Neonatal Anti-seizure Medication Exposure and Long-term Neurological Outcomes

Abstract Objective There is limited evidence for Anti-seizure medication (ASM) safety and long-term outcomes in neonates. Phenobarbital is the only ASM accepted by FDA for neonatal use, but it has been linked with adverse effects. Other ASMs are used off-label in neonates. We wanted to examine links between neonatal ASM exposure and later neurological outcomes. Methods We performed a retrospective observational study of 18,548 infants in intensive care, examining links between ASM exposure and neurological outcomes over follow-up period of median 4.5 years. The clinical data included comprehensive maternal, perinatal, and medication data. Multivariable cause-specific Cox models were used to estimate hazard ratios (HRs) for phenobarbital, levetiracetam, midazolam, and fosphenytoin exposure. Results Exposure to the median cumulative dose of phenobarbital was associated with increased HR for epilepsy (HR 1.35; 95% CI, 1.11–1.62) visual impairment (HR 1.20; 95% CI, 0.99–1.45), and intellectual disability (HR 1.18; 95% CI, 0.99–1.41). In contrast, levetiracetam was associated with smaller risk increases for cerebral palsy (HR 1.13; 95% CI, 1.03–1.23), epilepsy (HR 1.14; 95% CI 1.05–1.24) and visual impairment (HR 1.18; 95% CI 1.11–1.26). We did not find evidence of a dose-dependent phenobarbital effect, but increased maximum concentrations were associated with elevated hazard ratios for cerebral palsy (HR 1.48; 95% CI, 1.07–2.06) and epilepsy (HR 1.64; 95% CI, 1.14–2.35). Conclusion The results align with previous findings linking phenobarbital to neurodevelopmental harm and emphasize the need for its cautious use in neonates. Levetiracetam had more favorable safety profile.