Several reports have suggested benefit of vitamin A supplementation in measles, diarrhea, pneumonia, as well as reduction in childhood mortality(1). Although a 2000 WHO review concluded that there is no benefit in pneumonia(2), the current WHO position is that "the official guidelines need to be revised using current evidence"(3).

This systematic review attempts to plug the gap in current evidence by addressing two distinct clinical questions: (i) Does community-based vitamin A supplementation in children prevent the occurrence of pneumonia and/or its complications? and (ii) Does addition of vitamin A to standard therapeutic protocols improve the clinical outcome in childhood (community acquired) pneumonia? The relevant outcomes for the latter include cure rate, severity, duration, and complications of pneumonia; and adverse events following supplementation.

The Cochrane Library was searched with the term "vitamin A" and filter "Record Title" yielding 12 Cochrane Systematic Reviews, 50 other (systematic) Reviews, and 1547 Clinical Trials. Narrowing the search to ‘pneumonia’ and ‘respiratory infection’ yielded 2 Cochrane Reviews, 2 other Reviews, and 31 Clinical Trials. Simultaneous Medline search for randomized controlled trials yielded the following results: "(vitamin A) AND pneumonia" (25 citations), "(Vitamin A) AND (respiratory infection)" (62 citations), "(vitamin A) AND (lower respiratory)" (32 citations). A total of 41 trials were excluded for the following reasons: (i) recruited children with pre-existing pneumonia for further prophylaxis (n=3), (ii) included children with pre-existing illness (n=13), (iii) recruited specific participant sub-groups(n=9), (iv) evaluated a respiratory outcome not consistent with pneumonia (n=11), (v) did not describe a comparator group (n=5). Eleven trials exploring prophylactic role of vitamin A, and 9 trials examining therapeutic role were included in this review. Tables I and II summarize the character-istics of the included trials. Hand-searching of the bibliography of included trials identified several potential citations, but no additional trials could be included.

Table I Summary of RCTs Examining Vitamin A Supplementation for Prophylaxis of Childhood Pneumonia

Table II Summary of RCTs Examining Therapeutic Role of Vitamin A Supplementation in Childhood Pneumonia

There were two relevant Cochrane reviews on vitamin A, one evaluating vitamin A supplementation for prophylaxis(4) and the other for therapy(5). The prophylaxis review(4) included 9 trials; of these 3 are not justifiable – 2 recruited children with pneumonia rather than community-based children, and one measured respiratory outcomes not consistent with the definition of pneumonia. It is surprising that 5 relevant trials included in this EURECA systematic review (6,7,10,11,16) were not included in the Cochrane review. The therapy review(5) included 6 trials including two Chinese language trials. Besides the 4 English language trials, an additional 5 trials have been included here; 4 of these were inappropriately excluded from the Cochrane review(19,22,24,25) and one(23) was (inexplicably) not identified at all. Thus neither Cochrane review can be considered the best evidence on the subject.

Fig. 1 Meta-analysis of data reflecting children with pneumonia in prophylaxis trials.

Fig. 2 Meta-analysis of data reflecting mortality in therapy trials.

From the prophylaxis trials, data for four outcomes could be subjected to meta-analysis viz. number of children with pneumonia (Figure 1), incidence per person-time, pneumonia mortality and all-cause mortality. There was no difference between vitamin A and placebo for any of the outcomes. Data for five outcomes from the treatment trials could be subject to meta-analysis viz. Mortality (Figure 2), duration of hospitalization, duration of illness, complications and side effects. Here also, vitamin A did not perform better than placebo. One trial each reported absence of cure and hospitalization among out-patients; the results for vitamin A were similar to placebo. Table III presents a summary of the results of this systematic review and meta-analysis (random effects model). These data suggest that vitamin A supplementation has neither prophylactic nor therapeutic benefit for childhood pneumonia.

Table III



Summary of Results of Meta-Analysis

The 20 trials included in the two components of this systematic review comprise current best evidence from published literature. However, only 1 of the 9 prophylaxis trials could be classified as having low risk of bias(11), while 6(6,7,10,14,15,16) had high risk of bias owing to inadequacies in two or more of the following components: randomization, allocation concealment, blinding, incomplete outcome reporting, and selective outcome reporting. Five trials used serial doses of vitamin A/ placebo, but did not carry out follow-up beyond the period of supplementation(9,12-15). Two trials did not specify the sample size, necessitating indirect calculations(12,13). Two trials did not use definitions of pneumonia consistent with the WHO definition, but contributed data on mortality(13,16).

Seven of the nine therapy trials could be categorized as having low risk of bias(18-20,22, 24-25); two trials(17,21) had missing components affecting the quality grading. A variety of outcomes were measured in these trials, from which some data could be extracted for meta-analysis.

Some trials undertaking post-hoc sub-group analysis suggest that vitamin A could be beneficial in children with pre-existing vitamin A deficiency (determined by low serum retinol) and/or severe malnourished status. There is also data suggesting that supplementation could harm those with adequate baseline levels of serum retinol. This coupled with the fact that children with biochemical deficiency cannot be identified clinically; suggest that the first observation has little practical application. Since only 4 of 11 prophylaxis trials and 2 of 9 therapy trials did not exclude severely malnourished children, data on the second observation is too limited to draw definite conclusions. Therefore, neither issue has been explored further in this EURECA.

All the included trials were conducted in developing country populations; the lone developed country trial included Australian indigenous children. The fact that 5 prophylaxis trials and 1 therapy trial were conducted in the Indian sub-continent strengthens confidence in extendibility and applicability of the findings that vitamin A supplementation has no role from the perspective of childhood pneumonia.

Funding: None.

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