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CALCIUM AND PREVENTION OF PRE-ECLAMPSIA –
SUMMARY OF CURRENT EVIDENCEi
By Martha Carlough, IntraHealth
Hypertensive disorders of pregnancy (pre-eclampsia/eclampsia) complicate
approximately 5-10% of pregnancies globally and are associated with substantial
maternal and perinatal morbidity and mortality; estimated as the cause of death in
40,000 women annually. Approximately half these deaths are in Sub Saharan Africa
and half in Asia. Though the pathophysiology of pre-eclampsia/eclampsia is multifactorial and still not clearly understood, there is evidence to support that calcium
supplementation in pregnancy to women at risk and/or women with low calcium
intake reduces incidence of pre-eclampsia, complications of severe pre-eclampsia
and death due to eclampsia, and to a lesser extent, perinatal death. Although its
effect is only moderate (likely reducing maternal deaths due to pre-eclampsia by
approximately 20%) compared to other interventions including magnesium
sulphate and access to EmOC, it is an evidence based, potentially cost effective
intervention with large scale public health implications.
Adequate calcium intake is a global health concern
Although there are many approaches used by different organizations and regions in
estimating adequate dietary intake of calcium (and other
minerals/micronutrients)1 actual intake is considerably less in many populations.
Even in the US/Canada where consumption of animal products is high, female
adolescents 14-18 years of age (YOA) demonstrate reduced calcium intake for
metabolic needs and there are significant differences between racial groups with
average adult (AA) individuals consuming less calcium after 25 YOA.2 The AVERAGE
adult reproductive age female “adequate intake” is in the range of 1000-1200 mg
(for non-lactating women). Pregnant women need an average of 300 mg additional
calcium intake for a total of 1300-1500 mg / day to support metabolic needs.ii In
many countries and regions, daily intake is well below the recommended intake. 3
Region4
Calcium intake (mg/day)
World
Developed countries
Developing countries
Africa
Latin America
Near East
Far East
472
860
346
363
499
498
352
These different methods take into consideration: bioavailability, other health/lifestyle factors (e.g. sun exposure) and
methods of measurement (e.g. RDA or recommended daily allowance is intake level sufficient for almost all individuals in the
particular age group vs. AI or adequate intake which is derived from intakes of healthy individuals in a particular subgroup.
2
NIH, 2004
3
Institute of Medicine Food and Nutrition Board (1997). Dietary Reference Intakes for Calcium, Phosphorus, Magnesium,
Vitamin D, and Fluoride. National Academy Press, Washington, DC.
4
Food and Agriculture Organization of the United Nations, 2000
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Evidence on association of calcium supplementation with lower blood
pressure

This association is true for adults, pregnant women, people who have a
diagnosis of hypertension, and children whose mothers were supplemented
during pregnancy

More significant results are seen in populations with lower calcium intake
(<800mg/day)5

There is adequate evidence that supplementation of pregnant women
during the later part of pregnancy lowers risk of developing hypertension.
Cochrane systematic review of >15K pregnant women supplemented
between 20-32 weeks of gestation with relative risk of HTN =0.7 and 95% CI
0.57-0.86; for women with calcium intakes <900mg/day relative risk of
developing HTN =0.47 with 95% CI 0.29-0.76).6
Evidence on association of calcium supplementation during pregnancy with a
reduced the risk of severe pre-eclampsia, eclampsia and neonatal mortlaity
in women with low calcium intake
There have been observations (related to ethnic food choices and reduced risk of
pre-eclampsia in these populations) as well as limited clinical studies suggesting
that increasing calcium intake during pregnancy reduces pre-eclampsia but until
recently no large population, high quality data . In fact, a US based study (CPEP
trial) of almost 5000 nulliparous women with adequate calcium intake concluded
that there was no benefit which has resulted in lack of support and call for larger
studies and more clear evidence to support this potential intervention. 7

WHO randomized trial of 14,3K pregnant women with low dietary intake
(<600 mg/day).8 Supplementation of calcium supplementation (1.5 g/day)
was associated with a non-significant risk of pre-eclampsia (4.1% vs. 4.5%)
but a significant reduced relative risk of eclampsia (RR=0.68 with 95% CI
0.48-0.97), severe pre-eclampsia with complications (RR=0.68 with 95% CI
0.66-0.89) and neonatal mortality (RR=0.70 95% CI 0.56-0.88)

Cochrane Systematic review of 12 studies (15,206 women) including the
WHO randomized trial demonstrated reduced relative risk of pre-eclampsia
with calcium supplementation (RR=0.48 and 95% CI 0.33-0.69) with
greatest effect among high risk women (defined as pregnancy in
adolescence, previous pre-eclampsia or pre-existing HTN) with a RR=0.22
van Mierlo LA, Arends LR, Streppel MT, Zeegers MP, Kok FJ, Grobbee DE, Geleijnse JM. (2006). Blood pressure response to
calcium supplementation: a meta-analysis of randomized controlled trials. J Hum Hypertens, 8, 571-80.
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. Hofmeyr GJ, Atallah AN, Duley L. (2006). Calcium supplementation during pregnancy for preventing hypertensive disorders
and related problems. Cochrane Database Syst Rev , 19;3:CD001059.
7.
Levine, RJ, Hauth, JC, Curet, LB Sibai BM, Catalano PM, Morris CD. Et.al. Trial of calcium to prevent pre-eclampsia. NEJM.
1997.; 337:69-76.
8.
Villar J, Abdel-Aleem H, Merialdi M, Mathai M, Ali M, Zavaleta N. et.al. World Health Organization Randomized Trial of
calcium supplementation among low calcium intake pregnant women. Am J Obstet Gynecol 2006; 194: 639-49.
5.
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and 95% CI 0.12-0.42) and those with low calcium intake (defined as <900
mg) with a RR=0.36 and 95% CI 0.18-0.70)6 Other more modest effects in
this systematic review (not present in all studies or more rare event) include
maternal death/severe morbidity (RR=0.80 95% CI 0.65-0.97) and perinatal
death (RR=0.89 95% CI 0.73-1.09 – not achieving statistical significance.
Numerous global MCH organizations support the potential of calcium
supplementation in pregnant women with low intake in improving health
outcomes

The Lancet MCH Undernutrition series – Calcium supplementation could be
expected to prevent 21 500 maternal deaths and reduce DALYs by 620 000
based on modeling of reduction of pre-eclampsia by half and proportionate
reduction of maternal deaths due to hypertensive disorders.9 (if assumed
that this intervention has a similar effect on deaths due to hypertensive
disorders).

Global Alliance to Prevent Prematurity and Stillbirth - Calcium
supplementation is weakly recommended for the prevention of preterm
birth but strongly recommended for the prevention of pre-eclampsia.10

Bill and Melinda Gates Foundation – Recommend scale up feasibility of
calcium supplementation as an intervention which is cost effective, relatively
simple, and compatible with other interventions and of medium public
health impact.11

United Kingdom Department for International Development (DfID) –
Classified maternal calcium supplementation as an intervention with
sufficient evidence to be implemented in 36 high burden countries home to
90% of the global burden of stunting and cited evidence demonstrating that
micronutrients (calcium with iron and folic acid) could prevent 24% of all
maternal deaths.12

United Nations Children’s Fund –Ranks calcium supplementation in
pregnancy among interventions shown to improve maternal survival in
epidemiological studies, to be appropriate for universal application and
ready for wide-scale implementation. 13
Bhutta ZA, Ahmed T, Black RE, Cousens S, Dewey K, Giugliani E, Haider BA, Kirkwood B, Morris SS, Sachdev HP, Shekar M;
Maternal and Child Undernutrition Study Group. (2008). What works? Interventions for maternal and child undernutrition
and survival. Lancet , 371 (9610), 417-40.
10.
Menezes, EV;Mohammad, YY; Soomro T;Haws RA; Darmstadt GL; Bhutta ZA. (2009). Reducing stillbirths: prevention and
management of medical disorders and infections during pregnancy. BMC , 9 (1: S4).
11
. Cho, Duff Gillespie Sabrina Karklins Andreea Creanga Sadaf Khan NaHyun. (2007). Scaling Up Health Technologies. Report
prepared for the Bill & Melinda Gates Foundation.
12.
United Kingdom Department for International Development (DFID). (2009). The neglected crisis of undernutrition: Evidence
for action. http://www.dfid.gov.uk/
13.
United Nations Children’s Fund (UNICEF). . (2009). The state of the world’s children 2009. Maternal and Newborn Health .
http://www.reliefweb.int/rw/lib.nsf/db900sid/JBRN7NBDCM/$file/unicef_jan09.pdf?openelement
9.
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
White Ribbon Alliance – Mention calcium supplementation for the
prevention of Eclampsia and Pre Eclampsia among 16 interventions that can
save newborn lives.14

World Bank/ UNICEF/UNFPA/Partnership for Maternal, Newborn and Child
Health – Classify calcium supplementation in pregnancy as a proven
intervention to reduce maternal mortality and under 5 mortality by
reducing neonatal prematurity. 15

European Commission – Europe Aid - Maternal calcium supplementation for
improving maternal and birth outcomes was classified as having sufficient
evidence of effectiveness and feasibility to recommend implementation in all
36 countries with childhood stunting prevalence > 20%.16
Summary of evidence review:

While the CPEP trial of almost 5000 nulliparous women with adequate
calcium intake concluded that there was no significant benefit of calcium
supplementation after the first trimester on the reduction of eclampsia
which has resulted in lack of support and call for larger studies and more
clear evidence to support this potential intervention, the large WHO study
and Cochrane review strongly indicate benefit of calcium supplementation
among low calcium intake populations, and would be especially of benefit to
women at higher risk of severe PE/E.

The recommendation of this working group is to improve calcium intake of
pregnant women in populations with low calcium diet including a strong
evaluation component of the impact on severe pre eclampsia, eclampsia and
maternal death.
Recommendations to generate necessary program evidence:
There are still relevant research questions to be addressed. The improvement of
calcium intake prior or in early pregnancy could represent a greater improvement
on maternal outcome and in the modeling of blood pressure in the progeny. In
addition, research studies are required to assess feasible and universal
interventions to scale up improvement of calcium intake in populations with low
calcium diet. Below, a list of potentially relevant studies addressing the main
pending research questions.
. White Ribbon Alliance. (2006). Investing to save newborn lives.
http://www.whiteribbonalliance.org/Resources/Documents/Investing%20to%20Save%20Newborn%20Lives%20Initiative
%20Report.pdf
15
. World Bank/ UNICEF/UNFPA/Partnership for Maternal, Newborn and Child Health. . (2009). Health Systems for the
Millennium Development Goals: Country Needs and Funding Gaps. Background document for the Taskforce on Innovative
International Financing for Health Systems. Working Group 1: Constraints to Scaling Up and Costs.
16.
Claire Chastre. (2008). Enhancing EC’s contribution to address child and maternal undernutrition and its causes. EuropeAid .
http://ec.europa.eu/europeaid/infopoint/publications/europeaid/documents/eaue_child_and__maternal_undernutrition.pdf
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
Randomized trial(s) of the effects of calcium supplementation previous
to pregnancy i.e. on women with low calcium intake who are planning a
pregnancy, or on women with low calcium intake with previous
complications due to pre-eclampsia (severe pre-eclampsia, eclampsia,
perinatal loss).

Large scale population based effectiveness study to assess long term
impact of calcium diet improvement in populations with low calcium
intake.

Feasibility and acceptability studies on calcium intake improvement
through various distribution routes (calcium supplementation, food
fortification, market-based high calcium food supplementation) to
provide information on best ways to scale-up calcium intake at a
population level.

Operational research on the combination of calcium supplementation
strategies with other antenatal care based interventions (e.g. distribution
of Fe and folate, ITP for malaria
i. This document was prepared by on behalf of the Monitoring, Evaluation and Research Task Force of
the PE/E working group from accumulated peer reviewed publications as well presentations from the
experts at the 2nd meeting of the Technical Working Group (notably Dr. Fernando Althabe and Prof. Lelia
Duley). It is NOT original material and is intended as a working draft to inform further discussion and
planning.
1st draft by Martha C. Carlough, MD, MPH, UNC/CH and IntraHealth International, Inc: Revised by:
Fernando Althabe, Jose Belizan, and Gabriela Cormick.
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