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130 Developmental disorders
preterm infants, particularly in spastic diplegia following Preterm infants have higher rates of exposure to ascending
posthaemorrhagic hydrocephalus. This trend is also intrauterine infection. Even in populations with low rates
reported in an Australian population [2]. In the Swedish of bacterial vaginosis, chorioamnionitis and urinary infec-
data, dyskinetic CP has risen between 1983 and 1998 tion in pregnancy, the prevalence of positive amniotic fluid
from 0.17 to 0.28 per 1000 live births, mostly in term cultures and raised amniotic fluid cytokines remains high
infants. The birth prevalence by birthweight and gesta- in women who labour at less than 34 weeks [14].
tional age are shown in Table 1 [1].
While various inflammatory markers have been associ-
A worrying paper from the UK and Ireland [9] reported ated with neurodevelopmental disability and preterm
the 6-year outcomes of babies born at less than 26 weeks labour it is unclear whether cytokines can cross the
gestation in 1995. They assessed 241 (78%) of the 308 placenta and how much of the measured fetal load is
survivors and 160 classmates delivered at term who of maternal origin. Proinflammatory cytokines are rela-
served as controls. Forty-nine children (20%) had spastic tively large molecules which are unlikely to cross by
or dyskinetic CP (15% spastic diplegia, 1.7% hemiplegia, passive diffusion. Aaltonen et al. [15] using fresh pla-
3.7% quadriplegia and 0.3% dyskinetic CP). A further cental preparations found no evidence that cytokines
3.7% had hypotonia. Disabling CP occurred in 12% and such as interleukin (IL)-1b, IL-6 and tumour necrosis
was twice as common in boys as girls. The accompanying factor a cross the placenta in either direction, suggesting
editorial [10] quoted the chance of survival with no that cytokines measured in either maternal or fetal com-
disability in this study at 22, 23, 24 and 25 weeks as partments reflect local inflammation.
0%, 1%, 3% and 8%, respectively.
Nelson et al. [16] looked at DNA extracted from
A retrospective multicentre Californian study of infants archived blood samples from very preterm infants with
less than 25 weeks gestation with birth weights between CP and matched controls. They looked for the presence
501 and 1000 g compared 366 children born between of single nucleotide polymorphisms in proteins associ-
January 1993 and June 1996 with 473 born between July ated with nitric oxide production, thrombosis or thrombo-
1996 and December 1999 [11]. The early childhood prophylaxis, hypertension and inflammation. Genotypic
neurodevelopmental outcomes were not improved in the frequencies in several of the tested variants were differ-
later epoch, despite more aggressive perinatal and neo- entially distributed in children with CP and controls.
natal interventions such as surfactant therapy, delivery by These variations in coding may affect protein function/
Ceasarean section and the use of intrapartum antibiotics interaction, altering the balance between inflammation
and prenatal steroids. The prevalence of CP was similar and suppression.
in the two time periods (23% and 21%, respectively) but
cognitive impairment was increased in the later cohort. Graham et al. [17] performed a retrospective case-
control study over a 7-year period (19942001) of births
Wilson-Costello et al. [12] confirm an increased survival between 23 and 34 weeks of gestation with white matter
in very low birth weight infants but at the cost of a higher lesions and gestational age-matched controls. The inci-
prevalence of adverse outcomes. dence of significant acidosis at birth was similar in cases
and controls (2% and 3%, respectively). They concluded
The role of assisted conception techniques remains that severe intrapartum hypoxia/ischaemia was a rare
topical. A paper from Denmark [13] demonstrated a association with white matter injury in this preterm
statistically significant 80% increase in CP in children group. Cases, however, had significantly higher rates
conceived by in-vitro fertilization (IVF). of positive cultures of blood, cerebrospinal fluid and
tracheal fluid than controls. Histological chorioamnionitis
Infection, inflammation and hypoxia and funisitis were not associated with white matter injury.
The role of infection/inflammation in the aetiology of They suggest that multiple insults converge on cytokine
preterm birth has gained prominence in recent years. production as a final common pathway to central nervous
Table 1 Birth prevalence of cerebral palsy among babies of different gestational ages
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The origins of cerebral palsy Keogh and Badawi 131
system injury. While some insults cause direct damage increased risk of CP, accounting for 25% of all patients
others simply prime the immune system making the fetal [1] (Table 1).
brain more vulnerable. The rarity of hypoxia alone as a
cause of perinatal brain injury in term or preterm infants is Three further studies examined risk factors in preterm
further reviewed by Kendall and Peebles [18]. They also infants [24,25,26]. Risk factors classically associated
suggest a stepwise pathway of sensitization followed by with CP in term infants such as preeclampsia, male
injury so that mild hypoxia may be damaging if the babys gender, neonatal sepsis and Apgar scores were less
compensatory mechanisms have been downregulated or important in preterm infants. Absence of antenatal
disabled by another inflammatory insult. They explore the steroids, growth restriction, and adverse events in the
role of fever as a potential sensitizer of the brain and newborn period such as prolonged hypocarbia and post-
suggest that the control of fever by simple methods such natal steroids assume greater importance. A recent study
as sponging and paracetamol may have potential benefit. from the UK [27] was unable to confirm the increase in
CP associated with postnatal steroids.
Toso et al. [19] used the rat model to explore the potential
for inflammatory mediated CP. Using serial intracer- Multiple pregnancy
vical injections of lipopolysaccharide at the equivalents The different aetiological factors and patterns of CP
of 2836 weeks in human pregnancy they showed bio- in multiple pregnancies and singletons were addressed
chemical evidence of oligodendrocyte damage and delay by Bonellie et al. [28] using the Scottish register for
in some motor milestones. 19841990. Twins were 4.8 times more likely to develop
CP than singletons. Death of a co-twin increased the rate
Further support for a sequential model comes from of CP by a factor of six compared with when both twins
Australian work [20] examining the association between were liveborn. Twins were more likely to develop spastic
in-utero exposure to inflammation and grade III intra- quadriplegia while singletons were more likely to
ventricular haemorrhage, intraparenchymal echodensity develop dyskinetic or ataxic CP.
and CP in preterm infants. A strong association was
demonstrated between these outcomes and chorioamnio- While birth order in twins had no impact on the rate of
nitis and funisitis on placental examination. This associ- CP, discordance in weight was a significant independent
ation was not present when a full course of antenatal risk factor. Discordance of at least 30% was associated
steroids had been administered. Vohr et al. [21] also with a five times greater risk of CP, which was equally
showed a decreased risk of moderate to severe CP in distributed between the bigger and smaller twin.
infants exposed to antenatal steroids but an increase in
any CP or moderate to severe CP in babies exposed to CP occurred in twins and singletons at similar frequencies
postnatal steroids. in all gestational ages except at term (> 37 weeks) when
twins were at more than twice the risk. Between 28 and
An autopsy study by Back et al. [22] including 10 babies 31 weeks the risk of CP was actually lower for twins.
with evidence of periventricular leukomalasia (PVL) When considered by birth weight for gestational age,
searched for hypoxic markers called isoprostanes. twins had between 3.5 and 5.5 times higher rates of
Hypoxic/ischaemic damage to oligodendrocyte precur- CP in all quintiles of birth weight, the greatest variance
sors release F2-isoprostane whereas neuronal cells pro- being in the lowest quintile.
duce F4-isoprostane. F2 but not F4-isoprostane was
found in the areas of PVL. The authors suggest that It was concluded that being a twin carries an increased
oligodendrocyte, not neuronal hypoxia/ischaemia, is risk of CP independent of prematurity and birth weight.
important in the aetiology of PVL. Since other data suggest that IVF pregnancies carry an
increased risk of CP not simply explained by gestation or
Finally, Stoll et al. [23] examined the role of neonatal multiple birth, the high rate of twins with IVF may
infection in 6903 children born between 1993 and 2001 represent a particularly high risk group [13].
weighing less than 1000 g. Nearly two-thirds of children
had acquired infection in the newborn period and of these The Epipage study [28] reported an 8% incidence of
over 40% developed an injury resulting in CP, cognitive CP in singletons and 9% in twins born at 32 weeks or less.
impairment or both. CP was found in 16% of children who Pregnancy complications, such as growth restriction, were
had a neonatal infection compared with 8% in the not associated with CP in twins over and above the risk
absence of infection. from preterm birth itself. In fact the rate of CP associated
with delivery preterm of a growth-restricted infant was
Prematurity lower than for other causes of preterm delivery, perhaps
Despite falling CP rates in the Western Swedish Cerebral because such delivery is often by elective Caesarean
Palsy cohort, preterm infants remain at markedly section avoiding the inflammatory risks of labour.
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
132 Developmental disorders
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The origins of cerebral palsy Keogh and Badawi 133
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
134 Developmental disorders
24 Tran U, Gray PH, OCallaghan MJ. Neonatal antecedents for cerebral palsy in 36 Spinillo A, Montanari L, Bergante C, et al. Prognostic value of umbilical artery
extremely preterm babies and interaction with maternal factors. Early Hum Dev Doppler studies in unselected preterm deliveries. Obstet Gynecol 2005;
2005; 81:555561. 105:613620.
25 Takahashi R, Yamada M, Takahashi T, et al. Risk factors for cerebral palsy in 37 Laptook AR, OShea TM, Shankaran S, Bhaskar B. NICHD Neonatal Network.
preterm infants. Dev MedChild Neurol 2005; 81:545553. Adverse neurodevelopmental outcomes among extremely low birth weight
infants with a normal head ultrasound: prevalence and antecedents. Pediatrics
26 Livinec F, Ancel PY, Marret S, et al. Epipage Group. Prenatal risk factors for
2005; 115:673680.
cerebral palsy in very preterm singletons and twins. Obstet Gynecol 2005;
This paper looks at the relatively poor negative predictive value of a normal neonatal
105:134137.
head ultrasound in terms of excluding poor neurodevelopmental outcome.
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. 38 Ashwal S, Russma BS, Blasco BA, et al. Practice parameter: diagnostic
assessment of the child with cerebral palsy. Neurology 2004; 62:851863.
27 Jones RA. Collaborative Dexamethasone Follow-up Group. Randomized
This paper is included because it points out the importance of MRI in the workup of
controlled trial of dexamethasone in neonatal chronic lung disease: 13 to
a child with CP.
17 year follow-up study. I: Neurologic, psychological and educational out-
comes. Pediatrics 2005; 116:370378. 39 Krageloh-Mann I. Cerebral palsy: towards developmental neuroscience. Dev
This paper is important because it provides rare long-term follow-up of a very Med Child Neurol 2005; 47:435.
preterm cohort.
40 Bodensteiner JB, Johnson SD. Cerebellar injury in the extremely premature
28 Bonellie SR, Currie D, Chalmers J. Comparison of risk factors for cere- infant: newly recognized but relatively common outcome. J Child Neurol 2004;
bral palsy in twins and singletons. Dev Med Child Neurol 2005; 47:587 19:139142.
591.
41 Johnson SD, Bodensteiner JB, Lotze TE. Frequency and nature of cerebellar
This is a vitally important paper which examines in detail the features that are
injury in the extremely premature survivor with cerebral palsy. J Child Neurol
important in the aetiology of CP in twin pregnancy and compares the relative value
2005; 20:46.
of risks in singleton and twin pregnancies.
42 Sarnat HB. Watershed infarcts in the fetal and neonatal brainstem. An
29 Gibson CS, MacLennan A, Hague WM, et al. Associations between inherited
aetiology of central hypoventilation, dysphagia, Moibius syndrome and micro-
thrombophilias, gestational age and cerebral palsy. Am J Obstet Gynecol
gnathia. Eur J Paediatr Neurol 2004; 8:7187.
2005; 193:1437.
This is the preliminary report of the largest study currently available looking at the 43 Cowan F, Rutherford M, Groenendaal F, et al. Origin and timing of brain
inherited thrombophilias in CP and how their impact varies with age. The size of the lesions in term infants with neonatal encephalopathy. Lancet 2003; 361:
cohort and the exacting analysis make it of great value. 736742.
30 Nelson KB, Lynch JK. Stroke in newborn infants. Lancet Neurology 2004; 44 Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild
3:150158. systemic hypothermia after neonatal encephalopathy: multicentre randomised
trial. Lancet 2005; 365:663670.
31 Lee J, Croen LA, Backstrand KH, et al. Maternal and infant characteristics
The first of two randomized controlled trials giving hope that we may be able to
associated with perinatal arterial stroke in the infant. JAMA 2005; 293:723
modify the outcome of severe encephalopathy by more than just supportive
729.
therapy.
This paper tries to tie together some of the risk factors behind this important
perinatal pathology. 45 Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for
neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353:
32 Nelson KB, Dambrosia JM, Grether JK, Phillips TM. Neonatal cytokines and
15741584.
coagulation factors in children with cerebral palsy. Ann Neurol 1998; 44:
The second randomized controlled trial of hypothermia to prevent adverse out-
665675.
come in hypoxic ischaemic encephalopathy at this time is giving probably the most
33 Lynch JK, Han CJ, Nee LE, Nelson KB. Prothrombotic factors in children with promising results.
stroke or porencephaly. Pediatrics 2005; 116:447453.
46 Wyatt JS, Robertson NJ. Time for a cool head-neuroprotection becomes a
34 Costeff H. Estimated frequency of genetic and nongenetic causes of con- reality. Early Hum Dev 2005; 81:511.
genital idiopathic cerebral palsy in west Sweden. Ann Hum Genet 2004;
47 Papile L. Systemic hypothermia, a Cool therapy for neonatal hypoxic-
68:515520.
ischemic encephalopathy. N Engl J Med 2005; 353:16191620.
Mathematical analysis of prenatal and perinatal risk factors in a Swedish popula-
tion-based study. Analysis indicates that nearly 50% of etiologically undiagnosed 48 Mestan KK, Marks JD, Hecox K, et al. Neurodevelopmental outcomes of
term CP is genetically caused. premature infants treated with inhaled nitric oxide. N Engl J Med 2005; 353:
2332.
35 Redline RW. Severe fetal placental vascular lesions in term infants with
Nitric oxide in premature acute neonatal lung disease may have an impact on long-
neurologic impairment. Am J Obstet Gynecol 2005; 192:452457.
term cognitive function.
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 49 Stanley F, Blair E, Alberman E. Cerebral palsies: epidemiology and causal
value can be tapped. pathways. Cambridge: Cambridge University Press; 2000.
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.