July 9, 1997
Contrary to prevailing medical opinion, taking high doses of calcium during pregnancy does not prevent preeclampsia in women who do not have any risk factors for the disease, according to the largest, most comprehensive clinical trial of its kind to date. Preeclampsia is a disorder of pregnancy that can strike without warning, causing protein in the urine and high blood pressure. In turn, preeclampsia may progress to eclampsia hypertension and generalized convulsions which may be fatal.
The trial, reported in the July 10 New England Journal of Medicine, was conducted by researchers at the National Institute of Child Health and Human Development (NICHD) and several other academic and research institutions. Funding was provided by the NICHD and by the National Heart, Lung, and Blood Institute.
"Clearly, women need some calcium during pregnancy," said the study's principal investigator, Richard J. Levine, MD, of the Division of Epidemiology, Statistics, and Prevention Research at the NICHD. But in light of the results of our study, the high doses of calcium thought to prevent preeclampsia at best provide no apparent benefit, and at worst, could cause complications in certain high risk women."
Preeclampsia is a potentially life threatening complication of pregnancy in which a woman may develop dangerously high blood pressure and begin excreting protein in the urine. About 5 percent of first time mothers and 1 to 2 percent of mothers having subsequent pregnancies develop the condition. The authors note that preeclampsia is a leading cause of maternal death. Even in cases where the condition does not progress to eclampsia, the children born to mothers with preeclampsia may be small for their gestational age or may be born prematurely. This may, in turn, place them at risk for a variety of other complications of birth.
Although the high blood pressure accompanying preeclampsia can be treated with blood pressure lowering drugs, the only curative treatment for the overall condition is immediate delivery. The results of numerous previous clinical trials and two meta analyses strongly suggested that calcium supplementation could greatly reduce the risk of preeclampsia. In fact, a meta analysis of 9 smaller trials published last year and receiving widespread publicity concluded that calcium supplementation could reduce the risk of preeclampsia by 62 percent.
Dr. Levine said that the current study, which found no reduction in preeclampsia from calcium supplementation, enrolled a total of more than twice the number of women than took part in all 9 trials in last year's analysis. In addition, the women who took part in the current study took as much or more calcium a day as did the women in the previous trials.
Dr. Levine added that the discrepancy between the current finding and the earlier studies could be explained by a number of factors. For example, many of the earlier studies did not have a placebo control group. In addition, in contrast to the current study, two of the earlier studies selected only women in whom test results indicated high risk for preeclampsia. Moreover, the most recent meta analysis also included a study of women who experienced hypertension during pregnancy, but may not have had preeclampsia.
For their study, Dr. Levine and his co investigators recruited 4589 healthy first time mothers who were from 13 to 21 weeks pregnant. Roughly half (2295 women) were randomly assigned to take four calcium tablets per day, with each tablet containing 500 mg. of calcium. The remainder (2294 women) were given a placebo containing no calcium. Both groups of women were also given a multivitamin supplement containing 50 mg. of calcium.
Excluded from the study were women having conditions known to place them at increased risk for preeclampsia: diabetes, pre existing hypertension, kidney disease, being pregnant with twins, and having previously had the condition during an earlier pregnancy. Also excluded were women thought to be at risk for developing kidney stones a condition that potentially could be worsened by high doses of calcium. This group included women who had kidney disease, had high concentrations of blood calcium, had blood in the urine, had previously had kidney stones, or had family members who had kidney stones.
Overall, compliance with the study's instructions was good, with women in the calcium group taking the tablets 64 percent of the time and women in the placebo group taking them 67 percent of the time. The women in the calcium group consumed an average of about 2369 mg of calcium a day, and the women in the placebo group averaged 982 mg of calcium a day. The estimate of the women's calcium intake was derived from the foods they ate as well as the pills they took. The National Academy of Sciences' Recommended Daily Allowance for calcium for pregnant women is 1200 mg a day. Dairy products and certain other foods contain high amounts of calcium, with a cup of whole milk containing 291 mg., a cup of skim milk, 302 mg., a cup of shredded whole milk mozzarella cheese, 579 mg., and a cup of tofu made with calcium sulfate, 868 mg.
At the study's conclusion, the researchers found no significant difference in the occurrence of preeclampsia between the two groups, with about 6.9 percent of the calcium group and 7.3 percent of the placebo group developing preeclampsia. Moreover, the calcium treatment did not appear to reduce the severity of the disease or delay the amount of time it took a woman to develop preeclampsia. Nor could the researchers find any significant reduction in the risk of preeclampsia in women who had the highest compliance rates for taking the tablets. Also, there was no benefit of calcium supplementation in women who had the lowest calcium levels when they entered the study, or in adolescents the group thought to have the greatest need for calcium during pregnancy. Although the women taking high doses of calcium during the trial did not experience any ill effects at the study's conclusion, Dr. Levine said it is possible that some women taking large amounts of calcium could develop kidney stones, particularly if they have a high concentration of calcium in the blood, kidney disease, or a personal or family history of kidney stones. In addition, high doses of calcium might suppress the function of the parathyroid gland, placing the newborn at risk for low calcium levels.
Our results do not support the use of calcium supplementation for the prevention of preeclampsia in healthy, nulliparous women, the authors wrote. Dr. Levine noted that because the study did not include women at high risk for preeclampsia, it could not determine whether calcium supplementation would prevent the development of preeclampsia in this group of women.
Other authors of the paper were John C. Hauth and Robert L. Goldenberg, the University of Alabama at Birmingham; Luis B. Curet and Gary M. Joffe, the University of New Mexico Health Sciences Center in Albuquerque; Baha M. Sibai and Steven A. Friedman, the University of Tennessee College of Medicine in Memphis; Patrick M. Catalano and Alice M Petrulis, Metrohealth Medical Center, Case Western Reserve University in Cleveland, Ohio; Cynthia D. Morris and Sig Linda Jacobson, Oregon Health Sciences University, in Portland; Joy R. Esterlitz and Marian G. Ewell, The Emmes Corporation, Potomac, Maryland; Elizabeth G. Raymond, the NICHD and Family Health International, Research Triangle Park, North Carolina; Diane E. Bild and Jeffrey A. Cutler, the National Heart, Lung, and Blood Institute, NIH; and Rebecca DerSimonian, John D. Clemens and Mark A. Klebanoff, NICHD.