ARTICLE
EEG for Predicting Early Neurodevelopment in
Preterm Infants: An Observational Cohort Study
AUTHORS: Naoko Hayashi-Kurahashi, MD,a,b,c Hiroyuki
Kidokoro, MD,b,c,d Tetsuo Kubota, MD,b Koichi Maruyama,
MD,a,b Yuichi Kato, MD,b Toru Kato, MD,b,e Jun Natsume,
MD,c Fumio Hayakawa, MD,e Kazuyoshi Watanabe, MD,c,f
and Akihisa Okumura, MDg
aDepartment of Pediatric Neurology, Central Hospital of Aichi
Welfare Center for Persons with Developmental Disabilities,
Kasugai, Japan; bDepartment of Pediatrics, Anjo Kosei Hospital,
Anjo, Japan; cDepartment of Pediatrics, Nagoya University
Graduate School of Medicine, Nagoya, Japan; dDepartment of
Pediatrics, Washington University in St Louis, St Louis, Missouri;
eDepartment of Pediatrics, Okazaki City Hospital, Okazaki, Japan;
fFaculty of Health and Medical Science, Aichi Shukutoku
University, Nagakute, Japan; and gDepartment of Pediatrics,
Juntendo University Faculty of Medicine, Tokyo, Japan
KEY WORDS
EEG, preterm, neurodevelopmental
WHAT THIS STUDY ADDS: This study demonstrates precise
prognostic values of conventional EEG for predicting
neurodevelopmental outcome in the current perinatal care
setting. Additionally, its prognostic values are independent of
severe injury on neuroimaging and clinical risk factors.
abstract
ABBREVIATIONS
ASA—acute stage background EEG abnormality
CI—confidence interval
CP—cerebral palsy
CSA—chronic stage background EEG abnormality
DD—developmental delay
IVH—intraventricular hemorrhage
OR—odds ratio
PRS—positive rolandic sharp waves
PVL—periventricular leukomalacia
OBJECTIVE: To clarify the prognostic value of conventional EEG for the
identification of preterm infants at risk for subsequent adverse neurodevelopment in the current perinatal care and medicine setting.
All authors contributed to the planning of this study; Drs
Hayashi-Kurahashi, Kidokoro, Kubota, Maruyama, and Kato
assessed the cranial ultrasound, MRI, and the EEG findings; Drs
Hayashi-Kurahashi and Kidokoro performed the statistical
analyses; Dr Hayashi-Kurahashi wrote the first draft and Drs
Kidokoro, Watanabe, and Okumura revised it.
www.pediatrics.org/cgi/doi/10.1542/peds.2012-1115
doi:10.1542/peds.2012-1115
Accepted for publication Jun 5, 2012
Address correspondence to Hiroyuki Kidokoro, MD, Department
of Pediatrics, Washington University in St Louis, 660 South Euclid
Ave, St Louis, MO 63110. E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2012 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
WHAT’S KNOWN ON THIS SUBJECT: Previous studies suggest that
abnormal findings on conventional EEG during the neonatal
period are associated with death or severe brain injury in
preterm infants. However, large cohort studies on preterm EEG
for predicting later neurodevelopmental outcome remain scarce.
METHODS: We studied 780 EEG records of 333 preterm infants born
,34 weeks’ gestation between 2002 and 2008. Serial EEG recordings
were conducted during 3 time periods; at least once each within days
6 (first period), during days 7 to 19 (second period), and days 20 to 36
(third period). The presence and the grade of EEG background abnormalities were assessed according to an established classification
system. Neurodevelopmental outcomes were assessed at a corrected
age of 12 to 18 months.
RESULTS: Of the 333 infants, 33 (10%) had developmental delay and 34
(10%) had cerebral palsy. The presence of EEG abnormalities was significantly predictive of developmental delay and cerebral palsy at all 3
time periods: the first period (n = 265; odds ratio [OR], 4.5; 95%
confidence interval [CI], 2.2–9.4), the second period (n = 278; OR,
7.6; 95% CI, 3.6–16), and the third period (n = 237; OR, 5.9; 95% CI,
2.8–13). The grade of EEG abnormalities correlated with the incidence
of developmental delay or cerebral palsy in all periods (P , .001).
After controlling for other clinical variables, including severe brain
injury, EEG abnormality in the second period was an independent
predictor of developmental delay (OR, 3.2; 95% CI, 1.1–9.7) and cerebral palsy (OR, 6.8; 95% CI 2.0–23).
CONCLUSIONS: EEG abnormalities within the first month of life significantly predict adverse neurodevelopment at a corrected age of 12 to
18 months in the current preterm survivor. Pediatrics 2012;130:1–7
PEDIATRICS Volume 130, Number 4, October 2012
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Perinatal care and medicine in preterm
infants has made dramatic improvements over the past several decades.
However, preterm infants remain at high
risk for disabilities including cognitive,
motor, behavioral, emotional, and academic challenges, which occur in .50%
of children born extremely preterm.1
Early recognition of at-risk infants may
improve their neurodevelopmental outcomes because several neuroprotective
agents, such as caffeine and erythropoietin, are available to ameliorate
cerebral abnormalities in the preterm
population.2,3
Previous investigations in preterm
infants have shown that neonatal EEG
was predictive of neurodevelopmental
outcomes.4–6 However, those results
were from early studies conducted at
a time when the mortality rate and incidence of severe brain injury, such as
intraventricular hemorrhage (IVH) and
periventricular leukomalacia (PVL),
was high among preterm infants. Subsequent studies tended to focus on 1
specific characteristic of EEG abnormality to predict neurologic outcomes,
particularly the positive rolandic sharp
waves (PRS).7–9 However, PRS are rare
in current clinical practice, and a restricted assessment may underestimate
EEG abnormalities compared with a full
evaluation of background EEG abnormalities by using a comprehensive
classification system.
The aim of the current study was to determine the predictive value of conventional EEG for early neurodevelopmental
outcomes in the current perinatal care
and medicine/medical setting, with
a particular focus on EEG within the first
month of life.
METHODS
Participants
We recruited 436 preterm infants born
at 33 weeks’ gestation or less admitted
to the neonatal ICU in Anjo Kosei Hospital between February 2002 and April
2
2008. This hospital provides tertiary
level care for newborns in a district
with a population of ∼800 000. In total,
103 (24%) infants were excluded from
the study: 4 who had congenital chromosomal or cerebral anomalies, 8 who
had no EEG recordings during the study
period, 40 who were lost to follow-up,
13 who died within the first month of
life, 14 who died between the second
month of life and 12 months of corrected age, and 24 who had no developmental tests between 12 and 18
months of corrected age. Thus, the
current study included 333 infants for
whom adequate neurodevelopmental
outcome data were available at 12 to 18
months of corrected age. The findings
of EEG in 13 infants with PVL were
reported elsewhere10 and were also
included in this study.
Written informed consent for EEG recording was obtained from at least 1
parent of each infant. The study was
approved by the ethics committee of
Anjo Kosei Hospital.
EEG Recordings
At least 1 EEG recording was scheduled
for each of 3 time periods: within 72
hours of life, between days 7 and 14,
and 1 month after birth, which were
assigned on admission. All EEGs were
performed between 1 PM and 5 PM after
feeding by using a digital EEG system
(Nihon Kohden, Tokyo, Japan) and
recorded polygraphically along with an
electrocardiogram, respiratory movement, and electrooculogram at the
bedside for .40 minutes. At least 8
electrodes were placed at AF3, AF4, C3,
C4, O1, O2, T3, and T4, in accordance
with the international 10 to 20 system
as previously reported.10 Some of the
records were not obtained as scheduled, because the infant was in an unstable condition or hospital services
were not offered on the scheduled day.
Thus, EEGs recorded on days 1 to 6,
days 7 to 19, and days 20 to 36 were
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regarded as the first, second, and third
period, respectively.
EEG Assessment
A standardized grading system was
used to evaluate acute stage (ASA) and
chronic stage (CSA) background EEG
abnormalities in preterm infants as
previously described.11 ASA and CSA
were graded as mild, moderate, and
severe (Supplemental Information).10
ASA was characterized as suppressed
background activity with decreased
continuity, lower amplitude, and/or attenuated fast-wave background activity.
CSA was characterized by a disorganized
pattern (deformed d waves with abnormal sharp waves and abnormal
brushes) or as a dysmature pattern for
postmenstrual age.12,13 This classification was also applied to unilateral EEG
abnormalities. Additionally, the presence or absence of paroxysmal electrographic seizure activity was evaluated.
When 2 or more EEG recordings were
performed in a time period, the worst
ASA and CSA grades were used in the
study. Two of the authors independently evaluated all EEGs within 7 days
after the recording blinded to the clinical information. When the 2 observers’
judgment differed (,5% of the records), consensus was reached after
a discussion.
Neuroimaging
Cranial ultrasound with use of a 7.5-MHz
transducer was performed in all infants
every day during the first week of life
and thereafter at least twice a week
until discharge as routine care by
neonatologists. One of the authors
performed an additional cranial ultrasound to confirm the findings assessed
as abnormal or equivocal. Furthermore, 284 (85%) infants underwent MRI
at term equivalent age. Two authors
evaluated the cranial ultrasound and
MR images for the presence of grade III/
IV IVH or cystic PVL. IVH grading was
ARTICLE
defined according to the classification
of Papile et al.14 Cystic PVL was defined
as the presence of multiple cystic
lesions $3 mm in size in the bilateral
periventricular white matter.
Outcome Measurements
The infants’ neurodevelopmental outcome was assessed between 12 and 18
months of corrected age. The outcome
variables were developmental delay
(DD) or cerebral palsy (CP). DD was
diagnosed by using the Tsumori-Inage
Infant Developmental Scale or the Kyoto
Scale of Psychological Development
2001. These scales are standardized
and widely used developmental tests in
Japan.15,16 Significant DD was defined
as a developmental quotient of ,70 in
each developmental test. CP was diagnosed by pediatric neurologists
who had access to existing clinical
data for the children with the use of
standard criteria including the location of the impairment or body part
affected, such as hemiplegia or diplegia, and impairment of muscle tone
and reflexes; severity was assessed
based on gross motor function.17 Significant DD or CP was considered to be
an adverse neurodevelopmental outcome in the current study.
Statistical Analysis
Assuming a 25% incidence of EEG
abnormalities, we estimated a total
sample of n = 250 as having 80% statistical power to detect a difference of
proportion of 0.15 in outcome. The association between EEG abnormality
grade and the rate of outcome measures was determined by using the x2
test. The diagnostic accuracy of EEG
abnormalities was assessed by sensitivity, specificity, and positive and negative predictive values calculated from
contingency tables. Odds ratios (ORs)
and 95% confidence intervals (CIs) of
the x 2 analyses were a measure of the
strength of associations found in the
univariate analysis. A forced-entry multiple logistic regression model was used
to assess the association between EEG
abnormalities at each time period and
clinical confounders. The following variables were entered in the model as
covariants: EEG abnormalities in each
period, severe brain injury detected by
cranial ultrasound or MRI (ie, grade III/IV
IVH or cystic PVL), gestational age at
birth ,28 weeks, small for gestational
age, male gender, multiple birth, 5-minute Apgar score of ,6, inotrope use
(dopamine and/or dobutamine) of $5
mg/kg/min, postnatal corticosteroids,
and chronic lung disease defined as the
use of oxygen therapy or positive endexpiratory pressure at 36 weeks’ gestation. Logistic regression was used to
assess the association between EEG abnormalities and sedative use when
controlling for severe brain injury and
adverse outcomes. The Statistical Package for the Social Sciences version 16.0 J
for Windows (SPSS Inc., Chicago, IL) was
used to conduct the statistical tests. Twosided P values of ,.05 were considered
to be statistically significant.
RESULTS
Participant Characteristics
The perinatal characteristics of the 333
infants are shown in Table 1. Gestational age ranged from 22 to 33 weeks
with a mean (SD) of 30.1 (2.8) weeks.
Grade III/IV IVH was found in 13 infants
(4%), and cystic PVL was diagnosed in
17 (5%) infants. DD was diagnosed in
33 infants (10%), and 34 (10%) had CP
at 12 to 18 months of corrected age. In
total, 44 infants (13%) had an adverse
outcome of either DD or CP or both.
Of the 333 infants, EEG was performed
in 265 (80%) during the first period, in
278 (83%) during the second period,
and in 237 (71%) during the third period. The mean (SD) day of life on which
the EEG was obtained was 3.1 (1.2), 12.5
(3.5), and 28.1 (4.4) in the first, second,
and third period, respectively. No sig-
PEDIATRICS Volume 130, Number 4, October 2012
TABLE 1 Perinatal Characteristics of the
Infants
Total (n = 333)
Gestational age at birth, wk
,28 wk
Bodyweight at birth, g
,1000 g
Small for gestational age
Male gender
Multiple birth
Antenatal corticosteroids
Cesarean delivery
5 min Apgar score of ,6
Sedative agentsa
Necrotizing enterocolitis
Postnatal corticosteroids
Chronic lung disease at 36 wkb
Grade III/IV IVH
Cystic PVL
30.1 (2.8)
84 (25%)
1318 (456)
96 (29%)
25 (7.5%)
195 (59%)
99 (30%)
104 (31%)
274 (82%)
45 (14%)
27 (8.1%)
2 (0.6%)
22 (6.6%)
25 (7.5%)
13 (3.9%)
17 (5.1%)
Data are mean (SD) or n (%).
a Sedative use within 24 h before EEG recording.
b Chronic lung disease was defined as need of oxygen or
artificial respiratory support at 36 weeks’ postmenstrual
age.
nificant difference in characteristics
was found between the entire cohort of
333 infants and those who underwent
EEG recording in each time period , with
the exception that infants who received an EEG in the third period had
a younger gestational age at birth (29.4
[2.7] weeks, P = .001) and smaller birth
weight (1210 [429] g, P = .005). The rate
of infants with grade III/IV IVH, cystic
PVL, or adverse outcomes in each period was similar to that for the total
cohort.
Type or Grade of EEG Abnormality
and Outcome
EEG abnormality was observed in 81
(31%), 61 (22%), and 47 (20%) infants in
the first, second, and third periods,
respectively. ASA accounted for 52% of
the EEG abnormalities in the first period, but the rate decreased in the
second (15%) and third (8%) periods.
The majority of CSA was a disorganized
pattern; a dysmature pattern was observed in 1 infant in the second period
and in 2 other infants in third period. No
infant had severe ASA, whereas 6
infants had a severely disorganized CSA
pattern. The EEG abnormality grade was
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significantly correlated with the presence of DD or CP in all periods (all P ,
.001; Table 2). Electrographic seizure
was observed in 2 infants: 1 infant
presented CP and the other presented
DD and CP.
Predictive Value for Adverse
Outcomes
The sensitivity, specificity, and positive
and negative predictive value of all EEG
abnormalities or moderate to severe
abnormalities were evaluated in each
period (Table 3). The sensitivity and
specificity for predicting an adverse
outcome was relatively constant in
each period. The sensitivity and specificity of neuroimaging abnormalities
(grade III/IV IVH or cystic PVL) for predicting an adverse outcome were 0.57
(95% CI, 0.42–0.70) and 0.98 (95% CI,
0.96–0.99), respectively.
ORs for Clinical Variables and EEG
Abnormalities
Several clinical variables during the
neonatal period were predictive of the
neurodevelopmental outcome (Table 4).
Small for gestational age, a 5-minute
Apgar score of ,6, postnatal corticosteroids, and chronic lung disease at
36 weeks of postmenstrual age were
predictive of DD, and inotrope use of
$5 mg/kg per minute was predictive of
CP. The univariate analysis revealed
that abnormalities detected by neuroimaging techniques (grade III/IV IVH or
cystic PVL) had the highest ORs for
predicting DD and CP. Furthermore, the
univariate analysis showed that the OR
of EEG abnormality in any time period
was significantly predictive of DD and
CP. The multivariate logistic regression
model revealed that the presence of
EEG abnormalities in the second period
was a significant predictor for DD, and
that EEG abnormalities occurring in the
first and second periods were significant predictors for CP independent of
other clinical variables (Table 5).
Effect of Sedatives on EEG Findings
Of the 333 infants, 27 (8%) with 31 EEG
records received one or more sedatives
within 24 hours before the EEG recording. Of those, 19 infants received
a continuous dose of midazolam
(0.05–0.19 mg/kg per hour), 7 infants
received a total bolus dose of pentobarbital (9–17 mg/kg per day), and 2
received a continuous dose of morphine (6–22 mg/kg per hour). Of the 31
EEGs performed under sedation, 16
(52%) showed some grade of ASA.
Furthermore, we found a significant
relationship between sedative use and
the presence of ASA after controlling
for severe brain injury and adverse
TABLE 2 Severity of EEG Abnormalities and Outcomes
Outcomes
First period (n = 265)
DD and/or CP
DD
CP
Second period (n = 278)
DD and/or CP
DD
CP
Third period (n = 237)
DD and/or CP
DD
CP
Grade of EEG Abnormalities
None
Mild
Moderate
Severe
n = 184
14 (7.6)
10 (5.4)
9 (4.9)
n = 217
15 (6.9)
13 (6.0)
10 (4.6)
n = 190
18 (9.5)
12 (6.3)
13 (6.8)
n = 48
7 (15)
6 (13)
4 (8.3)
n = 40
12 (30)
8 (20)
8 (20)
n = 29
9 (31)
7 (24)
7 (24)
n = 32
14 (44)
9 (28)
14 (44)
n = 17
6 (35)
4 (24)
6 (35)
n = 17
8 (47)
6 (35)
8 (47)
n=1
1 (100)
1 (100)
1 (100)
n=4
4 (100)
4 (100)
4 (100)
n=1
1 (100)
1 (100)
1 (100)
Data are n (%). Developmental delay is defined as developmental quotient ,70 in standardized developmental tests between
12 and 18 months of corrected age.
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outcomes (P , .001). However, exclusion of the 31 EEG records from the
analyses did not change the predictive
values shown in Table 3 or the ORs
shown in Table 4 and did not alter our
conclusions.
DISCUSSION
The current study demonstrated that
EEG abnormalities within the first
month of life significantly predict an
adverse neurodevelopmental outcome
at 12 to 18 months of corrected age in
preterm infants. Although several previous studies have reported similar
findings, our study has several unique
characteristics: accurate predictive
values in current preterm survivors,
a detailed evaluation of background EEG
by the use of an established classification system, and a comparison with
other clinical prognostic variables.
The prognostic value of preterm EEGs
changes with advances in perinatal care
and medicine. The largest investigations
of the prognostic value of preterm EEG, all
conducted in the late 1980s and 1990s,
showed that EEGs had a high prognostic
value, and yet the mortality rate or the
incidence of severe brain injury such as
grade III/IV IVH or cystic PVL was as high
as 16% to 21%.18–20 In contrast, the
mortality rate in the present cohort was
6% in all live birth infants, and the incidence of severe brain injury was 9% in
survivors, which is consistent with current reports on preterm survivor
cohorts.21 Furthermore, the presence of
PRS, a well-known prognostic marker
of EEG abnormalities, was rare in our
study; it was observed in 2% of survivors and in 20% of survivors with severe brain injury. PRS are highly
associated with the severity of brain
injury,10,22 and our finding may reflect
the declining trend in severe brain injury. Thus, it is reasonable that our
study would show relatively lower
sensitivity and positive predictive values than previous older studies.
ARTICLE
TABLE 3 Predictive Values of EEG Abnormalities
Developmental Delay and/or Cerebral Palsy
Any grade of EEG
abnormality
First period
Second period
Third period
Moderate to severe
grade of EEG abnormality
First period
Second period
Third period
Sensitivity
Specificity
PPV
NPV
0.61 (0.45–0.75)
0.60 (0.44–0.74)
0.50 (0.35–0.66)
0.74 (0.68–0.80)
0.84 (0.79–0.88)
0.86 (0.80–0.90)
0.27 (0.19–0.38)
0.36 (0.25–0.49)
0.38 (0.26–0.53)
0.92 (0.88–0.95)
0.93 (0.89–0.96)
0.91 (0.86–0.94)
0.41 (0.27–0.58)
0.27 (0.15–0.43)
0.25 (0.14–0.41)
0.92 (0.88–0.95)
0.95 (0.92–0.97)
0.96 (0.92–0.98)
0.46 (0.30–0.62)
0.48 (0.28–0.68)
0.50 (0.29–0.71)
0.91 (0.87–0.94)
0.90 (0.85–0.93)
0.88 (0.83–0.91)
Data are proportions (95% CI). PPV, positive predictive value; NPV, negative predictive value.
TABLE 4 Risk Factors Associated With Developmental Delay or Cerebral Palsy
Variables
Gestational age at birth ,28 wk
Body weight at birth ,1000 g
Small for gestational age
Male gender
Multiple birth
5-min Apgar score of ,6
Inotrope $5mg/kg per min
Postnatal corticosteroids
Chronic lung disease at 36 wk
Sedative agents
Grade III/IV IVH or cystic PVL
Any grade of EEG abnormalities
First period (n = 265)
Second period (n = 278)
Third period (n = 237)
Moderate to severe grade of EEG abnormalities
First period (n = 265)
Second period (n = 278)
Third period (n = 237)
Developmental Delay
Cerebral Palsy
OR (95% CI)
P
OR (95% CI)
P
1.3 (0.60–2.9)
1.7 (0.81–3.6)
3.3 (1.2–8.9)
0.96 (0.46–2.0)
1.2 (0.56–2.6)
2.7 (1.2–6.3)
1.3 (0.42–3.9)
3.0 (1.0–8.7)
3.3 (1.2–8.9)
2.3 (0.79–6.4)
36 (14–89)
.48
.16
.027
.90
.63
.016
.42
.037
.027
.11
,.001
1.7 (0.81–3.7)
0.88 (0.39–2.0)
0.35 (0.05–2.7)
0.68 (0.33–1.4)
1.5 (0.74–3.2)
1.8 (0.75–4.7)
4.1 (1.7–9.8)
2.9 (0.98–8.3)
1.2 (0.35–4.3)
0.69 (0.16–3.0)
163 (51–525)
.15
.75
.25
.29
.25
.18
.003
.060
.48
.46
,.001
4.3 (1.8–9.9)
5.6 (2.5–12)
6.3 (2.7–15)
,.001
,.001
,.001
6.0 (2.6–14)
8.7 (3.7–20)
7.0 (3.1–16)
,.001
,.001
,.001
5.8 (2.4–14)
6.9 (2.6–19)
6.7 (2.3–19)
,.001
,.001
.002
14.0 (5.8–34)
12.1 (4.5–32)
10.0 (3.5–28)
,.001
,.001
,.001
TABLE 5 Multivariate Logistic Regression Model
Variables
Developmental Delay
Small for gestational age
5-min Apgar score of ,6
Grade III/IV IVH or cystic PVL
Any grade of EEG abnormalities in the second period
Cerebral Palsy
OR (95% CI)
P
OR (95% CI)
P
8.2 (2.3–29)
6.6 (1.4–32)
52 (15–176)
3.2 (1.1–9.7)
.001
.02
,.001
.034
NS
NS
89 (22–361)
6.8 (2.0–23)
NS
NS
,.001
.002
This table represents a result of multivariate logistic regression model with only significant variables after testing the
association between EEG abnormalities of a single recording in the second period and the other clinical variables, including
gestational age ,28 weeks, small for gestational age, multiple birth, male gender, postnatal corticosteroids use, 5-min
Apgar score of ,6, inotrope use of $5 mg/kg per minute, and chronic lung disease. NS, not significant. Note: R2 = 0.24 or 0.28
(Cox & Snell), 0.48 or 0.59 (Nagelkerke) for developmental delay or cerebral palsy, respectively.
Under thesecircumstances, allofourEEG
records were systematically evaluated
according to an established classification system, which is critical for the
assessment of EEG prognostic value.
The classification system used in the
current study comprised 2 EEG abnormalities, ASA and CSA, which reflect
chronological changes in brain damage.11 ASA, which shows suppressed
PEDIATRICS Volume 130, Number 4, October 2012
neuronal activity, is often observed
within several days after brain insult,
whereas CSA, which shows deranged
neuronal activity modulated by abnormal signaling from impaired axons in
the white matter and thalamus, is typically observed after recovery from
ASA. Previous studies on preterm EEGs
have focused on either the specific
characteristics of ASA (eg, decreased
continuity, prolonged interburst intervals)23,24 or CSA (eg, distinctive sharp
waves, PRS) EEG abnormalities.7–9,25
However, evaluations focusing on 1
specific component underestimate the
power of the EEG. A recent study
showed that neonatal EEG, assessed by
using a classification system similar to
ours, predicted the neurodevelopmental outcome in 61 preterm infants assessed at a mean age of 5.6 years
regardless of the age at which the EEG
recording was obtained.26 The disorganized CSA pattern is observed over
a longer period of time than the ASA in
preterm infants. Furthermore, preterm
infants exhibit disorganized CSA longer
than term infants with hypoxic ischemia
encephalopathy, often for 2 to 3 weeks.10
This difference between preterm and
term infants may be related to their
distinctive pathologies: in preterm infants, the dominant lesion is in the
periventricular white matter, whereas,
in term infants, the dominant lesion is
located in the cortex or thalamus. As
a result, the predictive values in the
current study were relatively constant
over the recording periods, whereas the
incidence of ASA differed between the
first and the following periods.
Several risk factors have been associated with subsequent adverse outcomes in preterm infants, including
prematurity, small for gestational age,
chronic lung disease, postnatal corticosteroid use, and brain injury27,28;
however, the current study, with the
use of the multivariate logistic regression model, revealed that direct
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assessment of the brain by using
EEG is a better predictor of adverse
outcomes than indirect information
provided by clinical risk factors.
Moreover, previous studies have
shown that EEG can detect milder
forms of brain injury during postnatal
days 5 to 14 with a higher sensitivity
than cranial ultrasound.29,30 Recent
reports have shown that .50% of
infants with very low birth weight have
milder forms of brain injury that are
detected by advanced MRI or postmortem histopathology.31 Thus, EEG
provides additional information independent of other clinical variables,
including severe brain injury detected
by cranial ultrasound, for predicting
early neurodevelopmental outcomes,
particularly CP.
Thus, EEG assessment provides the
earliest identification of at-risk preterm
infants for future intervention. Although
cranial ultrasound also contributes to
early detection of IVH or PVL, the
hyperechogenic characteristics are
commonly observed after 24 to 48 hours
after the insult. In contrast, evidence
suggests that abnormal findings on
conventional EEG or amplitudeintegrated EEG precede those on ultrasound.32,33 Our results show that
EEG has high specificity and negative
predicative value even within 72 hours
of life, suggesting that EEG is suitable
for early screening for infants at high
risk needing preventive intervention.
A strength of our study was the large
number of participants and the high
rate of follow-up. However, the study has
several limitations. First, some infants
did not undergo 3 EEGs as scheduled.
The infants recorded during the third
period had a younger gestational age
compared with the entire cohort,
because some of the infants with an
older gestational age were discharged
earlier than the scheduled EEG, which
may have affected the interpretation
of our results. Second, some infants
received sedatives, which could have
suppressed EEG background activity.34,35
However, in current neonatal intensive
care practice, sedatives or analgesics
are important agents for stabilizing
general condition or relieving pain in ill
preterm infants. EEG recordings obtained after the influence of sedatives
may provide an accurate prediction
under such conditions. Third, the current study focused on the assessment of
EEG within the first month of life for
early prediction. The abnormal findings
and their prognostic value for EEGs
taken at a later stage (eg, 40 weeks’
postmenstrual age) may be different,
particularly in extremely premature infants. Finally, neurodevelopmental assessment at 12 to 18 months of corrected
age may underestimate cognitive or
behavioral abnormalities. Follow-up
assessments at school age may be
more appropriate for evaluating developmental disabilities in preterm
children.
CONCLUSIONS
EEG abnormalities within the first
month of life are associated with adverse neurodevelopmental outcomes at
12 to 18 months of corrected age in
preterm infants. Although severe brain
injury such as grade III/IV IVH or cystic
PVL detected by cranial ultrasound
or MRI during the neonatal period is
the most significant marker for predicting adverse outcomes, EEG provides
prognostic value independent of neuroimaging findings and clinical risk
factors. A disorganized pattern without
PRS is common and is a better prognostic marker in conventional EEG in the
current neonatal care and medicine
setting.
ACKNOWLEDGMENTS
The authors thank the staff at Anjo
Kosei Hospital, including the physicians, nurses, clinical psychologists,
and clinical laboratory technicians in
the Division of Electrophysiology,
and, most importantly, the infants
and their families who participated
in this study.
REFERENCES
1. Larroque B, Ancel PY, Marret S, et al; EPIPAGE Study group. Neurodevelopmental
disabilities and special care of 5-year-old
children born before 33 weeks of gestation
(the EPIPAGE study): a longitudinal cohort
study. Lancet. 2008;371(9615):813–820
2. Doyle LW, Cheong J, Hunt RW, et al. Caffeine
and brain development in very preterm
infants. Ann Neurol. 2010;68(5):734–742
3. Neubauer AP, Voss W, Wachtendorf M,
Jungmann T. Erythropoietin improves neurodevelopmental outcome of extremely
preterm infants. Ann Neurol. 2010;67(5):
657–666
6
4. Clancy RR, Tharp BR, Enzman D. EEG in
premature infants with intraventricular
hemorrhage. Neurology. 1984;34(5):583–590
5. Lacey DJ, Topper WH, Buckwald S, Zorn WA,
Berger PE. Preterm very-low-birth-weight
neonates: relationship of EEG to intracranial
hemorrhage, perinatal complications, and
developmental outcome. Neurology. 1986;36
(8):1084–1087
6. Tharp BR, Scher MS, Clancy RR. Serial EEGs
in normal and abnormal infants with birth
weights less than 1200 grams—a prospective study with long term follow-up.
Neuropediatrics. 1989;20(2):64–72
HAYASHI-KURAHASHI et al
Downloaded from by guest on June 18, 2017
7. Marret S, Parain D, Jeannot E, Eurin D,
Fessard C. Positive rolandic sharp waves in
the EEG of the premature newborn: a five
year prospective study. Arch Dis Child.
1992;67(7):948–951
8. Baud O, d’Allest AM, Lacaze-Masmonteil T, et al.
The early diagnosis of periventricular leukomalacia in premature infants with positive
rolandic sharp waves on serial electroencephalography. J Pediatr. 1998;132(5):813–817
9. Vermeulen RJ, Sie LT, Jonkman EJ, et al.
Predictive value of EEG in neonates with
periventricular leukomalacia. Dev Med
Child Neurol. 2003;45(9):586–590
ARTICLE
10. Kidokoro H, Okumura A, Hayakawa F, et al.
Chronologic changes in neonatal EEG findings in periventricular leukomalacia. Pediatrics. 2009;124(3). Available at: www.
pediatrics.org/cgi/content/full/124/3/e468
11. Watanabe K, Hayakawa F, Okumura A. Neonatal EEG: a powerful tool in the assessment of brain damage in preterm infants.
Brain Dev. 1999;21(6):361–372
12. Hayakawa F, Okumura A, Kato T, Kuno K,
Watanabe K. Disorganized patterns: chronicstage EEG abnormality of the late neonatal
period following severely depressed EEG
activities in early preterm infants. Neuropediatrics. 1997;28(5):272–275
13. Hayakawa F, Okumura A, Kato T, Kuno K,
Watanabe K. Dysmature EEG pattern in EEGs
of preterm infants with cognitive impairment: maturation arrest caused by prolonged mild CNS depression. Brain Dev.
1997;19(2):122–125
14. Papile LA, Burstein J, Burstein R, Koffler H.
Incidence and evolution of subependymal
and intraventricular hemorrhage: a study
of infants with birth weights less than
1,500 gm. J Pediatr. 1978;92(4):529–534
15. Tsumori M, Inage N. Nyuyoji Seishin Hattatsu
Shindanho 0-3 Sai Made (in Japanese).
Tokyo, Japan: Dainihon Tosho; 1961.
16. Ikuzawa M, Matsushita Y, Nakase A. The Kyoto
Scale of Psychological Development (in
Japanese). 2nd ed. Kyoto, Japan: Nakanishiya
Publishers; 1995
17. Palisano R, Rosenbaum P, Walter S, Russell D,
Wood E, Galuppi B. Development and reliability of a system to classify gross motor
function in children with cerebral palsy. Dev
Med Child Neurol. 1997;39(4):214–223
18. Marret S, Parain D, Ménard JF, et al. Prognostic value of neonatal electroencephalography in premature newborns less than 33
weeks of gestational age. Electroencephalogr
Clin Neurophysiol. 1997;102(3):178–185
19. Maruyama K, Okumura A, Hayakawa F, Kato
T, Kuno K, Watanabe K. Prognostic value of
EEG depression in preterm infants for later
development of cerebral palsy. Neuropediatrics. 2002;33(3):133–137
20. Okumura A, Hayakawa F, Kato T, Kuno K,
Watanabe K. Developmental outcome and
types of chronic-stage EEG abnormalities in
preterm infants. Dev Med Child Neurol.
2002;44(11):729–734
21. Woodward LJ, Anderson PJ, Austin NC,
Howard K, Inder TE. Neonatal MRI to predict
neurodevelopmental outcomes in preterm
infants. N Engl J Med. 2006;355(7):685–694
22. Okumura A, Hayakawa F, Kato T, Kuno K,
Watanabe K. Positive rolandic sharp waves
in preterm infants with periventricular
leukomalacia: their relation to background
electroencephalographic abnormalities. Neuropediatrics. 1999;30(6):278–282
23. Benda GI, Engel RC, Zhang YP. Prolonged
inactive phases during the discontinuous
pattern of prematurity in the electroencephalogram of very-low-birthweight infants.
Electroencephalogr Clin Neurophysiol. 1989;
72(3):189–197
24. Menache CC, Bourgeois BF, Volpe JJ. Prognostic value of neonatal discontinuous EEG.
Pediatr Neurol. 2002;27(2):93–101
25. Biagioni E, Bartalena L, Boldrini A, Pieri R,
Cioni G. Electroencephalography in infants
with periventricular leukomalacia: prognostic features at preterm and term age. J
Child Neurol. 2000;15(1):1–6
26. Le Bihannic A, Beauvais K, Busnel A, de
Barace C, Furby A. Prognostic value of EEG
in very premature newborns. Arch Dis
Child Fetal Neonatal Ed. 2012;97(2):F106–
F109
27. Short EJ, Klein NK, Lewis BA, et al. Cognitive
and academic consequences of bronchopulmonary dysplasia and very low birth
weight: 8-year-old outcomes. Pediatrics.
PEDIATRICS Volume 130, Number 4, October 2012
28.
29.
30.
31.
32.
33.
34.
35.
2003;112(5). Available at: www.pediatrics.
org/cgi/content/full/112/5/e359
Morsing E, Asard M, Ley D, Stjernqvist K,
Marsál K. Cognitive function after intrauterine growth restriction and very preterm birth. Pediatrics. 2011;127(4). Available
at: www.pediatrics.org/cgi/content/full/127/
4/e874
Okumura A, Hayakawa F, Kato T, et al.
Abnormal sharp transients on electroencephalograms in preterm infants with
periventricular leukomalacia. J Pediatr.
2003;143(1):26–30
Kubota T, Okumura A, Hayakawa F, et al.
Combination of neonatal electroencephalography and ultrasonography: sensitive
means of early diagnosis of periventricular
leukomalacia. Brain Dev. 2002;24(7):698–
702
Volpe JJ. Brain injury in premature infants:
a complex amalgam of destructive and
developmental disturbances. Lancet Neurol. 2009;8(1):110–124
Kidokoro H, Kubota T, Hayashi N, et al. Absent cyclicity on aEEG within the first 24 h
is associated with brain damage in preterm infants. Neuropediatrics. 2010;41(6):
241–245
Bowen JR, Paradisis M, Shah D. Decreased
aEEG continuity and baseline variability in
the first 48 hours of life associated with
poor short-term outcome in neonates born
before 29 weeks gestation. Pediatr Res.
2010;67(5):538–544
Bell AH, Greisen G, Pryds O. Comparison of
the effects of phenobarbitone and morphine administration on EEG activity in
preterm babies. Acta Paediatr. 1993;82(1):
35–39
van Leuven K, Groenendaal F, Toet MC, et al.
Midazolam and amplitude-integrated EEG in
asphyxiated full-term neonates. Acta Paediatr. 2004;93(9):1221–1227
7
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EEG for Predicting Early Neurodevelopment in Preterm Infants: An
Observational Cohort Study
Naoko Hayashi-Kurahashi, Hiroyuki Kidokoro, Tetsuo Kubota, Koichi Maruyama,
Yuichi Kato, Toru Kato, Jun Natsume, Fumio Hayakawa, Kazuyoshi Watanabe and
Akihisa Okumura
Pediatrics; originally published online September 3, 2012;
DOI: 10.1542/peds.2012-1115
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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 © 2012 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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EEG for Predicting Early Neurodevelopment in Preterm Infants: An
Observational Cohort Study
Naoko Hayashi-Kurahashi, Hiroyuki Kidokoro, Tetsuo Kubota, Koichi Maruyama,
Yuichi Kato, Toru Kato, Jun Natsume, Fumio Hayakawa, Kazuyoshi Watanabe and
Akihisa Okumura
Pediatrics; originally published online September 3, 2012;
DOI: 10.1542/peds.2012-1115
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/early/2012/08/28/peds.2012-1115
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 © 2012 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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