Levetiracetam as the first‐line treatment for neonatal seizures: a systematic review and meta‐analysis

Abstract

Aim To assess the effectiveness and safety of levetiracetam when used as first‐line treatment of neonatal seizures. Method Four electronic databases, Medline, Embase, Web of Science, and ClinicalTrials.gov were systematically searched from inception until 20th November 2020. Randomized controlled trials (RCTs) and observational studies that included neonates born preterm and term were eligible for inclusion. The primary outcome measure was levetiracetam effectiveness, defined as seizure cessation within 24 hours of starting treatment. Secondary outcomes included short‐term adverse events, mortality before discharge, and long‐term neurodevelopmental outcomes. Results Fourteen studies assessing 1188 neonates were included: four RCTs, three observational trials with phenobarbital as the control arm, and seven observational studies of levetiracetam with no control arm. Pooled efficacy of levetiracetam from observational studies was 45% (95% confidence interval [CI] 34–57%) (GRADE – very low). Meta‐analysis of RCTs evaluating levetiracetam versus phenobarbital showed that both were equally effective (risk ratio [95% CI] 0.6 [0.30–1.20]) (GRADE – very low). Levetiracetam resulted in a lower risk of short‐term adverse events compared to phenobarbital (risk ratio [95% CI] 0.24 [0.06–0.92]) (GRADE – moderate). Interpretation Very low certainty of evidence suggests levetiracetam might not be more effective than phenobarbital. Moderate certainty of evidence indicates levetiracetam is associated with a lower risk of adverse events. Future trials on neonatal antiseizure medication therapy should include continuous electroencephalogram (EEG) monitoring as standard of care and enrol a homogenous population with similar seizure aetiology. Levetiracetam is effective in 45% of neonatal seizures. Levetiracetam might not be more effective than phenobarbital. Levetiracetam is likely to be safer than phenobarbital. Evidence available is limited and of very low certainty.

Efficacy and Safety of Levetiracetam vs. Phenobarbital for Neonatal Seizures: A Systematic Review and Meta-Analysis

“…Our results were consistent with another study ( 45 ). That study evaluated the efficacy of LEV vs. PB and found that there was low quality evidence suggesting that LEV might not be more effective than PB.…”

Treatment of seizures in the neonate: Guidelines and consensus‐based recommendations—Special report from the ILAE Task Force on Neonatal Seizures

“…Four additional systematic reviews reviewed first-line treatment with phenobarbital and/or levetiracetam, but without consensus-based guidelines. [95][96][97][98] In line with previous guidelines, phenobarbital is recommended as first-line ASM but now with better evidence. Phenobarbital should be used for the shortest duration possible with early discontinuation for neonates with acute provoked seizures responding to treatment.…”

“…A systematic review in 2012 summarized pharmacokinetic data for second‐line ASM, and a systematic review in 2013 94 came to similar conclusions as the WHO/ILAE/IBE guideline. Four additional systematic reviews reviewed first‐line treatment with phenobarbital and/or levetiracetam, but without consensus‐based guidelines 95–98 . In line with previous guidelines, phenobarbital is recommended as first‐line ASM but now with better evidence.…”

Self-limited Familial Neonatal Epilepsy due to the c.1589G > A Novel Pathogenic Variant in KCNQ2: A Family Report

“…20,21 Even though PB is the initial drug of choice as first-line treatment of neonatal-onset seizures, 22 some recent systematic reviews concluded that LEV can be used as a first-line antiseizure medication in neonates due to the efficacy, tolerability, and safety profile in neonatal-onset seizures. [23][24][25] Carbamazepine has also been shown to be safe and rapidly effective for the seizures in SLFNE in a previous study. 13 Sodium channel blockers such as carbamazepine and phenytoin are recommended in the treatment of neonatal seizures when a diagnosis of channelopathy is suspected, with a high level of agreement in the latest report from the ILAE (International League Against Epilepsy) task force on neonatal seizures.…”