We found that plasma vitamin A concentrations in children born to HIV-infected women in Tanzania were inversely associated with mortality up to 24 months of age. Higher plasma vitamin A concentration was protective against mortality among HIV-uninfected children in our study. Our results agree with those from a meta-analysis of eight community-based trials of vitamin A supplements to children aged 6–72 months which showed a 30% reduction in the risk of death in the supplemented group as compared to the control group [24
]. Randomized trials that provided vitamin A supplements to neonates showed mixed results with two trials from India and Indonesia showing a protective effect on mortality while a third from Zimbabwe showing no effect or a harmful effect [2–5
In our study, plasma vitamin A was not significantly associated with mother-to-child transmission (MTCT). In randomized trials from Tanzania [25
] and Zimbabwe [5
] vitamin A supplementation had an increased risk of transmission and/or mortality, while in two other trials vitamin A supplementation had no significant effect on transmission [26
]. Our findings on the relationship between plasma vitamin A and health outcomes are based on observational data analysis; although we have adjusted for a number of confounding variables, the presence of residual confounding cannot be excluded. Also, our study had limited statistical power to examine the association between plasma vitamin A and HIV transmission, especially in the first 6 months. We found no statistically significant association between vitamin A concentrations and symptoms indicative of respiratory infection or diarrhea. In a meta-analysis of five trials, vitamin A supplementation had no effect on the risk of acute respiratory tract infection [28
]. However in trials from Ecuador [29
] and Indonesia [30
], vitamin A was associated with an apparently higher risk of respiratory infections among children who were ‘better nourished’ with a protective association among under-nourished children. A meta-analysis of eight clinical trials showed no overall effect of vitamin A supplementation on diarrhea with an equal number of studies showing positive and negative effects [31
]. Our findings of a null relationship between plasma vitamin A and morbidity in the presence of a significant inverse association with mortality may also suggest that vitamin A is more important for reducing severity of infections rather than their incidence. One limitation of our study is that low plasma vitamin A concentration might be a result of an acute phase response and be a marker of advanced underlying disease [32
]. However, this does not appear to be a major factor in our study as the protective effect of higher vitamin A concentrations were evident after adjusting for serum albumin levels which is known to be a negative acute phase reactant.
Vitamin A is essential for optimal functioning of the immune system [33
]. Animal studies have shown a reduction in the number of circulating natural killer (NK) cells which are important for protection against viral infections during experimental vitamin A deficiency [34
We did not find any association between plasma vitamin B-12 concentrations and mortality or morbidity. Low serum B-12 levels were associated with faster progression to AIDS in a cohort of HIV-infected bisexual and homosexual men in North America [35
]. Multivitamin supplements including vitamin B-12 given to mothers during pregnancy and lactation have been shown to increase plasma levels of these vitamins in their children and was also protective against child morbidity in that cohort [36
]. Our study was limited by the use of plasma vitamin B-12 concentrations as the measure of vitamin B-12 deficiency as plasma levels may not accurately reflect bioavailable vitamin B-12 and total homocysteine or methymalonic acid in the blood may be better markers of B-12 status [38
]. The prevalence of vitamin B-12 deficiency in this cohort of children (8% at 6 weeks and 7% at 6 months of age) was also lower than that noted in studies from South America.
Results from this study add to the evidence from clinical trials among children 6 months and older about the beneficial effect of vitamin A in children even in settings with high HIV prevalence. Periodic vitamin A supplementation of children starting at 6 months is an inexpensive and simple intervention and has a major role in reducing child mortality in countries where vitamin A deficiency is a public health problem. Results from clinical trials currently underway that are assessing the effect of supplementation among children with B-complex vitamins including vitamin B-12 will be able to shed more light on the role of vitamin B-12 in child health.