Antecedents of Cerebral Palsy. Multivariate Analysis of Risk

Abstract

We examined prenatal and perinatal factors predicting cerebral palsy, using multivariate analysis to investigate which factors were most important and the proportion of cases for which they accounted. Maternal mental retardation, birth weight below 2001 g, and fetal malformation were among the leading predictors. Breech presentation was also a predictor, but breech delivery was not. A third of the children with cerebral palsy who had breech presentations had a major noncerebral malformation. Among 189 children with cerebral palsy, 40 (21 percent) had at least one of three clinical markers suggestive of asphyxia; only 17 of these 40 children (9 percent of all cases) lacked major congenital malformation or other intrinsic defects that might have contributed to an unfavorable outcome. When all the principal risk factors present by the time labor began were considered, the 5 percent of the population at highest estimated risk was seen to have contributed 34 percent of the cases. When all the risk factors present during the period beginning before pregnancy and extending through the nursery stay were included, the 5 percent at highest risk was seen to have contributed 37 percent of the cases. Thus, the inclusion of information about the events of birth and the neonatal period accounted for a proportion of cerebral palsy only slightly higher than that accounted for when consideration was limited to characteristics identified before labor began.

Full text

Antecedents of Cerebral Palsy and Perinatal
Death in Term and Late Preterm Singletons
Sarah McIntyre, BAppSc,MPS, Eve Blair, PhD, Nadia Badawi, FRACP,PhD, John Keogh, FRCOG,
and Karin B. Nelson, MD
OBJECTIVE: To examine the antecedents of cerebral palsy
and of perinatal death in singletons born at or after
35 weeks of gestation.
METHODS: From a total population of singletons born
at or after 35 weeks of gestation, we identified 494 with
cerebral palsy and 508 neonates in a matched control
group, 100 neonatal deaths, and 73 intrapartum stillbirths
(all deaths in selected birth years). Neonatal death and
cerebral palsy were categorized as without encephalop-
athy, after neonatal encephalopathy, or after neonatal
encephalopathy considered hypoxic–ischemic. We
examined the contribution of potentially asphyxial birth
events, inflammation, fetal growth restriction, and birth
defects recognized by age 6 years to each of these out-
comes and to intrapartum stillbirths.
RESULTS: The odds of total cerebral palsy after potentially
asphyxial birth events or inflammation were modestly
increased (odds ratio [OR] 1.9, 95% confidence interval
[CI] 1.1–3.2 and OR 2.2, 95% CI 1.0–4.2, respectively).
However, potentially asphyxial birth events occurred in
34% of intrapartum stillbirths and 21.6% of cerebral palsy
after hypoxic–ischemic encephalopathy. Inflammatory
markers occurred in 13.9% and 11.9% of these outcomes,
respectively. Growth restriction contributed significantly to
all poor outcome groups. Birth defects were recognized in
5.5% of neonates in the control group compared with 60%
of neonatal deaths and more than half of cases of cerebral
palsy without hypoxic–ischemic encephalopathy. In chil-
dren with cerebral palsy, a potentially asphyxial birth event,
inflammation, or both were experienced by 12.6%,
whereas growth restriction, a birth defect, or both were
experienced by 48.6% (P,.001).
CONCLUSION: Fetal growth restriction and birth defects
recognized by age 6 years were more substantial contrib-
utors to cerebral palsy and neonatal death than potentially
asphyxial birth events and inflammation.
(Obstet Gynecol 2013;122:869–77)
DOI: 10.1097/AOG.0b013e3182a265ab
LEVEL OF EVIDENCE: II
Two thirds of cerebral palsy arises in the 97% of
singletons born at or after 35 weeks of gestation.
1
The prevalence of cerebral palsy in these relatively
mature neonates, unlike that of survivors of very pre-
term birth, has not fallen in recent decades.
1,2
Our
knowledge of brain lesions in cerebral palsy has
improved with advances in neuroimaging, but the eti-
ology and prognostic value of these lesions remain
imperfectly understood.
3
Historically, research on
the etiologies of cerebral palsy in term and late pre-
term births has focused on asphyxial birth events.
More recently, the diversity of cerebral palsy etiology
has been explored with studies examining antenatal
factors including inflammation, suboptimal intrauterine
growth, malformations, multiple gestations, genetic fac-
tors,
4
and how risk factors may interact to form causal
pathways to cerebral palsy
5
; we aimed to build on
this work.
From the University of Sydney, Cerebral Palsy Alliance, University of Notre
Dame Australia, Darlinghurst, New South Wales, the Centre for Child Health
Research, University of Western Australia at the Telethon Institute for Child
Health Research, Perth, and the Cerebral Palsy Alliance, University of Notre
Dame Australia, Grace Centre for Newborn Care, the Children’s Hospital at
Westmead, the University of Sydney, and the University of Sydney, Sydney
Adventist Hospital, Sydney, Australia; the Department of Neurology, Children’s
National Medical Centre, Washington, DC; and the National Institute of Neuro-
logical Disorder and Stroke, National Institutes of Health, Bethesda, Maryland.
Supported by the Cerebral Palsy Research Foundation (S.M.), National Health
and Medical Research Council program grant no. 353514 (CCCP study and
E.B.), and the Macquarie Group Foundation and Cerebral Palsy Research Foun-
dation (N.B.).
The authors thank Linda Watson from the Western Australian Register of
Developmental Anomalies–Cerebral Palsy and Professor Carol Bower from the
Western Australian Register of Developmental Anomalies for providing access to
data from their respective registers.
Corresponding author: Sarah McIntyre, BAppSc, MPS, PhD, University of Sydney,
Cerebral Palsy Alliance, University of Notre Dame Australia, PO Box 560,
Darlinghurst 1300 NSW, Australia; e-mail: smcintyre@cerebralpalsy.org.au.
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2013 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/13
VOL. 122, NO. 4, OCTOBER 2013 OBSTETRICS & GYNECOLOGY 869
MS NO: AOG203259

The objective of this study was to gain more
specific information concerning pathways to perinatal
death or cerebral palsy in term and late preterm
singletons. We sought to identify etiologically more
homogenous groups of cerebral palsy and neonatal
death by stratifying according to newborn neurologic
status, then quantified the contributions of four major
risk factors: potentially asphyxial birth events, indica-
tors of inflammation, fetal growth restriction, and
birth defects, alone or in combination, to each of these
outcomes.
MATERIALS AND METHODS
This article reports on the total population case–control
study of cerebral palsy and perinatal death in Western
Australian births from 1980 to 1995.
6–8
Cerebral palsy
was defined as a disorder of movement, posture, or
both affecting activities of daily living resulting from
nonprogressive lesions or abnormalities of the develop-
ing brain.
1
Eligible cases of cerebral palsy for this study
comprised all registrants of the Western Australian
Cerebral Palsy Register (now called the Western Aus-
tralian Register of Developmental Anomalies–Cerebral
Palsy)
1
born in Western Australia between January 1,
1980, and December 31, 1995, excluding those whose
cerebral palsy was acquired postneonatally.
Perinatal and vital outcome data are available for
all Western Australian births in the Maternal Child
Health Research Database, which links statutory birth
and death registries with statutory pregnancy and
delivery information and includes more than 99.5% of
registered births. From this database, we selected
controls (matched for gestational age [within 1 week],
year of birth [within 12 months], and plurality) and
intrapartum stillbirths and neonatal deaths (deaths in
the first 28 days of life) in birth years specified in
Figure 1. We included all 791 children with cerebral
palsy born in or after 1980 (the year that the gesta-
tional age variable was added to the statutory birth
data set) who were available at the time of initiating
data collection. We limited etiologic heterogeneity by
selecting only singletons born at or after 35 weeks of
gestation, resulting in 508 participants in the control
group and 494 cerebral palsy cases. With these num-
bers, and considering that the direction of any associ-
ation would for most exposures be self-evident, we
estimated there was 80% or higher power at P,.05
to detect associations likely to be of clinical impor-
tance (odds ratios [ORs] less than 0.4 or greater than
1.8) if the exposure was observed in 5–50% of partic-
ipants in the control group.
This study was approved by the Princess Margaret
Hospital/King Edward Memorial Hospital Human
Research and Ethics Committee, individual hospital
and region human research and ethics committees,
ratified by the University of Sydney Human Research
and Ethics Committee and approved by the Confi-
dentiality of Health Information Committee of the
Western Australia Department of Health.
To achieve more homogenous etiologic groups,
we categorized cerebral palsy and neonatal death
according to presence or absence of moderate or
severe neonatal encephalopathy. Moderate or severe
neonatal encephalopathy was defined as any admis-
sion to special or intensive care (for neonatal death)
for 2 days or more (for cerebral palsy) with seizures,
abnormal consciousness (lethargic or comatose), or
abnormal tone.
9–11
Neonatal encephalopathy was cat-
egorized as hypoxic–ischemic only if there was also a
clinical diagnosis of birth asphyxia or hypoxic–ischemic
encephalopathy in the medical record and is now
referred to as hypoxic–ischemic encephalopathy.
We considered seven adverse outcomes: intrapar-
tum stillbirth; neonatal death without encephalopathy,
after neonatal encephalopathy, and after hypoxic–
ischemic encephalopathy; and cerebral palsy without
encephalopathy, after neonatal encephalopathy, and
after hypoxic–ischemic encephalopathy; and two com-
bined outcomes “all cerebral palsy”and “all neonatal
deaths”(Fig. 1). We examined the association of each
of these outcomes with four repeatedly identified risk
factors: 1) potentially asphyxial birth events: uterine
rupture, amniotic embolism, tight nuchal cord
(described by the treating clinician as “tight”;eg,
requiring cutting for delivery), cord prolapse, placental
abruption, severe intrapartum hemorrhage (a minimum
of 100 mL fresh blood), maternal cardiac arrest, or
severe shoulder dystocia
12,13
; 2) signs of inflammation:
maternal pyrexia (greater than 37.5°C), uterine tender-
ness, malodorous amniotic fluid, high leukocyte count,
maternal or fetal tachycardia, and inflammatory placen-
tal histology
14
; 3) fetal growth restriction: birth weight at
least two standard deviations below optimal for gesta-
tional age and gender, maternal height and parity,
15
or
to a decrease the risk of false-negatives with this restric-
tive criterion, a diagnosis of growth restriction noted in
the medical record; and 4) birth defects: a structural or
functional abnormality that is present at conception or
occurs before the end of pregnancy. We identified birth
defects by linking with the State Registry for birth
defects (Western Australian Register of Developmental
Anomalies), which collects information on defects diag-
nosedbyage6years.
16
For those with cerebral palsy, the predominant
motor impairment was categorized as spastic
hemiplegia, diplegia or quadriplegia, dyskinesia
870 McIntyre et al Antecedents of Cerebral Palsy OBSTETRICS & GYNECOLOGY

(dystonia or athetosis), or other (ataxia or isolated
hypotonia).
For each outcome group, we estimated frequen-
cies and proportions of each risk factor and pre-
dominant motor impairment. Odds ratios for each
outcome with each risk factor were estimated by
unconditional logistic regression using SAS 9.2 and
SPSS 19. Statistical significance was accepted at
a,.05. The proportion of each outcome group that
would be prevented were the risk factor removed in
isolation was estimated from the OR obtained on uni-
variate analysis using the equation: attributable
fraction5p(OR-1)/(1+p[OR-1]), where p is the pro-
portion of participants in the control group exposed
to that factor.
17
Median and interquartile ranges were
calculated for 5-minute Apgar scores.
RESULTS
Data were available for 508 participants in the control
group, 494 children with cerebral palsy, 100 neonatal
Western Australian
births 1980–1995
N=380,918
Cerebral palsy
cases from the
Western Australian
cerebral palsy register
(excluding postneonatal
and minimal cases)
n=782
Controls without
cerebral palsy
from the Maternal
Child Health Research
Database matched on
gestational age, year
of birth, and plurality
n=738
Intrapartum stillbirths
from 1985, 1987, 1989,
1991, 1993, and 1995;
n=289*
Excluded: n=288
Registered
after participant
selection: 12
Medical records not
located: 29
Multiple births and
singletons under
35 weeks of
gestational age: 247
Excluded: n=230
Multiple births
and singletons
under 35 weeks of
gestational age: 230
Excluded: n=216
Multiple pregnancies
and intrapartum
stillbirths under 35 weeks
of gestational age: 216
Neurologic status
in the newborn period:
No encephalopathy;
neonatal
encephalopathy
with clinical diagnosis
of hypoxic-ischemic
encephalopathy
Final groups for analysis
n=1,175
Total infants with
cerebral palsy
n=494†
Controls
n=508‡
Neonatal deaths
n=100
Intrapartum stillbirths
n=73
Neonatal deaths from
1985, 1987, 1991, 1995
n=336*
Excluded: n=236
Multiple births
and neonatal deaths
at under 35 weeks of
gestational age: 236
Neonatal
encephalopathy
n=60
No neonatal
encephalopathy
n=323
Hypoxic-ischemic
encephalopathy
n=103
No neonatal
encephalopathy
n=54
Neonatal
encephalopathy
n=24
Hypoxic-ischemic
encephalopathy
n=22
Singletons with cerebral
palsy at or above 35
weeks of gestation
n=494
Singleton controls at
or above 35
weeks of gestation
n=508
Singleton neonatal
deaths at or above 35
weeks of gestation
n=100
Singleton intrapartum
stillbirths
n=73
Fig. 1. Group selection from Western Australian total population. *Terminations and lethal birth defects excluded.
†
Includes
eight children with missing data for neurologic status in the newborn period.
‡
No hypoxic–ischemic encephalopathy; mild
neonatal encephalopathy.
McIntyre. Antecedents of Cerebral Palsy. Obstet Gynecol 2013.
VOL. 122, NO. 4, OCTOBER 2013 McIntyre et al Antecedents of Cerebral Palsy 871

deaths, and 73 intrapartum stillborn singletons born at
or after 35 weeks of gestation. There were no differ-
ences among these four groups with respect to
maternal age, number of previous births and number
of previous pregnancy losses, maternal epilepsy,
intellectual disability or other neurologic disorders,
coagulation disorders, or thyroid disease. Two pre-
conceptional factors were statistically different from
the control group. Of those with nonmissing data,
0.8% of participants in the control group, 1.6% of
cerebral palsy, 3.1% of neonatal deaths, and 1.4% of
intrapartum stillbirths had received treatment for
infertility. Private health insurance was held by
52.8% of mothers of participants in the control group,
46.8% of cerebral palsy, 36% of neonatal deaths, and
34.2% of intrapartum stillbirths and was the only
marker of social status widely available.
Eight children with cerebral palsy and missing
data for neonatal neurologic status were retained for
analyses of “all cerebral palsy”only. Of the 486
remaining children with cerebral palsy, 66.5% did
not exhibit encephalopathy, 12.4% exhibited neonatal
encephalopathy, and 21.2% were diagnosed with
hypoxic–ischemic encephalopathy (Table 1). Of the
100 neonates who died in the neonatal period, 22%
were diagnosed with hypoxic–ischemic encephalopa-
thy before death, a further 24% exhibited neonatal
encephalopathy, and 54% were not considered
encephalopathic (Table 2). Three participants in the
control group met our criteria for neonatal encepha-
lopathy but none for hypoxic–ischemic encephalopa-
thy. All 508 participants in the control group were
used as the comparison group. Apgar scores at 5
minutes were consistent with assigned neonatal neu-
rologic status: the median and interquartile range was
9 (interquartile range 9–9) for participants in the
control group and children with cerebral palsy with-
out encephalopathy, 9 (8–9) for children with cere-
bral palsy after neonatal encephalopathy, 4 (3–6) for
children with cerebral palsy after hypoxic–ischemic
encephalopathy, 9 (6–9) for neonatal deaths with-
out encephalopathy, 7 (5–8) for neonatal deaths with
encephalopathy, and 3 (1–5) for neonatal deaths
with hypoxic–ischemic encephalopathy.
The value for at least one of the four risk factors
was missing for no participants in the control group,
35 (7.1%) cerebral palsy cases, two (2%) neonatal
deaths, and one (1.4%) intrapartum stillbirth. Of those
with complete data, most (83%) of participants in the
control group, 40.5% of cerebral palsy, 23% of neonatal
Table 1. Distribution, Odds, and Central Estimate of Population-Attributable Fraction of Risk Factors in
Participants in the Control Group and Each Cerebral Palsy Outcome
Risk Factor
Cerebral Palsy
Control
(n5508)
No
Encephalopathy
(n5323)
Neonatal
Encephalopathy
(n560)
Hypoxic–Ischemic
Encephalopathy
(n5103) All* (n5494)
Potentially asphyxial birth event 24 (4.7) 15 (4.6) 5 (8.5) 22 (21.6) 42 (8.5)
Odds ratio (95% CI) Reference 1.0 (0.5–1.9) 1.9 (0.7–5.1) 5.5 (3.0–10)
†
1.9 (1.1–3.2)
†
Population-attributable
fraction central estimate (%)
04 17
†
4
†
Inflammation 12 (2.4) 7 (2.3) 3 (5.3) 12 (11.9) 22 (4.8)
Odds ratio (95% CI) Reference 1.0 (0.4–2.5) 2.3 (0.6–8.4) 5.6 (2.4–13)
†
2.1 (1.0–4.2)
†
Population-attributable
fraction central estimate (%)
03 10
†
3
†
Growth restriction 27 (5.3) 44 (13.7) 21 (35.0) 15 (14.6) 81 (16.5)
Odds ratio (95% CI) Reference 2.8 (1.7–4.7)
†
9.6 (5.0–18.5)
†
3.0 (1.6–5.9)
†
3.5 (2.2–5.5)
†
Population-attributable
fraction central estimate (%)
9
†
31
†
10
†
12
†
Birth defect at age 6 y 28 (5.5) 140 (43.3) 40 (66.7) 26 (25.2) 209 (42.3)
Odds ratio (95% CI) Reference 13.1 (8.4–20.4)
†
34.3 (17.8–66)
†
5.8 (3.2–10.4)
†
12.6 (8.3–19)
†
Population-attributable
fraction central estimate (%)
40
†
65
†
21
†
39
†
None of the above 424 (83.5) 138 (45.7) 9 (16.1) 39 (39.0) 186 (40.5)
CI, confidence interval.
Data are n (%) unless otherwise specified.
Denominators vary with the number of patients for whom the datum was missing; percentages given are those with a known value.
* Includes eight with missing data for neonatal neurologic status.
†
Statistically significant at P,.05.
872 McIntyre et al Antecedents of Cerebral Palsy OBSTETRICS & GYNECOLOGY

deaths and 40.3% of intrapartum stillbirths experienced
none of the four risk factors (Tables 1 and 2).
Potentially asphyxial birth events occurred with a
similar low frequency in control children and those with
cerebral palsy or neonatal death who were not enceph-
alopathic in the newborn period. Potentially asphyxial
birth events occurred most frequently in intrapartum
stillbirths (34.3%) and in children with cerebral palsy or
neonatal death after hypoxic–ischemic encephalopathy
(21.6% and 22.7%, respectively) (Tables 1 and 2). Tight
nuchal cord, intrapartum hemorrhage (including pla-
cental abruption), and cord prolapse accounted for
87 of the 100 events reported and there were no instan-
ces of amniotic embolism (see Appendix, available on-
line at http://links.lww.com/AOG/A420).
Indicators of inflammation showed a similar pat-
tern to potentially asphyxial birth events, being rare in
participants in the control group and in cerebral palsy
with or without neonatal encephalopathy, but occurring
in significantly higher proportions of intrapartum
stillbirths, neonatal deaths, and cerebral palsy with
hypoxic–ischemic encephalopathy (Tables 1 and 2).
Inflammation occurred in combination with potentially
asphyxial birth events in 8.2% of intrapartum stillbirths
but infrequently in neonatal death or cerebral palsy
(Table 3).
Our criteria for growth restriction (see Appendix,
http://links.lww.com/AOG/A420) were met by 5.3%
of participants in the control group and at least 13% of
each poor outcome, being highest in poor outcome
groups after neonatal encephalopathy. For each sub-
group of neonatal neurologic status, growth restriction
was associated with higher odds of neonatal death
than of cerebral palsy (Tables 1 and 2).
Birth defects recognized by age 6 years were
associated with significantly elevated ORs and with
the highest attributable fraction of the four risk factors
examined for all outcome groups except for intrapartum
Table 2. Distribution, Odds, and Central Estimate of Population-Attributable Fraction of Risk Factors in
Participants in the Control Group and Each Perinatal Death Outcome
Neonatal Death
Risk Factor
Control
(n5508)
Intrapartum
Stillbirth
(n573)
No Neonatal
Encephalopathy
(n552)
Neonatal
Encephalopathy
(n524)
Hypoxic–Ischemic
Encephalopathy
(n522) All (n5100)
Potentially asphyxial
birth event, n (%)
24 (4.7) 25 (34.3) 4 (7.7) 1 (3.9) 5 (22.7) 10 (10.0)
Odds ratio (95% CI) Reference 10.5 (5.6–20)* 1.7 (0.7–5.0) 0.8 (0.1–6.2) 5.9 (2.0–17)* 2.2 (1.0–4.8)*
Population-
attributable fraction
central estimate (%)
31* 3 0 19* 5*
Inflammation, n (%) 12 (2.4) 10 (13.9) 6 (11.3) 1 (3.9) 3 (14.3) 10 (10.0)
Odds ratio (95% CI) Reference 6.7 (2.8–6.1)* 5.4 (1.9–15)* 1.7 (0.2–13.2) 6.9 (1.8–27)* 4.6 (1.9–11)*
Population-
attributable fraction
central estimate (%)
12* 10.5* 1.5 12* 8*
Growth restriction, n (%) 27 (5.3) 16 (21.9) 12 (23.5) 11 (42.3) 7 (31.8) 30 (30.3)
Odds ratio (95% CI) Reference 5.0 (2.5–9.8)* 5.3 (2.6–11.7)* 13.1 (5.5–31)* 8.3 (3.1–22)* 7.7 (4.3–13.8)*
Population-
attributable fraction
central estimate (%)
17* 19* 41* 28* 26*
Birth defect at age 6 y,
n (%)
28 (5.5) 9 (12.3) 30 (57.7) 22 (84.6) 8 (36.4) 60 (60.0)
Odds ratio (95% CI) Reference 3.1 (1.3–7)* 34 (12.0–46)* 94 (30–292)* 9.7 (3.8–25)* 25.7 (14.9–45)*
Population-
attributable fraction
central estimate (%)
10* 55* 84* 32* 54*
None of the above, n (%) 424
(83.5)
29 (40.3) 14 (27.4) 3 (11.5) 6 (28.6) 23 (23.5)
CI, confidence interval.
Data are n (%) unless otherwise specified.
Denominators vary with the number of patients for whom the datum was missing; percents given are those with a known value.
* Statistically significant at P,.05.
VOL. 122, NO. 4, OCTOBER 2013 McIntyre et al Antecedents of Cerebral Palsy 873

stillbirths (Tables 1 and 2). They were identified in
almost half of the largest outcome group, cerebral palsy
without encephalopathy. Birth defects occurring in
combination with a potentially asphyxial birth event
or inflammation were seen in only a small proportion
of both cerebral palsy and neonatal death cases. Birth
defects and growth restriction were the most common
combination of risk factors, particularly in neonatal
death and cerebral palsy (Table 3). In children with
cerebral palsy, a potentially asphyxial birth event,
inflammation, or both was experienced by 12.6%,
whereas growth restriction, a birth defect, or both was
experienced by 48.6% (P,.001), making these the dom-
inant antecedents of term and late preterm singletons.
All cerebral palsy subtypes were represented
across all outcome groups (Table 4). Despite confirm-
ing the association between quadriplegia or dyskinesia
and hypoxic–ischemic encephalopathy, 65% of those
with quadriplegia or dyskinesia were not diagnosed
hypoxic–ischemic encephalopathy, and conversely
of 103 cases of cerebral palsy after hypoxic–ischemic
encephalopathy, 36 were not classified quadriplegic
or dyskinetic. Of the four risk factors, only birth
defects (OR 1.6, 95% confidence interval [CI] 1.1–2.3),
growth restriction (OR 1.7, 95% CI 1.1–2.8), and the
combination of growth restriction and a birth defect
(OR 1.9, 95% CI 1.1–3.6) significantly predicted quad-
riplegia or dyskinesia.
Table 3. Distributions and Odds of Combinations of Risk Factors in Participants in the Control Group,
Perinatal Deaths, and Cerebral Palsy
Factor Combination Control
Intrapartum
Stillbirth
Neonatal
Death
Cerebral
Palsy
Potentially asphyxial birth event and inflammation 1 (0.2) 4 (5.6) 0 2 (0.4)
OR (95% CI) Reference 29.4 (3.2–266)
Growth restriction and potentially asphyxial birth event 2 (0.4) 2 (2.8) 0 0
OR (95% CI) Reference 7.1 (1–51.4)
Growth restriction and inflammation 0 2 (2.8) 2 (2.0) 1 (0.2)
Potentially asphyxial birth event, inflammation and growth
restriction
0 2 (2.8) 1 (1.0) 0
Potentially asphyxial birth event and birth defect 1 (0.2) 0 2 (2.0) 11 (2.4)
OR (95% CI) Reference 11.5 (1.5–89)
Inflammation and birth defect 0 1 (1.4) 3 (3.1) 1 (0.2)
Growth restriction and birth defect 3 (0.6) 3 (4.2) 20 (20.4) 38 (8.3)
OR (95% CI) Reference 7.2 (1.4–36) 42.1 (12.2–145) 14 (4.3–45.8)
Growth restriction, birth defect, and potentially asphyxial
birth event
0 0 1 (1.0) 2 (0.4)
Growth restriction, birth defect, and inflammation 0 0 1 (1.0) 3 (0.7)
OR, odds ratio; CI, confidence interval.
Data are n (%) unless otherwise specified.
This table shows only statistically significant odds ratios for combinations experienced by participants in the control group.
Table 4. Distribution of Cerebral Palsy Type by Neonatal Neurologic Status
Cerebral Palsy Type
Without
Encephalopathy
Neonatal
Encephalopathy
Hypoxic–Ischemic
Encephalopathy
All Cerebral
Palsy*
Hemiplegia, n 125 15 11 154 (31.2)
% hemiplegia 81.2 9.7 7.1
Diplegia, n 69 5 19 94 (19)
% diplegia 73.4 5.3 20.2
Quadriplegia, n 51 25 39 116 (23.5)
% quadriplegia 44 21.6 33.6
Dyskinesia, n 38 8 28 75 (15.2)
% dyskinesia 50.7 10.7 37.3
Ataxia or hypotonia, n 40 7 6 55 (11.1)
% ataxia or hypotonia 72.7 12.7 10.9
Total 323 60 103 494 (100)
* Includes eight children with missing data for neonatal neurologic outcome.
Data are n or n (%).
874 McIntyre et al Antecedents of Cerebral Palsy OBSTETRICS & GYNECOLOGY

DISCUSSION
By defining more etiologically homogenous outcome
groups, limiting study participants to singletons at or
after 35 weeks of gestation, and stratifying by neonatal
neurologic status, our study identified stronger asso-
ciations for these risk factors and cerebral palsy or
perinatal death than previously published.
18
We were
also able to identify poor outcome groups that had
little or no association with these specific risk factors.
This more informative approach to considering the
etiologic pathways to term and late preterm cerebral
palsy and perinatal death allowed us to see which out-
comes were most related to each of these risk factors.
The term hypoxic–ischemic encephalopathy is
often understood to imply a uniform etiology. How-
ever, in this population of children with cerebral palsy
who had been diagnosed with neonatal hypoxic–
ischemic encephalopathy, only one child in five had
a clinically recognized potentially asphyxial birth
event, whereas one in eight had markers of inflamma-
tion, one in seven was growth-restricted, one in four
had a birth defect recognized by age 6 years, and two
in five had none of these factors. Similar etiologic
heterogeneity was found in neonatal deaths preceded
by a diagnosis of hypoxic–ischemic encephalopathy.
The most etiologically homogenous groups were neo-
natal death or cerebral palsy after neonatal encepha-
lopathy in which four in five and three in five
children, respectively, had a recognized birth defect.
As anticipated,
19
potentially asphyxial birth
events were most important for intrapartum stillbirth
with a population-attributable fraction of 31%. How-
ever, population-attributable fractions for cerebral
palsy or neonatal death after hypoxic–ischemic enceph-
alopathy were higher for birth defects than for poten-
tially asphyxial birth events, an unanticipated finding.
Potentially asphyxial birth events were not associated
with cerebral palsy in the absence of neurologic abnor-
mality in the newborn period, confirming the position
of the consensus statement.
12
Intrauterine inflammation was the least identified
risk factor but markers of inflammation available in
population studies are neither sensitive nor specific
and may underestimate its role. Inflammation can
produce clinical findings that closely mimic birth
asphyxia, so it is possible that in some children with
a diagnosis of hypoxic–ischemic encephalopathy, the
initiating pathologic process was inflammatory. Opti-
mal clinical management and strategies for prevention
require distinguishing neonatal neurologic depression
resulting from asphyxial injury from that associated
with inflammation or other processes.
20
That differential
diagnosis will require incorporation of information
from placental examination and may also require dis-
tinguishing inflammation resulting from infection
(chorioamnionitis or funisitis) from that resulting from
immunologic processes (chronic villitis).
21,22
Fetal growth restriction was an important factor in
all examined poor outcome groups and has been
shown in other studies to be an important predictor of
cerebral palsy,
4
neonatal encephalopathy,
9,23
and still-
birth.
19
Growth restriction is itself etiologically heter-
ogenous with maternal, fetal, and placental antecedents
that vary in their strength of association with cerebral
pathology.
7,24
Of note, the majority of neonates with
growth restriction and adverse outcomes in this study
also had a birth defect recognized by early childhood.
Birth defects have been recognized as risk factors
for cerebral palsy at least since 1955
25
but in the current
study were identified in a far greater proportion than is
usually reported with a population-attributable fraction
of 39% for total cerebral palsy. Only 1.7% considered
deformational, that is, possibly a result of the brain
damage that also caused cerebral palsy. This difference
may be related to our focus on term and late preterm
singletons because defects are identified in greater pro-
portions of term than preterm born children with cere-
bral palsy,
26
the inclusion of all defects occurring before
delivery (because many studies of cerebral palsy etiol-
ogy exclude birth defects, at least those of the brain and
spinal cord), and the inclusion of defects recognized
up to the age of 6 years.
27
Acceptance of defects with
delayed recognition raises the possibility of outcome
bias; in an effort to counter this bias, minor defects were
included in these analyses only if they were identified
neonatally, before the outcome of cerebral palsy was
known. The combination of growth restriction and
a birth defect was the strongest predictor of neonatal
death and quadriplegic or dyskinetic cerebral palsy. At
present, both birth defects and marked growth restric-
tion are exclusion criteria for trials of therapeutic hypo-
thermia. Birth defects are also exclusion criteria for
trials to improve neurologic outcomes associated with
growth restriction. Given the considerably elevated risk
this group faces, it may be necessary to investigate ante-
cedents and approaches to management for these two
risk factors, especially when they co-occur.
The strengths of this study include its prospective
design in a total geographically defined population
and ascertainment of birth defects as recorded in the
State Register up to 6 years of age. It includes perinatal
deaths and attempts to identify etiologically more
specific pathways by stratifying by neonatal neurologic
status. Among its limitations, antepartum stillbirths
were not included because retrospective data for these
VOL. 122, NO. 4, OCTOBER 2013 McIntyre et al Antecedents of Cerebral Palsy 875

occurrences were of relatively poor quality. Popula-
tion-attributable fractions estimate the clinically inter-
pretable fraction of the outcome preventable on the
isolated removal of an exposure by considering both
frequency of exposure and relative risk; however, they
must be interpreted cautiously. Our case–control study
design necessitates estimation of ORs, which overesti-
mate relative risk particularly when risks are high, re-
sulting in overestimation of population-attributable
fractions even if the exposure is indeed causal. The
medical records from which our data were extracted
were not created for research and certain potentially
important observations were not regularly available,
the most significant omission being placental histology.
Cerebral imaging was not routinely performed in this
era so perinatal stroke, a common cause of hemiplegic
cerebral palsy in term neonates,
28
is not reported.
Although these data are based on birth years 1980–
1995, the rate of cerebral palsy in term and late pre-
term singletons remained constant throughout the
study period and has been unchanged since.
1,2
Concurrent investigation of major risk factors in
a total population and categorization of outcomes by
neonatal neurologic status allows a better understand-
ing of the association of specific antecedents with
perinatal death and cerebral palsy than was previously
available. When 33 research priorities for the etiology
and prevention of cerebral palsy were recently agreed
on, more than one third focused on infection or
inflammation and hypoxia–ischemia, whereas none
addressed birth defects or growth restriction.
29
Surely,
research priorities in cerebral palsy need reconsidera-
tion. This study adds weight to the evidence that in
singletons born at or after 35 weeks of gestation, very
significant proportions of cerebral palsy and of perinatal
death are associated with antenatal maldevelopment.
REFERENCES
1. Watson L, Blair E, Stanley F. Report of the Western Australian
Cerebral Palsy Register to birth year 1999. Perth, Australia:
Telethon Institute for Child Health Research; 2006.
2. Himmelmann K, Hagberg G, Uvebrant P. The changing pano-
rama of cerebral palsy in Sweden. X. Prevalence and origin in the
birth-year period 1999–2002. Acta Paediatr 2010;99:1337–43.
3. Korzeniewski SJ, Birbeck G, DeLano MC, Potchen MJ, Paneth N.
A systematic review of neuroimaging for cerebral palsy. J Child
Neurol 2008;23:216–27.
4. Himmelmann K, Ahlin K, Jacobsson B, Cans C, Thorsen P.
Risk factors for cerebral palsy in children born at term. Acta
Obstet Gynecol Scand 2011;90:1070–81.
5. Blair E. Epidemiology of the cerebral palsies. Orthop Clin
North Am 2010;41:441–55.
6. McIntyre S, Badawi N, Brown C, Blair E. Population case-control
study of cerebral palsy: neonatal predictors for low risk term
singletons. Pediatrics 2011;127:e667–73.
7. Blair E, DeGroot J, Nelson K. Placental infarction identified by
macroscopic examination and risk of cerebral palsy in infants at
35 weeks of gestational age and over. Am J Obstet Gynecol
2011;205:124.e1–7.
8. Taylor CL, De Groot J, Blair EM, Stanley FJ. The risk of cere-
bral palsy in survivors of multiple pregnancies with co-fetal loss
or death. Am J Obstet Gynecol 2009;201:41.e1–6.
9. Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O’Sullivan F,
Burton PR, et al. Antepartum risk factors for newborn encepha-
lopathy: the Western Australian case-control study. BMJ 1998;
317:1549–53.
10. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal
distress. A clinical and electroencephalographic study. Arch
Neurol 1976;33:696–705.
11. Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling
for newborns with hypoxic ischaemic encephalopathy. The
Cochrane Database of Systematic Reviews 2007, Issue 1. Art.
No.: CD003311. DOI: 10.1002/14651858.CD003311.pub3.
12. MacLennan A. A template for defining a causal relation
between acute intrapartum events and cerebral palsy: interna-
tional consensus statement. BMJ 1999;319:1054–9.
13. Perlman JM. Intrapartum asphyxia and cerebral palsy: is there
a link? Clin Perinatol 2006;33:335–53.
14. Shatrov JB, Birch SC, Tam L, Quinlivan J, McIntyre S,
Mendz G. Chorioamnionitis and cerebral palsy: a meta-analysis.
Obstet Gynecol 2010;116;387–92.
15. Blair EM, Liu Y, de Klerk NH, Lawrence DM. Optimal fetal
growth for the Caucasian singleton and assessment of appropri-
ateness of fetal growth: an analysis of a total population perinatal
database. BMC Pediatr 2005;5:13.
16. Bower C, Rudy E, Callaghan A, Quick J, Cosgrove P, Watson L.
Report of the Western Australian Register of Developmental
Anomalies 1980-2010. Available at: http://www.kemh.health.
wa.gov.au/services/register_developmental_anomalies/warda.htm.
Retrieved January 10, 2013.
17. Rockhill B, Newman B, Weinberg C. Use and misuse of pop-
ulation attributable risk. Am J Public Health 1998;88:15–9.
18. McIntyre S, Taitz D, Keogh J, Goldsmith S, Badawi N, Blair E.
A systematic review of risk factors for cerebral palsy in children
born at term in developed countries. Dev Med Child Neurol
2013;55:499–508.
19. Flenady V, Koopmans L, Middleton P, Frøen JF, Smith GC,
Gibbons K, et al. Major risk factors for stillbirth in high-income
countries: a systematic review and meta-analysis. Lancet 2011;
377:1331–40.
20. Wintermark P, Boyd T, Gregas MC, Labrecque M, Hansen A.
Placental pathology in asphyxiated newborns meeting the cri-
teria for therapeutic hypothermia. Am J Obstet Gynecol 2010;
203:579.e1–9.
21. Kim MJ, Romero R, Kim CJ, Tarca AL, Chhauy S,
LaJeunesse C, et al. Villitis of unknown etiology is associated
with a distinct pattern of chemokine up-regulation in the feto-
maternal and placental compartments: implications for conjoint
maternal allograft rejection and maternal anti-fetal graft-versus-
host disease. J Immunol 2009;182:3919–27.
22. Hayes BC, Cooley S, Donnelly J, Doherty E, Grehan A,
Madigan C, et al. The placenta in infants .36 weeks gestation
with neonatal encephalopathy: a case control study. Arch Dis
Child Fetal Neonatal Ed 2013;98:F233–40.
23. Bukowski R, Burgett AD, Gei A, Saade GR, Hankins GD.
Impairment of fetal growth potential and neonatal encephalop-
athy. Am J Obstet Gynecol 2003;188:1011–5.
876 McIntyre et al Antecedents of Cerebral Palsy OBSTETRICS & GYNECOLOGY

24. Halliday HL. Neonatal management and long-term
sequelae. Best Pract Res Clin Obstet Gynaecol 2009;23:
871–80.
25. Eastman NJ, Deleon M. The etiology of cerebral palsy. Am J
Obstet Gynecol 1955;69:950–61.
26. RankinJ,CansC,GarneE,ColverA,DolkH,UldallP,etal.
Congenital anomalies in children with cerebral palsy: a population-
based record linkage study. Dev Med Child Neurol 2010;52:
345–51.
27. Bower C, Rudy E, Callaghan A, Quick J, Nassar N. Age at
diagnosis of birth defects. Birth Defects Res A Clin Mol Teratol
2010;88:251–5.
28. Wu YW, March WM, Croen LA, Grether JK, Escobar GJ,
Newman TB. Perinatal stroke in children with motor impair-
ment: a population-based study. Pediatrics 2004;114:612–9.
29. McIntyre S, Novak I, Cusick A. Consensus research priorities
for cerebral palsy: a Delphi survey of consumers, researchers
and clinicians. Dev Med Child Neurol 2010;52:270–5.
Harold A. Kaminetzky Award
The American College of Obstetricians and Gynecologists (the College) and Obstetrics & Gynecology
have established the Harold A. Kaminetzky Award to recognize the best paper from a non-U.S.
researcher each year.
Dr. Harold A. Kaminetzky, former College Secretary and President, as well as Vice President,
Practice Activities, has had a long career as editor of major medical journals. His last editorship
was as Editor of the International Journal of Gynecology and Obstetrics. Dr. Kaminetzky has also had a
long interest in international activities.
The Harold A. Kaminetzky Award winner will be chosen by the editors and a special committee
of former Editorial Board members. The recipient of the award will receive $2,000.
Read the journal online at www.greenjournal.org rev 7/2013
VOL. 122, NO. 4, OCTOBER 2013 McIntyre et al Antecedents of Cerebral Palsy 877