A C TA Obstetricia et Gynecologica

ACTA REVIE W

Risk factors for cerebral palsy in children born at term

KATE HIMMELMANN1 , KRISTINA AHLIN2 , BO JACOBSSON2 , CHRISTINE CANS3
& POUL THORSEN4
1
Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska University Hospital, Gothenburg, Sweden, 2 Department
of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska University Hospital, Gothenburg, Sweden, 3 Unité
d’Exploitation de l’Information Médicale, SIIM CHU de Grenoble, Grenoble, France, and 4 Department of Obstetrics and
Gynecology, Lillebaelt Hospital, Kolding, Denmark

Key words Abstract

Antenatal care and diagnosis, cerebral palsy,
high-risk pregnancy, neonatology, risk factor
Correspondence
Kate Himmelmann, Department of Pediatrics,
Institute of Clinical Sciences, Queen Silvia
Children’s Hospital, Sahlgrenska University
Hospital, SE-416 85 Gothenburg, Sweden.
E-mail: kate.himmelmann@vgregion.se
Conflict of interest
The authors have stated explicitly that there
are no conflicts of interest in connection with
this article.
Received: 19 July 2010
Accepted: 10 June 2011
DOI: 10.1111/j.1600-0412.2011.01217.x
Objective. To provide an overview of current research on risk factors for cerebral
palsy (CP) in children born at term and hypothesize how new findings can affect
the content of the CP registers worldwide. Design. A systematic search in PubMed
for original articles, published from 2000 to 2010, regarding risk factors for CP in
children born at term was conducted. Methods. Full text review was made of 266
articles. Main Outcome Measures. Factors from the prenatal, perinatal and neonatal
period considered as possible contributors to the causal pathway to CP in children
born at term were regarded as risk factors. Results. Sixty-two articles met the criteria
for an original report on risk factors for CP in children born at term. Perinatal
adverse events, including stroke, were the focus of most publications, followed by
genetic studies. Malformations, infections, perinatal adverse events and multiple
gestation were risk factors associated with CP. The evidence regarding, for example,
thrombophilic factors and non-CNS abnormalities was inconsistent. Conclusions.
Information on maternal and neonatal infections, umbilical cord blood gases at
birth, mode of delivery and placental status should be collected in a standardized
way in CP registers. Information on social factors, such as education level, family
income and area of residence, is also of importance. More research is needed to
understand the risk factors of CP and specifically how they relate to causal pathways
of cerebral palsy.

may be antenatal, peri- or neonatal, postneonatal, or com-

Introduction
Cerebral palsy (CP) is the most common physical disability
in childhood. Cerebral palsy is not a disease, but a syndrome
complex characterized by an aberrant control of movement
or posture, which appears early in life and leads to lifelong
motor disability (1). Perinatal and neonatal mortality have
decreased, maternal and neonatal care have undergone major
changes, but the overall prevalence of CP has remained stable
over the years, at between 1 and 3 per 1 000 live births (2–4).
Children with CP show different clinical patterns, half of them
with bilateral spastic type, a third with unilateral spastic type,
and the remaining with less common types, such as dyskinetic
and ataxic CP.
The underlying causes of CP are still poorly understood.
Several individual risk factors of CP have been identified, but
less is known about their interaction and how they might re-
late to different pathophysiological pathways. The risk factors
bined. Several areas of research have been of interest over the
years, and some of them have changed due to the development
of maternal and neonatal care; for example, the occurrence
of cerebral damage due to hyperbilirubinemia has decreased
dramatically in higher resource countries. It is also believed
that cerebral palsy is often the result of several predisposing
factors or causal pathways and seldom a single event (5). Risk
factors vary also by gestational age, and much research has
been focused on risk factors in children born preterm. How-
ever, the prevalence of CP in children born preterm is decreas-
ing (3). More knowledge regarding risk factors that could be
typical for CP in children born at term is needed, because
more than half of the children with CP are born at term.
Cerebral palsy registers are population databases originat-
ing from multiple sources, relying on a clear definition and
inclusion and exclusion criteria of CP (6). There are several
CP registers around the world. In Europe alone, there are at


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K. Himmelmann et al.
least 18 centers collecting population data on CP. Data col-
lection on CP is also performed in Australia, the USA and
Canada. Different registers may collect different informa-
tion. A collaborative research network, Surveillance of Cere-
bral Palsy in Europe (SCPE), is one example of collaboration
between CP registers with the purpose to harmonize infor-
mation collected, including a common definition and clas-
sification of CP (6). In 1998–1999, the SCPE performed an
assessment of risk factors for CP collected in CP registers. Of
19 considered variables, a standard minimum set of variables
was chosen on the basis of literature studies and availability
of data. An ideal set of variables was also defined and studies
planned. Other recent reviews have focused on a specific area,
such as restricted intra-uterine growth (7), umbilical cord pH
(8) or placental circulation (9).
The purpose of this report is to review the current research
of risk factors for CP for children born at term and to hy-
pothesize how the new findings can affect the content of the
CP registers across the world.
Material and methods
Sources
An extensive and systematic search in PubMed for original
articles, published from 1 January 2000 to 30 April 2010 re-
garding risk factors for CP in children born at term, was con-
ducted on 5 July 2010. Factors from the antenatal, perinatal
and neonatal period and considered as possible contributors
to the causal pathway to CP in children born at term were
regarded as risk factors. ‘Antenatal’ referred to the period
of pregnancy until the onset of labor resulting in delivery,
‘perinatal’ to the period from the onset of labor until the
seventh day of life and ‘neonatal’ to the period up to day 28.
Postneonatal factors were excluded.
The search covered the following factors: maternal factors
(such as reproductive history, medical conditions and preg-
nancy conditions); perinatal factors (such as cord complica-
tion, fetal distress and Apgar scores); and neonatal factors
(such as neonatal infection, neonatal seizures and meconium
aspiration). See Appendix for a full description of the search
terms.
Study selection
The search resulted in 1 048 articles being located. Abstracts
from these were reviewed by three of the authors and 266
were selected for full text review. Selection criteria were as
follows: all known risk factors for CP in children born at
term; the best possible quality and largest possible sample
found (population-based study, case–control study if avail-
able); original articles published from 1 January 2000 to
30 April 2010. Single case reports or review articles were
not included. Only articles written in English were included.

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Risk factors for cerebral palsy in term infants
To mirror the diversity of current research on risk factors for
CP in children born at term, some smaller studies and case
series were also selected.
Sixty-two articles met the criteria of original article report-
ing in risk factors for CP in children born at term, and were
included.
Results
There were several research areas of interest. Studies regard-
ing one or a few antenatal risk factors are listed in Table 1,
those regarding peri- and neonatal risk factors in Table 2
and 10 studies dealing with multiple risk factors in
Table 3. Most publications concerned perinatal adverse events
and hypoxia–ischemia, followed by genetic studies.
Antenatal risk factors
Five studies investigated infections, variably defined and
proven; all but one were case–control studies (10–14).
Chorioamnionitis, maternal urinary tract infection, neu-
rotropic virus infection and cytomegalovirus infection were
associated with a higher risk for CP.
Intra-uterine growth deviation, in both singletons and
twins, was correlated to an increased risk in two large
population-based studies (15,16). An additional study
described associations between antenatal stress and CP in
growth-restricted children (17).
Three studies regarding social deprivation were included.
Area of residence was important in two and socioeconomic
status in one study (18–20).
Genetic factors were considered in 12 studies (21–32), five
of which dealt with thrombophilic factors. Limited and con-
flicting evidence for a higher prevalence of thrombophilic
factors in CP was found. In four of the remaining genetic
studies, specific polymorphisms and haplotypes were associ-
ated with CP. Gene locations and deletions were suggested in
small studies for some inherited CP forms (30,31), while there
was no evidence for a significant contribution of genetics for
athetoid CP (32).
Malformation was the focus of four studies (33–36). Cere-
bral malformations were associated with CP, and in one study
intrapartum complications were more frequent in this group.
Two studies dealt with extracerebral malformations. An
association with CP was only found in one.
Five studies regarding multiple gestation were considered
(37–41). A surviving twin after co-twin fetal death appears
to have a higher risk for CP (37), while vanishing twin was
not significantly associated with CP in the surviving twin
(39). A fourfold increased risk for CP after multiple gesta-
tion was seen in a large study from five populations (40).
Spontaneously conceived triplets were at higher risk for CP
compared with those born after use of artificial reproductive
techniques (41).
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Table 1. Selected important findings from original papers regarding antenatal risk factors for CP in children born at term, published 1 January 2000 to 30 April 2010.

First author/year/ Study Number of

∗
study area design cases Risk factor for CP analyzed Results Comment

Infection
Wu YW 2003 (US) (10) CC 109 Chorioamnionitis (clinical diagnosis) OR 3.8 (1.5–10.1) Term/near term cases with
moderate to severe CP
Neufeld MD 2005 (US) CC (PB) 395 Maternal infection (any) OR 1.8 (1.1–2.8)
(11)
Gibson C 2006 (Australia) CC (PB) 227 Neurotropic virus infection OR 1.64 (1.17–2.28)
(12) Any virus OR 2.38 (1.15–4.92)
Herpes group B for hemiplegia
Pass RF 2006 (US) (13) C 34 Maternal infection with first trimester cytomegalovirus 2 of 34 developed CP
Risk factors for cerebral palsy in term infants

infection
Bax M 2006 (8 European Cross-sectional 400 Report of maternal infection during pregnancy 158 of 400 (39.5%)
centers) (14)
Intra-uterine growth deviation
Jarvis S 2003 (10 PB 4 503 <10th percentile GA 32–42weeks RR 3.7 (3.2–4.3) to 6.3 (4.9–8.2) Singletons with CP
European registers >97th percentile GA 32–42weeks RR 1.6 (1.1–2.2) to 3.1 (1.9–5.0)
within the SCPE) (15)

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Glinianaia SV 2006 (9 PB 373 <–1.28 to <0 SD RR 1.9 (1.1–3.3) to 3.7 (2.1–6.5) Twins with CP, 92% GA
European registers >1.28 SD RR 1.8 (0.9–3.4) n.s. 32–42weeks
within the SCPE) (16)
Li J 2009 (Denmark) (17) PB 6 542 Children born at term with intra-uterine growth restriction HR 2.01 (1.04–3.89) National cohort of 1 501 894
and mothers exposed to extremely severe prenatal stress
Social deprivation
Dolk H 2001 (UK) (18) PB 753 Total CP prevalence in the least deprived area 2.39 per 1 000 Residents in the area
Total CP prevalence in the most deprived area 3.67 per 1 000
Sundrum R 2005 (UK) (19) PB 293 CP and social class p=0.160 n.s. 94.1% born at term
CP and district of residence p=0.046
Hjern A 2008 (Sweden) C (PB) 1 437 Children from households with low socioeconomic status OR 1.4 (1.1–1.7) National cohort of 805 543
(20)
Thrombophilic risk factors
Reid S 2006 (Australia) CC 57 Factor V Leiden mutation in cases with CP due to 10.5 vs. 4% (0.026–0.185) p=0.012 Children with CP on the basis
(21) thrombosis compared with occurrence of the mutation in p=0.385 (n.s.) of vascular thrombosis
the population. (mean GA 39.4weeks)
Study group compared with 167 children with CP of
other origin: no difference


Senbil N 2007 (Turkey) CC 23 CP hemiplegia, factor V Leiden, protein C, lipoprotein-a, 13 of 23 had a coagulation abnormality 20 born at term
(22) prothrombin mutation and protein S were analyzed

Continued

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K. Himmelmann et al.

Table 1. Continued
First author/year/
study area
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Gibson CS 2005
(Australia) (23)
Yehezkely-Schildkraut
2005
(Israel) (24)
Smith RA 2001 (UK) (25)
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Gibson CS 2008
(Australia) (26)
Gibson CS 2008
(Australia) (27)
Pessoa de Barros EMK
2000 (Brazil) (28)
Kuroda MM 2007 (US)
(29)
McHale DP 2000 (UK) (30)
Lerer I. 2005 (Israel) (31)
Amor DJ 2001 (Australia)
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(32)
Croen LA 2001 (US)
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Study Number of
∗
design cases Risk factor for CP analyzed Results Comment
CC (PB) 443 Factor V Leiden, prothrombin and OR 0.99 (0.57–1.72) 225 born at term
K. Himmelmann et al.
methylenetetrahydrofolate reductase were analyzed.
Any thrombophilia and CP homozogous in term
CC 61 Factor V Leiden, prothrombin and One or more mutations p=0.348 40 born at term
methylenetetrahydrofolate) were analyzed
PB 27 CP hemiplegia and thrombophilia, Minor abnormalities in 6, considered 18 born at term
factor VIIIc level, antithrombin, protein C activity, equivocal in 5
protein C and S antigen, prothrombin, allele,
homocystein, factor V Leiden, APC resistance
Other genetic factors
CC 227 Cytokine polymorphisms All gestational ages including
Tumor necrosis factor-α in quadriplegia OR 1.8 (1.0–3.2) term
Mannose-binding lectin codon-54 in diplegia OR 2.1 (1.1–4.1)
Any polymorphism in mannose-binding lectin exon-1 OR 1.9 (1.1–3.6)
and diplegia
CC (PB) 443 Candidate genes, 28 single nucleotide polymorphisms
tested.
Inducible nitric-oxide synthase in term infants OR 1.6 (1.1–2.2)
Heterozygous
endothelial protein C receptor in term infants OR 1.6 (1.1–2.3)
CC 40 Presence of apolipoprotein E gene allele ε4 OR 14.8 (1.3–43)
CC 209 Presence of apolipoprotein E gene allele ε4 OR 3.4 (1.4–8.7) (GA in cases 32.8±6.3weeks)
Normal birthweight (69 cases) OR 3.3 (0.9–15.2) p=0.09 n.s.
Presence of apolipoprotein E gene allele ε2 OR 12.0 (1.6–247.2)
Case 4 Family with inherited ataxic CP Gene location on chromosome
9p12–q12
Case 9 9 children with CP, born to healthy, related fathers Deletion of the ANKRD15 gene was detected
Case 22 Hospital-based. Children born at term with athetoid CP. No CP in first or second degree relatives.
Other neurological disease in 6 of 22
families
Malformations
CC (PB) 172 Congenital abnormalities, Birthweight ≥2 500g OR 8.2 (3.5–19.3) Singletons with moderate to
Non-CNS abnormalities OR 1.4 (0.5–3.6) severe CP
Continued
Risk factors for cerebral palsy in term infants
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Table 1. Continued

First author/year/ Study Number of

∗
study area design cases Risk factor for CP analyzed Results Comment

Montenegro MA 2005 C 70 Cerebral malformations; intrapartum complications 52.8 vs 4.0% (p<0.001) Controls were children with
(Brazil) were more common in the cases epilepsy and normal MRI
Blair E 2007 (Australia) CC 128 Non-cerebral birth defects were more common in CP RR 2.7 (2.2–3.4) Results partly explained by
(35) ascertainment bias
Risk factors for cerebral palsy in term infants

Pharoah POD 2007 (UK) PB 2 253 Congenital anomalies RR 116.1 (84.0–162.3)

(36) Microcephaly RR 3.1 (1.9–4.8)
Cardiac septa malformation
Multiple gestation
Pharoah POD 2001 (UK) PB Prevalence of CP in surviving twin after co-twin fetal 40.5 per 1 000 responders (2/3 GA >32weeks
(37) death in children born >32weeks response rate)
Pharoah POD 2002 (UK) PB Prevalence in twins with like sex 13 of 6001 (2.2 per 1 000) Twins with normal

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(38) Prevalence in twins with unlike sex 4 of 3174 (1.3 per 1 000) n.s. birthweight
Newton R 2003 (UK) (39) CC 86 Vanishing twin. CP prevalence in surviving twin OR 2.2 (0.2–24.8) n.s.
Scher AI 2002 (Australia, PB Twins compared with singletons overall risk for CP 0.59 vs. 0.14% (p<0.0001) From 5 populations (1 year
US) (40) Co-twin dead/survived 5.40 vs. 0.48% (p<0.0001) survivors), mean GA
Discordant twins/non-discordant OR 0.6 (0.4–1.2) 39.2weeks
OR 1.7 (1.0–2.9)
Skrablin S 2007 (Croatia) C 94 Triplets followed for 24–144months 3 of 36 had CP 36 with GA >35weeks.
(41) Multivariate analysis OR 3.2 (1.5–6.5) Higher occurrence of CP in
spontaneously conceived
than assisted
Maternal trauma
Hayes B 2007 (Ireland) Cohort study 10 Children with CP born at term. Maternal trauma All had lesions on MRI consistent with the time of
(42) week 20–38 the trauma lesions

Note: Some risk factors may be of importance also in the perinatal period.
∗
Study design: PB, population based; CC, case–control; C, cohort study; or Case; GA, gestational age; CNS, central nervous system; OR, odds ratio; RR, relative risk; SCPE, Surveillance of Cerebral
Palsy in Europe; n.s., not significant.


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Table 2. Selected important findings from original papers regarding perinatal and neonatal risk factors for CP in children born at term, published 1 January 2000 to 30 April 2010.

First author/year/ Study Number of

∗
study area design cases Risk factor for CP analyzed Results Comment

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Events during labor and delivery
K. Himmelmann et al.

Evans K 2001 (UK) (48) C, CC 143 143 term cases of neonatal encephalopathy from 57 159 15 died, 16 developed CP. In 12, probable
consecutive births (incidence 2.62 per 1 000 births); 154 intrapartum cause.
controls. 76.9 vs. 15.6% (p<0.05)
In 12 of 13 with four-limb CP, the probable cause was 30.8 vs. 3.9% (p<0.05)
intrapartum factors.
Abnormal CTG

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Emergency cesarean section
Thorngren-Jerneck K PB Apgar score <7 at five minutes OR 31.4 (27.3–36.1) 1 028 705 term births
2001 (Sweden) (49)
Moster D 2001 (Norway) PB Apgar 0–3 at five minutes RR 81 (48–138) 235 165 births
(50) Apgar 4–6 at five minutes RR 31 (22–44)
Krebs L 2001 (Denmark) CC 87 Breech presentation and low Apgar score 4 cases, 1 control had CP, p=0.04 Controls with breech presentation
(51)
Herbst A 2001 (Sweden) C 1 050 Breech presentation; 20 with neonatal cerebral symptoms 3 of 20
(52) Vaginal delivery 1 of 20
Planned cesarean section
Redline RW 2005 (US) CC 64 Severe fetal placental vascular lesions in 33 of 64, compared p<0.001
(55) with 26 of 250
Menticoglou SM 2008 C 667 Term children out of 36 368 births admitted to the NICU with 20 developed CP possibly related to perinatal
(Canada) (56) neonatal encephalopathy, intracranial hemorrhage, infarction events
or edema on imaging, non-brain organ dysfunction, sepsis,
meningitis, herpes infection, ventilation support >48hours or
therapeutically paralyzed for respiratory support
Nielsen LF 2008 CC (PB) 117 Term cases with spastic CP OR 2.1 (1.0–4.2)
(Denmark) (57) Placental infarctions OR 2.0 (1.2–3.4)
Cord complication
Andersen GL 2009 PB 245 Singletons born at term in breech presentation OR 3.9 (1.6–9.7)
(Norway) (58) Severity or subtype did not differ
Perinatal stroke
Curry CJ 2007 (US) (59) C 60 Perinatal arterial stroke Mothers investigated 40 of 51 developed CP 36 of whom were born at term

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Prothrombotic risk factors in mothers 28 of 51
Prothrombotic risk factors in children 30 of 60
Golomb MR 2008 (US) C 111 Perinatal stroke 76 of 111 developed CP
(60) Delayed presentation p<0.0001
Bilateral cerebral artery infarct p<0.0063
Large-branch unilateral infarcts were associated with CP p<0.0018

Continued

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Risk factors for cerebral palsy in term infants
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Table 2. Continued

First author/year/ Study Number of

∗
study area design cases Risk factor for CP analyzed Results Comment

Sreenan C 2000 (Canada) C 46 Cerebral infarction in the neonatal period 22 (48%) developed CP
(61) Adverse perinatal events present in 75%, more often in
those with CP.
Seizures and abnormal finding on neurological
Risk factors for cerebral palsy in term infants

examination were predictive for disability

Brouwer AJ 2009 (The C 53 Intracranial hemorrhage 3 of 53 (8.6%) with intracranial hemorrhage
Netherlands) (53) developed CP
Hunt RW 2001 (Australia) Case 8 Neonatal venous sinus thrombosis. 2 of 6 had CP, 2 had motor delay
(43) Follow-up data on 6
Fitzgerald KC 2006 (US) C 42 Follow up of cases with cerebral sinovenous thrombosis. 18 of 29 had CP 36 of 42 born at term
(44) Outcome data in 29 of 41 survivors

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Parity
Mahony R 2009 (Ireland) C 77 839 Seizures with encephalopathy without sentinel event in 9 of 20 (45%) developed CP; 0 of 7 Retrospective follow-up study of
(54) children born to primiparous mothers developed CP 77 838 children (1989–2000)
Multiparous mothers

Meconium aspiration
Beligere N 2008 (US) (45) C 35 Hospital-based study. Three-year follow up completed in 29 2 of 29 had CP; 4 of 29 had severe global Mean GA 39.5weeks
delay
Hyperbilirubinemia
Ogunlesi TA 2007 C 22 Follow up after bilirubin encephalopathy 19 of 22 had CP
(Nigeria) (46)
Gkoltsiou K 2008 (UK) Case 5 Hyperbilirubinemia, serial ultrasound/MRI. All had lesions in 3 of 5 developed dyskinetic CP
(47) white matter and nucleus subthalamicus, 4 of 5 in gray
matter on MRI at 24months

Note: Some risk factors may be important in both periods.

∗
Study design: PB, population based; CC, case–control; C, cohort study; or Case; CTG, cardiotocography; MRI, magnetic resonance imaging; GA, gestational age; OR, odds ratio; RR, relative risk.


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K. Himmelmann et al.
K. Himmelmann et al. Risk factors for cerebral palsy in term infants

Table 3. Studies of multiple antenatal, intrapartum and/or perineonatal risk factors for CP in children born at term, published 1 January 2000 to
30 April 2010.

Intrapartum risk factors Perinatal and neonatal riskfactors

First author/year/area Antenatal risk factors OR/RRR/p-value OR/RR/p-value OR/RR/p-value

Walstab JE 2002 Essential hypertension RRR 10.10 Meconium-stained liquor RR 5.3

(Australia) (62) (1.13–90.25) (2.5–11.1)
Chorioamnionitis RRR 12.51 Abnormal antenatal CTG RR 8.3
(1.4–112.08) (1.2–56.3)
Emergency cesarean section RR 8.1
(2.5–26.0)
Placental infarct/stasis RR 4.5
(1.2–16.6)
Episiotomy RR 0.3 (0.1–1.0)
Cord around the neck RR 2.2
(1.0–4.8)
Walstab JE 2004 Intubation during resuscitation OR
(Australia) (63) 19.4 (2.5–149.0)
Any intubation during neonatal
period OR 44.0 (5.9–326.4)
Ventilation OR 36.1 (4.8–269.7)
Neonatal infection OR 29.0
(3.8–230.0)
Wu YW 2004 (US) (64) IUGR OR 5.1 (1.1–21.0) Cesaerean section urgent/emergency
OR 6.8 (2.7–16.6)
Five minute Apgar score <7 OR
23.6 (4.1–237.0)
Resuscitation at birth OR 4.5
(1.6–12.3)
Lee J 2005 (US) (65) Primiparity OR 3.4 (1.5–7.6) Prolonged rupture of membranes OR
Pre-eclampsia OR 4.9 (1.2–21.0) 4.9 (1.7–14.1)
Decreased fetal movement OR 7.1 Prolonged second stage of labor
(2.6–19.4) OR 8.9 (2.2–41.9)
Chorioamnionitis OR 3.1 (1.1–8.6) Fetal heart rate abnormality OR 5.0
(2.2–11.6)
Cord abnormality OR 4.1
(1.4–11.8)
Emergency cesarean delivery OR
3.8 (1.6–8.9)
Diagnosis of birth asphyxia
p<0.001
Resuscitation at birth OR 4.5
(2.1–9.9)
Greenwood C 2005 (UK) Pre-eclampsia OR 5.1 (2.2–12.0) Placental abruption OR 3.3 (1.1–10.0) Neonatal sepsis OR 10.6 (2.1–51.9)
(66) SGA OR 2.1 (1.2–3.4) Intrapartum pyrexia OR 13.1
(1.5–114.3)
Induction OR 2.1 (1.3–3.3)
Prelabor cesarean section OR 2.6
(1.1–6.3)
Stelmach T 2005 (Estonia) Bleeding after 20weeks OR 6.7 Emergency cesarean section OR 4.3 Apgar ≤7 at one minute OR 9.8
(67) (3.5–12.7) (1.8–10.5) (5.3–18.2)
Hypertension in the second half of Placental abruption OR 13.1 Apgar ≤7 at five minutes OR 15.0
the pregnancy OR 3.0 (1.6–5.4) (3.0–57.7) (7.2–31.3)
Pre-eclampsia OR 8.5 (1.8–39.6) Hypoxic event OR 13.3 (6.9–25.8) HIE OR 25.2 (10.2–62.6)
Fetal presentation other than Assisted ventilation OR 36.7
vertex OR 4.2 (2.2–8.1) (11.5–117)
Neonatal sepsis OR 7.6 (1.6–35.6)

Continued


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Risk factors for cerebral palsy in term infants K. Himmelmann et al.

Table 3. Continued

Intrapartum risk factors Perinatal and neonatal riskfactors

First author/year/area Antenatal risk factors OR/RR/p-value OR/RR/p-value OR/RR/p-value

Thorngren-Jerneck K Pre-eclampsia OR 1.5 (1.3–2.4) Abruptio placentae OR 8.6 (5.6–13.3)

2006 (Sweden) (68) Instrumental delivery OR 1.9
(1.6–2.3)
Emergency ceasean section OR 1.8
(1.6–2.0)
Breech presentation vaginally
delivered OR 3.0 (2.4–3.7)
Apgar score 3 at five minutes OR
498.0 (458.0–542.0)
Apgar score 6 at five minutes OR
62.0 (52.0–74.0)
Gurbuz A 2006 (Turkey) Birthweight <2 500g OR 3.4 Beat-to-beat variability OR 3.6
(69) (1.6–7.3) (1.5–8.9)
Late deceleration OR 3.6 (1.5–8.5)
Meconium-stained amnios OR 2.3
(1.3–4.1)
Apgar <7 at five minutes OR 16.9
(6.2–46.0)
Öztürk A 2007 (Turkey) Pre-eclampsia p≤0.01 Premature rupture of the membranes Prolonged jaundice p≤0.001
(70) p≤0.001 Neonatal seizures p≤0.01
Home births p≤0.001
Prolonged labor p≤0.001
Birth asphyxia p≤0.001
Drougia A 2007 (Greece) Small for gestational age OR 3.2 Duration of mechanical ventilation
(71) (1.3–8.3) OR 1.1 (1.1–1.2)
Sepsis and meningitis OR 4.9
(1.4–17.0)

OR, odds ratio; RRR, relative risk ratio; IUGR, intrauterine growth restriction; SGA, small for gestational age; HIE, hyopxic-ischemic encephalopathy;
CTG, cardiotocography.

A case series described CP after maternal trauma in preg-
nancy (42). All children had evidence of prenatal lesions con-
sistent with the time of the trauma on magnetic resonance
imaging.
Perinatal and neonatal risk factors
In two studies, where neonatal venous sinus thrombosis was
associated with CP, pre-eclampsia was present in half of the
children in one (43,44). In a hospital-based study of cases
with meconium aspiration syndrome, two of 29 developed
CP (45). Hyperbilirubinemia was investigated in two studies
(46,47), and high levels of bilirubin correlated with CP.
Among several studies of risk factors from delivery (48–58),
breech presentation was associated with a higher risk for CP.
Severe placental vascular lesions, meconium-stained amni-
otic fluid, placental abruption, cord complications, mater-
nal hypertension, pre-eclampsia, high maternal body mass
index, meconium aspiration, low Apgar score, seizures and
sepsis–meningitis were also among risk factors in several
studies. Perinatal stroke was associated with several risk fac-
tors in both the antenatal period and the perinatal period,
such as intra-uterine growth restriction and pre-eclampsia,
chorioamnionitis, low Apgar score, need for resuscitation and
male sex (59–61).
Discussion
There are several and heterogeneous risk factors at focus
in current research regarding cerebral palsy. In the present
review, we found several areas with intense research. Perinatal
events, including asphyxia and perinatal stroke, had attracted
the largest number of publications, followed by genetic stud-
ies (18–25). Perinatal stroke was associated with several risk
factors. Associations were found between infections (7–11),
central nervous system malformations, intra-uterine growth
restriction, social deprivation or multiple gestation and CP,
while the evidence regarding surviving twin affected by
co-twin (vanishing, dead or discordant), and the evidence
of higher prevalence of thrombophilic factors in CP was
ambiguous. One weakness with this study is that we have
limited the time period to the last decade. This study was
done to obtain an overview of where research is breaking
new ground, not only regarding recently suggested risk fac-
tors, but also new evidence regarding known risk factors.
However, the findings suggest that much more research is


C 2011 The Authors

1078 Acta Obstetricia et Gynecologica Scandinavica 

C 2011 Nordic Federation of Societies of Obstetrics and Gynecology 90 (2011) 1070–1081
K. Himmelmann et al.
needed to understand the risk factors for CP and specifically
how they relate to causal pathways of CP. When interpreting
data, one must bear in mind that the risk factors which it is
possible to identify and measure may be far from the origin
of a causal pathway.
Some earlier described risk factors were not dealt with
during the assigned publication period. For example, there
were no studies to be found in 2000 or later regarding thy-
roid disease in children born at term. There is a growing
body of research considering infections (7–11) and genetic
factors (18–25) as risk factors. To strengthen evidence, there
is a need for collection of biological material for future anal-
ysis of inflammatory and genetic factors, in case the child
develops CP. Gathering of biological information, however,
is related to substantial logistic problems. One possibility
would be to incorporate the gathering of genetic and inflam-
matory information into the already existing neonatal blood
sample screening programs for metabolic diseases. This may
be hampered by legislation in some countries, but should be
thoroughly discussed in the light of possible prevention of
some cases of CP. One recent finding of prenatal stress in
growth-restricted children could be included as subject for
studies (17), as well as the collection of social information
(18–20) in a standardized way. Neuroimaging, although not
covered in this review, is important to reveal malformations
as well as dating the cerebral lesion (72).
A CP register is a tool for answering questions regarding
the prevalence and characteristics of CP, but also the changing
panorama of risk factors for CP. The public health contribu-
tions of CP registers might be to reduce the frequency of CP
and to improve the quality of life of children with CP. Cere-
bral palsy registers are useful to clinicians by enabling them
to identify subgroups of children requiring specific etiologic
investigations, and also to provide more accurate informa-
tion to the parents of children with CP. It is essential that the
collection of data in these registers is updated and that CP
register holders consider modifying the information collected
regularly according to emerging knowledge in the field. This
review, albeit restricted as to publication dates, may serve as
a platform for such a revision and update. It may also serve
as an update for obstetricians, who deal with imminent risk
factors in prenatal care and maternity wards.
Conclusions
Information on maternal and neonatal infections, umbilical
cord blood gases at birth, mode of delivery and placental
status should be collected in a standardized way. Collection
of biological material to enable the examination of proteins
and DNA may be considered accompanying the risk factor
assessments. Information on social factors, such as education
level, family income, cohabitation of the parents to the child
and area of residence, is also of importance, but may apply to
children born preterm as well.

C 2011 The Authors
Acta Obstetricia et Gynecologica Scandinavica 
C 2011 Nordic Federation of Societies of Obstetrics and Gynecology 90 (2011) 1070–1081
Risk factors for cerebral palsy in term infants
Funding
The study was supported by grants from the European Com-
mission, ENSACP, grant agreement no. 2006127.
Supporting Information
Additional Supporting Information may be found in the on-
line version of this article:
Appendix S1. Search in PubMed
Please note: Wiley-Blackwell are not responsible for the con-
tent or functionality of any supporting materials supplied by
the authors. Any queries (other than missing material) should
be directed to the corresponding author for the article.
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