1. Calcium supplementation for preventing pre-eclampsia/eclampsia Justus Hofmeyr, for the Calcium and Pre-eclampsia (CAP) Study Group* *Fernando Althabe, Sadiqua Allie, John Anthony, José Belizán, Eduardo Bergel, Ana Pilar Betran, Eckhart Buchmann, Sue Fawcus, Justus Hofmeyr, Anne Horak, Stephen Munjanja, Adegboyega Oyebajo, Diane Sawchuck, Mandisa Singata, Peter von Dadelszen Effective Care Research Unit, University of the Witwatersrand, Fort Hare and Eastern Cape Department of Health

2. Mdantsane, Eastern Cape (near East London, South Africa)

3. Labour ward, Cecilia Makiwane Hospital

4. SA National Enquiry into Maternal Deaths 2005-2007 1729 622 383 223 108 34 Population mortality estimates 150-580/100 000

5. Outline: Calcium and Pre-eclampsia/eclampsia Epidemiology Cochrane review of randomized trials Implications for practice Research agenda

6. Lancet. 1952 Jan 12;1(6698):64-8

8. Hamlin RHJ. Prevention of pre- eclampsia. Lancet 1962;1:864-865

9. Eclampsia in Addis Ababa 1994 to ‘99 Tikur Anbessa and St Paul's Hospitals, Addis Ababa Eclampsia 7.1/1000 deliveries case fatality rate 13%. ? Change in diet Abate M, Lakew Z. Eclampsia a 5 years retrospective review of 216 cases managed in two teaching hospitals in Addis Ababa. Ethiop Med J. 2006 Jan;44(1):27-31.Abate MLakew Z

11. Pre-eclampsia and dietary calcium Low incidence of pre-eclampsia noted in: –Ethiopia (Hamlin 1962) –Guatemala (Belizan 1980) Postulated due to high calcium diets –Hamlin RHJ. Prevention of pre-eclampsia. Lancet 1962;1:864-5. –Belizan JM, Villar J. The relationship between calcium intake and edema, proteinuria, and hypertension-gestosis: an hypothesis. American Journal of Clinical Nutrition 1980;33:2202-10.

12. Calcium to reduce pre-eclampsia: Cochrane systematic review: 1998 Large reduction in pre-eclampsia in several small studies No significant effect in large US study (CPEP) ? Publication bias ? Different effects in populations with low and adequate dietary calcium Hofmeyr GJ, Atallah ÁN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database of Systematic Reviews 1998

13. World Health organization randomized trial of calcium supplementation among low calcium intake women. Villar J, Abdel-Aleem H, Merialdi M, Mathai M, Ali M, Zavaleta N, Purwar M, Hofmeyr GJ, thi Nhu Ngoc N, Campódonico L, Landoulsi S, Carroli G, Lindheimer M et al. Am J Obstet Gynecol 2006;194: 639-649 ↓ Revised Systematic Review : Hofmeyr GJ, Lawrie TA, Atallah ÁN, Duley L. Cochrane Database of Syst Reviews 2010

14. Calcium vs Placebo: Pre-eclampsia

15. Calcium vs Placebo: Proteinuria

16. Calcium vs Placebo: Eclampsia

17. Calcium vs Placebo: Maternal Death

18. Calcium vs Placebo: Maternal death/ severe morbidity

19. Calcium vs Placebo: HELLP syndrome

20. Hypothesis: Calcium supplementation in 2 nd half of pregnancy: ↓ blood pressure (↓ vascular tone) ↓ serious complications related to hypertension No effect on other organ dysfunction eg endothelial ↓ BP → ↓ early deliveries (induction/CS) → ↓ low birthweight → ↑ time to develop HELLP syndrome To prevent multisystem dysfunction may need adequate calcium from before pregnancy Hofmeyr GJ, Duley L, Atallah A. Dietary calcium supplementation for prevention of pre-eclampsia and related problems: a systematic review and commentary. BJOG. 2007; 114: 933-943

21. Future research: The CAP study The Calcium and Pre-eclampsia study Randomized trial: calcium 500mg daily vs placebo commencing before conception till 20 weeks Participants: women with previous pre-eclampsia who intend to conceive Routine calcium in second half of pregnancy If effective, next step trials of community level calcium supplementation by food fortification ? Place of Vitamin D supplementation Further research on ideal dose

22. Calcium: summary of evidence Epidemiological association of dietary calcium with huge discrepancies in rates of pre-eclampsia/ eclampsia Calcium supplementation in the second half of pregnancy reduces –pre-eclamsia (but not in largest trial) –Severe morbidity (about 20%) This benefit is sufficient to justify programs to supplement pregnant women with low calcium diets Ongoing research to determine whether pre- pregnancy supplementation will reproduce the more dramatic epidemiological differences

23. Other benefits and risks of calcium supplementation Reduced hypertension Reduced osteoporosis Reduced Urinary stones Improved insulin sensitivity in type 2 diabetes ? Reduced colorectal cancer ? Increased risk of coronary artery disease if excessive ?? Increased prostate cancer

24. Options for calcium supplementation programs Individual supplementation during pregnancy (limited to antenatal care attenders): –Individuals with low calcium diet –Populations with low calcium diet –Women at high risk of pre-eclampsia (Nulliparous, previous pre-eclampsia, risk factors, screening, etc) –All pregnant women Population supplementation: fortification of staple foods – Broad population coverage, except people who grow their own food. Population dietary education

26. Daily provisional supply of calcium per capita in developing and developed countries (FAO, 1990) REGION CALCIUM (mg) World Developed countries Developing countries Africa Latin America Near East Far East Others 472 860 346 363 499 498 352 402