Background: Febrile seizures (FS) are the most common convulsive events in early childhood, affecting 2–5 % of children between 6 and 60 months, with up to one-third experiencing recurrence. Although generally benign, recurrent FS cause significant caregiver anxiety and prompt consideration of pharmacological prophylaxis in high-risk cases. Over the last two decades, newer benzodiazepines, second-generation antiseizure medications, and neurohormonal agents have been investigated as alternatives to traditional regimens. Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines. PubMed, Scopus, and Web of Science were searched for studies published from 1 January 2000 to 30 June 2025 evaluating pharmacological strategies to prevent recurrent FS in children. Eligible designs included randomized controlled trials (RCTs), cohort studies, and systematic reviews reporting recurrence outcomes. Two independent reviewers screened, extracted data, and assessed risk of bias using Cochrane RoB 2 and the Newcastle–Ottawa Scale. Results: Seven studies (n = 577; 3 RCTs, 2 open-label RCTs, 2 cohorts) met inclusion criteria. Intermittent benzodiazepines significantly reduced FS recurrence compared to no prophylaxis. Across three trials, clobazam demonstrated superior efficacy and comparable tolerability to diazepam. Pilot and comparative studies of intermittent levetiracetam (LEV) reported recurrence rates <10 % with fewer behavioral adverse effects relative to clobazam. A single blinded RCT found melatonin non-inferior to diazepam while markedly reducing sedation. No post-2000 evidence supported continuous phenobarbital or valproate prophylaxis. Conclusions: Intermittent clobazam remains the best-supported agent for recurrent FS prevention, while LEV and melatonin are promising, safer alternatives requiring validation in large, multicenter, blinded RCTs. Current evidence supports a selective, individualized approach focused on high-risk children, with caregiver education and rescue strategies as the foundation of management.
Algarni et al. (Tue,) studied this question.