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October 2001; Volume 3; 76-79
By Mario Merialdi, MD, and José Villar, MD
Pregnancy-induced hypertension (PIH) is a common and potentially dangerous complication of pregnancy. PIH complicates approximately 10% of pregnancies1 and can be induced by pregnancy in normotensive women or aggravated in women with chronic hypertension.2 PIH commonly is categorized into three progressively severe types: gestational hypertension; pre-eclampsia (hypertension, proteinuria, and edema); and eclampsia (preeclampsia and convulsions or coma). In addition, women with chronic hypertension also can develop preeclampsia.2
PIH, especially if associated with proteinuria, is associated with increased perinatal mortality and morbidity1 and, along with infection and hemorrhage, is one of the major causes of maternal death. Despite extensive research on this disease, the etiology of PIH still is unknown and the only definitive treatment is delivery. However, early detection and appropriate management have resulted in significantly reduced maternal and perinatal mortality rates.2 Treatment with antihypertensive drugs can prevent the development of severe PIH,3 and treatment of eclampsia with magnesium sulfate reduces risk of further convulsions.
Nutritional interventions to prevent PIH, if successful, would have considerable clinical and public health implications, especially in developing countries where dietary deficiencies are prevalent and access to optimal obstetric care is limited. Recent epidemiological and experimental studies conducted in several countries have shown an inverse relationship between calcium intake and preeclampsia/eclampsia. Also, maternal calcium supplementation during pregnancy may reduce the risk of PIH.4
If scientific evidence shows that calcium supplementation reduces the incidence of pregnancy-induced PIH, programs to provide calcium supplementation in pregnancy would be a relatively cheap and accessible intervention for reducing the worldwide burden of preeclampsia and eclampsia.
Villar and Belizan conducted a systematic review of 10 clinical trials of the effect of maternal calcium supplementation on PIH.5 They found that baseline dietary calcium intake and the presence of risk factors for PIH were the two primary factors that were likely to modify the effect of calcium supplementation on the risk of PIH (see Table 1). Six of the 10 studies reviewed examined populations with a mean dietary calcium intake of less than 900 mg/d; the remaining four studies were conducted in populations with a higher mean dietary calcium intake.
In a stratified analysis, the results of the six studies in populations with a mean dietary calcium intake of less than 900 mg/d were pooled and compared with the results obtained by the four studies conducted in populations with a mean intake of greater than 900 mg/d. The risk of developing high blood pressure was decreased more by calcium supplementation in women with low dietary calcium intakes (relative risk [RR] 0.49, 95% confidence interval [CI] 0.38, 0.62) than in women with higher intakes (RR 0.90, 95% CI 0.81, 0.99). (See Table 2.) Similarly, calcium supplementation reduced the risk of preeclampsia significantly among women with low calcium intake (RR 0.32, 95% CI 0.21, 0.49) but not among women with adequate intake (RR 0.86, 95% CI 0.71, 1.05). (See Table 3.)
Villar and Belizan then stratified clinical trials by whether they included populations at low or high risk of developing PIH. Four trials were conducted in high-risk populations and six conducted in low-risk populations. The PIH risk factors were young maternal age (teenagers), previous history of preeclampsia, increased sensitivity to angiotensin II, and pre-existing hypertension.
The analysis showed that women at high risk of developing PIH benefited more from calcium supplementation than did low-risk women. In high-risk women, calcium supplementation reduced the incidence of PIH markedly more (RR 0.35, 95% CI 0.21, 0.57) than in low-risk women (RR 0.84, 95% CI 0.76, 0.92) (see Table 2). Similar results were observed in the reduction of risk of developing preeclampsia (compared to controls, in high-risk women, calcium supplementation resulted in a RR of 0.22, 95% CI 0.11, 0.43 compared to a RR of 0.79, 95% CI 0.65, 0.94 in the low-risk women). (See Table 3.)
In conclusion, the subgroup analysis performed by Villar and Belizan showed that there is promising evidence of a protective effect of calcium supplementation on PIH, especially in women with risk factors for PIH or with low dietary calcium intake.5 This analysis indicates that differences in baseline population characteristics may explain disparities in the results of trials studying the efficacy of similar interventions. Calcium supplementation during pregnancy is likely to be an effective strategy to reduce the incidence of PIH when provided to high-risk populations, or to populations with diets nutritionally deficient in calcium. In pregnant women with adequate calcium intake, the benefit of calcium supplementation has not been shown.5
Nutritional supplementation can be provided either to alleviate deficiency or, in non-deficient individuals, to obtain a pharmacological effect. Correcting calcium deficiency may be more beneficial in preventing PIH than providing this micronutrient in calcium-replete women, in whom supplementation is a pharmacological rather than a nutritional intervention.5 A possible mechanism of calcium supplements is to prevent the rise in parathyroid hormone that occurs with low calcium intake. Increased levels of parathyroid hormone may stimulate muscular contractility, and contribute to the vasoconstriction seen in PIH.6
Currently, the Department of Reproductive Health and Research at the World Health Organization is implementing a large multicenter and multinational randomized clinical trial to definitively assess the effectiveness of calcium supplementation as a preventive strategy for preeclampsia in women with low calcium intake. The results of this study, expected to include 8,500 women, will inform future recommendations on calcium supplementation during pregnancy. In the meantime, the present scientific evidence suggests a beneficial effect of calcium supplementation in calcium-deficient women. Women should be encouraged to consume at least 1,200 mg of calcium per day through diet or supplementation during pregnancy.
Drs. Merialdi and Villar are Medical Officers, Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland.
1. Report of National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000;183: S1-S22.
2. Cunningham FG, et al. Williams Obstetrics. New York: McGraw Hill; 1993.
3. Abalos E, et al. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2001;2:CD002252.
4. Atallah AN, et al. Calcium supplementation during pregnancy to prevent hypertensive disorders and related problems. Cochrane Database Syst Rev 2001;3: CD001059.
5. Villar J, Belizan JM. Same nutrient, different hypothesis: Disparities in trials of calcium supplementation during pregnancy. Am J Clin Nutr 2000;71: 1375S-1379S.
6. Belizan JM, et al. The relationship between calcium intake and pregnancy-induced hypertension: Up-to-date evidence. Am J Obstet Gynecol 1988;158:898-902.
7. Levine R, et al. Trial of calcium for prevention of preeclampsia. N Engl J Med 1997;337:69-76.
8. Belizan JM, et al. Calcium supplementation to prevent hypertensive disorders of pregnancy. N Engl J Med 1991;325:1399-1405.
9. Purwar M, et al. Calcium supplementation and prevention of pregnancy induced hypertension. J Obstet Gynaecol Res 1996;22:425-430.
10. Lopez-Jaramillo P, et al. Calcium supplementation and the risk of preeclampsia in Ecuadorian pregnant teenagers. Obstet Gynecol 1997;90:162-167.
11. Sanchez-Ramos L, et al. Prevention of pregnancy-induced hypertension by calcium supplementation in angiotensin II-sensitive patients. Obstet Gynecol 1994;84:349-353.
12. Lopez-Jaramillo P, et al. Dietary calcium supplementation and the prevention of pregnancy hypertension. Lancet 1990;335:293.
13. Villar J, Repke JT. Calcium supplementation during pregnancy may reduce preterm delivery in high-risk populations. Am J Obstet Gynecol 1990;163:1124-1131.
14. Lopez-Jaramillo P, et al. Calcium supplementation reduces the risk of pregnancy-induced hypertension in an Andes population. Br J Obstet Gynaecol 1989;96: 648-655.
15. Villar J, et al. Calcium supplementation reduces blood pressure during pregnancy: Results of a randomized controlled clinical trial. Obstet Gynecol 1987;70: 317-322.
16. Crowther CA, et al. Calcium supplementation in nulliparous women for the prevention of pregnancy-induced hypertension, preeclampsia and preterm birth: An Australian randomized trial. FRACOG and the ACT Study Group. Aust N Z J Obstet Gynaecol 1999;39: 12-18.
|Summary of the trials in the systematic review of calcium supplementation during pregnancy4|
Calcium Intake (mg)
|Levine et al7||USA||1,113 ± 691||1,135 ± 675||low risk||0.94 (0.77,1.16)|
|Belizan et al8||Argentina||642 ± 448||646 ± 396||
|Purwar et al9||India||336 ± 156||352 ± 142||low risk||0.17 (0.04, 0.77)|
|Lopez-Jaramillo et al10||Ecuador||628||605||high risk (teenagers)||0.21 (0.07, 0.58)|
|Sanchez-Ramos et al11||USA||630 ± 217||666 ± 226||high risk (Angiotensin II- sensitive patients)||0.31 (0.12, 0.84)|
|Lopez-Jaramillo et al12||Ecuador||
|high risk (positive roll over test)||0.09 (0.01, 1.48)|
|Villar and Repke13||USA||1,119 ± 677||1,336 ± 796||high risk (teenagers)||0.14 (0.01, 2.67)|
|Lopez-Jaramillo et al14||Ecuador||292 ± 126||low risk||0.15 (0.04, 0.66)|
|Villar et al15||Argentina, USA||1,129 ± 736||914 ± 478||low risk||0.36 (0.04, 3.24)|
|Crowther et al16||Australia||adequate||low risk||0.44 (0.21, 0.90)|
Presented are mean calcium intake and standard deviations, plus relative risk for preeclampsia (95% confidence interval) associated with calcium supplementation.
Subgroup analysis: Effect of calcium supplementation during pregnancy on relative risk of high blood pressure, by level of risk and dietary calcium intake5
|Subgroup||Calcium-Supplemented Subjects (Cases/Total Subjects)||Control Subjects(Cases/Total Subjects)||Relative Risk (95% CI)|
|Low risk (n = 6 trials)||611/3,146||732/3,161||0.84 (0.76, 0.92)|
|High risk (n = 3 trials)*||15/141||54/156||0.35 (0.21, 0.57)|
|Adequate calcium intake (³ 900 mg/d) (n = 4 trials)||547/2,505||614/2,517||0.90 (0.81, 0.99)|
Low calcium intake (< 900 mg/d) (n = 5 trials)
|79/782||172/800||0.49 (0.38, 0.62)|
Presented are results pooled from nine clinical trials. One clinical trial included preeclampsia as an outcome, but did not include pregnancy-induced hypertension.
|* Includes women at high risk for developing pregnancy-induced hypertension because they were teenagers, had preeclampsia previously, had pre-existing hypertension, or had increased sensitivity to angiotensin II.|
Subgroup analysis: Effect of calcium supplementation during pregnancy on relative risk of preeclampsia, by level of risk and calcium dietary intake5
|Subgroup||Calcium-Supplemented Subjects (Cases/Total Subjects)||Control Subjects (Cases/Total Subjects)||Relative Risk (95% CI)|
|Low risk (n = 6 trials)||188/3,146||240/3,161||0.79 (0.65, 0.94)|
|High risk (n = 4 trials)*||8/266||47/291||0.22 (0.11, 0.43)|
Adequate calcium intake (³ 900 mg/d) (n = 4 trials)
|169/2,505||174/2,517||0.86 (0.71, 1.05)|
Low calcium intake (< 900 mg/d) (n = 6 trials)
|27/907||90/935||0.32 (0.21, 0.49)|
Presented are results pooled from 10 clinical trials.
* Includes women at high risk for developing pregnancy-induced hypertension because they were teenagers, had preeclampsia previously, had pre-existing hypertension, or had increased sensitivity to angiotensin II.
An article on clinical trials of red yeast rice (Alternative Therapies in Women’s Health, July 2001) noted that a clinical trial had been performed with Cholestin, a standardized red yeast rice extract manufactured by Pharmanex. Apparently Pharmanex has reformulated the product without changing the name; the currently marketed version of Cholestin contains not red yeast rice, but policosanol, a beeswax product. Thanks to the alert reader who pointed this out, a review of clinical trials of policosanol will appear in a future issue.