The origins of cerebral palsy
John M. Keogha and Nadia Badawib
Purpose of review
Cerebral palsy is the most common and visible motor
disability of childhood. Its aetiology remains a topic of hot
debate between those who see it as a reflection of medical
mismanagement of an avoidable complication and those
who see its origins in the development of the fetal brain
affected at many points along a causal pathway to damage.
This review outlines the themes of research publications
over the year 2004/2005.
Recent findings
The review looks at recent findings relating to epidemiology,
infection and inflammation, prematurity, multiple pregnancy,
thrombophilias, genetics, placenta, neuroimaging and
rescue therapies in cerebral palsy.
Summary
Papers this year have helped clarify risk groups and identify
some areas (e.g. the management of thrombophilias and the
potential of induced hypothermia) with the potential to be
rapidly introduced into clinical practice. In this enigmatic
and multifactorial condition, however, progress remains
slow. New tools such as magnetic resonance imaging are
providing valuable insights into the lesions that result in
cerebral palsy but the pathways to injury remain unclear.
The future of cerebral palsy research lies in understanding
the complex interactions of multiple factors on the road to
cerebral palsy or in looking for final common pathways such
as inflammation which may be amenable to manipulation.
Keywords
cerebral palsy, inflammatory markers, neonatal
encephalopathy, neuroimaging, neuroprotection, multiple
births, prematurity
Curr Opin Neurol 19:129134. 2006 Lippincott Williams & Wilkins.
a
Hornsby Ku-Ring Gai Hospital, University of Sydney, Sydney, New South Wales,
Australia and bThe Childrens Hospital at Westmead, University of Sydney, Sydney,
New South Wales Australia
Correspondence to Nadia Badawi, Consultant Neonatologist, Clinical A/Professor
in Paediatrics and Child Health, Department of Neonatology, The Childrens
Hospital at Westmead, Locked Bag 4001, Wesmead, NSW 2145, Australia
Tel: +61 2 98452715; fax: +61 2 98452251; e-mail: nadiab@chw.edu.au
Sponsorship: NB is funded by a National Medical and Health Research Council of
Australia Career Development Award Grant
Current Opinion in Neurology 2006, 19:129134
Abbreviations
CP cerebral palsy
MRI magnetic resonance imaging
PVL periventricular leukomalasia
2006 Lippincott Williams & Wilkins
1350-7540
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Introduction
Though cerebral palsy (CP) is the commonest cause of
motor disability in childhood in many cases the aetiology
remains a mystery. Children with this condition and their
families require significant additional support from
medical, educational and social systems.
While there has been a welcome decline in the incidence
of CP among babies born prematurely [1,2], the stable
rate among term infants, the increasing survival of pre-
term infants and the improved longevity in CP overall
have increased the prevalence of this condition.
We review some of the key papers from 2004/2005 which
examine either the origins of CP or possibilities for its
prevention or amelioration.
Epidemiology of cerebral palsy
Because of the rarity of CP (two per 1000 live births),
population-based studies to determine risk factors are
expensive and difficult to mount. Most aetiological data
come from retrospective case-control studies [3].
Badawi et al. [4,5,6] linked the population-based
Western Australian Newborn Encephalopathy Cohort
to the Western Australian Cerebral Palsy Register [7].
They compared the characteristics among children whose
CP followed newborn encephalopathy with those with
CP following an uncomplicated neonatal course. Only
24% of all term CP followed newborn encephalopathy
(i.e. 76% had been normal in the newborn period), confirm-
ing that intrapartum causes of CP are uncommon. The
CP rate among children who survived moderate to severe
newborn encephalopathy at term was 13% (116/1000
term live births) and was highest among those children
with neonatal seizures [8]. CP following newborn en-
cephalopathy was more likely to be severe, to be of a spastic
quadriplegic or dyskinetic type and to be associated with
other disabilities. These children were nearly four times
more likely to die between the diagnosis of CP and age 6.
The Western Swedish Cerebral Palsy Group, a popu-
lation-based registry, published the ninth report looking
at births between 1995 and 1998 [1]. One hundred and
seventy children with CP were included. From the mid
1960s till the late 1980s the prevalence of CP rose steadily
due, in part, to the increased survival in preterm infants.
Since 1987 the rates of CP in this registry have been
falling steadily in both term and preterm infants. In
the 199598 cohort, this fall was most marked in very
129
 130 Developmental disorders
preterm infants, particularly in spastic diplegia following
posthaemorrhagic hydrocephalus. This trend is also
reported in an Australian population [2]. In the Swedish
data, dyskinetic CP has risen between 1983 and 1998
from 0.17 to 0.28 per 1000 live births, mostly in term
infants. The birth prevalence by birthweight and gesta-
tional age are shown in Table 1 [1].
A worrying paper from the UK and Ireland [9] reported
the 6-year outcomes of babies born at less than 26 weeks
gestation in 1995. They assessed 241 (78%) of the 308
survivors and 160 classmates delivered at term who
served as controls. Forty-nine children (20%) had spastic
or dyskinetic CP (15% spastic diplegia, 1.7% hemiplegia,
3.7% quadriplegia and 0.3% dyskinetic CP). A further
3.7% had hypotonia. Disabling CP occurred in 12% and
was twice as common in boys as girls. The accompanying
editorial [10] quoted the chance of survival with no
disability in this study at 22, 23, 24 and 25 weeks as
0%, 1%, 3% and 8%, respectively.
A retrospective multicentre Californian study of infants
less than 25 weeks gestation with birth weights between
501 and 1000 g compared 366 children born between
January 1993 and June 1996 with 473 born between July
1996 and December 1999 [11]. The early childhood
neurodevelopmental outcomes were not improved in the
later epoch, despite more aggressive perinatal and neo-
natal interventions such as surfactant therapy, delivery by
Ceasarean section and the use of intrapartum antibiotics
and prenatal steroids. The prevalence of CP was similar
in the two time periods (23% and 21%, respectively) but
cognitive impairment was increased in the later cohort.
Wilson-Costello et al. [12] confirm an increased survival
in very low birth weight infants but at the cost of a higher
prevalence of adverse outcomes.
The role of assisted conception techniques remains
topical. A paper from Denmark [13] demonstrated a
statistically significant 80% increase in CP in children
conceived by in-vitro fertilization (IVF).
Infection, inflammation and hypoxia
The role of infection/inflammation in the aetiology of
preterm birth has gained prominence in recent years.
Table 1 Birth prevalence of cerebral palsy among babies of different gestational ages
Gestational age Prevalence per 1000
(weeks) live births
< 28 76.6
2831 40.4
3236 6.7
> 36 1.11
Original table (data from Himmelmann et al. [1].
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Preterm infants have higher rates of exposure to ascending
intrauterine infection. Even in populations with low rates
of bacterial vaginosis, chorioamnionitis and urinary infec-
tion in pregnancy, the prevalence of positive amniotic fluid
cultures and raised amniotic fluid cytokines remains high
in women who labour at less than 34 weeks [14].
While various inflammatory markers have been associ-
ated with neurodevelopmental disability and preterm
labour it is unclear whether cytokines can cross the
placenta and how much of the measured fetal load is
of maternal origin. Proinflammatory cytokines are rela-
tively large molecules which are unlikely to cross by
passive diffusion. Aaltonen et al. [15] using fresh pla-
cental preparations found no evidence that cytokines
such as interleukin (IL)-1b, IL-6 and tumour necrosis
factor a cross the placenta in either direction, suggesting
that cytokines measured in either maternal or fetal com-
partments reflect local inflammation.
Nelson et al. [16] looked at DNA extracted from
archived blood samples from very preterm infants with
CP and matched controls. They looked for the presence
of single nucleotide polymorphisms in proteins associ-
ated with nitric oxide production, thrombosis or thrombo-
prophylaxis, hypertension and inflammation. Genotypic
frequencies in several of the tested variants were differ-
entially distributed in children with CP and controls.
These variations in coding may affect protein function/
interaction, altering the balance between inflammation
and suppression.
Graham et al. [17] performed a retrospective case-
control study over a 7-year period (19942001) of births
between 23 and 34 weeks of gestation with white matter
lesions and gestational age-matched controls. The inci-
dence of significant acidosis at birth was similar in cases
and controls (2% and 3%, respectively). They concluded
that severe intrapartum hypoxia/ischaemia was a rare
association with white matter injury in this preterm
group. Cases, however, had significantly higher rates
of positive cultures of blood, cerebrospinal fluid and
tracheal fluid than controls. Histological chorioamnionitis
and funisitis were not associated with white matter injury.
They suggest that multiple insults converge on cytokine
production as a final common pathway to central nervous
Prevalence per 1000
Birthweight (g) live births
< 1000 82
10001499 54
15002500 6.7
> 2500 1.2

system injury. While some insults cause direct damage
others simply prime the immune system making the fetal
brain more vulnerable. The rarity of hypoxia alone as a
cause of perinatal brain injury in term or preterm infants is
further reviewed by Kendall and Peebles [18]. They also
suggest a stepwise pathway of sensitization followed by
injury so that mild hypoxia may be damaging if the babys
compensatory mechanisms have been downregulated or
disabled by another inflammatory insult. They explore the
role of fever as a potential sensitizer of the brain and
suggest that the control of fever by simple methods such
as sponging and paracetamol may have potential benefit.
Toso et al. [19] used the rat model to explore the potential
for inflammatory mediated CP. Using serial intracer-
vical injections of lipopolysaccharide at the equivalents
of 2836 weeks in human pregnancy they showed bio-
chemical evidence of oligodendrocyte damage and delay
in some motor milestones.
Further support for a sequential model comes from
Australian work [20] examining the association between
in-utero exposure to inflammation and grade III intra-
ventricular haemorrhage, intraparenchymal echodensity
and CP in preterm infants. A strong association was
demonstrated between these outcomes and chorioamnio-
nitis and funisitis on placental examination. This associ-
ation was not present when a full course of antenatal
steroids had been administered. Vohr et al. [21] also
showed a decreased risk of moderate to severe CP in
infants exposed to antenatal steroids but an increase in
any CP or moderate to severe CP in babies exposed to
postnatal steroids.
An autopsy study by Back et al. [22] including 10 babies
with evidence of periventricular leukomalasia (PVL)
searched for hypoxic markers called isoprostanes.
Hypoxic/ischaemic damage to oligodendrocyte precur-
sors release F2-isoprostane whereas neuronal cells pro-
duce F4-isoprostane. F2 but not F4-isoprostane was
found in the areas of PVL. The authors suggest that
oligodendrocyte, not neuronal hypoxia/ischaemia, is
important in the aetiology of PVL.
Finally, Stoll et al. [23] examined the role of neonatal
infection in 6903 children born between 1993 and 2001
weighing less than 1000 g. Nearly two-thirds of children
had acquired infection in the newborn period and of these
over 40% developed an injury resulting in CP, cognitive
impairment or both. CP was found in 16% of children who
had a neonatal infection compared with 8% in the
absence of infection.
Prematurity
Despite falling CP rates in the Western Swedish Cerebral
Palsy cohort, preterm infants remain at markedly
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The origins of cerebral palsy Keogh and Badawi 131
increased risk of CP, accounting for 25% of all patients
[1] (Table 1).
Three further studies examined risk factors in preterm
infants [24,25,26]. Risk factors classically associated
with CP in term infants such as preeclampsia, male
gender, neonatal sepsis and Apgar scores were less
important in preterm infants. Absence of antenatal
steroids, growth restriction, and adverse events in the
newborn period such as prolonged hypocarbia and post-
natal steroids assume greater importance. A recent study
from the UK [27] was unable to confirm the increase in
CP associated with postnatal steroids.
Multiple pregnancy
The different aetiological factors and patterns of CP
in multiple pregnancies and singletons were addressed
by Bonellie et al. [28] using the Scottish register for
19841990. Twins were 4.8 times more likely to develop
CP than singletons. Death of a co-twin increased the rate
of CP by a factor of six compared with when both twins
were liveborn. Twins were more likely to develop spastic
quadriplegia while singletons were more likely to
develop dyskinetic or ataxic CP.
While birth order in twins had no impact on the rate of
CP, discordance in weight was a significant independent
risk factor. Discordance of at least 30% was associated
with a five times greater risk of CP, which was equally
distributed between the bigger and smaller twin.
CP occurred in twins and singletons at similar frequencies
in all gestational ages except at term (> 37 weeks) when
twins were at more than twice the risk. Between 28 and
31 weeks the risk of CP was actually lower for twins.
When considered by birth weight for gestational age,
twins had between 3.5 and 5.5 times higher rates of
CP in all quintiles of birth weight, the greatest variance
being in the lowest quintile.
It was concluded that being a twin carries an increased
risk of CP independent of prematurity and birth weight.
Since other data suggest that IVF pregnancies carry an
increased risk of CP not simply explained by gestation or
multiple birth, the high rate of twins with IVF may
represent a particularly high risk group [13].
The Epipage study [28] reported an 8% incidence of
CP in singletons and 9% in twins born at 32 weeks or less.
Pregnancy complications, such as growth restriction, were
not associated with CP in twins over and above the risk
from preterm birth itself. In fact the rate of CP associated
with delivery preterm of a growth-restricted infant was
lower than for other causes of preterm delivery, perhaps
because such delivery is often by elective Caesarean
section avoiding the inflammatory risks of labour.
 132 Developmental disorders
Thrombophilia
Inherited or acquired thrombophilias may impact on
placentation, placental vascular injury and clotting in
fetal vessels [29,30]. Perinatally acquired stroke
[30,31] occurs in 1 : 4000 pregnancies and underlies a
significant portion of hemiplegic CP, some spastic quad-
riplegic CP and neonatal seizures [30]. First addressed by
Nelson et al. in 1998 [32], the same group recently
demonstrated at least one prothrombotic abnormality
in the blood of 63% of 57 infants with ischaemic stroke
or porencephaly [30]. A group from South Australia [29]
reviewed 441 cases of CP and 883 controls born between
1986 and 1999, using archived dried blood samples. They
looked at four common polymorphisms: factor V Leidin
(FVL), prothrombin gene mutation (PGM G20210A),
and two singe base mutations of methylenetetrahydro-
folate reductase (MTHFR C677T and MTHFR
A1298C.) Term CP was not associated with any of these
thrombophilias. FVL and PGM were not found to be
associated with CP when they existed alone. MTHFR
C677T in its homozygous and heterozygous forms was
associated with a significant increased risk of diplegia,
especially less than 32 weeks. MTHFR A1298C in its
homozygous form was negatively associated with quad-
riplegia (odds ratio (OR) 0.33, 95% confidence interval
(CI) 0.1, 0.87). Combinations of thrombophilias had
additive effects. It is likely that thrombophilias usually
work as part of a causal sequence. For instance, in the area
of perinatal stroke other risk factors include nulliparity,
infertility, preeclampsia, emergency Caesarean section,
vacuum delivery, prolonged rupture of the membranes
and cord abnormalities, with 60% of affected infants
having three or more risk factors [31].
Genetics
Several references have already been made to the impact
of genetic polymorphisms potentiating inflammatory pro-
cesses or coagulation cascade activation [16,18,32,33]
or downregulating defences [18]. In an elegant math-
ematical analysis of data from the Swedish registry [34]
for infants born between 1959 and 1970, Costeff esti-
mated that 40% of cases of CP had a genetic basis (48% of
term and 24% of preterm cases). Genetic factors were
implicated in 60% of term hemiplegia, 45% of term
spastic diplegia, virtually all cases of pure ataxia and
32% of preterm spastic diplegia. In this analysis only
14% of term CP was attributable to a single perinatal
event in a previously normal infant.
Placenta
Some attention is at last being paid to the placenta, which
can provide information relating to vascular pathology,
malformations, structural variations, infection, cytoge-
netics, meconium exposure and possibly timing of insult.
Redline [35] looked at the placentae of 125 cases of
infants with severe neurological abnormalities and 250
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
term controls. Four lesions were found to be significantly
more common in cases than controls: fetal thrombotic
vasculopathy, villitis of unknown cause with obliterative
fetal vasculopathy, chorioamnionitis with severe fetal
vasculitis and meconium-associated vascular necrosis.
One or more was found in 52% of cases compared with
10% of controls (P < 0.0001). Such findings may underlie
the association between absent or reversed end diastolic
flow on umbilical artery Doppler studies and CP in
growth-restricted infants [36].
Neuroimaging
Neuroimaging is increasingly being used to help define
the origins of CP. Cranial ultrasonography has shortcom-
ings in terms of negative predictive value [37] as
demonstrated in a study of 1749 very low birth weight
survivors with a normal head ultrasound. Nearly 30% of
these infants had either CP or a Bayleys Mental Devel-
opmental Index Score less than 70 at 1822 months of
corrected age.
The advent of more freely available magnetic resonance
imaging (MRI) has revolutionized the capacity of clin-
icians to obtain detailed images of the brain neonatally
and in the investigation of CP [38]. It is likely that up to
7075% of cases of CP will show lesional patterns that
help narrow the likely timing of insult and differentiate
single episodes from recurrent insults [39]. Recent stu-
dies have highlighted the unexpectedly high (45%) inci-
dence of cerebellar lesions in CP babies less than
28 weeks or 1000 g [40,41].
Resolution issues mean that MRI, however, will still miss
important lesions such as watershed infarcts in the brain-
stem [42]. As we gain the capacity to increase resolution
and visualize function, many of the conditions now
considered idiopathic will fall into clearer diagnostic
groups.
Since the 2003 publication by Cowan et al. [43] examining
the MRI appearances in newborn encephalopathy, atten-
tion has again been focused on the perinatal period. This
was a hospital, not a population-based study with a
disproportionately large proportion of cases with intra-
partum hypoxia. It remains however surprising how few
had evidence of longstanding damage.
Rescue therapies
The ultimate goal of research is naturally to prevent CP
and with this aim in mind two randomized studies of
either selective head cooling or whole body hypothermia
in moderate and severe newborn encephalopathy have
now been published, with others nearing completion
[44,45,46,47]. The Cool-Cap trial [44] used abnor-
mal amplitude integrated electroencephalogram (EEG)
as an entry criterion and selectively cooled the head with

lesser degrees of body cooling. Shankaran et al. [45]
used whole body cooling with a lower core body tempera-
ture. The overall mortality/morbidity in both studies was
much higher than that seen in the population-based study
of moderate and severe newborn encephalopathy by
Badawi et al. [4,8]. As the diagnosis was apparent very
early to allow recruitment within 6 h of birth, it is possible
these babies had more severe encephalopathy. In the
Gluckman et al. paper [44] there was a decrease in a
combined index of death or severe disability at 18 months
which approached significance in the whole group
and which was significant in those with less severe
EEG changes at entry (adjusted OR 0.42; 0.220.80).
Shankaran and colleagues [45] using a similar combined
index showed a significant reduction (adjusted OR 0.72;
0.540.95), but without significant reduction in the inci-
dence of CP at 1822 months.
Nitric oxide has also attracted attention in terms of its
potential to improve neurodevelopmental outcome in
babies with neonatal respiratory distress. Although
randomized placebo-controlled trials of nitric oxide have
not shown a decrease in CP they have demonstrated a
significant decrease in the risk of cognitive impairment in
the treatment arm [48].
Conclusion
Recently there has been a radical change in our thinking
about the aetiology of CP. We have gone from simplistic
theories about single causes such as intrapartum
asphyxia, to the realization that in many cases a cascade
of contributory events on a causal pathway is more
likely [49]. Progress depends on teasing out these
pathways or finding final common pathways open to
manipulation.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
 of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 202204).
1 Himmelmann K, Hagberg G, Beckung E, et al. The changing panorama of
 cerebral palsy in Sweden. IX: Prevalence and origin in the birth-year period.
Acta Paediatr 2005; 94:287294.
This paper tracks the trends in a population-based cohort giving insight into the
patterns of change over time and the ground that was lost and is now being won
back.
2 Doyle LW, Anderson PJ, for the Victorian Infant Collaborative Study Group.
 Improved neurosensory outcome at 8 years of age of extremely low birth
weight children born in Victoria over three distinct periods. Arch Dis Child
Fetal and Neonatal Edition 2005; 90:F484F488.
A population-based description of the changing pattern of outcomes in very
preterm infants.
3 Reddihough DS, Collins KJ. The epidemiology and causes of cerebral palsy.
Aust J Physiother 2003; 49:712.
4 Badawi N, Kurinczuk JJ, Keogh JM, et al. Intrapartum risk factors for newborn
encephalopathy: the Western Australian case-control study. BMJ 1998;
317:15541558.
5 Badawi N, Kurinczuk JJ, Keogh JM, et al. Antepartum risk factors for newborn
encephalopathy: the Western Australian case-control study. BMJ 1998;
317:15491553.
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The origins of cerebral palsy Keogh and Badawi 133
6

Badawi N, Felix JF, Kurinczuk JJ, et al. Cerebral palsy following term newborn
encephalopathy: a population-based study. Dev Med Child Neurol 2005;
47:293298.
This unique cohort enables the authors to examine in detail the differences in the
type of CP and it association of children with CP following newborn encephalo-
pathy compared with those with a neurologically normal neonatal period.
7 Badawi N, Watson L, Petterson B, et al. What constitutes cerebral palsy?
Dev Med Child Neurol 1998; 40:520527.
8 Dixon G, Badawi N, Kurinczuk JJ, et al. Early developmental outcomes after
newborn encephalopathy. Pediatrics 2002; 109:2633.
9 Marlow N, Wolke D, Bracewell MA, Samara M, for the EPICure Study Group.
 Neurologic and developmental disability at six years of age after extremely
preterm birth. N Engl J Med 2005; 352:919.
This critical paper gives sobering data on a population cohort of extremely preterm
infants followed up to 6 years of age.
10 Vohr BR, Allen M. Extreme prematurity: the continuing dilemma. N Engl J Med
2005; 352:7172.
11 Hintz SR, Kendrick DE, Vohr BR, et al. Changes in neurodevelopmental
 outcomes at 18 to 22 months corrected age among infants of less than
25 weeks gestational age born in 19931999. Pediatrics 2005; 115:1645
1651.
This important paper suggests that adverse outcomes in infants less than
25 weeks are not decreasing despite intensive obstetric and neonatal input.
12 Wilson-Costello D, Friedman H, Minich N, et al. Improved survival rates with
 increased neurodevelopmental disability for extremely low birthweight infants
in the 1990s. Pediatrics 2005; 115:9971003.
Though survival has improved in very preterm infants over the last decade this has
come at the cost of an increased burden of disability.
13 Lidegaard O, Pinborg A, Andersen AN. Imprinting diseases and IVF: Danish
 National IVF cohort study. Hum Reprod 2005; 20:950954.
Further data on the important link between IVF and unexpected adverse outcomes,
in particular a significant increase in the risk of CP in IVF pregnancies.
14 Hagberg H, Mallard C, Jacobsson B. Role of cytokines in preterm labour and
 brain injury. BJOG 2005; 112:1618.
Even in low-risk populations, preterm labour is associated with exposure of the
fetus to significant inflammation.
15 Aaltonen R, Heikkinen T, Hakala K, et al. Transfer of proinflammatory cytokines
 across term placenta. Obstet Gynecol 2005; 106:802807.
Cytokines dont seem to cross the intact placenta so levels in the fetus represent
local inflammatory processes.
16 Nelson KB, Dambrosia JM, Iovannisci DM, et al. Genetic polymorphisms and
 cerebral palsy in very preterm infants. Pediatr Res 2005; 57:494499.
This paper gives further flesh to the idea that genetic polymorphisms may
predispose the fetus to damage from insults that another fetus would tolerate
without injury.
17 Graham EM, Holcroft CJ, Rai KK, et al. Neonatal cerebral white matter injury
 in preterm infants is associated with culture positive infections and only
rarely with metabolic acidosis. Am J Obstet Gynecol 2004; 191:1305
1310.
This important paper points out the infrequency of abnormal cord gases as an
association with preterm CP and the much greater role of infection in the aetiology
of this condition.
18 Kendall G, Peebles D. Acute fetal hypoxia: the modulating effect of infection.
 Early Hum Dev 2005; 81:2734.
This paper continues to develop the idea of a multistage aetiology for CP in which
one factor affects the capacity of the fetus to cope with another.
19 Toso L, Poggi S, Park J. Inflammatory-mediated model of cerebral palsy
with developmental sequelae. Am J Obstet Gynecol 2005; 193:933
941.
20 Kent A, Lomas F, Hurrion E, Dahlstrom JE. Antenatal steroids may reduce
adverse neurological outcome following chorioamnionitis: neurodevelopmen-
tal outcome and chorioamnionitis in premature infants. J Paediatr Child Health
2005; 41:186190.
21 Vohr BR, Wright LL, Poole WK, McDonald SA. Neurodevelopmental out-
comes of extremely low birth weight infants < 32 weeks gestation between
1993 and 1998. Pediatrics 2005; 116:635643.
22 Back SA, Luo NL, Mallinson RA, et al. Selective vulnerability of preterm white
 matter to oxidative damage defined by F2-isoprostanes. Ann Neurol 2005;
58:108120.
Tries to target identify the primary cell damaged in the pathogenesis of periven-
tricular leukomalacia.
23 Stoll BJ, Hansen NI, Adams-Chapman I, et al. Neurodevelopmental and
 growth impairment among extremely low-birth-weight infants with neonatal
infection. JAMA 2004; 292:23572365.
This paper focuses attention on the role of the neonatal course in the pathogenesis
of CP.
 134 Developmental disorders
24 Tran U, Gray PH, OCallaghan MJ. Neonatal antecedents for cerebral palsy in
extremely preterm babies and interaction with maternal factors. Early Hum Dev
2005; 81:555561.
25 Takahashi R, Yamada M, Takahashi T, et al. Risk factors for cerebral palsy in
preterm infants. Dev MedChild Neurol 2005; 81:545553.
26 Livinec F, Ancel PY, Marret S, et al. Epipage Group. Prenatal risk factors for
 cerebral palsy in very preterm singletons and twins. Obstet Gynecol 2005;
105:134137.
This paper reports on a large cohort of preterm infants from nine French regions
and discusses the risk factors associated with CP in twins and singletons.
27 Jones RA. Collaborative Dexamethasone Follow-up Group. Randomized
 controlled trial of dexamethasone in neonatal chronic lung disease: 13 to
17 year follow-up study. I: Neurologic, psychological and educational out-
comes. Pediatrics 2005; 116:370378.
This paper is important because it provides rare long-term follow-up of a very
preterm cohort.
28 Bonellie SR, Currie D, Chalmers J. Comparison of risk factors for cere-
 bral palsy in twins and singletons. Dev Med Child Neurol 2005; 47:587
591.
This is a vitally important paper which examines in detail the features that are
important in the aetiology of CP in twin pregnancy and compares the relative value
of risks in singleton and twin pregnancies.
29 Gibson CS, MacLennan A, Hague WM, et al. Associations between inherited
 thrombophilias, gestational age and cerebral palsy. Am J Obstet Gynecol
2005; 193:1437.
This is the preliminary report of the largest study currently available looking at the
inherited thrombophilias in CP and how their impact varies with age. The size of the
cohort and the exacting analysis make it of great value.
30 Nelson KB, Lynch JK. Stroke in newborn infants. Lancet Neurology 2004;
3:150158.
31 Lee J, Croen LA, Backstrand KH, et al. Maternal and infant characteristics
 associated with perinatal arterial stroke in the infant. JAMA 2005; 293:723
729.
This paper tries to tie together some of the risk factors behind this important
perinatal pathology.
32 Nelson KB, Dambrosia JM, Grether JK, Phillips TM. Neonatal cytokines and
coagulation factors in children with cerebral palsy. Ann Neurol 1998; 44:
665675.
33 Lynch JK, Han CJ, Nee LE, Nelson KB. Prothrombotic factors in children with
stroke or porencephaly. Pediatrics 2005; 116:447453.
34 Costeff H. Estimated frequency of genetic and nongenetic causes of con-
 genital idiopathic cerebral palsy in west Sweden. Ann Hum Genet 2004;
68:515520.
Mathematical analysis of prenatal and perinatal risk factors in a Swedish popula-
tion-based study. Analysis indicates that nearly 50% of etiologically undiagnosed
term CP is genetically caused.
35 Redline RW. Severe fetal placental vascular lesions in term infants with
 neurologic impairment. Am J Obstet Gynecol 2005; 192:452457.
The importance of this paper is that it tries to draw attention to the valuable
information the placenta can provide and the folly of throwing it away before its
value can be tapped.
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
36 Spinillo A, Montanari L, Bergante C, et al. Prognostic value of umbilical artery
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37 Laptook AR, OShea TM, Shankaran S, Bhaskar B. NICHD Neonatal Network.
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infants with a normal head ultrasound: prevalence and antecedents. Pediatrics
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This paper looks at the relatively poor negative predictive value of a normal neonatal
head ultrasound in terms of excluding poor neurodevelopmental outcome.
38 Ashwal S, Russma BS, Blasco BA, et al. Practice parameter: diagnostic
 assessment of the child with cerebral palsy. Neurology 2004; 62:851863.
This paper is included because it points out the importance of MRI in the workup of
a child with CP.
39 Krageloh-Mann I. Cerebral palsy: towards developmental neuroscience. Dev
Med Child Neurol 2005; 47:435.
40 Bodensteiner JB, Johnson SD. Cerebellar injury in the extremely premature
infant: newly recognized but relatively common outcome. J Child Neurol 2004;
19:139142.
41 Johnson SD, Bodensteiner JB, Lotze TE. Frequency and nature of cerebellar
injury in the extremely premature survivor with cerebral palsy. J Child Neurol
2005; 20:46.
42 Sarnat HB. Watershed infarcts in the fetal and neonatal brainstem. An
aetiology of central hypoventilation, dysphagia, Moibius syndrome and micro-
gnathia. Eur J Paediatr Neurol 2004; 8:7187.
43 Cowan F, Rutherford M, Groenendaal F, et al. Origin and timing of brain
lesions in term infants with neonatal encephalopathy. Lancet 2003; 361:
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44 Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild
 systemic hypothermia after neonatal encephalopathy: multicentre randomised
trial. Lancet 2005; 365:663670.
The first of two randomized controlled trials giving hope that we may be able to
modify the outcome of severe encephalopathy by more than just supportive
therapy.
45 Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for
 neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353:
15741584.
The second randomized controlled trial of hypothermia to prevent adverse out-
come in hypoxic ischaemic encephalopathy at this time is giving probably the most
promising results.
46 Wyatt JS, Robertson NJ. Time for a cool head-neuroprotection becomes a
reality. Early Hum Dev 2005; 81:511.
47 Papile L. Systemic hypothermia, a Cool therapy for neonatal hypoxic-
ischemic encephalopathy. N Engl J Med 2005; 353:16191620.
48 Mestan KK, Marks JD, Hecox K, et al. Neurodevelopmental outcomes of
 premature infants treated with inhaled nitric oxide. N Engl J Med 2005; 353:
2332.
Nitric oxide in premature acute neonatal lung disease may have an impact on long-
term cognitive function.
49 Stanley F, Blair E, Alberman E. Cerebral palsies: epidemiology and causal
pathways. Cambridge: Cambridge University Press; 2000.