Levetiracetam versus valproate for new-onset or previously treated but inadequately controlled epilepsy in children: a systematic review and meta-analysis of randomized controlled trials

Purpose: To compare the efficacy and safety of levetiracetam versus valproate in children with new-onset or previously treated but inadequately controlled epilepsy. Methods: We systematically searched PubMed, Scopus, Web of Science, and Cochrane Library from inception to April 2026 for randomized controlled trials (RCTs) comparing levetiracetam versus valproate in children (aged 0–18 years) with new-onset or previously treated but inadequately controlled epilepsy. Outcomes included seizure freedom, exploratory analyses of survival time without seizure and time to first seizure recurrence, change in aspartate aminotransferase (AST) levels, and adverse events. Results: Eight RCTs involving 1,000 participants were included. Seizure freedom did not differ significantly between treatments (5 studies, 655 participants; RR = 0.95, 95% CI: 0.83–1.09; P = 0.45; I² = 59.5%; low-certainty evidence). Exploratory time-related outcomes favored valproate but were limited by low-certainty evidence and inadequate handling of censoring. Levetiracetam was associated with lower AST levels, although this did not establish superior hepatic safety, and with fewer overall adverse events and less weight gain. Conclusions: No significant difference in seizure freedom was detected between levetiracetam and valproate, although the low-certainty finding was sensitive to one trial. Time-related outcomes favored valproate but were exploratory and limited by inadequate handling of censoring. Levetiracetam was associated with fewer overall adverse events and less weight gain, while behavioral and hepatic safety remained uncertain. Treatment should be individualized based on patient and medication-related factors.