Background Seizures are the most significant neonatal emergency, with implications on neurodevelopment and mortality. Evidence for the best management of them still remains limited. Phenobarbital is currently the most used drug for neonatal seizure management. The use of Levetiracetam as an alternative is increasing. It is hypothesised to have a better safety profile.

Objectives Assess the effectiveness and safety of levetiracetam when used as the first line treatment of neonatal seizures.

Methods Three electronic databases; MEDLINE, EMBASE, and Web of Science were systematically searched from inception until 20th November 2020. Randomized controlled trials (RCTs) and observational studies that included term and preterm neonates were eligible for inclusion. The primary outcome measure was effectiveness of levetiracetam, 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 14 studies assessing 1,188 neonates were included. Four were 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% CI- 34%-57%). Meta-analysis of RCTs evaluating levetiracetam versus phenobarbital showed that both were equally effective [RR (95% CI) - 0.6 (0.3–1.20)] (GRADE – Very low). Levetiracetam resulted in a lower risk of short-term adverse events compared to phenobarbital [RR (95% CI) - 0.24 (0.06–0.92)] (GRADE – Moderate).

Conclusions Very low-quality evidence suggests that levetiracetam might not be more effective than phenobarbital. Moderate quality evidence indicates levetiracetam is associated with a lower risk of adverse events.