HYPOXIC ISCHEMIC ENCEPHALOPATHY AND THE OBSTETRICIAN

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1 HYPOXIC ISCHEMIC ENCEPHALOPATHY AND THE OBSTETRICIAN DISCLOSURE I have nothing to disclose and have no real or potential conflicts with this presentation and its content. Michael P. Nageotte, M.D. CASE: 27 y.o. G2 P0 at 38 4/7 wks in spontaneous labor at Subsequent AROM by MD at /80%/0 station; moderate meconium; pitocin begun at 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 physician in his patient office; called at 1609 to L&D STAT. Arrives at bedside at 1620.

2 DELIVERY ROOM DATA Emergency primary L/T C/S under general anesthesia with skin incision at 1630 and delivery at 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

3 Question Should the admitting diagnosis to the NICU be hypoxic ischemic encephalopathy? A. Yes B. No 18% Yes 82% No Hypoxia Acidosis Asphyxia NOMENCLATURE Neonatal Encephalopathy Hypoxic Ischemic Encephalopathy (HIE) Cerebral Palsy Negligence What do these terms mean, are they different, what causes them and can they be prevented? It is critical to understand that the diagnostic labels applied to the neurologically depressed neonate have potentially profound consequences for the child, the family, the physicians for both mother and baby, the nurses and the hospital.

4 Hypoxia : Reduced amount of oxygen delivered to tissues; encephalopathy or brain injury unlikely in the fetus or newborn Hypoxemia: Reduced oxygen concentration in blood; associated with hypoxia but injury unlikely if adequate cerebral blood flow Hypoxia-Ischemia: Reduced oxygen and inadequate volume of blood delivered to tissues; can cause brain injury if both intracellular oxygen and glucose remain below critical levels Metabolic Acidosis: Low ph due to increased lactic acid in the blood reflecting severity of asphyxia and/or hypoxia-ischemia Respiratory Acidosis: Low ph due to increased carbon dioxide in blood; may protect the fetal/neonatal brain due to reflex cerebral vasodilation and increased cerebral blood flow Mixed Acidosis: Low ph reflecting both increased carbon dioxide (respiratory) and lactic acid (metabolic); most common form of clinically significant neonatal acidosis ASPHYXIA Condition of impaired gas exchange leading, if it persists, to progressive hypoxemia and hypercapnia with a significant metabolic acidosis resulting (World Federation of Neurology, 1993) This term describes a process of varying severity and duration rather than an endpoint and should not be applied to birth events unless specific evidence of markedly impaired intrapartum or immediate postnatal gas exchange can be linked to neurologic illness in the neonate (Low, 1997) NEONATAL ENCEPHALOPATHY NEONATAL ENCEPHALOPATHY A clinically defined syndrome of disturbed neurologic function in the earliest days of 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.

5 NEONATAL ENCEPHALOPATHY Applied in various clinical settings with altered neurologic signs in neonates born > 35 weeks Descriptive term which is often erroneously interchanged with such terms as hypoxia, acidosis and asphyxia particularly during the immediate neonatal period and continued throughout the medical chart Generally classified as mild, moderate or severe (Sarnat classification) with death or developmental impairment usually confined to infants with moderate or severe NE Potential Etiologies of Neonatal Encephalopathy Chronic persistent or acute fetal hypoxemia/ischemia Maternal/Fetal(FIRS)/Neonatal Infection Inborn errors of metabolism; genetics Trauma (skull fracture, CNS bleeding) Coagulation disorders, acute anemia Fetal/Neonatal Stroke; anomalies Unknown HYPOXIC ISCHEMIC ENCEPHALOPATHY Hypoxic Ischemic Encephalopathy Assumptions on the role of intrapartum events on newborn and neonatal status have given rise to the term hypoxic ischemic encephalopathy (HIE) HIE (post-asphyxial encephalopathy, birth asphyxia, 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

6 Question CEREBRAL PALSY Since the introduction of continuous fetal heart rate monitoring in, the reported rate of cerebral palsy in the developed world has: 80% A. increased B. decreased C. remained unchanged 17% 3% increased decreased remained unchanged CEREBRAL PALSY Cerebral palsy describes a group of conditions specifically involving motor disability of early onset which, despite a wide range of possible abilities and disabilities, must satisfy the following: 1) motor disorder (specifically, spasticity, dyskinesia, ataxia, mixed or hypotonia) is present by age of four 2) cerebral not peripheral nerve or muscular abnormality 3) arises early in development 4) is not progressive or degenerative but life-long and with no known cure 5) may or may not be associated with other neurological or intellectual abnormalities 6) if fetal asphyxia is implicated, the CP must be of the spastic quadriparetic or dyskinetic type CEREBRAL PALSY Associated impairments including vision, hearing, cognition, speech, epilepsy and behavioral disorders often accompany the motor impairment. The more severe the motor impairment, the more likely that a number of these impairments will add to the complexity of the disorder. For term and near term infants, if CP is present it is generally a more severe form with milder CP evident only in surviving preterm infants.

7 CEREBRAL PALSY The risk of CP increases substantially as gestational 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. Elective and Emergency C-Sections and Live Births with Cerebral Palsy in Western Australia, THREE ETIOLOGICAL GROUPS OF NEONATAL ENCEPHALOPATHY In a minority of cases, encephalopathy is likely due to hypoxia-ischemia, with specific MRI established abnormalities, following a recognized obstetrical sentinel event (e.g. uterine rupture, cord prolapse, maternal cardiac arrest). In such incontrovertible cases, HIE is frequently the accepted cause of encephalopathy but not all sentinel events result in HIE and one cannot implicate hypoxia-ischemia with 100% certainty because it is not possible to document blood flow and oxygenation of the fetal brain. THREE GROUPS OF NEONATAL ENCEPHALOPATHY In a second subset of encephalopathy cases, an etiology different from hypoxia-ischemia is identified (e.g. trauma, infection or specific metabolic disorder). The third group is the largest and presents a clinical conundrum as there is a lack of an obvious cause of the neurologic abnormalities identified. Different etiologies of encephalopathy must be kept in mind in all cases and a clear history of hypoxiaischemia associated with a sentinel event does not rule out other causes or contributors to the findings.

8 PRIMATE MODE OF TERM NEONATAL BRAIN INJURY (R. Myers, 1972, 1975) Specific regional distribution of injury associated with different durations and severities of experimental ischemia (rhesus) Prolonged partial asphyxia: cerebral white matter injury Acute profound asphyxia: deep gray nuclei (basal ganglia and thalamus) injury rarely with extension to white matter Magnetic Resonance Imaging Dramatically improved technology with visualization of myelination and changes in cerebral structures More sensitive and specific than U/S or CT Shows heterogeneous pattern, ranging from cortical dysplasia to focal infarcts and atrophy or basal ganglion lesions (related to insult timing/severity) Better anatomical resolution, particularly in the basal ganglia, thalamus and periphery of the cerebral cortex Detects discrete lesions in cerebellum and brain stem MRI PATTERNS OF INJURY-HIE AND ITS PRESUMED ETIOLOGIES 1) Selective neuronal necrosis of the cortex, predominantly the hippocampus and also the grey matter nuclei 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. So When Does the Injury Occur?

9 Question The majority of cases of cerebral palsy following a term gestation have an identifiable intrapartum sentinel event: A. True B. False 9% 91% Timing of Ischemic Brain Injury 80% to 90% before labor Multiple pregnancy/chorionicity 3 rd Trimester bleeding; cord entrapment Intrauterine infection/drugs Fetal coagulation disorders/stroke 10% to 20% intrapartum Rate of term stillbirth is 3x rate of NE; birth 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 Associations with Neonatal Encephalopathy Antepartum Risk Factors for Neonatal Encephalopathy in Term Neonates (N=164; Controls=400) O.R. 95% C.I. Fam Hx Seizures Fam Hx neurol. dis Infertility Rx Mat. Thyroid dis Severe Pre-eclampsia Bleeding in Pregnancy Viral Illness Abnormal placenta IUGR < 3rd % Postmaturity (Badawi, N, et al 1998;BMJ 317:1554)

10 Antepartum and Intrapartum Risk Factors for Neonatal Encephalopathy 69% had only antenatal risk factors 24% had antepartum and intrapartum risk factors 5% had only intrapartum risk factors IUGR and Neonatal Encephalopathy in Term Neonates O.R. > 90% ile % C.I % rd-9% < 3rd% (Badawi, N, et al 1998;BMJ 317:1554) (Badawi, N, et al 1998;BMJ 317:1554) Gestational Age and Neonatal Encephalopathy in Term Neonates (N=164 Controls=400) O.R. 95% C.I. 37 weeks weeks weeks weeks weeks weeks MRI/MRS TIMING OF INJURY There are no tools currently available to pinpoint the time of injury with any degree of accuracy. Although appropriate neonatal neuroimaging is the best method available, brain MRI/MRS can only implicate a time window that spans days, not hours or minutes. (Wu, Yvonne; Editorial, Annals of Neurology 2012 V.72: 151-2)

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

13 HIE--Clinical Aspects THANK YOU! Dominated by the ultimate occurrence of brain ischemia from diminished blood flow usually but not necessarily preceded or accompanied by 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 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 failure in brain cells; metabolism is disturbed, neuronal cell integrity is not maintained and cellular injury, dysfunction or neuronal cell death results. Reliable measures of such changes in fetal/newborn CNS are not available in current clinical settings. Poor surrogates include base deficit (>12 mmol/l), biomarkers, EFM, scalp/umbilical artery ph, etc. The argument that location and appearance of brain lesions establishes timing, severity and etiology remains open to debate as sentinel events are not always followed by specific MRI abnormalities. CEREBRAL PALSY 96% of singletons are born at or after 35 weeks and account for 2/3 of CP cases This group has been less extensively studied Much of the medical and lay literature on the causes of CP remains focused on the contribution of birth asphyxia EFM introduced to identify fetal asphyxia but has had no impact on decreasing CP

14 Partial (Chronic) Asphyxia 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 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) Asphyxia Profound acute insult lasting 25 minutes or greater damages nearly the entire brain with no useful patterns detected by any modality of imaging. 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 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).

15 5 Minute Apgar Score and Neonatal Encephalopathy in Term Neonates (N=164 Controls=400) % Intrapartum Risk Factors for Neonatal Encephalopathy in Term Neonates (N=164 Controls=400) O.R. 95% C.I % Maternal Pyrexia % 40.00% 20.00% 0.00% Cases Controls 5 M in Apgar <3 5 M in Apgar M in Apgar >6 Persistent OP Acute event Oper Vag Del Emergent C/S (Badawi, N, et al 1998;BMJ 317:1554) (Badawi, N, et al 1998;BMJ 317:1554) Mode of Delivery and Relative Risk for NE (N=164 Controls=400) Malpresentation and CP O.R. C.I. Mode of delivery RR p-value Spontaneous Vag Elective C/S (Badawi, N, et al 1998;BMJ 317:1554) Torfs (1990) Krebs Nelson et al--cp increased with breech CP not related to route of delivery 1. Torfs et al J Pediatr 1990; 116: Nelson et al JAMA 1984; 251: Krebs et al BR J Ob Gyn 1999; 106:943-7

16 Seizures and CP in Dublin Randomized EFM Study EFM I.A. Total live births Seizures 12 (.018%) 27(.041%)* NND after seizures 3 (.005%) 6(.009%) Survival after seizures 9 (.014%) 21(.032%) CP at age 4 3(0.005%) 3(0.005%) Total with CP 12 (.018%) 10(.015%) Insurance Status and Neonatal Encephalopathy in Term Neonates (N=164 Controls=400) O.R. C.I. Private 1 1 Public (Grant A, Lancet: Nov. 25, 1989)