Systematic Review: The Persistent Association Between Infant Antibiotic Exposure and Childhood Asthma After Accounting for Confounding by Indication and Reverse Causation

Background Early-life antibiotic exposure has been repeatedly associated with an increased risk of childhood asthma. However, this association is vulnerable to substantial methodological bias, particularly confounding by indication (CbI) and reverse causation (RC). This systematic review evaluates whether the association persists in studies employing advanced epidemiologic methods designed to mitigate these biases. Methods A systematic search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted from January 2010 through December 11, 2025 . Eligible publications included (1) primary observational studies (cohort or case-control designs) evaluating antibiotic exposure during infancy (0–24 months) and physician-diagnosed asthma at ≥ 4 years, and/or (2) systematic reviews/meta-analyses that explicitly evaluated or stratified results by approaches addressing CbI and/or RC (e.g., adjustment for respiratory tract infections, exclusion of early wheezing, or comparable bias-mitigation strategies). Study selection followed PRISMA 2020 guidelines. Methodological quality was assessed using the Newcastle–Ottawa Scale for primary studies; systematic reviews were assessed narratively for relevance to the review objective. Results Four eligible studies were included. Crude observational estimates reported in meta-analytic syntheses demonstrated a strong association (pooled OR ≈ 1.37). In analyses explicitly addressing CbI and RC, estimates attenuated but remained statistically significant (pooled OR 1.19; 95% CI, 1.11–1.28). In contrast, a nationwide sibling-matched cohort study eliminated the association for fetal exposures and non-respiratory indications, suggesting substantial familial confounding. A persistent association remained only for antibiotics prescribed for respiratory infections (sibling-matched HR 2.36), consistent with residual confounding by illness severity. Conclusion The association between infant antibiotic exposure and childhood asthma is largely explained by shared familial factors and residual confounding related to respiratory illness severity rather than a direct causal effect of antibiotics. While biological plausibility via gut microbiome disruption remains, current epidemiologic evidence does not strongly support causality. Further studies using advanced causal inference methods are warranted.