Vitamin A supplementation and child survival. Impact of large-dose vitamin A supplementation on childhood diarrhoea, respiratory disease and growth. The effect of vitamin A supplementation on tear fluid retinol levels of marginally nourished preschool children. Evaluation of safety of oral vitamin 'A' megadose co-administered with measles vaccination. Vitamin A supplementation fails to reduce incidence of acute respiratory illness and diarrhea in preschool-age Indonesian children. Effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections in young children in Brazil. Effects of vitamin A supplementation on intestinal barrier function, growth, total parasitic, and specific Giardia spp infections in Brazilian children: a prospective randomized, double-blind, placebo-controlled trial. Vitamin A supplementation and morbidity among preschool children in south India. Effect of vitamin A supplementation on immune function of well-nourished children suffering from vitamin A deficiency in China. Reduced seroconversion to measles in infants given vitamin A with measles vaccination. Tolerance of preschoolers to two dosage strengths of vitamin A preparation. No evidence of fontanelle-bulging episodes after vitamin A supplementation of 6- and 9-month-old infants in Guinea Bissau. The effect of massive doses of vitamin A on the signs of vitamin A deficiency in preschool children. Childhood mortality after a high dose of vitamin A in a high risk population. Simultaneous zinc and vitamin A supplementation in Bangladeshi children: randomised double blind controlled trial. Does vitamin A supplementation interact with routine vaccinations? An analysis of the Ghana Vitamin A Supplementation Trial. Randomised trial of effect of vitamin A supplementation on antibody response to measles vaccine in Guinea-Bissau, west Africa. Effect of vitamin A supplementation on childhood morbidity and mortality. Plasma retinol level, vitamin A supplementation and acute respiratory infections in children of 1-5 years old in a developing country. Respiratory Diseases Working Group. Vitamin A and zinc supplementation of preschool children. Vitamin A status of children with a history of respiratory syncytial virus infection in infancy. Reduced mortality among children in southern India receiving a small weekly dose of vitamin A. Efficacy of vitamin A in reducing preschool child mortality in Nepal. Vitamin A status in children who are prone to respiratory tract infections. Vitamin A supplementation and increased prevalence of childhood diarrhoea and acute respiratory infections. Effect of massive dose vitamin A on morbidity and mortality in Indian children. Vitamin A supplementation in children with recurrent respiratory infections. Effect of Vitamin A supplementation on the immune response to measles vaccination. Effect of vitamin A supplementation to mother and infant on morbidity in infancy. A double-blind, randomized, clinical trial of the effect of vitamin A and zinc supplementation on diarrheal disease and respiratory tract infections in children in Mexico City, Mexico. Supplementation with vitamin A reduces watery diarrhoea and respiratory infections in Mexican children. Vitamin A administered with measles vaccine to nine-month-old infants does not reduce vaccine immunogenicity. Effect of vitamin A supplementation on morbidity due to Plasmodium falciparum in young children in Papua New Guinea: a randomised trial. Vitamin A supplementation but not deworming improves growth of malnourished preschool children in eastern Zaire. Vitamin A supplementation in northern Ghana: effects on clinic attendances, hospital admissions, and child mortality. Ghana VAST Study Team. Impact of nutrition education and mega-dose vitamin A supplementation on the health of children in Nepal. Effect of deworming and vitamin A administration on serum vitamin A levels in preschool children. The beneficial effects of weekly low-dose vitamin A supplementation on acute lower respiratory infections and diarrhea in Ecuadorian children.
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. One hundred and seventy-two 0.5-3.0-year-old children in a mountainous area of northern Hebei Province of China were randomly assigned to a vitamin A supplementation group (n = 98) or a control group (n = 74) for a 1 year double-blind study. Capsules containing 200,000 IU vitamin A and 40 IU vitamin E were given to the children in the experimental group 3 and 9 months after baseline examination. During the 12 month study period, there was a significant reduction in the incidence of diarrhoea (P < 0.01) and respiratory disease (P < 0.01) in the children of the experimental group compared to the control. Risk of diarrhoea and respiratory disease were respectively 2.5 and 3.4 times higher in the control children. Serum retinol and IgA levels of the treatment group were significantly higher than that of control group (P < 0.01) 7 weeks after first supplementation. There was no significant difference in saliva IgA level between groups. No significant differences in growth were observed. It was concluded that supplementation with large doses of vitamin A decreased the incidence and severity of diarrhoea and respiratory disease in these children, possibly through enhanced activity of the immune system, but had no effect on growth over 1 year. Vitamin A has been determined in tear fluid and blood plasma of marginally nourished Thai children before and after supplementation with a single, oral dose of 110 mg retinyl palmitate. After two months a significant rise of tear fluid retinol levels of the supplemented group was observed as compared to the non-supplemented group, while after four months no difference could be found. Determination of vitamin A levels in tear fluid may be useful in clinical eye research, with special regard to xerophthalmia. nan Vitamin A supplementation of populations of vitamin A-deficient preschool-age children has been shown to reduce childhood mortality, but the primary preventive effects of such supplements on childhood infectious diseases have not been carefully evaluated. We conducted an individually randomized, placebo-controlled, double-masked trial among 1,407 Indonesian preschool-age children, to measure the effects of high dose vitamin A on acute respiratory and diarrheal illnesses. Signs and symptoms of morbidity were monitored using every other day home surveillance by trained interviewers. High dose vitamin A supplements increased the incidence of acute respiratory illnesses (ARI) by 8%, and acute lower respiratory illnesses (ALRI) by 39%. These detrimental effects on acute lower respiratory illnesses were most marked in children with adequate nutritional status (rate ratio 1.83, 95% confidence interval 1.257-2.669). In contrast, vitamin A tended to be protective of ALRI in chronically malnourished children (rate ratio 0.71, 95% confidence interval 0.375-1.331). There was no overall effect of high-dose vitamin A supplements on the incidence of diarrheal disease (rate ratio 1.06, 95% confidence interval 0.920-1.225). However, we found a significant interaction between supplementation and age: vitamin A increased the incidence of diarrhea in children < 30 mo of age, but tended to reduce the incidence in older children. The finding of a significant adverse effect of vitamin A supplements in adequately nourished children highlights the need to review the criteria for selecting populations of preschool-age children for vitamin A supplementation. A beneficial effect of periodic vitamin A supplementation on childhood mortality has been demonstrated, but the effect on morbidity is less clear. We investigated the effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections (ALRI) in children from northeastern Brazil in a randomised, double-blind, placebo-controlled community trial. 1240 children aged 6-48 months were assigned vitamin A or placebo every 4 months for 1 year. They were followed up at home three times a week, and data about the occurrence and severity of diarrhoea and ALRI were collected. Any child with cough and respiratory rate above 40 breaths per min was visited by a paediatrician. The overall incidence of diarrhoea episodes was significantly lower in the vitamin-A-supplemented group than in the placebo group (18.42 vs 19.58 x 10(-3) child-days; rate ratio 0.94 [95% Cl 0.90-0.98]). The benefit of supplementation was greater as regards severe episodes of diarrhoea; the incidence was 20% lower in the vitamin A group than in the placebo group (rate ratio 0.80 [0.65-0.98]). With the standard definition of diarrhoea (> or = 3 liquid or semi-liquid stools in 24 h) the effect of vitamin A on mean daily prevalence did not reach significance, but as the definition of diarrhoea was made more stringent (increasing number of stools per day), a significant benefit became apparent, reaching for diarrhoea with 6 or more liquid or semi-liquid stools in 24 h a 23% lower prevalence. We found no effect of vitamin A supplementation on the incidence of ALRI. The reduction in severity of diarrhoea may be the most important factor in the lowering of mortality by vitamin A supplementation. This study evaluates the effects of retinol on intestinal barrier function, growth, total parasites, and Giardia spp infections in children in northeastern Brazil.
                The study was a double-blind, randomized placebo-controlled trial (http://clinicaltrials.gov; register no. #NCT00133406) involving 79 children who received vitamin A 100,000-200,000 IU (n = 39) or placebo (n = 40) at enrollment, 4, and 8 months and were followed for 36 months. Intestinal barrier function was evaluated using the lactulose:mannitol ratio test. Stool lactoferrin was used as a marker for intestinal inflammation.
                The groups were similar with regard to age, sex, nutritional parameters (z scores), serum retinol concentrations, proportion of lactoferrin-positive stool samples, and intestinal barrier function. The lactulose:mannitol ratio did not change during the same time of follow-up (P > 0.05). The proportion of lactoferrin-positive samples evaluated at 1 month did not change between groups (P > 0.05). Total intestinal parasitic, specifically new, infections were significantly lower in the vitamin A treatment compared with control group; these were accounted for entirely by significantly fewer new Giardia infections in the vitamin A treatment group. The cumulative z scores for weight-for-length or height, length or height-for-age z scores, and weight-for-age did not change significantly with vitamin A intervention for 36 months of follow-up.
                These data showed that total parasitic infection and Giardia spp infections were significantly lower in the vitamin A treatment group when compared with the placebo group, suggesting that vitamin A improves the host's defenses against Giardia infections. A randomized, double-blind, placebo-controlled trial was conducted in an ongoing Growth Monitoring Research project in TamilNadu, India, to assess the impact of high-dose vitamin A supplementation on morbidity among mildly to moderately malnourished children aged < 3 y. Every 4 mo, the treatment group received 60 mg vitamin A (200,000 IU) whereas the control group received a placebo. Cases of xerophthalmia and severe malnutrition were excluded. Anthropometric measurements and serum retinol determinations were made at baseline and at the end of 1 y. Morbidity data were collected by trained village-level workers throughout the study period by using the weekly recall method. The two groups had similar nutritional status, serum retinol concentrations, age-sex composition, and other sociodemographic indicators at baseline. The mean number of episodes per child-year was 2.62 +/- 2.95 and 2.56 +/- 2.5 for respiratory illness and 1.9 +/- 2.2 and 1.77 +/- 1.77 for diarrhea for the vitamin A (n = 309) and placebo (n = 274) groups, respectively. The differences in respiratory and diarrheal morbidity between the two groups were not statistically significant and these findings remained unaltered after multivariate analysis in which the effects of age, sex, socioeconomic status, sanitation, etc, were considered. These findings are similar to other recent findings and indicate that vitamin A supplementation does not reduce common morbidity in children with mild-to-moderate vitamin A deficiency in areas where access to health care and immunization are good. To clearly clarify the protective effect of vitamin A supplementation on immune function of well-nourished children suffering from vitamin A deficiency.
                Three hundred sixty-two children in two kindergartens in Wuhan China were enrolled. Detailed dietary assessment and anthropometry were undertaken to facilitate the exclusion of malnourished children. Seventy vitamin A-deficient children with informed consent were randomly divided into the vitamin A-deficient-supplemented group and vitamin A-deficient placebo group, 35 vitamin A-sufficient children (age- and sex-matched with the vitamin A-deficient-supplemented group children) were selected as vitamin A-sufficient placebo group. The baseline and follow-up level of selected immune parameters of the 105 children in three intervention groups were compared.
                The total proportion of severe and marginal vitamin A-deficient children was 10.9 and 21.96%, respectively. At baseline, the serum complement C3 and sIgA level of vitamin A-sufficient children was significantly higher than that of vitamin A-deficient children (P < 0.05). However, the serum lysozyme level of vitamin A-sufficient children was inversely lower. After intervention, vitamin A-deficient-supplemented children increased serum vitamin A, complement C3 and sIgA level, but their serum lysozyme level inversely decreased.
                Vitamin A deficiency was still a serious health problem in children in China cities. Vitamin A supplementation was efficacious in ameliorating serum vitamin A status and partially impaired immune function of well-nourished children suffering from vitamin A deficiency. Administration of 100,000 IU vitamin A at the time of measles immunisation is currently recommended for infants in developing countries. However, the safety and value of giving vitamin A, a potent immune enhancer, with live measles virus vaccines are unknown. We conducted a randomised, double-blind, placebo-controlled clinical trial in Indonesia to evaluate the effect of simultaneous vitamin A supplementation on the immune response to measles immunisation at six months of age. 336 infants received either vitamin A (100,000 IU) or placebo when immunised with standard-titre Schwarz measles vaccine. 82% of infants seroconverted to measles. In a multiple logistic regression model adjusting for maternal antibody titres, vitamin A supplementation was associated with a lower likelihood of seroconversion to measles (odds ratio 0.40, 95% CI 0.19-0.88), and girls were less likely to seroconvert than boys (0.34, 0.15-0.76). Immunisation with standard-titre Schwarz vaccine at six months of age in this study population is characterised by high seroconversion rates. However, simultaneous high-dose vitamin A may interfere with seroconversion to live measles vaccine in infants with maternal antibody. The tolerance to two alternative large-dosage strengths of vitamin A preparation was determined in a double-blind study involving 2471 children in two municipalities in the Philippines. Each child, aged 1-6 y, not suffering from active xerophthalmia or from nausea and/or vomiting, headache, diarrhea, and fever, was randomly given 1 mL of a syrupy suspension later identified to contain 0, 60, or 30 mg vitamin A. Clinical evaluation of subjects was done by physicians 24 h and 1 wk after dosing. Nausea and/or vomiting and headache were twice as common among children given 60 mg than those given 30 mg. Severe vomiting (1.2%) was confined to those given 60 mg. Almost all experienced their symptoms within 24 h after dosing; symptoms lasted for no more than 12-24 h. The incidence of diarrhea and fever for vitamin A recipients was not significantly different from that of those receiving placebo. nan Marked seasonal variation in the prevalence of signs of vitamin A deficiency was found in the 2nd year of a continuing study of children age 0 to 4-1/2 years in a village in West Bengal, confirming results of a previous 18-month study. Administration of 200,000 IU of vitamin A every 4 months completely eliminated night blindness and prevented the development of new cases of Bitot's spot in a statistically significant number of children. The effectiveness of massive doses of vitamin A, administered at intervals of 4 months, as a short-term measure to fight the problem, was confirmed in this village. The study yielded additional evidence of the complex etiology of Bitot's spot, since alternate day dose of vitamin A in addition to massive therapy failed to eliminate these spots. To determine whether a single high dose of vitamin A given to all children in communities with high mortality and malnutrition could affect mortality and to assess whether periodic community wide supplementation could be readily incorporated into an ongoing primary health programme.
                Opportunistic controlled trial.
                Jumla district, Nepal.
                All children aged under 5 years; 3786 in eight subdistricts given single dose of vitamin A and 3411 in remaining eight subdistricts given no supplementation.
                Mortality and cause of death in the five months after supplementation.
                Risk of death for children aged 1-59 months in supplemented communities was 26% lower (relative risk 0.74, 95% confidence interval 0.55 to 0.99) than in unsupplemented communities. The reduction in mortality was greatest among children aged 6-11 months: death rate (deaths/1000 child years at risk) was 133.8 in supplemented children and 260.8 in unsupplemented children (relative risk 0.51, 0.30 to 0.89). The death rate from diarrhoea was also reduced (63.5 supplemented v 97.5 unsupplemented; relative risk 0.65, 0.44 to 0.95). The extra cost per death averted was about $11.
                The results support a role for Vitamin A in increasing child survival. The supplementation programme was readily integrated with the ongoing community health programme at little extra cost. To evaluate the effect of simultaneous zinc and vitamin A supplementation on diarrhoea and acute lower respiratory infections in children.
                Randomised double blind placebo controlled trial.
                Urban slums of Dhaka, Bangladesh.
                800 children aged 12-35 months were randomly assigned to one of four intervention groups: 20 mg zinc once daily for 14 days; 200 000 IU vitamin A, single dose on day 14; both zinc and vitamin A; placebo. The children were followed up once a week for six months, and morbidity information was collected.
                The incidence and prevalence of diarrhoea were lower in the zinc and vitamin A groups than in the placebo group. Zinc and vitamin A interaction had a rate ratio (95% confidence interval) of 0.79 (0.66 to 0.94) for the prevalence of persistent diarrhoea and 0.80 (0.67 to 0.95) for dysentery. Incidence (1.62; 1.16 to 2.25) and prevalence (2.07; 1.76 to 2.44) of acute lower respiratory infection were significantly higher in the zinc group than in the placebo group. The interaction term had rate ratios of 0.75 (0.46 to 1.20) for incidence and 0.58 (0.46 to 0.73) for prevalence of acute lower respiratory infection.
                Combined zinc and vitamin A synergistically reduced the prevalence of persistent diarrhoea and dysentery. Zinc was associated with a significant increase in acute lower respiratory infection, but this adverse effect was reduced by the interaction between zinc and vitamin A. The World Health Organization recommends vitamin A supplementation (VAS) at vaccination contacts after 6 mo of age to reduce mortality. However, it is unknown whether the effect of VAS is independent of vaccinations. One of the original VAS trials from Ghana had collected vaccination information.
                We reanalyzed the data to explore the hypothesis that VAS reduces mortality in children who had bacille Calmette-Guérin or measles vaccine as their most recent vaccine but increased mortality when diphtheria-tetanus-pertussis vaccine (DTP) was the most recent vaccine. On the basis of previous studies, we expected the effects to be strongest in girls.
                At enrollment, children aged 6-90 mo were randomly assigned to receive VAS or placebo every 4 mo for 2 y. Vaccination status was assessed at enrollment and after 1 and 2 y by reviewing the children's health cards. Lack of a health card was presumed to mean that the child had not been vaccinated.
                VAS had a beneficial effect only in children with no record of vaccination at enrollment (n = 5066); the mortality rate ratio (MRR) was 0.64 (95% CI: 0.47, 0.88) compared with 0.95 (95% CI: 0.72, 1.26) in children with one or more vaccinations (n = 6656). Among vaccinated children, the effect of VAS differed between boys (MRR: 0.74; 95% CI: 0.51, 1.08) and girls (MRR: 1.18; 95% CI: 0.84, 1.67) (P = 0.046 for interaction). VAS had a negative effect in measles-vaccinated girls who were missing one or more doses of DTP at enrollment, a group who often received DTP during follow-up (MRR: 2.60; 95% CI: 1.41, 4.80).
                The effect of VAS differed by vaccination status. This is potentially problematic because VAS is provided at vaccination contacts. WHO has recommended vitamin A supplementation for children aged 6 months or older in developing countries at the same time as immunisation. One study has reported significantly lower seroconversion ratios among children who have received vitamin A supplements with measles vaccine at age 6 months. The aim of our study was to assess the effect of vitamin A supplementation on antibody response to measles vaccination at age 9 months, which is the more common age for immunisation in developing countries.
                In an urban community in Guinea-Bissau, we did a randomised, double-blind, placebo-controlled study of the effect of simultaneous vaccination and vitamin A supplementation in 462 children who received either a two-dose schedule of measles vaccine at the ages of 6 months and 9 months (150 infants) or one dose of measles vaccine at age 9 months (312 infants). Children were followed up to the age of 18 months and a blood sample was then collected to assess the antibody response.
                397 (86%) of the children took part in the follow-up (52 [11%] had moved and 13 [3%] had died). Among children who received a two-dose vaccine schedule, seroconversion was 98%. There was no difference in seroconversion or geometric mean titre (GMT) for children receiving vitamin A compared with children receiving no supplement. Among children receiving only one dose of measles vaccine at age 9 months, seroconversion was 95%. The GMT was significantly higher in children receiving vitamin A than in those receiving no supplement (3704 vs 2439 mIU; GMT ratio 1.52 [1.22-1.88]). The effect on plasma antibody concentration in the blood was stronger for boys (3902 vs 1916 mIU; GMT ratio 2.04 [1.53-2.72]) than for girls (3502 vs 3017 mIU; GMT ratio 1.16 [0.85-1.58]) who had received vitamin A with measles vaccine. In a multivariate analysis of variance adjusted for sex, vitamin A supplementation was associated with higher antibody titres (p < 0.001). There was a significant interaction between vitamin A supplementation and sex (p = 0.02).
                There is no indication that simultaneous administration of measles vaccine and vitamin A supplements has a negative effect on measles immunity. Among the children who had received two doses of measles vaccine at the ages of 6 months and 9 months, supplements of vitamin A had no significant effect. Among children only receiving one dose of measles vaccine at age 9 months, 100,000 IU vitamin A increased antibody concentrations, especially for boys. In a double blind design, 1520 children aged < 10 years were individually randomised in vitamin A and placebo group in slums of Chandigarh. Children > 12, 6-12 and < 6 months of age received 200,000, 100,000, 500,000 I.U. of vitamin A respectively every 4 to 6 months during 15 months trial period. The prevalence of vitamin A deficiency was significantly reduced in vitamin A compared to placebo group during the follow-up period. In vitamin A group, incidence of diarrhoea and measles was significantly reduced but incidence of acute respiratory infections was not significantly different compared to control group. Risk of death was also significantly less in vitamin A group. Therefore, promotion of vitamin A rich diet or supplementation with synthetic vitamin A at 4-6 month interval should be a priority in populations where risk of vitamin A deficiency is high. To evaluate the relationship between vitamin A supplementation, plasma retinol level (PRL) and incidence, severity and duration of acute respiratory infect ions (ARI) in children 1-5 years old.
                A one year prospective randomized intervention study from June 1989 to May 1990 in Cikutra, a suburb of Bandung, Indonesia.
                Out of almost 2000 children aged 12-54 months, 269 were selected by stratified randomization. Vitamin A (200,000 IU orally) was administered at 6-monthly intervals in a double blind, placebo controlled programme. Every 2 weeks, primary health care workers collected data on respiratory symptoms in the children, and every month a pediatrician examined the children. Venous blood samples were obtained at the start and at 3 and 6 months for plasma retinol levels (PRL).
                The mean PRL at the start of the study was 20 +/- 8 micrograms/dl; 8% of the children showed a deficient level of less than 10 micrograms/dl. The incidence or ARI was 6.7 +/- 3.5 episodes per child per year with a mean duration of 5.3 +/- 3.1 days per episode. In vitamin A supplemented children the duration of ARI was slightly shorter (5.2 +/- 3.1 versus 5.6 +/- 3.1 days, P < 0.01) but no effect on the incidence or severity of ARI was detected. Low, and especially deficient, PRL had improved after 3 months and even after 6 months, but this was unrelated to vitamin A supplementation. There was also no relationship between PRL and incidence, severity or duration of ARI.
                Only a slight relationship is found between vitamin A supplementation and ARI duration in under-fives. To determine whether supplementation of vitamin A and/or zinc (Zn) improved serum levels of these nutrients and/or height and weight gains in preschool children, 22 to 66 months, living in Belize, Central America.
                Subjects received either Zn, vitamin A, Zn and vitamin A or a placebo, (70 mg Zn and/or 3030 RE vitamin A, once per week) for 6 months in a 2x2 factorial design. Forty-three children, from a population of 104 prescreened, completed the study; they were selected, prior to treatment, for low/marginal serum concentrations of these micronutrients.
                Serum Zn levels were greater (16%, p<0.001) for those who received Zn. In contrast, after vitamin A treatment there were no differences in serum vitamin A among groups. Although increases in height (+4.4 cm, p<0.001) and weight (+0.79 kg, p<0.001), compared with baseline values, were numerically greatest for children who received both supplements, only the vitamin A supplementation effect was significant, resulting in increased height (+1.4 cm, p<0.002) and greater weight gain (+0.15 kg, p<0.03) compared to those receiving no vitamin A. Vitamin A supplementation alone significantly increased (p<0.001) hemoglobin concentration.
                The results suggest that the preschool children in this study, prescreened for low/marginal serum concentrations from a larger population prior to treatment, were enduring inadequate vitamin A and, to a lesser degree, Zn nutriture. Height and weight gain were significantly increased in the subjects who received a single weekly supplement 3030 RE of vitamin A. In order to extend our earlier observation that children who experience frequent respiratory episodes may benefit from Vitamin A supplementation, 206 children aged 2-7 years who had been hospitalized for bronchiolitis during infancy were randomized into a controlled trial of Vitamin A supplementation. Of these, 149 met the criteria of protocol compliance after 12 months of follow-up. Mean plasma retinol at baseline was 39.2 micrograms/100 ml (s.e.m. = 1.0) and did not increase after 12 months (mean = 36.0 micrograms/100 ml, s.e.m. = 0.7) despite the older age of the cohort. The range observed (11.7-73.9 micrograms/100 ml) included some children at risk of marginal Vitamin A deficiency. Mean plasma retinol levels were 20% lower than those of children experiencing frequent respiratory episodes recorded earlier. Oral supplementation did not change plasma retinol levels, nor did it affect respiratory morbidity. 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.
                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.
                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.
                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. 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 susceptibility to acute respiratory infections was investigated in a randomized controlled trial. One hundred and forty-seven preschool-age children with a history of frequent respiratory illness were randomized into Vitamin A supplemented (450 micrograms/day) and placebo groups. Respiratory symptoms were recorded on a daily basis over a period of 11 months. The children who received the supplement experienced 19% fewer episodes of respiratory symptomatology (P less than 0.05) than their placebo counterparts, despite the fact that their plasma retinol levels did not change. Children with a prior history of lower respiratory illness or of allergy benefited most from supplementation. The plausibility of a role for Vitamin A in the aetiology of respiratory proneness is reviewed. There is uncertainty over whether vitamin A supplementation reduces morbidity among children with subclinical deficiency of the vitamin. Hence a double-blind, placebo-controlled trial of the effect of vitamin A supplementation on childhood morbidity was conducted among 11,124 children aged 6-83 months in the northwest of Haiti. After a random start, children were sequentially assigned by household units to receive either megadose vitamin A or placebo in three distribution cycles 4 months apart. 2 to 8 weeks after each administration of the vitamin A and placebo capsules, indicators of childhood morbidity were reassessed through interviews conducted in the homes of participating families. The vitamin A group was found to have an increased 2-week prevalence of all symptoms and signs of childhood morbidity assessed, including diarrhoea (rate ratio [RR] = 1.09, 95% confidence interval 1.05-1.14), rhinitis (RR = 1.02, 95% confidence interval 1.00-1.04), cold/flu symptoms (RR = 1.04, 95% confidence interval 1.01-1.06), cough (RR = 1.07, 95% confidence interval 1.03-1.11), and rapid breathing (RR = 1.18, 95% confidence interval 1.09-1.27). The study shows an increased 2-week prevalence of diarrhoea and the symptoms of respiratory infections after vitamin A supplementation. 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. nan A randomized controlled trial was conducted in 395 infants aged 9-12 months to determine the effect of Vitamin A supplementation on concurrently administered measles vaccine. Antibody response was measured using the plaque reduction neutralization assay. No statistically significant differences were demonstrated between the immune response in Vitamin A supplemented and unsupplemented children. Unlike some recent studies, we were unable to demonstrate an immune enhancing effect of Vitamin A supplementation. On the contrary, among children who were given Vitamin A, a lower, but statistically non-significant, proportion had protective antibody levels 6 months after vaccination. To assess the impact of Vitamin A supplementation to the mother soon after delivery and to the infant at six months on morbidity in infancy.
                Randomized double blind placebo controlled field trial.
                51 villages in two contiguous Primary Health Centers in Villupuram Health Unit District of Tamil Nadu, South India.
                909 newly delivered mother-and-infant pairs.
                Both mother and infant received Vitamin A (300,000 IU for mothers and 200,000 IU for children) in 311 instances (AA); mother received Vitamin A but infant received Placebo in 301 instances (AP); and both mother and infant received Placebo in the remaining 297 instances (PP).
                Incidence of diarrhea and Acute Respiratory Infection (ARI); distributions of infants by frequency of episodes and number of infected days.
                233 in the AA Group and 228 each in the AP and PP Groups were followed up regularly. The incidence of diarrhea in these infants was 97.4%, 96.9% and 94.7% in the three groups, mean number of diarrheal episodes was 4.4, 4.6 and 4.2 and median number of days in infancy with diarrhea was 26, 26 and 22 days, respectively. For ARI, the incidences were 96.6%, 95.6% and 96.1%, means were 4.8, 5.1 and 4.8 episodes, and the medians were 32, 34 and 34 days, respectively.
                Prophylactic administration of mega doses of Vitamin A to the mother soon after delivery and to the infant at six months do not have any beneficial impact on the incidence of diarrhea and ARI in infancy. The efficacy of micronutrient supplementation in improving childhood health and survival in developing countries may be specific to the micronutrient used and health outcome measured.
                We evaluated the effect of vitamin A and zinc supplementation on overall rates of childhood diarrheal disease and respiratory tract infections and rates stratified by household and personal characteristics.
                A double-blind, randomized, placebo-controlled trial was carried out in which 736 children aged 6-15 mo living in a periurban area of Mexico City were assigned to receive vitamin A every 2 mo, zinc daily, vitamin A and zinc together, or placebo. Children were followed for 12 mo to determine overall counts of diarrheal episodes and respiratory tract infections.
                Vitamin A supplementation was associated with a 27% increase in diarrheal disease [risk ratio (RR): 1.27; 95% CI: 1.10, 1.45; P < 0.001] and a 23% increase in cough with fever (RR: 1.23; 95% CI: 1.02, 1.47; P = 0.02), whereas zinc had no effect on these outcomes. Vitamin A supplementation decreased diarrhea in children from households with dirt floors but increased diarrhea in children from households with nondirt floors, piped water, and indoor bathrooms. Zinc supplementation decreased diarrhea in children from households with dirt floors and whose mothers were more educated. Vitamin A supplementation increased cough with fever in children from less-crowded households that lacked indoor bathrooms and in children of less-educated mothers.
                Vitamin A increases diarrheal disease and respiratory tract infections in young children in periurban areas of Mexico City. Vitamin A and zinc have more heterogeneous effects in different subgroups of children. Previous clinical vitamin A trials have found no consistent effect on diarrhoeal disease and respiratory tract infection. These inconsistent results may be due to the distinct effects vitamin A supplementation has among children stratified by factors related to socio-economic status, nutritional status and season. We evaluated the effect of supplementation on the overall incidence of diarrhoeal disease and respiratory tract infections and on the incidence among children stratified by these factors. A total of 188 children, aged 6-15 months, from periurban, marginalized communities of Mexico City were assigned to receive vitamin A ( < 12 months of age, 20,000 IU retinol; >or= 12 months, 45,000 IU retinol) or a placebo every 2 months, and were followed for up to 15 months. Project personnel visited households twice a week to determine the onset and duration of diarrhoeal disease and respiratory tract infections. Vitamin A supplementation had no significant effect on risk of overall diarrhoeal disease but reduced mild watery diarrhoea (incidence rate ratio (RR) 0.69; 95 % CI 0.50, 0.93) and cough with fever (RR 0.69; 95 % CI 0.48, 0.98). Vitamin A supplementation decreased diarrhoeal disease during the summer (RR 0.74; 95 % CI 0.57, 0.94), among non-stunted children (RR 0.69; 95 % CI 0.52, 0.93) and among children from households with better socio-economic measures. Heterogeneity in the response to vitamin A supplementation may reflect heterogeneity in the aetiology and epidemiology of diarrhoeal disease and respiratory tract infections and the impact that supplementation has on the immune response. After a report of reduced seroconversion to measles in infants, aged 6 mo, given vitamin A with their measles vaccination, serious concerns were raised regarding the safety of the WHO's recommendation that infants be supplemented with vitamin A at the time of measles immunization. To determine the impact of coadministered vitamin A on the antibody response to measles vaccine given to infants aged 9 mo, the more common age for immunization in developing countries, we conducted a randomized, double-blind, placebo-controlled trial in an urban slum community in Delhi. Infants (618) were randomly allocated to receive 30 mg vitamin A or a placebo with the measles immunization. Antibodies to measles were measured by ELISA in serum samples obtained at before (baseline) and 12 wk after immunization. Overall, the seroconversion rates did not differ between vitamin A (89.5%) and placebo (87.6%) groups. There were no significant differences in the geometric mean titers in the two groups (ratio of geometric means, 1.19; 95% confidence interval, 0.97-1.46). Among malnourished infants, the geometric mean titer was significantly greater in the vitamin A group compared to the placebo group (ratio of geometric means, 1.57; 95% confidence interval, 1. 18-2.0), but seroconversion rates did not differ. There were no differences in seroconversion rates and geometric mean titers in the two study groups among the well-nourished children. These results indicate that 30 mg vitamin A does not reduce the immune response to the coadministered vaccine and, therefore, can be continued to be given safely in public health programs. Many individuals at risk of malaria also have micronutrient deficiencies that may hamper protective immunity. Vitamin A is central to normal immune function, and supplementation has been shown to lower the morbidity of some infectious diseases. We investigated the effect of vitamin A supplementation on malaria morbidity.
                This randomised double-blind placebo-controlled trial of vitamin A supplementation took place in a P. falciparum endemic area of Papua New Guinea. Of 520 potentially eligible children aged 6-60 months, 480 were randomly assigned high-dose vitamin A (n=239) or placebo (n=241), every 3 months for 13 months. Malaria morbidity was assessed through weekly community-based case detection and surveillance of patients who self-reported to the health centre. Cross-sectional surveys were also done at the beginning, middle, and end of the study to assess malariometric indicators. Analyses were by intention to treat.
                The number of P. falciparum febrile episodes (temperature > or = 37.5 degrees C with a parasite count of at least 8000/microL) was 30% lower in the vitamin A group than in the placebo group (178 vs 249 episodes; relative risk 0.70 [95% CI 0.57-0.87], p=0.0013). At the end of the study P. falciparum geometric mean density was lower in the vitamin A than the placebo group (1300 [907-1863] vs 2039 [1408-2951]) as was the proportion with spleen enlargement (125/196 [64%] vs 148/207 [71%]); neither difference was significant (p=0.093 and p=0.075). Children aged 12-36 months benefited most, having 35% fewer febrile episodes (89 vs 141; relative risk 0.65 [14-50], p=0.0023), 26% fewer enlarged spleens (46/79 [58%] vs 67/90 [74%], p=0.0045), and a 68% lower parasite density (1160 [95% CI 665-2022] vs 3569 [2080-6124], p=0.0054). Vitamin A had no consistent effect on cross-sectional indices of proportion infected or with anaemia.
                Vitamin A supplementation may be an effective low-cost strategy to lower morbidity due to P. falciparum in young children. The findings suggest that clinical episodes, spleen enlargement, and parasite density are influenced by different immunological mechanisms from infection and anaemia. A randomized controlled trial was conducted in eastern Zaire to assess the effects of high dose vitamin A supplementation and regular deparasitation on the growth of 358 moderately malnourished preschool children, discharged from the hospital. The treatment groups received either vitamin A (60 mg of oily solution of retinyl palmitate, 30 mg if aged <12 mo) every 6 mo or mebendazole (500 mg) every 3 mo; the control group received no supplementation. Anthropometric data were gathered at baseline and after 6 and 12 mo of follow-up. Serum retinol concentrations were measured at baseline and after 3 mo. The three groups did not differ in sociodemographic indicators, age and sex composition, nutritional status and serum retinol concentrations at baseline. In children who were vitamin A deficient at baseline, adjusted mean weight and mid-upper arm circumference (MUAC) increments were higher in the vitamin A-supplemented group than in the control group [annual increment in weight and MUAC in vitamin A vs. control group: 2.088 vs. 1.179 kg (P = 0.029) and 2.24 vs. 0.95 cm (P = 0.012), respectively], whereas growth increment did not differ between the dewormed group and the control group. In children who were not vitamin A deficient at baseline, growth increment did not differ between the vitamin A-supplemented and control groups, whereas weight gain was lower in the dewormed group than in the control group. Vitamin A-supplemented boys gained more weight and height than control boys, whereas vitamin A-supplemented girls gained less height than control girls. Dewormed boys and girls gained less weight than control boys and girls. Programs to improve vitamin A status by high dose vitamin A supplementation may improve growth of preschool children who are vitamin A deficient, whereas deworming does not. Although most studies on the effect of vitamin A supplementation have reported reductions in childhood mortality, the effects on morbidity are less clear. We have carried out two double-blind, randomised, placebo-controlled trials of vitamin A supplementation in adjacent populations in northern Ghana to assess the impact on childhood morbidity and mortality. The Survival Study included 21,906 children aged 6-90 months in 185 geographical clusters, who were followed for up to 26 months. The Health Study included 1455 children aged 6-59 months, who were monitored weekly for a year. Children were randomly assigned either 200,000 IU retinol equivalent (100,000 IU under 12 months) or placebo every 4 months; randomisation was by individual in the Health Study and by cluster in the Survival Study. There were no significant differences in the Health Study between the vitamin A and placebo groups in the prevalence of diarrhoea or acute respiratory infections; of the symptoms and conditions specifically asked about, only vomiting and anorexia were significantly less frequent in the supplemented children. Vitamin-A-supplemented children had significantly fewer attendances at clinics (rate ratio 0.88 [95% CI 0.81-0.95], p = 0.001), hospital admissions (0.62 [0.42-0.93], p = 0.02), and deaths (0.81 [0.68-0.98], p = 0.03) than children who received placebo. The extent of the effect on morbidity and mortality did not vary significantly with age or sex. However, the mortality rate due to acute gastroenteritis was lower in vitamin-A-supplemented than in placebo clusters (0.66 [0.47-0.92], p = 0.02); mortality rates for all other causes except acute lower respiratory infections and malaria were also lower in vitamin A clusters, but not significantly so. Improving the vitamin A intake of young children in populations where xerophthalmia exists, even at relatively low prevalence, should be a high priority for health and agricultural services in Africa and elsewhere. The impact on vitamin A deficiency (VAD), wasting malnutrition, and excessive childhood mortality of two alternative approaches-nutrition education and mega-dose capsule distribution (6-12-month-olds: 100,000 IU; 1-5-year-olds: 200,000 IU)-in communities in Nepal are compared. Approximately 40,000 children from 75 locations in seven districts in two ecological settings (lowland and hills) took part in the study and were randomly allocated to intervention cohorts or a control group. At 24 months after the implementation of the project the reduction of risk for xerophthalmia was greater among children whose mothers were able to identify vitamin-A-rich foods (relative risk (RR) = 0.25; 95% confidence interval (CI) = 0.10-0.62) than among the children who received mega-dose capsules (RR = 0.59; 95% CI = 0.41-0.84). The risk of mortality at 2 years was reduced for both the nutrition education (RR = 0.64; 95% Cl = 0.48-0.86) and capsule distribution (RR = 0.57; 95% CI = 0.42-0.77) cohorts. The nutrition education programme was, however, more expensive to deliver than the capsule distribution programme. High rates of participation for children in the supplementation programme were achieved quickly. The nutrition education messages also spread rapidly throughout the study population (regardless of intervention cohort assignment). Practices, however, were slower to change. In communities where maternal literacy was low and channels of communication were limited the capsule distribution programme appeared to be more economical. However, there are economies of scale for nationwide education programmes that do not exist for capsule distribution programmes. Although nutrition education provides economies of scale and the promise of long-term sustainability, a comprehensive national programme requires both dietary supplementation and nutrition education components. nan Previous studies of large-dose vitamin A supplementation on respiratory morbidity have produced conflicting results in a variety of populations. The influence of malnutrition has not been examined in the majority of these trials. We hypothesized that weekly low-dose vitamin A supplementation would prevent respiratory and diarrheal disease morbidity and that malnutrition might influence the efficacy of vitamin A supplementation.
                In a randomized, double-blind, placebo-controlled field trial of 400 children, 6 to 36 months of age in a high Andean urban slum, half of the children received 10 000 IU of vitamin A weekly and half received placebo for 40 weeks. Children were visited weekly at home by physicians and assessed for acute diarrheal disease and acute respiratory infections.
                Acute diarrheal disease and acute respiratory infection did not differ globally or by severity between supplement-treated and placebo groups. However, the incidence of acute lower respiratory infection (ALRI) was significantly lower in underweight (weight-for-age z score [WAZ] <-2 SD) supplement-treated children than in underweight children on placebo (8.5 vs 22.3 per 10(3) child-weeks; rate ratio: 0.38 [95% CI: 0.17-0.85]). ALRI incidence was significantly higher in normal-weight (WAZ >-2 SD) supplement-treated children than in normal-weight children on placebo (9.8 vs 4.4 per 10(3) child-weeks; rate ratio: 2.21 [95% CI: 1.24-3.93]). By logistic regression analysis the risk of ALRI was lower in underweight supplement-treated children than in underweight children on placebo (point estimate 0.148 [95% CI: 0.034-0.634]). In contrast, risk of ALRI was higher in normal-weight supplement-treated children (WAZ >-1 SD to mean) than in normal-weight children on placebo in the same WAZ stratum (point estimate: 2.51 [95% CI: 1.24-5.05]). The risk of severe diarrhea was lower in supplement-treated children 18 to 23 months of age than in children on placebo in this age group (point estimate: 0.26 [95% CI: 0.06-1.00]).
                Weekly low-dose (10 000 IU) vitamin A supplementation in a region of subclinical deficiency protected underweight children from ALRI and paradoxically increased ALRI in normal children with body weight over -1 SD. Protection from severe diarrhea was consistent with previous trials. Additional research is warranted to delineate potential beneficial and detrimental interactions between nutritional status and vitamin A supplementation regarding ALRI.
VAS is effective in reducing all-cause mortality and we recommend universal supplementation for children under 5 in areas at risk of VAD. Further placebo-controlled trials of VAS in children between 6 months and 5 years of age are unnecessary, although studies that compare different doses and delivery mechanisms are needed.