title: An enigma: why vitamin A supplementation does not always reduce mortality even though vitamin A deficiency is associated with increased mortality.
abstract: BACKGROUND
  Vitamin A deficiency (VAD) is associated with increased mortality. To prevent VAD, WHO recommends high-dose vitamin A supplementation (VAS) every 4-6 months for children aged between 6 months and 5 years of age in countries at risk of VAD. The policy is based on randomized clinical trials (RCTs) conducted in the late 1980s and early 1990s. Recent RCTs indicate that the policy may have ceased to be beneficial. In addition, RCTs attempting to extend the benefits to younger children have yielded conflicting results. Stratified analyses suggest that whereas some subgroups benefit more than expected from VAS, other subgroups may experience negative effects.
  
  
  RESULTS
  We reviewed the potential modifiers of the effect of VAS. The variable effect of VAS was not explained by underlying differences in VAD. Rather, the effect may depend on the sex of the child, the vaccine status and previous supplementation with vitamin A. Vitamin A is known to affect the Th1/Th2 balance and, in addition, recent evidence suggests that vitamin A may also induce epigenetic changes leading to down-regulation of the innate immune response. Thus VAS protects against VAD but has also important and long-lasting immunological effects, and the effect of providing VAS may vary depending on the state of the immune system.
  
  
  CONCLUSIONS
  To design optimal VAS programmes which target those who benefit and avoid those harmed, more studies are needed. Work is ongoing to define whether neonatal VAS should be considered in subgroups. In the most recent RCT in older children, VAS doubled the mortality for males but halved mortality for females. Hence, we urgently need to re-assess the effect of VAS on older children in large-scale RCTs powered to study effect modification by sex and other potential effect modifiers, and with nested immunological studies.
authors.affiliation: Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark, OPEN, Institute of Clinical Research, University of Southern Denmark / Odense University Hospital, Odense, Denmark, cb@ssi.dk.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Benn
authors.affiliation: Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark, Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau and.
authors.forename: Peter
authors.initials: P
authors.lastname: Aaby
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rob J W
authors.initials: RJ
authors.lastname: Arts
authors.affiliation: Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Kristoffer J
authors.initials: KJ
authors.lastname: Jensen
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark, Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau and.
authors.forename: Ane B
authors.initials: AB
authors.lastname: Fisker
mesh_terms: D019587:Dietary Supplements; D006801:Humans; D007223:Infant; D007226:Infant Mortality; D016032:Randomized Controlled Trials as Topic; D012737:Sex Factors; D014611:Vaccination; D014801:Vitamin A / Q000008:administration & dosage*; D014802:Vitamin A Deficiency / Q000517:prevention & control*
chemical_list: D014801:Vitamin A
keywords: Vitamin A; child mortality; heterologous effects; vaccines