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Time (weeks)

Figure 7 Cumulative mortality of children randomized to 4-monthly placebo control (dashed line) versus 200,000 IU of vitamin A (solid line) during a large community trial in Sarlahi District, rural Nepal. From Sommer A and West KP Jr (1996) Vitamin A Deficiency: Health, Survival and Vision. New York: Oxford University Press.

and airway that may enhance resistance to infection months later. Additional confirmatory trials are under way in Southeast Asia and sub-Saharan Africa.

Finally, improving intake of VA, either preformed or as pro-vitamin A ^-carotene in amounts approximating a recommended dietary intake, may reduce the risk of pregnancy-related death where maternal mortality is high and deficiency evident by widespread night blindness during pregnancy. In rural Nepal, supplementing women with VA lowered mortality related to pregnancy from 704 to 385 deaths per 100,000 pregnancies (44%), likely due to less severe infection, eclampsia, anemia, and possibly other obstetric causes. Malnourished women (e.g., those with night blindness) may likely benefit most from supplemental VA intake. Additional trials addressing this question are under way in Bangladesh and Ghana.

Morbidity

Direct effects of VA on morbidity have been difficult to establish, possibly due to variation in disease sensitivity to VA and inherent problems in measuring the incidence, duration, and severity of morbidity in community studies. Vitamin A interventions exert modest, if any, impact on the prevalence of common childhood morbidities typically obtained by history. In contrast,

VA appears to reduce the severity of potentially fatal infections, such as measles, persistent diarrhea, dysentery, and falciparum malaria, especially in the presence of wasting malnutrition. The protective effect becomes stronger with episode severity. Thus, febrile illnesses appear to be more responsive to vitamin A than nonfebrile events. Illnesses for which care is sought show a response to VA. In a large trial in Ghana, VA supplementation decreased childhood clinic visits for illness (RR = 0.88), hospitalization rates for severe disease (RR = 0.62), and severity of illness among children admitted for diarrhea compared to placebo recipients. In Brazil, prior VA receipt had no effect on children's diarrheal episodes of 1 or 2 days' duration (RR = 0.97) but was increasingly protective against episodes lasting >3 days with four or more stools per day (RR = 0.91) and episodes of >3 days with five or more stools per day (RR = 0.80). Vitamin A treatment of measles has led to fewer and less severe complications and enhanced immunologic and clinical recovery. However, multiple treatment trials report little effect of vitamin A on recovery from childhood pneumonia. This remains a paradox given decades of experimental animal evidence linking VA deficiency to extensive metaplasia and keratinization and, presumably, greater susceptibility to pathogen invasion and infection of the respiratory tract.

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