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Original article
BCG vaccination at birth and early childhood hospitalisation: a randomised clinical multicentre trial
  1. Lone Graff Stensballe1,
  2. Signe Sørup2,
  3. Peter Aaby3,
  4. Christine Stabell Benn4,5,
  5. Gorm Greisen6,
  6. Dorthe Lisbeth Jeppesen7,
  7. Nina Marie Birk7,
  8. Jesper Kjærgaard8,9,
  9. Thomas Nørrelykke Nissen7,
  10. Gitte Thybo Pihl10,11,
  11. Lisbeth Marianne Thøstesen10,11,
  12. Poul-Erik Kofoed10,11,
  13. Ole Pryds7,
  14. Henrik Ravn5,12
  1. 1The Child and Adolescent Clinic 4072, Juliane Marie Centret, Rigshospitalet, Copenhagen University Hospital, Copenhagen Ø, Denmark
  2. 2Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen S, Denmark
  3. 3Bandim Health Project, Statens Serum Institut, Copenhagen S, Denmark
  4. 4Research Center for Vitamins and Vaccines (CVIVA), Statens Serum Institut, Copenhagen S, Denmark
  5. 5OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, Denmark
  6. 6The Neonatal Department, Juliane Marie Centret, Rigshospitalet, Copenhagen University Hospital, Copenhagen Ø, Denmark
  7. 7Department of Paediatrics, 460, Copenhagen University Hospital, Hvidovre, Hvidovre, Denmark
  8. 8Research Unit Womens’ and Childrens’ Health, The Child and Adolescent Clinic 4072, Juliane Marie Centret, Rigshospitalet, Copenhagen University Hospital, Copenhagen Ø, Denmark
  9. 9Denmark Copenhagen University Hospital, Copenhagen Ø, Denmark
  10. 10Department of Paediatrics, Kolding Hospital, Kolding, Denmark
  11. 11Institute of Regional Health Research, University of Southern Denmark, Denmark
  12. 12Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen S, Denmark
  1. Correspondence to Dr Lone Graff Stensballe, The Child and Adolescent Clinic 4072, Juliane Marie Centret, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen Ø DK-2100, Denmark; Lone.graff.stensballe{at}regionh.dk

Abstract

Background The BCG vaccine is administered to protect against tuberculosis, but studies suggest there may also be non-specific beneficial effects upon the infant immune system, reducing early non-targeted infections and atopic diseases. The present randomised trial tested the hypothesis that BCG vaccination at birth would reduce early childhood hospitalisation in Denmark, a high-income setting.

Methods Pregnant women planning to give birth at three Danish hospitals were invited to participate. After parental consent, newborn children were allocated to BCG or no intervention within 7 days of age. Randomisation was stratified by prematurity. The primary study outcome was number of all-cause hospitalisations analysed as repeated events. Hospitalisations were identified using The Danish National Patient Register. Data were analysed by Cox proportional hazards models in intention-to-treat and per-protocol analyses.

Results 4184 pregnant women were randomised and their 4262 children allocated to BCG or no intervention. There was no difference in risk of hospitalisation up to 15 months of age; 2129 children randomised to BCG experienced 1047 hospitalisations with a mean of 0.49 hospitalisation per child compared with 1003 hospitalisations among 2133 control children (mean 0.47), resulting in a HR comparing BCG versus no BCG of 1.05 (95% CI 0.93 to 1.18) (intention-to-treat analysis). The effect of BCG was the same in children born at term (1.05 (0.92 to 1.18)) and prematurely (1.07 (0.63 to 1.81), p=0.94). The effect was also similar in the two sexes and across study sites. The results were essentially identical in the per-protocol analysis and after adjustment for baseline characteristics.

Conclusions BCG vaccination at birth did not reduce the risk of hospitalisation for somatic acquired disease until 15 months of age in this Danish study population.

Trial registration number NCT01694108, results.

  • Bacillus Calmette-Guérin (BCG
  • hospitalisation
  • infant
  • vaccine
  • non-specific effect

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/archdischild-2016-310760

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    Footnotes

    • Contributors LGS conceived the idea and is the guarantor of the study. LGS, GG, DLJ, P-EK, OP supervised the collection of data by telephone interviews and clinical examinations and NMB, JK, TNN, GTP, LMT participated in this data collection. LGS, GG, P-EK, OP, CSB and PA constituted the Trial Steering Committee. LGS, HR and SS obtained the register-based data. HR, LGS and SS carried out data management. HR and LGS analysed the data. LGS drafted the manuscript. All authors read and approved the final manuscript.

    • Funding The study was funded by the three involved hospitals and by the Danish National Research Foundation (DNRF108).

    • Competing interests None declared.

    • Ethics approval The trial was approved by the Committees on Biomedical Research Ethics (J.no. H-3-2010-087), the Danish Data Protection Board (J.no. 2009-41-4141), and the Danish Medicines Agency (J.no. 2612-4356. EudraCT 2010-021979-85. Protocol 2009-323).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement A check of the validity of the data and analyses for this study can be arranged with the corresponding author. Request for access to a data copy should be directed to the Trial Steering Committee.