Original Article

Journal of Child Neurology

1-8
Efficacy of Fosphenytoin as First-Line ª The Author(s) 2020
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Antiseizure Medication for Neonatal DOI: 10.1177/0883073820947514
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Seizures Compared to Phenobarbital

Veronica Alix, MD1, Mansi James, DO1, Anthony H. Jackson, MD1,2,

Paul F. Visintainer, PhD3, and Rachana Singh, MD, MS1

Abstract
Currently used treatment protocols for neonatal seizures vary among centers with limited evidence to support the choice of a
given antiseizure medication. Because of concerns about the potential negative impact of phenobarbital on long-term neuro-
development outcomes, our unit transitioned to fosphenytoin as the first-line antiseizure medication. A retrospective obser-
vational cohort study was conducted to compare the acute and long-term outcomes of fosphenytoin and phenobarbital as
first-line antiseizure medication for neonatal seizure treatment. The 2 study groups had similar baseline characteristics for
neonatal variables as well as maternal antenatal complications. We did not find any differences in the acute outcomes between the
2 groups. However, significantly fewer infants in the fosphenytoin group had moderate-to-severe neurodevelopmental delay at
the 18- and 24-month assessments. In conclusion, although both medications were equally efficacious for acute neonatal seizure
control, fosphenytoin had the potential for significantly better neurodevelopmental outcomes at 18-24 months of age.

Keywords
neonatal seizures, antiseizure medications, fosphenytoin, phenobarbital, electroencephalogram

Received April 2, 2020. Received revised June 23, 2020. Accepted for publication July 12, 2020.

Introduction receptor, possibly enhancing the effect of GABA by extending

Neonatal seizures are common in term and preterm infants
with an incidence of 1.8 to 3.5/1000 live births in the United
States.1-3 They are often indicative of an underlying pathologic
process, such as hypoxic-ischemic encephalopathy, intracranial
hemorrhage, stroke, or sepsis.4 Recurrent neonatal seizures in
otherwise well-appearing neonates with negative workup may
be secondary to benign neonatal epilepsy.5 Neonatal seizures
are associated with high morbidity and mortality with out-
comes likely dependent on both the underlying etiology as well
as the seizure burden from uncontrolled seizures themselves.6
Several studies have demonstrated improved neurodevelop-
mental outcomes with treatment of electrographic seizures,
which in turn decreases the overall seizure burden.7-11 How-
ever, antiseizure medications by themselves have been known
to increase apoptotic injury to brain tissues in animal models.12-
14
Although these findings are difficult to replicate in human
subjects, emerging data appear to support the potential negative
impact of antiseizure medications themselves.15,16 There are no
evidence-based guidelines for the choice of first-line antisei-
zure medications for neonatal seizures.17-20 Currently, the most
common first-line antiseizure medication for new-onset neona-
tal seizures is phenobarbital. Phenobarbital binds to the GABA
the duration of chloride channel openings and allowing for
increased flow of chloride ions across the membrane.21,22 This
could cause neuronal hyperpolarization and can in fact be exci-
tatory in nature in neonates. When neuronal activity is abnor-
mally suppressed, the timing and sequence of synaptic
connections can be disrupted and it causes nerve cells to
receive signals to self-destruct resulting in apoptosis.23 Thus,
in addition to its variable efficacy for controlling seizures as
demonstrated in previous studies,24-26 phenobarbital may have
the potential for a negative impact on the developing brain. As
an alternative, fosphenytoin, a phosphate ester prodrug, is
equally efficacious with no known neurocognitive side effects.
1
Department of Pediatrics, Baystate Children’s Hospital, UMMS-Baystate,
Springfield, MA, USA
2
Department of Neurology, UMMS-Baystate, Springfield, MA, USA
3
Epidemiology & Biostatistics, Office of Research, UMMS-Baystate, Springfield,
MA, USA
Corresponding Author:
Rachana Singh, MD, MS, Division of Newborn Medicine, Baystate Children’s
Hospital, 759 Chestnut Street, Springfield, MA, 01199, USA.
Email: rsingh2@tuftsmedicalcenter.org
2 Journal of Child Neurology XX(X)
However, cardiac side effects have been reported.27 With data
from our study cohort, we sought to compare the efficacy of
fosphenytoin and phenobarbital as first-line antiseizure medi-
cation for neonatal seizure treatment and to assess the neuro-
developmental outcomes at 18-24 months of age. We
hypothesized that there would be no difference between these
2 antiseizure medications for our primary and secondary
outcomes.
Methods
The study included all full-term neonates admitted to and treated for
neonatal seizures at the level III neonatal intensive care unit at Bays-
tate Children’s Hospital, a tertiary care center in Western Massachu-
setts, during the study period of June 2008 to December 2018. All
infants were cared for in our neonatal intensive care unit until dis-
charge. None of them required transfer to a level IV center for care and
pediatric neurologists conducted the postdischarge follow-up. Infants
were identified using the ICD 9/ICD 10 codes for neonatal seizure,
irrespective of the etiology and followed through 18-24 months
postdischarge.
Study Design
The study employed a retrospective observational cohort design
that acquired follow-up data from electronic medical record
review. The cohort was composed of neonates admitted to our
level III neonatal intensive care unit during the study period. Neo-
nates were considered eligible for the study if they had a diagnosis
of clinically identified seizures that were also confirmed by
amplitude-integrated EEG and/or video EEG using a standard neo-
natal EEG montage,3 based on review of the detailed reports in the
infant’s electronic medical record. Data collection included mater-
nal antenatal as well as neonatal baseline characteristics and clin-
ical outcomes, including details pertaining to seizure diagnosis and
management. The primary outcome variable evaluated was the
efficacy of fosphenytoin vs phenobarbital as first-line treatment
for neonatal seizures. Efficacy was measured as total time for
complete resolution of seizures after administration of the
first-line antiseizure medication based on the video EEG, need for
a second-line antiseizure medication, and/or recurrence of seizures.
A single board-certified electroencephalographer (AHJ) interpreted
the video EEG data. Data that were collected and analyzed
included EEG seizure frequency, time of seizure onset as well as
time of last seizure, recurrence of seizure, time of administration
of antiseizure medication, addition of a second antiseizure medica-
tion, and plasma levels of the antiseizure medication. For both
groups, in rare instances, if the antiseizure medication initiation
time and seizure cessation time were documented as identical
in the medical record, then empirically 30 minutes of administra-
tion time (per clinical protocol) was added to compute the seizure
cessation time. Data were categorized by the identified etiology of
seizure: hypoxic-ischemic encephalopathy, intraventricular hemor-
rhage, infarction and other, and also seizure onset focus for both
location (frontal, temporal, occipital, or multifocal) and laterality
(left, right, or bilateral). The therapeutic hypothermia protocol for
hypoxic-ischemic encephalopathy was initiated in 2009 and all
eligible infants were provided this therapy as standard of care.
Data were collected for all infants with a diagnosis of
hypoxic-ischemic encephalopathy who also received therapeutic
hypothermia. Additionally, radiologic data were collected for head
ultrasonography as well as magnetic resonance imaging (MRI),
discharge home on any antiseizure medication as well as long-
term neurodevelopmental status. A pediatric neurologist and/or
pediatric developmental-behavioral specialist did the developmen-
tal status determination at 18-24 months of age. All of these
infants on initial outpatient follow-up by pediatric neurologists
were screened for developmental delays using the Denver Devel-
opment Screening test and ongoing future evaluation by a pediatric
developmental-behavioral specialist were done using Bayley
Scales of Infant and Toddler Development Screening Test.
Moderate-to-severe developmental delay was defined as either a
suspect or delayed assessment on the Denver Development Screen-
ing test and for scores below 2 SDs on the Bayley test.
The standard of care at our center had been the use of phenobarbital
as the first-line antiseizure medication for more than 2 decades. Fol-
lowing a literature review demonstrating the potential neurotoxicity
caused by phenobarbital, the neonatology as well as pediatric neurol-
ogy clinicians developed a new treatment algorithm for neonatal sei-
zures (Figure 1). This resulted in a switch to fosphenytoin as the
first-line antiseizure medication starting in 2015. The doses used are
shown in Figure 1 and conformed to the recommendations. Serum
levels for all antiseizure medication were checked and maintained
within recommended ranges. All antiseizure medications were admi-
nistered as an intravenous infusion (Figure 1) and transitioned to the
oral route if the infant was being discharged home on an antiseizure
medication. A second-line antiseizure medication was added per pro-
tocol if therapeutic serum levels were not achieved despite >2 boluses
of the first-line antiseizure medication, with ongoing seizure activity.
Infants requiring 2 or more antiseizure medications to control their
seizures, a repeat abnormal EEG, and/or abnormal neurologic findings
at discharge were prescribed an antiseizure medication to be continued
at home. Phenobarbital was the primary discharge antiseizure medica-
tion for all infants who were identified as needing ongoing seizure
treatment; thus, infants in the fosphenytoin group were transitioned to
phenobarbital if warranted because of concerns regarding the poor
bioavailability of oral phenytoin.
Seizure Diagnosis
Only full-term infants with clinical seizures confirmed on an
amplitude-integrated EEG and/or video EEG were included in the
cohort. As video EEG is available in our center 7 days a week during
the day, any infant admitted when video EEG was not available was
initially placed on amplitude-integrated EEG to confirm the clinical
diagnosis. All infants were transitioned to video EEG as soon as
feasible. Any infant with a suspected clinical seizure without an EEG
correlate was excluded. The amplitude-integrated EEG seizures were
confirmed by the neonatology attending physician caring for the infant
trained in amplitude-integrated EEG reading whereas a pediatric
board-certified electroencephalographer confirmed the video EEG
seizures
Statistical Analysis
Univariable comparisons of the 2 medication groups were conducted
with t tests for continuous outcomes and Fisher exact test for catego-
rical variables. Variables with an ordinal scale were analyzed using
the Wilcoxon rank-sum test. A comparison of medication groups on
time to seizure control was shown using a Kaplan-Meier curve, and a
difference in the curves was tested using the log-rank test. The
Alix et al 3

Neonatal Seizure Treatment

Protocol

Eligibility: Neonates 36 weeks gestation or older with suspected seizures or who qualify for
whole body cooling.

Monitoring:

1. Video EEG (vEEG) recording should be started as soon as possible. If the first seizure
or cooling occurs outside of regular business hours, amplitude- integrated EEG (aEEG)
can be used until vEEG is available
2. vEEG should be continued for a minimum of 24 hours. If there are no seizures, it can
be discontinued. If seizures persist, vEEG recording should continue until 24 hours
from the last electrographic seizure
3. If electrographic seizures are detected, proceed to treatment.

Treatment: In consultation with Pediatric Neurologist initiate treatment as:

1. Fosphenytoin IV 20mg Phenytoin Equivalent (PE)/kg x 1 (over 15 minutes, no faster

than 3 mg PE/kg per minute, Ref Neofax and Uptodate/Lexicomp)
a. Obtain phenytoin level 30 minutes after end of infusion (conversion T ½ of
fosphenytoin to Phenytoin = 8-15 minutes)
b. Target level is 20-25 mg/L
c. Assess EEG for response
d. Additional 5mg/kg boluses given to achieve desired level
2. If seizures continue 30 minutes beyond achieving therapeutic phenytoin level,
levetiracetam IV 40mg/kg x 1 (infuse over 15 minutes, Ref Up to Date/Lexicomp)
a. Assess EEG for response
3. If seizures continue 1 hour after administration of levetiracetam, phenobarbital IV
20mg/kg x 1 (infuse over 30 minutes, Ref Up to date/Lexicomp)
a. Obtain level 30 minutes after IV infusion (peak effect >/= 15 minutes)
b. Target level 20-40 mg/L
c. Assess EEG for response
d. If continued seizures, give additional boluses of 5mg/kg to a maximum of
40mg/kg ( Every 20-30 minutes; may depend if infant is in status vs. frequent
or occasional electrographic seizures)
4. If continued seizures, give pyridoxine (vitamin B6) IV 100mg/kg x 1; repeat if seizures
continue up to total of 400 mg IV ( and then consider pyridoxal-5-phosphate up to 40
mg/kg IV if seizures continue).
5. If continued seizures, folinic acid 3mg/kg/day divided into 2 doses
6. If continued seizures, consider midazolam drip, bumetanide, oxcarbazepine or
topiramate. These will have to be discussed with parents with consideration for
transferring to a higher level care center

Figure 1. Neonatal seizure treatment algorithm.

95% confidence intervals of the median time to seizure cessation for
each medication group are also reported. Statistical significance was
set at a critical level of 5%. As this was a descriptive observational
study, no adjustments for multiple comparisons were imposed. Statis-
tical power was based on the log-rank test to detect a reduction in the
risk of neurodevelopmental delay at 2 years (ie, HR 0.20) or equiva-
lently, a difference of about 30 percentage points (60% vs 90%)
between the medication groups. Thus, a sample of 105 patients
(80 receiving phenobarbital vs 25 receiving fosphenytoin) would pro-
vide about 70% power to detect the stated hazard ratio at a critical test
level of 5%. Analyses were performed in Stata 15 (StataCorp, College
Station, TX).
Results
A total of 103 infants were included in the study for the pur-
poses of analyses, of which 23 had received fosphenytoin as
first-line antiseizure medication and 80 had received phenobar-
bital as first-line antiseizure medication. Infants in both groups
4 Journal of Child Neurology XX(X)

Table 1. Clinical Characteristics.

Fosphenytoin Phenobarbital
Variable (n ¼ 23) (n ¼ 80) P value

Gestational age, wk, mean (SD); median (IQR) 38.4 (2.3); 39.0 (37.0, 40.0) 38.8 (2.7); 39.0 (38.0, 40.0) .55
Male 9 (39.1) 47 (58.8) .10
Birth weight, g, mean (SD) 3144.3 (630.6) 3307.4 (636.0) .28
Antenatal complication, n (%) .94
Maternal abruption 1 (8.3) 4 (7)
Maternal uterine rupture 0 (0) 1 (1.7)
Maternal chorioamnionitis 1 (8.3) 10 (17.2)
Fetal cord prolapse 0 (0) 1 (1.7)
Fetal shoulder dystocia 0 (0) 1 (1.7)
Other 10 (83.3) 40 (69.0)
Cesarean section 9 (39.1) 38 (47.5) .64
5-min Apgar score, median (IQR) 9.0 (3.0, 9.0) 8.0 (5.0, 9.0) .76
Clinical diagnosis, n (%) .81
HIE 9 (40.9) 28 (38.4)
IVH 0 (0) 1 (1.4)
Infarct 3 (13.6) 10 (13.7)
Hemorrhage 2 (9.1) 9 (12.3)
Hypoglycemia 1 (4.5) 1 (1.4)
Sepsis 1 (4.5) 1 (1.4)
Drug withdrawal syndrome 1 (4.5) 2 (2.7)
Other (metabolic, genetic) 5 (22.7) 22 (29.7)
Age at seizure onset, h, mean (SD); median (IQR) 86.7 (141.7); 21.0 (8.0, 160.0) 48.6 (71.1); 24.0 (10.0, 55.0) .74
Therapeutic hypothermia for HIE 4 (44.4) 13 (46.4) >.99

Abbreviations: HIE, hypoxic-ischemic encephalopathy; IQR, interquartile range; IVH, intraventricular hemorrhage.

had similar baseline characteristics for neonatal variables with
a mean gestational age at birth (38.4+ 2.3 weeks vs 38.8+ 2.7
weeks; P ¼ .55), male sex (39.1% vs. 58.8%; P ¼ .10), mean
birth weight (3144+630.6 g vs 3307.4+6316.0 g; P ¼ .28),
cesarean section as mode of delivery (39.1% vs 47.5%,
P ¼ .64), median 5-minute Apgar score (9.0 [interquartile
range, 3.0-9.0] vs 8.0 [interquartile range, 5.0-9.0]) as well as
maternal antenatal complications and neonatal clinical diag-
noses as shown in Table 1. For outcome variables there was
no difference in EEG findings for location or focality of sei-
zure; neuroimaging findings both for head ultrasonography
prior to discharge as well as brain MRI findings pre- and post-
discharge; time to treatment after seizure onset, recurrence of
seizures, need for a second-line antiseizure medications, and
discharge home on antiseizure medication as shown in Table 2.
The time to seizure control, a potential surrogate marker for
seizure burden, after first-line antiseizure medication adminis-
tration as measured in hours is shown in Figure 2. There was a
trend toward favoring fosphenytoin as compared to phenobar-
bital for time to seizure control after administration but it did
not reach the set statistical significance (log-rank test, P ¼ .06).
The median time to seizure control for the fosphenytoin group
was 0.5 hours (95% CI: 0.5-3 hours) compared with 1 hour
(95% CI: 0.5-15 hours) for the phenobarbital group. Follow-
up data were available for 21 infants (91.3%) in the fospheny-
toin group and 70 infants (87.5%) in the phenobarbital group.
We did find significantly fewer infants in the fosphenytoin
group vs phenobarbital group (4.8% vs 30.4%, P ¼ .02) with
moderate-to-severe neurodevelopmental delay at 18-24 months
of age.
Discussion
In this retrospective, nonrandomized cohort of full-term
infants, we found that there was no significant difference in
the efficacy of fosphenytoin vs phenobarbital for the treatment
of seizures. However, our small sample size precluded detect-
ing small or moderate differences in medications that might be
clinically meaningful. We did detect a statistically significant
association for better neurodevelopmental outcome at 18-24
months with fosphenytoin as compared to phenobarbital. This
association did not seem to be affected by the underlying etiol-
ogy for the seizures and would not be unexpected given the
number of animal studies that have demonstrated potential
negative effects of phenobarbital on early neurogenesis.15,28-30
Treatment of neonatal seizures is highly complex for many
reasons, including multiple etiologies, limited efficacy of med-
ications, and the potential for long-term poor neurodevelop-
mental outcomes. Clinicians have been using phenobarbital
as a first-line antiseizure medication for treating neonatal sei-
zures for decades despite the limited randomized controlled
trial evidence to support it, as noted in review articles on the
subject of treatment of neonatal seizures.31,32 In a survey of
31 US pediatric hospitals, the respondents were reported to
have been concerned about phenobarbital’s potential adverse
neurodevelopmental effects and the lack of evidence that
Alix et al 5

Table 2. Outcome Variables for first-line antiseizure medication.

Fosphenytoin Phenobarbital P
Variable (n ¼ 23) (n ¼ 80) value

Amplitude-integrated EEG, 21 (95.5) 47 (61.0) .001

n (%)
Full complement video EEG, 21 (100) 75 (96.2) >.99
n (%)
EEG seizure focus (side), n (%) .35
Right 7 (43.8) 12 (26.1)
Left 5 (31.3) 23 (50.0)
Bilateral 4 (25.0) 11 (23.9)
EEG seizure focus (site), n (%) .76
Frontal 1 (8.3) 6 (15.4)
Temporal 8 (66.7) 22 (56.4)
Occipital 0 (0) 4 (10.3)
Multifocal 3 (25.0) 7 (17.9) Figure 2. Kaplan-Meier curve to demonstrate a comparison of
Head ultrasonography, n (%) .16 medication groups for time to seizure control. Although there was a
IVH 0 (0) 6 (13.6 trend favoring fosphenytoin as compared to phenobarbital, it did not
Infarct 1 (33.3) 1 (2.3) reach statistical difference.
Other 2 (66.7) 37 (84.1)
MRI prior to discharge, n (%) .75 medication as well as need for an antiseizure medication at the
HIE 4 (25.0) 20 (30.8) time of discharge. These results are in agreement with a much
IVH 1 (6.3) 9 (13.8) earlier and frequently referenced study by Painter et al, where
Infarct 5 (31.3) 14 (21.5)
both phenobarbital and phenytoin were felt to be equally, but
Other 6 (37.5) 22 (33.8)
MRI postdischarge, n (%) .18 often incompletely, effective in treating seizures in neo-
HIE 1 (16.7) 2 (4.5) nates.34,35 However, that study did not use fosphenytoin, a pre-
Infarct 0 (0) 4 (9.1) sumably safer pro-drug of phenytoin. It was also different from
Resolved 3 (50) 10 (22.7) our study in that it looked at free plasma blood levels of both
Other 2 (33.3) 28 (63.6) phenobarbital and phenytoin and was not restricted to just
Therapeutic hypothermia for 4 (44.4) 13 (46.4) >.99 full-term infants with seizures. In addition, the reason for the
HIE, n (%)
high percentage of ineffectiveness of phenobarbital probably
Time to administration of first- 4.2 (6.1) 3.5 (8.1) .67
line medication from onset relates at least in part to its known mechanism of promoting
of seizures, h, mean (SD) an increase in GABA, an inhibitory neurotransmitter in older
Time to seizure control after 0.5 (0.5, 3) 1 (0.5, 15) .06 children and adults but having an excitatory effect on cortical
first-line medication neurons due to their high intracellular chloride in the neonatal
administration, h, median brain.36 Dzhala et al demonstrated that in human cortex brain
(95% CI) slices there is high NKCC1 (Na þ-K þ-Cl – co-transporter)
Recurrent seizures, n (%) 10 (47.6) 43 (54.4) .63
expression possibly supporting the hypothesis that human neo-
Need for second antiseizure 10 (43.5) 35 (43.8) >.99
medication, n (%) natal seizures may be poorly responsive to GABAergic drugs,
Discharge home on an 10 (55.6) 33 (55.9) >.99 such as phenobarbital, because of immaturity of transport of
antiseizure medication, n (%) Cl–.36 They also theorized that the known caudal-rostral pattern
18-month neurologic outcome, .02 of maturation of this Cl– transport system might well account for
n (%) 20 (95.2) 49 (69.6) the observation that GABAergic antiepileptic drugs would be
Normal to mild delay 1 (4.8) 21 (30.4) expected to inhibit motor manifestations of neonatal seizures
Moderate to severe delay
more so than cortical EEG activity. This therefore might account
Abbreviations: EEG, electroencephalography; HIE, hypoxic-ischemic for the phenomenon of electromechanical dissociation, not
encephalopathy; IVH, intraventricular hemorrhage; MRI, magnetic resonance uncommonly seen on the neonatal EEG. This hypothesis was
imaging.
further reinforced by a subsequent study by Glyks et al37 in
perinatal rat pups where they found that phenobarbital was more
phenobarbital treatment leads to improvement in long-term effective in decreasing thalamic epileptiform activity when
outcome. 33 However, there has been a continued non– compared to neocortical structures early on in development.
evidence-based consensus that phenobarbital should be the The significant differences in the long-term neurodevelop-
first-line drug for the treatment of neonatal seizures.26 mental outcomes at 18- and 24-months follow-ups is a promis-
In our cohort, we found similar efficacy for both fosphenytoin ing result from our cohort. The association of phenobarbital
and phenobarbital as assessed by acute outcomes related to neo- with poor long-term neurodevelopmental outcomes in our
natal seizures, irrespective of seizure etiology. Both of them cohort is similar to a study of all infants exposed to either
were partially effective, with similar need of a second-line phenobarbital or levetiracetam with neurodevelopmental
6 Journal of Child Neurology XX(X)
follow-up up to 2 years of age.38 Although in a different age
group than neonates, the findings of a large, randomized,
double-blind study of young children ages 8-36 months with
febrile seizures noted that phenobarbital can lead to significant
deleterious effects on cognition that lasted beyond the period of
administration of that drug, resulting in a decrease in the mean
IQ by 8.4 points compared with placebo.39
Despite being difficult to comparatively quantify the poten-
tial adverse neurodevelopmental effects on the developing
brain of phenobarbital with fosphenytoin, the effect of the sig-
nificantly longer exposure to phenobarbital due to its much
longer half-life (40-200 hours; Neofax 2019) compared to
fosphenytoin (18-60 hours; Neofax 2019), particularly in the
neonate, must be reckoned with. Additionally, phenobarbital
injectable formulations contain 10% alcohol and 67.8% propy-
lene glycol as compared to the preservative-free water-soluble
preparation of injectable fosphenytoin (Neofax 2019), which
may have a contributory negative impact on the developing
neonatal brain. In a rat pup model, CA1 hippocampal neurons
were adversely affected by acute exposure to high-dose phe-
nobarbital (75 mg/kg) on a single occasion, disrupting
GABAergic synaptic maturation and inhibitory synaptic devel-
opment.23 It should be noted that phenytoin, which blocks
voltage-gated sodium channels, is also implicated in causing
apoptotic neurodegenerative changes at least in rat brains at
doses similar to those given to humans.14
Although it is likely that neonatal seizures of themselves
may lead to adverse outcomes, especially in premature infants,
the severity and timing of the pathological process must be
considered to be a significant determinant for outcome as
well.40 In our study, although the time to seizure control after
first-line antiseizure medication administration did not reach
significance, there was definitely a trend for more rapid seizure
cessation in the fosphenytoin group. Although we were not able
to collect data on individual infant’s seizure burden, this find-
ing would support the contention that there may be at least
some significant adverse effect on neurodevelopment by phe-
nobarbital compared with fosphenytoin. This should be an area
of further research with larger number of subjects. Although
our study’s primary focus is on fosphenytoin and phenobarbi-
tal, we would be remiss in not mentioning the interest garnered
by levetiracetam, a relatively newer antiseizure medication. It
is designed to act through synaptic vesicle glycoprotein 2A
(SV2A), a protein believed to be involved in the release of
neurotransmitters.41 Initial data pertaining to its safety and
efficacy in controlling neonatal seizures, both as first-line and
adjunct, has been promising for the preterm as well as the term
neonatal population.42,43 At the time the initial data were pub-
lished, we were equally enthusiastic about levetiracetam when
it was available for use for neonatal seizures. However, anec-
dotally for the few infants treated with levetiracetam in our
unit, we noted failure to control seizure activity prompting the
need for an alternative antiseizure medication. Our impression
has been confirmed by the recent study published by Sharpe
et al that demonstrated phenobarbital to be more efficacious
than levetiracetam in a randomized clinical trial.44
Though not uniformly prospective and not randomized or
double-blind, our study does at least suggest, when treating
neonatal seizures, that we need to consider whether the anti-
epileptic drug we are using has a potential for adverse neuro-
developmental effects15,16 that may outweigh any benefit of
stopping either the motor manifestations and/or cortical EEG
activity associated with neonatal seizures. Until a safer, yet
effective, antiepileptic drug can be developed, it may be wiser
to use fosphenytoin as first-line antiseizure medication because
it is equally effective in terms of seizure control compared with
phenobarbital. Furthermore, because of its significantly shorter
half-life than phenobarbital, fosphenytoin would expose the
developing brain to a much briefer period of potentially neu-
rotoxic medication. There is no doubt that a large multicenter
prospective double-blind, randomized study, including only
video EEG–confirmed seizures, with long-term standardized
neurodevelopmental testing follow-up will be needed to lend
more statistically reliable support to such a hypothesis and
provide much needed evidence-based guidelines for the man-
agement of neonatal seizures.45 Until that happens and until
that new efficacious, safe, and neuroprotective antiepileptic
drug becomes available, we should keep an open mind as to
how to proceed given what is currently known.
Strengths and Limitations
Our study’s major strength is the relatively large cohort of
infants at a single center with availability of all data points in
the electronic medical record with an excellent follow-up rate
and relatively little loss of follow-up. Additionally, the same
group of pediatric neurologists and development behavioral
physicians utilizing standardized developmental screening tests
did the follow-up. However, as large as the cohort is, the sam-
ple size posed a major limitation. The sample size was only
large enough to detect large differences in outcome between
the medication groups. The study did not have sufficient power
to detect small or moderate differences in efficacy that may be
clinically meaningful. Thus, the absence of statistical signifi-
cance in efficacy should not be taken as evidence that efficacy
is equivalent for the 2 medications. Further, the large imbal-
ance between medication groups precluded statistical adjust-
ment for potential confounding factors that may influence
evaluation of treatment effects. In addition, inability to quan-
tify seizure burden or status epilepticus in individual infant are
limitations that we acknowledge, especially because clinical
electrographic and electrographic-only seizures have previ-
ously been reported to impact neurodevelopmental out-
comes.9,11 For these reasons, it is crucial that the results
described herein are replicated with much larger sample sizes.
Ideally, long-term neurodevelopmental follow-up outcomes
would further bolster confidence in any conclusion about out-
comes, due to the ability to use more statistically reliable mea-
sure (WPPSI-R). Definitive evaluation of the magnitude of
difference between fosphenytoin and phenobarbital, as sug-
gested by our study, may ultimately come from a large,
well-controlled randomized clinical trial.46,47
Alix et al
Conclusion
Both fosphenytoin and phenobarbital are equally efficacious as
a first-line antiseizure medication in neonatal seizure control.
Additionally, neonates treated with fosphenytoin had signifi-
cantly better neurodevelopmental outcomes at 18-24 months of
age, as compared to phenobarbital. Further multicenter
double-blinded randomized clinical trials are recommended
to confirm our findings.
Acknowledgement
The study was conducted at the level III neonatal intensive care unit at
Baystate Children’s Hospital, a tertiary care center in Western Mas-
sachusetts. This work had been presented at the 47th Annual Child
Neurology Society Meeting in Chicago, October 2018, as well as the
Pediatric Academic Societies Meeting in Baltimore, May 2019. The
authors gratefully acknowledge the contributions of their subjects, and
their subjects’ families, as well as Drs Herbert Gilmore, Beth Rosen,
David Dredge, and Brooke Surran who helped develop the seizure
treatment algorithm and provided care to many of the subjects pre-
and postdischarge.
Author Contributions
VA and MJ conceptualized and designed the study, designed the data
collection instruments, collected data, and reviewed and revised the
manuscript. PFV conducted the data analysis, interpreted the data, and
critically reviewed the manuscript. RS and AHJ coordinated and
supervised the data collection, interpreted the data analysis, drafted
the manuscript, and critically reviewed the initial manuscript as well
as the subsequent revised versions. In addition AHJ was the board-
certified electroencephalographer who read the video EEGs and
EEGs. All authors approved the final manuscript as submitted and
agreed to be accountable for all aspects of the work.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support for the
research, authorship, and/or publication of this article: This study was
funded by Department of Pediatrics, Baystate Children’s Hospital,
UMMS-Baystate.
ORCID iD
Rachana Singh, MD, MS https://orcid.org/0000-0001-7783-1214
Ethical Approval
The study was reviewed and approved by the Institutional Review
Board at Baystate Health.
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