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Pediatric Health (2009) 3(2), 111113 10.2217/PHE.09.6 2009 Future Medicine Ltd
CP [7]. While the effect of changing clinical
protocols regulating initiation of aggressive
interventions, per se, in preterm birth has not
received systematic attention in relation to CP
outcomes [1], fortunately results are available of
assessments of the long-term effects of several
specic clinical practices designed primarily to
reduce preterm birth-associated morbidity and
mortality. Surfactant-replacement therapy, pre-
and post-natal glucocorticoid administration
and prophylactic prenatal magnesium sulphate
were designed to ameliorate the physiologic
challenges of prematurity. With the exception
of postnatal glucocorticoid administration,
the long-term effects of these specic practices
have included either an apparent reduced risk
for subsequent CP [8,9] or increased survival
with no increased risk for disability (thus, an
absolute increase in the number of preterm
survivors with and without disability [10]). The
apparent benets of antenatal betamethasone
administration have led to additional studies
regarding the effects of repeat antenatal doses
with results suggesting lower respiratory dis-
tress syndrome and overall serious neonatal
morbidity with no increase in risk of CP at
2 years of age [11]. A recent assessment of the
effects of postnatal dexamethasone adminis-
tration targeting infants at very high risk for
chronic lung disease (CLD) revealed that it
improved pulmonary function and had no
increase in the combined outcome of mortality
or long-term neurodevelopmental outcome, but
did increase the rate of adverse neurodevelop-
mental outcome alone (specically an increased
rate of CP without cognitive impairment) [12].
Balancing the improved pulmonary morbidity
with the risk for impaired long-term neuro-
developmental outcome, postnatal dexametha-
sone appeared to be a benecial intervention for
infants specically at very high risk for CLD.
However, the investigators recommended more
trials at lower dosage levels, better targeting of
infants at high risk for CLD earlier after birth
and perhaps other glucocorticoids [12].
As the rate of preterm birth (<37 weeks ges-
tation) has risen in recent decades, so has the
survival rate among affected infants. This epi-
demiologic pattern has been remarkably consist-
ent across different populations in developed
countries. Less consistent has been the accom-
panying trend in the rate of associated neuro-
developmental impairment. Cerebral palsy (CP)
is the most common serious neuromotor disabil-
ity in childhood, affecting 1.53.5 out of every
1000 children overall, but with increasing prev-
alence as gestational age declines. Among popu-
lations for which data are available over time,
trends in reported rates of CP in preterm births
have been variable over the last two decades.
Some studies have reported declines, especially
since the mid-1990s [14], while others have
reported no change [5] or even an increase [6].
Direct comparison of rates across studies has
been hampered by methodological differences
(e.g., selected populations and their accompa-
nying CP rates reecting different birth weight
or gestational age groups, and differences in
follow-up time and birth cohort years). What
might be more clinically important sources of
variability in CP prevalence following preterm
birth, however, are differences in underlying
trends across populations in clinical practice
and potential etiologic factors.
An important clinical trend possibly affect-
ing population differences in CP rates is the
rate of assisted reproduction. This has increased
the risk for both multiple pregnancies and pre-
term birth among singletons, thereby appar-
ently increasing the numbers of children with
EDITORIAL
Cerebral palsy and preterm birth: how far
have we come?
An important clinical trend possibly affecting population differences
in CP [cerebral palsy] rates is the rate of assisted reproduction.
Diana E
Schendel
National Center on Birth Defects &
Developmental Disabilities,
Centers for Disease Control &
Prevention, 1600 Clifton Road, MS
E-86, Atlanta, GA 30333, USA
Tel.: +1 404 498 3845
Fax: +1 404 498 3550
dschendel@cdc.gov
Balancing the improved pulmonary
morbidity with the risk for impaired
long-term neurodevelopmental
outcome, postnatal dexamethasone
appeared to be a beneficial
intervention for infants specifically
at very high risk for CLD.
part of
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112 future science group www.futuremedicine.com
EDITORIAL Schendel
Rather than targeting preterm morbidity,
maternal antibiotics and electronic fetal moni-
toring (EFM) are clinical practices actually
targeting presumed etiologic factors in either
preterm birth or subsequent morbidity, or both;
perinatal infection in the case of antibiotics; and
fetal asphyxia in the case of EFM. Recent report
of the outcomes of the ORACLE I trial of anti-
biotic administration following preterm rupture
of membranes (PROM) revealed reduced death
or neonatal morbidity, but no reduction in CP
or other long-term developmental outcomes in
follow-up to 7 years [13]. The companion report
of the outcomes of the ORACLE II trial of the
same antibiotic treatment protocol but used in
preterm labor (PTL) revealed no reduction in
neonatal morbidity or death, but an increased
risk for CP from exposure to either or both trial
antibiotics [14]. In both trials, eligible women were
asymptomatic for infection. In terms of the CP
results, the investigators suggested that antibiotics
following PROM in asymptomatic women might
neither eradicate nor prevent intra-amniotic infec-
tion, while antibiotics during PTL may possibly
prolong gestation with subclinical infection or
have a direct adverse effect on the fetus. They
concluded that antibiotic treatment for asympto-
matic women during PTL is not advisable. While
not denying the likely etiologic contribution of
infection to preterm birth or CP, the investigators
further cautioned that a better understanding is
needed of the role of infection in PROM and the
role and wider developmental effects of antibiot-
ics during the perinatal period, especially given
the potential for inadvertent long-term harm.
Similarly, EFM appears to have no benet in the
setting of preterm birth, such as identifying pre-
term fetuses (2334 weeks) at risk for white mat-
ter damage (a major precursor of CP) [15] or CP
among preterm fetuses (2833 weeks) exposed to
intrauterine infection [16].
...we are still limited in our abilities
to decipher the actual patterns of CP
prevalence among preterm births
across different populations...
Thus, while laudable advances appear to have
been made with treatments designed to amel-
iorate the physiologic hazards of preterm birth
and reduce the potential for short- and long-term
morbidity, the effects of these treatments on CP
risk have been mixed. At the same time, ongo-
ing clinical trends of increasing rates of assisted
reproduction have increased the risk for CP via
their effect on preterm birth rates. Last, success in
reducing CP has not been achieved with interven-
tions targeting specic etiologic factors. While a
number of individual risk factors for CP in pre-
term birth have been identied, with a current
primary research focus on intra uterine infection
and inammation, understanding of the patho-
genetic mechanisms leading up to neurologic
injury is still very incomplete thereby hamper-
ing the ability to successfully launch p rimary
p revention activities.
...success in reducing CP has not
been achieved with interventions
targeting specific etiologic factors...
A number of factors are likely contributing
to the challenges of understanding CP patho-
genesis in preterm birth or how to successfully
intervene the same type of factors that also con-
found understanding of and hamper the ability
to success fully intervene against preterm birth
itself. First, there are likely to be a number of dif-
ferent etiologic pathways, with each pathway pos-
sibly involving a sequence of contributing events.
Therefore, we need to improve our abilities to
study event series and timing of injury, both in
terms of data collection and analytic approaches.
Better understanding of the contributing events
in an etiologic pathway might allow more sen-
sitive targeting of candidate patients and opti-
mal time points for interventions, for example,
determining whether antenatal steroids reduce
the effects of chorioamnionitis on the risk for
intraventricular hemorrhage and CP in preterm
birth less than 30 weeks [17] or increase neonatal
total thyroxine levels among preterm infants,
which could improve neonatal and long-term
neurologic outcomes [18]. Second, just as the risk
for CP varies by gestational age, it is also likely
that the pathogenetic mechanisms leading to
CP will vary, in part, due to concomitant ges-
tational variation in fetal maturity, especially in
the brain. Thus, we need further investigation
into the specic targets and mechanisms of injury
(e.g., the importance of oligodendrocyte not
neuronal hypoxia/ischemia in the etiology of
periventricular leucomalacia [19]) in studies with
robust samples sizes at different gestational ages.
Third, given the variability in outcome among
infants exposed to similar insults, genetic fac-
tors also might play a role in rendering fetal or
neonatal susceptibility. There have been very
few candidate gene studies for CP, although in
those that have been done there have been some
positive ndings for CP among preterm births
of single-nucleotide polymorphisms related
113
future science group Pediatric Health (2009) 3(2)
Cerebral palsy & preterm birth: how far have we come? EDITORIAL
to inammatory processes [20,21], or inherited
thrombophilias [22]. This is clearly a promising
area of study, but will require ambitious study
designs and sample sizes to adequately explore
geneenvironment interaction.
Thus, we are still limited in our abilities to
decipher the actual patterns of CP prevalence
among preterm births across different popula-
tions or fully account for the contributing factors.
Furthermore, we are still far from understanding
CP pathogenesis to the degree of launching a
successful primary prevention effort, including
prevention of preterm birth itself.
Financial & competing interests disclosure
The ndings and conclusions in this report are those of the
author and do not necessarily represent the ofcial position
of the Centers for Disease Control and Prevention. The
author has no relevant afliations or nancial involve-
ment with any organization or entity with a nancial
interest in or nancial conict with the subject matter or
materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
pending, or royalties.
No writing assistance was utilized in the production of
this manuscript.
Bibliography
1. Robertson CMT, Watt M-J, Yasui Y: Changes
in the prevalence of cerebral palsy for children
born very prematurely within a population-
based program over 30 years. JAMA 297,
27332740 (2007).
2. Himmelmann K, Hagberg G, Beckung E,
Hagberg B, Uvebrant P: The changing
panorama of cerebral palsy in Sweden. IX.
Prevalence and origin in the birth-year period
19951199. Acta Paediatrica 94, 287294
(2005).
3. Platt MJ, Cans C, Johnson A et al.: Trends in
cerebral palsy among infants of very low
birthwight (<1500 g) or born prematurely
(<32 weeks) in 16 European centres:
a database study. Lancet 369, 4350 (2007).
4. Wilson-Costello D, Friedman H, Minich N
et al.: Improved neurodevelomental outcomes
for extremely low birth weight infants in
20002002. Pediatrics 119, 3745 (2007).
5. Tommiska V, Heinonen K, Lehtonen L et al.:
No improvement in outcome of nationwide
extremely low birth weight infant populations
between 19961997 and 19992000.
Pediatrics 119, 2936 (2007).
6. Vincer MJ, Allen AC, Joseph KS, Stinson DA,
Scott H, Wood E: Increasing prevalence of
cerebral palsy among very preterm infants: a
population-based study. Pediatrics 118,
e1621-e1626 (2006).
7. Hvidtjrn D, Grove J, Schendel D et al.:

Cerebral palsy in children born after in vitro
fertilization: the role of preterm delivery a
population-based, cohort study. Pediatrics
118, 475482 (2006).
8. Roberts D, Dalziel S: Antenatal
corticosteroids for accelerating fetal lung
maturation for women at risk for preterm
birth. Cochrane Database Syst. Rev.
DOI: 10.1002/14651858.CD004454.pub2.
(2006).
9. Doyle LW, Crowther CA, Middleton P,
Marret S, Rouse D: Magnesium sulphate for
women at risk of preterm birth for
neuroprotection of the fetus. Cochrane
Database Syst. Rev. DOI: 10.1002/ 14651858.
CD004661.pub3. (2009).
10. Engle WA; Committee on Fetus and
Newborn: Surfactant-replacement therapy
for respiratory distress in the preterm and
term neonate. Pediatrics 121, 419432
(2008).
11. Crowther CA, Doyle LW, Haslam RR,
Hiller JE, Harding JE, Robinson JS:
Outcomes at 2 years of age after repeat doses
of antenatal corticosteroids. N. Engl. J. Med.
357, 11791189 (2007).
12. OShea TM, Washburn LK, Nixon PA,
Goldstein DJ: Follow-up of a randomized,
placebo-controlled trial of dexamethasone to
decrease the duration of ventilator
dependency in very low birth weight infants:
neurodevelopmental outcomes at 4 to
11 years of age. Pediatrics 120, 594602
(2007).
13. Kenyon S, Pike K, Jones DR, Marlow N,
Salt A, Taylor DJ: Childhood outcomes
after prescription of antibiotics to pregnant
women with preterm rupture of the
membranes: 7-year follow-up of the
ORACLE I trial. Lancet 372, 13101318
(2008a).
14. Kenyon S, Pike K, Jones DR,
Brocklehurst P, Marlow N, Salt A,
Taylor DJ: Childhood outcomes after
prescription of antibiotics to pregnant
women with spontaneous preterm labour:
7-year follow-up of the ORACLE II trial.
Lancet 372, 13191327 (2008).
15. Althaus JE, Petersen SM, Fox HE,
Holcroft CJ, Graham EM: Can electronic
fetal monitoring identify preterm neonates
with cerebral white matter injury? Obstet.
Gynecol. 105, 458465 (2005).
16. Sameshima H, Ikenoue T, Ikeda T,
Kamitomo M, Ibara S: Association of
nonreassuring fetal heart rate patterns and
subsequent cerebral palsy in pregnancies with
intrauterine bacterial infection. Am.
J. Perinatol. 22,181187 (2005).
17. Kent A, Lomas F, Hurrion E, Dahlstrom JE:
Antenatal steroids may reduce adverse
neurological outcome following
choriomanionitis: neurodevelopmental
outcome and chorioamnionitis in premature
infants. J. Paediatr. Child Health 41,
186190 (2005).
18. Martin CR, Van Marter LJ, Allred AN,
Leviton A; for the Developmental
Epidemiology Network: Antenatal
glucocorticoids increase early total thyroxine
levels in premature infants. Biol. Neonate 87,
273280 (2005).
19. Back SA, Luo NL, Mallinson RA et al.:
Selective vulnerability of preterm white
matter to oxidative damage dened by
F
2
-isoprostanes. Ann. Neurol. 58, 108120
(2005).
20. Gibson CS, MacLennan AH, Dekker GA
et al.: Candidate genes and cerebral palsy:
a population- based study. Pediatrics 122,
10791085 (2008).
21. Drdelmann M, Kerk J, Dressler F et al.:
Interleukin-10 high producer allele and
ultrasound-dened periventricular white
matter abnormalities in preterm infants:
a preliminary study. NeuroPediatrics 37,
130136 (2006).
22. Gibson CS, MacLennan AH, Hague WM
et al.; for the South Australian Cerebral
Palsy Research Group: Associations between
inherited thrombophilias, gestational age,
and cerebral palsy. Am. J. Obstet. Gynecol.
193, 1437.E11437.E12 (2005).
Afliation
Diana E Schendel, PhD
National Center on Birth Defects
& Developmental Disabilities, Centers for
Disease Control & Prevention,
1600 Clifton Road,
MS E-86, Atlanta, GA 30333, USA
Tel.: +1 404 498 3845
Fax: +1 404 498 3550
dschendel@cdc.gov