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Candidate Noninfectious Disease Conditions

D. Alnwick*

Important micronutrient deficiencies in at-risk populations can be addressed simultaneously with programmatically cost-effective results. Because of the interaction between many micronutrients, this would also be biologically effective.

With adequate investment and political support, the chances of eliminating iodine deficiency as a problem in women of reproductive age and young children and of eliminating vitamin A deficiency as a problem in young children in the future are high. To eliminate iron deficiency and folic-acid-dependent neural tube defects (FADNTDs) in low-income populations, a new set of approaches will have to be developed. These same approaches, if successful, could be used to tackle other important micronutrient deficiencies.

Introduction

Before the conference, a large number of health policy experts were asked to rank nine noninfectious disease conditions in the order of how feasible their elimination appeared to them, as well as to suggest other potential candidates. Only one additional condition was proposed: protein-energy malnutrition. Their responses showed that the four top-ranking candidates for elimination were iodine-deficiency disorders (IDDs), vitamin A deficiency, iron-deficiency anaemia, and folic-acid-dependent neural tube defects (FADNTDs). This article reviews the feasibility of eliminating these four conditions, which are caused by an inadequate dietary intake of one or more micronutrients. Our increasing understanding of the interaction between nutritional status and infection suggests that large-scale efforts to eradicate particular infectious diseases will probably be greatly strengthened if efforts are made simultaneously to eliminate specific micronutrient deficiencies.

Candidate Conditions for Elimination

Ten noninfectious disease conditions were proposed as potentially eliminable. The top four (mentioned above) are due to inadequate intake of a specific nutrient; the fifth, lead intoxication, is due to the excess dietary intake of an antinutrient; and the seventh, fluoride deficiency, is due to the inadequate intake of an ion that is arguably a nutrient.

It is surprising that vitamin D deficiency was not identified as a candidate for potential elimination. There is substantial evidence to indicate that vitamin D deficiency is still common in young children and women of child-bearing age in developing countries, particularly (but not exclusively) among people living north of latitude 30 (1). There is also evidence suggesting that the consequences of inadequate vitamin D intake on child health and survival are more damaging than believed so far (2).

Zinc deficiency was also not proposed as a candidate condition for elimination. This was perhaps because the respondents did not believe there was adequate consensus on its importance or on the feasibility of interventions. It is likely, however, that zinc deficiency is at least as prevalent as iron deficiency, that its harmful consequences for child survival and development are as important as those of the latter, and that a modification of interventions to reduce the prevalence of iron deficiency could simultaneously, and at little additional cost, also reduce the prevalence of zinc deficiency (3).

Women during the earliest period of pregnancy are the principal target group for both the elimination of IDDs and the prevention of FADNTDs. Improving the intake of both iodine and folate will also benefit other population groups, particularly young children and adolescents, and, in the case of folate, adults at risk of coronary heart disease (4). Traditionally, pregnant women have been the primary focus of efforts to prevent iron-deficiency anaemia, but increasing emphasis is being placed both on ensuring adequate iron status in women prior to pregnancy and on reducing iron-deficiency anaemia in young children (5).

Vitamin A deficiency has until recently been considered to be a problem almost exclusively of young children. However, there is growing recognition that in some countries, particularly in South Asia, a substantial proportion of pregnant women also suffer from vitamin A deficiency and that the implications for maternal health are as severe and important as those relating to child health and survival (6).

Need for Concerted Global Action

Micronutrient deficiencies contribute substantially to the high young-child mortality, poor maternal health, and high prevalence of childhood disability in developing countries (7,8). Although the control or elimination of noninfectious, micronutrient deficiency diseases in one country or region could certainly be achieved independently of actions elsewhere, there are strong reasons to support coordinated international action to eliminate micronutrient deficiencies in parallel with global efforts to eradicate infectious diseases. These include the exchange of experiences and technologies between countries, and the creation of a favourable international environment which will make action by any particular national government less risky. For example, when the intervention is food fortification, harmonization of standards between countries will help ensure that fortification does not become an impediment to trade between countries.

Eliminating Micronutrient Deficiencies Will Facilitate the Elimination or Eradication of Some Infectious Diseases

It is becoming increasingly clear that the high prevalence of general malnutrition and of some specific micronutrient deficiencies in developing countries, particularly among young children, increases the incidence, severity, duration and other characteristics of many of the infectious diseases that are considered to be candidates for elimination or eradication. Consequently, efforts to improve nutrition and eliminate micronutrient deficiencies should be seen as an important part of disease control, elimination, and eradication efforts. In addition, many of the infectious diseases being considered as candidates for elimination or eradication also contribute to malnutrition and micronutrient deficiency through reduced absorption of nutrients, increased utilization and loss of nutrients, and anorexia. Elimination or eradication of these infectious diseases will therefore improve nutrition.

The relationship between vitamin A deficiency, the immune system, and infectious diseases is perhaps the best understood of all micronutrient deficiency-infection interactions. In the last decade, epidemiological, immunological and molecular studies have yielded substantial evidence for a central role for vitamin A in ensuring optimum immune function (9). Measles is more severe and more likely to be life-threatening in children who are vitamin-A deficient (10). A study from Ghana (11) suggests that the incidence of measles may also be higher in vitamin-A-deficient children. The antibody response to measles vaccine, given in a single dose at 9 months of age, was greater in children who received vitamin A supplements in Guinea-Bissau (12,13). A depressed immune response to tetanus immunization in vitamin-A-deficient children was demonstrated in Indonesia (14).

The goal of global elimination of IDDs was adopted at the 1990 World Summit for Children principally because it was recognized that a substantial amount of mild and moderate mental impairment in children could be avoided if all women received an adequate iodine intake during pregnancy. There is recent evidence that, in areas of moderate and severe iodine deficiency, increasing the iodine intake of the population through supplements or the addition of iodine to irrigation water substantially reduces infant mortality, presumably by improving immune function (15).

There is some evidence that the incidence and severity of malaria infection is lower in young children supplemented with zinc or vitamin A in areas where these micronutrient deficiencies are common (3). Micronutrient deficiencies may play a role in other parasitic diseases. For example, zinc supplementation reduced the intensity of Schistosoma mansoni reinfections in Zimbabwe (16). There appear to have been no randomized controlled trials to determine the effect of improving micronutrient status on other parasitic infections, but animal studies suggest that vitamin A deficiency may increase the filariasis worm load and zinc deficiency may increase ascaris parasite loads (17,18). There is also evidence of a possible causal association between low serum retinol levels, low vegetable consumption, and risk of hepatocellular carcinoma, which is the main reason why viral hepatitis B is being considered as a possible candidate for eradication (19).

The observation that selenium and vitamin E deficiencies can cause a normally benign coxsackievirus in mice to mutate and become virulent, suggests that poor nutrition, in addition to compromising the immune system of the host, may also permanently influence the genetic make-up of the pathogen itself (20,21). If this observation is confirmed to be of significance in human populations, it will further change our understanding of the interaction of nutrition and infection.

Interventions to Eliminate Micronutrient Deficiencies

There are four major interventions that are likely to be effective in successfully eliminating -- within the next decade -- the four candidate micronutrient deficiencies in young children, women of child-bearing age, and pregnant women. These interventions are as follows: 1) the direct administration of a large "bolus" dose of a nutrient at infrequent intervals by a trained health worker to individuals in the target population at a health facility or during special mass campaigns akin to national immunization days; 2) the supply to families of lower-dose micronutrient supplements to be taken by at-risk members daily, weekly, or possibly monthly, over a period of several months or years -- these supplements might be provided through health facilities and schools or distributed through commercial channels at an affordable price; 3) the fortification of a "staple food" that is consumed in relatively constant amounts by the target groups; and 4) the manufacture and distribution (through commercial or other channels) of a specially designed fortified food, beverage, or food additive containing the desired micronutrients -- this product would be marketed or distributed so that the at-risk population had sufficiently increased intake of the candidate micronutrients. Table 1 shows a summary of recent experience with each of these four groups of interventions for each of the priority candidate conditions.

Large, Single Doses of Micronutrients Given Infrequently

The success achieved in reducing the prevalence of vitamin A deficiency in young children has hinged on the fact that relatively large doses the vitamin can be stored in the liver and released, as needed, over a period of up to 6 months. Liver stores can be built up by administering large oral doses of retinol to young children once every 4-6 months. This has proved to be a highly effective, low-cost way of improving the vitamin A status of tens of millions of young children. It is estimated that about 50% of young children at risk of vitamin A deficiency, in countries that recognize the problem, currently receive at least one high dose of vitamin A (22).

High-dose iodine supplements have been provided to women of child-bearing age through injections or through oral solutions of iodine in vegetable oil. However, with the increasing recognition that salt iodization is the method of choice for eliminating iodine deficiency almost everywhere, the need for large, periodic doses of iodine will in future be limited to populations who cannot be provided with iodized salt.

Injectable iron compounds were successfully used to control iron-deficiency anaemia in pregnant women in Sri Lanka, but this method has not been widely used elsewhere. Iron-deficiency anaemia in young children was controlled with injectable iron in some industrialized countries, but this method was discontinued following reports of adverse reactions.

Low-Dose Micronutrient Supplements, Taken Frequently at Home

In 48 developing countries there are national policies for routinely providing supplies of iron or combined iron/folate supplements to pregnant women, to be taken daily at home. In 29 of these countries it was estimated that at least 50% of pregnant women received supplements (UNICEF survey, 1997). There has recently been extensive debate on the effectiveness of daily iron supplementation programmes, focused on issues that reduced the impact of these programmes, such as inadequate logistics and supply, poor compliance due to side-effects, and inadequate absorption.

In some industrialized countries, the majority of pregnant women are advised to take multivitamin and mineral supplements, which have not been widely used in developing countries. In parts of Europe where iodine deficiency is a concern and where iodized salt is not widely consumed, pregnant women are generally advised to consume daily supplement tablets containing iodine.

A combined daily supplement containing folate, vitamin A, and iron could certainly be provided to large populations of women of child-bearing age in the form of a small daily tablet. Other essential micronutrients could easily be added to this tablet at very low additional cost including, for example, zinc, selenium, vitamin D, and the B group vitamins.

Although there is still no consensus on the relative effectiveness of daily versus weekly doses of iron in pregnancy, there is agreement that efforts to treat and prevent iron-deficiency anaemia before women become pregnant is desirable, and that long courses with small doses of iron are preferable to short courses of high doses.

Weekly supplements containing both iron and vitamin A could be provided to reproductive-age women and would probably be effective in improving iron and vitamin A status. Vitamin D could also be effectively added to such a weekly tablet. As it is not known whether folic acid or zinc status could be improved by the use of a weekly dose of these micronutrients, given as part of a combined weekly supplement, this is an important area for research.

Fortification of Widely Consumed Foods and Salt

Fortification of food and salt has enormous potential advantages. Public expenditure and the additional burden on the health sector can be kept to a minimum, especially as costs are generally low and can be easily passed on to the consumer. The requirements for successful fortification programmes are well documented (24). There are, however, few options for fortification of staple foods in the developing countries which have the greatest prevalence of micronutrient deficiencies. The four foods or condiments which are most amenable to fortification in low-income countries are, in decreasing order of importance, salt, sugar, vegetable oil, and cereal flour.

Salt has proven to be the vehicle of choice for delivering iodine to populations in North America and much of Europe for the last 60 years or more. Over the last 10 years, the salt industry in almost all developing countries has been approached by governments, international agencies, and other concerned parties and encouraged or required to fortify with iodine all salt sold for human and animal consumption. These efforts have been extremely successful. It is currently estimated that over 50% of all salt consumed in developing countries is now fortified, compared with less than 10% in 1990.

The possibility of adding other "target" nutrients to salt needs to be seriously considered. There is some experience with fortifying salt with iron (25), and a controlled trial of salt fortified with both iodine and iron is under way in Ghana. There are considerable technical obstacles to fortifying salt with reactive iron. If the present trials are successful, wider production of double-fortified salt may be possible. However, because of the additives and more complex processing required, the cost of double-fortified salt is likely to be substantially greater than that of salt fortified with iodine alone, and it is unlikely that many governments of developing countries will in the near future be able to require all salt to be double fortified.

The recent unsuccessful experience in attempting to support the large-scale fortification of the flavour enhancer monosodium glutamate (MSG) with vitamin A in Indonesia suggests that the large-scale fortification of salt with vitamin A is not feasible. There is currently no information on the feasibility of fortifying salt with folic acid or zinc. Such studies are urgently needed.

Fortification of "Special" Foods

A potentially promising approach to tackling multiple micronutrient deficiencies in at-risk populations is the production and promotion of a "special" food; for example, a flavoured drink mixture, or a flavoured powder that could be stirred into a child's food. A pilot study of such an intervention for young children and pregnant women -- using a low-cost drink mix powder -- has recently been completed in the United Republic of Tanzania with UNICEF support, and a study of the effectiveness of a fortified-powder sachet, which is added to a child's complementary food, is under way in Nicaragua, supported by the USAID OMNI Project.

Dietary Improvement

Dietary improvement, though critically important in itself, is unlikely to secure rapid progress in eliminating the priority micronutrient candidate conditions; hence its exclusion from the above short-list of priority interventions. Education to modify the composition of diets (independent of the two interventions discussed above) will have little impact on eliminating iodine deficiency, since foods naturally rich in iodine tend to be rare and expensive, or on eliminating FADNTDs. Education to increase the consumption of animal muscle or offal-based food, to increase the intake of iron absorption promoters such as vitamin C, and to reduce the intake of inhibitors such as tannin, will make a modest contribution to reducing iron deficiency. Education to increase the consumption by target groups of food containing pro-vitamin A carotenoid and animal products rich in retinol will also contribute to eliminating vitamin A deficiency, but the experience with present interventions suggests that this will rarely, if ever, be sufficient to move most members of a population group from deficiency to adequacy in a short period. The inclusion of vitamin A and iron deficiency elimination goals into the nutrition objectives of countries' agriculture and food policies must be encouraged, with the long-term objective that appropriate policies will help to sustain the elimination of these deficiencies, hence allowing some of the interventions listed above to be phased out by around 2020. Ongoing efforts to increase the vitamin A, iron, and zinc availability in staple foods through plant breeding need to be strongly encouraged, but for another decade or more are unlikely to substantially contribute to the goal of eliminating iron or vitamin A deficiency.

Conclusions

Elimination of Iodine Deficiency

The iodization of edible salt has proved to be a highly effective intervention in almost every country, and must be continued. Quality control and monitoring need to be strengthened. If the present rate of increase in the use of iodized salt continues, it is likely that within the next few years iodine deficiency will be eliminated as a public health problem in most countries. A major challenge ahead is to maintain political support for salt iodization programmes in countries where these programmes have succeeded in reducing the prevalence of visible signs of deficiency, such as goitre. Additional interventions, such as the iodization of irrigation water or the use of supplements, will be needed in areas where it is very difficult to iodize salt.

Elimination of Vitamin A Deficiency in Children

Expanded use of high-dose vitamin A supplements will substantially reduce the prevalence of vitamin A deficiency in young children. All countries where vitamin A deficiency exists as a public health problem, and all countries with high under-5-year-old mortality rates should promote routine use of high-dose vitamin A supplements, provided once every 4-6 months to all young children over the age of 6 months, generally, or on national immunization days. In countries where cereal flour or sugar is widely consumed in relatively constant amounts, the fortification of these foods with vitamin A is likely to help reduce vitamin A deficiency and anaemia among both young children and reproductive-age women.

Elimination of Iron-Deficiency Anaemia, FADNTDs, and Vitamin A Deficiency in Women

Fortification of staple foods with iron and folic acid will probably sharply reduce anaemia and FADNTDs in the limited number of developing countries where centrally processed staples are widely consumed. Routine micronutrient supplementation of reproductive-age women with supplements of folic acid, iron, and vitamin A, together with other micronutrients, would probably greatly contribute to the elimination of all three of these conditions. A combined daily supplement would be effective, but would be costly and compliance might be difficult to ensure. A weekly supplement may also be effective -- and would be cheaper -- but more research is needed on the effectiveness of weekly doses and on compliance in unsupervised settings.

Iron-Deficiency Anaemia in Young Children

Infants in all countries are at high risk of iron deficiency after 6 months of age because of their high iron needs associated with rapid growth. Low-birth-weight infants, who are born with lower iron stores, may be at high risk of deficiency at an even earlier age. Where iron-fortified infant foods are not widely and regularly consumed by young children, infants should receive iron supplements in the first year of life. Continued supplementation may be needed for another year if family diets are lacking in available iron.

References

  1. Alnwick D. Review of recent progress in tackling micronutrient malnutrition in developing countries. Should vitamin D be higher on the agenda? In: Norman AW et al., eds. Vitamin D: chemistry, biology and clinical applications of the steroid hormone. Proceedings of the Tenth Workshop on Vitamin D, Strasbourg, France, 24-29 May 1997. Riverside, CA, University of California, 1997.
  2. Muhe L. Case-control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. Lancet, 1997, 349: 1801-1804.
  3. Zinc for Child Health: Report of a meeting, Baltimore, MD, 17-19 November 1996. Baltimone, MD, Johns Hopkins School of Public Health (Child Health Research Project Special Report, June 1997, vol. 1, no. 1).
  4. Collaboration HLT. Lowering blood homocysteine with folic-acid-based supplements: meta-analysis of randomised trials. British medical journal, 1998, 316: 894-898.
  5. Viteri F. Prevention of iron deficiency. In: Howson C et al., eds. Prevention of micronutrient deficiencies: tools for policymakers and public health workers. Washington, DC, National Academy Press, 1998.
  6. Vitamin A supplements save pregnant women's lives. State of the world's children 1998. New York, UNICEF, 1998: 12-13.
  7. State of the world's children 1998. New York, UNICEF, 1998.
  8. Csete J. Malnutrition and disability. Child health dialogue, 1997, Issue 7. London, AHRTAG.
  9. Semba R. Effect of vitamin A supplementation on immunoglobulin G subclass responses to tetanus toxoid in children. Clinical journal of diagnostic laboratory immunology, 1994, 1(2): 172-175.
  10. Sommer A. Vitamin A, infectious disease, and childhood mortality. Journal of infectious diseases, 1993, 167: 1003-1007.
  11. Dollimore N. Measles incidence, case fatality, and delayed mortality in children with or without vitamin A supplementation in rural Ghana. American journal of epidemiology, 1997, 146: 646-654.
  12. Benn CS. Randomised trial of effect of vitamin A supplementation on antibody response to measles vaccine in Guinea-Bissau, West Africa. Lancet, 1997, 350: 101-105.
  13. Vindication of policy of vitamin A with measles vaccination. Lancet, 1997, 350: 81-82.
  14. Semba RD. Depressed immune response to tetanus in children with vitamin A deficiency. Journal of nutrition, 1992, 122: 101-107.
  15. DeLong R. Effect on infant mortality of iodination of irrigation water in a severely iodine-deficient area of China. Lancet, 1997, 350: 771-773.
  16. Friis H. Serum concentrations of micronutrients in relation to schistosomiasis and indicators of infection: a cross-sectional study among rural Zimbabwean schoolchildren. European journal of clinical nutrition, 1996, 50: 386-391.
  17. Sturchler D. Retinol deficiency and Dipetalonema vitea infection in the hamster. Journal of helminthology, 1985, 59: 201-210.
  18. Laubach HE. Effect of dietary zinc on larval burdens, tissue eosinophil numbers, and lysophospholipase activity of Ascaris suum infected mice. Acta tropica, 1990, 47: 205-211.
  19. Yu MW. Vegetable consumption, serum retinol level, and risk of hepatocellular carcinoma. Cancer research, 1995, 55: 1301-1305.
  20. Beck M. Increased virulence of coxsackievirus B3 in mice due to vitamin E or selenium deficiency. Journal of nutrition, 1997, 127: 996S-970S.
  21. Levander O. Nutrition and newly emerging viral diseases: an overview. Journal of nutrition, 1997, 127: 948S-950S.
  22. Alnwick D. Combating micronutrient deficiencies: problems and perspectives. Proceedings of the Nutrition Society, 1998, 57: 137-147.
  23. Lotfi M et al. Micronutrient fortification of foods: cur-rent practices, research and opportunities. The Micronutrient Initiative, Ottawa, 1996.
  24. Ranganathan S. Large-scale production of salt fortified with iodine and iron. Food and nutrition bulletin, 1996, 17: 73-78.

* Chief, Health Section, United Nations Children's Fund (UNICEF), New York City, New York, USA.



Table 1

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TABLE 1. Summary of interventions to correct iodine, vitamin A, iron, and folate deficiencies

 

 

Intervention category

Nutrient

Large periodic doses with immunization-like contacts

Low-dose supplements taken at home

Fortification of staple food

Provision of low-bulk, processed food, beverage or fortificant for home use, which contains multiple macronutrients

Iodine

Oral and injectable doses, given once every year; available, safe and effective; useful only where salt iodization is impossible or for “mopping up”

Feasible, but not widely tested; limited need due to effectiveness of salt iodization

Salt iodization proven to be widely feasible and effective

Very limited trials in El Salvador and United Republic of Tanzania

Vitamin A

High oral doses very effective in young children and postpartum women, extensively used

Feasible, but very limited experience with use

Sugar in Central America and Philippines; wheat or maize feasible

Ditto

Iron

History of use of injectable iron; effective in women; safety questioned in children

Effective, considerable experience; low cost; formulations for young children not yet available; growing evidence of effectiveness of weekly supplements

Long history of wheat fortification, little data on impact

Ditto

Folate

Not feasible

As for iron, but effectiveness of weekly supplements unknown

Recent introduction of cereal fortification in the USA and Australia

Ditto

 


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