Cerebral Palsy“What the Obstetrician Should

Know”Donna Dizon-Townson, MD, FACOG

Associate ProfessorDepartment of Obstetrics &

GynecologyDivision of Maternal – Fetal

MedicineUniversity of Utah Health Sciences

Center

Medical Director Urban South Region Clinical Programs

Intermountain Health Care

Cerebral PalsyHistorical 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 PalsyDefinition:

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

HypoxiaPrevalence

1.6 per 10,000

Cerebral PalsyPrevalence

1.5 – 2.5 cases of Cerebral Palsy /

1,000 Live births

Cerebral PalsyClassification Schemes• Type of Motor Dysfunction

– Spasticity – Most common– Flaccidity– Dyskinesis– Ataxia

• Muscle groups involved– Quadriplegia– Diplegia– Hemiplegia– Monoplegia

Cerebral PalsyClassification 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 PalsyClassification 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 PalsyBiologic and Demographic Risk

Factors • Maternal age and parity• Gender - Male > female • Multiple births• Prematurity • Intrauterine growth restriction• Intracranial hemorrhage• Periventricular leukomalacia

Cerebral PalsyMultiple 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 PalsyPrematurity

Gestational Age / Birthweight

Prevalence of CP

23 – 25 Weeks / 500 – 600 grams

25%

All infants < 1000 grams

5 – 10%

27 – 28 Weeks / 1000 grams

3%

36 Weeks 5 / 1000

Cerebral PalsyPrematurity

• 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 PalsyIntrauterine 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 PalsyIntrapartum Risk FactorsRisk Factor Odds Ratio

Chorioamnionitis 4.2

Prolonged rupture of membranes

2.3

Maternal infection 2.3

Preeclampsia 0.4

Delivery without labor

0.3

Growth restriction 1

Murphy et al Lancet 1995;346:1449-54.

CP increased with decreasing gestational age.Risk factors after adjusted for gestational age.

Cerebral PalsyRisk 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 PalsyBirth 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 PalsyApgar 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 PalsyPerinatal 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 PalsyInternational 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 PalsyBrain 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 CPSTUDY NO. LESION SURVIVORS

WITH CPPapile, 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 PalsySTUDY NO. LESION SURVIVORS

WITH CP

Devries, 1985

10 Extensive or

subcortical PVL

100%

Graziani, 1985

15 Large periventricular cysts or porencepha

ly

80%

Boyzynski, 1985

4 PVL 100%

Weindling, 1985

8 Periventricular cysts

100%

Smith, 1986 16 PVL 88%

Echolucent Parenchymal Lesions and Risk of Cerebral

PalsySTUDY 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 Maternal-Fetal 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

• 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

ACTOMgSO4

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

• 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

Maternal Candidates for Magnesium Sulfate for Fetal Neuroprotection

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?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).

Yes No

Do not initiate magnesium therapy for neuroprotection

Implementation:1. Load the patient with 6 g of magnesium sulfate IV over a total of 20-

30 minutes2. 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 No

Load 6 of magnesium sulfate IV over 20-30 minutes, and combine at 2 g per

hour until delivery or up to 12 hrs

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 GuidelinesMagnesium Sulfate Neuroprophylaxis for

the Very Preterm InfantSingleton 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 ProphylaxisKey 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…)

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

Continue maintenance infusion @ 2g/hr

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

At Risk

Low Risk

Intermountain Healthcare GuidelinesMagnesium Sulfate Neuroprophylaxis for

the Very Preterm Infant

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 PalsyThrombophilia 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 2Nelson 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