Analytical Evaluations of Limitations of Phenobarbital as 1 st -Line Therapy in Acute Neonatal Seizures: Comparison Assessment with Newer Antiepileptics

Background : Acute neonatal seizures are among the most common neurological emergencies during the neonatal period and are associated with increased mortality and long-term neurodevelopmental impairment. Phenobarbital has remained the conventional first-line antiseizure medication because of its rapid onset of action, intravenous availability, extensive clinical experience, and low cost. However, concerns regarding incomplete seizure control, adverse effects, and potential neurodevelopmental toxicity have raised questions regarding its position as the universal first-line therapy. Objectives: This analytical study aimed to evaluate the efficacy, safety limitations, and clinical outcomes associated with phenobarbital use in acute neonatal seizures and to compare its therapeutic profile with newer antiseizure medications, including levetiracetam, fosphenytoin, and lacosamide. Methods: A structured comparative analysis was performed using published clinical studies, randomized controlled trials, and evidence-based neonatal seizure management data. The analysis focused on seizure-control efficacy, adverse effects, pharmacological characteristics, neurodevelopmental concerns, and suitability of different antiseizure medications for individualized neonatal treatment strategies. Results: Phenobarbital demonstrated superior acute seizure-control efficacy, achieving complete seizure freedom in approximately 80% of neonates within 24 hours compared with approximately 28% with levetiracetam. However, 20–40% of neonates continued to experience seizures despite appropriate phenobarbital administration, particularly those with severe hypoxic-ischaemic encephalopathy, prematurity, structural brain injury, or refractory epilepsy. Higher cumulative phenobarbital exposure was associated with concerns regarding neuronal apoptosis, sedation, respiratory depression, hypotension, and adverse neurodevelopmental outcomes. Levetiracetam showed improved tolerability with fewer respiratory effects and less sedation but demonstrated lower immediate seizure-control efficacy. Fosphenytoin remained useful for refractory seizures but required cardiovascular monitoring, while lacosamide showed potential benefit with limited neonatal evidence. Conclusion: Phenobarbital remains an effective medication for rapid seizure termination in acute neonatal seizures; however, its limitations highlight the need for individualized treatment approaches. Future neonatal seizure management should balance rapid seizure suppression with neuroprotection and long-term developmental outcomes through integration of EEG monitoring, patient-specific characteristics, and emerging therapeutic options.