Original Article
Calcium Supplementation to Prevent Hypertensive Disorders of Pregnancy
N Engl J Med 1991; 325:1399-1405November 14, 1991
- Abstract
- Abstract
Background.
Calcium supplementation has been reported to reduce blood pressure in pregnant and nonpregnant women. We undertook this prospective study to determine the effect of calcium supplementation on the incidence of hypertensive disorders of pregnancy (gestational hypertension and preeclampsia) and to determine the value of urinary calcium levels as a predictor of the response.
Methods.
We studied 1194 nulliparous women who were in the 20th week of gestation at the beginning of the study. The women were randomly assigned to receive 2 g per day of elemental calcium in the form of calcium carbonate (593 women) or placebo (601 women). Urinary excretion of calcium and creatinine was measured before calcium supplementation was begun. The women were followed to the end of their pregnancies, and the incidence of hypertensive disorders of pregnancy was determined.
Results.
The rates of hypertensive disorders of pregnancy were lower in the calcium group than in the placebo group (9.8 percent vs. 14.8 percent; odds ratio, 0.63; 95 percent confidence interval, 0.44 to 0.90). The risk of these disorders was lower at all times during gestation, particularly after the 28th week of gestation (P = 0.01 by life-table analysis), in the calcium group than in the placebo group, and the risk of both gestational hypertension and preeclampsia was also lower in the calcium group. Among the women who had low ratios of urinary calcium to urinary creatinine (≤0.62 mmol per millimole) during the 20th week of gestation, those in the calcium group had a lower risk of hypertensive disorders of pregnancy (odds ratio, 0.56; 95 percent confidence interval, 0.29 to 1.09) and less of an increase in diastolic and systolic blood pressure than the placebo group. The pattern of response was similar among the women who had a high ratio of urinary calcium to urinary creatinine during the 20th week of gestation, but the differences were smaller.
Conclusions.
Pregnant women who receive calcium supplementation after the 20th week of pregnancy have a reduced risk of hypertensive disorders of pregnancy. (N Engl J Med 1991;325:1399–405.)
Media in This Article
Figure 1
Mean (±SE) Ratio of Urinary Calcium to Urinary Creatinine during Pregnancy in the Calcium and Placebo Groups.Figure 2
Percentage of Women in the Calcium and Placebo Groups in Whom Hypertensive Disorders of Pregnancy (Gestational Hypertension and Preeclampsia) Developed, According to the Week of Gestation.Article Activity
- Article
IN epidemiologic studies conducted a decade ago, we described an inverse relation between calcium intake and gestational hypertension and eclampsia.1 , 2 We also found that calcium supplementation lowered blood pressure in pregnant and nonpregnant women.3 4 5 These results have been supported by recent studies of hypertensive subjects6 and pregnant women.7 Although the mechanism of this effect is not yet understood, the largest reduction of blood pressure occurred among pregnant women with low pretreatment serum calcium concentrations and plasma renin activity, and women given calcium supplements had both lower blood pressure and higher levels of urinary calcium excretion.8 Conversely, low levels of urinary calcium excretion have been described in women with preeclampsia.9 Thus, lowering blood pressure through changes in calcium metabolism may prevent hypertensive disorders in pregnancy.4
On the basis of this evidence, we proposed10 that a large randomized, controlled trial be conducted to assess the preventive effect of 2 g of supplemental calcium per day on the incidence of hypertensive disorders of pregnancy. The results of such a trial are reported here.
Methods
Study Subjects
We conducted a multicenter, double-blind, randomized controlled trial to assess the effect of supplementation with 2 g of elemental calcium per day on the incidence of hypertensive disorders of pregnancy (gestational hypertension and preeclampsia). Women were considered to have gestational hypertension if measurements of blood pressure on two occasions at least six hours apart revealed a systolic blood pressure ≥140 mm Hg and a diastolic blood pressure ≥90 mm Hg after the 20th week of gestation in the absence of proteinuria. Women were considered to have preeclampsia if they met the criteria for gestational hypertension and had proteinuria (protein, >0.3 g per liter) on examination of at least two separate (more than six hours apart) random urine specimens obtained after the 20th week of gestation. The women were enrolled at three affiliated hospitals of the Centro Rosarino de Estudios Perinatales, Rosario, Argentina. Two are public institutions serving patients with low socioeconomic status, and the other hospital is private, serving patients of medium-to-high socioeconomic status.11
Pregnant women who sought prenatal care before the 20th week of gestation between January 1987 and September 1989 were screened for possible enrollment. They were eligible for the study if they were nulliparous, had singleton pregnancies, were less than 20 weeks pregnant at the time of the first interview, and had blood pressures below 140/90 mm Hg (mean of five measurements). Gestational age was estimated from the date of the last menstrual period and confirmed by ultrasonography; women in whom the two estimates of gestational age differed by more than 10 days were excluded from the study. None of the women had any clinical or laboratory evidence of present or past disease, none were taking any medications, and all had normal oral glucose-tolerance tests. The study was approved by the Joint Human Voluntary Committee of the Centro Rosarino de Estudios Perinatales and the participating hospitals, and all the women gave informed, written consent.
Treatment Protocol
A total of 1194 pregnant women were enrolled in the study (580 at the public hospitals and 614 at the private hospital). They were randomized at each hospital by a random-sample generator program provided by the Epistat Statistical Package. A complete set of numbered, sealed, opaque envelopes containing the randomization codes was sent to each of the three hospitals. The series of bottles (one bottle for each scheduled prenatal visit) containing all the tablets needed for the entire pregnancy were kept at the central unit. When a woman was enrolled and the corresponding envelope was opened at the hospital, the study number was revealed to the central unit. Thus, the woman, the nurses, and the physicians responsible for prenatal care were all unaware of the woman's treatment status. The nurses and physicians were also responsible for distributing the bottles of medications, taking blood-pressure measurements, and collecting blood and urine samples at the follow-up visits, which were scheduled at 23, 25, 27, 31, and 35 weeks and then weekly until delivery.
The calcium tablets were specially prepared for this study by a local pharmaceutical company (Bachiarri Laboratories, Rosario, Argentina). Each calcium tablet contained calcium carbonate (500 mg of elemental calcium) and granulated starch. The placebo tablets contained lactose and granulated starch and were identical to the calcium tablets with respect to weight, size, flavor, and color. Two tablets from each patient's total supply were obtained at random, and their calcium content was determined by an independent laboratory. The mean (±SD) calcium content of the tablets was 470±12 mg, and that of the placebo tablets was 6.7±0.1 mg. Each woman was instructed and continually encouraged to take four tablets per day, for a total daily calcium supplementation of 2000 mg in the calcium group. Dietary calcium intake was estimated for all patients enrolled during the first four months of the study by the 24-hour dietary-recall method. We made no attempt to alter dietary intake during the study.
Treatment compliance was assessed at each prenatal visit; at that time, the bottle that had been in use was collected and a new bottle was given to the woman. The tablets remaining in the old bottle were counted, and the number of tablets actually taken was divided by the number required. In the first 780 women studied, urinary calcium excretion was also measured to evaluate compliance with treatment,8 , 12 at 20, 25, 27, 31, and 35 weeks of gestation; calcium excretion was measured in the first urine specimen after an overnight fast. The results were expressed as the ratio of calcium to creatinine in the urine.
At each visit, the blood pressure was measured five times with the patient seated after 10 minutes of rest, and the mean value was used in the analysis. Blood-pressure measurements were validated by repeated measurements in randomly selected women. The correlation coefficients of these repeated measures were most often above 0.70. Clinic staff members who obtained lower values were retrained in the method of blood-pressure measurement, and their technique and results were then closely monitored. Blood pressures were measured with four random-zero sphygmomanometers rotated monthly among the centers and calibrated every three weeks.
Serum total calcium and magnesium concentrations and urinary calcium excretion were measured by direct colorimetric methods; urinary creatinine excretion was measured by the alkaline picrate method. Serum phosphate was measured by the colorimetric method of Fiske and Subbarow, and serum uric acid was measured by the enzymatic uricase reaction.
Statistical Analysis
The main end point or dependent variable of the trial was the incidence of hypertensive disorders of pregnancy. No woman had eclampsia during the study. Although the rates of hypertensive disorders of pregnancy were calculated with use of both phase 4 and phase 5 Korotkoff sounds for diastolic blood pressure,13 the results based on the phase 5 sound are presented, for conformity with recent National Institutes of Health recommendations14 and to allow comparisons with most other published reports. Patients in whom gestational hypertension or preeclampsia developed were treated according to the routine protocol of the participating hospitals and were considered to have completed the study at that point for the purpose of this analysis. Nevertheless, data were collected on the outcomes of pregnancy and neonatal outcomes for all these patients as well.
The a priori hypothesis was that calcium supplementation would reduce the incidence of hypertensive disorders of pregnancy in the calcium group as compared with the placebo group.10 The sample size had a statistical power of 70 percent to detect a true difference equal to the observed reduction in hypertensive disorders of pregnancy, a power of 60 percent to detect differences in the incidence of gestational hypertension, and a power of 25 percent to detect differences in the incidence of preeclampsia.
All women were included in the treatment group to which they had been assigned, regardless of any problems that occurred during follow-up or as a consequence of noncompliance with treatment. Comparisons between treatment and placebo groups were performed with the chi-square test or t-test (two-tailed) and calculations of odds ratios and 95 percent confidence limits.15 Life-table analysis was used for comparisons between groups at different times during pregnancy (Kaplan–Meier estimates and log-rank test).
Results
A total of 601 women were randomly assigned to the placebo group, and 593 were assigned to the calcium group. The difference in the size of each group was within the expected limit.16 Twenty-seven women (2.3 percent) were lost to follow-up after randomization (13 in the placebo group and 14 in the calcium group) but before they started any treatment, and therefore were not included in the follow-up analyses. Follow-up was incomplete for 46 women in the placebo group and 52 women in the calcium group because of a change of hospital, physician, or residence. Nonetheless, all were included in the analyses up to the time when they were lost to follow-up. For the subgroup with incomplete follow-up, information about delivery was available for 12 women in the placebo group and 17 women in the calcium group.
Thus, a total of 588 women in the placebo group and 579 in the calcium group were included in the final analyses. The study groups were very similar at the time of randomization with respect to several clinical, demographic, and biochemical variables, with the exception of whether there was a history of previous abortions (Table 1Table 1
Characteristics of the Women at the Time of Random Assignment to the Calcium Group or the Placebo Group.*). The results were very similar when the 27 women who were lost to follow-up immediately after randomization were included in the analysis. Information on calcium intake was available for 87 women in the placebo group and 86 women in the calcium group who enrolled during the first four months of the study. The mean (±SD) intake of calcium per day was 642±448 mg and 646±396 mg in the placebo and calcium groups, respectively.Treatment Compliance
The number of tablets taken by the women as determined by pill counts was very similar in both groups. On average, the women in the placebo group took 86 percent of the tablets and the women in the calcium group took 84 percent. Seventy-four percent of the women in the placebo group and 69 percent of those in the calcium group took more than 80 percent of the planned number of tablets throughout their pregnancies.
The ratio of urinary calcium to urinary creatinine was used to indicate compliance with calcium supplementation in the first 780 women (374 women in the calcium group and 406 in the placebo group) enrolled in the study. As shown in Figure 1Figure 1
Mean (±SE) Ratio of Urinary Calcium to Urinary Creatinine during Pregnancy in the Calcium and Placebo Groups., the ratios in the two groups were similar at the time of randomization. The values were higher in the calcium group at all times thereafter; the highest ratio in this group occurred during the 27th week of gestation.Calcium Supplementation and Incidence of Hypertensive Disorders of Pregnancy
Data on the frequency of hypertensive disorders of pregnancy in the two groups are shown in Figure 2Figure 2
Percentage of Women in the Calcium and Placebo Groups in Whom Hypertensive Disorders of Pregnancy (Gestational Hypertension and Preeclampsia) Developed, According to the Week of Gestation. and Table 2Table 2
Effect of Calcium Supplementation on the Incidence of Hypertensive Disorders of Pregnancy.. We used a life-table analysis to compare the probability of hypertensive disorders of pregnancy, according to the week of gestation, in the two groups. The risk of a diagnosis of a hypertensive disorder of pregnancy was significantly lower (P = 0.01) in the calcium group during the follow-up period than in the placebo group, and this protective effect was more evident after the 28th week of gestation (Fig. 2).The overall treatment effect is shown in Table 2. The incidence of gestational hypertension was 10.7 percent in the placebo group and 7.2 percent in the calcium group (odds ratio, 0.64; 95 percent confidence interval, 0.43 to 0.96), and the incidence of preeclampsia was 3.9 percent in the placebo group and 2.6 percent in the calcium group (odds ratio, 0.65; 95 percent confidence interval, 0.35 to 1.25). The overall rates of hypertensive disorders of pregnancy were 14.8 percent in the placebo group and 9.8 percent in the calcium group (odds ratio, 0.63; 95 percent confidence interval, 0.44 to 0.90).
Stratified Analysis According to Base-Line Urinary Calcium Excretion
The women in each treatment group were classified as having low or high base-line ratios of urinary calcium to urinary creatinine if their values were ≤0.62 or >0.62 mmol per millimole, respectively; 0.62 was the median value for the total population at the time of randomization. The calcium and placebo groups were compared at the two levels with respect to all the variables included in Table 1. The groups were very similar with respect to these variables, except that the mean (±SD) base-line ratio of urinary calcium to urinary creatinine was lower in the low-ratio group than the high-ratio group (0.36±0.14 vs. 1.13±0.59 mmol per millimole).
Among the women with low base-line ratios of urinary calcium to urinary creatinine, calcium supplementation reduced the rate of hypertensive disorders of pregnancy from 13.2 percent in the placebo group to 7.8 percent in the calcium group (odds ratio, 0.56; 95 percent confidence interval, 0.29 to 1.09). No significant treatment effect was found in the calcium group with high base-line ratios (9.4 percent in the calcium group vs. 11.0 percent in the placebo group; odds ratio, 0.84; 95 percent confidence interval, 0.71 to 1.71).
Figure 3Figure 3
Percentage of Women in the Calcium and Placebo Groups in Whom Hypertensive Disorders of Pregnancy (Gestational Hypertension and Preeclampsia) Developed, According to Base-Line Ratios of Urinary Calcium to Urinary Creatinine. shows the probability that a hypertensive disorder of pregnancy would develop according to the base-line ratio of urinary calcium to urinary creatinine and treatment group, obtained from a life-table analysis. Among the women with low base-line ratios, those in the calcium group were less likely to have a hypertensive disorder of pregnancy than those in the placebo group (P = 0.08). Among the women with high base-line ratios, those in the calcium group had a slightly lower risk of such a disorder after the 33rd week of gestation.Blood-Pressure Changes during Pregnancy
Treatment effects on blood pressure were calculated as adjusted for base-line (20th week of gestation) blood pressure with a repeated-measure analysis (multivariate analysis of variance), according to the week of gestation, and as blood-pressure differences from the 20th week through term. For all groups, diastolic and systolic blood pressure increased from the 20th week to term, as expected.13 The mean adjusted systolic blood pressure in the calcium group was 112.1 mm Hg at term, as compared with 113.2 mm Hg in the placebo group (P = 0.08). There was a significant interaction between time (weeks of gestation) and treatment (P = 0.006 by multivariate analysis of variance). The mean (±SD) increase in systolic blood pressure from the 20th week of gestation to term was 9.4±9.9 mm Hg in the placebo group and 8.2±9.1 mm Hg in the calcium group (95 percent confidence interval for the difference between means, 0.11 to 2.29).
At term, the mean adjusted diastolic blood pressure was 75.0 mm Hg in the placebo group and 74.3 mm Hg in the calcium group. No interaction effect between the number of weeks of gestation and treatment was found for diastolic blood pressure. The mean increase in diastolic blood pressure between the 20th week of gestation and term was 8.7±9.2 mm Hg in the placebo group and 8.0±8.6 mm Hg in the calcium group (95 percent confidence interval for the difference between means, —0.4 to 1.8).
Stratified analyses of blood-pressure values according to base-line ratios of urinary calcium to urinary creatinine are shown in Figure 4Figure 4
Mean Increase in Systolic and Diastolic Blood Pressure from the 20th Week of Gestation to Term in the Calcium and Placebo Groups, According to Base-Line Ratios of Urinary Calcium to Urinary Creatinine.. For both systolic blood pressure and diastolic blood pressure, the women with low base-line ratios who received supplemental calcium had the least increase in blood pressure. By term, the mean increase in systolic blood pressure was 6.4±9.6 mm Hg for this group, which was lower than that in the corresponding placebo group (8.9±9.5 mm Hg; 95 percent confidence interval for the difference between means, 1.4 to 3.6). For diastolic blood pressure, the mean increase among women in the group with low base-line ratios who received calcium supplementation was 6.9±7.7 mm Hg, which was also lower than that in the corresponding placebo group (8.8±9.3 mm Hg; 95 percent confidence interval for the difference between means, 0.9 to 2.9). No treatment effect was found in the group with high base-line ratios.Biochemical Values
Serum phosphate and total calcium concentrations were evaluated according to the week of gestation and treatment group. The serum phosphate concentrations were similar in the two groups. There was, however, a decline in serum phosphate levels in both groups, from 1.03±0.11 mmol per liter at the 20th week of gestation to 0.97±0.09 mmol per liter at term. Serum calcium values were very similar in the two treatment groups at the beginning of the study and at all times during the follow-up period.
Other Outcomes of Pregnancy
The incidence of complications of pregnancy, such as premature rupture of membranes, diabetes mellitus, and third-trimester hemorrhage, and the numbers of hospital admissions and medical treatments were very similar in the two groups. The rates of urinary tract infection were the same (9.0 percent) in the two groups (Table 3Table 3
Outcomes of Pregnancy According to Treatment Group.*).There were 13 perinatal deaths — 6 in the calcium group and 7 in the placebo group (Table 3). In the placebo group, four deaths were associated with hypertension and abruptio placentae, whereas none of those in the calcium group were related to these conditions.
Preterm Deliveries
It has previously been suggested that there is an association between calcium supplementation and greater gestational age7 and lower rates of preterm delivery17 in high-risk populations. In this study, the incidence of birth before 37 weeks of gestation was 6.3 percent in the calcium group and 6.8 percent in the placebo group. Stratified analysis according to the base-line ratio of urinary calcium to urinary creatinine suggests, although this is contrary to the tendency observed above, a protective effect in the 173 women in the group with high base-line ratios who received calcium (3.5 percent), as compared with the 198 women in the placebo group with high ratios at base line (6.1 percent; odds ratio, 1.8; 95 percent confidence interval, 0.6 to 5.5).
Side Effects
Possible side effects and symptoms reported by the women, including gastrointestinal and neurologic symptoms, were monitored during pregnancy. No differences or specific patterns that could be related to treatment status were found.
Discussion
We found in this double-blind, randomized, controlled trial that supplementation with 2 g of calcium per day decreased the incidence of hypertensive disorders of pregnancy. A low ratio of urinary calcium to urinary creatinine at the 20th week of pregnancy was a good predictor of this effect. We think that these results probably represent a biologic effect of calcium supplementation. The study design resulted in groups that were very similar. As is consistent with the natural history of the disease, the preventive effect was evident as early as the 28th week of gestation.
Furthermore, all other reported studies conducted in very different populations4 , 7 , 17 18 19 20 have demonstrated a trend toward a protective effect of calcium supplementation for hypertensive disorders of pregnancy. We calculated the magnitude of this effect, including the results of this study, using meta-analysis21; the typical odds ratio was 0.46 (95 percent confidence interval, 0.35 to 0.60).
The calcium supplementation had no side effects. It is also unlikely that the increase in urinary calcium excretion would cause a higher incidence of renal stones,22 since the duration of supplementation was short and there is a large increase in urinary excretion of inhibitors of crystal formation in normal pregnant women.23 Nevertheless, we suggest that patients be carefully screened for a history of renal disease and chronic urinary tract infections before high doses of calcium are recommended.
The mechanisms involved in the lower incidence of hypertensive disorders in the calcium group are not understood. Disturbances in calcium metabolism, including an association between calcium absorption and hypertension, have been demonstrated in hypertensive subjects.24 These alterations could also be present in women with gestational hypertension or preeclampsia. For instance, intraerythrocyte calcium levels were reported to be higher in women with gestational hypertension.25 The intracellular ionized calcium concentration in platelets and sensitivity to angiotensin II are increased in women with preeclampsia,26 , 27 and they have larger increases in platelet concentrations of intracellular calcium in response to arginine vasopressin early in pregnancy.28 Finally, preeclampsia is a hypocalciuric state.9 , 29 , 30 Therefore, considerable evidence suggests an association between preeclampsia and alterations in calcium metabolism that could be mediated by changes in the hormonal regulation of calcium metabolism.10
On the other hand, high calcium intake is associated with increased serum calcium levels,31 lower parathyroid hormone concentrations,31 , 32 and a reduction in renal calcium reabsorption — all of which act to increase urinary calcium excretion — as well as with lower blood pressure4 , 5 and a lower rate of hypertensive disorders of pregnancy. By lowering serum levels of parathyroid hormone, calcium supplementation could reduce intracellular calcium concentrations in such cells as vascular smooth-muscle cells, diminishing their responsiveness to pressure stimuli and therefore lowering blood pressure.10
Supported by a grant (3-P-86–0040) from the International Development Research Center in Canada.
We are indebted to L. Sainz, M. Osta, L. Girgenti, M. Reale, A. Nasi, M.A. Barreiro, M. Lopez, A. Bouzon, and C. Sosa for their help with data collection; to Drs. D. Degiovanni, J.C. Nardin, E. Paquez, and C. Maggi for making hospital activities possible; to Drs. G. Carroli, J. Corbelli, J. Cellerino, J. Malamud, H. Paez, and E. Zanuttini for their help in the recruitment and follow-up of the patients; to I. Quaglia, H. Borda, M. Barroso, and R. Aimar for technical assistance; to the nurses, staff, and physicians of Maternidad Martin, Hospital Roque Saenz Peña, and Sanatorio de la Mujer; and to J. Starks for assistance in the preparation of the manuscript.
Source Information
From the Centro Rosarino de Estudios Perinatales, Rosario, Argentina. Address reprint requests to Dr. Villar at Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, 1211 Geneva 27, Switzerland.
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