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

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Indian Journal of Pediatrics Aims and scope Submit manuscript



To review whether levetiracetam is non-inferior to phenobarbitone as the first-choice antiseizure medication (ASM).


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.


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.


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.

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Authors and Affiliations



JK, BY: Conceived the idea, retrieved, and analyzed the data, and drafted the manuscript; JM, JY: Critical inputs in the protocol writing and data analysis and critically reviewed the manuscript; JKS: Critical inputs in the protocol, data analysis, interpretation of results, and revision of the initial draft. All authors approved the final version of the manuscript and are accountable for all aspects. JK and JKS will act as guarantors of the manuscript.

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Correspondence to Jitendra Kumar Sahu.

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Supplementary file1 (DOCX 32 KB)

Supplementary file2 (DOCX 18 KB)

Supplementary file3 (DOCX 17 KB)

Supplementary file4 (DOCX 17 KB)


Supplementary Fig. S1 Risk of bias graph: A Review authors' judgment about each risk of bias item; B Risk of bias summary (DOCX 547 KB)


Supplementary Fig. S2 Forest plot showing a comparison of levetiracetam and phenobarbitone for adverse outcomes (DOCX 658 KB)

Supplementary Fig. S3 Funnel plot for primary outcome (DOCX 179 KB)

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Kumar, J., Yadav, B., Meena, J. et al. Levetiracetam versus Phenobarbitone for Management of Neonatal Seizures: A Systematic Review and Meta-analysis. Indian J Pediatr (2023).

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