Background
Vitamin A deficiency (VAD) is a major public health problem in low- and middle-income countries, affecting 190 million children under five years of age. VAD predisposes children to increased risk of a range of problems, including respiratory diseases, diarrhoea, measles, and vision problems, and it can lead to death. Previous studies show that giving synthetic vitamin A supplementation (VAS) to children aged six months to five years who are at risk of VAD can reduce the risk of death and some diseases. This is an update of the previous review.
Review question
This review evaluated the effect of synthetic VAS compared to placebo (dummy tablet) or no intervention for preventing illness and death in children aged six months to five years.
Review methods
We searched different databases that contain both published and unpublished results of medical studies. The literature search was updated in March 2021. We included only randomised control trials (RCTs: a study in which participants are randomly allocated to one or more treatments); these are considered the best form of experimental studies in research literature. We combined the results mathematically to obtain overall estimates of effectiveness of VAS against illness and death.
Study characteristics
The update identified no new studies. The 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. 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. The average age of the children was about 33 months. Most studies included equal numbers of boys and girls and lasted about one 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.
Key results
The 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 VAS reduces overall risk of death and death due to diarrhoea by 12%. VAS does not specifically reduce death due to measles, respiratory infections, or meningitis, but it can reduce new occurrences of diarrhoea and measles. There was no effect on incidence of respiratory disease or admissions to hospital due to diarrhoea or pneumonia. Giving oral synthetic vitamin A to children at risk of VAD reduces the risk of night blindness and tiny flakes of protein in the eye called Bitot's spots. 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.
Certainty of evidence
We rated the overall certainty of 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 certainty of evidence to be high for benefits of VAS against overall risk of death and death due to diarrhoea. For the other outcomes, we rated the evidence as low or moderate. One large, recently conducted study, which included about one 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. This update did not identify and new eligible studies and the conclusions remain the same.
This update identified no new eligible studies and the conclusions remain the same. VAS is associated with a clinically meaningful reduction in morbidity and mortality in children. 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 VAD, it would be unethical to conduct placebo-controlled trials.
Vitamin A deficiency (VAD) is a major public health problem in low- and middle-income countries, affecting 190 million children under five years of age and leading to many adverse health consequences, including death. Based on prior evidence and a previous version of this review, the World Health Organization has continued to recommend vitamin A supplementation (VAS) for children aged 6 to 59 months. The last version of this review was published in 2017, and this is an updated version of that review.
To assess the effects of vitamin A supplementation (VAS) for preventing morbidity and mortality in children aged six months to five years.
We searched CENTRAL, MEDLINE, Embase, six other databases, and two trials registers up to March 2021. We also checked reference lists and contacted relevant organisations and researchers to identify additional studies.
Randomised controlled trials (RCTs) and cluster-RCTs evaluating the effect of synthetic VAS in children aged six months to five years living in the community. We excluded studies involving children in hospital and children with disease or infection. We also excluded studies evaluating the effects of food fortification, consumption of vitamin A rich foods, or beta-carotene supplementation.
For this update, two review authors independently assessed studies for inclusion resolving discrepancies by discussion. We performed meta-analyses for outcomes, including all-cause and cause-specific mortality, disease, vision, and side effects. We used the GRADE approach to assess the quality of the evidence.
The updated search identified no new RCTs.
We identified 47 studies, involving approximately 1,223,856 children. Studies were set 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 studies included equal numbers of girls and boys and lasted about one year. The mean age of the children was about 33 months. 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 VAS compared with control using a fixed-effect model (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.93; high-certainty evidence).
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 children; high-certainty evidence). There was no evidence of a difference for VAS on mortality due to measles (RR 0.88, 95% CI 0.69 to 1.11; 6 studies, 1,088,261 children; low-certainty evidence), respiratory disease (RR 0.98, 95% CI 0.86 to 1.12; 9 studies, 1,098,538 children; low-certainty evidence), and meningitis. VAS reduced the incidence of diarrhoea (RR 0.85, 95% CI 0.82 to 0.87; 15 studies, 77,946 children; low-certainty evidence), measles (RR 0.50, 95% CI 0.37 to 0.67; 6 studies, 19,566 children; moderate-certainty evidence), Bitot's spots (RR 0.42, 95% CI 0.33 to 0.53; 5 studies, 1,063,278 children; moderate-certainty evidence), night blindness (RR 0.32, 95% CI 0.21 to 0.50; 2 studies, 22,972 children; moderate-certainty evidence), and VAD (RR 0.71, 95% CI 0.65 to 0.78; 4 studies, 2262 children, moderate-certainty evidence). However, there was no evidence of a difference on incidence of respiratory disease (RR 0.99, 95% CI 0.92 to 1.06; 11 studies, 27,540 children; low-certainty evidence) 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 children; moderate-certainty evidence).