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Randomized Controlled Trial
. 2010 Mar 9:340:c1101.
doi: 10.1136/bmj.c1101.

Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates: two by two factorial randomised controlled trial

Christine Stabell Benn  1 , Ane Baerent Fisker, Bitiguida Mutna Napirna, Adam Roth, Birgitte Rode Diness, Karen Rokkedal Lausch, Henrik Ravn, Maria Yazdanbakhsh, Amabelia Rodrigues, Hilton Whittle, Peter Aaby
Affiliations
Randomized Controlled Trial

Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates: two by two factorial randomised controlled trial

Christine Stabell Benn et al. BMJ. .

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.

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Conflict of interest statement

Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare (1) No financial support for the submitted work from anyone other than their employer; (2) No financial relationships with commercial entities that might have an interest in the submitted work; (3) No spouses, partners, or children with relationships with commercial entities that might have an interest in the submitted work; (4) No non-financial interests that may be relevant to the submitted work.

Figures

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Fig 1 Trial profile
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Fig 2 Cumulative mortality during the first year of life for all children
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Fig 3 Cumulative mortality during the first year of life for boys
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Fig 4 Cumulative mortality during the first year of life for girls
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Fig 5 Causes of deaths by intervention group and sex. The “Other problems” category includes AIDS related deaths, sudden death, tumours, encephalitis, and hepatitis
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