Abstract / Summary
Importance Evidence on maternal influenza infection during pregnancy and offspring neuropsychiatric risk remains inconsistent and limited by methodologic concerns. Objective To evaluate the association of maternal influenza infection during pregnancy and offspring neuropsychiatric risk. Design, Setting, and Participants This binational cohort study included mother-child pairs from the National Health Insurance Service birth cohort in South Korea (discovery cohort) and the JMDC (previously Japan Medical Data Center) birth cohort in Japan (replication cohort). Children born between January 1, 2010, and December 31, 2017, were included in the study and followed up until December 31, 2023. Exposure A first recorded maternal influenza diagnosis during pregnancy. Main Outcomes and Measures The primary outcome was first postnatal diagnosis of any neuropsychiatric disorder in offspring, including severe neuropsychiatric disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, and intellectual disability. Stabilized inverse probability of treatment weighting was applied to adjust for confounding. Weighted Cox proportional hazards models estimated adjusted hazard ratios (AHRs) and 95% CIs. Subgroup analyses were conducted by trimester and season of infection, and sibling-comparison analyses used exposure-discordant sibling pairs. Data analysis was performed from September 2025 to July 2026. Results The discovery cohort included 2 564 435 mother-child pairs (mean [SD] maternal age, 31.9 [4.1] years; 1 293 773 [50.5%] male offspring), of whom 35 973 (1.4%) were exposed to maternal influenza during pregnancy. The replication cohort included 181 681 pairs (92 738 [51.0%] male offspring), of whom 11 198 (6.2%) were exposed. In stabilized inverse probability of treatment weighting–based analyses, maternal influenza infection was associated with an increased risk of any neuropsychiatric disorder in the discovery cohort (AHR, 1.09; 95% CI, 1.04-1.14) and replication cohort (AHR, 1.10; 95% CI, 1.02-1.19). Sibling-comparison analyses included 33 191 and 7842 mother-child pairs in the discovery and replication cohorts, respectively; there was not a statistically significant association in the discovery cohort (AHR, 0.98; 95% CI, 0.89-1.09) and replication cohort (AHR, 1.04; 95% CI, 0.88-1.22). Conclusions and Relevance In this binational cohort study of mother-child pairs in South Korea and Japan, the modest population-level association between maternal influenza infection during pregnancy and the risk of any neuropsychiatric disorder in offspring was attenuated and not statistically significant in sibling-comparison analyses in either cohort. These findings suggest that familial factors may account for the association observed in the population-level analysis.