1. Objectives

To evaluate the effect of vitamin A supplementation for preventing morbidity and mortality in children aged six months to five years

2. How studies were identified

The following databases were searched in April 2010:

• CENTRAL (The Cochrane Library 2010, Issue 2)
• MEDLINE
• EMBASE
• LILACS
• CINAHL
• mRCT
• Global Health
• African Index Medicus
• World Health Organization International Clinical Trials Registry (ICTRP)

Reference lists were also searched and the authors directly contacted researchers and organizations

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials, including cluster-randomized trials. Two quasi-randomized trials were included post-hoc

3.2 Study participants

Children aged six months to five years living in the community

(Studies that exclusively enrolled children in hospital and children with disease or infection were excluded, and study authors were requested to supply disaggregated data if some children met inclusion criteria while others did not. If disaggregated data were not available, the study was included if >50% of the children met the inclusion criteria)

3.3 Interventions

Oral synthetic vitamin A supplementation, at various doses and frequencies, compared to placebo or usual treatment

(Co-interventions must have been identical in both groups. Studies evaluating the effects of food fortification, the consumption of vitamin A rich foods, and beta-carotene supplementation were excluded)

3.4 Primary outcomes

• All-cause mortality

Secondary outcomes included cause-specific mortality due to diarrhoea, measles, meningitis and lower respiratory tract infection (LRTI); cause-specific morbidity including the incidence and prevalence of diarrhoea, measles, malaria, meningitis, LRTI, Bitot’s spots, night blindness and xerophthalmia; side effects and vitamin A deficiency status as measured by serum retinol

4. Main results

4.1 Included studies

Forty-three randomized trials, enrolling 215,633 children, were included in this review

• Four trials did not report data that could be included in meta-analyses, reducing the number of included children to 215,043; and individual study sample size ranged from 35 to 29,236 children
• Six trials compared vitamin A supplementation to usual treatment while 37 were placebo-controlled
• Length of follow-up was around one year for most studies, and the median age of participants was 30.5 months

4.2 Study settings

• Australia (2), Bangladesh, Belize, Brazil (2), China (3), Congo, Ecuador, Ghana, Guinea-Bissau (3), Haiti, India (14), Indonesia (5), Mexico (2), Nepal (3), the Philippines, Sudan and Thailand
• Sixteen studies were conducted in urban settings and 24 in rural settings

4.3 Study settings

How the data were analysed
Oral synthetic vitamin A supplementation was compared to placebo or treatment as usual for the prevention of morbidity and mortality in children. Data were meta-analyzed using fixed-effects models. For dichotomous outcomes, risk ratios (RR) and 95% confidence intervals (CI) were calculated, and for continuous outcomes, standardized mean differences (SMD) and corresponding 95% CI were calculated using Hedges g. Outcomes measured at different time points were collapsed for one overall analysis. Data from cluster-randomized trials were adjusted for clustering, and only the first time period from crossover trials was used in analyses. Investigation of heterogeneity was limited to study-level data to avoid aggregation bias, with the following subgroup analyses planned:

• By dose: standard (≤100,000 IU for children six to 11 months of age, and ≤200,000 IU for children 12 months to five years of age) versus high (above standard dose)
• By frequency of supplementation: low (≥ six months between doses) versus high (< six months between doses)
• By location: continent
• By age group: six to 12 months versus one to five years
• By sex

Sensitivity analyses were conducted for the primary outcome excluding studies at high risk of bias for sequence generation, studies with imputed intra-class correlation coefficients (ICC) and studies awaiting assessment. Random-effects models were also conducted and funnel plots drawn for all outcomes with ten or more studies.

Results
Mortality
All-cause mortality
Seventeen trials including 194,795 children reported on the primary outcome of all-cause mortality, in which supplementation with vitamin A was associated with a 24% reduction in the risk of death (RR 0.76, 95% CI [0.69 to 0.83], p<0.00001). Moderate statistical heterogeneity was present (I²=48%, p=0.02).

Subgroup and sensitivity analyses
The overall effect did not differ significantly by location, age group, or sex (all p≥0.12 for differences between subgroups). Subgroup analysis by dose and frequency were not conducted due to lack of data. In sensitivity analyses, bias due to sequence generation and small study effects did not influence the overall effect, and increasing the ICC did not appreciably change the effect size. Adding data from one study awaiting assessment to the analysis reduced the effect size, but it remained statistically significant with a 12% reduction in risk of mortality with vitamin A supplementation (RR 0.88, 95% CI [0.84 to 0.94]).

Cause-specific mortality
Diarrhoea-related mortality was statistically significantly reduced in the vitamin A group compared to the control group (RR 0.72, 95% CI [0.57 to 0.91], p=0.005; 7 trials). Meta-analysis of data from five trials reporting on measles mortality produced a non-significant reduction in risk with vitamin A supplementation (RR 0.80, 95% CI [0.51 to 1.24], p=0.31). Treatment with vitamin A also did not significantly reduce the risk of mortality from meningitis (RR 0.57, 95% CI [0.17 to 1.88], p=0.36; 3 trials), or from LRTI (RR 0.78, 95% [0.54 to 1.14], p=0.20; 7 trials).

Morbidity
Infection and hospitalization
The incidence of diarrhoea was statistically significantly reduced by 15% with vitamin A supplementation (RR 0.85, 95% CI [0.82 to 0.87], p<0.00001; 13 trials), although a high degree of heterogeneity was present (I²=95%, p<0.00001). In pooled analysis of two trials reporting on the prevalence of diarrhoea, vitamin A supplementation was associated with an 8% increase in the risk of having diarrhoea (RR 1.08, 95% CI [1.05 to 1.12], p<0.00001). In six trials reporting on the incidence of measles, a statistically significant 50% reduction in risk with vitamin A treatment was found (RR 0.50, 95% CI [0.37 to 0.67], p<0.00001). The incidence of malaria was significantly reduced in the treatment group in one trial (RR 0.73, 95% CI [0.60 to 0.88], p=0.0013; 174132 children), while in two trials reporting on malaria prevalence, no significant difference was found between groups (RR 0.72, 95% CI [0.42 to 1.23], p=0.27). The incidence and prevalence of LRTI were not reduced with vitamin A supplementation (RR 1.14, 95% CI [0.95 to 1.37], p=0.15; 9 trials, and RR 0.46, 95% CI [0.21 to 1.03]; 2 trials, respectively). No trials reported data on measles prevalence, or on meningitis incidence or prevalence. In one trial, the reduction in the risk of hospitalization with vitamin A supplementation did not reach statistical significance (RR 0.64, 95% CI [0.40 to 1.02], p=0.058; 1185 children); however, the number of hospitalizations was reduced by a statistically significant 38% (RR 0.62, 95% CI [0.42 to 0.93]).

Vision
The incidence of Bitot’s spots was measured in one trial, in which no significant effect of vitamin A treatment was observed (RR 0.93, 95% CI [0.76 to 1.14]); however, there was a statistically significant reduction in the prevalence of Bitot’s spots (RR 0.45, 95% CI [0.33 to 0.61], p<0.00001; 4 trials). Night blindness was reduced in both incidence (RR 0.53, 95% CI [0.28 to 0.99], p=0.047; 1 trial) and prevalence (RR 0.32, 95% CI [0.21 to 0.50], p<0.00001; 2 trials) in the treatment group relative to controls. While three trials reported no combined effect on the incidence of xerophthalmia (RR 0.85, 95% CI [0.70 to 1.03], p=0.11), pooled analysis of two trials demonstrated a 69% reduction in its prevalence (RR 0.31, 95% CI [0.22 to 0.45], p<0.00001).

Vitamin A deficiency
In meta-analysis of four trials, a 29% reduction in the risk of vitamin A deficiency was observed (RR 0.71, 95% CI [0.65 to 0.78], p<0.00001; 2262 children), although heterogeneity was substantial (I²=78%, p=0.004). Serum vitamin A levels were significantly increased in the treatment group compared to controls (SMD 0.31, 95% CI [0.26 to 0.36], p<0.00001; 13 trials/6623 children), again with significant heterogeneity (I²=95%, p<0.00001).

Adverse effects
Vomiting within 48 hours of treatment was increased by 175% in the vitamin A group compared to controls (RR 2.75, 95% CI [1.81 to 4.19], p<0.00001; 3 trials/2994 children). The risk of having a bulging fontanel was not found to differ significantly by treatment group in one trial (RR 5.00, 95% CI [0.24 to 103.72], p=0.30; 885 children).

5. Additional author observations*

The primary outcome of all-cause mortality was at low risk of bias. Although all studies reporting on this outcome were conducted in developing countries, the presence of unexplained heterogeneity suggested that the effect size might differ according to background levels of vitamin A deficiency or the prevalence of other co-morbidities.

Vitamin A supplementation reduced all-cause mortality and the incidence of diarrhoea and measles in children aged six months to five years. Night blindness, Bitot’s spots and xerophthalmia were also reduced with vitamin A supplementation. Although few studies reported on adverse effects, the risk of vomiting was increased in the short-term following vitamin A supplementation. Overall, these findings support vitamin A supplementation for the prevention of morbidity and mortality in children under five years of age in areas at risk of vitamin A deficiency.

Future trials could evaluate different doses of vitamin A, investigating the potential for a reduction in vomiting with smaller, yet still beneficial, doses. The effects of vitamin A supplementation on the pathogenicity of relevant organisms and disease pathways could also be examined. Other long-term outcomes such as growth could be evaluated in future editions of this review.