Exposure to antibiotics during pregnancy or early infancy and the risk of autoimmune disease in children: A nationwide cohort study in Korea > 연구성과

Background: Emerging evidence suggests that prenatal or early-life exposure to antibiotics may contribute to the development of autoimmune diseases in children. However, previous studies investigating this association have yielded conflicting and inconclusive results, partly due to challenges related to confounding by indication and underlying genetic or familial factors.

Methods and findings: A nationwide cohort study was conducted using mother-child linked claims database of Korea's National Health Insurance Service between 2008 and 2021. Among individuals with diagnosis of infections, children exposed to antibiotics during pregnancy or early infancy were compared to those who were not exposed. The autoimmune-related outcomes of interest were the onset of type 1 diabetes, juvenile idiopathic arthritis, inflammatory bowel disease (ulcerative colitis, Crohn's disease), systemic lupus erythematosus, and Hashimoto's thyroiditis. The antibiotic-exposed pregnancies were compared to unexposed pregnancies using inverse probability of treatment weighting (IPTW) methods to adjust for potential imbalances and confounding by indication. Also, sibling-matched analyses were performed to minimize bias from within-family confounders. Cox proportional hazard model was applied to assess associations, and clinically relevant subgroup analyses, including sex, subclasses and exposed timing of antibiotics were also conducted. Before IPTW, we identified 1,516,574 exposed children and 1,186,516 unexposed children for pregnancy analysis, and 1,925,585 exposed and 1,421,464 unexposed for the infancy analysis. In the pregnancy analysis within the infection-restricted population, IPTW analyses showed null association between antibiotic exposure and autoimmune diseases, including type 1 diabetes (IPTW HR 1.14, 95% CI [0.96, 1.35], p-value = 0.132), juvenile idiopathic arthritis (HR 1.02, 95% CI [0.85, 1.22], p-value = 0.830), ulcerative colitis (HR 1.02, 95% CI [0.76, 1.37], p-value = 0.895), Crohn's disease (HR 1.16, 95% CI [0.98, 1.36], p-value = 0.076), systemic lupus erythematosus (HR 0.70, 95% CI [0.49, 1.01], p-value = 0.053), and Hashimoto's thyroiditis (HR 1.06, 95% CI [0.91, 1.23], p-value = 0.448). In the infancy analysis within the infection-restricted population, IPTW analyses showed no substantial differences in autoimmune disease risk between exposed and non-exposed groups for type 1 diabetes (IPTW HR 1.05, 95% CI [0.88, 1.26], p-value = 0.594) and juvenile idiopathic arthritis (HR 1.11, 95% CI [0.93, 1.33], p-value = 0.253), ulcerative colitis (HR 0.95, 95% CI [0.67, 1.36], p-value = 0.776), Crohn's disease (HR 1.07, 95% CI [0.91, 1.25], p-value = 0.403), systemic lupus erythematosus (HR 1.46, 95% CI [0.95, 2.26], p-value = 0.087), and Hashimoto's thyroiditis (HR 1.14, 95% CI [0.97, 1.33], p-value = 0.104). These results also showed similar associations in sibling-matched analyses. Subgroup analyses showed that maternal use of cephalosporins or antibiotics during first or second trimester was associated with a small increased risk of Crohn's disease in pregnancy analysis, while antibiotic exposure in males or during the first two months of life was associated with a modestly increased risk of autoimmune thyroiditis in infancy analysis. The primary limitations of this study include potential residual confounding due to unmeasured variables.

Conclusions: In this nationwide cohort study, we found no association between early-life antibiotic exposure and the overall risk of autoimmune diseases in children. These findings underscore the importance of ensuring that antibiotic use during pregnancy and early infancy is guided by clear clinical indications and highlight the need for further research to explore subgroup-specific risks in greater detail.