IJE Advance Access originally published online on April 30, 2007
International Journal of Epidemiology 2007 36(2):290-293; doi:10.1093/ije/dym048
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Cochrane Column
South African Cochrane Centre, Medical Research Council, PO Box 19070, Tygerberg 7505, South Africa. Email: taryn.young{at}mrc.ac.za
This month we feature the Cochrane Review assessing the effect of calcium supplementation during pregnancy on the occurrence of high blood pressure, and adverse maternal, fetal and neonatal outcomes.
The aim of the Column is to highlight Cochrane Reviews of relevance to public health, and to stimulate debate on relevance, feasibility and acceptability. The Cochrane Collaboration (http://www.cochrane.org) is an international, non-profit organization that prepares and disseminates up-to-date systematic reviews on the effects of healthcare interventions in order to help people make well-informed decisions. Systematic reviews aim to answer focused healthcare questions by systematically identifying and evaluating all relevant research studies and synthesizing their results.
If you are interested in contributing to the Cochrane Column or The Cochrane Collaboration, contact me at the South African Cochrane Centre.
A summary of Cochrane reviews relevant to health promotion and public health is available at http://www.vichealth.vic.gov.au/cochrane/
Dietary calcium supplementation and pre-eclampsia
1Department of Obstetrics and Gynaecology, East London Hospital Complex, PB X9047, East London 5201, South Africa, and Effective Care Research Unit.
2Evidence Based Medicine and Emegence Medicine, Universidade Federal de São Paulo.
3Obstetric Epidemiology, University of Leeds, UK.
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Introduction |
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High blood pressure with or without proteinuria causes considerable maternal and perinatal morbidity and mortality worldwide. Hypertensive disorders account for up to 40 000 maternal deaths annually.1 This means strategies to reduce the risk of hypertensive disorders of pregnancy are potentially important for public health.
Researchers first described an inverse relationship between calcium intake and hypertensive disorders of pregnancy in 1980.2 They observed that Mayan Indians in Guatemala had a high calcium intake pre-eclampsia and eclampsia incidence was low. The Mayan Indians traditionally soak their corn in lime before cooking. Pre-eclampsia is reportedly uncommon in Ethiopia where the diet, among other features, contained high levels of calcium.3 These observations were supported by other epidemiological and clinical studies, and led to the hypothesis that an increase in calcium intake during pregnancy could reduce high blood pressure and pre-eclampsia among women with low dietary calcium.
This hypothesis was tested in several randomized trials commencing in the late 1980s. These trials suggested a potential beneficial effect from calcium supplementation. New evidence is now available from a very large trial in communities with low dietary calcium intake.4 The objective of the Cochrane review is to assess the effect of calcium supplementation during pregnancy on the risk of high blood pressure and related maternal, fetal and neonatal adverse outcomes.
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Methods |
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We searched the Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Central Register of Controlled Trials (March 2006) for randomized trials comparing at least 1 g daily of calcium during pregnancy with placebo. Eligibility and trial quality were assessed. Data were extracted and analysed using Review Manager software.
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Results |
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Twelve trials (15 528 women) were included, all of good quality. Most women were low risk and had low dietary calcium. High blood pressure was less common in women allocated to calcium supplementation compared with placebo [relative risk (RR) 0.70; 95% confidence interval (CI) 0.57–0.86, random effects model; n = 14 946, 11 trials] as was pre-eclampsia (RR 0.48; 95% CI 0.33–0.69; n = 15 206, 12 trials) (Figure 1). Effect estimates were larger in trials of women at high risk of pre-eclampsia (RR 0.22; 95% CI 0.12–0.42; n = 587, 5 trials) and those with low baseline calcium intake (RR 0.36; 95% CI 0.18–0.70; n = 10 154, 7 trials).
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Maternal death combined with serious maternal morbidity was lower with supplement (RR 0.80; 95% CI 0.65–0.97; n = 9732, 4 trials); but the HELLP syndrome (haemolysis, elevated liver enzymes and low platelets), was more common (RR 2.67; 95% CI 1.05–6.82; n = 12 901, 2 trials). There was no overall effect on the risk of pre-term birth, or stillbirth or death before discharge from hospital.
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Discussion |
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Calcium supplementation with at least 1 g of calcium was associated with a halving in the relative risk of pre-eclampsia. Women with an adequate dietary intake of calcium were the only subgroup for which this was not statistically significant. The greatest reduction in risk appeared to be for women at high risk and for those with low baseline dietary calcium intake.
Although the relative risk of pre-eclampsia was reduced, this was not clearly reflected in any reduction in severe pre-eclampsia, eclampsia, or admission to intensive care. The relative risk of the composite outcome ‘maternal death or severe morbidity’ was reduced by 20% (95% CI 35–3%) for women allocated calcium supplementation. The HELLP syndrome was more common in the two trials reporting this.
Heterogeneity in the results seems to be largely associated with study size, with the small studies having more strongly positive results. A possible explanation may be that there is publication bias, with small studies that failed to report an effect for calcium supplementation not being published. The relatively modest effects found in the large trials contrast with the large differences reported in observational studies between populations with adequate and those with low dietary calcium intake. Possible explanations for these differing results include dietary calcium being a marker for other aetiological factors; starting supplementation in the middle trimester of pregnancy may be too late to be fully effective; the earlier observational studies may have exaggerated the potential benefits of calcium, perhaps due to unresolved confounding factors.
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Conclusion |
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The reduction in pre-eclampsia, and in ‘maternal death or severe morbidity’, support the use of calcium supplementation during pregnancy for women with low dietary intake.
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Notes |
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Based on: Hofmeyr GJ, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD001059
[GenBank]
. DOI: 10.1002/14651858.CD001059.pub2. 
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1 Villar J, Say L, Shennan A, Duley L, et al. Methodological and technical issues related to the diagnosis, screening, prevention and treatment of pre-eclampsia and eclampsia. Int J Gynecol Obstet (2004) 85:S28–S41.[CrossRef][Medline]
2 Belizan JM, Villar J. The relationship between calcium intake and edema, proteinuria, and hypertension-gestosis: an hypothesis. Am J Clin (1980) 33:2202–10.
3 Hamlin RHJ. Prevention of pre-eclampsia. Lancet (1962) 1:864–65.
4 Villar J, Abdel-Aleem H, Merialdi M, Ali M, et al. World Health Organisation randomized trial of calcium supplementation among low calcium intake pregnant women. Am J Obstet Gynecol (2006) 194:639–49.[CrossRef][ISI][Medline]
Commentary: Pregnant women benefit from calcium supplementation, but practical considerations remain
International Micronutrient Malnutrition Prevention and Control Program (IMMPaCt), Maternal and Child Nutrition Branch, Division of Nutrition and Physical Activity, U.S. Centers for Disease Control and Prevention (CDC), 4770 Buford Hwy, NE, MS K-25 Atlanta, GA 30341-3724, USA.
Although a recent Cochrane Review concludes that calcium supplementation during pregnancy can lower the risk of hypertension-related disorders,1 its full recommendation as a formal intervention cannot be made at this time. Research gaps concerning the bioavailability of calcium supplements in the presence of other nutrients—as well as potential technical limitations and adherence problems, particularly in developing countries—preclude changing current guidelines to recommend a more complex nutrition regimen.2
Hypertension complicates approximately 9% of all pregnancies worldwide, and pre-eclampsia and eclampsia are a major cause of maternal and perinatal morbidity and mortality. Currently, pre-eclampsia and gestational hypertension are considered either separate diseases affecting similar organs or different severities of the same underlying disorder.3 Based on available estimates and case-fatality rates, some authors have suggested that up to 40 000 women, most in developing countries, die of pre-eclampsia or eclampsia each year.2
A recent systematic review to determine the distribution of causes of maternal deaths found wide regional variation.4 Hypertensive disorders were reported as the cause of 16.1% of maternal deaths in developed countries, 9.1% in Africa, 9.1% in Asia and 25.7% in Latin America and the Caribbean.
Although calcium supplementation may seem a feasible intervention in developed and developing countries to reduce the risk of hypertension and pre-eclampsia during pregnancy, several issues need to be addressed before such a recommendation can be made. One is the bioavailability of calcium from supplements, which depends on whether they are consumed with food, their solubility and the size of the dose. The most effective dose, frequency, calcium compound and tablet characteristics need further study before clear recommendations can be issued. Additionally, calcium interacts with iron, zinc, magnesium and phosphorus, important micronutrients that are also needed during pregnancy.5 Calcium inhibits iron absorption in a dose-dependent and dose-saturable fashion, which suggests that calcium supplementation should be separated in time from the recommended daily iron and folic acid supplementation, when used. Calcium concentration in multiple vitamin and mineral supplements for pregnancy is much lower than the amounts used in the trials in this Cochrane Review for the purposes of reducing the risks of hypertensive disorders. In fact, the WHO/UNICEF/UNU multiple micronutrient supplement does not contain calcium.6
Calcium supplementation could be a major health service and technological challenge, especially in developing countries.7 Strategies should be developed for preparation, storage, distribution, quality control and compliance with daily supplements for large sections of the pregnant population. The cultural, financial, or educational barriers to changing policy and practice from iron and folic acid supplementation schemes require evaluation. Limited success in the implementation of iron and folic acid supplementation has been attributed in many instances to inadequate infrastructure and poor compliance, particularly in developing countries.8 Changing current guidelines to a more complex nutrition intervention that includes calcium needs further assessment, in terms of both practicality and cost-effectiveness.
From Pena-Rosas JP, Casanueva E. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems: RHL commentary (dated December 15, 2006). The WHO Reproductive Health Library, No 10, Update Software Ltd, Oxford, 2007. http://www.rhlibrary.com
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Sources of support: International Micronutrient Malnutrition Prevention and Control Program (IMMPaCt), Division of Nutrition and Physical Activity, US Centers for Disease Control and Prevention, Atlanta, GA, USA. The authors would like to thank Lawrence Grummer-Strawn, Deborah Galuska and Rick Hull from the Centers for Disease Control and Prevention (CDC) for their comments and wise criticism of this text.
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References |
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TopIntroductionMethodsResultsDiscussionConclusionReferencesAcknowledgementsReferences References |
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1 Hofmeyr GJ, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database of Systematic Reviews (2006) (Issue 3). Art. No. CD001059. DOI: 10.1002/14651858. CD001059. pub2.
2 Pena-Rosas JP, Casanueva E. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. RHL Commentary (2007) (Issue 10). The WHO Reproductive Health Library.
3 Villar J, Carroli G, Wojdyla D, et al. Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions? Am J Obstet Gynecol (2006) 194:921–31.[CrossRef][ISI][Medline]
4 Khan KS, Wojdyla D, Say L, Gulmezoglu M, Van Look PFA. WHO Analysis of causes of maternal death: a systematic review. Lancet (2006) 367:1066–74.[CrossRef][ISI][Medline]
5 Whiting SJ, Wood RJ. Adverse effects of high-calcium diets in humans. Nutr Rev (1997) 55:1–9.[ISI][Medline]
6 UNICEF. Multiple micronutrient supplements to enhance foetal and infant survival, growth ad development. Workshop to review effectiveness trials, June 15–18, 2004: Bangkok. Report.
7 Villar J, Say L, Shennan A, et al. Methodological and technical issues related to the diagnosis, screening, prevention, and treatment of pre-eclampsia and eclampsia. Int J Gynecol Obstet (2004) 85:S28–S41.[CrossRef][Medline]
8 Mora JO. Iron supplementation: overcoming technical and practical barriers. J Nutr (2002) 132(4):853S–855S.
Commentary: Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems
Women's Health and HIV Research Group, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
Hypertensive disorders of pregnancy are major causes of maternal deaths and morbidity worldwide and in South Africa, it was the commonest direct cause of maternal deaths in the period 2002–04.1 Furthermore, the aetiology of pre-eclampsia/eclampsia syndrome, a condition unique to human pregnancies, remains unknown. It is therefore not surprising that there have been numerous epidemiological studies attempting to link factors related to diet and the frequency of hypertensive disorders. In this review, a case is made for calcium supplementation during pregnancy to prevent hypertensive disorders. Most of these early studies had small sample sizes, however one of the larger trials by Levine et al.2 performed in nulliparas in a healthy population with probably a good daily calcium intake did not show any relationship. The largest trial, the recent WHO study which included over 14 000 women only found that there was less high blood pressure with calcium supplementation than with placebo. Nonetheless, the Cochrane review3 on calcium supplementation in pregnancy found a reduction in pre-eclampsia and in maternal deaths or severe morbidity from the 12 trials included in the analysis.
Implementing the recommendation of the authors presents numerous challenges, particularly for poor countries. The seeds of pre-eclampsia are laid early in pregnancy, namely, the first trimester, therefore if supplementation is going to be used, it needs to begin prior to pregnancy or at least from 12 weeks gestation. Most women in the public sector hospitals in South Africa, only initiate antenatal care at approximately 20 weeks gestation. Furthermore, the financial costs of calcium supplementation and the appropriate dose of calcium still needs to be established. While we wait for the actual aetiology of pre-eclampsia to be studied, it seems reasonable to follow the suggestion that calcium supplementation be combined with low dose aspirin for women at risk of pre-eclampsia.
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1 Department of Health. Saving Mothers. (2006) Third Report on Confidential Enquiries into Maternal Deaths in South Africa, the 2002–2004: Pretoria: DOH.
2 Levine RJ for the CPEP Study Group. Calcium for pre-eclampsia prevention (CPEP): a double-blind placebo-controlled trial in healthy nulliparas. Am J Obstet Gynecol (1997) 176:S2.[ISI]
3 Hofmeyr GJ, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database of Systematic Reviews (2006) (Issue 3). Art. No. CD001059. DOI: 10.1002/14651858. CD001059. pub2.
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