Levetiracetam versus phenobarbital as first-line therapy for neonatal seizures: a comprehensive systematic review and meta-analysis with meta-regression of 26 studies involving 9,854 neonates

BACKGROUND: Phenobarbital (PB) has long been considered the standard first-line therapy for neonatal seizures, despite suboptimal efficacy and concerns about neurotoxicity and adverse cardiopulmonary effects. Levetiracetam (LEV), a newer antiseizure medication with a more favorable safety profile, has emerged as a potential alternative. This systematic review and meta-analysis aimed to compare the efficacy and safety of LEV versus PB when used as first-line treatment for neonatal seizures. METHODS: A systematic search of PubMed, Scopus, and Web of Science from inception to September 2025 identified eligible randomized controlled trials (RCTs) and observational studies comparing first-line LEV with PB in neonates. Data were pooled using random-effects models to calculate risk ratios (RRs) with 95% confidence intervals (CIs). Heterogeneity, publication bias, and potential effect modifiers were explored through subgroup, and meta-regression analyses. RESULTS: Twenty-six studies (13 RCTs and 13 observational cohorts) including 9,854 neonates (LEV = 1,601; PB = 8,253) were analyzed. The overall rate of seizure control did not differ significantly between LEV and PB (RR = 0.92, 95% CI 0.82-1.03; p = 0.16). Subgroup analyses by study design yielded consistent findings. LEV was associated with significantly fewer adverse events (RR = 3.59, 95% CI 1.85-6.95; I² = 86%), particularly lower risks of hypotension (RR = 3.90, 95% CI 1.94-7.87) and respiratory depression (RR = 2.06, 95% CI 1.23-3.47) compared with PB. Mortality rates were similar between groups (RR = 1.27, 95% CI 0.84-1.91). Meta-regression revealed that higher gestational age and birth weight were associated with better seizure control, whereas older age at seizure onset predicted poorer response. CONCLUSION: LEV and PB demonstrate comparable efficacy for first-line treatment of neonatal seizures; however, LEV provides a more favorable safety and tolerability profile, particularly with respect to cardiopulmonary stability. These findings support the consideration of LEV as an alternative first-line agent, especially in neonates at risk for hemodynamic or respiratory compromise. Further large, high-quality RCTs with standardized EEG confirmation and long-term neurodevelopmental follow-up are warranted.