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

BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.c1101 (Published 09 March 2010) Cite this as: BMJ 2010;340:c1101
  1. Christine Stabell Benn, senior researcher12,
  2. Ane Bærent Fisker, clinician2,
  3. Bitiguida Mutna Napirna, obstetrician 3,
  4. Adam Roth, clinician 4,
  5. Birgitte Rode Diness, clinician 2,
  6. Karen Rokkedal Lausch, clinician2,
  7. Henrik Ravn, senior statistician1,
  8. Maria Yazdanbakhsh, professor5,
  9. Amabelia Rodrigues, research director 2,
  10. Hilton Whittle, professor6,
  11. Peter Aaby, professor12
  1. 1Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark
  2. 2Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau
  3. 3Maternidade, Hospital Nacional Simão Mendes, Bissau, Guinea-Bissau
  4. 4Department of Medical Microbiology, Lund University, Malmö, Sweden
  5. 5Department of Parasitology, Leiden University, Leiden, Netherlands
  6. 6The MRC Laboratories, Fajara, POB 273, Gambia
  1. Correspondence to: C S Benn, Bandim Health Project, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark cb{at}ssi.dk
  • Accepted 18 February 2010

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.

Footnotes

  • Since the research was conducted, author Bitiguida Mutna Napirna has died.

  • Contributors: CSB, ARoth, MY, ARodrigues, HW, and PA designed the study. CSB, ARoth, and PA initiated the study. ABF, BMN, BRD, and KRL were responsible for the recruitment and follow-up of participants. CSB was responsible for the statistical analysis, with assistance from HR and PA. CSB wrote the first draft of the paper. All authors contributed to and approved the final version of the paper. CSB was the chief investigator and is the guarantor.

  • Funding: The study was funded by the EU (ICA4-CT-2002-10053), the Danish Medical Research Council, University of Copenhagen, March of Dimes, and the Ville Heise Foundation. The Bandim Health Project received support from DANIDA and the Danish National Research Foundation. PA holds a research professorship grant from the Novo Nordisk Foundation. The funding agencies had no role in the study design, in the data collection, analysis, and interpretation, or in the writing of the report.

  • 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.

  • Ethical approval: The protocol was approved by the Danish Central Ethics Committee and the Guinean Ministry of Health’s Research Coordination Committee.

  • Data sharing: No additional data available.

  • Accepted 18 February 2010

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