Best Practice & Research Clinical Obstetrics and Gynaecology

Vol. 18, No. 3, pp. 425–436, 2004

doi:10.1016/j.bpobgyn.2004.02.011
available online at http://www.sciencedirect.com

Antenatal risk factors for cerebral palsy

Bo Jacobsson* MD, PhD

Department of Obstetrics and Gynaecology, Institute for the Health of Women and Children,
Perinatal Centre, Sahlgrenska University Hospital/East, SE-416 85 Göteborg, Sweden

Gudrun Hagberg BA, BM, PhD

Department of Pediatrics, Institute for the Health of Women and Children, Perinatal Centre,
Queen Silvia Children’s Hospital, Göteborg, Sweden

Two of every 1000 live-born children develop cerebral palsy (CP). The aetiology of CP is often
unclear and because CP is a symptom complex rather than a disease, clinically defined at 4– 5
years of age, it is not surprising that there are considerable problems associated with
epidemiological studies of its aetiology. The only reason for the CP concept is that it emanates
from an insult to a growing, developing brain and a dynamic clinical picture from static pathology.
Evidence suggests that 70 –80% of CP cases are due to prenatal factors and that birth asphyxia
plays a relatively minor role (, 10%). Some antenatal risk factors are repeatedly observed to be
related to CP: low gestational age, male gender, multiple gestation, intrauterine viral infections
and maternal thyroid abnormalities. Recently, intrauterine infection/inflammation with a maternal
response (consisting of chorioamnionitis) and a fetal inflammatory response (consisting of
funicitis or elevated interleukin-6 in fetal plasma) has been found to be related to white matter
injury and CP. Some risk factors are associated with CP at all gestational ages whereas others
mostly affect term or preterm infants, e.g. intrauterine growth restriction seems to be a risk
factor in term infants. There also seems to be an association between autoimmune and
coagulation disorders and CP.

Key words: antenatal risk factors; cerebral palsy; diplegia; fetal inflammatory response
syndrome; hemiplegia; intrauterine growth restriction.

Cerebral palsy (CP) is the most common physical disability in childhood, affecting about
2 per 1000 live-born children. Although major changes in neonatal and obstetric care in
industrialized countries have brought about a striking decrease in perinatal mortality, no
change in the prevalence of CP has been observed.1,2 The absence of the (presumably)
expected drop serves as a reminder that better obstetric and neonatal care does not
necessary reduce the prevalence of undesired conditions. CP is defined as a group of
non-progressive, but often changing, motor impairment syndromes, secondary to

* Corresponding author. Tel.: þ46-313434100; Fax: þ 46-31-254-387.

E-mail address: bo.jacobsson@obgyn.gu.se (B. Jacobsson).

1521-6934/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.
426 B. Jacobsson and G. Hagberg

lesions or abnormalities of the brain and arising in the early stages of development.3 CP
is a symptom complex rather than a disease. It is a concept emanating from an insult to
a growing, developing brain and thus is a dynamic changing clinical picture deriving from
static pathology.4 CP diagnosed during the first 2 years of life sometimes resolves
during early childhood, especially when functional impairment is mild.5 – 7 In one study,
mild CP had resolved in 72% of cases on re-examination at age seven.5 This indicates
that the child must be at least 4 or 5 years old before a reliable diagnosis can be made.2
Nonetheless, children with resolved CP were almost 10 times more likely to be
mentally retarded, which indicates that the neurological abnormalities observed were a
valid indication of antecedent brain damage rather than a variation on the normal.5,8
The main form of CP is defined both in terms of the topographical distribution of the
motor disorder (diplegia, hemiplegia, tetraplegia) and the presumed neuropathological
site of the lesion, i.e. spasticity (cortex), dystonic/dyskinetic (basal ganglia) and ataxia
(cerebellum).
The aetiology of CP is still poorly understood. It is not surprising that there are
considerable problems associated with epidemiological studies of CP aetiology: the
long time lag between recognition of CP and the presumed brain damage,
disagreements among examiners about clinical findings in patients, and changes in
clinical findings over time. Due to the lack of a definitive test for CP, multiple and
different possible causes also constitute a challenge in this context.8 In most cases, the
cause of CP remains unknown but some risk factors have repeatedly been observed to
be related to CP, i.e. low gestational age2,8, low Apgar scores9, male gender8, multiple
gestation10, intrauterine viral infections (e.g. rubella, cytomegalovirus)11 – 13, iodine
deficiency14, exposure to methyl mercury during pregnancy12,15 and maternal
thyroid abnormalities.12,16 Some of these risk factors are associated with CP at all
gestational ages but others primarily affect either term or preterm infants. It is also
important to distinguish between risk factors and known causes of CP. Therefore, a
concept of ‘causal pathways’—a sequence of interdependent events that results in a
brain injury and CP—has been developed.17

TIMING OF THE INJURY

Intrapartum factors producing asphyxia were traditionally assumed to be the

principal cause of CP. However, this assumption was reconsidered during the 1980s
and 1990s and today it is suggested that 70 –80% of cases of CP are due to prenatal
factors and that birth asphyxia plays a relatively minor role.17 Intrapartum asphyxia is
believed to account for around 10% of CP in term and near-term infants.8 However,
this perspective was challenged by the recently published, Swedish population-based
CP report by the Hagberg group, which showed birth asphyxia to be the likely cause
of CP in 28% of term children with CP2—three times higher than the figure usually
quoted.8 However, ‘birth asphyxia’ is a poorly defined term related to a sequence
initiated by hypoxia18 and its clinical signs are non-specific.8 Using indirect signs of
birth asphyxia, recent studies suggest that: (1) birth asphyxia might not be such an
important cause of CP as was previously assumed but that it might sometimes
constitute one element of a multifactorial cause; (2) neonatal signs associated with
birth asphyxia might be early manifestations of CP from a variety of causes, of which
birth asphyxia is only one; and (3) the majority of pathways to CP commence
antenatally.8,16,18 – 20
 Antenatal risk factors for cerebral palsy 427

The International Cerebral Task Force suggested the following criteria to assess
whether CP could be related to intrapartum events: (1) metabolic acidosis in
umbilical arterial cord or very early neonatal blood samples (pH , 7.00 and base
deficit $ 12 mmol/l); (2) early onset of severe or moderate neonatal encephalo-
pathy in infants born at 34 weeks or later; and (3) spastic quadriplegia or dyskinetic
CP type.21
Imaging of the brain has become an important tool in the drive to a better
understanding of the timing and aetiology behind CP. It has been shown that the
morphology of brain damage strongly relates to the stage of brain development at
which the insult occurs. Cerebral malformations are secondary to insults during
the first 20 gestational weeks, periventricular white matter damage is secondary to
insults between 24 and 34 weeks and grey matter damage to insults after 34 weeks
of gestation.22 Periventricular white matter damage was the most common cause in
a representative series of bilateral spastic CP, comprising 37/56 (66%) of cases23,
one-third of which were born at term, emphasizing that such damage frequently
occurs prenatally. Recent preliminary results of the first 180 scans from The
European Cerebral Palsy Study showed that 13% revealed brain malformations/
miscellaneous, 44% white matter damage, 16% cortical/subcortical damage,
16% basal ganglia damage, and 12% normal22; results that concur with the study
by Krageloh-Mann et al.23 Thus, some 75% of all CP is caused during the late
second or third trimester.

PRE-EXISTING FACTORS

For a long time, maternal social factors were considered to be associated to CP—an
assumption supported by more recent studies. Low maternal age (, 20 years)
and advanced maternal age (. 35 years)24, high parity25, nulliparity24, a short or
long interpregnancy interval26,27 and a history of previous intrauterine fetal death33,34
are among these factors. Late menarche, irregular menstruation and long inter-
menstrual interval are menstruation-related factors that relate to CP.27 Low social class
is related to CP in children with normal birth weight.28,29 Several pre-existing
maternal conditions, such as intellectual disability, epilepsy30, diabetes24 and thyroid
disease30,31 are related to CP.
Genetic disease is a rare factor underlying CP and is found mainly among ataxic
types. High paternal age has been reported to relate to athetotic/dystonic and
hemiplegic CP, which might indicate that these cases arise from recent dominant
mutations.32 During recent years, it has become more apparent that stroke can
affect fetuses, neonates and young children and cause brain injury and CP.33 There
seems to be an association between autoimmune and coagulations disorders and
CP.34 Reports of factor V Leiden mutation and hemiplegic CP have prompted this
research.35
An increased risk of CP is seen if an elder sister or brother has CP.2,30 Male
gender has repeatedly been found to constitute a risk factor for CP.17
Infertility treatment has been shown to be related to CP. Children born after in vitro
fertilization are at increased risk of CP.36 These risks are largely (but not totally) due to
the high frequency of twin pregnancies, low birth weight and preterm birth among
babies born after in vitro fertilization.
428 B. Jacobsson and G. Hagberg

PREGNANCY AND FETAL FACTORS

Congenital malformation

Congenital malformations in general, and specific brain malformation conditions in

particular, are seen more often in children with CP16,27,30,37 – 39 and other
developmental disabilities.40 Multiple minor anomalies outside the central nervous
system have also been considered to be related to CP.41 Neuronal migration disorders
are related to CP.17 Any interruption of the normal processes of neuronal generation
and migration results in brain malformations and variable degrees of neurological
dysfunction, including within the motor system.
All congenital malformations are of antenatal origin and arise during the first 20
gestational weeks. Damaging influences depend on timing as on much as the event itself.
Situations or events interfering with migration and differentiation of the motor cortex,
basal ganglia or cerebellum might be the expression of abnormal genes or hostile fetal
environments resulting from maternal disease, toxicity, infections or trauma. The vast
majority of CP children with congenital malformations are born at term.2 Neonatal
encephalopathy (strongly related to CP) is more common among children with
congenital malformations.42 Some children with abnormal cerebral development
appear neurologically depressed at birth, exhibit neonatal encephalopathy and can be
misdiagnosed as having birth asphyxia.43 Modern imaging techniques, such as magnetic
resonance imaging, enable identification of more children with these conditions and
have contributed to the rapid increase in knowledge of these conditions.23,44 – 46 No
relationship between brain malformation in children with CP and neonatal encephalo-
pathy has been found in the Swedish panorama studies.2

Gestational age

Low gestational age is the most important risk factor for CP (Figure 1). As an effect of
the success of neonatal intensive care during the last three decades, ensuring an
increasing survival of children born very and extremely preterm, the prevalence of CP
120
Cases of CP per 1000 live births

100

80

60

40

20

0
<28 29 31 33 35 37 39 41
Gestational age (weeks)

Figure 1. Prevalence of CP per 1000 live births according to gestational age (data from ref. 2).
 Antenatal risk factors for cerebral palsy 429

Proportion
28% 15% 58%
of all CP

Proportion
1% 4% 95%
of all births

Moderate preterm
Very preterm Term
or near term

< 32 weeks 32–36 weeks > 37 weeks

Figure 2. Proportion of CP according to gestational age (data from ref. 2).

among preterm children has risen.2,47 About 28% of CP cases are born very preterm,
compared to 1% of all births (Figure 2).2 The main form of CP related to low gestational
age is spastic diplegia; congenital malformations are exceptional in these children.2

Multiple gestation

The higher risk of CP in multiple births has been known for many years. Multiple
pregnancy is related to preterm delivery, intrauterine growth restriction, birth defects
and intrapartal complications. Although CP can be related to all these events, the main
reason is apparently associated with preterm birth or the antenatal death of a
co-twin or co-triplet.10,48,49 The death of one twin can affect the neurological
development of the survivor.17 The live-born co-twin of a fetus dying in utero has a 20%
overall risk of cerebral impairment.48

Pregnancy complications

Pre-eclampsia seems to have different associations to CP in different gestational age

groups. In term infants, pre-eclampsia is associated to CP.50 However, in preterm infants
the issue of whether there is a decreased risk of CP in pre-eclampsia cases is still under
debate.51 – 55 This has raised concern about pre-eclampsia as a potential confounder,
raising the estimated degree of association between chorioamnionitis and CP.56
Abruptio placentae has also been suggested to be associated with a higher risk of CP,
especially in the hemiplegic and moderately preterm (32 – 36 weeks) groups.55
There has also been a hypothesis that delivery without contractions among preterm
infants (e.g. caesarean section or cervical insufficiency) would constitute a decreased
risk of CP as a result of the mechanisms leading to delivery in these cases.55 However,
no difference was found between cases and controls with regard to spontaneous onset
of labour (preterm prelabour rupture of membranes and preterm delivery) in one of
our studies.55 Other researchers have found spontaneous onset of labour to be a risk
factor for CP in preterm infants.57
430 B. Jacobsson and G. Hagberg

Congenital and perinatal infections

Congenital and perinatal infections affecting the fetus and neonate can result in central
nervous disease with severe consequences to the developing brain. Virtually all
organisms involved in these infections can invade the central nervous system of the
fetus such that the infections might not yield any clinically discernible sign at birth but
might manifest as significant morbidity—such as developmental delay, CP or
sensorineural hearing loss—later in life.58
Viral infections in pregnancy, including the most common congenital viral infections
(TORCH: toxoplasmosis (caused by a parasite), rubella, cytomegalovirus, herpes
simplex virus), are known causes of long-term neurodevelopmental disabilities. In
industrialized countries, the proportion of CP attributable to TORCH infections is
estimated to be 5% or less.17
Chorioamnionitis and intrauterine infection/inflammation are well-known risk
factors for CP.59 – 62 The debate now concerns whether these factors mostly affect
preterm51,55,62 or term infants63, as well as the mechanisms involved.64,65
Fever during pregnancy or delivery has also been found to be related to CP.55,63
Fever during delivery might be confounded by increased temperature due to physical
exertion during delivery, epidural analgesia or other non-infectious factors that raise
the body temperature. In cases of fever during delivery, fetal exposure to a hostile
intrauterine environment might be shorter and less intense than in cases of intrauterine
infection, in which fever starts before the onset of delivery. However, maternal fever is
known to be just the tip of the iceberg in relation to intrauterine infection and
inflammation.66,67 Another infection-related variable of interest is the use of antibiotics
during pregnancy or delivery. There are indications that this variable can serve as an
indicator not only of ongoing or previous infection but also of prolonged intrauterine
exposure to bacteria, bacterial products and cytokines.68

The inflammatory hypothesis

The inflammatory/cytokine hypothesis (initially proposed by Leviton and Adinolfi) is an
important prenatal hypothesis that suggests that a maternal infection can lead to
elevated fetal blood and brain cytokine levels, which might result in central nervous
damage and subsequent CP.65,69,70 Leviton extended the hypothesis, suggesting that
cytokines such as tumour necrosis factor (TNF)-a, produced in response to microbial
invasion of the amniotic fluid, contributed to both preterm birth and periventricular
white matter damage.65 Dammann and Leviton put forward additional arguments in
favour of this hypothesis by finding support for four other subhypotheses: (1) that
cytokines are present in all three relevant compartments (i.e. uterus, fetal circulation
and brain); (2) that cytokines might cross boundaries between relevant compartments
(placenta and blood brain barrier); (3) that cytokines might contribute to the
occurrence of intraventricular haemorrhage; and (4) that cytokines might be involved
in the induction of white matter damage.71 An overview is presented in Figure 3.
Furthermore, Romero and Gomez have shown that the fetal response is the most
important predictor of the infants’ outcome; these researchers coined the fetal
inflammatory response syndrome (FIRS) concept.72,73
An association between proinflammatory cytokines such as interleukin (IL)-6 and
IL-8 in amniotic fluid and CP has been observed in a preterm population.61
Furthermore, IL-6 in amniotic fluid is related to intraventricular haemorrhage and
elevated IL-6, IL-1a and TNF-a to periventricular leukomalacia (PVL).60,74,75
 Antenatal risk factors for cerebral palsy 431

White matter
Cerebral palsy
damage

Uterine Intrauterine Preterm

colonization infection birth

Prepregnancy Pregnancy Perinatal/neonatal Childhood

//
Figure 3. Possible relationship between pre-pregnant uterine colonization, intrauterine infection/inflamma-
tion, periventricular leukomalacia and cerebral palsy (modified from ref. 95).

Both intraventricular haemorrhage and PVL are strongly associated to the development
of CP. Two important studies have shown that blood inflammatory cytokine levels
were significantly higher in term infants that developed CP than in controls34, but this
relationship was not found in preterm neonates.76

Intrauterine growth restriction

Intrauterine growth restriction (IUGR) entails an increased risk of neonatal morbidity

and mortality and also seems to affect brain development.77,78 Some specific alterations
in the brain of IUGR infants, including restriction of the volume of grey matter79, a
reduced amount of total DNA in glia cells and neurons, and changes in cerebral
haemodynamics, have been reported.80 This is also supported by animal studies
showing reduced oxygen delivery to the brain and retarded growth of the forebrain and
cerebellum.81,82 IUGR has therefore been hypothesized to be related to brain injury
and CP. A ‘brain-sparing mechanism’ has been suggested to prevent or reduce the
severity of brain injury in growth-restricted children.83 Several mechanisms have been
suggested for the relation between IUGR in term babies and CP. The abnormal growth
might play a direct role in causing CP or in utero brain injury, and could trigger
abnormal growth. Alternatively, a separate process, such as placental insufficiency,
could cause both the growth retardation and brain injury.
There are several concepts of IUGR and information on true IUGR is often missing
from retrospective studies. The most common proxy for IUGR is small for gestational
age (SGA), often defined as less than 2 2 SD from the mean birth weight or from
intrauterine growth curves based on ultrasonically estimated fetal weights.84,85
However, SGA is a heterogeneous category, including not only growth-restricted
infants but also infants with chromosomal abnormalities and small healthy infants as
well. There are at least three ways to obtain information on true intrauterine growth
restriction: (1) by serial ultrasound estimates during pregnancies in which a decreased
growth is detected; (2) by anthropometric measures postnatally; and (3) by using
individualized or customized growth standards. The individualized or customized
growth standards set an optimal fetal growth rate for each pregnancy as part of an
attempt to separate the infant afflicted by true intrauterine growth restriction from the
small, healthy infant.86
432 B. Jacobsson and G. Hagberg

Some studies have found a dose – response-like relationship between SGA and CP
in term infants.24,87 – 90 No such clear association has been found in preterm
infants55, but there are some indications of a similar relationship between SGA and
CP in two large preterm studies.24,90 No data are available for true IUGR but
preliminary data from a Swedish study that used Gardosi’s customized percentiles to
the full extent indicate such an association between children born at term with a
history of IUGR and CP.91

SUMMARY

The diversity of the CP diagnosis, and its antecedents, is one of the major challenges in
the study of CP aetiology. This is not surprising, given that CP is not defined according
to aetiology or pathology. It seems that various clinical pictures arise from a single
cerebral pathology and, likewise, that many different cerebral pathologies can result in
a similar clinical entity.92 There are several known antenatal risk factors of CP:
developmental, vascular, infectious, genetic, metabolic and toxic.93 Adverse antenatal
events might either cause brain damage themselves or make the infant more vulnerable
to the normal asphyxiating events during delivery.92 Experimental animal studies
indicate that bacterial endotoxin sensitizes the immature brain to the effect of an
asphyxiating event.64 The results of clinical studies indicate that maternal infections can
increase the effect of asphyxia.94 The inflammation hypothesis is currently under
investigation in some large prospective studies, including the ELGAN (extremely low
gestational age neonates) study in the US.

Practice points
† the prevalence of CP is 2 cases in every 1000 live births
† although major changes in neonatal and obstetric care in industrialized
countries have brought about a striking decrease in perinatal mortality, no
change in the prevalence of CP has been observed
† low gestational age is the most important risk factor for CP and a little bit less
than half of CP cases are born preterm
† few cases (, 10%) of CP are explained by asphyxia during delivery
† congenital malformations in general, and specific brain malformation conditions
in particular, are more often seen in children with CP, mostly those born
at term
† congenital and perinatal infections—bacterial, viral and protozoal—can be
involved in the development of CP
† the inflammatory hypothesis is one of the important prenatal hypotheses,
according to which maternal infection can lead to elevated fetal blood and brain
cytokine levels, which might result in central nervous damage and
subsequent CP
† a dose– response relationship has been found between the small for gestational
age state and CP in term infants and corresponding preliminary data is now
available regarding intrauterine growth restriction indicating the same findings
 Antenatal risk factors for cerebral palsy 433

Research agenda
† develop strategies for the prevention of CP associated with periventricular
leukomalacia (PVL), which begins in utero. If the baby has signs of a fetal
inflammatory response syndrome should it be kept in utero or should it be
delivered?
† develop a better understanding of the many causal pathways that all lead to CP

ACKNOWLEDGEMENTS

The study was supported by The Frimurare Barnhus Foundation, Linnea and Josef
Carlsson’s Foundation, Folke Bernadotte’s Foundation and the Mayflower Foundation.

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