Calcium supplementation in pregnancy does not appear to reduce the risk for preeclampsia, contrary to the conclusions of previous reviews of the evidence, according to a new Cochrane review.

Preeclampsia is the most severe hypertensive disorder of pregnancy; these disorders are a leading cause of maternal and perinatal morbidity and mortality globally. Preeclampsia is estimated to affect 3%-8% of all pregnancies, causing 42,000 maternal deaths and over half a million perinatal deaths every year.

The World Health Organization currently recommends that pregnant women in populations with low dietary calcium intake take 1.5-2 g of a daily calcium supplement to reduce the risk for preeclampsia. The evidence underpinning the recommendation, however, has long been mixed.

The idea that adequate calcium intake could lower the risk for preeclampsia initially arose from observational studies that found lower rates of the condition in populations with high calcium intake. Randomized controlled trials (RCTs) starting in the late 1980s suggested a beneficial effect from calcium supplementation, but larger studies conducted later on did not confirm these results.

This new review excluded studies in a 2018 review that were deemed problematic due to methodological flaws, inappropriate eligibility of participants, or other concerns that reduced their reliability.

“Our updated analysis shows that once you account for issues like small-trial effects and publication bias, the evidence supporting calcium supplementation to prevent preeclampsia simply doesn’t hold up,” first author Catherine Cluver said in a statement. “This marks a major shift from earlier reviews, and it’s crucial that clinicians and policymakers understand how much the evidence base has changed.”

The findings also suggested no likely benefit from calcium supplementation on severe maternal morbidity, stillbirth, or preterm delivery before 37 weeks. The analysis showed no effect from calcium supplements was seen on maternal death, maternal adverse effects, neonatal death, and perinatal loss, defined as death of a fetus or baby between 22 weeks gestation and 7 days postpartum.

The findings elicited “humility” and a sense of the need for “recalibration in the field” for Yalda Afshar, MD, PhD, an associate professor of maternal fetal medicine at the University of California Los Angeles (UCLA) and codirector of the UCLA Cardio-Obstetrics Program. “These results highlight an important truth: maternal health still suffers from fundamental gaps in biological understanding,” she told Medscape Medical News.

Given how rigorous the methodology was in the review, Afshar said the evidence from large, well-designed trials is especially compelling but not necessarily surprising.

“Over the past decade, signals of benefit had already begun to weaken, and biological plausibility is shaky,” she said. “The elephant in the room is this: We do not fully understand preeclampsia or preterm birth, and we are trying to prevent it.”

The hypothesis supporting calcium’s role in preeclampsia relied on its influence on vascular smooth muscle tone, endocrine signals, and uterine contractility, Afshar explained. “Those mechanisms are real, but apparently not the levers that determine the course of a complex, multisystem disorder like preeclampsia,” she said.

Instead of relying on calcium as a preventive strategy for hypertensive disorders of pregnancy, Afshar said, “the emphasis must remain on early identification of risk, evidence-based surveillance, aspirin prophylaxis where indicated, and timely management of hypertensive disease when it arises.”

Diana S. Wolfe, MD, MPH, a professor of ob/gyn, maternal-fetal medicine, and cardiology, and the obstetric director of Maternal Fetal Medicine Cardiology Joint Program at Montefiore Einstein, Bronx, New York, was similarly unsurprised by the findings.

Calcium supplementation in pregnancy is still important, Wolfe told Medscape Medical News, but not for preventing preeclampsia. “The take-home message is that aspirin is highly recommended for preeclampsia prevention, especially in those people who are at high risk for preeclampsia,” she said, and that “calcium supplementation is harmless in pregnancy and can have other benefits.”

There are other medications out there that are being looked at for preeclampsia prevention, including statins, but there’s still not enough evidence to make any recommendations for other prophylactic treatments, Wolfe added.

The authors searched CENTRAL, MEDLINE, Embase, four other databases, and two trial registrations for all RCTs through January 2025 that compared calcium supplementation in pregnancy with placebo or standard care, or that compared low-dose calcium supplements with high doses. The primary outcomes were preeclampsia or perinatal loss, but for trials that reported them, the authors also looked at the outcomes of maternal death, severe maternal morbidity, adverse effects, preterm delivery before 37 weeks, neonatal death, severe neonatal morbidity, or stillbirth.

They identified 10 RCTs with a total of 37,504 participants. Eight of the trials, with 15,504 women, compared calcium with placebo, and two trials of a combined 22,000 women compared low-dose (< 1000 mg) and high-dose (at least 1000 mg) calcium supplementation. The analysis excluded 20 trials that had been included in the previous review, including 11 because of changes in eligibility criteria and nine that are awaiting classification due to concerns about their reliability.

“After excluding unreliable studies, we found that the supposed benefit of calcium supplementation on preeclampsia disappeared,” Cluver said in a statement. 

Findings from 15,365 women in six trials found little to no difference in the risk for preeclampsia with calcium supplementation (risk ratio [RR], 0.83; 95% CI, 0.67-1.04). A sensitivity analysis that excluded trials with fewer than 500 participants similarly found no significant difference in preeclampsia risk between those who took calcium supplements and those who took a placebo or received standard care, based on high-certainty evidence from four trials with a total of 14,730 women (RR, 0.92; 95% CI, 0.79-1.05).

Calcium supplements also did not reduce preterm delivery before 37 weeks based on four trials with 14,429 women.

The evidence showed no effect on maternal death, based on three trials with 9430 total women. The fact that maternal death was rare contributed to the uncertainty. Very low certainty evidence from four trials with 13,300 women also showed no effect on neonatal death.

When the researchers looked at the studies comparing low and high doses of calcium, they found no significant differences in preeclampsia (low certainty), maternal death (very low certainty), preterm delivery before 37 weeks (moderate certainty), and perinatal loss or stillbirth (high certainty).

“This review redirects us toward the questions that truly matter: What triggers the cascade of preeclampsia? Why does the placenta, that brilliant, temporary organ, sometimes misfire in ways we cannot yet anticipate? And what are the earliest molecular cues of abnormal vascular remodeling in pregnancy? Until we illuminate those fundamental mechanisms, no supplement or intervention, calcium or otherwise, can be expected to solve a problem whose biology remains largely unmapped,” Afshar said.

“Future research must go upstream into early placental development, immune-vascular interactions, and genetic and epigenetic factors that predispose certain pregnancies to hypertension long before symptoms appear,” she said. “We need tools that allow us to detect, and ultimately modify, the earliest signals of abnormal placentation, well before 12 weeks. We need to stop trying to fix preeclampsia mid-pregnancy and instead understand and intervene in the first trimester biology where the disease actually originates.” 

This challenge will require “investment in mechanistic science, innovation in early pregnancy diagnostics, and research that reflects the diversity of the global populations most affected,” Afshar added.

The research received some funding from the World Health Organization. The authors had no disclosures. Afshar reported consulting for J&J MedTech and BillionToOne, unrelated to hypertensive disorders of pregnancy. Wolfe had no disclosures.

Tara Haelle is a science/health journalist based in Dallas.