Abstract
OBJECTIVE: Epilepsy is a known potential outcome following acute provoked neonatal seizures, but its onset, treatment patterns, and health care utilization through childhood remain poorly characterized. This study aimed to define the incidence and timing of postneonatal epilepsy, identify perinatal predictors, and describe the clinical burden of epilepsy among survivors of acute provoked neonatal seizures through early childhood. METHODS: This prospective, multicenter cohort study followed neonates with acute provoked seizures from the Neonatal Seizure Registry (NSR-II) in an extended follow-up through early childhood (Developmental Functional Evaluation). Neonatal clinical and neuroimaging data were collected, and epilepsy outcomes (including semiology, treatments, and health care use) were assessed annually through at least 5 years via structured interviews and medical record review. Kaplan-Meier and Cox proportional hazards models evaluated epilepsy risk, with data censored at loss to follow-up. RESULTS: Among 282 neonates evaluated for epilepsy in NSR-II, 183 (65%) continued into the extended follow-up study. Across the entire follow-up period through early childhood, 50 (18%) developed epilepsy, with a cumulative incidence of 21.6% (95% confidence interval [CI] = 16.7%-27.7%). Earlier epilepsy onset was associated with ≥3 days of neonatal seizures (hazard ratio [HR] = 2.8, 95% CI = 1.5-5.2), abnormal discharge neurological exam (HR = 2.4, 95% CI = 1.3-4.4), and deep gray/brainstem injury (HR = 2.4, 95% CI = 1.2-4.7). Prematurity (<37 weeks) was associated with later epilepsy onset (HR = 3.7, 95% CI = 2.0-6.8). Half (50%) of children with epilepsy developed intractable epilepsy, and 40% required intensive care unit admission. Despite this, only one child received vagus nerve stimulation, and none underwent other epilepsy surgeries. SIGNIFICANCE: These findings highlight the early and persistent epilepsy risk after neonatal seizures. Preterm infants face increased risk later in childhood compared to infants born at term. Risk factor stratification may improve early surveillance, guide clinical decisions, and support family counseling. The underutilization of epilepsy surgery in this cohort suggests multifactorial barriers that warrant further investigation.