Title: Levetiracetam Versus Phenobarbital as First‑Line Therapy for Neonatal Seizures: A Meta‑analysis of Randomized Controlled Trials
Authors: Ana Leticia Fornari Caprara, Jamir Pitton Rissardo
Conference: 2026 ANA Annual Meeting, San Diego, CA
OBJECTIVE
Phenobarbital remains the standard first‑line treatment (1LT) for neonatal seizures (NS) despite concerns regarding efficacy and safety. Levetiracetam has gained widespread use as an alternative, but randomized evidence is conflicting. We performed a meta‑analysis of randomized controlled trials (RCTs) comparing levetiracetam with phenobarbital as 1LT for NS.
METHODS
We systematically identified RCTs PubMed-indexed enrolling neonates treated with levetiracetam or phenobarbital as initial antiseizure medication (ASM). The primary outcome was seizure freedom (SF) within 24 hours. Secondary outcomes included 1LT failure, requirement for rescue ASM, adverse events (AEs), and mortality. Risk ratios (RRs) were pooled using a Mantel–Haenszel random‑effects model with REML. Heterogeneity was quantified using the I2 statistic. Numbers needed to treat (NNT) and harm (NNH) were estimated from absolute risk differences.
RESULTS
Six RCTs (levetiracetam=245; phenobarbital=216) were included. Levetiracetam did not significantly increase SF compared with phenobarbital (RR 1.23, 95% CI 0.86–1.76; I2=72%). On meta‑regression, trials using clinical seizure diagnosis demonstrated higher SF rates with levetiracetam (RR 1.38, 95% CI 1.01–1.88), whereas the single trial using continuous EEG‑confirmed seizures showed superior efficacy of phenobarbital (RR 0.30, 95% CI 0.17–0.54). 1LT failure (RR 0.87, 95% CI 0.52–1.44) and need for rescue ASM (RR 0.73, 95% CI 0.46–1.17) did not differ significantly between groups. Levetiracetam was associated with fewer AEs overall (RR 0.33, 95% CI 0.15–0.71), particularly hypotension (RR 0.30, 95% CI 0.13–0.68). No differences were observed between groups for respiratory depression (RR 0.63, 95% CI 0.32–1.25), bradycardia (RR 0.44, 95% CI 0.13–1.53), or mortality rates (RR 1.17, 95% CI 0.46–2.95). Levetiracetam increased SF by 3.3% (NNT ≈ 30), whereas phenobarbital increased hypotension by 9.1% (NNH ≈ 11).
CONCLUSIONS
Levetiracetam does not demonstrate consistent superiority over phenobarbital as 1LT for NS control. However, levetiracetam shows a more favorable short‑term safety profile. RCTs assessing different NS diagnoses are needed to confirm results.
Citation
Caprara AL, Rissardo JP. Levetiracetam Versus Phenobarbital as First‑Line Therapy for Neonatal Seizures: A Meta‑analysis of Randomized Controlled Trials. Ann Neurol 2026;100(Suppl 37):S160.