Vitamin A Supplementation and BCG Vaccination at Birth in Low Birthweight Neonates: Two by Two Factorial Randomised Controlled Trial

Christine Stabell Benn, senior researcher1,2, Ane Bærent Fisker, clinician2, Bitiguida Mutna Napirna, obstetrician 3, Adam Roth, clinician 4, Birgitte Rode Diness, clinician 2, Karen Rokkedal Lausch, clinician2, Henrik Ravn, senior statistician1, Maria Yazdanbakhsh, professor5, Amabelia Rodrigues, research director 2, Hilton Whittle, professor6, Peter Aaby, professor1,2

1 Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark , 2 Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau , 3 Maternidade, Hospital Nacional Simão Mendes, Bissau, Guinea-Bissau , 4 Department of Medical Microbiology, Lund University, Malmö, Sweden , 5 Department of Parasitology, Leiden University, Leiden, Netherlands , 6 The MRC Laboratories, Fajara, POB 273, Gambia

Correspondence to: C S Benn, Bandim Health Project, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark This e-mail address is being protected from spambots. You need JavaScript enabled to view it

 

Abstract

Objective To investigate the effect of vitamin A supplementation and BCG vaccination at birth in low birthweight neonates.

Design Randomised, placebo controlled, two by two factorial trial.

Setting Bissau, Guinea-Bissau.

Participants 1717 low birthweight neonates born at the national hospital.

Intervention 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.

Main outcome measure 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 [ClinicalTrials.gov] .