Supplemental Table 1. Breakdown of Newcastle Ottawa scale scores for included studies a. Case control studies Case definition Representativeness Selection of controls Definition of controls Comparability Ascertainment Methods for cases and controls Non response Card et al Castiglione et al Gearry et al Han et al Shaw et al 2010 Shaw et al 2011 Van Kruiningen et al Virta et al b. Cohort studies Representativeness Selection of unexposed Ascertainment of exposure Outcome not present at start Comparability Assessment of outcome Sufficient duration of follow up Adequate follow up Hviid et al* Kronman et al* Margolis et al = point given for category
Supplemental Table 2. Summary of extra data provided by study authors Gearry et al Hviid et al Kronman et al Shaw et al 2011 Van Kruiningen et al Virta et al Extra data provided CD and UC with any antibiotic exposure (raw numbers) IBD, CD, and UC with type of antibiotic (raw numbers) IBD, CD, and UC with exposure magnitude (number of antibiotic courses) (raw numbers) IBD with any antibiotic exposures (raw numbers) IBD with exposure magnitude (number of antibiotic courses) (raw numbers) IBD with type of antibiotic (raw numbers) IBD, CD, and UC with type of antibiotic (raw numbers) IBD, CD, and UC with exposure magnitude (number of antibiotic courses) (raw numbers) CD with any antibiotic exposure (raw numbers) IBD, CD, and UC with type of antibiotic (raw numbers)
Supplemental Table 3. Risk of new onset IBD stratified by number of antibiotic dispensations Number of antibiotic dispensations Total cases with exposure Total controls with exposure Adjusted risk (HR/OR/RR with 95% CI) Card et al 1 62 192 OR CD 1.57 (1.07 2.29) 2 to 5 81 258 OR CD 1.50 (1.05 2.14) 5 or more 20 50 OR CD 1.51 (0.82 2.78) Hviid et al 1 to 2 32 IBD 14 CD 18 UC 3 to 4 21 IBD 11 CD 10 UC 5 to 6 15 IBD 6 CD 9 UC 7 or more 16 IBD 8 CD 8 UC n/a RR IBD 1.63 (0.92 2.91) RR CD 2.94 (1.18 7.31) RR UC 1.11 (0.54 2.32) n/a RR IBD 2.07 (1.03 4.18) RR CD 5.12 (1.69 15.53) RR UC 1.12 (0.45 2.80) n/a RR IBD 2.76 (1.27 5.97) RR CD 5.30 (1.49 18.87) RR UC 1.86 (0.71 4.87) n/a RR IBD 2.93 (1.34 6.40) RR CD 7.32 (2.14 24.99) RR UC 1.59 (0.57 4.39) Kronman et al 1 to 2 n/a n/a HR IBD 3.13 (1.54 6.36) HR CD 1.61 (1.30 2.00) HR UC 1.28 (0.97 1.70) 2 or more n/a n/a HR IBD 5.15 (2.36 11.25) HR CD 1.94 (1.49 2.52) HR UC 1.65 (1.16 2.35) Shaw et al 2010 1 n/a n/a OR IBD 2.9 (1.2 7.0) 2 to 4 n/a n/a OR IBD 2.9 (1.2 7.8) 5 or more n/a n/a OR IBD 5.0 (1.3 18.9) Shaw et al 2011 1 n/a n/a OR IBD 1.18 (1.05 1.32) OR CD 1.27 (1.07 1.51) OR UC 1.11 (0.94 1.30) 2 n/a n/a OR IBD 1.35 (1.16 1.57) OR CD 1.48 (1.19 1.85) OR UC 1.25 (1.01 1.54) 3 or more n/a n/a OR IBD 1.54 (1.32 1.80) OR CD 1.45 (1.15 1.84) OR UC 1.62 (1.32 1.99) Virta el al 1 to 3 40 CD 78 UC 4 to 6 37 CD 72 UC 204 (CD controls) 344 (UC controls) 196 (CD controls) 273 (UC controls) OR CD 1.61 (0.72 3.56) OR UC 1.07 (0.66 1.74) OR CD 1.68 (0.74 3.79) OR UC 1.18 (0.71 1.98)
7 to 10 63 CD 88 UC 11 or 16 46 CD 50 UC 171 (CD controls) 307 (UC controls) 154 (CD controls) 239 (UC controls) OR CD 3.19 (1.43 7.13) OR UC 1.28 (0.77 2.15) OR CD 2.70 (1.18 6.19) OR UC 0.89 (0.51 1.55)
Supplemental Table 4. Indications for antibiotic use by study a. Included Studies Card et al Van Kruiningen et al Gearry et al Han et al Shaw et al 2010 Shaw et al 2011 Castiglione et al Virta et al Margolis et al Hviid et al Infections associated with antibiotic use For All Antibiotics Otitis Media 61% (n = 26) Other 19% (8) Upper respiratory 12% (5) Lower respiratory 9% (4) For Metronidazole (only reported this) associated with cases Other noninfectious gastroenteritis 20.7 % (n = 163) Other abd/pelvis symptoms 10% (78) GI system symptoms 9.4% (74) Other female genital inflammation 4.8% (38) Diverticula of intestine 4.2% (33) Special examinations 3.8% (30) Other intestinal disorders 3.2% (25) Functional digestive disorders not elsewhere classified 3.1% (24) Anal fissure and fistula 2.7% (21) Anal and rectal abscess 1.4% (11) Idiopathic proctocolitis 1.4% (11) Ill defined intestinal infections 1.4% (11) Female genital symptoms 1.3% (10) GI hemorrhage 1.3% (10) Other urinary tract disorders 1.3% (10) Diabetes mellitus 1.2% (9) Intestinal infection not elsewhere classified 1% (8) Other cellulitis/abscess 1% (8) Other 27% (212) Tetracyclines Acne Kronman et al For Metronidazole (only reported this) n = 14,506 Vaginitis/vaginosis 34.9% Oral infections 15.1% Gastrointestinal symptoms 7.5% Giardia or other infection treated with metronidazole 3.1% Not specified 39.5%
b. Excluded Studies that used infections as surrogate marker for antibiotic use Wurzelman et al Hildebrand et al Infections associated with antibiotic use For CD Pharyngitis Tonsilitis Colds * no significant associations for UC Pneumonia