Cerebral Palsy after Neonatal Encephalopathy: How Much Is Preventable?

Jarred Garfinkle, MDCM1,2, Pia Wintermark, MD3,4, Michael I. Shevell, MDCM1,2,3, Robert W. Platt, PhD3,5,
and Maryam Oskoui, MDCM, MSc1,2,3, on behalf of the Canadian Cerebral Palsy Registry*
Objectives To determine the expected proportion of term cerebral palsy (CP) after neonatal encephalopathy (NE)
that could theoretically be prevented by hypothermia and elucidate the perinatal factors associated with CP after
NE in those who do not meet currently used clinical criteria required to qualify for hypothermia (cooling criteria).
Study design Using the Canadian CP Registry, we categorized children born at $36 weeks with birth weight
$1800 g with CP after moderate or severe NE according to the presence or absence of cooling criteria. Maternal,
perinatal, postnatal, and placental factors were compared between the 2 groups. A number needed to treat of 8
(95% CI 6-17) to prevent one case of CP was used for calculations.
Results Among the 543 term-born children with CP, 155 (29%) had moderate or severe NE. Sixty-four of 155
(41%) met cooling criteria and 91 of 155 (59%) did not. Shoulder dystocia was more common in those who did
not meet cooling criteria (OR 8.8; 95% CI 1.1-71.4). Low birth weights (20% of all singletons), small placentas
(42%), and chorioamnionitis (13%) were common in both groups.
Conclusions The majority of children with CP after NE did not meet cooling criteria. An estimated 5.1% (95% CI
2.4%-6.9%) of term CP after NE may be theoretically prevented with hypothermia. Considering shoulder dystocia
as an additional criterion may help recognize more neonates who could potentially benefit from cooling. In all cases,
a better understanding of the antenatal processes underlying NE is essential in reducing the burden of CP. (J Pediatr
2015;167:58-63).
See editorial, p 8 and
related article, p 25

herapeutic hypothermia has proven to be an effective neuroprotective intervention and has been applied increasingly to
neonates with specific clinical criteria and moderate or severe neonatal encephalopathy (NE) within the first 6 hours of
life.1-3 The number of such neonates needed to treat (number needed to treat; NNT) to prevent 1 subsequent case of
cerebral palsy (CP) is 8 (95% CI 6-17) according to recent meta-analyses.2,3 Some pediatric neurologists are hoping that hypothermia will reduce the frequency of CP in term-born neonates with NE, but the overall proportion of term CP that could be
prevented by hypothermia in this population has not yet been established.4
Furthermore, there is no neuroprotective strategy for term neonates with NE who do not meet current clinical criteria for
hypothermia.5 More specific information concerning the pathways to CP in this population is needed before potentially effective therapies can be developed and applied.6,7 Using the Canadian Cerebral Palsy Registry (CCPR), we aimed to investigate
term-born children with later CP after moderate or severe NE. The objectives were: (1) to determine the expected proportion
of term CP after NE that could theoretically be prevented by hypothermia; and (2) to elucidate the perinatal factors associated
with CP after NE in those who do not meet the clinical criteria required to qualify for hypothermia.

Methods
The study was conducted using data extracted from the CCPR, which builds on
the development and implementation of the Cerebral Palsy Register of Qu
ebec.
The CCPR captures cases of CP identified through both pediatric rehabilitation
centers and university hospitals at which provincial pediatric neurology and
developmental pediatric services are located, from the birth year of 1999 until
2011. The registry covers most of Quebec, the greater Toronto area of Ontario,
and the entire provinces of British Columbia, Alberta, Nova Scotia, and

CCPR
CP
HIE
NE
NNT

Canadian Cerebral Palsy Registry

Cerebral palsy
Hypoxic-ischemic encephalopathy
Neonatal encephalopathy
Number needed to treat

From the 1Department of Neurology/Neurosurgery,

McGill University; 2Division of Pediatric Neurology,
McGill University Health Centre; 3Department of
Pediatrics, McGill University; 4Division of Neonatology,
McGill University Health Center; and 5Department of
Epidemiology, Biostatistics, and Occupational Health,
McGill University, Montreal, Quebec, Canada
*List of members of the Canadian Cerebral Palsy Registry
is available at www.jpeds.com (Appendix).

bec has been funded
The Cerebral Palsy Register of Que

seau de recherche sur le de

veloppement, la
by the Re

et le bien-e
^tre de lenfant (RSDE) des Fonds de
sante




Recherche en Sante du Quebec and NeuroDevNet National Centre of Excellence. The authors declare no
conflicts of interest.
0022-3476/$ - see front matter. Copyright 2015 Elsevier Inc.
All rights reserved.
http://dx.doi.org/10.1016/j.jpeds.2015.02.035

58

Vol. 167, No. 1
July 2015

Newfoundland, and includes more than one-half (approximately 18 million individuals) of the Canadian population.
Once cases are identified, parental consent is obtained, and
the maternal and childs records are reviewed. These data
are supplemented by a standardized parental interview and
physical examination of the child by a pediatric neurologist,
developmental pediatrician, or child physiatrist. Local ethics
board approval was obtained from each participating institution. The Montreal Childrens Hospital-McGill University
Health Center research ethics board provided central
approval for data storage, analysis, and overall operations.
To be enrolled in the CCPR, a child must be at least 2 years
of age and meet current diagnostic consensus criteria for CP,
which include a clinical diagnosis of a nonprogressive motor
impairment resulting from a presumably early insult to the
developing brain.8 The diagnosis is confirmed whenever
possible at 5 years of age, and the children without CP were
removed from the registry.9 Patients within the CCPR
included for analysis in this study: (1) were born
at $ 36 weeks; (2) had a birth weight of $1800 g; and (3) fulfilled criteria for moderate or severe NE during the first week
of life. We then categorized the neonates according to the
presence or absence of currently used clinical criteria
required to qualify for hypothermia (cooling criteria).
Criteria for NE were derived from the Sarnat score.10
Neonates with moderate NE were either lethargic, hypotonic, manifested seizures, or had decreased reflexes. Those
with severe NE manifested either flaccid coma, brainstem
findings, or difficult-to-control seizures. Clinical cooling
criteria were derived from the National Institute of Child
Health and Human Development randomized controlled
trial of therapeutic hypothermia and the Position Statement of the Canadian Paediatric Society.11,12 Neonates
were required to have evidence of both fetal and
neonatal distress. Fetal distress was evident by at least
one of the following: (1) sentinel event (abruptio placenta,
cord accident, uterine rupture, or shoulder dystocia); (2)
pH # 7.0 or base deficit $16 mEq/L from the umbilical
cord or blood collected within the first hour of life; or
(3) severe fetal heart rate abnormalities. Neonatal
distress was evident by at least one of the following: (1)
Apgar score # 5 at 10 minutes; or (2) delivery room resuscitation (intubation, cardiac massage, or administration of
epinephrine or normal saline bolus). For the purposes of
cooling group assignment, when the 10-minute Apgar
score or pH was not documented in the records, they
were assumed to have been normal, and when sentinel
events, severe fetal heart rate abnormalities, and delivery
room resuscitation were not documented in the records,
they were assumed to have been absent.
Maternal, paternal, perinatal, postnatal, and placental factors were compared in an attempt to identify variables that
potentially distinguish those who met cooling criteria from
those who did not.
Birth weight, placental weight, and placental-to-birth weight
percentiles of singletons were based on sex and gestation by the
use of contemporary Canadian percentile curves.13,14

Seven randomized controlled trials have evaluated hypothermia and each assessed the incidence of CP. Two subsequent meta-analyses established that the NNT to prevent
one case of CP was 8 (95% CI 6-17 and 6-16).2,3 This NNT
is applicable to our cohort of children with CP who: (1)
had moderate or severe NE; and (2) met clinical cooling
criteria.
Statistical analysis was performed with SPSS 20.0 (SPSS
Inc, Chicago, Illinois). For comparisons between the two
groups, the c2 test or 2-sided Fisher exact test were used
for univariate analysis of categorical variables as appropriate
and the Student t test for continuous variables. ORs and their
95% CIs were calculated where appropriate. A P of <.05 was a
priori considered significant. We applied unconditional logistic regression analysis selectively when 2 variables that
act along the same causal pathway were significant.

Results
Between 1999 and June 2011, a total of 1001 patients were
enrolled into the CCPR. Of these, 543 were $36 weeks gestation and had a birth weight $1800 g. Of them, 155 of 543
(29%) had a history of moderate or severe NE (it is this group
that comprises the study cohort) and 388 of 543 (71%) did
not (361 did not have moderate or severe NE and 27 did
not have documentation of a neurologic examination during
the neonatal period). Among those with NE, 64 of 155 (41%)
met currently used cooling criteria, but 91 of 155 (59%) did
not. Cord or first hour of life blood pH was available in 62 of
64 and 65 of 91 neonates, and 10-minute Apgar score was
available in 55 of 64 and 53 of 91 neonates in either group
(Table I). In 41 of 47 cases (87%) in which the 10-minute
Apgar score was unavailable, the 5-minute Apgar score was
>5. Eleven neonates with NE who met cooling criteria
(17%) and 2 who did not meet them (2%) were actually
cooled, all of whom were born in 2009 or later. Among
those without moderate or severe NE, 9 of 388 (2%)
otherwise met cooling criteria (2 with mild NE and 7
without NE), and 379 of 388 (98%) did not meet cooling
criteria (5 with mild NE and 374 without NE) (Figure;
available at www.jpeds.com).
The features and degree of NE in the 155 children with
moderate or severe NE are summarized in Table II.
Hypotonia as a feature of NE was significantly more
common in those who met cooling criteria (P = .020). The
clinical characteristics of children with CP after NE are
listed in Table I. There were no significant differences
between the 2 groups with respect to antenatal maternal
and paternal variables. Thirty of 151 (20%) singletons were
<10th percentile for weight (similar in both groups).
Signs of perinatal distress, such as low pH, cesarean delivery, low Apgar scores, and resuscitation at birth requiring
intubation, cardiac massage, or epinephrine, were significantly more common in those who met cooling criteria
(P < .0001), as expected. Overall, 22 of 64 (34%) of those
who met cooling criteria vs 8 of 91 (9%) of those who did
not had an abruptio placenta, uterine rupture, or cord
59

THE JOURNAL OF PEDIATRICS

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Table I. Clinical characteristics of children with CP and

NE (n = 155)
Clinical criteria for
hypothermia
Clinical factors
Maternal and paternal
Maternal age, years, mean  SD
Maternal university studies, n (%)
Paternal university studies, n (%)
Maternal ethnicity white, n (%)
Paternal ethnicity white, n (%)
Gravida $2, n (%)
Parity $2, n (%)
Aborta $1, n (%)
Hypertension, n (%)
Gestational diabetes, n (%)
Insulin-dependent gestational
diabetes, n (%)
Trauma during the pregnancy, n
(%)
Bleeding during first trimester, n
(%)
Bleeding during second trimester,
n (%)
Bleeding during third trimester, n
(%)
Alcohol use, n (%)
Tobacco use, n (%)
Maternal illness, n (%)
Twin pregnancy, n (%)
Pre-eclampsia, n (%)
TORCH infection, n (%)
GBS positive, n (%)
Perinatal
Gestational age, wk
Gestational age 36-38 + 6 wk,
n (%)
Gestational age 41-43 wk,
n (%)
Male sex, n (%)
Congenital malformation, n (%)
Birth weight, g
Birth weight <10th percentile,
n (%)
Birth weight $90th percentile,
n (%)
Cesarean delivery, n (%)
Maternal fever during labor or
delivery, n (%)
Prolonged rupture of membranes,
n (%)
Chorioamnionitis, n (%)
Abruptio placenta, n (%)
Shoulder dystocia, n (%)
Uterine rupture, n (%)
Cord accident, n (%)
pH, mean  SDz
Apgar at 1, mean  SD
Apgar at 5, mean  SDx
Apgar at 10, mean  SD{
Resuscitation at birth, n (%)
Postpartum
Sepsis, n (%)
Administration of antibiotics for
10 days, n (%)
Seizures during the first 24 hours,
n (%)
Seizures during the first 72 hours,
n (%)
Multisystem involvement, n (%)

60

Table I. Continued
Clinical criteria for
hypothermia
Clinical factors

Yes (n = 64) No (n = 91) P value

30.6  5.2
26 (41)
23 (36)
46 (72)
43 (67)
34 (53)
44 (69)
26 (41)
7 (11)
3 (5)
1 (2)

Vol. 167, No. 1

29.5  5.8
38 (42)
27 (30)
69 (76)
68 (75)
49 (54)
55 (60)
32 (35)
10 (10)
15 (17)
6 (7)

.56
1.00
.49
.58
.37
1.00
.31
.51
.97
.039*
.241

8 (13)

8 (9)

.49

7 (11)

13 (14)

.79

2 (5)

5 (6)

.75

4 (6)

6 (7)

.96

11 (17)
16 (25)
13 (20)
1 (2)
2 (3)
8 (13)
12 (19)

18 (20)
13 (14)
21 (23)
3 (3)
4 (4)
6 (7)
15 (17)

.46
.099
.46
.64
.89
.29
.58

39.5  1.2
12 (19)

39.3  1.5
29 (32)

.46
.032*

12 (19)

24 (26)

.11

34 (53)
54 (59)
8 (13)
15 (17)
3284  575 3390  558
15 (24)
15 (17)

.51
.65
.255
.31

4 (6)

10 (11)

.40

44 (69)
6 (9)

24 (26)
13 (14)

6 (9)

13 (14)

9 (14)
11 (17)
1 (2)
3 (5)
12 (19)
6.98  0.20
1.6  1.6
3.9  2.2
4.9  2.5
64 (100)

10 (11)
0 (0)
11 (12)
0 (0)
7 (8)
7.21  0.10
5.1  3.0
7.1  2.5
7.1  2.4
41 (45)

4 (6)
8 (13)

3 (3)
6 (7)

.69
.30

49 (77)

56 (62)

.10

55 (86)

68 (76)

.28

60 (94)

57 (63)

<.0001*
(continued )

<.0001*
.27
.37
.76
<.0001*
.015*
.068
.048*
<.0001*
<.0001*
<.0001*
<.0001*
<.0001*

Yes (n = 64) No (n = 91) P value

Icterus, n (%)
8 (13)
Placental,**
Placental weight, g
547  169
Placental weight <10th
23 (51)
percentile, n (%)
Placental weight $90th
1 (2)
percentile, n (%)
Placental weight/birth weight ratio
22 (49)
<10th percentile, n (%)
Placental weight/birth weight ratio
1 (2)
$90th percentile, n (%)

18 (20)

.44

601  159
16 (33)

.114
.096

1 (2)

1.00

16 (33)

.14

4 (8)

.36

GBS, group B streptococcus; TORCH, toxoplasmosis, other (syphilis, varicella-zoster, parvovirus B19), rubella, cytomegalovirus, and herpes.
*P < 0.05
Singletons only (n = 63 and 88, respectively).
zpH available in 62/64 and 65/91 neonates.
x5-minute Apgar scores available in 62/64 and 88/91.
{10-minute Apgar scores available in 55/64 and 53/91.
**Placentas available in 45/63 and 48/88 singletons.

accident (P < .0001). Multisystem involvement, defined as

NE and an objectively documented impairment in at least
one other system, was almost uniformly documented in those
who met cooling criteria (60/64 [94%]).
Shoulder dystocia, in contrast to the other sentinel
events, was 8 times more common in those with NE
who did not meet cooling criteria (OR 8.8; 95% CI 1.171.4, P = .015). Gestational diabetes was 4 times more
common in those who did not meet cooling criteria (OR
4.0; 95% CI 1.1-14.5, P = .039). Only 4 of the 11 (36%)
neonates with shoulder dystocia who did not meet cooling
criteria were born to a mother with gestational diabetes.
Their mean pH, available in 9 of 11 of them, was 7.17
(SD  0.10). Shoulder dystocia was still significantly
more common in those who did not meet cooling criteria
after adjusting for gestational diabetes in an unconditional
logistic regression analysis (OR 1.8; 95% CI 1.0-3.2;
P = .042). Chorioamnionitis, which was diagnosed histologically or when there was a maternal fever of undetermined origin, was present in 9 of 63 (14%) and 10 of 88
(11%) of singletons in either group.
Placentas were available for analysis in 93 of 151 (62%) singletons. Interestingly, 39/93 (42%) placentas were <10th
percentile for weight, and 38 of 93 (41%) were <10th percentile for placental weight-to-birth weight ratio; neither factor
differed significantly between the 2 groups.

Discussion
Approximately 1 in 4 children with CP in this registry born at
$36 weeks gestation and with a birth weight $1800 g had a
history of moderate or severe NE, less than one-half of whom
met clinical cooling criteria. In the Western Australian CP
Register between 1980 and 1995, one-third of term children
had antecedent moderate or severe NE.6 In the Oxford
Garfinkle et al

ORIGINAL ARTICLES

July 2015

Table II. Features and degree of encephalopathy of

children with CP and moderate or severe NE (n = 155)
Met clinical criteria for
hypothermia
Degree and features
Degree
Moderate
Severe
Features
Lethargy
Hypotonia
Seizures
Decreased reflexes
Flaccid coma
Difficult-to-control seizures

Yes (n = 64)

No (n = 91)

44 (69)
20 (31)

70 (77)
21 (23)

15 (23)
45 (70)
55 (86)
16 (25)
7 (11)
20 (31)

21 (23)
46 (51)
68 (76)
15 (17)
4 (4)
21 (23)

P value
.17

1.00
.020*
.28
.22
.20
.27

*P < .05.

Regional Health Authority Registry between 1984 and 1987,

one-fifth of term children had evidence of NE.15 However,
neither of these registry-based studies, conducted in the
pre-cooling era, evaluated the proportion of children with
CP after NE that met cooling criteria. The Western Australian
CP Register estimated that 63% of term neonates with CP after NE had hypoxic-ischemic encephalopathy (HIE) determined on the basis clinical diagnoses entered into the medical
record, but sentinel events were documented in only onefifth of those labeled as HIE. These authors use of HIE
may have been less specific than the clinical cooling criteria
we used.6,7
On the basis of an NNT of 8 (95% CI 6-17), theoretically, if all 64 neonates who had NE and met cooling
criteria had been cooled, an estimated 8 (64/8; 95% CI
64/17-64/6 = 3.8-10.7) would not have developed CP.
Therefore, of all 155 children born at term with CP after
NE, an estimated 5.1% (8/155  100%; 95% CI 3.8/15510.7/155  100% = 2.4%-6.9%) could have theoretically
been spared CP with the application of hypothermia. There
are limitations inherent in this estimate, which we address
in the sections to follow.
The majority of children with CP after NE did not meet
the current cooling criteria (59%), and many of them likely
had NE due to causes other than hypoxic-ischemic injury.
Shoulder dystocia may be an exception whereby neonates
with NE who did not meet clinical cooling criteria still suffered from hypoxic-ischemic injury. Shoulder dystocia is
known to complicate approximately 1% of deliveries.16 In
our study, it was present in 2% of those who met cooling
criteria and 12% of those who did not, and remained
more frequent in those who did not meet cooling criteria after adjusting for gestational diabetes, suggesting that neonates with NE and shoulder dystocia and later CP do not
necessarily manifest clinical signs of both fetal and
neonatal distress. In one study, the mean umbilical artery
pH of shoulder dystocia cases was only 0.04 lower than the
mean pH of all vaginal deliveries.17 In our study, the mean
cord or first hour of life blood pH in neonates with shoulder
dystocia who did not meet cooling criteria was 7.17, which is

within the normal range. This can be explained by the fact

that compression of the fetal carotid vessels by maternal tissue at the level of the pelvic outlet may cause isolated cerebral hypoxia rather than systemic acidosis. The cord blood
pH, which reflects the systemic circulation, may fail to
reflect the actual degree of underlying cerebral pathology.
On the basis of our data, caregivers should not be reassured
by a cord pH over 7 in neonates with shoulder dystocia, as
these neonates may indeed be at risk of developing CP.
Additional prospective studies are needed to properly assess
the neurodevelopmental outcomes of children with NE after
shoulder dystocia. At the very least, when the cord pH is
within normal limits, a blood gas could be performed in
these neonates within the first hour of life, as it may better
reflect possible cerebral injury.
Current recommendations that only neonates with moderate or severe NE be treated with hypothermia may be too
restrictive.12 This recommendation is based on the randomized controlled trials, which were designed to exclude infants
who did not demonstrate moderate or severe NE.2,3,11,18
However, in our registry, 2% of children with CP born at
$36 weeks gestation with a birth weight $1800 g met cooling criteria in the absence of moderate or severe NE. Only 2
of them had mild NE, but we suspect that mild NE was
underreported. Our study is not the first to suggest that clinical signs of fetal and neonatal distress in the absence of
moderate or severe NE are not uniformly benign. For
instance, one randomized controlled trial, in violation of
its protocol, enrolled 42 neonates classified as having mild
NE at less than 6 hours of life; 28.5% of them later died
or developed major disability.18 In a recent retrospective
cohort study, 20% of neonates with perinatal acidemia
and mild NE had abnormal short-term outcomes.19 Our
study looking at children with CP thus further emphasizes
the need to collect prospective data on the neurologic outcomes of neonates with mild NE to evaluate whether they
should qualify for hypothermia.
Both groups included a large proportion of singletons with
small placentas, low birth weights (less than the 10th percentile for gestation), and chorioamnionitis, but the incidence of
these 3 variables did not differ between the 2 groups.
Similarly, single-center cohort studies of: (1) neonates
with NE subsequent to a broad definition of hypoxicischemic injury; and (2) neonates meeting criteria for hypothermia found high frequencies of these variables.20,21 A
meta-analysis found that both low birth weights and chorioamnionitis are established risk factors for CP in termborn children.22 Even neonates with signs of perinatal
depression and subsequent CP have a high frequency of antenatal complications.23 The fact that these risk factors for NE
and later CP frequently are present in both groups of neonates suggests that the pathway to CP frequently involves
antenatal processes in both groups. A case-control study of
CP in term and late preterm singletons examining the potential contribution of sentinel events, inflammation, fetal
growth restriction, and birth defects estimated that growth
restriction and inflammation contributed to a total of 20%

Cerebral Palsy after Neonatal Encephalopathy: How Much Is Preventable?

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of CP in infants with NE with HIE and 34% in those with NE

not otherwise specified.6 Antenatal and placental processes
may predispose neonates to later CP, regardless of whether
there are signs of fetal and/or neonatal distress. A better understanding of these other mechanisms will be paramount in
reducing the burden of CP following NE, especially because
hypothermia addresses only a minority of these patients.
The strengths of this study include its prospective design in
a geographically defined population, the large number of
cases of CP in term-born children based on well-defined
diagnostic criteria, and the precise categorization of children
into well-defined groups. Moreover, placental data were
available for almost two-thirds of the cohort. We attempted
to identify etiologically more specific pathways by focusing
our analysis on those with moderate or severe NE and dichotomizing them according to the presence or absence of cooling criteria. By requiring signs of both fetal and neonatal
distress, we applied current clinical criteria used to evaluate
neonates for hypothermia. Assuming, for cooling group
assignment purposes, that undocumented pH were in all
cases normal represents a limitation but provides a more
conservative estimate. In addition, our registry does not
include information on the onset of NE, but rather specifies
whether the neonate had NE in the first week of life as originally defined.10 In calculating the proportion of term CP after NE that cooling could theoretically prevent, we first
assumed that the onset of NE was within 6 hours of life (as
used in the randomized controlled trials of hypothermia),
but it is probable that the onset was beyond 6 hours of life
in some.
Neonatal seizures, which were very common in the first
24 hours of life in this study, would mostly have occurred
after 6 hours of life.24 As such, our estimate may overemphasize the proportion of term CP after NE that cooling
could theoretically prevent. Fortunately, the degree of NE
usually improves over time, so we should not have greatly
overestimated the number of neonates with moderate or severe NE during the first 6 hours of life.25 We made a second
assumption in applying the NNT derived from the metaanalyses to our cohort: that the neonates with NE did not
receive hypothermia. We acknowledge that 11 of the 64 neonates with NE who met cooling criteria actually were
cooled.
Moreover, the NNT from the meta-analyses was based on a
more heterogeneous group including neonates who died,
which may introduce some bias into our calculations. Finally,
cerebral magnetic resonance imaging was not routinely performed in this era. Therefore, we were not permitted to
further characterize the neonates with NE according to their
precise neuroanatomic injury type.
Unfortunately, cooling addresses only a minority of CP after NE. Future studies should evaluate the neurodevelopmental outcomes of neonates with shoulder dystocia and
NE in the absence of acidemia or neonatal distress and of neonates meeting clinical cooling criteria in the absence of
moderate or severe NE. Despite the limitations inherent in
applying the NNT derived from the meta-analyses, our esti62

Vol. 167, No. 1

mate of the proportion of term CP after NE that could be prevented by hypothermia should encourage further research on
the antenatal processes underlying NE to develop other preventative strategies to reduce the burden of CP. n
Submitted for publication Jul 4, 2014; last revision received Dec 29, 2014;
accepted Feb 9, 2015.
Reprint requests: Maryam Oskoui, MDCM, MSc, Division of Pediatric
Neurology Montreal Childrens Hospital, 2300 Tupper Street, A-512 Montreal,
Quebec, H3H 1P3. E-mail: maryam.oskoui@mcgill.ca

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50 Years Ago in THE JOURNAL OF PEDIATRICS

Primary Liver Cell Carcinoma Associated with Biliary Cirrhosis Due to
Congenital Bile Duct Atresia
Okuyama K. J Pediatr 1965;67:89-93

kuyamas 1965 report on the development of liver cell carcinoma in a child with biliary atresia demonstrates what
was once the inevitable natural history of this disorder. Of interest, reflection on this case underscores the advances that have been made in the management of this devastating disease.
Biliary atresia is a rapidly progressive obstructive cholangiopathy of infants. Untreated, 90% of affected children die
by 36 months of age from complications related to biliary cirrhosis. Malignant transformation, usually hepatocellular
carcinoma, is a well-recognized complication of end-stage liver disease and, although rare, has been documented in
patients with biliary atresia, with an estimated prevalence of 0.73%-2.44%.1
Fortunately, surgical, medical, and radiographic advancements have dramatically improved the outcomes of children diagnosed with biliary atresia. Dr Morio Kasais development of the hepatoportoenterostomy procedure enabled
the placement of a surgical conduit to allow bile drainage and arrest the progression of biliary atresia. Although the
outcomes following hepatoportoenterostomy are variable and likely related to multiple factors, the overall improved
survival following portoenterostomy ensured long-term survival in affected patients for the first time.
Augmenting the surgical innovations were medical and radiographic advancements to improve the care for children
with biliary atresia. Prevention of cholangitis, stimulation of choleresis, and aggressive nutritional support have collectively improved the medical care provided to children following portoenterostomy. Additionally, as it relates to
Okuyamas original report, biomarkers such as alpha-fetoprotein and improved imaging using gadoliniumethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) enhanced magnetic resonance imaging have
enabled early detection of malignant transformation with resultant timely intervention.
Finally, although Kasai portoenterostomy and optimal medical management allowed survival beyond 3 years of life,
disease progression occurred in the majority of patients. However, with the advent of liver transplant, there has been a
clear reversal of fortune for children diagnosed with biliary atresia. Although survival rates in 1965 hovered around
10%, families today can expect survival rates above 90%.2
James E. Squires, MD, MS
Division of Gastroenterology
Cincinnati Childrens Hospital Medical Center
Cincinnati, Ohio
http://dx.doi.org/10.1016/j.jpeds.2014.12.073

References
1. Kim JM, Lee SK, Kwon CH, Joh JW, Choe YH, Park CK. Hepatocellular carcinoma in an infant with biliary atresia younger than 1 year. J Pediatr
Surg 2012;47:819-21.
2. Ryckman FC, Fisher RA, Pedersen SH, Balistreri WF. Liver transplantation in children. Semin Pediatr Surg 1992;1:162-72.

Cerebral Palsy after Neonatal Encephalopathy: How Much Is Preventable?

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www.jpeds.com

Vol. 167, No. 1

Appendix
Additional members of the Canadian Cerebral Palsy Registry
include:
John Andersen, MD (Glenrose Rehabilitation Hospital,
Edmonton, AB), David Buckley, MBChB (Janeway Childrens Hospital, St. Johns, NL), Darcy Fehlings, MD (Bloorview Kids Rehab, Toronto, ON), Adam Kirton, MD, MSc
(Alberta Childrens Hospital, Calgary, AB), Alison Moore,
MD (Alberta Childrens Hospital, Calgary, AB), Esias van Rensburg, MD (BC Childrens Hospital, Vancouver, BC), and
Ellen Wood, MD (IWK Health Centre, Halifax, NS).

Cerebral Palsy
1001

Cerebral Palsy,
36 weeks and
BW 1800g
543

Moderate to
severe NE
155 (29%)

Excluded: n = 458
< 36 weeks: 350
Unknown GA: 93
BW < 1800g: 1
Unknown BW: 14

No moderate to
severe NE
388 (71%)

Cooling Criteria
9 (2%)

No Cooling Criteria
379 (98%)

Included in
analysis

Cooling Criteria
64 (41%)

No Cooling Criteria
91 (59%)

Figure. Flow chart. BW, body weight; GA, gestational age.

63.e1

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