Association between prenatal exposure to acid-suppressive medications and subsequent risk of autoimmune diseases in offspring: a nationwide birth cohort study in South Korea.

BACKGROUND: Although acid-suppressive medications are commonly used during pregnancy and may influence immune development in offspring, studies examining their association with pediatric autoimmune diseases remain limited. Therefore, we aimed to investigate the association between prenatal exposure to acid-suppressive medications and the risk of autoimmune diseases in offspring, using a nationwide birth cohort from South Korea. METHODS: This large-scale, nationwide mother-child cohort study in South Korea was conducted from January 1, 2009, to December 31, 2023, using data from the National Health Insurance Service of Korea. We evaluated the risk of autoimmune diseases in offspring following prenatal exposure to acid-suppressive medications, including histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs). The outcome was defined as the occurrence of systemic autoimmune diseases, autoimmune endocrine diseases, autoimmune thyroid diseases, autoimmune hepatitis, and other autoimmune conditions, classified according to International Classification of Diseases, 10th Revision codes (ICD-10). After applying propensity score-based overlap weighting, we used Cox proportional hazards models to estimate the risk, presenting adjusted hazard ratios (aHRs) with 95% confidence intervals (95% CIs). Sensitivity analyses were conducted by medication type, pregnancy trimester of exposure, time-dependent risk, and through various stratifications. In addition, we accounted for within-family clustering in the sibling comparison analysis with each mother treated as a separate stratum. RESULTS: Among the 3,012,992 mother-child pairs initially identified, a total of 2,777,119 children met the inclusion criteria. Of these, 507,845 pairs were exposed to prenatal acid-suppressive medications, and the mean follow-up duration was 9.6 years [standard deviation (SD): 2.4]. In the overlap-weighted cohort (404,550 pairs exposed and 404,551 pairs unexposed), prenatal exposure to acid-suppressive medications was modestly associated with increased risks of systemic autoimmune diseases (aHR: 1.11, 95% CI 1.01-1.21) and other autoimmune diseases (aHR: 1.09, 95% CI 1.05-1.12), such as lupus erythematosus, psoriasis, and rheumatoid arthritis. However, the high numbers needed to harm (37,716 and 6102 per year, respectively) indicate that the absolute excess risks were small, with insignificant sibling-comparison findings (aHR: 0.89, 95% CI 0.77-1.03, and aHR: 0.97, 95% CI 0.92-1.02, respectively). For any autoimmune disease, first-trimester exposure was associated with a slightly elevated risk (aHR: 1.09, 95% CI 1.06-1.13). CONCLUSIONS: Modest associations were observed between prenatal exposure to acid-suppressive medications and pediatric autoimmune diseases; however, the low absolute excess risks and null findings from the sibling comparison analysis, which provides stronger control for unmeasured shared familial factors, indicate limited clinical concern. Nevertheless, exposure during the first trimester may warrant careful clinical consideration.