Prophylactic Phenobarbital Administration After Resolution of Neonatal

Seizures: Survey of Current Practice

Ronnie Guillet and Jennifer M. Kwon
Pediatrics 2008;122;731-735
DOI: 10.1542/peds.2007-3278

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://www.pediatrics.org/cgi/content/full/122/4/731

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ARTICLE

Prophylactic Phenobarbital Administration After

Resolution of Neonatal Seizures: Survey of
Current Practice
Ronnie Guillet, MD, PhDa, Jennifer M. Kwon, MD, MPHb

aDepartment of Pediatrics, Division of Neonatology, and bDepartment of Neurology, Division of Child Neurology, Golisano Children’s Hospital at Strong, University of

Rochester Medical Center, Rochester, New York

The authors have indicated they have no financial relationships relevant to this article to disclose.

What’s Known on This Subject What This Study Adds

There is wide variation among practitioners regarding the continuation of phenobarbi- This study provides data on the current use of phenobarbital after resolution of neonatal
tal treatment after resolution of neonatal seizures. Recurrent seizures may be deleterious seizures among child neurologists and neonatologists. Considerable variation still exists,
to the developing brain, as may be prolonged exposure to phenobarbital. but the duration of treatment may be shorter than in the past.

ABSTRACT
OBJECTIVE. Child neurologists and neonatologists often discharge newborn infants with
phenobarbital treatment for weeks to months despite the absence of continuing
seizure activity. We conducted a national survey to determine the degree of variation www.pediatrics.org/cgi/doi/10.1542/
peds.2007-3278
in this practice.
doi:10.1542/peds.2007-3278
METHODS. Surveys were sent to a randomly generated list of board-certified child Key Words
neurologists (N ⫽ 609) and neonatologists (N ⫽ 579). The survey consisted of 3 parts, neonatal seizures, phenobarbital, survey
that is, questions related to overall attitudes and practices, specific patient scenarios, Accepted for publication Jan 9, 2008
and respondent demographic characteristics. Responses were tabulated and analyzed Address correspondence to Ronnie Guillet,
for all respondents combined and for child neurologists and neonatologists sepa- MD, PhD, Department of Pediatrics, Division of
Neonatology, Box 651, Golisano Children’s
rately. Variation in practices between respondents and the consistency between the Hospital at Strong, University of Rochester
respondents’ stated use of phenobarbital in practice and their answers to various Medical Center, 601 Elmwood Ave, Rochester,
clinical scenarios were evaluated. NY 14642. E-mail: ronnie㛭guillet@urmc.
rochester.edu
RESULTS. Responses were received from 118 child neurologists (20.7%) and 125 neo- PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright © 2008 by the
natologists (23.1%). There was wide variation in practices, with little difference in American Academy of Pediatrics
the response frequencies between child neurologists and neonatologists. Physicians
were more likely to respond yes to continuation of phenobarbital treatment in a
given clinical situation than would be predicted on the basis of their answers regarding overall frequency of use.

CONCLUSIONS. Since the survey of practices 15 years ago, child neurologists and neonatologists are reporting less
frequent and shorter phenobarbital treatment after resolution of neonatal seizures, although there remains consid-
erable variation in practices. Moreover, what physicians report as their practice in general is inconsistent with how
they respond to specific clinical cases of neonatal seizures. Pediatrics 2008;122:731–735

N EONATAL SEIZURES ARE a common problem, affecting 1 to 4 per 1000 live births.1–3 Child neurologists and
neonatologists generally agree on the appropriate evaluation and initial pharmacologic treatment of neonatal
seizures. However, the best time to stop medication administration is not clear. Two surveys of practice, performed
10 years apart, illustrate the wide variation among specialties in discontinuing medications. Boer and Gal4 surveyed
neonatologists and neurologists in the early 1980s and reported that the usual duration of treatment for patients with
neonatal seizures varied from ⬍1 month to 3 to 5 years. Relatively few providers (⬍15%) discontinued medications
during the first month of life, and many (⬎35%) continued medications for ⬎6 months. Small proportions (8% of
neonatologists and 15% of neurologists) reported recommending 1 to 2 years of continued treatment or more.
Similarly, in 1993, Massingale and Buttross5 reported that the duration of treatment ranged from ⱕ3 months (40%)
to ⱖ1 year (11%) in a survey of neonatologists.
Informal discussions with neonatologists and child neurologists suggest that, although the frequency of contin-
uation of phenobarbital treatment at the time of discharge may not be changing, the duration of treatment may be
decreasing over time. Published surveys describing current practices are lacking. Therefore, we sought to determine
the overall frequency with which term infants with neonatal seizures currently are discharged from the hospital
with phenobarbital treatment, the usual duration of outpatient treatment for infants discharged from the
hospital with phenobarbital therapy, and whether there are differences in practices as a function of the

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 TABLE 1 Demographic Characteristics of Respondents
Characteristics of Specialist’s Practice n (%)
Child Neurologists Neonatologists
(N ⫽ 118) (N ⫽ 125)
Geographic location of practicea
Northeast 32 (27) 29 (23)
South 33 (28) 40 (32)
Midwest 20 (17) 34 (27)
West 33 (28) 22 (18)
Work setting No response: 2 (2) No response: 7 (6)
Academic 77 (65) 64 (51)
Private practice 39 (33) 54 (43)
Affiliated nursery level No response: 9 (8) No response: 2 (2)
Level I (well-child care only) 2 (2) 2 (2)
Level II (special care) 5 (4) 3 (2)
Level III (almost all services) 37 (31) 63 (50)
Level IV (all services, including extracorporeal 65 (55) 55 (44)
membrane oxygenation, computed
tomography, and surgery)
Affiliated NICU size No response: 9 (8) No response: 0 (0)
⬍10 beds 8 (7) 3 (2)
10–29 beds 25 (21) 35 (28)
30–49 beds 36 (30) 41 (33)
50–60 beds 15 (13) 23 (18)
⬎60 beds 25 (21) 23 (18)
Associated training programs
Pediatrics residency 91 (77); no response: 6 (5) 80 (64); no response: 0 (0)
Pediatric neurology residency 60 (51); no response: 6 (5) 69 (55); no response: 4 (3)
Neonatology fellowship 60 (51); no response: 10 (8) 58 (46); no response: 2 (2)
Have local guidelines for care of infants with 29 (24); no response: 13 (11) 21 (17); no response: 4 (3)
neonatal seizures
No. of infants with neonatal seizures cared for in No response: 6 (5) No response: 3 (2)
nursery
⬍1 per mo 13 (11) 44 (35)
1–3 per mo 45 (38) 61 (49)
⬎3 per mo 54 (46) 17 (14)
a Northeast includes Connecticut, Massachusetts, Maine, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, and Vermont;

South includes Alabama, Arkansas, Washington, DC, Delaware, Florida, Georgia, Kentucky, Louisiana, Maryland, Mississippi, North Carolina,
Oklahoma, Puerto Rico, South Carolina, Tennessee, Texas, Virginia, and West Virginia; Midwest includes Iowa, Illinois, Indiana, Kansas, Michigan,
Minnesota, Missouri, North Dakota, Nebraska, Ohio, South Dakota, and Wisconsin; West includes Alaska, Arizona, California, Colorado, Hawaii,
Idaho, Montana, New Mexico, Nevada, Oregon, Utah, Washington, and Wyoming.

subspecialty training of the responsible physician
and/or the presumed cause of the seizure. These data
should help establish the study parameters for a fu-
ture, randomized, clinical trial.
METHODS
A survey of practices was developed with the help of
focus groups and experts in the area of neonatal neurol-
ogy. Questions were pilot-tested for clarity and were
revised after input from the reviewers. There were 3
distinct sections of the 9-page questionnaire, that is, 18
general questions regarding practices and attitudes, 14
questions on phenobarbital usage in specific clinical sit-
uations, and 15 demographic items.
A license was purchased from the American Board of
Medical Specialties for use of a randomly generated list
of board-certified child neurologists and neonatologists.
Each physician on the list was sent a printed copy of the
survey, with a cover letter offering them the option
either to complete the printed copy of the survey or to
complete the survey on-line by using the SurveyMon-
key Web site (www.surveymonkey.com). A reminder
postcard was sent to nonresponding physicians ⬃3
weeks after the initial mailing. The link to the Survey-
Monkey questionnaire was included on the postcard.
Three weeks later, a second printed copy of the survey
was sent to everyone who had not yet completed the
survey.
Survey data were compiled in a single spreadsheet by
using SurveyMonkey and then were exported to Stata 9
(Stata, College Station, TX) for analysis. Responses were
tabulated and analyzed for all respondents combined
and for child neurologists and neonatologists separately.
The responses to individual questions were evaluated by
using standard summary statistics, and practice varia-
tions were quantified by using coefficients of variation.
Correlations between several pairs of questions regard-
ing the use of prophylaxis were analyzed by using Mc-
Nemar’s test. The ability of respondents to predict their
own behavior in specific, hypothetical, clinical situations

732 GUILLET, KWON

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 TABLE 2 Respondents’ Use of Phenobarbital After Initial Seizure tinue phenobarbital therapy after resolution of seizures
Treatment prescribe it for ⱕ3 months, a smaller number suggest
that phenobarbital therapy be continued for 3 to 6
n (%)
months, and almost no one prescribes it for a longer
Child Neurologists Neonatologists period (Table 2). There was no difference overall or as a
(N ⫽ 118) (N ⫽ 125) function of specialty in stated preferences to use prophy-
Use of maintenance phenobarbital No response: 4 (3) No response: 3 (2) laxis as a function of geographic region, nursery size,
after loading dose presence or absence of pediatric residency, pediatric
Always 20 (17) 36 (29) neurology, or neonatology training programs, number
Sometimes 84 (71) 83 (66)
of infants cared for per month, or year of completion of
Rarely 10 (8) 3 (2)
Never 0 (0) 0 (0)
subspecialty training. The coefficients of variation for the
Usual starting dose of No response: 1 (1) No response: 0 (0) questions most relevant to clinical practice were ⬎0.2,
phenobarbital maintenance, which supports the notion that there is wide variability
if used in thinking and actual practices.
⬍4 mg/kg per d 22 (19) 14 (11) Furthermore, the responses to the question, “Do you
4–6 mg/kg per d 86 (73) 109 (87) typically discharge patients home on phenobarbital after
⬎6 mg/kg per d 9 (8) 2 (2) resolved neonatal seizures?” did not predict how the
Use of prophylactic phenobarbital No response: 1 (1) No response: 0 (0) respondents reacted to a given clinical scenario. Physi-
treatment cians were more likely to respond yes to continuation of
Always 6 (5) 9 (7)
phenobarbital treatment for a given scenario (Table 3)
Sometimes 85 (72) 81 (65)
Rarely 22 (19) 27 (22)
than would be predicted on the basis of their answers
Never 4 (3) 8 (6) regarding the overall frequency of continuation of phe-
Duration of prophylactic No response: 7 (6) No response: 90 (72) nobarbital therapy (P ⬍ .01, McNemar’s test). We used
phenobarbital treatment receiver operating characteristic methods to quantify
⬍1 mo 9 (8) 3 (2) further how well the responses to the questions on
1–3 mo 53 (45) 10 (8) current practices predicted responses to questions re-
⬎3–6 mo 44 (37) 7 (6) lated to a specific scenario. Surprisingly, the respon-
⬎6 mo 0 (0) 1 (1) dents’ views of community practices seemed to be a
Not applicable; never use 3 (2) 2 (2) slightly better predictor of how the respondents would
prophylaxis
react to specific scenarios. In no case was the area under
Do not know; I do not follow 2 (2) 12 (10)
these patients
the curve ⬎0.75 (the value typically used to indicate a
Monitoring of drug levels No response: 1 (1) No response: 15 (12) robust predictor6).
Never 4 (3) 4 (3)
Routinely 40 (34) 47 (38) DISCUSSION
Only if possible seizures 5 (4) 4 (3) The decision to continue antiepileptic treatment after
Only if possible side effects 1 (1) 1 (1) hospital discharge for infants with neonatal seizures is
Only if possible seizures, side 67 (57) 54 (43) based on limited data. The rationale for using antiepi-
effects, or other clinical leptic drugs at discharge is to decrease the likelihood of
indication (eg, compliance) seizure recurrence. The rationale for not using prophy-
lactic antiseizure treatment at discharge is either because
of possible brain growth inhibition, as seen in animal
was evaluated by using receiver operating characteristic models,7 or because of perceived low likelihood of sei-
curve methods. These analyses were all conducted by zure recurrence/timing of recurrence.3,8 The relevant
using Stata. The University of Rochester institutional data for neonates are limited to retrospective reviews,
review board approved the study. cohort studies of patients with neonatal seizures moni-
tored prospectively for outcomes, with or without a
RESULTS standardized approach to outpatient care, and animal
Of 770 child neurologists and 1696 neonatologists in the studies on the effects of chronic phenobarbital exposure
American Board of Medical Specialties database, 609 child on brain growth.7
neurologists and 579 neonatologists were randomly se- Observational studies found no difference in seizure
lected and sent surveys. Of those, 66 surveys were returned recurrence (epilepsy) when antiepileptic treatment was
as undeliverable and 20 practitioners declined to partici- stopped early versus later.9,10 Overall, approximately one
pate. Responses were received from 118 child neurologists fourth of infants with neonatal seizures have ⱖ1 addi-
(20.7%) and 125 neonatologists (23.1%). Few respon- tional seizure in infancy or childhood, irrespective of the
dents (9.5%) used the electronic option to complete the use of prophylaxis.11 Although risk assessment scores12
survey. Respondents represented a wide geographic area and electroencephalographic criteria13 have been pro-
and work-setting spectrum (Table 1). posed as determinants of the need for continued treat-
There was wide variation in practices, with little ment, there is no evidence that either has been validated
difference in the response frequencies for individual in other populations or widely adopted.
questions between child neurologists and neonatolo- Farwell et al14 reported a randomized, clinical trial of
gists (Table 2). The majority of physicians who con- prophylactic phenobarbital use in children 8 to 36

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 TABLE 3 Responses to Individual Scenarios
Summary of Scenario Presented Proportion, %
Use of Duration of Prophylaxis, if Used
Phenobarbital
Prophylaxis NR ⬍1 mo 1–3 mo ⬎3–6 mo ⬎6 mo
HIE: Apgar score of 3 at 20 min; cord pH of 6.6; clinical seizures at 12 h; EEGs with severe
background suppression and no electrical seizures; MRI scan with diffuse ischemic
damage
Child neurologists 58.2 4.6 3.1 38.5 36.9 16.9
Neonatologists 46.3 7.1 1.8 39.3 39.3 12.5
HIE: Apgar scores of 3 at 5 min and 6 at 10 min; clinical and electrical seizures on day 1;
abnormal MRI scan on day 14; home on day 16 with some nasogastric feedings
Child neurologists 76.4 3.5 1.2 44.2 39.5 11.6
Neonatologists 80.2 8.3 5.2 28.1 39.6 18.8
HIE: Apgar score of 8 at 5 min; home at 36 h, readmitted later that day with clinical
seizures; normal EEG on day 2; MRI scan on day 5 with HIE
Child neurologists 66.7 10.5 4.0 39.5 46.5 10.5
Neonatologists 51.7 8.2 11.5 32.8 39.3 8.2
Cerebral infarction: Apgar scores of 9 and 9; clonic movements at 6 min of age; EEG at
4 h with focal right temporal lobe seizures; CT and MRI scans with cerebral
infarction in distribution of right MCA; follow-up EEGs without electrical seizures
Child neurologists 80.7 3.4 4.5 46.1 25.8 20.2
Neonatologists 70.8 8.2 5.6 31.2 38.8 15.3
Unknown cause: Apgar scores of 8 and 9; apnea at 24 h; EEGs on days 1, 4, and 6 with
seizures; MRI, culture, and metabolic evaluation results normal; phenytoin
administered and then carbamazepine added, with resolution of seizures at 3 wk
Child neurologists 43.8 3.6 14.6 29.1 21.8 30.9
Neonatologists 68.1 23.4 3.9 11.7 28.6 32.5
GBS meningitis: clinical seizures noted at 12 h; CSF cultures positive for GBS; EEG after
loading dose of phenobarbital with no electrical seizures; possible subdural
hemorrhage and/or MCA infarction on MRI scans
Child neurologists 53.8 3.6 1.8 44.6 33.9 16.1
Neonatologists 31.7 2.7 5.4 37.8 29.7 24.3
Infarction: Apgar scores of 2 and 8; clinical seizures by 8 h; focal seizures on EEG at 10 h,
after 20 mg/kg phenobarbital; decreased electrical seizures after second dose of
phenobarbital; no electrical seizures on days 3 and 4; MRI/MRA scans with left
parietal and occipital lobe infarctions
Child neurologists 90.6 2.1 2.1 35.8 40.0 20.0
Neonatologists 84.9 6.0 7.0 33.0 39.0 15.0
HIE indicates hypoxic-ischemic encephalopathy; MRA, magnetic resonance angiography; EEG, electroencephalogram; CT, computed tomographic; MCA, middle cerebral artery; GBS, group B
streptococcus; CSF, cerebrospinal fluid; NR, no response given to the question about duration.

months of age with febrile seizures. Importantly, there
was no difference at initial or later follow-up evaluations
in the frequency of recurrent febrile seizures or later
nonfebrile seizures.15 In addition, there were significant
differences in subsequent neurodevelopmental assess-
ments in the short term and in the longer term between
the 2 groups, with the children who were treated with
phenobarbital for 2 years experiencing worse outcomes.
Because the prevention of seizure recurrence was the
reason why children with febrile seizures were being
treated with phenobarbital, this practice has been aban-
doned.
Compared with the results of surveys of practice per-
formed 15 years5 and 25 years4 ago, the current survey
confirms the trend toward shorter durations of pheno-
barbital use after resolution of neonatal seizures. How-
ever, this remains a widespread practice. Although prac-
titioners may report that they never or rarely continue
phenobarbital treatment after discharge, their inclina-
tion, when they are presented with specific clinical cases,
may be to use phenobarbital as prophylaxis for recurrent
seizures more often than not. The clinical vignettes in
the survey were chosen to represent a range of severities
and to mirror the spectrum and frequencies of causes
seen in practice. Even allowing for the possibility that
the scenarios included in the survey were more “serious”
or complex than those seen in everyday practice, some
physicians who answered never to the question on over-
all usage responded that they would continue pheno-
barbital treatment after discharge for up to 4 of the 7
children described. Although practice has evolved to-
ward decreased duration of phenobarbital treatment af-
ter resolution of neonatal seizures, phenobarbital is still
prescribed for a significant proportion of patients.
This survey was intended to reflect current practices
of both neonatologists and pediatric neurologists in a
wide variety of settings across the United States. We
chose not to limit the participants to those in academic
centers and thus did not target either training program
directors or division chiefs. Instead, we chose to send the

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survey to a randomly selected group of board-certified
physicians, in an attempt to decrease bias related to age,
practice location or type, gender, or affiliation with
training programs. Our response rate of 20%, despite
multiple reminders, was lower than we hoped for. Al-
though response rates generally are thought to be re-
lated to response bias, there is evidence that this may not
be the case.16 We acknowledge that the survey was
lengthy and demanded careful thought. This was
brought up during pilot-testing of the survey, and sev-
eral people at professional meetings admitted that this
was a primary barrier to completion of the survey. An-
other comment heard repeatedly is that requests for
surveys for specialists are now very commonplace and,
over time, all forms of surveys have had lower response
rates. Also, we chose not to compensate individuals for
completion of the survey.
Examination of the characteristics of the respondents
and nonrespondents in our study suggested that they
were nearly identical in their geographic distribution.
Other characteristics, such as whether the practitioners
were in academic or private practice, were more difficult
to compare, given the basic information (name and ad-
dress) provided by the American Board of Medical Spe-
cialties. In our analyses, however, no aspect of work
setting (academic affiliation, size of NICU, presence of
training programs, or geographic location) or training
(year of training) was associated with preferences to
prescribe phenobarbital prophylaxis. Therefore, we
think that the data from this sample of almost 250 phy-
sicians who currently care for infants with neonatal
seizures are representative of overall (and admittedly
inconsistent) practices at this time.
Animal models suggest that the neonatal brain is
vulnerable to repeated seizures.17–20 However, exposure
of the developing brain to phenobarbital for prolonged
periods may have deleterious consequences.14,15,21 Ex-
trapolation from the results of a randomized, clinical trial
of phenobarbital prophylaxis after febrile seizures in
children suggests that phenobarbital may be ineffective
in preventing seizure recurrence and may affect brain
development adversely.14,15 Therefore, a randomized,
clinical trial is needed to determine whether outcomes
are improved or impaired for infants who continue phe-
nobarbital treatment in the absence of continuing sei-
zure activity.
ACKNOWLEDGMENTS
This survey was supported by a Clinical Trials Planning
Grant (R34 HD050102) awarded to Dr Guillet.
We appreciate the time and effort of all those who
provided input during development of the questionnaire
and of Whitney Beck, a participant in the University of
Rochester Summer Research Program for Undergradu-
ates.
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PEDIATRICS Volume 122, Number 4, October 2008 735
 Prophylactic Phenobarbital Administration After Resolution of Neonatal
Seizures: Survey of Current Practice
Ronnie Guillet and Jennifer M. Kwon
Pediatrics 2008;122;731-735
DOI: 10.1542/peds.2007-3278
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