Preterm Labor, Infection and Cerebral Palsy
Errol R. Norwitz, M.D., Ph.D.
Associate Professor, Yale University School of Medicine
Associate Director, Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and
Reproductive Sciences, Yale-New Haven Hospital, New Haven, Connecticut, U.S.A.
________________________________________________________________________________________________
Cerebral palsy refers to a group of chronic conditions that are characterized by abnormal control of
movement or posture. These conditions are all cerebral in origin, arise early in life, and are nonprogressive [1-3]. These conditions are frequently accompanied by seizure disorders, sensory impairment,
and/or cognitive limitation. Cerebral palsy is heterogeneous is both its clinical manifestations and its
causation. It is now clear that no more than 10% of all cases of cerebral palsy occur as a result of an
intrapartum event [1-5]. This review will summarize briefly our current understanding of the prevalence
and etiology of cerebral palsy before focusing on two specific risk factors: preterm birth and intrauterine
infection.
The diagnosis of cerebral palsy is typically made at age 2 to 3 years. However, few studies have been
willing to wait this length of time for a definitive diagnosis to be made. For this reason, many investigators
as well as consensus committees have chosen to focus on surrogate endpoints, namely neonatal
encephalopathy or hypoxic-ischemic encephalopathy (HIE). Neonatal encephalopathy refers to “a clinical
phenomena of compromised neurological function in the term or near-term infant, (which) manifests
during the first few days after birth” [6]. HIE refers to a subset of the much broader category of neonatal
encephalopathy, in which the etiology is felt to be intrapartum hypoxic-ischemic injury. Before intrapartum
hypoxic acidemia can be considered as the cause of neurologic injury, a set of specific criteria defined by
several recent national and international consensus panels – including, among others, the International
Cerebral Palsy Task Force [2], the American College of Obstetricians and Gynecologists (ACOG) [7], and
the American Academy of Pediatrics [8] – must be met. These are summarized in Table 1. Moreover, the
only two forms of cerebral palsy that have been associated with HIE are spastic quadriplegia and
dyskinetic cerebral palsy [1,6,9,10]. Many cases of newborn encephalopathy do not result in cerebral palsy.
The bulk of evidence indicates that intrapartum HIE is an infrequent cause of cerebral palsy [1-5].
Table 1: Criteria to define an acute intrapartum hypoxic-ischemic event*
 Profound metabolic or mixed acidemia (pH <7.00) in an umbilical cord arterial blood sample,
if obtained
 Persistent Apgar score of 0 to 3 for longer than 5 minutes
 Evidence of neonatal neurologic sequelae (seizures, coma, or hypotonia)
 Neonatal multiorgan system dysfunction.
* Data from (a) International Cerebral Palsy Task Force. International consensus statement. Br Med J
1999; 319:1054-9; (b) American College of Obstetricians and Gynecologists. Committee Opinion no.
137. Washington, DC: ACOG, 1994; and (c) American Academy of Pediatrics. Pediatrics 1986; 7:1148.
HISTORICAL PERSPECTIVE
Although cerebral palsy has existed throughout history, it was not described in the medical literature until
1844 when W.J. Little, an orthopedic surgeon who specialized in operating on childhood contractures,
outlined a sequence beginning with difficult labor (“asphyxia neonatorum”) followed by neonatal seizures
and, eventually, spastic motor paralysis [11]. (Interestingly, Little’s disease – spastic diplegia – is no longer
believed to result from intrapartum events [12].) The term “cerebral palsy” is attributed to Sir William
Osler
who,
in
1889,
associated
the condition with asphyxia of the newborn following complicated deliveries [13]. The first to question the
causal relationship between a difficult delivery and cerebral palsy was Sigmund Freud. Before turning his
attention to psychiatry, Freud was a neurologist with a particular interest in handicapped children. An
astute observer, Freud noted that children with cerebral palsy often had other manifestations of cerebral
injury that suggested brain damage early in gestation rather that injury around the time of delivery.
Unfortunately, the “intrapartum asphyxia theory” of cerebral palsy gained ascendance again in the late
1970s and has persisted. Whether by ignorance or convenience [4] and despite substantial epidemiologic
evidence demonstrating that cerebral palsy is caused by entities other than intrapartum hypoxia in greater
than 90% of cases [1-5], intrapartum mismanagement and resultant HIE remains uppermost in the minds
of
non-obstetric
care
providers
as
a
major
cause
of
cerebral
palsy.
Fetal acidosis and cerebral palsy: Where did we go wrong?
It seems clear that severe hypoxic ischemic injury to the fetus in its most extreme form, such as that seen
after a complete placental abruption or uterine rupture, may lead to fetal demise or long-term neurologic
handicap, including cerebral palsy. However, it remains highly controversial as to whether milder forms of
fetal acidosis and/or hypoxemia can cause cerebral palsy. In rhesus monkeys, Myers et al [14] demonstrated that partial asphyxia may eventually lead to long-term cerebral lesions that resemble, but are not
identical
to,
the
lesions of cerebral palsy seen in the human infant. In a retrospective case-control study, Richmond et al
[15] found that abnormal fetal heart rate recordings were identified more frequently in children that
subsequent developed cerebral palsy. However, the authors themselves concluded that “optimal
management of fetal distress” would be expected to decrease the prevalence of cerebral palsy “by only
16%” [15]. Other investigators have been unable to demonstrate any association between fetal heart rate
patterns and subsequent neurologic development [16].
PREVALENCE
Cerebral palsy is the most serious handicap of intrauterine and early neonatal life, and is the major cause of
medicolegal disputes in obstetrics [17]. Cerebral palsy is the most common developmental disability in the
United States, affecting approximately half a million residents. According to the statistics of the Centers
for Disease Control (CDC) of the United States (1991-1994), the average annual prevalence rate is 2.8 per
1,000 children ages 3 to 10 [18]. Annually, at least 8,000 new cases are diagnosed in infants in the United
States alone and a further 1,500 are identified in children of preschool age [19].
In 1986, Nelson and Ellenberg [20] observed that “despite earlier optimism that cerebral palsy was
likely to disappear with the advent of improvements in obstetrical and neonatal care, there has apparently
been no consistent decrease in it frequency in the past decade or two.” These conclusions have been
confirmed by other investigators (Figure 1) [21-23]. These observations likely speak to the fact that the
causes of newborn encephalopathy and cerebral palsy are heterogeneous, and many causal pathways start
either periconceptionally or in the early antepartum period.
Figure 1: Cerebral palsy rates per 1,000 live births, 1970 to 2000.
Data from Clark SL, Hankins GDV. Am J Obstet Gynecol 2003;
188:628.
ETIOLOGY
New insights into the origins of cerebral palsy have recently transformed the old concept that most cases of
cerebral palsy begin in labor. There are many causes, including developmental abnormalities, metabolic
abnormalities, autoimmune and coagulation disorders, trauma, infection, and antepartum or intrapartum
hypoxia
in the fetus or newborn [1-5,7,18,19,21-25]. Efforts to identify possible causes of cerebral palsy require
skills from many disciplines. In a given clinical scenario, however, it may be difficult to assess which
features are causally related to the cerebral injury. In many instances, the etiology remains unknown. Risk
factors for newborn encephalopathy are summarized in Table 2 and Figures 2 and 3. A discussion of all of
these risk factors is beyond the scope of his monograph and has been reviewed in detail elsewhere
[21,22,24-27]. The remainder of this monograph will therefore focus on two specific risk factors:
prematurity and intrauterine infection.
Table 2. Risk factors for newborn encephalopathy*
Preconceptional factors
 Increased maternal age
 Primiparity
 Unemployed, unskilled laborer, or
housewife
 No private health insurance
 Infertility treatment
 Family history of seizures
 Family history of neurologic
disorders
Antepartum factors









Male fetus
Maternal thyroid disease
Severe preeclampsia/eclampsia
Bleeding in pregnancy
Viral illness during pregnancy
Prematurity
Postterm pregnancy
Placental abnormalities
Intrauterine growth restriction in
the fetus
 Structural anomalies in the fetus
 Twin pregnancy
Intrapartum factors
 Intrapartum fever
 Prolonged rupture of
membranes
 Thick meconium
 Malpresentation and
malposition
 Intrapartum hypoxia
 Acute intrapartum events
(including cord prolapse,
abruptio placentae, uterine
rupture, maternal seizures)
 Forceps delivery
 Emergency cesarean delivery
* Data from Badawi N, et al. Br Med J 1998; 317:1549; Badawi N, et al. Br Med J 1998; 317:1554;
Ellis M, et al. Br Med J 2000; 320:1229; and Adamson SJ, et al. Br Med J 1995; 311:598.
Figure 2: Risk factors for newborn encephalopathy.
Data from Badawi N, et al. Br Med J 1998; 317:1549 and
Badawi N, et al. Br Med J 1998; 317:1554.
Figure 3: Distribution of risk factors for
newborn encephalopathy. Data from
Badawi N, et al. Br Med J 1998; 317:1554.
Prematurity
Preterm birth (defined as delivery before 37 weeks’ gestation) occurs in 7-10% of all deliveries, but
accounts for over 85% of all perinatal morbidity and mortality [28.29]. Approximately 20% of preterm
deliveries are iatrogenic and are performed for maternal or fetal indications, including intrauterine growth
restriction, preeclampsia, placenta previa, and non-reassuring fetal testing [30]. Of the remaining cases of
preterm birth, around 30% occur in the setting of preterm premature rupture of the membranes, 20-25%
result from intra-amniotic infection, and the remaining 25-30% are due to spontaneous (unexplained)
preterm labor [30,31]. Unfortunately, despite intense efforts, the ability of obstetric care providers to
prevent preterm labor and birth is limited. Indeed, the incidence of preterm delivery continued to rise in
2002, reaching a high of 12.1% [32]. This observation has been attributed primarily to assisted
reproductive technology and to an increase in multiple pregnancies.
Epidemiologic studies have clearly shown an association between premature birth and cerebral palsy.
Williams et al, for example, found a cerebral palsy frequency of 3.2% among live births <29 weeks’
gestation, 2.8% at 29-32 weeks, 0.3% at 33-36 weeks, and 0.07% at 37 weeks [33]. Paradoxically, similar
statistics
from developing countries often appear more favorable, because premature infants in such countries rarely
survive long enough to manifest signs of cerebral palsy. In developed countries, on the other hand,
improvements in neonatal care have led to vastly improved survival rates at the expense of an increased
incidence of long-term neurologic injury.
Intrauterine exposure to infection
A diagnosis of intrauterine infection (chorioamnionitis) during pregnancy is associated with an increased
risk of cerebral palsy in infants with a birth weight 2,500 g [24,34-37]. In very premature infants, the
association between infection and cerebral palsy has been less consistent and, when present, less strong
[24,38]. Intrauterine exposure to infections other than toxoplasmosis, rubella, cytomegalovirus, and herpes
simplex virus (TORCH) is believed to account for approximately 12% of cases of otherwise unexplained
spastic cerebral palsy in non-malformed singleton infants of normal birth weight [34]. Although the ‘gold
standard’ for the diagnosis is often reported as a positive amniotic fluid culture, chorioamnionitis remains
primarily a clinical diagnosis. Unfortunately, the clinical definition is imprecise and, for the same
specimen, there is often disagreement between the histologic indicators and the clinical diagnosis [39].
Epidural analgesia in labor, for example, is associated with an increased risk of intrapartum fever resulting
in more antibiotics being administered and more infants being evaluated for sepsis, but this does not
appear to translate into higher rates of postpartum infection or neonatal infectious morbidity [40,41].
The association between intrauterine infection and fetal and newborn neurologic injury (including
neonatal encephalopathy and cerebral palsy) is almost certainly causal. In a rabbit model, for example,
Yoon et al [42] demonstrated that intrauterine infection leads to white matter lesions in the fetal brain that
resemble the lesions of infection-associated cerebral palsy seen in the human infant. It is possible that the
association with newborn encephalopathy may be mediated either directly by fetal infection, indirectly
through inflammatory cytokines, or both [43-48]. In many patients with intrauterine infection, elevated
levels of lipoxygenase and cyclooxygenase pathway products can be demonstrated in maternal serum, fetal
serum, and amniotic fluid [44,46]. There are also increased concentrations of cytokines (including
interleukin-1, interleukin-6, and tumor necrosis factor-) in the serum and amniotic fluid of such women
[44,46,47], which may predate the development of clinical chorio-amnionitis by weeks or even months
[48].
If infection is causally related to brain injury, can antibiotic therapy prevent the development of
cerebral palsy? Existing randomized trials of the use of antibiotics during pregnancy were designed
primarily to investigate short-term perinatal outcome measures and have not been large enough or willing
to follow the children long enough to examine whether such therapy can reduce the risk of cerebral palsy.
Because of the possibility of harmful consequences of the widespread administration of antibiotics during
pregnancy,
an
evaluation
of
the
safety and efficacy of such medications in pregnancy should require randomized clinical trials that include
the evaluation of long-term neurologic outcomes. Such studies are still awaited.
CAN WE PREVENT CEREBRAL PALSY?
Despite the severe clinical and socioeconomic significance, no effective clinical strategies have yet been
developed to prevent or counteract this condition [3,25]. However, a few approaches are worthy of further
comment:
(1) After adjustment for confounding variables, preeclampsia appears to be independently protective
against neurologic injury and possibly against the development of cerebral palsy [49,50]. The exact
mechanism by which preeclampsia exerts its protective effect is not known. Antenatal corticosteroids
may have a similar protective effect [51], and some authorities have suggested that preeclampsia may
exert its effect by increasing production of endogenous steroids.
(2) There are recent data to suggest that antepartum magnesium sulfate administration may be
associated
with a decreased incidence of cerebral palsy [50,52-55]. This association was initially noted by Kuban
et al [49] in very low birth weight infants born to women who were given magnesium for seizure
prophylaxis in the setting of preeclampsia, but has more recently been confirmed in a number of other
retrospective analyses [50,52-54] with a reported crude odds ratio of 0.11 (95% CI: 0.02-0.81) [54].
This effect appears to be independent of steroid therapy [54,55]. Moreover, the effect is also observed
in infants born of pregnancies not complicated by preeclampsia [52]. The proposed mechanism of
action
is
speculative,
but
magnesium
may act to increase threshold and decrease excitability in membranes of neurons and muscle cells.
Some investigators have suggested that magnesium may reduce the prevalence of cerebral palsy simply
by increasing the death rate among susceptible fetuses and infants. Indeed, during the Magnesium and
Neurologic Endpoints Trial (MagNET), a large randomized clinical trial designed to test the
neuroprotective effect of magnesium sulfate in the setting of preterm labor (not preeclampsia), the
occurrence of excess total pediatric mortality in the children exposed to magnesium (10 of 75 fetuses
randomized to magnesium or saline control versus 1 of 75 infants randomized to “other” tocolytics or
saline control; P=0.02) led to early termination of the trial [55,56]. The authors concluded that, despite
the alarming findings in MagNET, it is conceivable that exposures to doses of magnesium sulfate less
than those used for aggressive tocolysis may be neuroprotective without being lethal [56]. This
conclusion may be supported by the recently published Magpie Trial [57], a clinical study of 10,141
women with preeclampsia randomized in 33 countries to receive either magnesium sulfate or placebo
for seizure prophylaxis. This study showed no substantive short-term harmful effects of magnesium
sulfate on the fetus. Because of the ongoing controversy, it is not currently standard of care to
administer antenatal magnesium sulfate to women threatening to deliver extremely premature infants.
(3) There is some evidence to suggest that perinatal brain injury following an intrapartum hypoxic
ischemic event may evolve, at least in part, over a period of hours or days, thereby providing a possible
window of opportunity for early intervention. Preliminary studies on the use of neonatal hypothermia
treatment suggest that such an approach may provide some neuroprotective effect [58,59]. Until
further studies are available, however, such treatment should be regarded as investigational.
(4) Elective cesarean delivery prior to labor is protective against the development of cerebral palsy
[22,26]. However, cesarean delivery after the onset of labor likely mitigates against this protective
effect. Reviewing pooled data from nine industrialized countries, Clark and Hankins concluded that
“despite
a
5-fold
increase
in the rate of cesarean section based, in part, on the electronically derived diagnosis of ‘fetal distress’,
cerebral palsy prevalence has remained stable” [23].
CONCLUSIONS
Cerebral palsy is a syndrome since the etiologies are varied. Considerable evidence suggests that no more
than 10% of all cases of cerebral palsy occur as a result of an intrapartum event. A better understanding of
the pathophysiologic mechanisms responsible for fetal and infant brain injury will further our knowledge
about disorders of neurologic development, including cerebral palsy. There are as yet no effective
strategies
available
for the prevention and/or treatment of fetuses and newborns at risk for cerebral palsy.
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