Vaccination and Risk for Developing Inflammatory Bowel Disease: A Meta-Analysis of Case–Control and Cohort Studies

doi:10.1016/j.cgh.2015.04.179

Clinical Gastroenterology and Hepatology

Volume 13, Issue 8, August 2015, Pages 1405-1415.e1

https://doi.org/10.1016/j.cgh.2015.04.179 Get rights and content

Background & Aims

Environmental factors may play a key role in the pathogenesis of inflammatory bowel disease (IBD). Whether vaccination is associated causally with IBD is controversial. We performed a meta-analysis of case–control and cohort studies on the association between vaccination and the risk for IBD.

Methods

Studies and abstracts investigating the relationship between vaccination and subsequent risk for developing IBD were reviewed. Childhood or adult immunizations with any vaccine type, at any dose, and with any vaccine schedule were used as inclusion criteria.

Results

Eleven studies were included in the systematic review and meta-analysis: 8 case–control studies and 3 cohort studies. Studied vaccines were bacille Calmette–Guérin), vaccines against diphtheria, tetanus, smallpox, poliomyelitis, pertussis, H1N1, measles, rubella, mumps, and the combined measles, mumps, and rubella vaccine. Only a few details about vaccine type or route of administration were found in studies. Overall, there was no association between childhood immunization and risk for developing IBD: bacille Calmette–Guérin, relative risk (RR) of 1.04 (95% confidence interval [CI], 0.78–1.38), diphtheria, RR of 1.24 (95% CI, 0.80–1.94), tetanus, RR of 1.27 (95% CI, 0.77–2.08), smallpox, RR of 1.08 (95% CI, 0.70–1.67), poliomyelitis, RR of 1.79 (95% CI, 0.88–3.66), an measles containing vaccines, RR of 1.33 (95% CI, 0.31–5.80) in cohort studies, and RR of 0.85 (95% CI, 0.60–1.20) in case–control studies. Subgroup analysis for Crohn’s disease (CD) and ulcerative colitis (UC) found an association between the poliomyelitis vaccine and risk for developing CD (RR, 2.28; 95% CI, 1.12–4.63) or UC (RR, 3.48; 95% CI, 1.2–9.71). The RR of developing IBD after H1N1 vaccination was 1.13 (95% CI, 0.97–1.32).

Conclusions

Results of this meta-analysis show no evidence supporting an association between childhood immunization or H1N1 vaccination in adults and risk of developing IBD. The association between the poliomyelitis vaccine and the risk for CD or UC should be analyzed with caution because of study heterogeneity.

Section snippets

Search Strategy and Study Selection

A systematic review and meta-analysis was conducted in accordance with guidelines for systematic reviews and meta-analyses published previously.²⁵ A computerized search of the medical English and non-English literature was conducted using MEDLINE (1970 to June 2014), EMBASE, and the Cochrane central register of controlled trials. Studies and abstracts investigating the relationship between vaccination and subsequent risk for the development of IBD were reviewed. Only randomized controlled

Literature Search

The search strategy identified 428 citations, and 412 articles were excluded after reviewing the title and abstract (Supplementary Figure 1). Sixteen studies were retrieved for evaluation and 5 studies were excluded. Three studies were epidemiologic studies on IBD incidence during a vaccination campaign without estimation of the risk, 1 study was a case report, and 1 study did not have a control group. Finally, 11 studies were included in this systematic review and meta-analysis,11, 12, 13, 14,

Discussion

Since the report by Thompson et al,¹² the controversy about the risk of developing IBD after childhood immunization still is ongoing. This study reported that vaccination with the live measles vaccine was a risk for the development of consequent inflammatory disease, such as CD or UC. However, many publications after this report investigating vaccination with measles-containing vaccines did not show any association between immunization and IBD. Epidemiologic studies also investigated other

Acknowledgments

The authors thank the Digestscience Foundation for its non-financial support.

References (34)

D.C. Baumgart et al.
Inflammatory bowel disease: cause and immunobiology
Lancet
(2007)
A. Cortot et al.
[Inflammatory bowel disease: genetic or environmental diseases?]
Gastroenterol Clin Biol
(2009)
J. Halfvarson et al.
Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics
Gastroenterology
(2003)
E.V. Loftus
Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences
Gastroenterology
(2004)
G. Pineton de Chambrun et al.
Aluminum enhances inflammation and decreases mucosal healing in experimental colitis in mice
Mucosal Immunol
(2014)
N.P. Thompson et al.
Is measles vaccination a risk factor for inflammatory bowel disease?
Lancet
(1995)
M. Feeney et al.
A case-control study of measles vaccination and inflammatory bowel disease. The East Dorset Gastroenterology Group
Lancet
(1997)
T.S. Hansen et al.
Environmental factors in inflammatory bowel disease: a case-control study based on a Danish inception cohort
J Crohns Colitis
(2011)
D.L. Morris et al.
Measles vaccination and inflammatory bowel disease: a national British Cohort Study
Am J Gastroenterol
(2000)
S.Y. Shaw et al.
Early childhood immunizations are not associated with pediatric IBD: a population-based analysis
Gastroenterology
(2012)

A. Schattner

Consequence or coincidence? The occurrence, pathogenesis and significance of autoimmune manifestations after viral vaccines

Vaccine

(2005)

F. Kanwal et al.

Systematic reviews and meta-analyses

Clin Gastroenterol Hepatol

(2012)

R. DerSimonian et al.

Meta-analysis in clinical trials

Control Clin Trials

(1986)

L. Barreto et al.

Polio vaccine development in Canada: contributions to global polio eradication

Biologicals

(2006)

E. Griffiths et al.

Polio vaccine: the first 50 years and beyond

Biologicals

(2006)

D.A. Geier et al.

Thimerosal: clinical, epidemiologic and biochemical studies

Clin Chim Acta

(2015)

A. Hviid et al.

Impact of routine vaccination with a pertussis toxoid vaccine in Denmark

Vaccine

(2004)

Cited by (18)

Epidemiology of Pediatric Inflammatory Bowel Disease
2023, Gastroenterology Clinics of North America
Environmental Risk Factors for Inflammatory Bowel Diseases: An Umbrella Review of Meta-analyses
2019, Gastroenterology
Citation Excerpt :
A total of 145 meta-analytic estimates were retained for the main analysis: 74 (51%) reported effects that were significant at P < .05 and 32 (22%) at P < .001. The putative environmental factors pertained to lifestyles and hygiene (n = 16),6,18–30 surgeries (n = 2), exposure to drugs (n = 3),37–42 dietary intake and nutrients (n = 22),43–55 and microorganisms and vaccinations (n = 28).56–69 The AMSTAR 2 rating for all studies was determined to be critically low (31 studies, 60%) or low (21 studies, 40%) (Supplementary Table 4).
Multiple environmental factors have been associated with the development of inflammatory bowel diseases (IBDs). We performed an umbrella review of meta-analyses to summarize available epidemiologic evidence and assess its credibility.
We systematically identified and appraised meta-analyses of observational studies examining environmental factors and risk of IBD (Crohn’s disease [CD] or ulcerative colitis [UC]). For each meta-analysis, we considered the random effects estimate, its 95% confidence interval, the estimates of heterogeneity, and small-study effects, and we graded the evidence according to prespecified criteria. Methodologic quality was assessed with AMSTAR (ie, A Measurement Tool to Assess Systematic Reviews) 2.
We examined 183 estimates in 53 meta-analyses of 71 environmental factors related to lifestyles and hygiene, surgeries, drug exposures, diet, microorganisms, and vaccinations. We identified 9 factors that increase risk of IBD: smoking (CD), urban living (CD and IBD), appendectomy (CD), tonsillectomy (CD), antibiotic exposure (IBD), oral contraceptive use (IBD), consumption of soft drinks (UC), vitamin D deficiency (IBD), and non–Helicobacter pylori–like enterohepatic Helicobacter species (IBD). We identified 7 factors that reduce risk of IBD: physical activity (CD), breastfeeding (IBD), bed sharing (CD), tea consumption (UC), high levels of folate (IBD), high levels of vitamin D (CD), and H pylori infection (CD, UC, and IBD). Epidemiologic evidence for all of these associations was of high to moderate strength; we identified another 11 factors associated with increased risk and 16 factors associated with reduced risk with weak credibility. Methodologic quality varied considerably among meta-analyses. Several associations were based on findings from retrospective studies, so it is not possible to determine if these are effects of IBD or the results of recall bias.
In an umbrella review of meta-analyses, we found varying levels of evidence for associations of different environmental factors with risk of IBD. High-quality prospective studies with analyses of samples from patients with recent diagnoses of IBD are needed to determine whether these factors cause or are results of IBD and their pathogenic mechanisms.
Human papillomavirus vaccination and risk of autoimmune diseases: A large cohort study of over 2 million young girls in France
2017, Vaccine
Citation Excerpt :
Studies have also failed to show an association with tuberculosis or smallpox vaccines [35], or H1N1 influenza vaccines [36]. However, an increased risk of IBD has been reported following poliomyelitis and pertussis vaccinations [37,38]. Lastly, a post-licensure study conducted at European authorities’ request using CPRD database (UK) has recently reported an almost four-fold higher risk of thyroiditis associated with the bivalent vaccine (RR: 3.75 [95% CI: 1.25–11.31]) [39].
Whether human papillomavirus (HPV) vaccination could induce or trigger autoimmune diseases (AID) has been questioned, and potentially contributes to low immunization coverage in France. This study evaluated the association between HPV vaccination and the risk of AID using routinely collected data sources.
All girls aged 13–16 years between 2008 and 2012, covered by the general health insurance scheme and without history of HPV vaccination or AID, were included and followed using French nationwide databases. Fourteen neurological, rheumatological, haematological, gastrointestinal or endocrine AID, were identified from ICD-10 codes allocated to hospital stays and long-term illnesses or by marker drugs. Their incidence was compared between girls exposed and non-exposed to HPV vaccination, using a Cox model adjusted for inclusion year, geographic area, socio-economic indicators, healthcare use level and other immunizations.
Among 2,252,716 girls, 37% received HPV vaccine and 4,096 AID occurred during a mean follow-up time of 33 months. The incidence of AID was not increased after exposure to HPV vaccination, except for Guillain-Barré syndrome (GBS) (incidence rate of 1.4 among exposed [20 cases] versus 0.4 per 100,000 PY among unexposed [23 cases]; adjusted HR: 3.78 [1.79–7.98]). This association persisted across numerous sensitivity analyses and was particularly marked in the first months following vaccination. Under the hypothesis of a causal relationship, this would result in 1–2 GBS cases attributable to HPV vaccine per 100,000 girls vaccinated.
Our study provides reassuring results regarding the risk of AID after HPV vaccination, but an apparently increased risk of GBS was detected. Further studies are warranted to confirm this finding.
Tuberculosis Vaccines
2017, Plotkin's Vaccines
Multidisciplinary Perinatal Care in IBD
2023, Journal of Crohn's and Colitis
Environmental risk factors for inflammatory bowel disease
2022, United European Gastroenterology Journal

View all citing articles on Scopus

: This article has an accompanying continuing medical education activity on page e130. Learning Objective–Upon completion of this activity, successful learners will be able to discuss the implication of vaccination and environmental factors in the development of inflammatory bowel disease.

: Conflicts of interest The authors disclose no conflicts.

View full text

Original articleSystematic reviews and meta-analysesVaccination and Risk for Developing Inflammatory Bowel Disease: A Meta-Analysis of Case–Control and Cohort Studies

Background & Aims

Methods

Results

Conclusions

Section snippets

Search Strategy and Study Selection

Literature Search

Discussion

Acknowledgments

Lancet

Gastroenterol Clin Biol

Gastroenterology

Gastroenterology

Mucosal Immunol

Lancet

Lancet

J Crohns Colitis

Am J Gastroenterol

Gastroenterology

Vaccine

Clin Gastroenterol Hepatol

Control Clin Trials

Biologicals

Biologicals

Clin Chim Acta

Vaccine

Original article
Systematic reviews and meta-analyses
Vaccination and Risk for Developing Inflammatory Bowel Disease: A Meta-Analysis of Case–Control and Cohort Studies