Background. Undernutrition causes over 3.5 million child deaths a year, with vitamin A deficiency alone responsible for almost 0.6 million child deaths per year1. Vitamin A supplementation of children above 6 months of age has been shown to reduce overall mortality by 23%. The effect of vitamin A supplementation in newborns on morbidity and mortality is less clear, with three studies in India, Indonesia and Nepal showing reductions in neonatal mortality of 22%, 64% and 15% respectively, but with 2 other trials in Africa reporting no effect. In view of the expected health benefits of improved vitamin A status of infants, WHO currently recommends that women should receive a high dose (200.000 IU ) of vitamin A within the first 6 weeks postpartum, in order to improve maternal vitamin A status, the vitamin A content of breast milk, and thereby the vitamin A status of their infants. However, several recent trials in which women received 200.000 IU vitamin A directly post-partum, reported no improvement in vitamin A status of either mother or her infant at 6 mo of age, not even after doubling the dose to 400.000 IU. In these studies vitamin A was given within a week of delivery, the current typical practice even though WHO actually states a window of 6 weeks after delivery. In contrast, 2 earlier studies in Bangladesh and Indonesia reported a large impact of post-partum maternal supplementation on vitamin A status in infants at 6 mo of age. In these studies, women received a high dose vitamin A supplement not directly post-partum, but somewhere in the first 6 weeks after delivery. The WHO recommendation on maternal post-partum vitamin A supplementation was based on the effects observed in these earlier studies, but the more recent studies suggest now that this intervention is not effective, and that millions of women are receiving a high dose vitamin A supplement without clear benefits for vitamin A status of either the women or their children. The difference in timing between the earlier studies and the recent studies of giving the vitamin A may hold the key, and we believe we have identified the biological reason why timing of the supplementation could be of the utmost importance: the inflammatory response to delivery.
Delivery induces a considerable physiological inflammatory response, with a distinct acute phase response, of the same magnitude as seen for instance in pulmonary tuberculosis patients. We believe that the lack of effect of the current practice of giving a high dose vitamin A supplement directly post-partum is due to the acute phase response induced by the delivery, and that the intervention would be successful if the supplementation was given after the acute phase response has faded away after 3 - 6 weeks. There is currently no data available on the vitamin A bioavailability in lactating women, but a study in Zambian pre-school children investigated the effectiveness of a high dose vitamin A supplementation campaign in children, and showed that this was only successful in children without inflammation. Children who had signs of inflammation had no increase in vitamin A status. Inflammation and the accompanying acute phase response are also known to affect the availability of other micronutrients besides vitamin A, such as iron and zinc.
Objective(s) and Hypothesis(es):
Hypothesis The acute phase response (APR) induced by delivery reduces vitamin A bioavailability, and interferes with current maternal post-partum high dose vitamin A supplementation programs worldwide.
Objective 1 To determine the effects of the acute phase response on vitamin A bioavailability.
Objective 2 To determine the time course of the acute phase response after delivery.
Overall goal To improve the effectiveness of the current WHO recommendation of post-partum maternal high dose vitamin A supplementation by determining the optimal timing for supplementation in relation to the post-partum APR.
Design and Methods:
A randomised, placebo-controlled, double-blind trial in 400 women, comparing the effects of the recommended dose of 200.000 IU of vitamin A given within the first week post-partum (current practice, 200 women) with the effect when given at 6 weeks post-partum, which is still within the WHO recommended intervention window (200 women). Main outcomes will be maternal and infant vitamin A status 6 months post-partum, breast milk vitamin A concentrations and the time-course of acute phase response, to establish the optimal time after delivery for vitamin A supplementation. Secondary outcomes will be morbidity of the infants during the first 6 months of life and anthropometrical indices of the infants at 6 mo of age.
Potential Impact:
If our hypothesis is true, the current global health strategy of postpartum vitamin A supplementation to improve vitamin A status of mothers and infants can be made effective just by changing the timing. This will have significant implications for global health policies, with important consequences for infant survival worldwide by improving vitamin A status and reducing morbidity and mortality from infectious diseases during the first 6 months of life. Moreover, results of the study will have important consequences for other micronutrient health programs, such as vitamin A supplementation for children above 6 months of age and iron or zinc supplementation programs, as these are also affected by the acute phase response. Overall, the results of this research will contribute to improving child survival worldwide.
