HYPOXIC ISCHEMIC DISCLOSURE ENCEPHALOPATHY AND • I have nothing to disclose and have no real or potential conflicts with this presentation and its THE OBSTETRICIAN content.

Michael P. Nageotte, M.D.

CASE: 27 y.o. G2 P0 at 38 4/7 wks in spontaneous labor at 0830. Subsequent AROM by MD at 1230-- 4/80%/0 station; moderate meconium; pitocin begun at 1245. Category I-II FHR; cervical exam at 1545: vtx/8/90%/+2; pitocin infusion at 4 mu/min; external FHR/UC monitors; IV analgesia PRN. Management by nurses other than the single MD exam (AROM) at 1230--physician in his patient office; called at 1609 to L&D STAT. Arrives at bedside at 1620. DELIVERY ROOM DATA

• Emergency primary L/T C/S under general anesthesia with skin incision at 1630 and delivery at 1632 • 2310 gm SGA male; tight NC x3 with thin cord; thick meconium; Apgars 1/4/4 at one, five and ten minutes • Cord gases: Artery 6.99/115/10/-12; Vein 7.04/84/15/-8 • Several intubations and full CPR in Delivery Room • In NICU, early onset seizures; unable to oxygenate well and requiring intubation; Admit Dx: “Hypoxic Ischemic Encephalopathy”; transfer to Level III for total body cooling despite IUGR Question NOMENCLATURE Should the admitting diagnosis to the NICU be hypoxic ischemic encephalopathy? • Hypoxia • Acidosis A. Yes 82% • Asphyxia B. No • Neonatal Encephalopathy • Hypoxic Ischemic Encephalopathy (HIE) 18% • Cerebral Palsy • Negligence

es o Y N

It is critical to understand that the What do these terms mean, are diagnostic labels applied to the they different, what causes them neurologically depressed neonate have and can they be prevented? potentially profound consequences for the child, the family, the physicians for both mother and baby, the nurses and the hospital. ASPHYXIA Hypoxia : Reduced amount of oxygen delivered to tissues; encephalopathy or brain injury unlikely in the fetus or newborn • Condition of impaired gas exchange leading, if it Hypoxemia: Reduced oxygen concentration in blood; associated persists, to progressive hypoxemia and hypercapnia with hypoxia but injury unlikely if adequate cerebral blood flow with a significant metabolic acidosis resulting Hypoxia-Ischemia: Reduced oxygen and inadequate volume of blood delivered to tissues; can cause brain injury if both (World Federation of Neurology, 1993) intracellular oxygen and glucose remain below critical levels • This term describes a process of varying severity and Metabolic Acidosis: Low pH due to increased lactic acid in the duration rather than an endpoint and should not be blood reflecting severity of asphyxia and/or hypoxia-ischemia applied to birth events unless specific evidence of Respiratory Acidosis: Low pH due to increased carbon dioxide markedly impaired intrapartum or immediate postnatal in blood; may protect the fetal/neonatal brain due to reflex gas exchange can be linked to neurologic illness in the cerebral vasodilation and increased cerebral blood flow neonate (Low, 1997) Mixed Acidosis: Low pH reflecting both increased carbon dioxide (respiratory) and lactic acid (metabolic); most common form of clinically significant neonatal acidosis

NEONATAL ENCEPHALOPATHY NEONATAL • A clinically defined syndrome of disturbed neurologic function in the earliest days of ENCEPHALOPATHY life in a neonate at or beyond 35 weeks of gestation, manifested by subnormal level of consciousness or seizures often accompanied by difficulty with initiating and maintaining respiration and with various degrees of depression of both muscle tone and reflexes. NEONATAL ENCEPHALOPATHY Potential Etiologies of Neonatal • Applied in various clinical settings with altered Encephalopathy neurologic signs in neonates born > 35 weeks • Chronic persistent or acute fetal • Descriptive term which is often erroneously hypoxemia/ischemia interchanged with such terms as hypoxia, acidosis • Maternal/Fetal(FIRS)/Neonatal Infection and asphyxia particularly during the immediate • Inborn errors of metabolism; genetics neonatal period and continued throughout the medical chart • Trauma (skull fracture, CNS bleeding) • Generally classified as mild, moderate or severe • Coagulation disorders, acute anemia (Sarnat classification) with death or • Fetal/Neonatal Stroke; anomalies developmental impairment usually confined to • Unknown infants with moderate or severe NE

Hypoxic Ischemic Encephalopathy • Assumptions on the role of intrapartum events on newborn and neonatal status have given rise to the term HYPOXIC ISCHEMIC hypoxic ischemic encephalopathy (HIE) • HIE (post-asphyxial encephalopathy, birth asphyxia, ENCEPHALOPATHY perinatal asphyxia) describes a subset of NE present in the first week of life in term/near term infants believed to have experienced significant hypoxemia/asphyxia prior to or during labor and delivery • Findings: altered consciousness, tone and reflexes; the most severe state characterized by hypotonia, apnea/respiratory depression, coma and seizures • Diagnosis confirmed with specific MRI changes Question Since the introduction of continuous fetal heart rate monitoring in, the reported rate of cerebral palsy in

CEREBRAL PALSY the developed world has: 80% A. increased B. decreased

C. remained unchanged 17% 3%

ed g an ch increased decreased n u d ne ai m re

CEREBRAL PALSY CEREBRAL PALSY Cerebral palsy describes a group of conditions specifically involving motor disability of early onset • Associated impairments including vision, hearing, which, despite a wide range of possible abilities and disabilities, must satisfy the following: cognition, speech, epilepsy and behavioral disorders 1) motor disorder (specifically, spasticity, dyskinesia, often accompany the motor impairment. ataxia, mixed or hypotonia) is present by age of four • The more severe the motor impairment, the more 2) cerebral not peripheral nerve or muscular abnormality likely that a number of these impairments will add to 3) arises early in development the complexity of the disorder. 4) is not progressive or degenerative but life-long and • For term and near term infants, if CP is present it is with no known cure generally a more severe form with milder CP evident 5) may or may not be associated with other neurological or intellectual abnormalities only in surviving preterm infants. 6) if fetal asphyxia is implicated, the CP must be of the spastic quadriparetic or dyskinetic type Elective and Emergency C-Sections and CEREBRAL PALSY Live Births with Cerebral Palsy in • The risk of CP increases substantially as gestational Western Australia, 1980-2009 age at birth decreases with < 32 weeks gestation being the strongest risk factor for CP. • While death and CP in the very preterm have declined steadily since the mid 1990s, this has had little impact on the overall prevalence of CP as births < 34 weeks comprise only 2% of all births. • Term and late preterm infants are at low risk for CP yet comprise 60% of CP cases (term/late preterm neonates account for 98% of all births). • Term CP rates have remained remarkably stable with the rate of 2/1000 consistent throughout the developed world for the past several decades.

THREE ETIOLOGICAL GROUPS OF THREE GROUPS OF NEONATAL NEONATAL ENCEPHALOPATHY ENCEPHALOPATHY • In a minority of cases, encephalopathy is likely due • In a second subset of encephalopathy cases, an etiology to hypoxia-ischemia, with specific MRI established abnormalities, following a recognized obstetrical different from hypoxia-ischemia is identified (e.g. sentinel event (e.g. uterine rupture, cord prolapse, trauma, infection or specific metabolic disorder). maternal cardiac arrest). • The third group is the largest and presents a clinical • In such incontrovertible cases, HIE is frequently conundrum as there is a lack of an obvious cause of the accepted cause of encephalopathy but not all the neurologic abnormalities identified. sentinel events result in HIE and one cannot • Different etiologies of encephalopathy must be kept in implicate hypoxia-ischemia with 100% certainty mind in all cases and a clear history of hypoxia- because it is not possible to document blood flow and oxygenation of the fetal brain. ischemia associated with a sentinel event does not rule out other causes or contributors to the findings. PRIMATE MODE OF TERM Magnetic Resonance Imaging NEONATAL BRAIN INJURY (R. • Dramatically improved technology with visualization Myers, 1972, 1975) of myelination and changes in cerebral structures • Specific regional distribution of injury • More sensitive and specific than U/S or CT associated with different durations and • Shows heterogeneous pattern, ranging from cortical severities of experimental ischemia (rhesus) dysplasia to focal infarcts and atrophy or basal • Prolonged partial asphyxia: cerebral white ganglion lesions (related to insult timing/severity) matter injury • Better anatomical resolution, particularly in the basal ganglia, thalamus and periphery of the • Acute profound asphyxia: deep gray nuclei cerebral cortex (basal ganglia and thalamus) injury rarely • Detects discrete lesions in cerebellum and brain stem with extension to white matter

MRI PATTERNS OF INJURY-HIE AND ITS PRESUMED ETIOLOGIES

1) Selective neuronal necrosis of the cortex, So When Does the Injury predominantly the hippocampus and also the grey matter nuclei Occur? 2) Leucomalacia of periventricular to subcortical white matter 3) Focal or more generalized infarction  There is dynamism to the MRI pattern until the final pattern is achieved. Question Timing of Ischemic Brain Injury The majority of cases of cerebral palsy following a • 80% to 90% before labor term gestation have an identifiable intrapartum – Multiple pregnancy/chorionicity sentinel event: – 3rd Trimester bleeding; cord entrapment A. True 91% – Intrauterine infection/drugs B. False – Fetal coagulation disorders/stroke • 10% to 20% intrapartum • Rate of term stillbirth is 3x rate of NE; birth

9% may be interrupting a fetal continuum to death in utero with recurrent or near fatal insults

True False (Yudkin PL, Ped Perinatal Epidemiol 1988; 156:170)

Antepartum Risk Factors for Neonatal Encephalopathy in Term Neonates (N=164; Controls=400) O.R. 95% C.I. • Fam Hx Seizures 2.55 1.3-4.9 Antepartum Associations with • Fam Hx neurol. dis. 2.73 1.2-6.4 • Infertility Rx 4.43 1.1-17.6 Neonatal Encephalopathy • Mat. Thyroid dis. 9.7 2.0-47.9 • Severe Pre-eclampsia 6.3 2.3-17.7 • Bleeding in Pregnancy 3.6 1.3-9.9 • Viral Illness 3.0 1.5-5.8 • Abnormal placenta 2.97 1.2-3.7 • IUGR < 3rd % 38.2 9.4-154.8 • Postmaturity 13.2 5.0-34.8 (Badawi, N, et al 1998;BMJ 317:1554) Antepartum and Intrapartum Risk IUGR and Neonatal Encephalopathy Factors for Neonatal Encephalopathy in Term Neonates O.R. 95% C.I. • 69% had only antenatal risk factors • > 90% ile 1 1 • 24% had antepartum and intrapartum • 10-90% 1.5 .66-3.6 risk factors • 3rd-9% 4.4 1.4-13.4 • 5% had only intrapartum risk factors • < 3rd% 38.23 9.4-154.8

(Badawi, N, et al 1998;BMJ 317:1554) (Badawi, N, et al 1998;BMJ 317:1554)

Gestational Age and Neonatal Encephalopathy in Term Neonates MRI/MRS TIMING OF INJURY (N=164 Controls=400) O.R. 95% C.I. • There are no tools currently available to • 37 weeks 2.4 1.1-5.0 pinpoint the time of injury with any degree of • 38 weeks 1.1 0.9-1.6 accuracy. Although appropriate neonatal neuroimaging is the best method available, • 39 weeks 1 1 brain MRI/MRS can only implicate a time • 40 weeks 1.4 1.2-1.7 window that spans days, not hours or minutes. • 41 weeks 3.3 2.1-5.4 • 42 weeks 13.2 5.0-34.8 (Wu, Yvonne; Editorial, Annals of Neurology 2012 V.72: 151-2)

Summary RECOMMENDATIONS • Intrapartum hypoxia-ischemia associated with about • Correct and consistent usage of nomenclature 30% of cases of neonatal encephalopathy. • Documentation of umbilical artery/vein pH in all • The majority of cases of HIE result in normal children. preterm, multiples or depressed neonates • Approximately 15-20% of all cases of cerebral palsy are • Early assessment/triage of neonate for cooling therapy associated with clear intrapartum hypoxia-ischemia. • Clear and consistent language in the diagnoses and • In the vast majority of encephalopathic infants, communication among all health care providers including those who meet the clinical and MRI criteria • Careful fetal/neonatal evaluations for birth defects/IUGR for HIE, the exact mechanism and timing of brain • Early MRI/MRS (24-96 hours if possible) and repeat injury remains unknown and unknowable. before discharge to assess nature and general timing of • Regarding neonatal encephalopathy, there is a lot we injury with interpretation by skilled neuroradiologists do not know and we do not know how to prevent • Involvement of family in evaluation and management neonatal brain injury. • Multidisciplinary intensive assessment of all HIE cases HIE--Clinical Aspects

• Dominated by the ultimate occurrence of brain ischemia from diminished blood flow usually but not necessarily preceded or accompanied by THANK YOU! hypoxemia (diminished amount of oxygen in the blood supply) • Brain injury results from hypoxemia causing myocardial disturbance leading to the critically important loss of CNS vascular autoregulation resulting in ischemia (hypoperfusion injury) • Timing and severity of hypoxemia/ischemia as well as the gestational age, presence of co-morbidities and potentially preceding events strongly influence the presence and degree of resultant neuropathology

DIAGNOSIS OF HIE CEREBRAL PALSY • Established when cerebral blood flow is sufficiently reduced that oxygen content of the blood delivered to the brain is below the level needed to avoid energy • 96% of singletons are born at or after 35 failure in brain cells; metabolism is disturbed, weeks and account for 2/3 of CP cases neuronal cell integrity is not maintained and cellular injury, dysfunction or neuronal cell death results. • This group has been less extensively studied • Reliable measures of such changes in fetal/newborn • Much of the medical and lay literature on CNS are not available in current clinical settings. the causes of CP remains focused on the • Poor surrogates include base deficit (>12 mmol/L), contribution of birth asphyxia biomarkers, EFM, scalp/umbilical artery pH, etc. • The argument that location and appearance of brain • EFM introduced to identify fetal asphyxia lesions establishes timing, severity and etiology but has had no impact on decreasing CP remains open to debate as sentinel events are not always followed by specific MRI abnormalities. • In the < 34 week fetus, partial (chronic) asphyxial injury typically noted in the periventricular white matter, the region with the most tenuous perfusion, sparing the Partial (Chronic) Asphyxia subcortical white matter and cortex • In the > 34 week fetus, partial asphyxial injury is noted in the mature intervascular boundary zones (“watershed”) which include the periventricular white matter, subcortical white matter and cerebral cortex in the boundary regions. The deep gray matter structures of the cerebrum are typically spared in such patients. • Periventricular white leukomalacia (PVL) is an imaging finding (ultrasound or MRI) of preterm fetuses at risk for CP from in utero/intrapartum/perinatal injury

• Profound acute insult lasting 25 minutes or greater damages nearly the entire brain with no useful patterns detected by any modality of imaging. Profound (Acute) Asphyxia • Arrests of shorter duration show specific patterns that vary with the state of brain maturity. • Such profound acute events when <32 weeks result in injury primarily to the lateral thalami. • At 34-36 weeks, hippocampus, lentiform nucleus, and perirolandic cortex may be injured. • By 40 weeks, the corticospinal tracts are affected from the internal capsule to the perirolandic cortex within the basal ganglia (likely due to the higher metabolic activity in these areas of the brain). 5 Minute Apgar Score and Neonatal Intrapartum Risk Factors for Neonatal Encephalopathy in Term Neonates Encephalopathy in Term Neonates (N=164 Controls=400) (N=164 Controls=400)

100.00% O.R. 95% C.I.

80.00% • Maternal Pyrexia 3.82 1.4-10.1

60.00% 5 Min Apgar <3 • Persistent OP 4.29 1.7-10.5 5 Min Apgar 3-6 40.00% 5 Min Apgar >6 • Acute event 4.40 1.3-15.2 20.00% • Oper Vag Del 2.34 1.2-4.7 0.00% • Emergent C/S 2.17 1.1-4.64 Cases Controls

(Badawi, N, et al 1998;BMJ 317:1554) (Badawi, N, et al 1998;BMJ 317:1554)

Mode of Delivery and Relative Risk for NE Malpresentation and CP (N=164 Controls=400) O.R. C.I. • Torfs (1990) 1 3.8 1.6-9.1 • Mode of delivery • Krebs 2 1.6 0.9-2.4 RR p-value Nelson et al--CP increased with breech – Spontaneous Vag 1.0 1.0 CP not related to route of delivery – Elective C/S 0.17 0.05-0.56

1. Torfs et al J Pediatr 1990; 116:615-19 (Badawi, N, et al 1998;BMJ 317:1554) 2. Nelson et al JAMA 1984; 251:1843-48 3. Krebs et al BR J Ob Gyn 1999; 106:943-7 Seizures and CP in Dublin Insurance Status and Neonatal Randomized EFM Study Encephalopathy in Term Neonates (N=164 Controls=400) EFM I.A. O.R. C.I. • Total live births 6527 6552 • Seizures 12 (.018%) 27(.041%)* • Private 1 1 • NND after seizures 3 (.005%) 6(.009%) • Public 3.5 1.3-9.6 • Survival after seizures 9 (.014%) 21(.032%) • CP at age 4 3(0.005%) 3(0.005%) • Total with CP 12 (.018%) 10(.015%)

(Grant A, Lancet: Nov. 25, 1989)