Levetiracetam versus Phenobarbitone for Management of Neonatal Seizures: A Systematic Review and Meta-analysis.

OBJECTIVES: To review whether levetiracetam is non-inferior to phenobarbitone as the first-choice antiseizure medication (ASM). METHODS: The authors searched Medline, Embase, Web of Science, Scopus, and Cochrane Library for randomized controlled trials (RCTs) published until May 31, 2023. RCTs comparing the efficacy and safety of levetiracetam and phenobarbitone as first-line ASM in neonatal seizures were included. Random effects meta-analysis was performed, and the Risk of Bias version 2 tool was used for quality assessment. RESULTS: Eleven RCTs enrolling 821 neonates [mostly term, with hypoxic-ischemic encephalopathy (HIE)] were included. There was no significant difference in seizure control between levetiracetam and phenobarbitone (10 RCTs, 786 participants; relative risk RR: 1.11; 95% CI: 0.79, 1.54; I2- 88%). Neonates in the levetiracetam group had a significantly lower incidence of hypotension (RR: 0.28; 95% CI: 0.09, 0.86), respiratory depression (RR: 0.36, 95% CI: 0.19, 0.66), and depressed sensorium (RR: 0.52, 95% CI: 0.27, 1.00). Three studies compared neurodevelopmental outcomes; however two of them were cross-over trials where infants received both drugs. Only one RCT enrolled pure cohorts and showed better neurodevelopment in the levetiracetam group at one month of age. CONCLUSIONS: With the limitation of very-low certainty evidence, the results of this systematic review suggest that levetiracetam may be non-inferior to phenobarbitone for managing neonatal seizures. Considering a better safety profile and marginally better neurodevelopment in the short term, levetiracetam may be considered an initial choice for managing neonatal seizures. REGISTRATION NUMBER: PROSPERO (CRD42023438018).