Antibiotics and Risk of New Onset Inflammatory Bowel Disease:

A Meta-Analysis

Ryan Ungaro1, Charles Bernstein2, Richard Gearry3, Anders Hviid4,

Kaija-Leena Kolho5, Matthew Kronman6, Souradet Shaw2, Herbert

Van Kruiningen7, Jean-Frédéric Colombel1, Ashish Atreja1

2013 CCFA Advances in Inflammatory Bowel Diseases Conference

1. Ichan School of Medicine at Mount Sinai, New York, NY 2. University of Manitoba, Winnipeg, Canada 3. University of Otago, Christchurch, New Zealand

6. Seattle Children’s Hospital, Seattle, Washington 7. University of Connecticut, Storrs, Connecticut

4. Statens Serum Institut, Coopenhagen, Denmark 5. University of Helsinki, Helsinki, Finland

Disclosures

Nothing to Disclose

Background

● Medications emerging as risk factor for IBD● Antibiotics may increase risk of CD and UC1

● However some studies have found no association2,3

● Few studies have reported risk associated with specific antibiotic classes

1. De Vroey et al. Am J Gastroenterol. 2010;105(12)2. Castiglione F et al. J Crohns Colitis. 2012;6(3)3. Van Kruiningen et al. Inflamm Bowel Dis. 2005;11(4)

Study Aims

1. To examine antibiotic use as a risk factor for new onset IBD, CD and UC

2. To evaluate if effect of antibiotics different in children versus adults

3. To determine IBD risk with specific antibiotic classes

Methodology

● Meta-analysis of Observational Studies in Epidemiology (MOOSE)1

● Search strategy○ Medline, Embase and Cochrane

databases○ Search keywords:

■ Inflammatory bowel disease, Crohn’s disease, ulcerative colitis, antibiotics, penicillin, cephalosporin, tetracycline, fluoroquinolone, macrolide, sulfonamide, metronidazole

1. Stroup DF, et al. JAMA 2000;283.

Methodology

● Inclusion criteria○ Cohort or case-control ○ Data on exposure to antibiotics prior to new

diagnosis of IBD (CD, UC, or both)● Data collection

○ Two reviewers extracted data○ Authors contacted if data not available in

published manuscript (7 studies)● Data analysis

○ Random-effects model to determine overall pooled estimates and 95% confidence intervals (CI)

○ The Newcastle-Ottawa Scale (NOS) to assess study quality1

1. Wells et al. Accessed at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

Search Results

4508 Citations Retrieved2558 from Pubmed1798 from Embase149 from Cochrane3 from Backward Snowballing

1234 Review Articles Excluded

3274 Original Articles

3259 Articles Excluded by Title and Abstract Review

16 Original Articles 5 Studies Excluded After Full Text Review

● 3 used surrogate for antibiotic use

● 1 without controls

● 1 insufficient data available

11 Articles Included● 8 Case-Control● 3 Cohort

* provided extra data

1. Wells et al. Accessed at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

Case-Control StudiesStudy Year Country Cases, n Controls,

nPopulation Age, years

Quality Score(NOS)1

Card et al 2004 UK 587 CD 1460 41.64 (mean) 8

Van Kruiningen et al*

2005 Belgium 74 CD 140 24 (mean) 7

Gearry et al* 2010 New Zealand 638 CD, 653 UC

600 20 or older (no average given)

8

Han et al 2010 New Zealand 315 CD 536 45.6 (mean) 5

Shaw et al* 2010 Canada 27 CD, 9 UC 360 8.4 (mean) 7

Shaw et al* 2011 Canada 1025 CD, 1218 UC

22,346 43.4 (mean) 6

Castiglione et al 2012 Italy 468 CD, 527 UC

562 36 (median, CD)37 (median, UC)

3

Virta et al* 2012 Finland 233 CD, 362 UC

2380 9.7 (mean, CD)8.5 (mean, UC)

8

Pediatric studies highlighted

Cohort Studies

Study Year Country Cases, n Cohort Size, n

Population Age, years

Quality Score(NOS) 1

Margolis et al

2010 UK CD 71, UC 99, 37 IBDU

94,487 22.1 (mean) 9

Hviid et al* 2011 Denmark 50 CD, 67 UC

577,627 3.4 (mean) 8

Kronman et al*

2012 UK 449 CD, 272 UC, 27 IBDU

1,072,426 17 or younger (no average given)

9

* provided extra data

1. Wells et al. Accessed at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

IBDU = IBD, type unclassifiedPediatric studies highlighted

Included Studies

● 11 total studies with 7,208 patients diagnosed with IBD○ 3,937 patients with CD○ 3,207 patients with UC○ 64 patients with IBDU

● Majority studies (9 of 11) explicitly excluded some time period prior to new diagnosis of IBD ○ Range from 3.9 months to 4 years○ Limit confounding by diagnostic delay

IBDU = IBD, type unclassified

Antibiotic exposure associated with increased overall risk of new onset IBD

I2 = 82.35, p = 0.00

(CD)(UC)

Antibiotic exposure and risk of new onset IBD in adults and children

I2 = 48.78, p = 0.099

I2 = 48.78, p = 0.099

I2 = 90.07, p = 0.00

Adults

Children

OR 1.431 (95% CI 1.116-1.834)

OR 1.894 (95% CI 1.237-2.989)

(CD)

(UC)

Antibiotic exposure associated with increased risk of new onset CD

I2 = 84.87, p = 0.00

Antibiotic exposure and risk of new onset CD in adults and children

I2 = 89.97, p = 0.00

I2 = 0.00, p = 0.63

AdultsOR 1.565 (95% CI 1.177-2.081)

ChildrenOR 2.747 (95% CI 1.723-4.379)

Antibiotic exposure NOT associated with increased risk of new onset UC

I2 = 47.41, p = 0.07

Antibiotic exposure and risk of new onset UC in adults and children

I2 = 72.71, p = 0.012

I2 = 0.00, p = 0.87

AdultsOR 1.058(95% CI 0.851-1.316)

ChildrenOR 1.112(95% CI 0.773-1.602)

Most classes of antibiotics are associated with increased risk of new onset IBD

Antibiotic Class Number of Studies

Providing Data

Pooled OR (95% CI) P value HeterogeneityI2 (p value)

Metronidazole 3 5.010 (1.646 - 15.245) 0.005 I2 = 91.018 (0.000)

Quinolones 3 1.789 (1.027 - 3.118) 0.040 I2 = 85.901 (0.001)

Broad-spectrum penicillins

3 1.313 (1.143 - 1.509) 0.000 I2 = 70.824 (0.032)

Tetracyclines 4 1.301 (1.173 - 1.443) 0.000 I2 = 0.000 (0.794)

Cephalosporins 4 1.268 (1.143 - 1.407) 0.000 I2 = 6.703 (0.360)

Macrolides 4 1.231 (1.112 - 1.363) 0.000 I2 = 20.012 (0.290)

Sulfonamides 4 1.174 (1.058 - 1.302) 0.003 I2 = 0.000 (0.396)

Penicillin 3 1.117 (0.761 - 1.639) 0.572 I2 = 74.191 (0.021)

Limitations

● Data compiled from retrospective studies○ Questionnaire studies subject to recall

bias● Range in the quality of studies (based on

QOS scale)● Significant heterogeneity in certain analyses● Different antibiotic exposure exclusion time

periods

Summary

● Antibiotic exposure increases odds of new diagnosis IBD

● Antibiotic use increases risk new onset CD but not UC

● CD risk greatest in children ● Most antibiotic classes associated with IBD

○ Penicillin not associated○ Metronidazole and quinolones most

strongly associated

Discussion

2. Perez-Cobas et al. Gut. 2013; 62(11).1. Manichanh C et al.Nat Rev Gastroenterol Hepatol. 2012;;9(10).

3. Gradel KO et al. Gastroenterology. 2009;137.

• Antibiotics may increase IBD risk by altering microbiome

• Alternatively, association may be surrogate marker for increased risk infections in CD

Thank You

● Ashish Atreja● Jean-Frederic Colombel

● Charles Bernstein● Richard Gearry● Anders Hviid● Kaija-Leena Kolho ● Matthew Kronman● Souradet Shaw ● Herbert Van Kruiningen

● Crohn’s and Colitis Foundation of America