence of spontaneous preterm births between the groups.

In terms of secondary and safety outcomes, neither trial showed any advantage of the 1500-mg dose over the 500-mg dose. These results were consistent across various analyses, including fixed- and random-effects meta-analyses. The meta-analyses did not reveal any significant differences between the two dosage groups in the risks of preeclampsia, preterm birth, or other secondary and safety outcomes.

Conclusion

Overall, the results from these trials suggest that a low-dose calcium supplementation of 500 mg daily is noninferior to a higher dose of 1500 mg daily in reducing the risk of preeclampsia and may be effective in reducing the risk of preterm birth, particularly in specific settings like India.