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© 2003 The American Society for Nutritional Sciences J. Nutr. 133:1640S-1644S, May 2003

Supplement: Nutrition as a Preventive Strategy against Adverse Pregnancy Outcomes

Potential Cost-Effectiveness of Nutrition Interventions to Prevent Adverse Pregnancy Outcomes in the Developing World 1 ,2

Dwight J. Rouse3

Center for Research in Women's Health, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL 35249

3 To whom correspondence should be addressed. E-mail: drouse{at}uab.edu.


   ABSTRACT
TOP
 ABSTRACT
LITERATURE CITED
 
The potential cost-effectiveness of antenatal nutrition interventions to improve pregnancy outcomes in the developing world has not undergone formal evaluation. Furthermore, the effectiveness of antenatal care in improving maternal or fetal and neonatal health has been questioned. However, reasonably compelling evidence from randomized trials shows that nutrition interventions can prevent both infant (iodine supplementation) and maternal (vitamin A and ß-carotene supplementation) deaths, and informal analysis suggests that the cost-effectiveness of nutrition interventions would be comparable and, in some cases, markedly superior to several standard antenatal interventions. Future efforts to establish the cost-effectiveness of nutrition interventions in developing countries will depend on conducting large, pragmatic clinical trials that use region- and resource-appropriate interventions with mortality or valid, incontrovertibly severe morbidity endpoints. If such trials establish effectiveness, credible cost-effectiveness analyses can then be performed.

KEY WORDS: • cost-effectiveness • nutrition intervention • pregnancy outcomes • developing world

In 1993 the World Health Organization (WHO) 4 (1) estimated the global incidence and associated maternal mortality from the main obstetric complications worldwide (Table 1). Most maternal mortality occurs in the developing world. Although less reliably estimable, maternal morbidities such as anemia, reproductive tract infections and lifelong disabilities such as obstetric fistulae are assumed to be directly proportional to maternal mortality. WHO estimates of neonatal deaths and their causes worldwide are shown in Table 2. Like maternal deaths, neonatal deaths likely represent the end of a disease continuum, and many sick infants not ill enough to die are nonetheless permanently impaired by pregnancy or birth events. The linked nature of maternal health and fetal and infant health is reflected in Table 3.


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  		TABLE 1 Estimated global incidence and mortality from the main obstetric complications1

 

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  		TABLE 2 Neonatal deaths in developing countries (1993)1

 

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  		TABLE 3 How complications affect mother and infant1

 
To address the high rates and disproportionate developing world burden of maternal and neonatal morbidity and mortality, WHO developed the Mother-Baby Package as a universal mechanism by which to achieve the goals of the International Safe Motherhood Initiative (1). This initiative was inaugurated in Nairobi, Kenya, in 1987 and subsequently endorsed by over 150 countries. Thus, the Mother-Baby Package is both the de jure and de facto model of developing world pregnancy and newborn care. It has undergone cost evaluation and it provides a baseline strategy against which to compare the addition or substitution of nutrition interventions in pregnancy. More recently, WHO launched the Making Pregnancy Safer Initiative, a program with the same broad goals as the Safe Motherhood Initiative (2).

Economic analysis considerations

Several factors are relevant to the assessment of cost-effectiveness of developing world pregnancy interventions. First, because the Mother-Baby Package consists of a cluster of interventions designed to be integrated with and in most cases delivered through existing health systems, the package does not cost the same in all settings. Thus, some variability of the cost of the package is to be expected, and estimates range from $1 per capita in poor isolated areas to $6 per capita in settings of lower fertility and a higher prevalence of hospital deliveries (3). Note also cost per capita as opposed to cost per pregnancy was used for the evaluation; although this metric captures the add-on nature of the package to existing health services, it does not lend itself to traditional cost-effectiveness analysis. Individual cost inputs, as a proportion of the total, have been estimated for the Mother-Baby Package (Table 4) (3). Drugs, the most analogous component of the package to a nutrition intervention, account for only a small proportion (12%, or $0.12–$0.72) of the total cost of the Mother-Baby Package (3).


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  		TABLE 4 World Health Organization mother and infant package cost by input1

 
Second, to the extent that the Mother-Baby Package depends on existing resources and infrastructure, its costs are marginal costs; the costs associated with any additional pregnancy interventions, which are overlaid on (or substituted for a component of) the Mother-Baby Package, are likewise marginal. As such, nutrition interventions with any effectiveness are likely to be highly cost-effective because the additional costs of implementing them in the setting of an established infrastructure and delivery system are low.

Third, standard cost-effectiveness measures such as U.S. dollars per deaths averted, U.S. dollars per life-years gained, U.S. dollars per quality-adjusted life years (QALYs) gained and U.S. dollars per disability-adjusted life-years (DALYs) gained may fail to capture the full economic value of a mother, especially in the developing world where the economic value of a mother's life may be underestimated. The DALY was conceptualized by the World Bank and complements the QALY. Both measures attempt to compress the amount of life and the quality of life into one metric. The DALY assigns disability weights to health states (e.g., 0.33 to deafness) whereas the QALY assigns utility scores (e.g., 0.67 for deafness). Thus QALYs are years of healthy life lived—counted up from birth—and DALYs are years of healthy life lost—subtracted from the expected lifespan (4). These measures, if applied solely to a mother, are too reductive. As pointed out by Tinker (3), a mother's death has serious consequences for her children. According to a study in Bangladesh, if a woman dies after delivery, the newborn infant she leaves behind is almost certain to die (3). Even older children are likely to suffer; another study in Bangladesh found that children (up to age 10) whose mothers die are 3–10 times more likely to die within 2 y than are those with living parents (3).

A study in Tanzania also suggests that a woman's death has a negative effect on children's education by delaying school enrollment for younger children and causing older children to leave school to take on household tasks (e.g., cooking, cleaning and collecting water and firewood) (3). Moreover, a woman's death deprives the family of an essential source of income in many developing countries. This is especially problematic when a woman heads the household or when her income goes to meeting basic needs (e.g., food, medicines and school fees) whereas a man's income goes to alcohol and cigarettes (3). Jowett (5) noted that improving the health of women contributes directly to the health of children and more broadly to reducing poverty. These broad economic effects are hard to estimate with precision and thus may not be adequately reflected in summary measures of cost-effectiveness. On the other hand, standard effectiveness and cost-effectiveness measures highlight the health and economic burden of pregnancy in the developing world, even though in this century HIV/AIDS will continue to cause an increasing proportion of disability and death (Table 5) (5).


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  		TABLE 5 Leading causes of death and illness in women aged 15–44 y in low-income countries, 19901

 
The World Bank (6) estimated that in terms of U.S. dollars/DALY gained, family planning and antenatal and delivery care are 2 of the 6 most cost-effective clinical services for low-income countries. For example, antenatal and delivery care was estimated by the World Bank to cost $60/DALY gained. In Guinea, antenatal and delivery care at health centers has been estimated to cost $109/life-year saved (7).

Another consideration in the assessment of the cost effectiveness of developing world pregnancy interventions is that antenatal care may not prevent neonatal or maternal morbidity and mortality. McDonagh (8) reviewed the effectiveness of antenatal care and concluded that there are substantial grounds to doubt the effectiveness of the procedures collectively called antenatal care. Antenatal care, as part of Maternal Child Health Services, was exported from developed to developing countries because it was believed to be an appropriate and beneficial service, but the justification for use under the conditions in developing countries is not apparent. Questions were first asked about the possible lack of effect of antenatal care on maternal mortality as early as 1932 and have not been answered satisfactorily, especially regarding developing countries.

Thus it is on the above unstable foundation—variable costs across settings, all costs essentially marginal, traditional measures of cost-effectiveness probably too reductive and no effectiveness established for many pregnancy interventions—that the potential cost-effectiveness of nutrition interventions to reduce adverse pregnancy outcomes is grounded. Moreover, it is worth bearing in mind that even for the archetypal and near universally recommended (9) pregnancy nutrition supplements folate and iron, compelling evidence of effectiveness in reducing the occurrence of adverse maternal or fetal and neonatal outcomes is not available (10– 12).

Estimated cost-effectiveness of individual Mother-Baby Package component interventions

Selected published cost-effectiveness analyses of various antenatal interventions that are used (or recommended) in the developing world are summarized in Table 6. The literature is characterized by inconsistency of methodology and outcome metrics as well inconsistent consideration of potential benefits for both components of the maternal-fetal dyad. Given the importance of maternal health and fetal and neonatal health, the literature on the cost-effectiveness of antenatal interventions in the developing world can best be summarized as incomplete.


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  		TABLE 6 Cost-effectiveness analyses of various antenatal interventions

 
Other antenatal interventions appropriate to the developing world have been demonstrated in randomized clinical trials to be effective and lend themselves to simple cost-effectiveness analysis. For example, in a randomized trial of mass therapy for presumptive sexually transmitted disease during pregnancy in Rakai, Uganda (20), the absolute reduction in low birth weight and preterm birth with antibiotic therapy was 2% (number needed to treat: 50) and in early neonatal death was 0.4% (number needed to treat: 250). If the therapy (1 g azithromycin, 400 mg cefixime and 2 g metronidazole) costs $2.00, then the cost-effectiveness of presumptive therapy could be estimated at $100/low-birth-weight preterm delivery averted and $500/neontal death averted. Obviously, if the intervention was less costly, its cost-effectiveness would be improved. At an intervention cost of $0.50, cost effectiveness would improve to $25/low-birth-weight preterm delivery averted and $125/neonatal death averted. A risk-targeted antibiotic intervention was evaluated in Kenya (21) and found to be effective, with a more favorable number needed to treat. Pregnant women with a poor obstetric history were randomly assigned to receive a single oral dose of a third generation cephalosporin between 28 and 32 wk gestation. Women receiving the antibiotic gave birth to low-birth-weight (<2500 g) infants at a rate of 19% versus a rate of 33% for the placebo group. This 14% absolute reduction translates to a number needed to treat of 7. Thus, at an antibiotic cost of $2.00 (estimated), the cost-effectiveness of targeted antibiotic therapy would be $14.00/low-birth-weight delivery avoided.

Promising and likely cost-effective neonatal interventions have been evaluated as well. For example, Bang et al. (22) reported a near 50% reduction in neonatal and infant mortality with home-based neonatal care. For every 18 infants treated, one death was averted. They estimated the cost of delivering the neonatal care at $5.30, which translates to a cost per death averted of $95.40.

Potential cost-effectiveness of nutrition interventions to prevent adverse pregnancy outcomes

Published formal cost-effectiveness analyses of nutrition interventions to improve pregnancy outcomes in the developing world are rare to nonexistent. In large part this may be due to the paucity of effectiveness data for antenatal nutrition interventions in the developing world. Few randomized clinical trials of adequate power and with mortality endpoints have been conducted. Two notable exceptions are maternal supplementation with iodine and with vitamin A or ß-carotene.

    Iodine supplementation. In two randomized trials conducted in extremely iodine-deficient areas (in New Guinea and Zaire) (23), iodine supplementation (in the form of maternal iodized oil injection) was associated with significant reductions in death during infancy and early childhood. Overall, in both trials the relative risk of death was 0.71 (95% confidence interval [CI]: 0.56–0.90) (93/695, or 13.3% versus 139/736, or 18.9%). This translates to a number needed to treat to prevent a death of 18. Thus, if the cost of the intervention were $1.00, iodine supplementation in areas of extreme deficiency would have a cost-effectiveness of $18/infant or early child death avoided. At an intervention cost of $0.10, the cost-effectiveness of iodine supplementation would be approximately $1.80/infant or early child death avoided. However, the feasibility of this intervention may be compromised by the injectable route of delivery.

    Vitamin A or ß-carotene supplementation. In a double-blind cluster-randomized trial in Nepal (24), weekly low-dose supplementation with vitamin A or ß-carotene was associated with a 44% (95% CI: 0.07%–0.61%) reduction in maternal mortality, from 645/100,000 to 385/100,000 (number needed to treat: 385). At an intervention cost of $0.50 (estimated) the cost-effectiveness of this intervention would be $193/maternal death averted. At an intervention cost of $0.05, the cost-effectiveness would be $19/maternal death averted. However, the inferences that can be drawn from this trial were disputed by some (25– 27), and the safety and feasibility of the intervention (which was delivered weekly to women in their homes) are not completely established (28). The authors, while acknowledging the need for replication, rightly responded that intention-to-treat analysis of mortalities across randomized supplement groups that is based on all deaths and pregnancies during a common follow-up period is a valid basis for inference (29).

Potential comparative cost-effectiveness of nutrition interventions

The potential cost-effectiveness of two antenatal nutrition interventions is compared in Table 7 with several other interventions including 1) interventions that have been subjected to formal cost-effectiveness analysis and are currently recommended and offered as part of routine antenatal care in many parts of the developing world (syphilis screening and treatment, tetanus and malaria prevention and asymptomatic bacteriuria screening and treatment); 2) an intervention for which rigorous effectiveness data are available, formal cost-effectiveness analysis has been performed and that is beginning to become an established component of antenatal care in some parts of the developing world (perinatal HIV transmission prevention); and 3) another intervention of probable effectiveness that has not undergone formal cost-effectiveness analysis (presumptive sexually transmitted disease therapy).


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  		TABLE 7 Comparative cost-effectiveness of individual antenatal interventions

 
Summary

The potential cost-effectiveness of antenatal nutrition interventions in the developing world has not undergone formal evaluation, and the effectiveness of antenatal care in improving maternal or fetal and neonatal health has been questioned. However, reasonably compelling evidence that nutrition interventions can prevent both infant (iodine supplementation) and maternal (vitamin A or ß-carotene supplementation) deaths is available from randomized trials, and informal analysis suggests that the cost-effectiveness of nutrition interventions would be comparable and in some cases markedly superior to several standard antenatal interventions. The impact of nutrition interventions could be profound. If the results of the Nepal vitamin A or ß-carotene trial could be generalized to the wider developing world, as many as 200,000 maternal deaths per year might be preventable through this simple intervention. Likewise, if severe iodine deficiency were prevalent in one-half of the developing world, iodine supplementation might prevent over 100,000 neonatal and early childhood deaths annually.

What is needed?


   FOOTNOTES
 
1 Manuscript prepared for the USAID-Wellcome Trust workshop on "Nutrition as a preventive strategy against adverse pregnancy outcomes," held at Merton College, Oxford, July 18–19, 2002. The proceedings of this workshop are published as a supplement to The Journal of Nutrition. The workshop was sponsored by the United States Agency for International Development and The Wellcome Trust, UK. USAID's support came through the cooperative agreement managed by the International Life Sciences Institute Research Foundation. Supplement guest editors were Zulfiqar A. Bhutta, Aga Khan University, Pakistan, Alan Jackson (Chair), University of Southampton, England, and Pisake Lumbiganon, Khon Kaen University, Thailand. Back

2 Financial support provided by a midcareer investigator award—NICHD #1–K24HD01375–01. Back

4 Abbreviations used: CI, confidence interval; DALY, disability-adjusted life year; QALY, quality-adjusted life year; WHO, World Health Organization. Back


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