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Risk of Inflammatory Bowel Disease following Bacille Calmette–Guérin and Smallpox Vaccination: A Population-based Danish Case–Cohort Study

Villumsen, Marie MS*,†; Jess, Tine MD, DMSci; Sørup, Signe MS*; Ravn, Henrik MS, PhD*; Sturegård, Erik MD, PhD§; Benn, Christine Stabell MD, DMSci*; Aaby, Peter MDSci*; Roth, Adam MD, PhD*,§

doi: 10.1097/MIB.0b013e318281f34e
Original Clinical Articles

Background: Childhood immunology has been suggested to play a role in development of inflammatory bowel disease (IBD) based on the studies of childhood vaccinations, infections, and treatment with antibiotics. Bacille Calmette–Guérin (BCG) and smallpox vaccinations were gradually phased-out in Denmark for children born between 1965 and 1976, hence allowing the study of subsequent risk of Crohn’s disease and ulcerative colitis in a unique prospective design.

Methods: The Copenhagen School Health Records Register contains detailed documentation of vaccination. Among the background cohort of individuals born between 1965 and 1976 (N = 47,622), cases with Crohn’s disease (n = 218) and ulcerative colitis (n = 256) were identified through linkage to the Danish National Patient Registry. The vaccination status of the cases was compared with that of a subcohort (n = 5741) of the background cohort and analyzed in a case–cohort design.

Results: No difference in risk of IBD was observed between individuals vaccinated and unvaccinated with BCG (hazard ratio = 0.95; 95% confidence interval, 0.75–1.19) or smallpox vaccine (hazard ratio = 1.01; 95% confidence interval, 0.77–1.32). This was also the case for Crohn’s disease and ulcerative colitis separately. However, BCG given before 4 months of age may decrease the risk of IBD (hazard ratio = 0.43; 95% confidence interval, 0.20–0.93).

Conclusions: This prospective long-term case–cohort study shows that BCG and smallpox vaccination do not cause IBD later in life. These findings are important for the etiological understanding of IBD and of clinical importance because BCG is still one of the most commonly used childhood vaccinations, smallpox vaccine has been reintroduced in the U.S. military, and both vaccines may be used as vectors in new vaccines.

Article first published online 24 April 2013Supplemental Digital Content is Available in the Text.

*Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark;

Institute of Preventive Medicine, Copenhagen University Hospitals, Frederiksberg, Denmark;

Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; and

§Department of Medical Microbiology, Labmedicin Skåne, Lund University, Lund, Sweden.

Reprints: Marie Villumsen, MS, Bandim Health Project, Statens Serum Institut, 5 Artillerivej, DK-2300 Copenhagen S, Denmark (e-mail:

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

M. Villumsen was supported by an unrestricted PhD-grant from the Graduate School in Public Health Science, University of Copenhagen, and the Lundbeck Foundation. T. Jess was supported by a Female Research Leader grant (no.09-066323) from the Danish Council of Independent Research. C. S. Benn holds a starting grant from the ERC (ERC-2009-StG-243149).

The authors have no conflicts of interest to disclose.

Received October 29, 2012

Accepted November 15, 2012

© Crohn's & Colitis Foundation of America, Inc.
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