Early childhood caries (ECC), dental decay in children under six, is a highly prevalent but preventable condition. ECC results from disruptions in the oral microbiome, and emerging evidence suggests these disruptions may impact immune development beyond the oral cavity 1. Asthma often begins early in life and follows varying trajectories influenced by immune and microbial exposures. Because the oral cavity is an early site of immune exposure, dysbiosis of the oral microbiota in infancy may influence immune maturation and subsequent risk of allergy and asthma 2. However, existing studies on this topic are cross-sectional, limiting causal inference. Moreover, there is accumulating evidence of differences in immune and respiratory responses by sex, suggesting that sex may act as an effect modifier in this context 3. For these reasons, we aimed to investigate the longitudinal associations between ECC and childhood asthma trajectories and assess sex-based effect modification. We used data from the Baby (B) cohort of the Longitudinal Study of Australian Children (LSAC), an Australian nationally representative population-based birth cohort initiated in 2004 and followed biennially to age 15 years (Figure S1). ECC experience by age five was defined as parent-reported dental decay, tooth fillings, or extractions due to decay. Asthma trajectories from ages 6 to 15 years were derived using group-based trajectory modelling of repeated reports of doctor-diagnosed asthma, asthma medication use, or wheeze 4. The four identified trajectories were: always low-risk, late-onset, early-persistent, and early-resolving asthma 4. Multinomial logistic regression was employed, adjusting for potential confounders and incorporating posterior probabilities of membership as regression weights (Figure S2). Among 4195 children with complete data, baseline characteristics were similar between those with and without ECC, except that children with ECC were more likely to be socioeconomically disadvantaged (Table 1). There was no evidence of an overall association between ECC and asthma trajectories when boys and girls were analysed together (Figure 1). However, sex significantly modified these associations. Boys with ECC had higher odds (mOR:1.32; 95% CI:1.07–1.62) of developing early-persistent asthma (Figure 1). Girls with ECC had higher odds (mOR:1.46; 95% CI:1.08–1.98) of developing early-resolving asthma compared with girls without ECC. We observed consistent patterns in the absolute risk differences in trajectory membership by ECC status (Table S1). After excluding children who used asthma medication, the associations were no longer evident overall or in boys, but girls with ECC still had higher odds of early-persistent asthma (Table S2). Several biological mechanisms may underlie this sex-specific modification. Sex hormones modulate both microbial composition and immune function 5, 6. Boys in early childhood generally exhibit stronger pro-inflammatory cytokine responses than girls 5, which may increase their susceptibility to persistent airway inflammation triggered by interactions with inhaled oral microbiome. Conversely, hormonal changes in girls are associated with more rapid immune maturation and airway growth 6, which may facilitate symptom resolution but do not necessarily protect against long-term declines in lung function. This study has limitations. ECC was parent-reported rather than clinically assessed, which may have introduced non-differential misclassification and biased estimates toward the null. We lacked direct oral microbiome and immune biomarker data, limiting mechanistic interpretation. Residual confounding by unmeasured factors may remain despite adjustments. Findings are observational and require confirmation in studies with objective microbial and immune measures and experimental designs. In a large, nationally representative Australian birth cohort, the associations between ECC and asthma trajectories differed by sex: girls with ECC were more likely to develop early-resolving asthma, whereas boys with ECC were more likely to develop early-persistent asthma. The findings are observational and should be interpreted cautiously until experimentally validated. If confirmed, these findings support the potential of ECC prevention strategies as an early-life intervention for promoting both oral and respiratory health. C.H., A.J.L., D.J.L., and A.S. contributed to conception and design of the study. Y.J.H. contributed to data acquisition and curation. C.H. conducted the statistical analyses, with contributions from Y.J.H., D.J.L., A.S., and A.J.L., who contributed to the analysis plan, interpretation of findings, and provided overall supervision. S.C.D., S.G.D., and R.J.B. contributed to the interpretation of findings and critically revised the manuscript for important intellectual content. All authors contributed to drafting and or critical revision of the manuscript, approved the final version for publication, and agree to be accountable for all aspects of the work, including ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. We acknowledge the data custodians, investigators, and study participants of the Longitudinal Study of Australian Children (LSAC), which was conducted in partnership with the Department of Social Services (DSS), the Australian Institute of Family Studies (AIFS), and the Australian Bureau of Statistics (ABS). Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australasian University Librarians. This research received no external funding. The Longitudinal Study of Australian Children (LSAC), also known as Growing Up in Australia, is funded by the Australian Government Department of Social Services (DSS). S.C.D. has received investigator-initiated grants from GlaxoSmithKline (GSK) and Sanofi Regeneron, and partnership grants from Astra Zenica for unrelated research. A.J.L. has received an investigator-initiated grant from GlaxoSmithKline (GSK) and Sanofi Regeneron for unrelated research. He has received investigational product (EpiCeram TM) free of charge from Primus Pharmaceuticals for use in unrelated research. C.H., A.S., Y.J.H., S.G.D., R.J.B., and D.J.L. declare that they have no relevant conflicts of interest. The GrowingUp in Australia website provides information on accessing the data supporting this study: https://growingupinaustralia.gov.au/data-and-documentation/accessing-lsac-data. The data can be accessed from the Australian Data Archive (ADA) portal after the application for data access is granted. Data S1: Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Handoko et al. (Mon,) studied this question.