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

The BMJ

Mar 2010

DOI: 10.1136/bmj.c1101

Citations:113

Influential Citations:2

Interventional (Human) Studies

Enhanced Details

Methods

Design: Randomised, placebo-controlled, two-by-two factorial trial conducted in Bissau, Guinea-Bissau. Participants: 1717 low birthweight neonates (<2.5 kg) born at the national hospital; followed to 12 months; 758 boys and 959 girls. Randomised to vitamin A or placebo and to early BCG versus delayed BCG.

Intervention

One-time oral dose of vitamin A: 25,000 IU retinyl palmitate in 0.5 ml oil, given at birth.

Results

Vitamin A supplementation at birth did not reduce overall infant mortality: mortality rate ratio 1.08 (95% CI 0.79-1.47) after adjusting for early BCG; No interaction with BCG (P=0.73). Sex-specific effects showed a trend toward benefit in boys (MRR 0.74, 95% CI 0.45-1.22) and potential harm in girls (MRR 1.42, 95% CI 0.94-2.15). When combined with the complementary trial in normal birthweight neonates, overall mortality ratio 1.08 (95% CI 0.86-1.34) with a significant sex interaction (P=0.01): boys ~0.80 (0.58-1.10); girls ~1.41 (1.04-1.90). Conclusion: Implementing neonatal vitamin A supplementation in Guinea-Bissau would not be beneficial and may be harmful for girls; future trials should explore sex-differential effects and interactions with vaccination timing.

Limitations

Cause of death determined by verbal autopsy with broad categories; multiple subgroup analyses raise risk of spurious findings; not all vaccinations followed standard sequences; variation in vaccination timing and records; generalizability may be limited to similar settings.

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. show less