Table 2.

Summary of clinical studies of anticonvulsant therapy.

Study Aim	Study Type	Study Outcome	Number of Participants	Reference
Seizures and outcome	Observational	High seizure burden in babies with HIE were associated with abnormal outcome, with or without hypothermia.	47	[4]
	Observational	HIE infants treated with hypothermia with clinical seizures had more extensive injury on MRI scans and delayed neurodevelopment at 18–24 months.	97	[5]
	Observational	High seizure burden and persistent abnormal aEEG background in HIE infants treated with hypothermia was associated with poor prognosis.	30	[6]
	Observational	High seizure burden was associated with higher mortality and abnormal neurological exam at discharge in infants with HIE, ischemic stroke or intracranial hemorrhage.	426	[8]
	Observational	Seizure severity in newborns with perinatal asphyxia was independently associated with brain injury.	90	[16]
	Observational	Clinical seizures were are associated with worse neurodevelopmental outcome, independent of hypoxic-ischemic injury severity.	77	[17]
	Observational	Clinical seizures were not associated with death, disability or lower developmental scores after adjusting for HIE severity.	208	[21]
	Observational	Seizures were not independently predictive of outcome, due to collinearity with HIE severity.	486	[20]
Treating electrographic and clinical seizures, or clinical seizures only	RCT	EEG monitoring for treatment of electrographic seizures in HIE infants was associated with a reduction in seizure burden. Higher seizure burden is associated with more severe brain injury and lower neurodevelopment scores at 18 to 24 months.	69	[18]
	RCT	Trend for reduction in seizure duration when treating electrographic seizures. Seizure duration is associated with severity of brain injury.	42	[19]
HIE and epilepsy	Observational	Infants with severe but not moderate HIE were associated with developing epilepsy at 24 months.	92	[23]
Hypothermia treatment and epilepsy	Observational	Reduced rates of epilepsy up to 8 years of age in cohort treated with hypothermia for HIE.	151	[24]
Phenobarbital efficacy	Observational	Subclinical seizures were more common in preterm infants. 63% of preterm and term infants with seizures failed to respond to phenobarbital.	611	[48]
	RCT	Phenobarbital was associated with a 27% reduction in incidence of seizures for neonates with severe asphyxia.	31	[59]
Phenobarbital vs. phenytoin efficacy	RCT	Either phenobarbital or phenytoin controlled seizures in less than half of the neonates.	59	[47]
Effectiveness of levetiracetam	Observational	Levetiracetam was associated with reducing 50% of seizures in 35% of infants.	23	[52]
	Observational	Levetiracetam monotherapy provided seizure control in 47% of infants.	36	[53]
Phenobarbital vs. levetiracetam efficacy	RCT	Improvement in tone and posture of infants treated with levetiracetam but not phenobarbital.	30	[54]
	RCT	First-line levetiracetam achieved better seizure control than phenobarbital for neonatal seizures.	100	[55]
	RCT	First-line phenobarbital treatment was more effective than levetiracetam for neonatal seizures.	85	[57]
Hypothermia efficacy for seizures	Observational	Hypothermia reduced seizure burden for neonates with moderate HIE.	107	[60]
	Observational	Hypothermia reduced seizures for infants with HIE at 6 months follow up.	56	[61]
	Observational	0/5 neonates with stroke treated with hypothermia had seizures, compared to 7/10 who were not treated with hypothermia.	15	[62]
	Observational	Neonates born in a tertiary cooling center had fewer seizures and improved seizure-free survival compared to those born in a non-cooling center without active therapeutic hypothermia.	5059	[63]
Bumetanide efficacy	RCT	Bumetanide add-on to phenobarbital for treatment of neonatal seizures did not improve seizure control and increased the risk of hearing loss.	30	[64]
		Phenobarbital plus bumetanide for treatment of seizures in neonates with HIE showed reduced seizure burden compared to phenobarbital plus placebo.	53	[65]
Anticonvulsant adverse effects	Observational	Phenobarbital for the treatment of febrile seizures is associated with lower language/verbal scores at school age, and did not reduce the rate of seizure reoccurrences.	139	[66]
	Observational	Anticonvulsant use for infants with moderate/severe HIE were independently associated with death/disability at 18 months.	208	[67]