title: Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates: two by two factorial randomised controlled trial.
abstract: OBJECTIVE
  To investigate the effect of vitamin A supplementation and BCG vaccination at birth in low birthweight neonates.
  
  
  METHODS
  Randomised, placebo controlled, two by two factorial trial.
  
  
  METHODS
  Bissau, Guinea-Bissau.
  
  
  METHODS
  1717 low birthweight neonates born at the national hospital.
  
  
  METHODS
  Neonates who weighed less than 2.5 kg were randomly assigned to 25 000 IU vitamin A or placebo, as well as to early BCG vaccine or the usual late BCG vaccine, and were followed until age 12 months.
  
  
  METHODS
  Mortality, calculated as mortality rate ratios (MRRs), after follow-up to 12 months of age for infants who received vitamin A supplementation compared with those who received placebo.
  
  
  RESULTS
  No interaction was observed between vitamin A supplementation and BCG vaccine allocation (P=0.73). Vitamin A supplementation at birth was not significantly associated with mortality: the MRR of vitamin A supplementation compared with placebo, controlled for randomisation to "early BCG" versus "no early BCG" was 1.08 (95% CI 0.79 to 1.47). Stratification by sex revealed a significant interaction between vitamin A supplementation and sex (P=0.046), the MRR of vitamin A supplementation being 0.74 (95% CI 0.45 to 1.22) in boys and 1.42 (95% CI 0.94 to 2.15) in girls. When these data were combined with data from a complementary trial among normal birthweight neonates in Guinea-Bissau, the combined estimate of the effect of neonatal vitamin A supplementation on mortality was 1.08 (95% CI 0.87 to 1.33); 0.80 (95% CI 0.58 to 1.10) in boys and 1.41 (95% CI 1.04 to 1.90) in girls (P=0.01 for interaction between neonatal vitamin A and sex).
  
  
  CONCLUSIONS
  The combined results of this trial and the complementary trial among normal birthweight neonates have now shown that, overall, it would not be beneficial to implement a neonatal vitamin A supplementation policy in Guinea-Bissau. Worryingly, the trials show that vitamin A supplementation at birth can be harmful in girls. Previous studies and future trials should investigate the possibility that vitamin A supplementation has sex differential effects. Trial registration ClinicalTrials.gov NCT00168610.
authors.affiliation: Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark. cb@ssi.dk
authors.forename: Christine Stabell
authors.initials: CS
authors.lastname: Benn
authors.forename: Ane Baerent
authors.initials: AB
authors.lastname: Fisker
authors.forename: Bitiguida Mutna
authors.initials: BM
authors.lastname: Napirna
authors.forename: Adam
authors.initials: A
authors.lastname: Roth
authors.forename: Birgitte Rode
authors.initials: BR
authors.lastname: Diness
authors.forename: Karen Rokkedal
authors.initials: KR
authors.lastname: Lausch
authors.forename: Henrik
authors.initials: H
authors.lastname: Ravn
authors.forename: Maria
authors.initials: M
authors.lastname: Yazdanbakhsh
authors.forename: Amabelia
authors.initials: A
authors.lastname: Rodrigues
authors.forename: Hilton
authors.initials: H
authors.lastname: Whittle
authors.forename: Peter
authors.initials: P
authors.lastname: Aaby
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D001500:BCG Vaccine / Q000008:administration & dosage*; D005260:Female; D006169:Guinea-Bissau / Q000453:epidemiology; D006801:Humans; D007223:Infant; D007226:Infant Mortality; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007271:Injections, Intradermal; D008297:Male; D011379:Prognosis; D012621:Seasons; D015996:Survival Rate; D014801:Vitamin A / Q000008:administration & dosage*; D014802:Vitamin A Deficiency / Q000178:diet therapy* / Q000401:mortality; D014815:Vitamins / Q000008:administration & dosage*
chemical_list: D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D014815:Vitamins; D014801:Vitamin A