Maternal Influenza Infection During Pregnancy and Risk of Attention-Deficit/Hyperactivity Disorder in Offspring

Maternal infections during pregnancy have been implicated in offspring neurodevelopmental disorders, but evidence regarding influenza infection, and antiviral treatments remains limited. This study examined the associations between maternal influenza infection and prenatal oseltamivir exposure with attention-deficit/hyperactivity disorder (ADHD) in offspring.

We conducted a nationwide population-based birth cohort study in Taiwan including 2,231,264 mother-child dyads born between 2004 and 2015. Maternal influenza infection during pregnancy was identified from medical records and categorized by trimester. ADHD in offspring was ascertained using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and Tenth Revision, Clinical Modification (ICD-10-CM) codes. We employed Cox proportional hazards models and sibling-comparison analyses to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs), adjusting for maternal characteristics, comorbidities, and child-specific factors.

During the follow-up period, of the mothers, 116,080 (5.2%) were diagnosed with influenza during pregnancy. In addition, 102,717 children in the unexposed group (4.86%) and 6,620 children in the exposed group (5.36%) were diagnosed with ADHD. In the partially adjusted model, any trimester of maternal influenza exposure showed a small but statistically significant association with offspring ADHD (aHR 1.04, 95% CI 1.02-1.06). However, in the sibling-comparison analysis, which accounts for shared familial and genetic factors, this association was no longer significant (aHR 1.02, 95% CI 0.96-1.08). Prenatal exposure to oseltamivir among influenza-infected mothers was not significantly associated with an increased risk of ADHD in offspring in the sibling-comparison model (aHR 0.46, 95% CI 0.08-2.67).

Our initial analyses suggested a very small though statistically significant association between maternal influenza infection during pregnancy and offspring ADHD , but sibling-comparison analysis revealed no significant risk, pointing to familial confounding. Additionally, prenatal oseltamivir exposure may not increase ADHD risk, supporting the safety of antiviral management during pregnancy.