In the recent calcium for preeclampsia prevention (CPEP) trial from the National Institutes of Health (NIH), Levine and colleagues randomized 4589 healthy primiparas to 2 g daily elemental calcium vs. placebo. All of the women enrolled in this double-blind, multi-center trial between 13 and 21 weeks’ gestational age and continued the supplements throughout pregnancy. Preeclampsia was eventually diagnosed in 6.9% of the calcium supplementation group vs. 7.3% of the control group, a statistically insignificant difference (relative risk 0.94; 95% confidence interval, 0.76-1.16). The onset of preeclampsia was not delayed in the study group.
The incidence of milder forms of pregnancy-associated hypertension was also similar in both groups, whose mean systolic and diastolic blood pressures were roughly equal. The calcium and placebo groups had similar perinatal outcomes. Levine et al looked specifically for evidence that calcium supplementation might benefit either very young women or women whose baseline dietary calcium intake was low, but they found no such effects in either subgroup. Incidentally, the calcium supplements did not appear to increase the incidence of nephrolithiasis in the study group. The investigators conclude that elemental calcium supplementation during pregnancy did not prevent preeclampsia or other types of pregnancy-associated hypertension and did not improve perinatal outcomes. (Levine RJ, et al. N Engl J Med 1997;337:69-76.)
COMMENT BY STEVEN G. GABBE, MD
More than a dozen clinical trials as well as a series of meta-analyses have supported the beneficial effect of calcium supplementation in reducing preeclampsia. Many of these studies were conducted outside the United States, studied populations with a low dietary calcium intake, examined relatively small numbers of patients, did not include a placebo group, or included only women at high risk for preeclampsia. The large prospective, randomized study by Levine et al has none of these deficiencies and clearly demonstrates that calcium supplementation does not prevent preeclampsia. During pregnancy, the Recommended Dietary Allowance (RDA) for calcium is 1200 mg daily. Even in women with the lowest baseline dietary calcium intakes (33-581 mg daily) or in those with the greatest calcium requirements (adolescents age 12-16 years), calcium supplementation proved to be of no benefit. Fortunately, calcium supplementation did not increase the risk of renal calculi.
Given the increased maternal and perinatal morbidity and mortality associated with the hypertensive complications of pregnancy, the results of this study are disappointing. Calcium, like low-dose aspirin, has proven to be of no benefit. Yet, this information allows us to end the controversy on two therapies that were once thought to reduce the risk of preeclampsia and should stimulate us to investigate new strategies.
COMMENT BY ELIZABETH MORRISON, MD
Despite many recent advances in peripartum care, preeclampsia remains the leading cause of maternal mortality worldwide. Its substantial impact on perinatal morbidity and mortality presents equally daunting challenges for providers of maternity care. Those of us who provide this care are naturally interested in any potentially sound approaches to preventing preeclampsia, particularly because we lack effective screening tests to determine which women are at risk of developing hypertensive complications. The Calcium for Preeclampsia Prevention (CPEP) trial is by far the largest randomized study to date that has addressed these important issues.
Many clinicians became interested in calcium supplementation because earlier studiesmost of them lacking randomization or controlsoffered encouraging preliminary results. The results of the CPEP trial, awaited with great interest, are discouraging. This well-designed study enrolled a large number of women, assessed compliance, and looked at a number of clinically relevant outcomes. It demonstrates definitively that in low-risk populations, elemental calcium supplementation does not prevent or delay either preeclampsia or its substantial perinatal morbidity.
An interesting question is whether diets rich in calcium-containing foods, such as dairy products, might provide more benefit in preventing preeclampsia. An analogous situation is the failure of antioxidant supplements to replicate the apparent health benefits of diets high in fruits and vegetables. Given the critical importance of these questions, clinicians will hope to see the NIH study followed soon by others that examine preeclampsia prevention from additional innovative perspectives.
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