Improving child survival through vitamin A supplementationBMJ 2011; 343 doi: https://doi.org/10.1136/bmj.d5294 (Published 25 August 2011) Cite this as: BMJ 2011;343:d5294
- 1Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA
- 2Departments of Nutrition, Epidemiology, and Global Health, Harvard School of Public Health
Worldwide, nearly 8.8 million children die each year before they reach their 5th birthday.1 More than two thirds die from infectious diseases such as pneumonia, diarrhoea, and malaria. Although these are sobering figures, childhood mortality has been substantially reduced over the past decade partly as a result of the expansion of child survival interventions to prevent and treat major causes of childhood mortality.
In the linked systematic review and meta-analysis (doi:10.1136/bmj.d5094), Mayo-Wilson and colleagues assess the effects of vitamin A supplementation on mortality and morbidity in children 6 months to 5 years of age.2 Routine preventive treatment of all children 6-59 months of age with high dose vitamin A supplements is a core intervention to improve child survival supported by Unicef, the World Health Organization, governments, and donors in areas of high mortality and endemic vitamin A deficiency. Capsules are now distributed biannually in at least 60 countries, with average annual coverage rates nearing 80%.3 Initially launched as an initiative to prevent xerophthalmic blindness, universal vitamin A supplementation was expanded as a life saving intervention mainly on the basis of meta-analyses that showed average reductions in all cause mortality of 23-30% coupled with low costs of implementation.4 5
Since its discovery in 1913, no nutrient has been as well studied or as fraught with controversy as vitamin A. Critics of high dose vitamin A supplementation have expressed concerns about the inconsistent evidence base for such programmes, arguing that not all trials of vitamin A supplementation have shown protective effects on all cause mortality and that it may increase the incidence of respiratory infections, particularly in children who are not vitamin A deficient.6 7 8 9 Proponents argue that most studies have found beneficial effects on all cause mortality, and that evidence on other major causes of death including diarrhoea and measles has been fairly consistent.
Lingering uncertainties were compounded by the presentation at the 2007 Micronutrient Forum of findings from the largest randomised trial ever undertaken, the DEVTA (de-worming and vitamin A) trial.10 This cluster randomised open control trial of biannual supplementation with 200 000 IU vitamin A investigated more than one million children aged 12-59 months in rural north India. Preliminary results of all cause mortality were null, but the investigators noted that the results were also consistent with a reduction of 12% (relative risk 0.96, 95% confidence interval 0.88 to 1.05).10 Four years later, the study remains unpublished for uncertain reasons. Until this trial is published and its quality assessed it cannot be properly evaluated or integrated into the larger body of evidence. Yet the null findings, particularly given the large size of the trial, have left lingering questions. Is vitamin A supplementation effective? Might harmful effects of supplementation on some infections be cancelling out beneficial effects on others? Do changes need to be made to the delivery strategy, such as reducing the dosage and increasing the frequency or using a targeted rather than universal approach?
Mayo-Wilson and colleagues’ meta-analysis tackles at least some of these questions. It reports a 24% reduction in all cause mortality associated with synthetic oral vitamin A supplements, a finding that is virtually unchanged from previous analyses, despite the inclusion of nine extra studies.4 5 The meta-analysis is unprecedented in its depth and methodological rigour, incorporating a wider number of morbidity and mortality outcomes than previous reviews of preschool vitamin A supplementation. This is important because some previous reviews have examined either morbidity or mortality, but not both, leaving questions as to whether inconsistent findings may have resulted from differences in approaches to inclusion and exclusion criteria versus other sources of heterogeneity.
The results of the sensitivity analysis including the DEVTA trial also help to allay some of this uncertainty. Its inclusion reduces the all cause mortality benefit from 24% to 12%, yet the result remains statistically significant and clinically meaningful. Vitamin A supplementation has been ranked as one of the most cost effective child survival interventions. Even if it only saves half as many lives as previously estimated, it is probably still exceptionally cost effective and worth funding.11
Although the review is an important step in helping to clarify the effects of vitamin A on mortality and morbidity, several important questions remain. Given that 41% of all deaths in children under 5 take place during the first 28 days of life, could vitamin A supplementation of this younger age group help to accelerate progress?1 Trials in Ghana, India, and Tanzania coordinated by WHO and funded by the Bill and Melinda Gates Foundation should help to assess the potential for vitamin A to save newborn lives.12
Another question that needs further research is the role of vitamin A supplementation in malaria. Just one study has examined the effect of vitamin A supplements on the incidence of malaria, and it showed a significant 30% reduction (0.70, 0.57 to 0.87). Given that malaria is responsible for 8% of deaths in children, further research on this association is warranted.
Most national vitamin A programmes supplement children twice a year, yet evidence suggests that more frequent supplementation could reduce mortality even further.5 Research into alternative dosing approaches and delivery mechanisms, with proper evaluation, might enable programmes to be more effective. Lastly, as previous meta-analyses have stated, no more placebo controlled trials of preschool vitamin A supplementation are needed. Instead, effort should focus on finding ways to sustain this important child survival initiative and fine tune it to maximise the number of lives saved.
Cite this as: BMJ 2011;343:d5294
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.