Systematic review and meta-analysis of levetiracetam efficacy in pediatric epilepsy patients

BACKGROUND AND OBJECTIVES: Levetiracetam (LEV) is widely used in pediatric epilepsies because of its favorable pharmacokinetics, ease of administration, and perceived tolerability. However, its comparative efficacy relative to established antiseizure medications (ASMs) in children remains uncertain. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate LEV efficacy in pediatric epilepsies and compare outcomes vs placebo and active comparators. METHODS: We systematically searched PubMed/MEDLINE and Embase (2000-6 August 2025) for RCTs enrolling patients 16 years or younger with epilepsy and reporting seizure freedom and/or ≥50% responder rate. Trials including both pediatric and adult patients were eligible if pediatric participants were represented. Comparisons included LEV vs placebo or active ASMs as monotherapy or adjunctive therapy. Primary outcomes were seizure freedom and responder rate at the trial's primary endpoint or, if not specified, longest reported follow-up. We assessed risk of bias using Cochrane Risk of Bias 2. We pooled risk differences (RDs) with 95% CIs using random-effects models, stratified by comparator and epilepsy subtype. RESULTS: We included 25 RCTs (4,070 participants): 23 contributed to pooled meta-analyses. Across 25 trials, the mean age ranged from 0.4 to 39.3 years, reflecting pediatric-only and mixed-age RCTs; 43.8% were female. In placebo/no-therapy-controlled trials (mainly add-on studies), LEV was associated with higher seizure freedom (RD 11.0%; 95% CI 5.3%-16.7%) and responder rates (RD 24.3%; 95% CI 19.1%-29.4%). In active-comparator-controlled trials (mainly monotherapy head-to-head studies), LEV showed no overall advantage vs active comparators for seizure freedom (RD -2.4%; 95% CI -5.6% to 0.7%) or responder rate (RD -7.4%; 95% CI -23.0% to 8.1%). Fourteen trials were at high risk of bias. Sensitivity analyses confirmed benefit vs placebo but showed significant disadvantage vs active comparators in low risk-of-bias trials. Findings in pediatric-only trials (16 RCTs; 1,380 participants) were consistent with the overall results. DISCUSSION: LEV confers benefit vs placebo, mostly as adjunctive therapy, but does not consistently outperform established ASMs in pediatric epilepsies and may be inferior in some subgroups when higher-quality evidence is considered. Limitations include substantial heterogeneity, frequent high risk of bias, variable follow-up durations, publication bias, and limited pediatric-only comparative data.