Levetiracetam vs. Phenobarbital for neonatal seizures: evaluation of a paradigm shift

Objective: Although phenobarbital (PB) is commonly used as a first-line anti-seizure drug (ASD) for neonatal seizures, in 2015 we chose to replace it with levetiracetam (LEV), a third-generation ASD. In this study, we compared the safety and efficacy of LEV and PB as first-line ASDs, considering the years before and after modifying our treatment protocol for neonatal seizures. Methods: We performed a retrospective study of 108 consecutive neonates with EEG-confirmed seizures treated with first-line LEV or PB in 2012-2020. Results: First-line ASD was LEV in 33 (31%) and PB in 75 (69%) neonates. The etiology included hypoxic-ischemic encephalopathy (HIE) in 31% of cases, intracranial hemorrhage in 15%, ischemic stroke in 9%, and neonatal-onset genetic epilepsy in 19%. Forty-two of 108 (39%) neonates achieved seizure freedom following first-line therapy. Treatment response did not vary by first-line ASD in the full cohort (p = 0.28) or in the HIE subgroup (p = 0.52). Treatment response was lowest for neonates with a higher seizure burden, particularly for neonates with status epilepticus than those with rare seizures (p<0.001) but did not differ by sex, gestational age, etiology, or EEG background. Adverse events were noted in 22 neonates treated with PB and only in one treated with LEV (p<0.001). Conclusion: PB was associated with more adverse events than LEV, and the two ASDs were equally but incompletely effective in treating neonatal seizures, thus confirming LEV as a safe and effective alternative to PB as a first-line therapy in these neonates.
Keywords: Neonatal seizures, Phenobarbital, Levetiracetam, term neonates, preterm neonates