Supplementary Material for: Is the risk of developing a Crohn’s disease increased after appendectomy? A systematic review of the literature and meta-analysis

Introduction
The effect of appendectomy on the development of Crohn’s disease (CD) is a matter of debate. The aim of this systematic review and meta-analysis is to gather the latest published data to determine whether patients with a history of appendectomy have an increased risk of developing CD or not.

Methods
MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for case-control and cohort studies assessing the risk of developing CD after appendectomy. The pooled adjusted and not adjusted Odds Ratio (OR) with 95% confidence intervals (CI) were calculated for case-control studies. Heterogeneity was assessed. Studies were ranked using the Newcastle-Ottawa Scale (NOS) and were all of good quality.

Results
Fourteen case-control studies and 6 cohort studies were included. Meta-analysis of case-control studies (33’243 patients) of raw Odds Ratio shows a positive association between appendectomy and CD (OR: 1.51, 95% CI: 0.97 to 2.36, I2=87%), which was not statistically significant (p=0.069). The meta-analysis of adjusted Odds Ratio shows that appendectomy represents a statistically significant risk factor for the development of CD (OR: 1.86, 95% CI: 1.01 to 3.45, p=0.047. I2=89%).

Conclusion
Appendectomy appears to be a risk factor for the development of CD. However, the discrepant results obtained by meta-analysis of unadjusted OR, the heterogeneity between studies, and the lack of precision of the magnitude of the association mandate confirmation by a large epidemiological study.