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Background <p>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.</p> Methods <p>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.</p> Results <p>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; <i>p</i> = 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.</p> Conclusion <p>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.</p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月10日

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  • Mostafa Hossam El Din Moawad,
  • Abdelrahman M. Elettreby,
  • Ibraheem M. Alkhawaldeh,
  • Hamza A. Abdul-Hafez,
  • Ali Mohammad Asar Mohammad Ali,
  • Omar Mohamed Helal,
  • Mohamed Karawya,
  • Abdallah AlHusan,
  • Malik Allahham,
  • Youcef Chair,
  • Hadeel Amin Al Kabi,
  • Ibrahim Serag,
  • Mohamed Abouzid

摘要

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.