Cerebral Palsy
“What the Obstetrician Should Know”
Donna Dizon-Townson, MD, FACOG
Associate Professor
Department of Obstetrics & Gynecology
Division of Maternal – Fetal Medicine
University of Utah Health Sciences Center
Medical Director Urban South Region
Clinical Programs
Intermountain Health Care
Cerebral Palsy
Historical Perspectives
• 1862 William John Little, orthopedic surgeon,
“spastic rigidity” related to pregnancy
complications and preterm birth
• 1897 Freud classification scheme based on
affected muscles
• 1898 Osler first to use term “cerebral palsies
of children”
• Sarah McNutt lecturer on relationships of
complications of labor, difficult deliveries,
errors of obstetricians, and spastic rigidity
Neonatal Encephalopathy
Definition:
Defined clinically on the basis of a constellation
of findings including a combination of
abnormal consciousness, tone and reflexes,
feeding, respiration, or seizures and can result
from a myriad of conditions
(multisystem organ dysfunction)
Cerebral Palsy
Definition:
Neuromuscular disability characterized by
aberrant control of movement or posture
appearing early in life and not the result of
recognized progressive disease
Intrapartum Ischemic /
Hypoxemic Event
Neonatal Encephalopathy
Cerebral Palsy
NOT Caused by Birth Asphyxia
• Epilepsy without cerebral palsy
• Mental retardation without cerebral
palsy
• Attention-deficit hyperreactivity
disorder
Cerebral Palsy
• May or may not be associated with a
seizure disorder
• May or may not be associated with
mental retardation
• Only an endpoint for a variety of CNS
insults which may occur
– Prenatal
– Perinatal
– Postnatal
Etiologic Mechanisms for
Cerebral Palsy
Neonatal Encephalopathy
• 19% nonstringent criteria for intrapartum
hypoxia
• 10% experienced a significant intrapartum
event
– 69% only antepartum risk factors
– 25% had both antepartum and intrapartum risk
factors
– 4% only intrapartum risk factors
– 2% no identifiable risk factor
– 70% secondary to events arising before onset of
labor
Neonatal Encephalopathy
Attributed to Intrapartum Hypoxia
Prevalence
1.6 per 10,000
Cerebral Palsy
Prevalence
1.5 – 2.5 cases of Cerebral Palsy /
1,000 Live births
Cerebral Palsy
Classification Schemes
• Type of Motor Dysfunction
–
–
–
–
Spasticity – Most common
Flaccidity
Dyskinesis
Ataxia
• Muscle groups involved
–
–
–
–
Quadriplegia
Diplegia
Hemiplegia
Monoplegia
Cerebral Palsy
Classification Schemes
• Spastic Cerebral Palsy
–
–
–
–
–
Most common
Hypertonia and rigidity - “Clasp – knife”
Contractures abnormal curvature of spine
Cerebral cortex and pyramidal tract injury
Periventricular injury more likely to
affect the lower extremities
Cerebral Palsy
Classification Schemes
• Dyskinetic Cerebral Palsy
– Injury of basal ganglia and
extrapyramidal tracts
– Impaired voluntary muscle control
– Bizarre twisting motions with
exaggerated posturing
– Increased muscle tone – “Lead pipe”
– Association with kernicterus
Motor Pathways and Ventricles
Cerebral Palsy
• Overall prevalence of CP unchanged
• Change of certain subtypes of CP
– Dyskinetic choreoathetoid CP decreasing due to
decrease Rh isoimmunization and improved care
for pregnancy complicated by isoimmunization
– Spastic diplegia CP increasing due to increasing
survival of extremely premature neonate
– Most common CP term infants spastic
quadriplegia
Cerebral Palsy
Biologic and Demographic Risk Factors
• Maternal age and parity
• Gender - Male > female
• Multiple births
• Prematurity
• Intrauterine growth restriction
• Intracranial hemorrhage
• Periventricular leukomalacia
Cerebral Palsy
Multiple Births
• RR for CP twin is 5 – 6 X singleton
• RR for CP triplet 5 – 6 X twins
• Increase risk for CP due to tendency of
multiple gestation to deliver preterm
• Risk for CP substantially increased if
intrauterine death of one or more of
fetuses
– 10 – 15 X when both fetuses alive
– 60 X liveborn singleton
Cerebral Palsy
Prematurity
Prevalence of Cerebral Palsy by
Birth Weight and Gestational Age
Cerebral Palsy
Prematurity
Gestational Age /
Birthweight
23 – 25 Weeks /
500 – 600 grams
All infants
< 1000 grams
27 – 28 Weeks /
1000 grams
36 Weeks
Prevalence of CP
25%
5 – 10%
3%
5 / 1000
Cerebral Palsy
Prematurity
• U.S. Collaborative Perinatal Project
studied infants born between 1959 - 1966
– 9% of cases of CP attributed to infants
surviving with a birthweight < 1500 grams
• Later studies more than 30% of children
with CP had birthweights < 1500 grams
• These findings have been confirmed in
Sweden (9-18%), Australia (6-13%), and
United Kingdom (5-21%)
Cerebral Palsy
Intrauterine Growth Restriction
• U.S. Collaborative Perinatal Project
– In the absence of hypoxia-related factors,
IUGR not associated with increase of CP
– In the presence of hypoxia-related factors,
IUGR more likely to be neurologically
abnormal
Berg et al Early Hum Dev 1989:271-83.
Cerebral Palsy
Western Australia studies
– Many pathways leading to CP, with each
contributing a small proportion
– 50% of cases of CP (vs.. 14% of controls) had one
or more of risk factors
– No risk factor present in more than 11% of cases
– Most risk factors present in less than 5% of cases
– Antepartum (35%), intrapartum (9%),
postpartum (10%)
Stanley, 1984; Blair and Stanley, 1988, 1990.
Cerebral Palsy
Intrapartum Risk Factors
Risk Factor
Odds Ratio
Chorioamnionitis
4.2
Prolonged rupture of
membranes
Maternal infection
2.3
Preeclampsia
0.4
Delivery without labor
0.3
Growth restriction
1
CP increased with decreasing gestational age.
Risk factors after adjusted for gestational age.
2.3
Murphy et al Lancet 1995;346:1449-54.
Cerebral Palsy
Risk Factors
• Long or short interpregnancy intervals
• Birth defect
• Low birth weight
• Low placental weight
• Abnormal fetal position
• Abruptio placenta
Torfs et al J Pediatr 1990;116:615-19.
Cerebral Palsy
Birth Asphyxia
• Imprecise terms used to describe impaired
fetal placental gas exchange
–
–
–
–
Hypoxia
Asphyxia
Ischemia
Fetal distress
• Use of better terms
– Metabolic acidemia
– Newborn encephalopathy
– Hypoxic ischemic encephalopathy
Cerebral Palsy
Apgar Scores
• Earlier gestational age, lower the Apgar
scores despite normal umbilical cord gases
• U.S. Collaborative Perinatal Project
– CP significantly with very low Apgar scores
persisting for long periods of times
– 5-minute score < 3, CP develops in 5%
– Most term infants with very low Apgar scores do
not develop CP
– Only Apgar scores < 3 for 20 minutes or longer
the risk of CP 50%
Cerebral Palsy Prevalence / 100 Survivors
by Apgar Score and Postnatal Age
Cerebral Palsy
Perinatal Asphyxia
• All of the following criteria must be
present
– Profound umbilical artery metabolic or
mixed acidemia (pH < 7.00)
– Persistence of an Apgar score of 0 – 3 for
longer than 5 minutes
– Neonatal neurologic sequelae
– Multisystem organ dysfunction
ACOG Technical Bulletin #163, January, 1992.
Cerebral Palsy
International Consensus Statement
• All of the following must be present to
make a causal relationship between CP and
an acute intrapartum event
– CP must be of a spastic quadriplegic or
dyskinetic type
– Early onset of severe or moderate neonatal
encephalopathy in a baby born at 34 weeks or
later
– Evidence of metabolic acidosis intrapartum fetal,
umbilical arterial cord or very early neonatal
blood samples (pH < 7.00)
MacLennan BMJ 1999;319:1054-59.
Relative Risk of Neonatal Death in Preterm and Term Infants
with Five-Minute Apgar Scores of 0 to 3 and Various Degrees
of Umbilical-Artery Blood Acidemia
Cerebral Palsy
Brain Lesions
• Intracranial hemorrhage
– US periventricular echodensities
– Preterm neonates
• Periventricular leukomalacia
– Cerebral white matter echolucencies
– Preterm and term neonates
• Two best neonatal predictors of
cerebral palsy
Echodense Parenchymal Brain
Lesions and Risk of CP
STUDY
NO.
LESION
SURVIVORS
WITH CP
Papile, 1983
17
Grade IV ICH
86%
Pape, 1985
20
Grade IV ICH
40%
Catto-Smith,
1985
3
ICH
67%
Guzetta, 1986
22
Periventricular
parenchymal
echodensity
86%
Graham, 1987
3
Parenchymal
hemorrhage
100%
Cooke, 1987
32
Parenchymal
hemorrhage or
extension
100%
TOTAL
97
67%
Incidence of Cystic Periventricular
Leukomalacia (PVL) According to
Gestational Age
Echolucent Parenchymal Brain
Lesions and Risk of Cerebral Palsy
STUDY
NO.
LESION
SURVIVORS
WITH CP
Devries, 1985
10
Extensive or
subcortical
PVL
100%
Graziani, 1985
15
Large
periventricular
cysts or
porencephaly
80%
Boyzynski,
1985
4
PVL
100%
Weindling,
1985
8
Periventricular
cysts
100%
Smith, 1986
16
PVL
88%
Echolucent Parenchymal Lesions
and Risk of Cerebral Palsy
STUDY
NO.
LESION
SURVIVORS
WITH CP
Graham, 1987
13
Cystic PVL
62%
Fawer, 1987
11
Extensive PVL
73%
Stewart, 1987
10
Cysts
80%
Cooke, 1987
32
Porencephalic
cysts
69%
Total
127
80%
Risk Factors for
Periventricular Leukomalacia
Pathway to Cerebral Palsy in
Preterm Infants
Ongoing Research Involving
Cerebral Palsy
1. BEAM - Beneficial Effects of
Antenatal Magnesium
2. Thrombophilias and Cerebral Palsy
Magnesium Sulfate
• Nelson and Grether, 1995 – Retrospective
case - control analysis of CP in infants with
birth weights < 1500 g
– 3 / 42 infants with CP exposed to MgSO4
– 27 / 75 infants with CP not exposed to MgSO4
– Statistically significant with an OR = 0.14
Magnesium Sulfate
• Schendle, 1996 – Population based cohort
study evaluated maternal Mg SO4
exposure, CP, and mental retardation in
children with birthweights < 1500 g born
1986 – 1988
– n = 519 infants survived infancy
– 17% exposed to MgSO4
– Exposure to MgSO4 reduction (OR = 0.11)
Magnesium Sulfate
• Hauth, 1998 – Retrospective case – control
study of 398 infants with birthweights of
500 – 1000 grams
• 1 year follow-up
• 212 received MgSO4: CP 7.6%
• 186 No MgSO4: CP 19%
Hauth JC et al AJOG, 1998, 172:419.
B.E.A.M.
• Beneficial Effects of Antenatal Magnesium
• National Institutes of Health MaternalFetal Medicine Network
• Prospective randomized control trial of
MgSO4 versus placebo in n=3,000 fetuses
between 24 – 31.6 weeks gestation
• 3 Year complete neurologic follow - up
B.E.A.M.
• Multicenter, placebo-controlled,
double-blind randomized trial
• Women imminent risk for delivery
between 24 – 31 weeks randomized
– MgSO4 – 6 gm bolus constant infusion 2
gm/hr OR placebo
• Primary outcome
– Composite of stillbirth or infant death by
1 year of age OR moderate – severe
cerebral palsy at or beyond 2 years of age
Rouse et al. N Engl J Med 359;9:895-905.
B.E.A.M.
• 2241 women randomized
• Baseline characteristics same
• Follow up achieved for 95.6% of children
• Rate of primary outcome not
significantly different between Mg
group vs. placebo group
– 11.3 and 11.7%; RR, 0.97; 95% CI, 0.77- 1.23
Rouse et al. N Engl J Med 359;9:895-905.
B.E.A.M.
• Secondary analysis
• Moderate – severe cerebral palsy
occurred less in the MgSO4 group
– 1.9 vs. 3.5%; RR, 0.55; 95% CI, 0.32 – 0.95
• Risk of death did not differ
– 9.5 vs. 8.5%; RR, 1.12; 95% CI, 0.85-1.47
• No woman had a life threatening event
Rouse et al. N Engl J Med 359;9:895-905.
B.E.A.M.
• Concluded fetal exposure to MgSO4
before anticipated early preterm
delivery did not reduce the combined
risk of moderate or severe cerebral
palsy or death, although the rate of
cerebral palsy was reduced among
survivors.
Rouse et al. N Engl J Med 359;9:895-905.
Effect of Magnesium Sulfate Given for
Neuroprotection Before Preterm Birth:
A Randomized Control Trial
ACTOMgSO4
• Randomized controlled trial at 16 tertiary
hospitals in Australia and New Zealand
• 1062 women < 30 weeks birth planned or
expected within 24 hrs Feb 1996 – Sept 2000
• Follow up of surviving children at 2 yrs
Crowther, et al. JAMA , 2003;290 No 20: 2669-76 .
ACTOMgSO4
• Women randomized to 4gm bolus / 20 min
followed maintenance 1gm/ hr
• Outcome Measures
– Total pediatric mortality
– Cerebral palsy
– Combined outcome of death OR cerebral
palsy at 2 years of age
Crowther, et al. JAMA , 2003;290 No 20: 2669-76
ACTOMgSO4
• Total pediatric mortality
– 13.8 vs. 17.1%; RR, 0.83; 95% CI, 0.64-1.09
• Cerebral palsy in survivors
– 6.8 vs. 8.2%; RR, 0.83; 95% CI, 0.54-1.27
• Combined death or cerebral palsy
– 19.8 vs. 24.0%; RR, 0.83; 95% CI, 0.66-1.03
• Substantial gross motor dysfunction
– 3.4 vs. 6.6%; RR, 0.51; 95% CI, 0.29
• Combined death or motor dysfunction
– 17.0 vs. 22.7%; RR,0.75; 95% CI, 0.59 – 0.96
Crowther, et al. JAMA , 2003;290 No 20: 2669-76
ACTOMgSO4
• Concluded MgSO4 given to women
immediately before very preterm birth may
improve important pediatric outcomes
• No serious harmful effects were seen
Crowther, et al. JAMA , 2003;290 No 20: 2669-76
Maternal Candidates for Magnesium Sulfate
for Fetal Neuroprotection
• 23w0d-31w6d gestational age
• Preterm labor with cervical change and high
likelihood of delivery within 12 hours
• Preterm Premature rupture of membranes
• Suspected cervical insufficiency with a high likelihood
of delivery within 12 hours
• Planned delivery for medical indications or obstetric
complications that can safely be delayed for
magnesium therapy
Reeves SA, Gibbs RS, Clark SL. Magnesium for fetal neuroprotection. Am J Obstet Gynecol 2011;204:202.e1-4.
Does the patient meet any exclusions?
Yes
Do not initiate
magnesium therapy
for neuroprotection
No
Exclusions from Protocol:
• Intrauterine fetal demise
• Maternal sever preeclampsia
(these patients are placed on
magnesium for seizure
prophylaxis)
• Fetuses with lethal anomalies
• Maternal contraindications to
magnesium sulfate (eg.
Myasthenia gravis, renal
failure).
Implementation:
1. Load the patient with 6 g of magnesium sulfate IV over a total of 2030 minutes
2. Run a maintenance infusion of 2 g per hour until delivery or 12
hours have elapsed.
Reeves SA, Gibbs RS, Clark SL. Magnesium for fetal neuroprotection. Am J Obstet Gynecol 2011;204:202.e1-4.
The patient returns with risk of preterm delivery and meets
the above criteria. Has patient been off of magnesium for
more than 6 hours?
Yes
Load 6 of magnesium sulfate IV over
20-30 minutes, and combine at 2 g per
hour until delivery or up to 12 hrs
No
Restart magnesium at 2 g per hour IV
until delivery or up to 12 hours
Reeves SA, Gibbs RS, Clark SL. Magnesium for fetal neuroprotection. Am J Obstet Gynecol 2011;204:202.e1-4.
Intermountain Healthcare Guidelines
Magnesium Sulfate Neuroprophylaxis for
the Very Preterm Infant
Singleton or twins <28.0 weeks gestation
At risk for delivery within 12 hours
-
Preterm labor (active labor, >4cm dilated, PPROM, abruption, concerning
fetal status, oligohydramnios, IUGR, etc…)
No contraindications to Magnesium Sulfate
Recommend Magnesium Sulfate Prophylaxis
Key counseling points:
- Temporary maternal side effects
- Risk of moderate or severe CP in surviving babies reduced by ~50% (RR is
0.55)
- Otherwise routine OB care for that condition will be provided (steroids,
tocolysis, antibiotics, etc…)
Intermountain Healthcare Guidelines
Magnesium Sulfate Neuroprophylaxis for
the Very Preterm Infant
Initiate Therapy
-
-
6 grams IV bolus over 20-30 minutes
Maintenance infusion at 2g/hr
Continue until delivery or until 12 hours of therapy
Reassess Risk if Undelivered
after 12 hours of therapy
At Risk
Continue maintenance
infusion @ 2g/hr
Low Risk
Discontinue Magnesium Sulfate Infusion
Risk of imminent delivery returns < 28 weeks
-Re-initiate therapy
Risk of imminent delivery returns < 28 weeks
-Do not re-initiate therapy
Thrombophilia and
Cerebral Palsy
• Case series of 3 babies with neonatal
cerebrovascular disorders including
ischemic infarction, hemorrhagic
stroke, and hemiplegic cerebral palsy
• All 3 were heterozygous for factor V
Leiden
Thoransen et al Ann Neurol 1997;42:372-5.
Thrombophilia and
Cerebral Palsy
Cerebral Palsy and Thrombi in
Placental Vessels of the Fetus
• Kraus, 1997 – Retrospective case series of
placental pathology in 15 infants with CP
• 11 / 15 Placenta contained thrombi in the
distribution of fetal vessels
• 4 / 15 Alternate basis for injury identified
• 1 / 15 Autopsy confirmed cerebral
thrombi / infarcts in infant who died at 1
month of age
Kraus et al Hum Pathol 1997;28:248-8.
Placental Lesions Associated with
Neurologic Impairment and Cerebral Palsy
in Very Low-Birth-Weight Infants
• Redline, 1998 –Retrospective case – control study
• 60 Singleton, very low-birth-weight (< 1.5 kg)
infants delivered 1983 – 91 and 59 controls
• Subsequent neurologic impairment diagnosed at
20 months corrected age (42 / 60 with CP)
• 2 Types of placental vascular lesions associated
with neurologic impairment
– Nonocculusive thrombi ( p < 0.04)
– Severe villous edema (p < 0.01)
Redline et al Arch Pathol Lab Med 1998;122:1091-8.
Neonatal Cytokines Coagulation
Factors in Children with Cerebral Palsy
Thrombophilia
Children with CP
(n=31)
Control Children
(n=65)
Antiphospholipid
Antibody (> 1:100)
3
0
AT III (31 mg/dL)
5
0
Factor V Leiden
(>11 ug/mL)
8
1
Protein C (>117%)
11
1
Protein S (>130%)
7
0
1 or More
20
2
Nelson et al, Ann Neurol;1998;44:665-75.
Factor V Leiden May Predispose
Fetuses to Cerebral Palsy
• Mutidisciplinary Cerebral Palsy clinic
at Primary Childrens Medical Center
• Buccal swabs of both affected child
and biologic parents
• 6 / 28 (21%) children with CP carried
factor V Leiden
• 14 / 403 (3%) Utah population
• P < 0.05
D. Dizon-Townson et al AJOG SMFM, 2000.
What the Obstetrician Can Do
1) Be knowledgeable about risk factors for
Cerebral Palsy
2) Take a thorough family history including
genetic and clotting disorders
3) Find a reason to obtain umbilical artery
cord gas measurements and make sure to
document the results
4) Find a reason to send the placenta to
pathology and voice your concerns to the
pathologist