Levetiracetam Has Better Safety Profile Than Phenobarbital for Neonatal Seizures

Levetiracetam was non-inferior to phenobarbital but had a more acceptable safety profile as a first-line antiseizure medication (ASM) among neonatal patients, according to study findings published in the journal Pediatric Neurology.

Neonatal seizures are associated with cognitive and motor impairment as well as post-neonatal epilepsy. The oldest and most commonly used first-line ASM for the neonatal population is phenobarbital, however, it has been associated with neuronal apoptosis and impaired synaptic maturation in animal models and adverse events of hypotension, respiratory suppression, and sedation among neonatal patients. As such, levetiracetam has become increasingly more used as a first-line ASM in the neonatal setting.

To compare phenobarbital with levetiracetam, researchers reviewed retrospective data collected between 2011 and 2020 at the University Children’s Hospital Zurich in Switzerland. Response to treatment was defined as complete cessation of electroencephalogram (EEG) seizure following ASM administration with no additional ASM needed.

The patients (N=108) included 56% girls, 82% were born at term, mean birthweight was 3155 (range, 600-4950) g, and Apgar score at 5 minutes was 7 (range, 0-10). The seizure etiologies were structural vascular (32%), hypoxic-ischemic (30%), genetic (17%), metabolic (8%), infectious (6%), structural (5%), and unknown (8%).

The patients had rare seizures (33%), occasional seizures (21%), frequent seizures (23%), or status epilepticus (22%). The EEG findings were normal (9%), mildly or moderately abnormal (12%), or severely abnormal (79%) and neurological statuses were normal (36%), mildly abnormal (19%), or moderately to severely abnormal (44%).

A total of 75 patients received phenobarbital and 33 received levetiracetam. Patients groups were well balanced for demographic and seizure characteristics.

More than half of patients had a complete response to first-line levetiracetam (55%) and phenobarbital (64%). For patients who received a second-line ASM administration, the complete response rate was 35% for levetiracetam and 24% for phenobarbital.

Response to first-line ASM was associated with:

• status epilepticus (incidence rate ratio [IRR], 3.53; 95% CI, 2.14-6.07; P <.001),
• frequent seizures (IRR, 3.26; 95% CI, 1.93-5.71; P <.001), and
• occasional seizures (IRR, 2.22; 95% CI, 1.23-4.08; P =.010) compared with rare seizures.

Compared with levetiracetam, phenobarbital was not associated with a higher likelihood of response to first-line ASM (IRR, 0.99; 95% CI, 0.69-1.45; P =.95).

Similarly, response to second-line ASM was associated with status epilepticus (IRR, 6.22; 95% CI, 1.89-33.5; P =.013) and frequent seizures (IRR, 4.95; 95% CI, 1.44-27.1; P =.032) compared with rare seizures. Compared with levetiracetam, phenobarbital was not associated with a higher likelihood of response to second-line ASM (IRR, 1.23; 95% CI, 0.73-2.05; P =.43).

No seizure etiology was a significant predictor for treatment response.

A quarter of patients who received phenobarbital had adverse effects of hypotension, respiratory suppression, and sedation compared with a single case among patients who received levetiracetam.

The major limitation of this study was the small sample size.

These data indicated that levetiracetam and phenobarbital were similarly efficacious for the treatment of neonatal seizure, but levetiracetam was associated with a superior safety profile. These data supported the use of levetiracetam over phenobarbital as the first-line ASM treatment option.

“Our findings suggest that LEV [levetiracetam] may be a safe and effective alternative to PB [phenobarbital] as a first-line therapy in these neonates,” the researchers concluded.