Association between proton pump inhibitor use and the risk of inflammatory bowel disease: A systematic review and meta-analysis

Table 1 Characteristics and summary of included studies

Ref.	Country	Study design	Journal	Sample size	Age	Sex (female %)	Definition of PPIs use	Effect estimates	Quality score	Follow-up duration	Key covariates
Räisänen et al[25], 2023	Finland	Case-control study	Front Pediatr	2389	16.7 ± 1.2	57%	At least one PPI purchase record within 6 months prior to diagnosis	aOR = 8.38 (95%CI: 1.09-64.35)	NOS: 5	NA	Age, sex, area of residence, preterm birth, maternal socioeconomic status, number of antibiotic uses before the age of 3, use of systemic glucocorticoids
Onwuzo et al[19], 2023	United States	Cross-sectional study	Cureus	45586150	18-65	NA	PPI related records in the database	UC: AOR = 2.09 (95%CI: 1.98-2.06); CD: AOR = 2.79 (95%CI: 2.75-2.84)	AHRQ: 8	NA	Age, sex, NSAIDs, smoking, alcoholism, GERD, IBS, and metabolic syndrome
Abrahami et al[13], 2023	United Kingdom	Cohort study	Gut	1820890	> 18	54.5%, 56.6%	Receive PPI prescriptions for the first time on record	HR = 1.05 (95%CI: 0.90-1.22)	NOS: 8	4.2 years	Age, sex, year of cohort entry, BMI, smoking, alcohol-related disorders, autoimmune conditions, NSAIDs, HRT, oral contraceptives, DPP-4 inhibitors, antibiotics, statins, evidenced-based indications and off-label indications, faecal occult blood testing or colonoscopy, mammography, PSA testing, influenza and pneumococcal vaccinations, total number of unique drug classes
Schwartz et al[24], 2019	United States	Case-control study	J Pediatr Pharmacol Ther	1427	≤ 21	43.3%, 51.5%	At least one PPI prescription within 2 years to 5 years prior to diagnosis	aOR = 3.60 (95%CI: 1.10-11.74)	NOS: 6	NA	Age, sex, race, clinic location, number of antibiotic prescriptions, proportion of adults who are high-school graduates, and proportion of family households with below-poverty-level income
Xia et al[14], 2021	United States, United Kingdom	Cohort study	Gastroenterology	647407	57.2 ± 11.2, 59.9 ± 7.3	66.6%	Patients reported regular use of PPI in the past	HR = 1.42 (95%CI: 1.22-1.65)	NOS: 8	12 years, 8.1 years	Race, BMI, menopausal status, smoking, alcohol, physical activity, diet quality, fruit and vegetable intake, family history of IBD, GERD, gastric or duodenal ulcer, GI bleeding, multivitamin, NSAIDs, aspirin, statin, oral contraceptive, postmenopausal hormone use, colonoscopy/sigmoidoscopy, IBS, immune-mediated inflammatory diseases, self-reported overall health and longstanding disease

PPI: Proton pump inhibitor; aOR: Adjusted odd ratio; CI: Confidential interval; NOS: Newcastle-Ottawa Scale; NA: Not available; UC: Ulcerative colitis; CD: Crohn’s disease; AHRQ: Agency for Healthcare Research and Quality; HR: Hazard ratio; NSAIDs: Non-steroidal anti-inflammatory drugs; GERD: Gastro-oesophageal reflux disease; IBS: Irritable bowel syndrome; BMI: Body mass index; HRT: Hormone replacement therapy; DPP-4: Dipeptidyl peptidase-4; PSA: Prostate-specific antigen; GI: Gastrointestinal.

Table 2 Sensitivity analysis on proton pump inhibitor use and risk of inflammatory bowel disease

Study omitted	OR	95%CI
		Lower limit	Upper limit
Räisänen et al[25], 2023	1.71	1.01	2.88
Onwuzo et al[19], 2023	1.40	0.98	1.98
Abrahami et al[13], 2023	2.17	1.35	3.49
Schwartz et al[24], 2019	1.70	0.99	2.94
Xia et al[14], 2021	2.14	1.07	4.30

OR: Odds ratio; CI: Confidential interval.