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

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

Labour ward, Cecilia Makiwane Hospital

SA National Enquiry into Maternal Deaths 2005-2007

1729

622

383

223 108

34

Population mortality estimates 150-580/100 000

Outline: Calcium and Pre-eclampsia/eclampsia

• Epidemiology• Cochrane review of randomized trials• Implications for practice• Research agenda

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

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

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.

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.

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 calciumHofmeyr GJ, Atallah ÁN, Duley L. Calcium supplementation

during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database of Systematic Reviews 1998

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 SystematicReview :Hofmeyr GJ, Lawrie TA,Atallah ÁN, Duley L.Cochrane Database ofSyst Reviews 2010

Calcium vs Placebo: Pre-eclampsia

Calcium vs Placebo: Proteinuria

Calcium vs Placebo: Eclampsia

Calcium vs Placebo: Maternal Death

Calcium vs Placebo:Maternal death/ severe morbidity

Calcium vs Placebo: HELLP syndrome

Hypothesis:Calcium supplementation in 2nd 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 pregnancyHofmeyr 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

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

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

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

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

Daily provisional supply of calcium per capita in developing and developed

countries (FAO, 1990)

REGION CALCIUM (mg)

WorldDeveloped countriesDeveloping countries

AfricaLatin AmericaNear EastFar EastOthers

472860346363499498352402