Influenza With and Without Oseltamivir Treatment and Neuropsychiatric Events Among Children and Adolescents.

Importance: Reports of pediatric neuropsychiatric events during influenza treatment with oseltamivir have prompted public concerns. However, whether oseltamivir or influenza infection is associated with increased risk of neuropsychiatric events remains unclear. Objective: To determine the association between influenza, oseltamivir, and serious neuropsychiatric events. Design, Setting, and Participants: This retrospective cohort study was conducted in a population-based ambulatory setting during the 2016 to 2017 and 2019 to 2020 influenza seasons. Follow-up began on the first day of the influenza season and continued through the earliest occurrence of an outcome event, loss of enrollment, death, age 18 years, or end of the season or study. Children aged 5 to 17 years enrolled in Tennessee Medicaid were for eligible for inclusion. Data analysis was completed from July 2023 to March 2025. Exposures: Each person-day of follow-up was assigned to 1 of the following 5 mutually exclusive exposure groups: (1) untreated influenza; (2) treated influenza; (3) posttreatment period (period between oseltamivir completion and end of influenza period); (4) influenza prophylaxis; and (5) no exposure. Main Outcomes and Measures: The primary outcome was a neuropsychiatric event requiring hospitalization, and events were identified using a validated algorithm. Poisson regression estimated incidence rate ratios (IRRs) while accounting for relevant covariates measured on each person-day. Sensitivity analyses examined robustness of findings to alternate exposure and outcome definitions, time-varying outcome risk, negative control outcome, and unmeasured confounding. Results: Among 692 975 eligible children, a total of 692 295 children (median [IQR] age, 11 [7-14] years; 50.3% female) experienced 1230 serious neuropsychiatric events (898 neurologic and 332 psychiatric) during 19 688 320 person-weeks of follow-up. Among the 151 401 influenza episodes, 66.7% (95% CI, 66.5%-67.0%) were dispensed oseltamivir (60.1% [95% CI, 59.6%-60.6%] among those at high risk for influenza complications). The most common events overall were mood disorders (36.3%) and suicidal or self-harm behaviors (34.2%). Compared with untreated influenza, event rates were lower during oseltamivir-treated influenza periods (IRR, 0.53; 95% CI, 0.33-0.88) and posttreatment periods (IRR, 0.42; 95% CI, 0.24-0.74). Subanalyses suggest that this finding is driven more by a reduction in neurologic events (IRR, 0.45; 95% CI, 0.25-0.82) than psychiatric events (IRR, 0.80; 95% CI, 0.34-1.88). Sensitivity analyses suggest misclassification or unmeasured confounding would not explain these findings. Conclusions and Relevance: In this cohort study, oseltamivir treatment during influenza episodes was associated with a reduced risk of serious neuropsychiatric events. These findings support oseltamivir use for prevention of these influenza-related complications.