Early-Onset Neonatal Infection and Epilepsy in Children.

Importance: Epilepsy is a common neurological disorder in childhood. It remains unclear whether early-onset sepsis is associated with epilepsy and to what extent early-onset meningitis may contribute to its development. Objective: To study the association between early-onset neonatal infection and childhood epilepsy. Design, Setting, and Participants: Nationwide, population-based, register-based cohort study of all Danish live-born singletons with at least 35 completed gestational weeks at birth without major congenital anomalies in Denmark between 1997 and 2013 with follow-up until 2021 or age 18 years, whichever came first. Data were analyzed from February 2024 to January 2025. Exposures: Early-onset infection was defined as an invasive bacterial infection during the first week of life. Diagnosed infection was defined by diagnostic codes of sepsis or meningitis, while culture-positive infection only included those with bacterial pathogens cultured from blood or cerebrospinal fluid. Main outcomes and measures: Epilepsy was defined as a hospital diagnosis or at least 2 redeemed prescriptions of antiepileptic medication. The association between diagnosed sepsis and epilepsy was investigated with multivariable Cox regression to estimate adjusted hazard ratios (HR) with 95% CIs. Associations for the remaining definitions of infection were investigated using person-time incidence rate ratios (IRR). Results: Among 981 869 children, the median (IQR) gestational age was 40 (39-41) weeks, 501 615 (51%) were male, 8154 (0.8%) were diagnosed with sepsis, and 152 (<0.1%) were diagnosed with meningitis. Of these, 257 children had culture-positive sepsis and 32 had culture-positive meningitis. The incidence rate of epilepsy was 1.6 per 1000 person-years for children with diagnosed sepsis compared with 0.9 per 1000 person-years for children without an infection, resulting in an adjusted HR of 1.85 (95% CI, 1.60-2.13). Culture-positive sepsis was also associated with an increased risk of epilepsy (IRR, 2.70; 95% CI, 1.08-5.56), while the highest risks were observed in children with meningitis both diagnosed (IRR, 9.85; 95% CI, 5.52-16.27) and verified by culture (IRR, 16.04; 95% CI, 5.21-37.46). Conclusions and relevance: In this nationwide cohort study, early-onset neonatal sepsis was associated with an approximately 2-fold increased risk of childhood epilepsy. As expected, early-onset meningitis was associated with an even higher risk of epilepsy with an approximately 10-fold increase.