1. 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

2. 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

4. 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)

5. 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

6. Intrapartum Ischemic / Hypoxemic Event Neonatal Encephalopathy Cerebral Palsy

7. NOT Caused by Birth Asphyxia Epilepsy without cerebral palsy Mental retardation without cerebral palsy Attention-deficit hyperreactivity disorder

8. 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

9. Etiologic Mechanisms for Cerebral Palsy

10. 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

11. Neonatal Encephalopathy Attributed to Intrapartum Hypoxia Prevalence 1.6 per 10,000

12. Cerebral Palsy Prevalence 1.5 – 2.5 cases of Cerebral Palsy / 1,000 Live births

13. Cerebral Palsy Classification Schemes Type of Motor Dysfunction – Spasticity – Most common – Flaccidity – Dyskinesis – Ataxia Muscle groups involved – Quadriplegia – Diplegia – Hemiplegia – Monoplegia

14. 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

15. 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

16. Motor Pathways and Ventricles

17. 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

18. Cerebral Palsy Biologic and Demographic Risk Factors Maternal age and parity Gender - Male > female Multiple births Prematurity Intrauterine growth restriction Intracranial hemorrhage Periventricular leukomalacia

19. 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

20. Cerebral Palsy Prematurity

21. Prevalence of Cerebral Palsy by Birth Weight and Gestational Age

22. Cerebral Palsy Prematurity 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 Weeks5 / 1000

23. 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%)

24. 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.

25. 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.

26. Cerebral Palsy Intrapartum Risk Factors Risk FactorOdds Ratio Chorioamnionitis4.2 Prolonged rupture of membranes 2.3 Maternal infection2.3 Preeclampsia0.4 Delivery without labor0.3 Growth restriction1 Murphy et al Lancet 1995;346:1449-54. CP increased with decreasing gestational age. Risk factors after adjusted for gestational age.

27. 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.

28. 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

29. 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%

30. Cerebral Palsy Prevalence / 100 Survivors by Apgar Score and Postnatal Age

31. 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.

32. 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.

34. 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

35. 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

36. Echodense Parenchymal Brain Lesions and Risk of CP STUDYNO.LESION SURVIVORS WITH CP Papile, 198317Grade IV ICH86% Pape, 198520Grade IV ICH40% Catto-Smith, 1985 3ICH67% Guzetta, 198622Periventricular parenchymal echodensity 86% Graham, 19873Parenchymal hemorrhage 100% Cooke, 198732Parenchymal hemorrhage or extension 100% TOTAL9767%

37. Incidence of Cystic Periventricular Leukomalacia (PVL) According to Gestational Age

38. Echolucent Parenchymal Brain Lesions and Risk of Cerebral Palsy STUDYNO.LESION SURVIVORS WITH CP Devries, 198510Extensive or subcortical PVL 100% Graziani, 198515Large periventricular cysts or porencephaly 80% Boyzynski, 1985 4PVL100% Weindling, 1985 8Periventricular cysts 100% Smith, 198616PVL88%

39. Echolucent Parenchymal Lesions and Risk of Cerebral Palsy STUDYNO.LESION SURVIVORS WITH CP Graham, 198713Cystic PVL62% Fawer, 198711Extensive PVL73% Stewart, 198710Cysts80% Cooke, 198732Porencephalic cysts 69% Total12780%

40. Risk Factors for Periventricular Leukomalacia

41. Pathway to Cerebral Palsy in Preterm Infants

42. Ongoing Research Involving Cerebral Palsy 1.BEAM - Beneficial Effects of Antenatal Magnesium 2.Thrombophilias and Cerebral Palsy

43. 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

44. 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)

45. 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.

46. 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

47. 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.

48. 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.

49. 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.

50. 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.

51. 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.

52. 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

53. 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

54. 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

55. 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.

56. 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 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.

57. The patient returns with risk of preterm delivery and meets the above criteria. Has patient been off of magnesium for more than 6 hours? YesNo 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.

58. 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…)

59. 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 Guidelines Magnesium Sulfate Neuroprophylaxis for the Very Preterm Infant

60. 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.

61. Thrombophilia and Cerebral Palsy

62. 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.

63. 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.

64. Neonatal Cytokines Coagulation Factors in Children with Cerebral Palsy ThrombophiliaChildren with CP (n=31) Control Children (n=65) Antiphospholipid Antibody (> 1:100) 30 AT III (31 mg/dL)50 Factor V Leiden (>11 ug/mL) 81 Protein C (>117%)111 Protein S (>130%)70 1 or More202 Nelson et al, Ann Neurol;1998;44:665-75.

65. 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.

68. 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