Primary Prevention of Preeclampsia and Eclampsia: Aspirin and Calcium
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February 2012
Primary Prevention of
Preeclampsia and Eclampsia:
Aspirin and Calcium M A IL ING A D DR E S S
PO Box 900922
Seattle, WA 98109
USA
Technology Opportunity Assessment
A D DR E SS
2201 Westlake Avenue
Prepared for the Merck for Mothers Program Suite 200
Seattle, WA, USA
TEL: 206.285.3500
FAX: 206.285.6619
www.path.orgCopyright © 2013, Program for Appropriate Technology in Health (PATH). All rights reserved. Cover photo credit: PATH/Heng Chivoan. Funding for this technology assessment was provided by Merck.
Primary Prevention of Preeclampsia and Eclampsia: Aspirin
and Calcium
Summary
WHO recommends calcium supplementation during pregnancy for all women living in areas where
dietary calcium intake is low and low-dose aspirin for women at high risk of developing
preeclampsia/eclampsia. A range of supplements exist to address these recommendations.
Statement of Need
Preeclampsia (PE) is a life-threatening disorder that only occurs during pregnancy, childbirth, and the
postpartum period and is characterized by high blood pressure (hypertension) and protein in the urine
(proteinuria). Convulsions (also known as “fits”) with signs of PE indicate eclampsia, although
convulsions occasionally occur in the absence of hypertension with proteinuria. Preeclampsia and
eclampsia (PE/E) are among the leading causes of maternal death and disability worldwide. The World
Health Organization (WHO) estimates that PE/E account for at least 16% of maternal deaths in low-
resource settings that lack the skilled providers and facilities required for prevention, identification, and
management of the condition.1 In most regions, PE/E rank second only to hemorrhage as a specific, direct
cause of maternal death. The risk of PE/E varies greatly depending on where a woman lives; the risk that
a woman in a low-resource country will die of PE/E is approximately 300 times greater than that for a
woman in a high-resource country.2
Of all pregnancies, up to 10% are complicated by hypertension3; PE/E account for about half of these
cases worldwide.4 While the incidence of PE varies greatly worldwide, WHO estimates the number of
new cases of PE to be seven times higher in low-resource countries (2.8% of live births) than in high-
resource countries (0.4% of live births).5 A woman with PE in a low-resource country is subsequently
three times more likely to progress to eclampsia (2.3%) than a woman in a high-resource country (0.8%).4
Reducing morbidity and mortality from PE requires primary prevention, and where that fails, timely
identification and access to the treatment package for severe PE/E.* Unfortunately, although 80% of
pregnant women receive antenatal care at least once in low-resource countries, only slightly more than
half receive the WHO-recommended minimum of four antenatal visits.6 Consequently, they do not have
access to primary prevention interventions or screening for—or identification of—PE. Additionally,
although most cases of eclampsia present in the third trimester of pregnancy, with about 80% of eclamptic
seizures occurring intrapartum or within the first 48 hours following delivery, only around 50% of births
* The treatment package includes in-patient monitoring, anticonvulsive and antihypertensive therapy, optimal timing of childbirth, and skilled
attendance at birth.
1were attended by skilled health personnel in the WHO African Region and the WHO South-East Asia
Region.6
Given the serious barriers that currently exist for seeking and accessing obstetric services, primary
preventive interventions can help reduce morbidity and mortality in all pregnant women but most
significantly in those women who either might not receive treatment or receive it too late to prevent
serious morbidity and mortality. WHO has recently recommended the following interventions for the
prevention of PE7: (1) In areas where dietary calcium intake is low, calcium supplementation during
pregnancy (at doses of 1.5 g–2.0 g elemental calcium per day) is recommended for all women, but
especially those at high risk of developing PE†; and (2) low-dose acetylsalicylic acid (aspirin, at doses of
75 mg) is recommended for women at high risk of developing the condition. While evidence-based
primary prevention interventions currently exist, there is a clear need for finding ways to increase access
to them by ensuring they are relatively simple to administer, are acceptable to the pregnant women taking
them, are affordable, are easily available worldwide, can be integrated relatively easily into current
logistics systems, and are also sustainable.
Technology Solutions Landscape
Aspirin
Acetylsalicylic acid, also known as aspirin, is a cheap, widely available drug used as an analgesic to
relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication.
Aspirin also has an antiplatelet effect by inhibiting the production of thromboxane which under normal
circumstances binds platelet molecules together to create a patch over damaged walls of blood vessels. Its
antiplatelet effect is the theoretical benefit in preventing PE. In 2011, WHO reviewed evidence on
prevention and treatment of PE/E and developed recommendations based on clinical evidence. In this
review, they found that the use of antiplatelet agents in women at “high risk” for developing PE was
associated with a significant reduction in the risk of gestational hypertensions.‡
In addition, there was a statistically significant risk reduction in the development of PE among women
who received antiplatelet agents compared with placebo which remained consistent across risk groups for
PE, although it was more marked among high-risk women. These data led WHO to make a strong
recommendation to give low-dose aspirin (75 mg/day) for the prevention of PE in women at high risk of
developing the condition. The WHO guideline development group recommended that the dose nearest to
75 mg be used in settings where 75 mg aspirin tablets are not available.7
† Factors predisposing women to PE and recommendations for which women should receive primary preventive interventions should be based on
the local epidemiology of PE.
‡ Women are regarded as being at high risk of developing PE if they have one or more of the following risk factors: previous PE, diabetes,
chronic hypertension, renal disease, autoimmune disease, and multiple pregnancies. This is not an exhaustive list but can be
adapted/complemented based on the local epidemiology of PE.7
2Aspirin should be taken with or followed by a full glass of water and taken with food to lessen
gastrointestinal (GI) side effects. The main undesirable side effects of aspirin taken by mouth are GI
ulcers, stomach bleeding, and tinnitus, especially in higher doses. There are many forms of aspirin
available on the market: hard tablets, enteric-coated tablets, extended-release tablets, capsules, caplets,
chewable tablets, orally disintegrating tablets, dispersible tablets, rectal suppositories, and gum.
Enteric-coated aspirin is specially formulated to pass through the stomach unaltered and to dissolve in the
intestines, reducing GI side effects. Extended-release technology is a mechanism used in tablets or
capsules to dissolve slowly and release a drug over time. Enteric-coated or extended-release aspirin
tablets should not be crushed, chewed, broken, or opened. The chewable tablet form of aspirin must be
chewed before swallowing. Orally disintegrating tablets are placed directly in the mouth and should
dissolve right away, without water. Dispersible tablets break up in water and must be stirred in a small
glass of water until dispersed and drunk immediately. Rectal suppositories must be stored in a cool place
to prevent melting before insertion and must be inserted into the rectum, and the lowest available dose is
120 mg. Aspergum is available in gum tablets of 325 mg and must be chewed thoroughly but not
swallowed and followed with a full glass of water.
Widely available forms of aspirin with doses of 75 mg to 81 mg include hard tablets, enteric-coated
tablets, dispersible tablets, chewable tablets, and tablets (81 mg) with calcium (300 mg). The least
expensive form of aspirin is the hard tablet without an enteric coating. In general, aspirin is very
inexpensive and available in most countries, but prices vary from country to country and by manufacturer.
Most efforts to develop new forms of aspirin are driven by the pharmaceutical companies. A literature
review did not reveal any donors currently funding efforts to develop aspirin forms specific for the
prevention of PE/E, and there do not appear to be any efforts attempting to develop a combination aspirin
(75 mg) and calcium (1.5 g–2 g) tablet for this purpose.
Calcium
Calcium carbonate as a large, white pill with a chalky coating is the most common form, usually
containing 500 mg of calcium with vitamin D to facilitate the absorption of calcium. Several types and
forms of calcium supplements are available on the commercial market in Western countries and in some
developing countries where pharmaceuticals are produced or imported. There are side effects associated
with calcium supplements, similar to those experienced in some women taking iron including
gastrointestinal upset and constipation. There are more serious side effects from taking large doses of
calcium, presumably in people who are replete. These problems include kidney stones, nausea and
vomiting, frequent urination and others. While calcium causes gastrointestinal side effects in some
people, calcium carbonate is known to ameliorate indigestion in others. There is also the issue that
calcium has the ability to block iron absorption, and this led WHO to recommend that concomitant
administration of the two should be avoided.5
3One of the most common forms of calcium carbonate in the United States is as chewable tablets without
vitamin D to neutralize stomach acid and the discomfort from it. The dose of calcium in these antacid
supplements range from 500 mg to 800 mg per tablet. Calcium citrate, also as a pill, is another
formulation of calcium and is better absorbed (although calcium carbonate also is well absorbed
compared with other minerals) and seems to impart fewer side effects, although the cost is higher than
calcium carbonate. There also are flavored, chewable calcium supplements (e.g., chocolate truffles and
gummies) which are much more expensive.
Making calcium affordable will be a challenge for international programs. In addition, even after calcium
is available in whatever form, it will take countries time to vet and adapt the new guidelines. A few
countries already recommend calcium for pregnant women but not at the 1.5‒2.0 gram dose. Currently,
there is probably no source of calcium that provides 1.5‒2.0 grams in one dose/pill. To implement the
WHO recommendation, the right formulation of calcium is needed as one pill, and it is imperative that
implementation considers existing micronutrient supplementation. As calcium tablets are often large and
chalky, adherence may be low, and alternatives, such as “calcium sprinkles” have been explored. A study
in Nepal to determine the preference of users between two different antenatal calcium formulations,
powder (in a sachet) and tablets, found that there was a clear preference for tablets.8
A problem with giving iron and calcium together is that they compete for absorption in the gut. Calcium,
because it is given in gram amounts, will reduce iron absorption by 50%,9,10 which would be an
undesirable outcome, given that maternal anemia is a ubiquitous problem in developing countries and
continues to be a major cause of maternal deaths. The medical compliance literature has also shown that
compliance is better with one rather than two pills per day.11
Researchers at the Hospital for Sick Children in Toronto, through its affiliate SickKids, obtained a Saving
Lives at Birth Grand Challenge grant to develop a daily microencapsulated micronutrient powder that
contains iron, folic acid, and calcium called “Prenatal Sprinkles.” The powder will contain differential
time-released nutrients to ensure that iron and calcium are dissolved and absorbed in different parts of the
bowel, thus helping with iron and calcium absorption and preventing calcium-iron interactions.12 Plans
are to prepare different types of supplements (e.g., tablets, micronutrient powders, chewable tablets) and
conduct consumer acceptability and efficacy trials to determine the best preparation. The combined
prenatal supplements can potentially reduce maternal morbidity and mortality related to hypertensive
disease and anemia.
Gap Analysis
The major hurdle to making aspirin available at doses of 75 mg is the absence of national guidelines
promoting its use for the prevention of PE/E. Even if it is in the guidelines, lower-dose aspirin tablets will
need to be added to essential medicines lists and to national logistics systems. Providers will need to be
trained in its use and on how to counsel women to take it and prevent or manage side effects.
4The WHO document on preventing and treating PE/E gives little guidance on how giving calcium should
be implemented and what the effect of giving large amounts of calcium (3‒4 times recommended daily
requirement) would have on the rest of the diet or iron-folic acid supplements. In addition, calcium as a
supplement to the diet or to prevent PE/E§ is not currently on the WHO list of priority medicines for
mothers and children (2011) or the WHO Model List of Essential Medicines (2011). These lists are
updated every two years and require submission of an application for inclusion to the secretary of the
Expert Committee for the Selection and Use of Essential Medicines.**
Aspirin and calcium need to be purchased and delivered to antenatal care clinics or where women live
through community-based distribution. Health care workers at all levels of the care continuum would
need to be trained in their use, how to educate women on their use to increase compliance, and how to
manage side effects. Donors, governments, or women themselves need to pay for the product which
means that the supplement needs to be relatively low-cost and highly valued. Adequate supplies need to
be accompanied with addressing demand-side issues—compliance may be affected by the size of the pill
(a problem with current calcium pills), color, and coating. Consumer acceptability research with women
is needed as to the form of tablet they would prefer taking and how to address other compliance issues,
which will help facilitate long-term compliance throughout pregnancy.
Investment Opportunity
If a supplement is developed with both calcium and iron that is efficacious in reducing PE/E and anemia,
there is the promise of reducing one-third of maternal deaths. This could generate donor and government
commitment to financing the supplies needed to have this impact. The international health community
should, therefore, closely follow results from the current studies being conducted by the Hospital for Sick
Children in Toronto.
Another promising idea is the development of a tablet that contains both aspirin and calcium with doses
for preventing PE/E. Tablets on the market that contain both aspirin and calcium are manufactured for
postmenopausal women to prevent osteoporosis and heart disease and only contain 300 mg of calcium
which is far below the recommended dosage for the prevention of PE/E. It is currently not known if this
combination (aspirin [75 mg] + calcium [1.5 g–2 g]) is possible or cost effective and if pharmaceutical
companies feel it would be lucrative to develop such a tablet. Research and development efforts as well as
a market analysis are necessary to evaluate if such a product could be developed at a low enough cost that
will induce pharmaceutical companies to produce it and countries to introduce it into their list of essential
medicines.
§
Calcium is available in the form of chalk for using on chalk boards.
**
http://www.who.int/mediacentre/factsheets/fs325/en/.
5Making aspirin and calcium available in one tablet for the prevention of PE/E would greatly simplify
efforts to prevent these conditions. To make such a tablet available, a significant investment would be
necessary to:
Research and identify if the combination is pharmaceutically possible.
Research and identify the acceptability of developing such a combination given that WHO
recommends administration of aspirin only for women at risk of PE/E.
Conduct cost and market analyses to evaluate if such a tablet would be cost effective and would
be taken up by countries.
Develop the combination tablet through manufacture and clinical trials.
Pilot test an introduction to document implementation; disruptions; impact; sustainability; lessons
learned; financial and service costs; and feedback from women, providers, and managers.
Conduct advocacy efforts to increase demand of the product.
Commercialize the product.
6References
1. Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PFA. WHO analysis of causes of maternal
death: a systematic review. The Lancet. 2006;367(9516):1066–1074.
2. Engender Health. Balancing the Scales: Expanding Treatment for Pregnant Women With Life-
Threatening Hypertensive Conditions in Developing Countries, A Report on Barriers and Solutions to
Treat Preeclampsia & Eclampsia. New York: EngenderHealth; 2007. Available at:
http://www.engenderhealth.org/files/pubs/maternal-health/EngenderHealth-Eclampsia-Report.pdf.
3. Craici I, Wagner S, Garovic VD. Preeclampsia and future cardiovascular risk: formal risk factor or
failed stress test? Therapeutic Advances in Cardiovascular Disease. 2008;2(4):249–259.
4. Roberts JM, Cooper DW. Pathogenesis and genetics of preeclampsia. The Lancet. 2001;357:53–56.
5. Dolea C, AbouZahr C. Global Burden of Hypertensive Disorders of Pregnancy in the Year 2000.
Geneva: World Health Organization (WHO); 2003. Global Burden of Diseases 2000.
6. WHO. World Health Statistics Part I: Health-Related Millennium Development Goals. Geneva: WHO;
2011. Available at:
http://www.who.int/gho/publications/world_health_statistics/EN_WHS2011_Part1.pdf.
7. WHO. WHO Recommendations for Prevention and Treatment of Preeclampsia and Eclampsia.
Geneva: WHO; 2011. Available at http://whqlibdoc.who.int/publications/2011/9789241548335_eng.pdf.
8. Puadel D, Aryal S, Sharma G, Khannal L. Acceptability and compliance of calcium supplementation
among pregnant women in South-West Nepal. 13th ASCON Poster Display Abstract. 2011.
9. Hallberg L, Brune M, Erlandsson M, Sandber AS, Rossander-Hultén L. Calcium: effect of different
amounts of nonheme and heme-iron absorption in humans. Am. J. Clin. Nutr. 1991;53:112‒119.
10. Hallberg, L, Rossander-Hultén L, Brune M, Gleerup A. Inhibition of haem-iron absorption by
calcium. British Journal of Nutrition. 1993;69(2):553‒540.
11. Galloway R, McGuire J. Determinants of compliance with iron supplementation: supplies, side
effects, or psychology? Social Science and Medicine. 1994;39(3):381‒90.
12. Page on Saving Lives at Birth: A Grand Challenge for Development. SickKids website. Available at:
http://www.sickkids.ca/AboutSickKids/Newsroom/Past-News/News/Grand-Challenge-for-
Development.html. Accessed: January 18, 2012.
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