Diarrhea, respiratory infections, and growth are not affected by a weekly low-dose vitamin A supplement: a masked, controlled field trial in children in southern India. 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. Effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections in young children in Brazil. Vitamin A supplementation fails to reduce incidence of acute respiratory illness and diarrhea in preschool-age Indonesian children. Vitamin A supplementation in northern Ghana: effects on clinic attendances, hospital admissions, and child mortality. Ghana VAST Study Team. Randomized placebo-controlled clinical trial of the effect of a single high dose or daily low doses of vitamin A on the morbidity of hospitalized, malnourished children. Simultaneous zinc and vitamin A supplementation in Bangladeshi children: randomised double blind controlled trial. Vitamin A supplementation and increased prevalence of childhood diarrhoea and acute respiratory infections. Impact of massive dose of vitamin A given to preschool children with acute diarrhoea on subsequent respiratory and diarrhoeal morbidity. The beneficial effects of weekly low-dose vitamin A supplementation on acute lower respiratory infections and diarrhea in Ecuadorian children.
Incidence, duration, and severity of diarrhea and respiratory symptoms were monitored weekly for 1 y in 15,419 children 6-60 mo of age in a randomized, placebo-controlled, masked clinical trial conducted in southern India. Half the children received weekly doses of 8.7 mumol (2500 microgram) vitamin A and 46 mumol (20 mg) vitamin E (treated) and the other half, 46 mumol vitamin E (control). Medical and ocular examinations and anthropometric measurements were obtained before and after 52 wk of intervention. Ocular examinations also were obtained after 26 wk. Supplements were delivered weekly from calibrated dispenser bottles by community health volunteers who also recorded each mother's recall of daily morbidity of her child during the previous week. Baseline characteristics of treated and control subjects were similar and documented a prevalence of 11% xerophthalmia and 72% undernutrition. Weekly treatment with the low-dose vitamin A supplement did not influence the incidence, severity, or duration of diarrhea or respiratory infections and did not influence linear or ponderal growth. 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. 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. 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. 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 effect of high-dose vitamin A supplementation on recovery from morbidity and on recovery from nosocomial morbidity of hospitalized children has been poorly studied and results are conflicting. The effect of daily, low doses has never been assessed. We investigated the effect of a single high dose and daily, low doses of vitamin A on diarrhea, acute lower respiratory tract infections (ALRIs), and all-cause fevers in 900 hospitalized preschool-age children in the Democratic Republic of Congo in a randomized, double-blind, placebo-controlled clinical trial. The high-dose treatment group received 200,000 IU vitamin A (100,000 IU if aged <12 mo) orally on the day of admission, the low-dose treatment group received 5000 IU vitamin A/d until discharge. Data on all-cause morbidity were collected daily. Mortality rates were not significantly different among the 3 groups. High-dose vitamin A supplementation had no significant effect on the duration of moderate or severe diarrhea nor on the duration and incidence of ALRIs and all-cause fevers. Children in the high-dose group with no edema had an increased risk of severe nosocomial diarrhea (relative risk: 2.42; 95% CI: 1.15, 5.11). Low-dose vitamin A supplementation significantly reduced the incidence of severe diarrhea in severely malnourished children (relative risk: 0.21; 95% CI: 0.07, 0.62) but showed no significant effect on the duration of moderate or severe diarrhea or on the duration and incidence of ALRIs and all-cause fevers. Supplementation with high doses of vitamin A did not reduce morbidity in this population of malnourished and subclinically vitamin A-deficient children; daily, low doses appeared more beneficial for severely malnourished children. 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. 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. To assess the impact of vitamin A supplementation on morbidity from acute respiratory tract infections and diarrhoea.
                Double blind randomised placebo controlled field trial.
                An urban slum area in New Delhi, India.
                900 children aged 12-60 months attending a local health facility for acute diarrhoea of less than seven days' duration randomly allocated to receive vitamin A 200,000 IU or placebo.
                Incidence and prevalence of acute lower respiratory tract infections and diarrhoea during the 90 days after termination of the enrolment diarrhoeal episode measured by twice weekly household surveillance.
                The incidence (relative risk 1.07; 95% confidence interval 0.92 to 1.26) and average number of days spent with acute lower respiratory tract infections were similar in the vitamin A supplementation and placebo groups. Among children aged 23 months or less there was a significant reduction in the incidence of measles (relative risk 0.06; 95% confidence interval 0.01 to 0.48). The incidence of diarrhoea was also similar (relative risk 0.95; 0.86 to 1.05) in the two groups. There was a 36% reduction in the mean daily prevalence of diarrhoea associated with fever in the vitamin A supplemented children older than 23 months.
                Results were consistent with a lack of impact on acute lower respiratory tract related mortality after vitamin A supplementation noted in other trials and a possible reduction in the severity of diarrhoea. 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.
This unexpected result is outside our current understanding of the use of vitamin A for preventing acute LRTIs. Accordingly, vitamin A should not be given to all children to prevent acute LRTIs. Despite its benefits in preventing diarrhoeal illnesses, vitamin A supplementation has only a limited effect in preventing acute LRTIs. Positive effects appear limited to populations with acute and chronic under nutrition. Low-dose vitamin A appears to have fewer side effects and at least equal benefit to a high dose of vitamin A.