Use of calcium and vitamin D for prevention of pre-eclampsia/eclampsia

Justus Hofmeyr, for the Calcium and Pre-eclampsia (CAP) Study Group* *Fernando Althabe, John Anthony, Jos Belizn, Eduardo Bergel, Ana Pilar Betran, Eckhart Buchmann, Gabriela Cormack, Sue Fawcus, Justus Hofmeyr, 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

Outline:
Vitamin D and pre-eclampsia:
Epidemiology Randomized trials

Calcium and pre-eclampsia:

Epidemiology Cochrane review of randomized trials Implications for practice Research agenda

Vitamin D and Pre-eclampsia: Epidemiology

Several observational studies have shown an association between low Vitamin D intake or serum levels (25(OH)D)*, and pre-eclampsia, but reports inconsistent**
*Wei S et al. Longitudinal vitamin D status in pregnancy and the risk of pre-eclampsia BJOG.. 2012 Mar 29 *Woodham PC et al. Midgestation maternal serum 25hydroxyvitamin D level and soluble fms-like tyrosine kinase 1/placental growth factor ratio as predictors of severe preeclampsi.a Hypertension 2011 Dec;58(6):1120-5 **Nassar N et al. Systematic review of first-trimester vitamin D normative levels and outcomes of pregnanc.y Am J Obstet Gynecol 2011 Sep;205(3):208.e1-7

Vitamin D supplementation in pregnancy

Systematic review: 6 small randomized trials (1023 women) Vit D plus calcium: 400 women Vit D alone: 623 women Statistically borderline reduction in low birthweight No data on effect of Vit D alone on Pre-eclampsia Numbers too small for meaningful analysis

De-Regil LM et al. Vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev. 2012 Feb

Ongoing research
Large trial of Vitamin D supplementation in pregnancy completed (Bhutta et al) Results expected soon Watch this space

In view of the deficiencies of protein, calcium and vitamin B1 in the average Australian diet, especially of those who have toxaemia....

Hamlin 1962: Experience in Ethiopia

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

Market Addis Ababa

Pre-eclampsia and dietary calcium

Low incidence of pre-eclampsia noted in Guatemala (Belizan 1980) Postulated due to high calcium diets
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 calcium
Hofmeyr GJ, Atallah N, 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, Campdonico 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 N, Duley L. Cochrane Database of Syst 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: 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 prepregnancy supplementation will reproduce the more dramatic epidemiological differences

Calcium and Pre-eclampsia Trial

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

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 dose excessive Tablets a bit expensive, and heavy to transport

 Individual supplementation during pregnancy (limited to antenatal care attenders):

Options for calcium supplementation programs

All pregnant women Individuals/populations with low calcium diet Women at high risk of pre-eclampsia (Nulliparous, previous pre-eclampsia, risk factors, screening, etc) ?consider lower dosage eg 500mg/day

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
World Developed countries Developing countries Africa Latin America Near East Far East Others CALCIUM (mg)

472 860 346 363 499 498 352 402

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 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

Food fortification: Advantages

rapid improvements in the micronutrient intake and status of a population cost-effective public health intervention if consumed regularly will maintain body stores fortified staple foods will provide physiological doses of micronutrients does not require changes in existing food patterns does not depend on compliance minimal risk of toxicity, when properly designed and regulated

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

Hamlin 1962: Experience in Ethiopia

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

Vitamin D and mortality

Has been suggested that increasing vitamin D levels is associated with reduceed mortality Grant WB. An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr. 2011 Sep;65(9):1016-26.