Hofmeyr_Burden of Calcium Deficiencies and Evidence for Their Impact on Maternal and Neonatal...

7/30/2019 Hofmeyr_Burden of Calcium Deficiencies and Evidence for Their Impact on Maternal and Neonatal Mortality

1/40

Burden of Calcium Deficiencies andEvidence for their Impact on Maternal

and Neonatal MortalityJustus 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, StephenMunjanja, Natalia Novikova, Adegboyega Oyebajo,Tina Purnat, Jim Roberts, Diane Sawchuck, Mandisa

Singata, Kate Teela, Peter von Dadelszen


2/40

g

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


3/40

Labour ward, Cecilia Makiwane Hospital


4/40


5/40


6/40


7/40

Outline:

Calcium and pre-eclampsia:EpidemiologyCochrane review of randomized trials

Effects on the neonate

New review on low-dose calcium supplementation Implications for practice

Research agenda


8/40

Eclampsia per10,000 births

Difference in rates ofeclampsia between

rich and poorcountries isspectacular

Must be a biologicalreason

To what extent is this

differences due tocalcium deficiency?

Can we change it?0

50

100

150

200

250

UK 1920's UK 1990's Chandigarh,

India 1990's


9/40

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


10/40

Daily provisional supply of calciumper capita in developing and developed

countries (FAO, 1990)

REGION CALCIUM (mg)

World

Developed countriesDeveloping countries

Africa

Latin America

Near East

Far East

Others

472

860346

363

499

498

352

402


11/40

RHJ Hamlin Lancet 1952Dietary modification program in Sydney


12/40

Hamlin RHJ. Prevention of pre-eclampsia.

Lancet 1962;1:864-865

Hamlin 1962: Experience in Ethiopia


13/40

Market Addis Ababa


14/40

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 betweencalcium intake and edema, proteinuria, andhypertension-gestosis: an hypothesis.American Journal of Clinical Nutrition1980;33:2202-10.


15/40

Calcium to reduce pre-eclampsia:Cochrane systematic review: 1998

Large reduction in pre-eclampsia in several smallstudies

No significant effect in large US study (CPEP)

? Publication bias

? Different effects in populations with low andadequate dietary calcium

Hofmeyr GJ, Atallah N, Duley L. Calciumsupplementation during pregnancy for preventinghypertensive disorders and related problems. Cochrane

Database of Systematic Reviews 1998


16/40

World Health organization randomized trial ofcalcium supplementation among low calcium intakewomen.

Villar J, Abdel-Aleem H, Merialdi M, Mathai M, Ali M, ZavaletaN, Purwar M, Hofmeyr GJ, thi Nhu Ngoc N, CampdonicoL, 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


17/40

Calcium vs Placebo: Pre-eclampsia


18/40

Calcium vs Placebo: Proteinuria


19/40

Calcium vs Placebo: Eclampsia


20/40

Calcium vs Placebo: Maternal Death

C l i l b


21/40

Calcium vs Placebo:Maternal death/ severe morbidity

P bi h


22/40

Preterm birth


23/40

Perinatal death


24/40

Childh d d l i


25/40

Childhood dental caries

C l i f id


26/40

Calcium: summary of evidence Epidemiological association of dietary calcium deficiency with

pre-eclampsia/ eclampsia

Calcium supplementation in late pregnancy reducespre-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 supplementpregnant women with low calcium diets

Ongoing research to determine whether pre-pregnancysupplementation will reproduce the more dramatic

epidemiological differences


27/40

Based on this evidence: World Health Organization has recently

recommended calcium supplementation with 1.5 to2g calcium daily to pregnant women with lowdietary calcium intake


28/40

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 dailyrecommended 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


29/40

WHO recommendation: comment The second largest randomized trial, conducted in

North America (CPEP), compared calcium 2gdaily vs placebo in women with normal calciumintake.

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 physiologicaldietary levels.

ibl h f l i


30/40

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. Wepostulated reduced hypertension may maskunderlying pre-eclampsia, which left untreatedprogresses to HELLP syndrome


31/40

Low dose calcium supplementation for

preventing pre-eclampsia: a systematic

review and commentaryJ Hofmeyr, on behalf of the Calcium and Pre-eclampsia (CAP) StudyGroup: Jos Belizn, Eduardo Bergel, Ana Pilar Betran, EckhartBuchmann, Gabriela

Cormick, FranceDonnay, Sue Fawcus,David Hall, StephenMunjanja, Adegboyega

Oyebajo, Tina Purnat,Jim Roberts,Diane Sawchuck,Mandisa Singata,Kate Teela,

Peter von Dadelszen

d l i i h d


32/40

Low dose calcium review: Methods Cochrane methodology

Primary inclusion criteria:Calcium supplementation


33/40


34/40

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 8-12 weeks of pregnancy was a trend to reducedmiscarriage (1/29 versus 8/31, RR 0.06, 95% CI

0.00 to 1.04).


35/40

Conclusions

Available evidence supports the probableeffectiveness of low-dose calciumsupplementation

Low quality of evidence requires furtherresearch

If the WHO recommendation of 1.5 to 2g

calcium daily is not achievable, it isreasonable to use a lower dosage (eg 500mgdaily)


36/40

Timing of calcium supplementation

Trials to date have supplemented duringpregnancy, 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 incidenceof pre-eclampsia (and thus preterm birth)

C l i d P l i T i l


37/40

Calcium and Pre-eclampsia Trial

The Calci m and Pre eclampsia (CAP)


38/40

The Calcium and Pre-eclampsia (CAP)study

Randomized trial: calcium 500mg daily vs placebocommencing before conception till 20 weeks

All women receive routine calcium in second half ofpregnancy

Participants: women with previous pre-eclampsiawho intend to conceive

366 women recruited to date If effective, next step will be food fortification

Our analysis plan includes measuring effect on

miscarriage.

Options for calci m s pplementation


39/40

Options for calcium supplementationprograms

Individual supplementation during pregnancy(limited to antenatal care attenders):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 staplefoods Broad population coverage, except peoplewho grow their own food.

Population dietary education


40/40

Thank you

Hofmeyr_Burden of Calcium Deficiencies and Evidence for Their Impact on Maternal and Neonatal...

Documents

Transcript of Hofmeyr_Burden of Calcium Deficiencies and Evidence for Their Impact on Maternal and Neonatal...