Postnatal Steroids and Febrile Seizure

Susceptibility in Preterm Children

Yi-Fang Tu, MD, PhD,a,b Lan-Wan Wang, MD, PhD,c,d Shan-Tair Wang, MD, PhD,e Tsu-Fu Yeh, MD,d Chao-Ching Huang, MDa,d,f

OBJECTIVE: To investigate risk factors, seizure characteristics, and outcomes of febrile seizure

abstract

(FS) in children born very preterm.

METHODS: This study used a prospective registry data set of 844 preterm infants (birth

weight <1500 g and gestational age <32 weeks) admitted to NICUs from 2001 to 2009 in
southern Taiwan. We investigated the prevalence, risks, seizure patterns, and outcomes of
FS in children aged 5 years.
RESULTS: Among 575 children (follow-up rate, 85.8%) followed up for 5 years, 35 (6.1%)
developed FS. The FS and non-FS groups were comparable regarding their mean gestational
age, birth weight, 5-minute Apgar score <6, and prenatal and postnatal complications. No
difference was observed in the use of prenatal corticosteroids between the 2 groups. The
FS group had a significantly higher rate of postnatal corticosteroid treatment than the
non-FS group, even after adjusting for confounding factors (odds ratio, 5.4 [95% confidence
interval, 1.915.8]; P = .006). No differences were observed in IQs or subsequent epilepsy
rates between the 2 groups. Although no difference was observed in the age of FS onset
or neurodevelopmental outcomes between the 2 groups, children with FS who received
postnatal corticosteroid treatment had a significantly lower mean body temperature
during the first FS attack compared with those who did not receive postnatal corticosteroid
treatment (38.6 0.4C vs 39.2 0.6C; P = .034).
CONCLUSIONS: Children born very preterm have a higher rate of FS, and postnatal

corticosteroid treatment was associated with FS susceptibility in these children.

aDepartment of Pediatrics, National Cheng Kung University Hospital, bInstitute of Clinical Medicine, and eInstitute
of Gerontology, College of Medicine, National Cheng Kung University, Tainan, Taiwan cDepartment of Pediatrics,
Chi Mei Medical Center, Tainan, Taiwan; and Departments of dPediatrics, College of Medicine, and fDepartment
of Pediatrics, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

Dr Tu designed the study, interpreted the data, and drafted the manuscript; Dr S.T. Wang and Dr
L.W. Wang performed statistical data analysis and interpretation; Dr Yeh interpreted the data and
critiqued the manuscript; Dr Huang conceptualized the study, interpreted the data, and revised
the manuscript; and all authors approved the nal manuscript as submitted and agree to be
accountable for all aspects of the work.
DOI: 10.1542/peds.2015-3404
Accepted for publication Jan 26, 2016
Address correspondence to Chao-Ching Huang, MD, Department of Pediatrics, College of Medicine,
Taipei Medical University, #250, Wu-Hsing St, Hsin-Yi District, Taipei City, 11031, Taiwan. E-mail:
huangped@tmu.edu.tw

WHATS KNOWN ON THIS SUBJECT: Febrile seizure

(FS) is a common neurologic disorder in children.
Low birth weight and perinatal complications are
risk factors for FS. No population study has focused
on FS in a preterm population, which has a higher
rate of perinatal and neonatal complications.
WHAT THIS STUDY ADDS: The cumulative incidence
of FS was high (6.1%) in 5-year-old children who
were born very preterm. Postnatal corticosteroid
treatment increased the FS risk and seizure
susceptibility during febrile illness in children born
very preterm.

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright 2016 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant
to this article to disclose.

To cite: Tu Y, Wang L, Wang S, et al. Postnatal Steroids

and Febrile Seizure Susceptibility in Preterm Children.
Pediatrics. 2016;137(4):e20153404

Downloaded from by guest on January 22, 2017

PEDIATRICS Volume 137, number 4, April 2016:e20153404

ARTICLE

Febrile seizure (FS) is the most

common neurologic disorder in
children, with an incidence of 2%
to 5% in children aged <5 years.1,2
Epilepsy develops in 2% to 6% of
children with a history of FS.1,2 In
addition to genetic factors, biological
and environmental factors are critical
sources of risk for FS. Previous studies
have shown that maternal illness, low
birth weight, perinatal complications
or medications, and certain neonatal
characteristics increase the risk of
FS.37 Moreover, FS risk is higher in
children born with a low gestational
age and perinatal complications or
those requiring perinatal medication,
suggesting that exposure to adverse
events in early life can predispose
young children to FS.8
Advances in neonatal intensive care
have improved the survival rate of
very preterm infants; however, the
incidence rate of neurodevelopmental
impairments is high.9 Preterm infants
often experience hypoxic-ischemic
and infectious insults during the
prenatal, perinatal, and postnatal
periods.10 Adverse events in the
early life of preterm infants may
therefore increase the occurrence of
FS. A casecontrol study of seizures
at a university hospital found that the
incidence of FS was 13.5% (8 of 59) in
children born very preterm, compared
with 5% (3 of 60) in term control
children.11 However, to the best of
our knowledge no population study
has focused on FS in children born
very preterm. The goal of the present
study, therefore, was to explore the
risk factors, seizure characteristics,
and neurodevelopmental outcome
of FS in young children born very
preterm by using a prospective
registry data set of preterm infants in
southern Taiwan.

METHODS
Study Population
This prospective study enrolled
844 very preterm infants (birth
weight <1500 g and gestational age

<32 weeks) admitted to the NICUs of

4 tertiary referral centers in Tainan
City, southern Taiwan, from June
2001 to December 2009. Infants
with congenital or chromosomal
anomalies and those who died before
discharge were excluded. Data on
demographic factors and medical
complications during the prenatal,
perinatal, and postnatal periods were
collected after obtaining parental
consent. After discharge, all infants
were followed up at 6, 12, and 24
months and again at 5 years. During
the follow-up visits, pediatricians
performed neuromotor examinations,
and psychologists administered
developmental assessment tests.10,
12 Parents were interviewed and
completed a questionnaire on the
seizure history of their children.
This follow-up study was approved
by the institutional review board
of National Cheng Kung University
Hospital. Informed consent was
obtained from the parents of preterm
infants.

Neurodevelopmental Outcome
Assessment
At 6, 12, and 24 months, cognitive
and motor outcomes were assessed
by using the mental and psychomotor
development indices of the Bayley
Scales of Infant Development
Second Edition.10 The Chinese
version of the Wechsler Preschool
and Primary Scale of Intelligence
Revised was used to assess the
verbal, performance, and full-scale
IQs of 5-year-old children born very
preterm.

Parent Interview and Questionnaire

At the follow-up visits, the parents
completed a questionnaire on their
childs history of FS or afebrile
seizure (including related seizure
types) and medication used. After
the assessment, the pediatrician
examined the responses and
discussed the history and neurologic
findings with the parents. Medical
records were further reviewed in
Downloaded from by guest on January 22, 2017

cases in which a history of seizures

was reported.13

Denition of FS
FS is defined as a seizure occurring
in children aged between 6 months
and 5 years that was associated with
fever (body temperature >38C)
not caused by infection of the
central nervous system. Diagnosis
of FS cannot be made for patients
with a history of neonatal seizures,
unprovoked seizures, or other
acute symptomatic seizures.1,2,13
Simple FS is characterized by single,
generalized, and brief seizures
(<15 minutes), whereas complex FS
is characterized by focal onset and
prolonged duration (>15 minutes) or
the occurrence of multiple seizures
within 24 hours.14 Febrile status
epilepticus is defined as an FS lasting
>30 minutes.

Denition of Predictor Variables

Predictor variables of FS were
categorized according to FS
occurrence during the prenatal,
perinatal, or postnatal period. During
the prenatal period, gestational
diabetes mellitus was defined as
any degree of glucose intolerance
with onset or first recognition
during pregnancy.10,15 Preeclampsia
was defined as pregnancy-induced
hypertension (arterial blood
pressure >140/90 mm Hg) during
the second half of gestation. The use
of prenatal magnesium sulfate or
corticosteroids was recorded. During
the perinatal period, prolonged
rupture of membranes was defined
as the occurrence of ruptures >18
hours before delivery. During the
postnatal period, infants with
respiratory distress syndrome who
received mechanical ventilation
and those with symptomatic
patent ductus arteriosus who
required indomethacin therapy or
surgical ligation were recorded.
Bronchopulmonary dysplasia
was defined as a supplemental

TU et al

total of 575 children (follow-up rate,

85.8%) were available for analysis at
the age of 5 years (mean SD, 5.0
0.1 years). Among them, 36 patients
developed FS, although 1 child was
excluded because of a history of
neonatal seizure, thus yielding an FS
prevalence rate of 6.1% (35 of 575)
in young children born very preterm
(Fig 1).

FIGURE 1
Flowchart of the recruitment of very preterm infants admitted to NICUs and follow-up of the infants
who survived to the age of 5 years.

oxygen requirement at 36 weeks of

postconception age.16 Retinopathy of
prematurity was graded into 5 stages
(IV) according to the International
Classification of Retinopathy of
Prematurity.17 Intraventricular
hemorrhage was classified
into 4 grades (IIV), and cystic
periventricular leukomalacia was
defined as periventricular echolucent
cystic lesions on ultrasonography.18,19
Preterm infants with evolving or
established bronchopulmonary
dysplasia were treated with lowdose hydrocortisone for 12 days
(1 mg/kg/d for 9 days followed
by 0.5 mg/kg/d for 3 days).20,21
The demographic factors assessed
included gender, gestational
age, birth weight, and head
circumference.

Statistical Analyses
Differences in demographic factors,
medical complications, and the
neurodevelopmental outcome

PEDIATRICS Volume 137, number 4, April 2016

between children born very preterm

who developed FS and those who
did not were determined by using
Fishers exact test for categorical
variables and the Mann-Whitney
U test for numerical variables. The
potential predictors with significance
levels of P < .05 in univariate analysis
or with clinical significance were
entered into a multivariate logistic
regression model to calculate odds
ratios (ORs) and 95% confidence
intervals (CIs). All analyses were
performed by using SPSS version
17 (IBM SPSS Statistics, IBM
Corporation, Armonk, NY).

RESULTS
Among the 844 very preterm infants
enrolled in this study, 165 (19.5%)
died before discharge from the NICU.
Among the 679 infants who survived,
7 infants with congenital anomalies
(3 with chromosomal anomalies and
4 with congenital brain anomalies)
were excluded, and another 97
infants were lost to follow-up. A
Downloaded from by guest on January 22, 2017

The mean age of FS onset was

2.7 1.3 years. The demographic
and medical factors of the FS and
non-FS groups are listed in Table
1. No significant differences were
observed in gender, mean gestational
age, or mean birth weight and head
circumference between the FS and
non-FS groups. The 2 groups were
comparable regarding maternal
complications during pregnancy (eg,
gestational diabetes, preeclampsia,
eclampsia), 5-minute Apgar score
(<6), and postnatal complications
related to preterm birth (eg,
respiratory distress syndrome
requiring surfactants, symptomatic
patent ductus arteriosus requiring
surgical ligation, retinopathy of
prematurity, bronchopulmonary
dysplasia, intraventricular
hemorrhage, cystic periventricular
leukomalacia). No difference was
observed in the use of prenatal
corticosteroids or magnesium sulfate
or postnatal indomethacin between
the 2 groups. The FS group had a
significantly higher rate of postnatal
corticosteroid treatment than the
non-FS group (OR, 5.4 [95% CI,
1.915.8]; P = .006).
We also examined the association
between postnatal corticosteroid
exposure and FS susceptibility
by using a multivariate logistic
regression model. After adjustment
for potential confounding factors
(gender, gestational age, birth
weight, 5-minute Apgar score <6,
bronchopulmonary dysplasia,
grade IIIIV intraventricular
hemorrhage, and cystic
periventricular leukomalacia),
postnatal corticosteroid therapy still

demonstrated prognostic significance

for FS (OR, 7.9 [95% CI, 2.030.7];
P = .003) (Table 2).
At follow-up, no significant difference
was observed in the cognitive or
motor developmental scores at
24 months or in the IQs at 5 years
between the FS and non-FS groups.
The 2 groups were also comparable
regarding the rate of subsequent
epilepsy (Table 3). Moreover,
we investigated the association
of postnatal corticosteroid use
with the neurodevelopmental
outcome and seizure characteristics
of children with FS (Table 4).
In the FS group, children with
postnatal corticosteroid treatment
did not have worse 24-month
neurodevelopmental outcomes
or IQs at 5 years of age compared
with those without postnatal
corticosteroid treatment. No
difference was observed in the age of
FS onset, occurrence of complex FS or
febrile status epilepticus, recurrence
rate of FS, or development of epilepsy
between the 2 groups. However,
in the FS group, children with
postnatal corticosteroid treatment
had a significantly lower mean body
temperature during the first FS attack
than did those without postnatal
corticosteroid treatment (38.6
0.4C vs 39.2 0.6C; P = .034).

DISCUSSION
Based on our research, the present
study is the first to focus specifically
on FS in a population of children born
very preterm. Our study revealed a
high cumulative FS incidence of 6.1%
in children born very preterm. The FS
and non-FS groups were comparable
regarding maternal complications
during pregnancy, gestational
age, postnatal complications, and
neurodevelopmental outcomes
at 5 years of age. However, the
children in the FS group had a
significantly higher rate of postnatal
corticosteroid treatment. In the
FS group, children with postnatal

TABLE 1 Demographic Factors and Complications During the Prenatal, Perinatal, and Postnatal
Periods in Children Born Very Preterm With or Without FS
Characteristic
Demographic data
Male sex
Gestational age, wk
Birth weight, g
Head circumference, cm
Prenatal complications
Gestational diabetes
Preeclampsia/eclampsia
Perinatal complications
Prolonged rupture of membranes
5-min Apgar score <6
Postnatal complications
Respiratory distress syndrome
Patent ductus arteriosus
Bronchopulmonary dysplasia
Retinopathy of prematurity (stage III or
higher)
Grade III/IV IVH
Cystic periventricular leukomalacia
Medical treatments
Prenatal period
Magnesium sulfate
Corticosteroids
Postnatal period
Corticosteroids
Indomethacin
Oxygen, d
Ventilator, d

FS (n = 35)

Non-FS
(n = 539)

OR (95% CI)

22 (62.9)
28.8 2.7
1120 245
25.9 2.1

285 (52.8)
29.0 2.8
1141 273
25.8 2.3

.296
.886
.563
.737

1 (2.8)
4 (11.4)

8 (1.5)
79 (14.7)

1.9 (0.215.8)
0.7 (0.32.1)

.440
.805

11 (31.4)
4 (11.4)

164 (30.4)
82 (15.2)

1.0 (0.52.2)
0.7 (0.22.0)

.923
.633

17 (48.5)
14 (40.0)
11 (31.4)
5 (14.3)

297 (55.1)
174 (32.3)
120 (22.3)
47 (8.7)

0.8 (0.41.6)
1.4 (0.72.8)
1.6 (0.83.3)
1.7 (0.64.6)

.594
.360
.220
.237

3 (8.6)
2 (5.7)

30 (5.6)
24 (4.6)

1.6 (0.55.4)
1.3 (0.35.6)

.448
.673

3 (8.6)
20 (57.1)

49 (9.1)
308 (57.1)

0.9 (0.33.1)
1.0 (0.52.0)

.888
.910

5 (14.3)
10 (28.6)
38.3 32.1
8.4 15.3

16 (3.0)
151 (28.0)
40.4 31.9
7.2 12.9

5.4 (1.915.8)
1.0 (0.52.1)

.006
.997
.724
.642

Data are presented as n (%) or mean SD. IVH, intraventricular hemorrhage.

TABLE 2 Postnatal Corticosteroids and the Risk of FS in Children Born Very Preterm
Characteristic
Male sex
Gestational age, wk
Birth weight, g
5-min Apgar score <6
Bronchopulmonary dysplasia
Postnatal corticosteroids
Grade III/IV IVH
cPVL

Crude OR (95% CI)

0.7 (0.22.0)
1.6 (0.83.3)
5.4
(1.915.8)
1.6 (0.55.4)
1.3 (0.35.6)

Adjusted OR (95% CI)

.296
.886
.563
.633
.220
.006

0.5 (0.21.8)
1.2 (0.43.8)
7.9 (2.030.7)

.524
.696
.132
.311
.715
.003

.448
.673

1.7 (0.56.3)
1.1 (0.25.5)

.434
.897

cPVL, cystic periventricular leukomalacia; IVH, intraventricular hemorrhage.

TABLE 3 Neurodevelopmental Outcome at 24 Months and 5 Years in Children Born Very Preterm With
or Without FS
Outcome
Neurodevelopmental outcome
24-mo BSID-II
Mental development index
Psychomotor development index
5-y WPPSI-R
Performance IQ
Verbal IQ
Full-scale IQ
Subsequent epilepsy

FS (n = 35)

Non-FS (n = 539)

87.1 15.6
86.2 18.0

86.4 16.8
87.6 16.3

.980
.754

85.3 17.2
87.6 15.3
85.3 15.2
2 (5.7)

85.7 16.0
90.8 14.8
87.4 14.7
13 (2.4)

.803
.341
.595
.231

Data are presented as n (%) or mean SD. BSID-II, Bayley Scales of Infant DevelopmentSecond Edition; WPPSI-R, Wechsler
Preschool and Primary Scale of IntelligenceRevised, Chinese version.

Downloaded from by guest on January 22, 2017

TU et al

TABLE 4 Association of Postnatal Corticosteroids With the Neurodevelopmental Outcome and Seizure
Characteristics of Children Born Very Preterm With FS
Outcome

Neurodevelopment outcome
24-mo BSID-II
Mental development index
Psychomotor development index
5-y WPPSI-R
Performance IQ
Verbal IQ
Full-scale IQ
First FS characteristics
Simple FS
Complex FS
Febrile status epilepticus
Age of onset, mo
Body temperature at attack, C
Recurrence rate of FS
Development of epilepsy after FS

Postnatal Corticosteroids

Yes (n = 5)

No (n = 30)

84.8 5.8
82.8 8.6

87.5 16.8
86.8 19.2

.448
.163

81.8 14.2
84.8 12.9
81.6 13.5

85.8 17.8
88.3 15.8
85.9 15.6

.477
.257
.421

5 (100)
0
0
36.4 17.2
38.6 0.4
1 (20)
0

26 (86.7)
4 (13.3)
1 (3.3)
32.4 16.5
39.2 0.6
11 (36.7)
2 (6.7)

.999
.999
.999
.620
.034
.640
.999

Data are presented as n (%) or mean SD. BSID-II, Bayley Scales of Infant DevelopmentSecond Edition; WPPSI-R, Wechsler
Preschool and Primary Scale of IntelligenceRevised, Chinese version.

corticosteroid treatment did not have

worse neurodevelopmental outcomes
compared with those without
postnatal corticosteroid treatment.
In addition, in the FS group, children
with postnatal corticosteroid
treatment had significantly lower
body temperatures during the
first FS attack than those without
postnatal corticosteroid treatment.
Our findings suggest that children
born very preterm are susceptible
to FS, and postnatal corticosteroid
treatment is associated with the FS
risk and seizure susceptibility during
febrile illness in children born very
preterm.
The incidence of FS is 2% to 5% in
children aged <5 years, with the
peak incidence occurring in the
second year of life. The prevalence
of FS in Europe and the United
States is estimated to be 2% to 5%
in the pediatric population, whereas
the prevalence is 1.5% in other
countries such as China.1 A previous
population study in southern Taiwan
(in which only 2% of the patients
were born preterm) revealed a
cumulative FS incidence of 2.4%
in children aged 3 years.13 Other
studies have also shown that low
birth weight and prematurity are

PEDIATRICS Volume 137, number 4, April 2016

risk factors for FS.38 In the present

study, we found that the cumulative
incidence of FS was 4% (23 of 575)
at the age of 3 years in children
born very preterm and 6.1% (35 of
575) in those at age 5 years; both
of these outcomes are considerably
higher than the reported incidence
in the general population.1,8,13 The
reason for this discrepancy remains
unknown. FS may be associated with
the vulnerability of the developing
brain or complications or medication
used during early life.
Premature infants are at a high
risk of various hypoxic-ischemic
and infectious insults because
of pulmonary immaturity,
cardiovascular insufficiency, and
sepsis.10 Hypoxic-ischemic or
infectious events in early life can
alter neuronal excitability and are
associated with seizure susceptibility
in later life.22,23 Therefore, the
increase in FS occurrence in children
born very preterm could be due to
several related adverse events of
hypoxia-ischemia or infection during
early life.
In addition, studies have indicated
that early changes in the function and
structure of the neural system after
Downloaded from by guest on January 22, 2017

stress contribute to susceptibility

to FS and epilepsy.24,25 A previous
study suggested that the excitatory
neuropeptide corticotropinreleasing hormone (CRH), the
genetic expression of which is
activated by stress, is associated with
developmental seizures.26 CRH, a
proconvulsive molecule, functions
not only as a hypothalamic-releasing
factor but also as a modulator of
limbic circuit excitation. Neuronal
populations that synthesize CRH or
possess CRH receptors are abundant
in the limbic system, particularly
the amygdala and hippocampus.27
Young children may be particularly
susceptible to seizure because the
CRH receptor is the main receptor
bound during stressful experiences in
young animals,28 and increased levels
of CRH, CRH receptors, and CRHbinding protein have been observed
postmortem in the brains of children
with generalized epilepsy.29 CRH is
a likely candidate for modulating
excitability in response to triggers
such as fever in the developing
brain.26 These findings suggest that
the increased risk of FS in children
born very preterm may be related
to characteristic neural substrates
such as the upregulated CRH system
induced by early-life stress in the
immature brain.
During the neonatal period,
corticosteroids are commonly
used to treat bronchopulmonary
dysplasia, which is a common cause
of long-term adverse pulmonary
and neurodevelopment outcomes
in preterm infants.12,30 Our study
found that postnatal corticosteroid
exposure is associated with a high FS
risk and low seizure susceptibility
during febrile illness in children
born very preterm; however,
the underlying pathophysiology
remains unknown. Hippocampal
glucocorticoid receptors and
CRH, which are involved in
neuronal seizure susceptibility
and behavior, have been identified
as possible targets of early-life

corticosteroid effects. Excess earlylife glucocorticoid exposure may

lead to decreased glucocorticoid
receptor expression and increased
CRH expression in neurons.31
These findings suggest that the
use of neonatal corticosteroids
may be associated with a risk of FS
by upregulating CRH in the brain
regions involved in the circuitry that
processes stressful stimuli.26
Furthermore, in numerous
animal models, corticosterone
supplementation has led to
morphologic or functional changes
in hippocampal structures that
are similar to those in patients
with temporal lobe epilepsy.24,
32 Administration of high-dose
glucocorticoids has resulted in
hippocampal atrophy, loss of
pyramidal cells in the CA1 and
CA3 regions, and inhibition of
dentate granule cell neurogenesis.33
These abnormal changes are
supported by the observation that
early-life stress facilitates seizure
development.34 This effect on seizure
development can be mediated by
corticosterone: the facilitating effect
of corticosterone on chemicalinduced status epilepticus in rat
pups is inhibited by a corticosterone
synthesis blocker, thus confirming
the crucial role of corticosterone
in seizure susceptibility.35 High
corticosterone levels in early

life are believed to irreversibly

impair the inhibitory control of the
hypothalamicpituitaryadrenal axis;
the disinhibition of this chronic stress
axis may induce upregulation of CRH
from the paraventricular nucleus.26
In addition, Qaheri et al36 reported
that neonatal dexamethasone
exposure in rat pups decreased the
convulsion threshold in adult life.
Collectively, these reports regarding
corticosteroid use during early life
support our finding that postnatal
corticosteroid treatment reduces
the seizure threshold during febrile
illness in children born very preterm.
Because our results might be post hoc
findings based on the small sample
size, and other unknown confounding
factors may exist, a long-term
follow-up study of FS with a larger
sample of children born very preterm
is necessary to validate our results.
The survival status was a potential
common effect of corticosteroid use
and FS. Because we included only
survivors, we could have introduced
selection bias that rendered spurious
associations between the steroid
use and FS. Nonetheless, this bias
may have had only a minor effect on
our finding because the mortality
rate of FS is very rare.37 Regarding
model selection, we considered that
multiplicity testing might increase
the false-positive rate in our study.
However, our main finding remained

significant after adjusting for type

I errors. An experimental study of
hyperthermia-induced seizures
may delineate the neurobiologic
mechanisms underlying increased
seizure susceptibility after postnatal
corticosteroid treatment.

CONCLUSION
The present study indicates that
children born very preterm are
susceptible to FS, and that the
use of postnatal corticosteroids is
associated with the FS risk in these
children.

ACKNOWLEDGMENTS
We express our gratitude to the
patients, their caretakers, and the
clinical and laboratory staff from
National Cheng Kung University
Hospital. We also thank Ying-Chia
Wu, Wen-Jung Chang, Ming-Yang Su,
and Wen-Hao Yu for their valuable
assistance.

ABBREVIATIONS
CI:confidence interval
CRH:corticotropin-releasing
hormone
FS:febrile seizure
OR:odds ratio

FUNDING: Supported by grants from National Cheng Kung University Hospital (NCKUH-10105002 and 10407014) and the Taiwan National Science Council (NSC 1002314-B-006-045 MY2 and 103-2314-B-006-017-MY3; MOST 103-2314-B-038-062-MY3).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conicts of interest to disclose.

REFERENCES
1. Baram TZ, Shinnar S. Febrile Seizures.
San Diego, CA: Academic Press;
2002
2. Patterson JL, Carapetian SA, Hageman
JR, Kelley KR. Febrile seizures. Pediatr
Ann. 2013;42(12):249254
3. Visser AM, Jaddoe VW, Hofman A,
et al. Fetal growth retardation and
risk of febrile seizures. Pediatrics.
2010;126(4). Available at: www.

pediatrics.org/cgi/content/full/126/4/
e919

Pre-eclampsia and febrile convulsions.

Arch Dis Child. 2003;88(8):726727

4. Vestergaard M, Wisborg K, Henriksen

TB, Secher NJ, Ostergaard JR, Olsen
J. Prenatal exposure to cigarettes,
alcohol, and coffee and the risk
for febrile seizures. Pediatrics.
2005;116(5):10891094

6. Landreau-Mascaro A, Barret B, Mayaux

MJ, Tardieu M, Blanche S; French
Perinatal Cohort Study Group. Risk
of early febrile seizure with perinatal
exposure to nucleoside analogues.
Lancet. 2002;16:359(9306):583584

5. Vestergaard M, Basso O, Henriksen

TB, Ostergaard J, Secher NJ, Olsen J.

7. Nelson KB, Ellenberg JH. Prenatal

and perinatal antecedents of

Downloaded from by guest on January 22, 2017

TU et al

febrile seizures. Ann Neurol.

1990;27(2):127131

hemorrhage: a study of infants with

birth weights less than 1,500 gm. J
Pediatr. 1978;92(4):529534

29. Wang W, Dow KE, Fraser DD. Elevated

corticotropin releasing hormone/
corticotropin releasing hormone-R1
expression in postmortem brain
obtained from children with generalized
epilepsy. Ann Neurol. 2001;50(3):404409

8. Vestergaard M, Christensen J.
Register-based studies on febrile
seizures in Denmark. Brain Dev.
2009;31(5):372377

19. Govaert P, de Vries LS. An Atlas of

Neonatal Brain Sonography. 2nd ed.
London, UK: MacKeith; 2010

9. Volpe JJ. Brain injury in premature

infants: a complex amalgam of
destructive and developmental
disturbances. Lancet Neurol.
2009;8(1):110124

20. Committee on Fetus and Newborn.

Postnatal corticosteroids to treat
or prevent chronic lung disease
in preterm infants. Pediatrics.
2002;109(2):330338

30. Gupta S, Parasanth K, Chen CM, Yeh

TF. Postnatal corticosteroids for
prevention and treatment of chronic
lung disease in the preterm newborn.
Int J Pediatr. 2012;2012:315642

21. Watterberg KL, Gerdes JS, Gifford

KL, Lin HM. Prophylaxis against
early adrenal insufciency to
prevent chronic lung disease in
premature infants. Pediatrics.
1999;104(6):12581263

31. Levitt NS, Lindsay RS, Holmes MC,

Seckl JR. Dexamethasone in the
last week of pregnancy attenuates
hippocampal glucocorticoid receptor
gene expression and elevates blood
pressure in the adult offspring
in the rat. Neuroendocrinology.
1996;64(6):412418

10. Wang LW, Lin YC, Wang ST, Yeh TF,

Huang CC. Hypoxic/ischemic and
infectious events have cumulative
effects on the risk of cerebral palsy in
very-low-birth-weight preterm infants.
Neonatology. 2014;106(3):209215
11. Herrgrd EA, Karvonen M, Luoma
L, et al. Increased number of
febrile seizures in children born
very preterm: relation of neonatal,
febrile and epileptic seizures and
neurological dysfunction to seizure
outcome at 16 years of age. Seizure.
2006;15(8):590597
12. Yeh TF, Lin YJ, Lin HC, et al. Outcomes
at school age after postnatal
dexamethasone therapy for lung
disease of prematurity. N Engl J Med.
2004;350(13):13041313
13. Huang CC, Wang ST, Chang YC, Huang
MC, Chi YC, Tsai JJ. Risk factors for a
rst febrile convulsion in children: a
population study in southern Taiwan.
Epilepsia. 1999;40(6):719725
14. Shinnar S. Febrile seizures. In:
Swaiman KF, Aschwal S, Ferriero DM,
Schor NF, eds. Swaiman's Pediatric
Neurology. Vol 1. 5th ed. Philadelphia,
PA: Elsevier/Saunders; 2012:790797
15. American Diabetes Association.
Diagnosis and classication of
diabetes mellitus. Diabetes Care.
2009;32(suppl 1):S62S67
16. Jobe AH, Bancalari E.
Bronchopulmonary dysplasia.
Am J Respir Crit Care Med.
2001;163(7):17231729
17. An international classication of
retinopathy of prematurity. Pediatrics.
1984;74(1):127133
18. Papile LA, Burstein J, Burstein R,
Kofer H. Incidence and evolution of
subependymal and intraventricular

PEDIATRICS Volume 137, number 4, April 2016

22. Glass HC, Hong KJ, Rogers EE, et al.

Risk factors for epilepsy in children
with neonatal encephalopathy. Pediatr
Res. 2011;70(5):535540
23. Galic MA, Riazi K, Heida JG, et al.
Postnatal inammation increases
seizure susceptibility in adult rats. J
Neurosci. 2008;28(27):69046913
24. Jols M. Stress, the hippocampus,
and epilepsy. Epilepsia. 2009;50(4):
586597
25. Greenwood R, Golding J, Ross E, Verity
C. Prenatal and perinatal antecedents
of febrile convulsions and afebrile
seizures: data from a national cohort
study. Paediatr Perinat Epidemiol.
1998;12(suppl 1):7695

32. Barrot M, Abrous DN, Marinelli M,

Roug-Pont F, Le Moal M, Piazza
PV. Inuence of glucocorticoids on
dopaminergic transmission in the rat
dorsolateral striatum. Eur J Neurosci.
2001;13(4):812818
33. McEwen BS, Magarinos AM. Stress and
hippocampal plasticity: implications
for the pathophysiology of affective
disorders. Hum Psychopharmacol.
2001;16(S1):S7S19
34. Sawyer NT, Escayg A. Stress and
epilepsy: multiple models, multiple
outcomes. J Clin Neurophysiol.
2010;27(6):445452

26. Baram TZ, Hatalski CG. Neuropeptidemediated excitability: a key triggering

mechanism for seizure generation in
the developing brain. Trends Neurosci.
1998;21(11):471476

35. Lai MC, Yang SN, Huang LT. Neonatal

isolation enhances anxiety-like
behavior following early-life
seizure in rats. Pediatr Neonatol.
2008;49(2):1925

27. Chen Y, Andres AL, Frotscher M,

Baram TZ. Tuning synaptic
transmission in the hippocampus
by stress: the CRH system. Front Cell
Neurosci. 2012;6:13

36. Qaheri SN, Ali AB, Alalwaan AA,

Ahmed FA, Ahmed MM, Kamal AH.
Neonatal dexamethasone exposure
in rats resulted in hippocampal
learning and memory defects with
decreased convulsion threshold later
in adult life. Neurosciences (Riyadh).
2013;18(4):388390

28. Baram TZ, Chalmers DT, Chen C,

Koutsoukos Y, De Souza EB. The CRF1
receptor mediates the excitatory
actions of corticotropin releasing
factor (CRF) in the developing rat
brain: in vivo evidence using a
novel, selective, non-peptide CRF
receptor antagonist. Brain Res.
1997;770(12):8995

Downloaded from by guest on January 22, 2017

37. Vestergaard M, Pedersen MG,

Ostergaard JR, Pedersen CB, Olsen
J, Christensen J. Death in children
with febrile seizures: a populationbased cohort study. Lancet.
2008;372(9637):457463

Postnatal Steroids and Febrile Seizure Susceptibility in Preterm Children

Yi-Fang Tu, Lan-Wan Wang, Shan-Tair Wang, Tsu-Fu Yeh and Chao-Ching Huang
Pediatrics 2016;137;; originally published online March 24, 2016;
DOI: 10.1542/peds.2015-3404
Updated Information &
Services

including high resolution figures, can be found at:

/content/137/4/e20153404.full.html

References

This article cites 32 articles, 8 of which can be accessed free

at:
/content/137/4/e20153404.full.html#ref-list-1

Subspecialty Collections

This article, along with others on similar topics, appears in

the following collection(s):
Fetus/Newborn Infant
/cgi/collection/fetus:newborn_infant_sub
Neonatology
/cgi/collection/neonatology_sub
Neurology
/cgi/collection/neurology_sub
Neurologic Disorders
/cgi/collection/neurologic_disorders_sub

Permissions & Licensing

Information about reproducing this article in parts (figures,

tables) or in its entirety can be found online at:
/site/misc/Permissions.xhtml

Reprints

Information about ordering reprints can be found online:

/site/misc/reprints.xhtml

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright 2016 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from by guest on January 22, 2017

Postnatal Steroids and Febrile Seizure Susceptibility in Preterm Children

Yi-Fang Tu, Lan-Wan Wang, Shan-Tair Wang, Tsu-Fu Yeh and Chao-Ching Huang
Pediatrics 2016;137;; originally published online March 24, 2016;
DOI: 10.1542/peds.2015-3404

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/137/4/e20153404.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2016 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from by guest on January 22, 2017