Abstract: We identified 47 studies (4 of which are new to this review), involving approximately 1,223,856 children. Studies took place in 19 countries: 30 (63%) in Asia, 16 of these in India; 8 (17%) in Africa; 7 (15%) in Latin America, and 2 (4%) in Australia. About one-third of the studies were in urban/periurban settings, and half were in rural settings; the remaining studies did not clearly report settings. Most of the studies included equal numbers of girls and boys and lasted about a year. The included studies were at variable overall risk of bias; however, evidence for the primary outcome was at low risk of bias. A meta-analysis for all-cause mortality included 19 trials (1,202,382 children). At longest follow-up, there was a 12% observed reduction in the risk of all-cause mortality for vitamin A compared with control using a fixed-effect model (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.93; high-quality evidence). This result was sensitive to choice of model, and a random-effects meta-analysis showed a different summary estimate (24% reduction: RR 0.76, 95% CI 0.66 to 0.88); however, the confidence intervals overlapped with that of the fixed-effect model. Nine trials reported mortality due to diarrhoea and showed a 12% overall reduction for VAS (RR 0.88, 95% CI 0.79 to 0.98; 1,098,538 participants; high-quality evidence). There was no significant effect for VAS on mortality due to measles, respiratory disease, and meningitis. VAS reduced incidence of diarrhoea (RR 0.85, 95% CI 0.82 to 0.87; 15 studies; 77,946 participants; low-quality evidence) and measles (RR 0.50, 95% CI 0.37 to 0.67; 6 studies; 19,566 participants; moderate-quality evidence). However, there was no significant effect on incidence of respiratory disease or hospitalisations due to diarrhoea or pneumonia. There was an increased risk of vomiting within the first 48 hours of VAS (RR 1.97, 95% CI 1.44 to 2.69; 4 studies; 10,541 participants; moderate-quality evidence). Vitamin A supplementation is associated with a clinically meaningful reduction in morbidity and mortality in children. Therefore, we suggest maintaining the policy of universal supplementation for children under five years of age in populations at risk of VAD. Further placebo-controlled trials of VAS in children between six months and five years of age would not change the conclusions of this review, although studies that compare different doses and delivery mechanisms are needed. In populations with documented vitamin A deficiency, it would be unethical to conduct placebo-controlled trials.

Plain-language summary: This review includes 47 RCTs representing 1,223,856 children. Studies took place in 19 countries: 30 (63%) in Asia, 16 of which were in India; 8 (17%) in Africa; 7 (15%) in Latin America, and 2 (4%) in Australia. The average age of children was about 33 months. Most of the studies included equal numbers of boys and girls and lasted about a year. The quality of the included studies was variable; however, it was unlikely that death rates were influenced by potential errors in the conduct of the studies. Data on the effect of VAS for the prevention of death were available from 19 of the included studies, and the combined results indicate that vitamin A reduces overall risk of death and death due to diarrhoea by 12%. Vitamin A does not specifically reduce death due to measles, respiratory infections, or meningitis, but it can reduce new occurrences of diarrhoea and measles. Giving oral synthetic vitamin A to children at risk of VAD reduces the risk of night blindness. It also improves levels of vitamin A in their blood. The only reported side effect was risk of vomiting within 48 hours of taking vitamin A in large doses, as recommended by the World Health Organization. We rated the overall quality of the evidence using the GRADE approach, which considers methodological flaws within studies, consistency in reporting of results across studies, extent to which results apply to other settings, and effectiveness of treatments. Based on these criteria, we judged the overall quality of the evidence to be high for benefits of VAS against overall risk of death and death due to diarrhoea. For the rest of the outcomes, we rated the evidence as low or moderate. One large, recently conducted study, which included about 1 million children, did not show any effect of VAS; however, when this study was combined with other, well-conducted studies, VAS still had beneficial effects for the prevention of death and illness. In summary, VAS can reduce risk of illness and death in children aged 6 to 59 months of age who are at risk of VAD.