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Vitamin A Deficiency Disorders:
Origins of the Problem and Approaches to Its Control

By Alfred Sommer, MD, MHS

Dr. Sommer is dean of The Johns Hopkins University Bloomberg School of Public Health.

If - and it remains a big "if" - "golden rice" and its variants prove safe and effective, they will be a valuable new tool for controlling vitamin A deficiency. Under the most optimistic of circumstances, however, they will never solve the global problem by themselves. This review attempts to place this new tool in perspective.

Vitamin A deficiency disorders encompass the full spectrum of clinical consequences associated with suboptimal vitamin A status.(1) These disorders are now known to include reduced immune competence resulting in increased morbidity and mortality (largely from increased severity of infectious diseases); night blindness, corneal ulcers, keratomalacia and related ocular signs and symptoms of xerophthalmia; exacerbation of anemia through suboptimal absorption and utilization of iron; and other conditions not yet fully identified or clarified (e.g., retardation of growth and development).(2)

Magnitude and Distribution

Clinical and sero-epidemiologic studies and surveys indicate that vitamin A deficiency is widespread throughout the developing world. Vitamin A deficiency has long been recognized in much of South and Southeast Asia (India, Bangladesh, Indonesia, Vietnam, Thailand, the Philippines) by the common presentation of clinical cases of xerophthalmia (night blindness to permanently blinding keratomalacia). Subsequent studies in Africa, where it had been less well recognized, indicated that a large proportion of pediatric blindness was due to acute deterioration in vitamin A status during measles and similar childhood infections.(3, 4)

Vitamin A deficiency was found to increase childhood morbidity and mortality(2, 5-10) in populations in which xerophthalmia was not readily recognized(11) and in greater numbers than would be expected solely from the increase in mortality associated with xerophthalmia.(2, 12) This discovery led to the recognition that seemingly mild biochemical deficiency, insufficient to cause xerophthalmia, accounts for large numbers of preventable childhood deaths.

The extent and distribution of vitamin A deficiency and its consequences are remarkably well established. Numerous local and national surveys have been conducted. In countries where they have not been conducted, data from nearby countries with similar characteristics (under-5-year mortality, poverty, diet) allow for judicious extrapolation. The few intensive national surveys linked to longitudinal studies(13) and extrapolations from sero-surveys and community-based randomized intervention trials show that vitamin A deficiency poses a significant problem in more than 70 countries.(14) Recent calculations suggest that roughly 150 million children are deficient: every year 10 million children develop xerophthalmia, 500,000 children are permanently blinded from xerophthalmia and 1 to 2 million children die unnecessarily.(15)

Vitamin A deficiency disorders have not been quantified in women of childbearing age. Older anecdotal reports(16, 17) and recent surveys(18, 19) indicate that night blindness from vitamin A deficiency is common among pregnant women in India, Indonesia, Bangladesh, Nepal and elsewhere, particularly during the latter half of pregnancy. Most surveys reveal rates of night blindness of 10% or more during pregnancy in populations in which the children are commonly deficient.(1) A recent large-scale randomized placebo-controlled trial of vitamin A or beta-carotene supplementation in Nepali women reduced maternal mortality by approximately 40%,(20, 21) an effect that persisted for at least one year postpartum.(22)

Vitamin A deficiency disorder affects large numbers of young children and women of childbearing age throughout the developing world. Current estimates do not include China, where recent visits with nutritionists and pediatricians in the southwestern regions identified cases of xerophthalmia and where a recent UNICEF survey revealed depressed serum retinol values and night blindness during pregnancy in large, impoverished regions.(23-25) The size of the global problem is therefore likely to grow as additional data are gathered.

Origins of Deficiency

Children begin life with an urgent need for vitamin A. Full-term infants - even those of well-nourished mothers in wealthy countries - are born with barely enough vitamin A to sustain them during the first few days of life. During the first six months of life they need at least 125 mg of retinol equivalents daily to prevent xerophthalmia and about 300 mg to thrive (and accumulate adequate liver stores of 20 mg per gram of liver).(1, 26, 27)

The only significant source of vitamin A for young infants is breast milk (or equivalent formulas). Except when mothers suffer from severe protein-energy malnutrition, the quantity of breast milk is roughly similar around the globe, but the concentration of vitamin A in that milk varies dramatically with the vitamin A status of the mother.(26, 28) When mothers are vitamin A deficient, breast milk concentrations will be low. Without supplemental vitamin A, their infants will become deficient.

Children in developing countries are at risk of consuming a vitamin A-deficient diet throughout life, not just during early infancy. Although Western populations receive abundant preformed vitamin A from animal products (eggs, butter, cheese, liver, processed foods fortified with vitamin A), poor rural populations in developing countries rely on beta-carotene, a precursor of vitamin A found in dark-green leafy vegetables, carrots and colored fruits (mango and papaya). Even when abundant, these are poor substitutes for animal sources of the preformed vitamin: many children do not like dark-green leafy vegetables; fruits are often costly, sold as a cash crop or highly seasonal (e.g., mangos); and many vegetables bind beta-carotene tightly to their cellular matrices, yielding little during digestion. Recent data indicate that the bioavailability (and bioconversion) of dark-green leafy vegetable sources of beta-carotene is much lower than previously supposed,(29, 30) with perhaps no more than 2% to 4% being absorbed, converted to vitamin A, and made available to meet metabolic needs.

Children in the developing world probably need more vitamin A than do their better nourished Western counterparts. Diarrhea, childhood exanthematous diseases and respiratory infections are more common in poor rural populations, further reducing vitamin A absorption (diarrhea) while increasing utilization (measles) and excretion (respiratory infection).

Why young children in developing countries are deficient in vitamin A is clear. Their greatest risk of becoming vitamin A deficient is during the first few years of life, when their diets are the least diverse, growth (hence need) is greatest and they are at highest risk of life-threatening infections. As they enter their school-age years these factors begin to moderate even though deficiency persists and mild manifestations (e.g., night blindness and Bitot's spots) remain common.

Why women are so frequently deficient is less clear. They also have a similarly unvaried diet that is largely deficient in good sources of preformed vitamin A. Pregnancy and lactation place additional burdens on their meager vitamin A stores. Other consequences of pregnancy probably explain why deficiency is most severe - and night blindness most common - during the latter half of pregnancy. Even though pregnancy-related night blindness spontaneously disappears during the early postpartum period, the underlying deficiency does not. As a consequence these women suffer an increase in mortality for at least one year postpartum.(20-22)

Combating Vitamin A Deficiency

There is global agreement on the need to combat vitamin A deficiency.(2, 14) More than 70 countries have formal intervention programs, although only a few (Nepal, Indonesia, Tanzania, Bangladesh, Vietnam) have made significant, discernible progress. Three basic strategies exist for increasing vitamin A intake: increasing the consumption of foods rich in vitamin A and provitamin A; fortifying commonly consumed dietary items with vitamin A (or beta-carotene); and providing large, periodic, vitamin A supplements to high-risk populations.

Dietary Diversification

Many nutritionists consider increasing the consumption of natural dietary sources of vitamin A to be the logical long-range solution to deficiency. Despite occasional demonstration projects and correlational analyses,(31) little definitive evidence exists that vitamin A sufficiency can be achieved - let alone sustained - through traditional food sources, particularly those available to poor, rural, high-risk populations. As noted, vegetables are poor sources of provitamin A beta-carotene. Although they contain considerable quantities of beta-carotene, these are not readily bioavailable. It needs to be shown that vulnerable children can consume quantities of dark-green leafy vegetables sufficient to normalize their vitamin A status.

Adults may be able to obtain sufficient vitamin A by consuming far larger amounts of vegetables and fruits than children consume or through the greater diversity of their diet, but this too needs documentation. In at least two studies, women provided daily with large helpings of dark-green leafy vegetables failed to significantly improve their vitamin A status(29, 32) in contrast to those fed cookies containing pure synthetic (therefore readily absorbed) beta-carotene.(29) Introducing animal sources of preformed vitamin A (e.g., eggs) into the diet might make a significant difference but remains beyond the resources (and cultural patterns) of many of the populations at highest risk.

Fortification by Conventional Means

Fortifying dietary items with preformed vitamin A or beta-carotene is a proven strategy for preventing deficiency.(33) In the early 1900s Denmark legislated vitamin A fortification of margarine because its growing dairy exports deprived the poorer classes of once-abundant butter, for which they initially substituted vegetable oil-based margarine, which is naturally devoid of vitamin A. In the United States, Western Europe and most wealthy countries, a wide variety of dietary items is fortified with vitamin A (milk, margarine, cereal products). Developing countries have experimented with fortifying a range of products with vitamin A (monosodium glutamate, wheat, noodles, sugar). To date, only sugar fortification, primarily in Latin America, has taken hold.(34)

Traditional fortification techniques require a dietary item that is consumed in suitable quantities by the groups at highest risk; is processed at a limited number of sites where the fortificant can be conveniently added; stabilizes vitamin A during its normal shelf life in the marketplace (vitamin A is unstable in salt, making salt unsuitable for vitamin A but fine for delivering iodine); results in little increase in cost to the consumer; and has acceptable organoleptic qualities (color, smell, taste). These requirements have been difficult to achieve for high-risk poor populations that generally consume a monotonous diet devoid of expensive, centrally processed items.

Fortification by Genetic Modification

In an attempt to overcome some of the obstacles facing conventional fortification, scientists have begun to genetically modify traditional dietary items to produce beta-carotene. Monsanto produced rape seed and mustard rich in beta-carotene and, more recently, scientists funded by the Rockefeller Foundation produced a strain of rice - golden rice - genetically modified to produce beta-carotene.(35) This may well herald an important strategy for controlling vitamin A deficiency, particularly because rice is the dietary staple of many of the most-deficient populations.

Some hurdles need to be surmounted before golden rice or its variants can have an effect. The strains must be able to grow under the varied conditions in countries with vitamin A-deficient populations. The yield and the cost must be attractive to the farmer (or benefit from public sector subsidization). The organoleptic qualities of the rice must be acceptable to the target population (women and children). The beta-carotene needs to be bioavailable, the degree dependent on its concentration in the rice, the matrices to which it is bound, the effect of traditional cooking methods and the amount consumed.

Although genetically modified rice could go a long way toward controlling vitamin A deficiency, it will never completely solve the problem. Many deficient populations do not consume rice, and even within traditional rice-consuming countries, some high-risk groups will not be able to afford it.

Supplementation

Vitamin A (retinol) supplements - naturally occurring (as in cod liver oil) or synthetically derived (multivitamin preparations) - have long been used to prevent vitamin A deficiency and its associated disorders.(2, 36) Vitamin A is a component of prenatal and infant multivitamins routinely consumed by Western populations. Periodic administration of large doses of vitamin A to children was pioneered in India(37) and advanced globally after the first major international meeting on the control of vitamin A deficiency in 1974.(32)

Periodic supplementation is the most widely implemented intervention for controlling vitamin A deficiency in the developing world. Countries have found these programs to be relatively easy and quick to initiate at relatively modest marginal cost.(2, 38) Supplements are extremely inexpensive, at 2 to 4 cents per dose of 200,000 international units (IU). Most of the cost is for the gelatin capsule; the cost for the vitamin A is less than 1 cent.

The major cost for (and impediment to) population-wide supplementation is the delivery system. Recommendations called for the administration of 200,000 IU every 4 to 6 months to all children 12 to 60 months of age. Unfortunately, that often requires a delivery mechanism such as that presently used successfully in a number of countries (e.g., Nepal and Bangladesh). In Nepal, 37,000 village women volunteers reach more than 2 million children during special "Vitamin A Days" held twice every year.(39)

To better use existing delivery channels, many countries have piggybacked vitamin A distribution onto regular immunization efforts. In particular, 25,000 or 50,000 IU of vitamin A is given to young children at ages 6, 10, and 14 weeks when they receive their diptheria, pertussis and tetanus immunizations. A fourth dose (100,000 IU) is administered at age 9 months with measles immunization.(40) The rationale for this schedule is that an existing distribution mechanism is available, minimizing the marginal cost of delivery; a high risk of deficiency exists during the first year of life (200,000 IU is given to mothers 6 to 8 weeks postpartum to boost breast milk vitamin A concentration); and infants are at greatest risk for the consequences of deficiency, particularly mortality. Coverage achieved by supplement distribution programs has dramatically risen in the past two years, largely because vitamin A administration was included in national immunization days, which were designed to deliver polio vaccine. More than 40 countries reported covering more than 80% of their target children with vitamin A supplements during 1998.(1, 41)

Although randomized controlled clinical trials have demonstrated the value of periodic supplementation,(2) in practice it has proved difficult to reach children after the first year of life; indeed, with immunization rates falling below expected targets, these too have not met their goals. To compound the problem, national immunization days will soon be phased out.

A recent multinational trial sponsored by the World Health Organization (WHO) suggests that the present regimen of dosing mothers with 200,000 IU postpartum and their children three times in the first 14 weeks of life with 25,000 IU does not improve vitamin A status much beyond age 6 months.(42) In response, a recent informal consultation organized by WHO recommended that doses to infants and mothers be increased: 400,000 IU to postpartum women (in two doses during the preconceptual period) and 50,000 IU to infants at least three times before age 6 months. Although the effect of these increases is yet to be ascertained, evidence suggests they will be safe and effective.(27)

Safety Considerations

Undue concern over vitamin A toxicity, a rare and transient condition,(43) has complicated the design of intervention strategies and unnecessarily diverted attention and commitment from effective control strategies. Because safety relates to the prevention of deficiency, only two issues arise: teratogenicity and acute toxicity.

Very large doses of vitamin A during the first trimester of pregnancy can be teratogenic, so high-dose supplementation of women of childbearing age is only recommended during the infertile postpartum period.(40) Acute toxicity, although harmless and transient, can result in nausea and vomiting. If mothers notice and are concerned, it might result in lower compliance rates, so supplement size is adjusted for the child's age. Even so, young children who might inadvertently receive multiples of the recommended dose (in addition to increased amounts in breast milk) will not suffer significant, permanent sequelae.(1) The implications for intervention strategies are minimal.

Diet

Traditional foods cannot produce teratogenic or toxic effects. For deficient populations the primary source of vitamin A is vegetables, which lack the preformed vitamin. Ingesting large quantities of carrots and other carotenoid-rich vegetables may produce high carotene levels, but these are harmless. Because the body regulates conversion of beta-carotene to vitamin A, serum retinol does not rise to toxic levels.

Fortification

Programs that add retinyl palmitate (preformed vitamin A) to dietary items carefully adjust the level of fortification to benefit consumers whose diets are most deficient without exposing wealthier segments of society, whose diets might be richer in preformed vitamin A, from consuming excessive amounts. These programs take pains to achieve a balance that best serves both groups. The choice of vehicle can optimize this relationship.

Fortifying a product or a specific package of that product (e.g., the smallest packets of monosodium glutamate) uniquely ingested by those who are most deficient increases the amount of vitamin A that can be safely added. Nonetheless, ongoing surveillance is valuable in identifying isolated groups or individuals who purposely purchase and consume large doses of supplements on a sustained basis.

Fortification through genetic modification poses no risks of vitamin A toxicity. Genetically modified crops (e.g., golden rice, enriched canola oil) produce beta-carotene, not preformed vitamin A.

Supplementation

This intervention is potentially the most problematic because it is theoretically possible to overdose the recipient through frequent, inadvertent dosing. From a practical standpoint, however, serious or sustained side effects require very high, frequent and persistent dosing (50,000 to 100,000 IU daily for 3 to 6 months).(1, 27, 40, 43) An often expressed concern is that a child might receive three or even four high-dose supplements within a month (a regular distribution, a dose during measles, plus a third or fourth from an overly zealous local health worker). The worst result, however, would be a day or two of nausea and vomiting. This risk pales in comparison with the millions of children who would otherwise die or be blinded.

Conclusions

A decade ago the public health and nutrition communities recognized the need to improve the vitamin A status of young children throughout the developing world.(44) The World Bank has estimated that vitamin A supplementation (the only approach they modeled) was among the most cost-effective health interventions available, at less than US$1 per disability-adjusted life year.(45) Although more than 70 countries have embraced the global goal of eliminating vitamin A deficiency as a public health problem, progress has been slow, largely because of the costs and logistical challenges to changing behavior (diets), delivering large-dose supplements regularly, and fortifying traditional dietary items. A number of bilateral and international agencies recently recommitted themselves to these efforts, even as continuing research expands the implications of deficiency. New tools, such as genetically modified staple crops, could provide important strategies and stimulate these global efforts.

References

1. Report of the XX IVACG Meeting, Hanoi, February, 2000. ILSI Press: Washington, DC (in preparation).

2. Sommer A, West KP. Vitamin A Deficiency. Oxford: Oxford University Press, 1996.

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4. Foster A, Sommer A. Childhood blindness from corneal ulceration in Africa: causes, prevention, and treatment. Bull WHO 1986;64:619-623.

5. Sommer A, Hussaini G, Tarwotjo I, Susanto D. Increased mortality in children with mild vitamin A deficiency. Lancet 1983;2:585-588.

6. Sommer A, Tarwotjo I, Djunaedi E, West KP, Loeden AA, Tilden R, Mele L, Aceh Study Group. Impact of vitamin A supplementation on childhood mortality. A randomized controlled community trial. Lancet 1986;1:1169-1173.

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8. Rahmathullah L, Underwood BA, Thulasiraj RD, Milton RC, Ramaswamy K, Rahmathullah R, Babu G. Reduced mortality among children in Southern India receiving a small weekly dose of vitamin A. N Engl J Med 1990;323:929-935

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11. Ghana VAST Study Team. Vitamin A supplementation in northern Ghana: effects on clinic attendances, hospital admissions, and child mortality. Lancet 1993;342:7-12.

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13. Sommer A, Tarwotjo I, Hussaini G, Susanto D, Soegilharto T. Incidence, prevalence and scale of blinding malnutrition. Lancet 1981;1:1407-1408.

14. Grant JP. The State of the World's Children. Oxford: Oxford University Press, 1995.

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22. Pradhan L, the NNIPS Study Team. Reduction in maternal mortality associated with vitamin A supplementation extends beyond perinatal period (in preparation).

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24. Yip R. Personal communication, September 2000.

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30. de Pee S, West CE, Permaesih D, Martuti S, Muhilal, Hautvast JGAJ. Orange fruit is more effective than are dark-green, leafy vegetables in increasing serum concentrations of retinol and ß-carotene in schoolchildren in Indonesia. Am J Clin Nutr 1998;68:1058-1067.

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38. West KP, Sommer A. Delivery of Oral Doses of Vitamin A to Prevent Vitamin A Deficiency and Nutritional Blindness. A State-of-the-Art Review. Rome, Italy: United Nations Administrative Committee on Coordination-Subcommittee on Nutrition, 1987.

39. Nepali Technical Assistance Group. When a vitamin A supplementation program turns into a long-term strategy. Kathmandu, Nepal, July, 2000

40. WHO/UNICEF/IVACG Task Force. Vitamin A Supplements: a Guide to Their Use in the Treatment and Prevention of Vitamin A Deficiency and Xerophthalmia. 2nd ed. Geneva: World Health Organization, 1997.

41. Schultink W. Personal communication, March 2, 2000.

42. WHO/CHD Immunisation-Linked Vitamin A Supplementation Study Group. Randomised trial to assess benefits and safety of vitamin A supplementation linked to immunisation in early infancy. Lancet 1998;352:1257-1263.

43. Bauernfeind JC. The Safe Use of Vitamin A. A Report of the International Vitamin A Consultative Group (IVACG). Washington, DC: Nutrition Foundation, 1980:1-44.

44. Sommer A. Vitamin A deficiency and childhood mortality (editorial). Lancet 1992;339:864.

45. World Bank. The World Bank World Development Report 1993: Investing in Health. Oxford University Press 1993.