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Comprehensive recommendations for the assessment and control of vitamin A deficiency (VAD) were rigorously reviewed and revised by a working group and presented for discussion at the XX International Vitamin A Consultative Group meeting in Hanoi, Vietnam. These recommendations include standardized definitions of VAD and VAD disorders. VAD is defined as liver stores below 20 micro g (0.07 micro mol) of retinol per gram. VAD disorders are defined as any health and physiologic consequences attributable to VAD, whether clinically evident (xerophthalmia, anemia, growth retardation, increased infectious morbidity and mortality) or not (impaired iron mobilization, disturbed cellular differentiation and depressed immune response). An estimated 140 million preschool-aged children and at least 7.2 million pregnant women are vitamin A deficient, of whom >10 million suffer clinical complications, principally xerophthalmia but also increased mortality, each year. A maternal history of night blindness during a recent pregnancy was added to the clinical criteria for assessing vitamin A status of a population, and the serum retinol criterion for a "public health problem" was revised to 15% or more of children sampled having levels of <20 micro g/dL (0.7 micro mol/L). Clinical trials and kinetic models indicate that young children in developing countries cannot achieve normal vitamin A status from plant diets alone. Fortification, supplementation, or other means of increasing vitamin A intake are needed to correct widespread deficiency. To improve the status of young infants, the vitamin A supplements provided to mothers during their first 6 wk postpartum and to young infants during their first 6 mo of life should be doubled.

Vitamin A deficiency (VAD) is an important problem in many developing countries. If population data are unavailable or outdated for common indicators of VAD, a surrogate indicator may suggest whether a problem is likely and full-scale assessment is necessary. The Global Vitamin A Initiative report suggests that the under-five mortality rate (U5MR) might serve that purpose; a U5MR >70 indicates that VAD of public health importance is likely. Should the U5MR be used as a surrogate indicator? If so, is 70 the appropriate cutoff? U5MR data were collected for countries where the United Nations Children's Fund supports programs, along with unpublished vitamin A survey data from the World Health Organization. U5MR distribution was compared in countries with and without VAD. Sensitivity and specificity using U5MR cutoffs of 70 and 50 were calculated and compared with the presence of VAD as proven by a survey. Countries with a U5MR >40 have a VAD problem, about 70% of countries with a U5MR between 20 and 50 have VAD, and about 25% of countries with a rate <20 still have VAD. With a cutoff of 50, the U5MR relates well to the existence of a VAD problem in regions where malnutrition problems are most prominent. Decreasing the cutoff from 70 to 50 increased the sensitivity of the criterion and included nine additional deficient countries. A cutoff of 40 would increase sensitivity but would include countries with localized rather than nationwide problems. It is proposed that a country with a U5MR >50 likely has a VAD problem that requires immediate or continuing action. These actions include proper, formal assessment of the vitamin A status of the population, vitamin A capsule distribution and other program actions. Countries with a U5MR between 20 and 50 should assume they have a VAD public health problem until surveys prove otherwise.

Vitamin A deficiency is very prevalent and contributes substantially to morbidity and mortality among young children in developing countries. We identify and quantify three causes of vitamin A deficiency in young children based on data available in the literature: maternal vitamin A deficiency resulting in low concentrations of vitamin A in breast milk, inadequate dietary intake of vitamin A during and after weaning and prevalent illness. We developed a set of recursive equations to estimate the amount of vitamin A in the liver as a function of age over the first 2 y of life. To apply the equations, we selected a best estimate value for each input parameter as the most representative of a typical child in a developing country. Because of the great variability that exists for each variable, we also carried out sensitivity analyses, substituting more extreme values for input parameters. We then estimated stores, assuming a child in a developing country also receives the newly revised vitamin A supplementation regimen recommended by the World Health Organization. Without supplementation, a typical child in a developing country is not able to attain and maintain "minimally adequate" liver vitamin A stores. To overcome this deficit by eating fruits and vegetables alone, the child would need to increase portion sizes about 10-fold. If the child receives the new supplementation regimen, his or her liver stores will still be far short of the average American child (i.e., exceedingly far from toxic levels). However, our estimates indicate that the new supplementation regimen will permit a typical child in a developing country setting to attain minimally adequate vitamin A stores during the first 2 y of life.

Supplementation has many potential advantages over fortification and dietary approaches for improving micronutrient intake. Pregnant and lactating women and infants are most likely to benefit from supplementation. Recent experience with vitamin A supplementation in young children has proved to be remarkably successful. Demonstrated efficacy of vitamin A supplements for improved child survival in many settings and a technical consensus on how to implement interventions were major factors in achieving this success. Bilateral and UN agencies worked together so that in 1999 80 % of children under 5 years of age in the least-developed countries received a vitamin A capsule in the last 6 months. At least one million child lives saved were associated with the increase in coverage in the last 2 years of the 1990s. Experience with Fe-folate supplements has not been as successful. Whilst a technical consensus has been reached on how to implement programmes to control Fe deficiency, the lack of convincing evidence of efficacy of Fe-folate supplements in terms of maternal and child survival outcomes has undoubtedly contributed to the limited pursuit of effective action. A new multiple micronutrient supplement for use amongst women of reproductive age in developing countries has been formulated. UNICEF is employing the supplement in programmes aimed at helping to prevent low birth weight. The new supplement is likely to be more efficacious than Fe-folate supplements for both maternal and child survival and development outcomes. Successful completion of rigorous efficacy trials will be critical for creating the political support needed to achieve universal coverage.

It has been proposed that Pasteurella multocida can invade the host tissues via the mucous membrane. Vitamin A (VitA) deficiency has been associated with mucous membrane damage, such as squamous metaplasia. The objective of this study was to determine the early stages in the pathogenesis of P. multocida in VitA-deficient turkeys and clinically healthy turkeys. Fifteen-week-old VitA-deficient and clinically healthy turkeys were inoculated with P. multocida P-1059, a virulent strain, and the portal of entry, invasion, and localization of P. multocida were studied by microbial examination of the trachea, liver, and lung and histologic examinations of internal organs. Higher mortality was found in VitA-deficient turkeys. Pasteurella multocida was first reisolated from the trachea, secondarily from the liver and blood, and finally from the lung in both groups. Invasion of P. multocida into tissues occurred between 3 hr and 24 hr postinoculation in both groups. Our findings suggest that altered membrane integrity in VitA-deficient birds did not appear to change the time course of the systemic spread of P. multocida infection in turkeys and that the increased mortality seen in the VitA-deficient turkeys may be associated with immune system impairment.

Country-specific activity and coverage data were used to estimate the childhood mortality impact (deaths averted) and costs of integrating vitamin A supplements into immunization campaigns conducted in 1998 and 1999. More than 94 million doses of vitamin A were administered in 41 countries in 1998, helping to avert nearly 169,000 deaths. During 1999, delivery of more than 97 million doses in 50 countries helped avert an estimated 242,000 deaths. The estimated incremental cost per death averted was US$72 (range: 36-142) in 1998 and US$64 (range: 32-126) in 1999. The estimated average total cost of providing supplementation per death averted was US$310 (range: 157-609) in 1998 and US$276 (range: 139-540) in 1999. Costs per death averted varied by campaign, depending on the number and proportion of the child population reached, number of doses received per child, and child mortality rates.

Night blindness due to vitamin A deficiency is common during pregnancy among women in Nepal. The authors assessed the risk of maternal death during and after a pregnancy with night blindness among women participating in a cluster-randomized, placebo-controlled vitamin A and beta-carotene supplementation trial in Nepal from July 1994 to September 1997. Subjects were 877 women with night blindness and 9,545 women without night blindness during pregnancy. Women were followed from the time they declared that they were pregnant through the end of the study, representing a median follow-up of 90 weeks (interquartile range: 64-121 weeks). Mortality of night-blind women in the placebo group was 3,601 per 100,000 pregnancies. In comparison, the relative risk of dying among nonnight-blind women in the placebo group was 0.26 (95% confidence interval (CI): 0.13, 0.55), and the relative risk among women with or without night blindness in the vitamin A/beta-carotene group was 0.32 (95% CI: 0.10, 0.91) and 0.18 (95% CI: 0.09, 0.36), respectively. Night-blind women were five times (95% CI: 2.20, 10.58) more likely to die from infections than were women who were not night blind. These findings show that night blindness during pregnancy is a risk factor of both short- and long-term mortality among women. Vitamin A/beta-carotene supplementation ameliorates this risk to a large extent.

Vitamin A deficiency impairs epithelial integrity and systemic immunity and increases the incidence and severity of infections during childhood. However, findings from vitamin A supplementation trials are not consistent. Supplementation has resulted in significant reductions in mortality in several (but not all) large community-based trials among apparently healthy children. In hospital-based studies, vitamin A supplements have been consistently found to reduce the severity of measles infection, but no effect on nonmeasles respiratory infections has been observed. In some cases, the supplements were associated with an apparently increased risk of lower respiratory infection. Vitamin A supplements also reduced the severity of diarrhea in most (but not all) trials. Potential explanations for the differences in efficacy across trials are reviewed. While vitamin A supplementation is effective in reducing total mortality and complications from measles infections, it is likely to be more effective in populations suffering from nutritional deficiencies.

Objectives: To determine whether vitamin A supplements result in reduced mortality among HIV-infected and uninfected children., Design: Randomized, double blind, placebo-controlled trial., Methods: Starting in April, 1993, we randomized 687 children age 6 months to 5 years who were admitted to the hospital with pneumonia. Children who were severely malnourished or had clinical signs of vitamin A deficiency were excluded. At baseline children received placebo or 400 000 IU (or half that for infants) of vitamin A, in addition to standard treatment for pneumonia. They received further doses of the same regimen 4 and 8 months after hospital discharge. Sera from children were tested for HIV antibodies by enzyme-linked immunosorbent assay and Western blot tests. For positive children <15 months of age, HIV infection was confirmed by amplified heat-denatured HIV-p24 antigen assays with confirmatory neutralization assays. HIV status was ascertained for 648 of 687 enrolled children. The mean duration of follow-up was 24.4 months (SD = 12.1)., Results: Of 648 children 58 (9%) were HIV-infected. Compared with uninfected children, all-cause mortality was higher among HIV-infected children, as was mortality caused by pneumonia or diarrhea (P < 0.001 for each). Overall vitamin A supplements resulted in a 49% reduction in mortality [relative risk (RR), 0.51; 95% confidence interval (CI), 0.29 to 0.90, P = 0.02]. Vitamin A supplements reduced all-cause mortality by 63% among HIV-infected children (RR 0.37; CI 0.14 to 0.95, P = 0.04) and by 42% among uninfected children (RR 0.58, CI 0.28 to 1.19, P = 0.14). Vitamin A supplements were also associated with a 68% reduction in AIDS-related deaths (P = 0.05) and a 92% reduction in diarrhea-related deaths (P = 0.01)., Conclusion: Vitamin A deficiency, which is common among children in many developing countries, is particularly severe among HIV-infected children. Our findings indicate that vitamin A supplements, a low cost intervention, reduce mortality of HIV-infected children.

Two approaches to improve vitamin A nutriture are compared: nutrition education and mega-dose capsule distribution. The impact of these programmes on vitamin A deficiency (VAD), wasting malnutrition, and excessive childhood mortality are compared for approximately 40,000 children who were assigned to either intervention cohorts or a control group from 75 sites within seven districts in two ecological settings (Terai, or lowland, and hills) of Nepal. Twenty-four months after the implementation of the project, the reduction of risk of xerophthalmia was greater among children of mothers who were able to identify vitamin A-rich foods [relative risk (RR) = 0.25; 95% CI = 0.10-0.62] than among children who received mega-dose capsules (RR = 0.59; 95% CI = 0.41-0.84). The risk of mortality at two years was reduced for both the nutrition education cohort (RR = 0.64; 95% CI = 0.48-0.86) and capsule distribution cohort (RR = 0.57; 95% CI = 0.42-0.77). The nutrition education program, however, was more expensive to deliver than the capsule distribution programme. High rates of participation in the supplementation programme were achieved within a short period. The nutrition education message spread rapidly throughout the study population, although practice was slower to change. Where maternal literacy was low and channels of communication were limited, the capsule programme appeared to be more cost-effective. However, economies of scale for nationwide programmes exist for nutrition education programmes that do not exist for capsule distribution programmes. A comprehensive national programme requires both dietary supplementation and nutrition education.

This is an update of knowledge on the role of the vitamin A status in determining child mortality, morbidity and growth. Recent information confirms the earlier conclusion of Beaton et al. that a 23% reduction in young child mortality results following improvements in the vitamin A status. Studies show that the mortality effect is primarily due to reductions in deaths due to acute gastroenteritis and measles but not acute respiratory infections (ARI) and malaria. While improvement of the vitamin A status enhances the survival of older preschool children, it remains unclear whether it benefits infants (i.e. < 6 months). Vitamin A supplementation does not reduce the overall incidence and prevalence of common childhood illness; however, it reduces the incidence of more severe episodes of diarrhea. Also, vitamin A supplementation either during and/or immediately after the illness does not improve its symptomatology. Finally, contrary to earlier expectations, recently completed, placebo-controlled randomized interventions have failed to detect improvements in child growth.

Vitamin A deficiency is one of the most common nutrient deficiency syndromes in children from developing countries. It is also correlated with the increased severity and incidence of certain infections. Until recently, vitamin A research was focused on preventing xerophthalmia and blindness in Third World Countries and on the development of synthetic retinoid molecules, with lower toxicity than vitamin A, for the treatment of skin diseases. However, there has been a major shift of emphasis in the last five to ten years. There is a risk of death from xerophthalmia, primarily from complications with infectious diseases. Intermittent treatment with the very large doses of vitamin A prescribed to combat blindness was shown to be effective. This suggests that vitamin A may affect specific elements of the immune system. High-dose vitamin A supplements have been given, at widely-spaced time intervals, to preschool children in communities where vitamin A deficiency causes xerophthalmia and blindness, over the last 20 to 30 years. A strong correlation between mortality and xerophthalmia was identified. Death then became the principal outcome measured because it was easier to detect than xerophthalmia, particularly in large clinical trials in high risk regions where clinical expertise was minimal and vitamin A deficiency was a commoner cause of death than blindness. Other, food-based approaches to the treatment and prevention of vitamin A deficiency, involving foods naturally rich in retinol or carotenoid, or foods artificially fortified with these nutrients, should be developed.

Given the demonstrated efficacy of vitamin A supplements in reducing childhood mortality, health officials now have to decide whether it would be efficient to target the supplements to high risk children. Decisions about targeting are complex because they depend on a number of factors; the degree of clustering of preventable deaths, the cost of the intervention, the side-effects of the intervention, the cost of identifying the high risk group, and the accuracy of the 'diagnosis' of risk. A cost-effectiveness analysis was used in the Philippines to examine whether vitamin A supplements should be given universally to all children 6-59 months, targeted broadly to children suffering from mild, moderate, or severe malnutrition, or targeted narrowly to pre-schoolers with moderate and severe malnutrition. The first year average cost of the universal approach was US$67.21 per death averted compared to $144.12 and $257.20 for the broad and narrow targeting approaches respectively. When subjected to sensitivity analysis the conclusion about the most cost-effective strategy was robust to changes in underlying assumptions such as the efficacy of supplements, clustering of deaths, and toxicity. Targeting vitamin A supplements to high risk children is not an efficient use of resources. Based on the results of this cost-effectiveness analysis and a consideration of alternate strategies, it is apparent that vitamin A, like immunization, should be provided to all pre-schoolers in the developing world. Issues about targeting public health interventions can usefully be addressed by cost-effectiveness analysis.

The maternal factors that contribute to high mortality rates among infants born to women with human immunodeficiency virus (HIV) are unclear. We followed 474 HIV-infected mothers and their infants in Malawi from pregnancy through the infants' 12th month of life. Of the 474 HIV-infected pregnant women, 300 (63.3%) were deficient in vitamin A (serum level of vitamin A, <1.05 micromol/L). Mean serum vitamin A levels among mothers whose infants died were 0.78 +/- 0.03 micromol/L compared with 1.02 +/- 0.02 micromol/L among mothers whose infants had survived for the first 12 months of life (P <.0001). The overall infant mortality rate was 28.7%. We divided HIV-positive mothers into six groups according to serum vitamin A levels (micromol/L) as follows: group 1, <0.35; group 2, between 0.35 and 0.70; group 3, between 0.70 and 1.05; group 4, between 1.05 and 1.40; group 5, between 1.40 and 1.75; and group 6, >1.75. Infant mortality rates for each group were 93.3%, 41.6%, 23.4%, 18.5%, 17.7%, and 14.2%, respectively (P < .0001). Maternal vitamin A deficiency during HIV infection may contribute to increased infant mortality.

Although a role for vitamin A in immunity to infectious diseases has long been suggested, only in the last decade have epidemiological, immunologic, and molecular studies yielded substantial evidence for a central role. The recent discovery of retinoic acid and retinoid X receptors has provided a molecular basis for the action of vitamin A and its metabolites at the level of gene activation. At least a dozen clinical trials have now demonstrated that vitamin A supplementation reduces severe morbidity and mortality from infectious diseases among children who have acute measles or who are from areas in which vitamin A deficiency is endemic. Vitamin A deficiency is an immunodeficiency disorder characterized by widespread alterations in immunity, including pathological alterations in mucosal surfaces, impaired antibody responses to challenge with protein antigens, changes in lymphocyte subpopulations, and altered T- and B-cell function. Vitamin A and its metabolites are immune enhancers that have been shown to potentiate antibody responses to T cell-dependent antigens, increase lymphocyte proliferation responses to antigens and mitogens, inhibit apoptosis, and restore the integrity and function of mucosal surfaces. Vitamin A and related retinoids may have potential applications in therapy for some infectious diseases.

The current accessibility and sophistication of hardware and software has made it possible to design high-quality data management systems for community-based trials in resource-poor environments. We designed, implemented, and operated an effective data management system for the Nepal Nutrition Intervention Project Sarlahi (NNIPS), a placebo-controlled community trial to assess the impact of vitamin A supplementation on the preschool mortality of 38,000 children in the Sarlahi district of Nepal. A data center was established in Kathmandu, approximately 8 hr drive from the study area. The trial is now completed and over 200,000 forms have been processed. The majority of potential data discrepancies were identified and corrected by field workers during the interviews. Supervisors and forms editors located at the field office corrected most data errors. Once forms reach Kathmandu, the average number of data entry errors was 3.1 per 10,000 keystrokes for the eight data entry operators employed during the study. Extensive computerized checking of data during data entry found out-of-range, missing, or inconsistent data in only 1% of forms. Timely analysis of field worker performance provided ongoing feedback to supervisors and analysis for the Data Safety and Monitoring Committee, and for publication of results.

Meta-analyses on 6 of 12 studies of the effect of improvement of the vitamin A status of deficient children living in poverty and social and biological deprivation conclude that mortality reduction can be expected. The demonstrated effects on incidence, prevalence and severity of specific morbidities under these conditions have been variable.

Increased consumption of dietary vitamin A is advocated as a long-term solution to vitamin A deficiency. We prospectively examined the relationship of dietary vitamin A intake and child mortality among 28,753 Sudanese children aged 6 mo to 6 y, who participated in a trial of vitamin A supplementation. After 18 mo of follow-up, 232 children died. Total dietary vitamin A intake was strongly and inversely associated with risk of mortality. The age- and sex-adjusted relative risk (RR) of mortality for a comparison of children in extreme quintiles was 0.35 (95% CIs 0.21-0.60; P for trend over quintiles < 0.0001). Even after possible confounding by socioeconomic variables was adjusted for, vitamin A intake was significantly protective (multi-variate relative risk 0.53). Dietary vitamin A intake was especially protective among children who were wasted and stunted or who had diarrhea or cough. These prospective data support an important role of dietary vitamin A in reducing childhood mortality in developing countries.

Vitamin A was first discovered in 1913. Its deficiency was soon associated in animal models and case reports with stunting, infection, and ocular changes (xerophthalmia) resulting in blindness. The ocular consequences dominated clinical interest through the early 1980s. A longitudinal prospective study of risk factors contributing to vitamin A deficiency and xerophthalmia revealed a close, dose-response relationship between the severity of mild preexisting vitamin A deficiency and the subsequent incidence of respiratory and diarrheal infection (relative risk [RR], 2.0-3.0) and, most dramatically, death (RR, 3.0-10.0). Subsequent community-based prophylaxis trials of varying design confirmed that vitamin A supplementation of deficient populations could reduce childhood (1-5 years old) mortality by an average of 35%. Concurrent hospital-based treatment trials with vitamin A in children with measles revealed a consistent reduction in measles-associated mortality in Africa of at least 50%. It is now estimated that improving the vitamin A status of all deficient children worldwide would prevent 1-3 million childhood deaths annually.

Objective: A two-part meta-analysis of studies examining the relationship of vitamin A supplementation and child mortality., Data Sources: We identified studies by searching the MEDLARS database from 1966 through 1992 and by scanning Current Contents and bibliographies of pertinent articles., Study Selection: All 12 vitamin A controlled trials with data on mortality identified in the search were used in the analysis., Data Extraction: Data were independently extracted by two investigators who also assessed the quality of each study using a previously described method., Data Synthesis: We formally tested for heterogeneity across studies. We pooled studies using the Mantel-Haenszel and the DerSimonian and Laird methods and adjusted for the effect of cluster assignment of treatment groups in community-based studies. Vitamin A supplementation to hospitalized measles patients was highly protective against mortality (DerSimonian and Laird odds ratio, 0.39; 95% confidence interval, 0.22 to 0.66; P = .0004) (part 1 of the meta-analysis). Supplementation was also protective against overall mortality in community-based studies (DerSimonian and Laird odds ratio, 0.70; clustering-adjusted 95% confidence interval, 0.56 to 0.87; P = .001) (part 2 of the meta-analysis)., Conclusions: Vitamin A supplements are associated with a significant reduction in mortality when given periodically to children at the community level. Factors that affect the bioavailability of large doses of Vitamin A need to be studied further. Vitamin A supplements should be given to all measles patients in developing countries whether or not they have symptoms of vitamin A deficiency.

Previous studies of the effect of 6-monthly vitamin A supplementation on child mortality have given conflicting results. In other trials, more frequent doses of vitamin A have significantly reduced mortality among children at risk of vitamin A deficiency. We have done a double-blind, placebo-controlled trial of vitamin A supplementation in the Sudan among 28,753 children aged 9-72 months at risk of vitamin A deficiency. Children were assigned to receive either 200,000 IU vitamin A and 40 IU vitamin E every 6 months (vitamin A group) or 40 IU vitamin E alone (placebo group). During the 18 months of follow-up, there were 120 deaths (8.4/1000) in the vitamin A group and 112 (7.9/1000) in the placebo group (relative risk 1.06, 95% confidence interval 0.82-1.37). Controlling for geographic site, round of observation, anthropometry, morbidity, dietary intake of vitamin A, sex, and all baseline differences between the two groups did not change the results. Children living in poor and unsanitary environments, younger children, and those sick, stunted, wasted, or consuming diets low in vitamin A were at a significantly higher risk of dying. The lack of an effect of large-dose vitamin A supplementation on mortality, despite a clear association between dietary vitamin A and mortality, underscores the need to identify factors that modify the efficacy of vitamin A supplements as a public-health measure. Reducing poverty, improvements in sanitation, and access to adequate diets should remain the main goals to improve child survival.

During January to March 1991, 38 mallards (Anas platyrhynchos) found dead from a group of approximately 600 overwintering on the South Saskatchewan River were examined. Thirty birds died from starvation, four had disseminated Staphylococcus aureus infection, and the cause of death of four birds was not determined. All six birds from which the esophagus was examined microscopically, including the four birds with staphylococcosis, had squamous metaplasia of the submucosal glands, a lesion pathognomonic for vitamin A deficiency. Vitamin A deficiency may occur in mallards and other waterfowl that overwinter north of traditional wintering areas and rely on grains deficient in carotenoids.

Reported are estimates of the prevalence in developing countries of physiologically significant vitamin A deficiency and the number of attributable deaths. The WHO classification of countries by the severity and extent of xerophthalmia was used to categorize developing countries by likely risk of subclinical vitamin A deficiency. Using vital statistics compiled by UNICEF, we derived population figures and mortality rates for under-5-year-olds. The findings of vitamin A supplementation trials were applied to populations at-risk of endemic vitamin A deficiency to estimate the potential impact of improved vitamin A nutriture in reducing mortality during preschool years. Worldwide, over 124 million children are estimated to be vitamin A deficient. Improved vitamin A nutriture would be expected to prevent approximately 1-2 million deaths annually among children aged 1-4 years. An additional 0.25-0.5 million deaths may be averted if improved vitamin A nutriture can be achieved during the latter half of infancy. Improved vitamin A nutriture alone could prevent 1.3-2.5 million of the nearly 8 million late infancy and preschool-age child deaths that occur each year in the highest-risk developing countries.

Community trials of the efficacy of vitamin A supplementation in reducing preschool childhood mortality have produced conflicting results. To resolve the question, a randomised, double-masked, placebo-controlled community trial of 28,630 children aged 6-72 months was carried out in rural Nepal, an area representative of the Gangetic flood plain of South Asia. Randomisation was carried out by administrative ward; the vitamin-A-supplemented children received 60,000 retinol equivalents every 4 months and placebo-treated children received identical capsules containing 300 retinol equivalents. After 12 months, the relative risk of death in the vitamin-A-supplemented compared with the control group was 0.70 (95% confidence interval 0.56-0.88), equivalent to a 30% reduction in mortality. The trial, which had been planned to last 2 years, was discontinued. The reduction in mortality was present in both sexes (relative risk for boys 0.77; for girls 0.65), at all ages (range of relative risks 0.83-0.50), and throughout the year (0.76-0.67). The reduction in mortality risk was not affected by acute nutritional status, as measured by arm circumference. Thus, periodic vitamin A delivery in the community can greatly reduce child mortality in developing countries.

The effect of vitamin A supplementation on preschool child morbidity and mortality was assessed in a prospective double-blind placebo-controlled study around Hyderabad, India. Every six months 200,000 IU vitamin A was given to 7691 children (treatment group) whereas 8084 children received a placebo (control group). Morbidity and mortality data were collected every three months. Risk of respiratory infection was higher in children with mild xerophthalmia than in children with normal eyes. Vitamin A supplementation had no effect on morbidity status. Mortality rates were similar in the two groups; it was highest in children who did not receive either vitamin A or placebo. The findings suggest that vitamin A supplementation alone may not reduce child mortality.

Background: Clinical vitamin A deficiency affects millions of children worldwide, and subclinical deficiency is even more common. Supplemental vitamin A has been reported to reduce mortality among these children, but the results have been questioned., Methods: We conducted a randomized, controlled, masked clinical trial for one year in southern India involving 15,419 preschool-age children who received either 8.7 mumol (8333 IU) of vitamin A and 46 mumol (20 mg) of vitamin E (the treated group) or vitamin E alone (the control group). Vitamin supplements were delivered weekly by community health volunteers who also recorded mortality and morbidity. Weekly contact was made with at least 88 percent of the children in both study groups. The base-line characteristics of the children were similar and documented a high prevalence of vitamin A deficiency and undernutrition., Results: One hundred twenty-five deaths occurred, of which 117 were not accidental. The risk of death in the group treated with vitamin A was less than half that in the control group (relative risk, 0.46; 95 percent confidence interval, 0.30 to 0.71). The risk was most reduced among children under 3 years of age (6 to 11 months--relative risk, 0.28; 95 percent confidence interval, 0.09 to 0.85; 12 to 35 months--relative risk, 0.46; 95 percent confidence interval, 0.26 to 0.81) and among those who were chronically undernourished, as manifested by stunting (relative risk, 0.11; 95 percent confidence interval, 0.03 to 0.36). The symptom-specific risk of mortality was significantly associated with diarrhea, convulsions, and other infection-related symptoms., Conclusions: The regular provision of a supplement of vitamin A to children, at a level potentially obtainable from foods, in an area where vitamin A deficiency and under-nutrition are documented public health problems contributed substantially to children's survival; mortality was reduced on average by 54 percent.

Recent investigations conducted in Indonesia have identified an important role for adequate vitamin A nutriture in preventing mortality in young children. A randomized, community-based trial of vitamin A supplementation in northern Sumatra demonstrated a 34 per cent reduction in mortality among pre-school aged children who received twice yearly vitamin A supplementation. These results have stimulated renewed interest in vitamin A as a potentially important mediator of improved child survival. Cost and efficiency considerations are important in these types of trials but must be balanced with logistical constraints that are unique to these environments. A number of these issues are discussed and some general guidelines are proposed for such investigations.

Retinoids have chemopreventive activity for epithelial tumors in a variety of systems, including the two-stage tumorigenesis system of mouse skin in which only the promotion stage is inhibited. We asked whether dietary vitamin A deficiency could affect the skin tumorigenic response, prior to major changes in body weight or general health of the animals. Two regimens were tested to induce vitamin A deficiency. SENCAR mice were either (a) fed a vitamin A-deficient diet from 4 or 9 weeks of age or (b) their mothers were fed the diet from the time of birth of the experimental animals which were then weaned on the same diet. The latter regimen produced typical symptoms of vitamin A deficiency in the offspring by Weeks 12-14 and all the mice died by Week 19; the former regimen permitted sufficient accumulation of retinol and its esters to sustain life for up to 45 and 75 weeks, respectively, in the majority of mice. For our experiments, vitamin A depletion was produced by placing the mothers on the deficient diet at birth of the experimental animals. A single topical dose of 20 micrograms of 7,12-dimethylbenz(a)anthracene (DMBA) was used as the initiator at 3 weeks of age and 1 to 2 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA) once weekly as the tumor promoter for 10 weeks (from Week 4 through 13 of the experiment). Fifty-five % of mice (n = 40) on Purina laboratory chow (mean body weight, 31.4 g) developed skin tumors (2.58 per mouse) at 12 weeks, versus 2.5% (0.05 papillomas per mouse) of mice (n = 40) kept on the purified vitamin A-deficient diet (mean body weight, 30.3 g), a 98% decrease in tumor/mouse. Retinoic acid (RA) (1-3 micrograms/g diet) supplementation after Week 12 caused a rapid tumorigenic response in 95% of the mice by week 22. This tumor response occurred to a reduced extent in the absence of continued TPA treatment up to Week 13. Even though tumor incidence increased within 1 week of RA and 95% of the mice showed the tumorigenic response, the number of tumors per mouse was about 50% of that observed in mice maintained on standard Purina diet. This was confirmed in an experiment in which the mice were maintained for life either on Purina or on the RA (3 micrograms/g) containing purified diet, the latter being the control group for the effect of vitamin A deficiency on skin tumorigenesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Preschool-age rural Indonesian children were reexamined every 3 months for 18 months. An average of 3135 children were free of respiratory disease and or diarrhea at the examination initiating each of the six, 3-month follow-up intervals. Children with mild xerophthalmia (night blindness and/or Bitot's spots) at the start and end of an interval developed respiratory disease and diarrhea at twice (p less than 0.001) and three times (p less than 0.001) the rate, respectively, of children with normal eyes during the same interval, independent of age and anthropometric status (weight for length). The risk of respiratory disease and diarrhea were more closely associated with vitamin A status than with general nutritional status. These results may explain much of the excess mortality recently reported for mildly vitamin A-deficient children.

This year marks the 75th anniversary of the discovery of vitamin A by E.V. McCollum. Interest over the past 40 years has focused almost exclusively on the ocular complications of deficiency. Recent data from Indonesia, India, Thailand, Tanzania, Guatemala and elsewhere are reorienting concerns. Observational studies indicate that vitamin A--deficient children grow poorly, are more anemic, have more infections and are more likely to die than their peers, and that the magnitude of many of these consequences is directly related to the severity of the deficiency, even after adjusting for other variables. The few supplementation trials completed to date support these conclusions. Even after excluding children with frank deficiency at baseline, vitamin A-supplemented children have grown faster, developed higher hemoglobin values, and died less frequently (by 30-60%) than their nonsupplemented peers. The great surprise is not the central role vitamin A plays in each of these areas (McCollum and others recognized this long ago), but that this single nutrient can so profoundly affect children who are subject to multiple adverse influences.