Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial

Date reviewed 1/14/20

Neonatal seizures are associated with poor outcomes and fail to respond to the most common treatments. Phenobarbital and phenytoin have long been used, but often fail to control seizures. Acute side effects of phenobarbital include hypotension, respiratory suppression and sedation and chronic exposure may cause decreased cognitive ability which is thought to be 2/2 to accelerated apoptosis which has been demonstrated in animal models. Levetiracetam has good efficacy in the older population and an excellent safety profile. 

What is the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment of neonatal seizures?

Multicenter, randomized, blinded, controlled trial. Primary endpoint was complete seizure freedom for 24hrs. Secondary outcomes included seizure cessation for 48hrs, rate of achieving and maintaining seizure freedom for 1hr, sub-analysis of the primary outcome measure for subjects with HIE who underwent therapeutic hypothermia.  

Eighty percent of patients in the phenobarbital group remained seizure free for 24hrs compared with 28% of patients assigned to the levetiracetam group which correlates with a relative risk of 0.35 (95% CI 0.22-0.56) 

Strengths: Well conducted RCT. Treatment/response with real-time response to cEEG detected seizures  

Limitations: Small patient volume, not powered to analyze adverse effects. 12 patients excluded after randomization because neurophysiologists did not confirm randomization. These patients were thought to be having clinically significant seizures by the NICU staff, and thus in the ED this would likely be a patient we would be treating. Short end point without patient centered outcomes analyzed 


Phenobarbital is more effective than levetiracetam for the treatment of neonatal seizures  

Sharpe C, Reiner GE, Davis SL, et al. Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial [published correction appears in Pediatrics. 2021 Jan;147(1):]. Pediatrics. 2020;145(6):e20193182. doi:10.1542/peds.2019-3182