By Ahizechukwu C. Eke, MD, PhD, MPH
Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
In pregnancy, calcium supplementation was well tolerated and reduced the risk of preeclampsia and preterm birth, with no significant differences observed between low-dose and high-dose supplementation.
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.
The increasing prevalence of adverse pregnancy outcomes, encompassing complications such as preeclampsia, gestational hypertension, preterm birth, low birth weight, and fetal growth restriction, is a concerning trend in recent times.1 These complications present substantial risks to both maternal and fetal health during pregnancy, and are associated with significant morbidity and mortality.1 The rise in adverse pregnancy outcomes can be attributed to a complex interplay of factors, including shifts in maternal demographics, lifestyle choices, healthcare accessibility, and environmental influences.2 Consequently, efforts are underway to prevent or mitigate these adverse outcomes through the judicious use of essential nutrients during pregnancy.
Among various essential nutrients, calcium plays a pivotal role in ensuring healthy pregnancy outcomes, including improved nerve transmission, hormone secretion, and decreased risk of blood clotting.3 Several studies have investigated the effects of calcium supplementation during pregnancy on maternal and fetal health outcomes.4 A meta-analysis by Hofmeyr et al in 2018 demonstrated that calcium supplementation (≥ 1 g/day) reduced the risk of hypertension and preeclampsia by approximately 35% and 55%, respectively, among women with low dietary calcium intake.5 This protective effect is thought to involve the vasodilatory properties of calcium, which may improve endothelial function and reduce vascular resistance. Although high-dose calcium supplementation (> 1,500 mg/day) has been associated with reduced risks of preeclampsia and gestational hypertension, concerns regarding gastrointestinal side effects and potential adverse outcomes have been raised.6 Conversely, low-dose calcium supplementation (≤ 1,500 mg/day) has emerged as a promising intervention with fewer adverse effects. Hence, in recent years, there has been growing interest in investigating the effects of low-dose calcium supplementation during pregnancy on reducing adverse pregnancy outcomes. In this study, Dwarkanath and colleagues offered valuable insights into how calcium supplementation may prevent preeclampsia by conducting two independent randomized trials of calcium supplementation in India and Tanzania to assess the noninferiority of a 500-mg daily dose to a 1500-mg daily dose of calcium supplementation.7
This randomized clinical trial recruited women older than 18 years of age who met the following criteria: nulliparous status, gestational age < 20 weeks at enrollment, intention to remain in the trial area until six weeks postpartum, and provision of written informed consent. Women were ineligible for enrollment if they had a history, signs, or symptoms of nephrolithiasis; a history of parathyroid disorder or thyroidectomy; or a medical condition requiring digoxin, phenytoin, or tetracycline therapy.7 Participants were randomly allocated in a 1:1 ratio to receive either 500 mg or 1,500 mg of elemental calcium supplementation daily. The primary efficacy outcomes assessed were preeclampsia and preterm birth. Preeclampsia was defined as meeting at least one of the following criteria from 20 weeks of gestation until delivery: gestational hypertension with proteinuria among participants without chronic hypertension, gestational proteinuria among participants with chronic hypertension (superimposed preeclampsia), clinical diagnosis of preeclampsia, or the development of preeclampsia with severe features with or without proteinuria. Proteinuria was defined as a dipstick reading of at least 1+. Preterm birth was defined as the delivery of a live infant before 37 weeks of gestation. Secondary outcomes included gestational hypertension, preeclampsia with severe features, pregnancy-related death, fetal death, stillbirth (occurring at ≥ 28 weeks of gestation), low birth weight (< 2,500 g), small for gestational age, and infant death before 42 days of age. Safety outcomes included maternal hospitalization (excluding hospitalization for delivery) and third-trimester severe anemia (defined as a hemoglobin concentration < 7.0 g/dL).7
The India and Tanzania trials were powered and analyzed independently. To achieve a statistical power exceeding 80%, assuming a two-sided type-1 error rate of 5%, and accounting for a dropout rate of 10%, a total sample size of at least 22,000 women (11,000 in each trial) was necessary. This sample size allowed for the detection of treatment differences on the primary endpoints, with noninferiority margins set at a relative risk of 1.54 for preeclampsia and 1.16 for preterm birth. The primary analysis followed an intention-to-treat approach. The investigators screened 33,449 women in Tanzania and 45,186 women in India to enroll 22,000 participants (10,000 in each trial) between March 2019 and March 2022. Baseline characteristics were comparable between the groups. Among the 22,000 nulliparous pregnant women included in both trials, the cumulative incidence of preeclampsia was 3.0% in the 500-mg group and 3.6% in the 1,500-mg group in the India trial (relative risk [RR], 0.84; 95% confidence interval [CI], 0.68, 1.03) and 3.0% and 2.7%, respectively, in the Tanzania trial (RR, 1.10; 95% CI, 0.88, 1.36).
In both trials, the 500-mg calcium dose was noninferior to the 1,500-mg dose concerning the risk of preeclampsia. The preterm birth rate was 11.4% in the 500-mg group and 12.8% in the 1,500-mg group in the India trial (RR, 0.89; 95% CI, 0.80, 0.98), falling within the noninferiority margin of 1.16. However, in the Tanzania trial, the respective rates were 10.4% and 9.7% (RR, 1.07; 95% CI, 0.95, 1.21), exceeding the noninferiority margin. No significant differences in secondary and fetal outcomes were observed between the groups in both trials, and meta-analysis of outcomes from both trials showed no significant distinctions between the groups. Median adherence to calcium supplementation was 97.7% (interquartile range [IQR], 93.2-99.2) in the India trial and 92.3% (IQR, 82.7-97.1) in the Tanzania trial.
COMMENTARY
The results of this clinical trial indicate that low-dose calcium supplementation was noninferior to high-dose calcium and shows potential as an effective preventive therapy for preeclampsia and preterm birth.7 Despite the potential benefits of low-dose calcium supplementation in pregnancy, several challenges and considerations merit attention. First, individual variations in calcium metabolism and dietary intake may influence the response to supplementation, highlighting the importance of personalized approaches.
Second, the optimal dosage, timing, and duration of calcium supplementation require clarification through additional research, since conflicting findings exist in the literature. Third, serum calcium sampling of a small number of pregnant women in both trial arms before and after treatment, a crucial step in demonstrating that preeclampsia prevention was aided by replenished calcium levels from supplementation, was not mentioned. It is plausible that calcium supplementation may lower blood pressure by reducing intracellular calcium and parathyroid hormone secretion, which reduces vascular smooth muscle contractility; but ionized calcium, which is the most important measure of the body’s actual calcium status, remain unchanged during pregnancy, raising concerns about the need for calcium supplementation.8,9 Furthermore, research on preeclampsia risk, blood calcium concentrations, and dietary calcium intake showed that pregnant women with low calcium intake had normal serum calcium levels.10 Finally, interactions between calcium supplementation and other nutrients or medications must be elucidated to ensure safety and efficacy.
Nevertheless, low-dose calcium supplementation represents a promising intervention for improving maternal and fetal health outcomes during pregnancy. By addressing maternal calcium insufficiency and supporting fetal skeletal development, calcium supplementation may reduce the prevalence of adverse pregnancy outcomes, such as preeclampsia, preterm birth, gestational hypertension, and osteoporosis. However, further research is needed to optimize supplementation protocols, identify high-risk populations, and elucidate the long-term implications for maternal and offspring health. Ultimately, integrating low-dose calcium supplementation into prenatal care strategies has the potential to enhance pregnancy outcomes and promote lifelong health for both mothers and their children.
The results of this study may not apply to all pregnant women. Although low calcium levels might increase preeclampsia risk in low- and middle-income countries, hypocalcemia is unlikely to explain the rising prevalence of preeclampsia in high-income countries, since most meals are calcium-fortified. Although the World Health Organization recommends routine calcium supplementation (1,500 mg to 2,000 mg daily) during pregnancy to mitigate preeclampsia, the American College of Obstetricians and Gynecologists (ACOG) states that there is insufficient evidence at this time to recommend calcium supplements for preventing preeclampsia and preterm birth in women at risk for these conditions.11 Instead, ACOG recommends the use of low-dose aspirin (81 mg/day), initiated between 12 and 28 weeks of gestation, to prevent preeclampsia.12
REFERENCES
- Torosyan N, Aziz D, Quesada O. Long-term sequelae of adverse pregnancy outcomes. Maturitas 2022;165:1-7.
- Souza JP, Day LT, Rezende-Gomes AC, et al. A global analysis of the determinants of maternal health and transitions in maternal mortality. Lancet Glob Health 2024;12:e306-e316.
- Brown LL, Cohen BE, Edwards E, et al. Physiological need for calcium, iron, and folic acid for women of various subpopulations during pregnancy and beyond. J Womens Health (Larchmt) 2021;30:207-211.
- Omotayo MO, Dickin KL, O'Brien KO, et al. Calcium supplementation to prevent preeclampsia: Translating guidelines into practice in low-income countries. Adv Nutr 2016;7:275-278.
- Hofmeyr GJ, Lawrie TA, Atallah ÁN, Torloni MR. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 2018;10:CD001059.
- Li K, Wang XF, Li DY, et al. The good, the bad, and the ugly of calcium supplementation: A review of calcium intake on human health. Clin Interv Aging 2018;13:2443-2452.
- 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.
- Cormick G, Belizán JM. Calcium intake and health. Nutrients 2019;11:1606.
- Soma-Pillay P, Nelson-Piercy C, Tolppanen H, Mebazaa A. Physiological changes in pregnancy. Cardiovasc J Afr 2016;27:89-94.
- Gupta A, Kant S, Pandav CS, et al. Dietary calcium intake, serum calcium level, and their association with preeclampsia in rural north India. Indian J Community Med 2016;41:223-227.
- World Health Organization. Guideline: Calcium Supplementation in Pregnant Women. World Health Organization; 2013.
- [No authors listed]. ACOG Committee Opinion No. 743: Low-dose aspirin use during pregnancy. Obstet Gynecol 2018;132:e44-e52.
