Vitamin A supplementation every 6 months with retinol in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial

Abstract

Background: In north India, vitamin A deficiency (retinol <0·70 μmol/L) is common in pre-school children and 2-3% die at ages 1·0-6·0 years. We aimed to assess whether periodic vitamin A supplementation could reduce this mortality.

Methods: Participants in this cluster-randomised trial were pre-school children in the defined catchment areas of 8338 state-staffed village child-care centres (under-5 population 1 million) in 72 administrative blocks. Groups of four neighbouring blocks (clusters) were cluster-randomly allocated in Oxford, UK, between 6-monthly vitamin A (retinol capsule of 200,000 IU retinyl acetate in oil, to be cut and dripped into the child's mouth every 6 months), albendazole (400 mg tablet every 6 months), both, or neither (open control). Analyses of retinol effects are by block (36 vs 36 clusters). The study spanned 5 calendar years, with 11 6-monthly mass-treatment days for all children then aged 6-72 months. Annually, one centre per block was randomly selected and visited by a study team 1-5 months after any trial vitamin A to sample blood (for retinol assay, technically reliable only after mid-study), examine eyes, and interview caregivers. Separately, all 8338 centres were visited every 6 months to monitor pre-school deaths (100,000 visits, 25,000 deaths at ages 1·0-6·0 years [the primary outcome]). This trial is registered at ClinicalTrials.gov, NCT00222547.

Findings: Estimated compliance with 6-monthly retinol supplements was 86%. Among 2581 versus 2584 children surveyed during the second half of the study, mean plasma retinol was one-sixth higher (0·72 [SE 0·01] vs 0·62 [0·01] μmol/L, increase 0·10 [SE 0·01] μmol/L) and the prevalence of severe deficiency was halved (retinol <0·35 μmol/L 6%vs 13%, decrease 7% [SE 1%]), as was that of Bitot's spots (1·4%vs 3·5%, decrease 2·1% [SE 0·7%]). Comparing the 36 retinol-allocated versus 36 control blocks in analyses of the primary outcome, deaths per child-care centre at ages 1·0-6·0 years during the 5-year study were 3·01 retinol versus 3·15 control (absolute reduction 0·14 [SE 0·11], mortality ratio 0·96, 95% CI 0·89-1·03, p=0·22), suggesting absolute risks of death between ages 1·0 and 6·0 years of approximately 2·5% retinol versus 2·6% control. No specific cause of death was significantly affected.

Interpretation: DEVTA contradicts the expectation from other trials that vitamin A supplementation would reduce child mortality by 20-30%, but cannot rule out some more modest effect. Meta-analysis of DEVTA plus eight previous randomised trials of supplementation (in various different populations) yielded a weighted average mortality reduction of 11% (95% CI 5-16, p=0·00015), reliably contradicting the hypothesis of no effect.

Funding: UK Medical Research Council, USAID, World Bank (vitamin A donated by Roche).

Figure 1

Flow diagram for the 72 mainly rural administrative blocks randomly allocated 5 years of 6-monthly vitamin A or open control AWC: anganwadi (ie, courtyard) child-care centre. In these 72 blocks, 8338 child-care centres were followed up, with total population at ages 1·0–6·0 years 1 million and 5 million child-years at risk in the 5 years between May, 1999, and April, 2004. *AWC catchment areas correspond approximately to villages; it was determined before randomisation which AWCs were then functional, and hence potential study areas; loss of an AWC to follow-up was defined by having only 1–6 follow-up visits (mean only 3, as against 12 in included AWCs), and was generally because the AWC had ceased to function.

Figure 2

Times when treatment was to be given and mortality monitored, and range of ages (1·0–6·0 years) and dates (May, 1999–April, 2004) for inclusion in main analyses of child mortality Shaded area indicates more than 2 years’ treatment already received. Diagonal lines describe involvement of children born on May 1 in 1995, 1998, and 2001. With 1 million children of age 1·0–6·0 years at any one time, 5 million child-years at risk are included.

Figure 3

Correlation between 72 block-specific average numbers of infant and child deaths per child-care centre (AWC) during the entire study The inter-block correlation (illustrated here) between numbers of infant and child deaths per AWC was 68·7% ignoring trial treatment allocation (or 68·4% given the four-way allocation to albendazole, retinol, both or neither), and ranged from 66–71% within the four treatment groups. Mortality at ages 0–6 months had correlation 99·3% with infant and 68·2% with child mortality.

Figure 4

Published results from the eight large previous trials of regular vitamin A supplementation and child mortality, DEVTA results, and weighted averages of results from the other eight trials and from all nine trials Heterogeneity between eight previous trials p=0·010; heterogeneity between DEVTA and subtotal of eight previous trials p=0·0010. Methods as in appendix p 9. Calculation of a weighted average does not assume the mortality rate ratios (RRs) in different studies are the same. The equivalent numbers of deaths are approximately additive when calculating weighted averages, but are not used in calculations. *95% CI to 2 dp derived from study publications. †Number of deaths (vitamin A vs control) in a large, 50:50 individually randomised trial that would yield the same RR and CI. Trials were excluded if they had a total of fewer than 20 such deaths, recruited patients with disease, or gave single-dose treatment. ‡From the inverse-variance-weighted average of log RR in each separate trial.