All infants are born with very limited vitamin A stores of about 6 mmol which is less than a 2 week supply. During the first 6 months of life, healthy well nourished infants more than double the size of their liver and increase by five-fold its vitamin A concentration, increasing total vitamin A stores more than ten-fold to 70 mmol. They do this by drinking an adequate volume of breast milk from a well-nourished mother, or commercial infant formula. Thus, vitamin A "deficiency" is physiological at birth and during early infancy, but is normally overcome by 6 months of age. However many breast-fed infants of undernourished mothers will remain vitamin A deficient at 6 months and will need additional vitamin A to attain normal physiological stores. Studies from Bangladesh, Brazil and Indonesia reported that a quarter to over 90% of the 6- month old infants studies had inadequate liver stores.

Vitamin A supplementation (VAS) has reduced childhood mortality worldwide, and it is one of the most important public health advances of the last century. In many third world countries including India, one half of all deaths in children under the age of five years can be linked to malnutrition. Acute respiratory tract infections (chiefly pneumonia) and diarrhoeal disease remains the leading cause of pediatric deaths world wide, surpassing even tuberculosis, malaria or HIV. The WHO has determined that pneumonia alone cause one fifth of all deaths in children under 5 years and accounts for an astonishing 8.2% of all worldwide disability and premature death.

The immunosupression of malnutrition is mostly related to micronutrient and vitamin deficiencies, rather than simple calorie deficiency. Restitution of the immune response is thus a strategy for combating childhood mortality. Supplementation effectively complements the other 2 major strategies for improving child health worldwide, vaccination and improved case management.

VAS greatly reduces measles specific mortality and has been shown to reduce overall mortality in children 6 months and older in a great majority of community studies worldwide, including India. A consistent benefit against diarrhoeal disease has usually been noted in most of these trials. Thus public health authorities worldwide recommend that all children at risk of vitamin A deficiency receive VAS, regardless of their nutritional or vitamin status. Commonly administered doses of vitamin A are 100,000 IU for infants and 200,000 IU for children 1 year of age or older, given every 4 to 6 months

Intriguingly, though acute lower respiratory tract infections (pneumonia) is the leading cause of death in children worldwide, large scale field trials of VAS have found no evidence of any beneficial effect on pneumonia. The WHO confirms that VAS has no consistent overall protective or detrimental effect on pneumonia specific mortality in children aged between 6 months and 5 years of age. Thus the paradox. A agent that reduces the overall childhood mortality by » 30% in clinical trials has no effect on the major cause of death in this age group!

The answer to this may be unpleasantly simple. It appears likely from recent evidence that VAS is protective against pneumonia in malnourished children and is paradoxically detrimental for adequately nourished children. Thus there is a differential effect of vitamin A on the basis of the child’s vitamin A nutritional status. A decreased rate of pneumonia in supplemented malnourished children might be accompanied by an increased rate in supplemented well-nourished children. Overall deaths might still fall in this age group since deaths are concentrated in the malnourished group without any decrease in the pneumonia rate. This explanation fits the meta-analysis results being cited by the WHO that worldwide deaths but not pneumonia rates are reduced by VAS.

Two recently published studies from Ecuador and Tanzania have confirmed the above findings. The study from Ecuador by Sempertegui et al found a large increase in the rates of pneumonia in well nourished children who received low dose (10,000 IU) weekly VAS when compared with control subjects and a clearly protective effect of VAS for malnourished children. The authors suggested on the basis of these findings that vitamin A supplementation may only be appropriate for targeted population.

Fawzi et al, conducted the study in Tanzania, in children aged 6 to 60 months with acute pneumonia in a region with high (9%) incidence of HIV. They reported that VAS given at the time of hospitalization for pneumonia and then 4 and 8 months after discharge when compared with placebo, was associated with an apparently increased risk of respiratory tract infections and clinic visits over the following year. This effect was most prominent in children who were seronegative for HIV, whereas there was an apparent reduction in the risk in HIV positive children. They also found that overall children who received vitamin A had a significantly lower risk of severe watery diarrhoea but not all diarrhoea when compared with placebo.

The explanations for these differential effects could be a (as yet unconfirmed) adverse effect of vitamin A on the immune system of healthy, vitamin A- replete children with a beneficial effect in deficient children. Another potential explanation is that VAS in adequately nourished children may augment the immune response to inappropriate levels. Thus the increased cough or diarrhoea may be an indication of an improved inflammatory response secondary to the pharmacologic effects of a large dose of vitamin A.

If the differential effects of VAS on pneumonia and diarrhoea observed in these 2 landmark studies are real, then the public implications are enormous. Even in countries like India, with substantial malnutrition there are many children who are not vitamin A deficient and who might be harmed by VAS. Targeted and not population wide supplementation might then prove to be the optimal choice, minimizing harm and maximizing benefits. Mass administration campaigns may have to be altered to include an assessment for vitamin A deficiency. This assessment could be done by the use of simple, sound and proven surrogate markers for vitamin A deficiency such as low weight for age. Alternate dosing regimens may also be need to be studied if the currently used large supraphysiological doses of vitamin A are immunomodulating.

Lancet 2000; 356:422-24
Journal of Pediatrics 2000; 137:660-7
Pediatrics 1999; 104:e1