Burden of Calcium Deficiencies and Evidence for their Impact on Maternal and Neonatal Mortality

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, David Hall, France Donnay, Sue Fawcus, Justus Hofmeyr, Stephen Munjanja, Natalia Novikova, Adegboyega Oyebajo, Tina Purnat, Jim Roberts, Diane Sawchuck, Mandisa Singata, Kate Teela, Peter von Dadelszen

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

Labour ward, Cecilia Makiwane Hospital

Outline:
Calcium and pre-eclampsia:
Epidemiology Cochrane review of randomized trials Effects on the neonate New review on low-dose calcium supplementation Implications for practice Research agenda

Eclampsia per 10,000 births

250 200

150

100

50

0 UK 1920's UK 1990's Chandigarh, India 1990's

Difference in rates of eclampsia between rich and poor countries is spectacular Must be a biological reason . To what extent is this differences due to calcium deficiency? Can we change it?

Pre-eclampsia: burden of disease

For the mother:
Second most common obstetric cause of death Increased risk of caesarean section, cerebrovascular accident, pulmonary oedema and renal failure

For the baby:

Growth impairment Stillbirth Major cause of preterm birth

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

RHJ Hamlin Lancet 1952

Dietary modification program in Sydney

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

Preterm birth

Perinatal death

Childhood dental caries

 Epidemiological association of dietary calcium deficiency with pre-eclampsia/ eclampsia Calcium supplementation in late pregnancy reduces pre-eclamsia by 64% (but only 8% in largest trial) Severe morbidity by 20% Preterm birth by 10% (borderline significance) Perinatal death by 14% (borderline significance) Childhood systolic hypertension by 40% Childhood dental caries by 25% 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

Calcium: summary of evidence

Based on this evidence:

World Health Organization has recently recommended calcium supplementation with 1.5 to 2g calcium daily to pregnant women with low dietary calcium intake

WHO recommendation: comment

Based only on trials of 1.5 to 2 g of calcium daily 1.5 to 2 g calcium daily is above the daily recommended dietary calcium of 1 to 1.2 g. 1.5g elemental calcium daily weigh about 1kg for a 20 week supply. Ingestion of 3 large tablets daily may be difficult The cost of calcium is moderately high Calcium at doses >800 mg/day decreases iron absorption. Possible harm from too much calcium 1.5g too high to achieve with food fortification

WHO recommendation: comment

The second largest randomized trial, conducted in North America (CPEP), compared calcium 2g daily vs placebo in women with normal calcium intake. Actual median intakes were 2369g in calcium group vs 982g with placebo Additional supplementation of women with adequate dietary calcium had no measurable effect on pre-eclampsia Therefore unlikely that megadoses of calcium have more benefit than doses to achieve physiological dietary levels.

Possible harm from calcium

? Myocardial infarction (EPIC-Heidelberg cohort study) Gambia study: calcium 1.5 g daily during pregnancy may cause rebound bone demineralisation following pregnancy. Our Cochrane review identified an unexpected increase in HELLP syndrome with calcium supplementation only in late pregnancy. We postulated reduced hypertension may mask underlying pre-eclampsia, which left untreated progresses to HELLP syndrome

Low dose calcium supplementation for preventing pre-eclampsia: a systematic review and commentary
J Hofmeyr, on behalf of the Calcium and Pre-eclampsia (CAP) Study Group: Jos Belizn, Eduardo Bergel, Ana Pilar Betran, Eckhart Buchmann, Gabriela Cormick, France Donnay, Sue Fawcus, David Hall, Stephen Munjanja, Adegboyega Oyebajo, Tina Purnat, Jim Roberts, Diane Sawchuck, Mandisa Singata, Kate Teela, Peter von Dadelszen

Low dose calcium review: Methods

Cochrane methodology Primary inclusion criteria:
Calcium supplementation <1g without co-supplements Secure allocation concealment (low risk of bias) Double blinding with placebo

If the above criteria failed to produce adequate data, we planned to include:

quasi-randomized trials trials without placebo control trials of multiple supplements,

with appropriate caution in the interpretation

Results
All trials used 500mg daily Consistent 60% reduction in pre-eclampsia across all 9 trials (2234 women) Significant reduction for all high quality trials; and all trials of calcium alone An unexpected finding in one high quality trial of calcium plus antioxidants commencing at 812 weeks of pregnancy was a trend to reduced miscarriage (1/29 versus 8/31, RR 0.06, 95% CI 0.00 to 1.04).

Conclusions
Available evidence supports the probable effectiveness of low-dose calcium supplementation Low quality of evidence requires further research If the WHO recommendation of 1.5 to 2g calcium daily is not achievable, it is reasonable to use a lower dosage (eg 500mg daily)

Timing of calcium supplementation

Trials to date have supplemented during pregnancy, mainly after 20 weeks Pre-eclampsia is caused by defective placentation in the first trimester May require adequate calcium before and in early pregnancy to reverse the large epidemiological discrepancies in incidence of pre-eclampsia (and thus preterm birth)

Calcium and Pre-eclampsia Trial

 Randomized trial: calcium 500mg daily vs placebo commencing before conception till 20 weeks All women receive routine calcium in second half of pregnancy Participants: women with previous pre-eclampsia who intend to conceive 366 women recruited to date If effective, next step will be food fortification Our analysis plan includes measuring effect on miscarriage.

The Calcium and Pre-eclampsia (CAP) study

 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

Thank you