Neonatal Encephalopathy Mary E. D’Alton, MD Willard C. Rappleye Professor of Obstetrics &...

Neonatal Encephalopathy

Mary E. D’Alton, MDMary E. D’Alton, MDWillard C. Rappleye Professor of Obstetrics & GynecologyWillard C. Rappleye Professor of Obstetrics & Gynecology

New York Presbyterian HospitalNew York Presbyterian Hospital

Columbia University College of Physicians & SurgeonsColumbia University College of Physicians & Surgeons

Facts

• CP rate 1.5/1000

• No change in last 40 years

• No geographic/economic boundaries

Clark S, Hankins GDV. AJOG 2003

0

5

10

15

20

25

1970 1975 1980 1985 1990 1995 2000

Cesarean Section Rate

Cerebral Palsy Rate

Charge by Dr. Frank Miller

“To create a multidisciplinary task force to

review and consider the current state of

scientific knowledge about the mechanisms

and timing of possible etiologic events which

may result in neonatal encephalopathy and

cerebral palsy.”

Task Force on Neonatal Encephalopathy and Cerebral Palsy Committee Members

Gary Hankins, MD, FACOG, Chair

Mary D’Alton, MD, FACOG

Mark Ira Evans, MD, FACOG

Larry Gilstrap, MD, FACOG

Richard Depp, III, MD, FACOG

Roger K. Freeman, MD, FACOG

Richard P. Green, MD, FACOG

Task Force on Neonatal Encephalopathy and Cerebral Palsy Committee Members

James A. McGregor, MD, FACOG

Karin B. Nelson, MD

Susan Ramin, MD, FACOG

Robert Resnik, MD, FACOG

Michael Speer, MD

Louis Weinstein, MD, FACOG

Stanley Zinberg, MD, MS

Neonatal Encephalopathy andCerebral Palsy Task Force Consultants

James Barkovich, MD – Professor of Radiology, Neurology, Pediatrics, and Neurosurgery

Kurt Benirschke, MD – Professor Emeritus of Pathology and Reproductive Medicine

Robert R. Clancy, MD – Professor of Neurology and Pediatrics, Pediatric Regional Epilepsy Program

Gabrielle A. DeVeber, MD – Director, Canadian Pediatric Ischemic Stroke Registry

Ronald Gibbs, MD – Professor and Chairman, OB/Gyn

Gregory Locksmith, MD – Assistant Professor, OB/Gyn

Neonatal Encephalopathy andCerebral Palsy Task Force Consultants

Jeffrey Perlman, MD, PhD – Professor of Pediatrics and OB/Gyn

Julian N. Robinson, MD – Assistant Professor, OB/Gyn

Dwight J. Rouse, MD – Associate Professor, OB/Gyn George R. Saade, MD – Professor, OB/Gyn

Diana E. Schendel, PhD – Centers for Disease Control and Prevention

Rodney E. Willoughby, Jr., MD – Associate Professor, Pediatrics

Marjorie R. Grafe, MD – Professor, Placental Pathology

Methods

• Five meetings over 3 years

• Extensive consultation with clinicians and scientists

• Consensus development

• Draft and redraft

Methodology

• Throughout the process, primary source documents were cited to the fullest extent possible.

• Comments solicited from a number of professional organizations:– American Academy of Pediatrics– The Canadian Paediatric Society– The Child Neurology Society– The Society for Maternal-Fetal Medicine– The March of Dimes Birth Defects Foundation

• The Centers for Disease Control and Prevention, Department of Health and Human Services

• The National Institute of Child Health and Human Development

• The Royal Australian and New Zealand College of Obstetricians and Gynaecologists

• The Society of Obstetricians and Gynaecologists of Canada.

Methodology

Most Peer-Reviewed Document

on the Subject

Neonatal Encephalopathy – “A clinically defined syndrome of disturbed neurological function in the infant at or near term during

the first week after birth, manifested by difficulty with initiating and maintaining

respiration, depression of tone and reflexes, altered level of consciousness,

and often seizures.”

Differential Dx: Neonatal Encephalopathy

• Developmental abnormalities

• Metabolic abnormalities

• Autoimmune disorders

• Coagulation disorders

• Infections

• Trauma

• Hypoxia

• IUGR

• Multiple gestations

• Antepartum hemorrhage

• Chromosomal abnormalities

• Persistent breech/transverse lie

Blair, Devel Med Child Neurol 35:449

On the Diagnosis of Birth Asphyxia

• Relies on:– Clinical markers of fetal distress (MSAF/Abn FHR)– Laboratory markers (Cord pH or base excess)– Newborn status (Apgars, time to respirations)

• No data to support:– Equivalence of criteria– Specificity to intrapartum asphyxia

• Potential for misclassification enormous

Relationship of Intrapartum Asphyxia to Neonatal Encephalopathy and Cerebral Palsy

IntrapartumAsphyxia

NeonatalEncephalopathy

CerebralPalsy

x

“Epidemiological studies suggest that in about 90% of cases of cerebral palsy intrapartum hypoxia could not be the cause of cerebral palsy and in the remaining 10% intrapartum signs compatible with damaging hypoxia may have had antenatal or intrapartum origins.”

Key Publications - ACOG• Committee Opinion #49, Nov 1986/1989

– Use and Misuse of the Apgar Score– Committee on Obstetrics: MFM (ACOG)– Committee on Fetus and Newborn (AAP)

• ACOG Technical Bulletin #163, January 1992– Fetal and Neonatal Neurologic Injury

• Committee on Obstetric Practice #137, April 1994– Fetal Distress and Birth Asphyxia

• Committee on Obstetric Practice #197, Feb 1998– Inappropriate Use of the Terms Fetal Distress and Birth

Asphyxia

Badawi, BMJ 317:1549

Antepartum Risk Factors for Newborn Encephalopathy:

The Western Australian Case-Control Study

• Metropolitan Western Australia June 93-Sept 95• All 164 term infants with moderate/severe encephalopathy• Controls – 400 randomly selected• Stats

– Birth prevalence of moderate/severe newborn encephalopathy 3.8/1000 term live births

– Neonatal Fatality 9.1%• Conclusions

– Causes of newborn encephalopathy are heterogeneous and many of the causal pathways start before birth


3.57

2.97

2.07

3.82

2.23

2.17

2.73

2.55

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5

Intrapartum Fever

Mod/Severe Antepartum Bleeding

Viral Illness

Family Hx Neurological Disorder

Family Hx Seizure

Instrumental Delivery

Emergency C/S

Abnormal Placental Appearance

Adjusted Odds Ratio

Preconceptional

Intrapartum

Antepartum

Risk Factors for Newborn Encephalopathy



9.7

6.3

4.37

4.44

4.29

4.43

0 2 4 6 8 10 12

Maternal ThyroidDisease

Severe Preeclampsia

Acute IntrapartumEvent

Infertility Treatment

IUGR 3-9%tile

OP Presentation

Adjusted Odds Ratio

Preconceptional

Intrapartum

Antepartum

38.23

2.07

0 5 10 15 20 25 30 35 40 45

IUGR <3%tile

Abnormal PlacentalAppearance

Antepartum


0.17

0.17

00.51

Elective C/S

No Labor



Distribution of Risk Factors for Newborn Encephalopathy

Antepartum risk factors only (69%)

Antepartum risk factors and intrapartum

hypoxia (25%)

Intrapartum hypoxia only (4%)

Unknown (2%)

Blair & Stanley, J Pediatr 112:515

Intrapartum Asphyxia: A Rare Cause of Cerebral Palsy

“It was estimated that in only 8% (15/183) of all

the children with spastic cerebral palsy was

intrapartum asphyxia the possible cause of their

brain damage.”


Theoretical Scenarios for Timing of Neurological Insult in

Newborn Encephalopathy

Antepartum period Intrapartum period Neonatal period Newborn

outcome

1 Insult Encephalopathy

2 Insult Further Insult Encephalopathy



Nelson, NEJM 334:613

Uncertain Value of Electronic Fetal Monitoring in Predicting Cerebral Palsy

• Population– Four California counties 1983-1985– Singleton – Birthweight > 2500 gm– Survival to age 3 and EFM (N=78)– Moderate/severe cerebral palsy

• Abnormal FHR– Multiple late decelerations– Decreased beat to beat

• Controls– Matched appropriately (N=300)

Nelson, NEJM 334:613

Uncertain Value - Continued

PatternCP

N=78ControlN=300 OR

Tachycardia N (%) N (%)

> 160 22 (28.2) 85 (28.3) 1.0 (0.6-1.7)

> 180 5 (6.4) 16 (5.3) 1.3 (0.4-3.4)

Bradycardia

< 100 27 (34.6) 75 (25.0) 1.5 (0.9-2.5)

< 80 13 (16.7) 35 (11.7) 1.5 (0.8-3.0)

Multiple Lates 11 (14.1) 12 (4.0) 3.9 (1.7-9.3)

Mult. Lates or BTB 21 (26.9) 28 (9.3) 3.6 (1.9-6.7)

NEJM 334:613

Nelson

“The 21 children with cerebral palsy who had

multiple late decelerations or decreased

variability in heart rate monitoring represented

only 0.19 percent of singleton infants with birth

weights of 2500 g or more who had these fetal-

monitoring findings, for a false positive rate of

99.8%.

Extrapolation from Nelson by Hankins

1. Based on multiple lates or persistent decreased beat to beat variability 500 cesarean sections are required to prevent 1 case of cerebral palsy!

2. Future uterine rupture rate 0.5% = 2.5 ruptures

40% risk of neonatal death or CP = 1.0

3. Future risk of previa and accreta 10-20 x RR

4. Excess maternal risk of cesarean– EBL at least doubled– Infection 5-10 x RR– DVT/PE 5 x RR

“It is not possible at the current time to

prospectively recognize during labor

the point in time when a reduction in

cerebral perfusion results in

irreversible brain injury.”

Jeffrey M. Perlman, M.D.

“Any claims to the contrary are not

supported by any scientific merit.”

ACOG Task Force on Neonatal

Encephalopathy and Cerebral Palsy

Key Publications: www.bmj.com

A Template for Defining a Causal Relationship Between Acute Intrapartum Events and Cerebral Palsy

• Method:– Multidisciplinary review of pertinent medical literature– Open to any and all who might add

• Goal:1. Benefit research into causation and prevention of CP2. Help those who offer expert opinion when counseling (parents or

would be parents) or giving opinions in court.

• Participation Invited:– All members Perinatal Society ANZ– International scientific contributors

• Paper redrafted 8 times until consensus reached• Need for timely updates acknowledged

http://www.bmj.com/

Panel Members Discipline Institution

Alastair MacLennan (Chair) Obstetrics and Gynecology University of Adelaide

Fiona Stanley EpidemiologyInstitute for Child Health Research, Perth

Eve Blair EpidemiologyInstitute for Child Health Research, Perth

Greg Rice Fetal PhysiologyRoyal Women’s Hospital, Melbourne

Peter Stone Obstetrics and Gynecology University of Otago

Jeffrey Robinson Obstetrics and Gynecology University of Adelaide

David Henderson-Smart Perinatal Medicine University of Sydney

Victor Yu Neonatal Intensive Care Monash Medical Centre

Michael Harbord Pediatric Neurologist Flinders Medical Centre

Panel Members Discipline Institution

Leon Stern Pediatric RehabilitationCrippled Children’s Association of South Australia

Helen Chambers Perinatal PathologyWomen’s and Children’s Hospital, Adelaide

Margaret Furness RadiologyWomen’s and Children’s Hospital, Adelaide

Tina Hayward RadiologyWomen’s and Children’s Hospital, Adelaide

Kerena Eckert Midwifery ResearchWomen’s and Children’s Hospital, Adelaide

Christopher Boundy

Barrister and Solicitor Adelaide

Susan Merrett Medical Administrator SA Health Commission

Mark Kenny Medico Legal ServicesWomen’s and Children’s Hospital, Adelaide

International Consensus Conference

Template Criteria to Define an Acute Intrapartum Hypoxic Event

• Essential criteria1. Evidence of a metabolic acidosis in intrapartum

fetal, umbilical arterial cord or very early neonatal blood samples. pH < 7.00 and base deficit > 12 mMol/L and;

2. Early onset of severe or moderate neonatal encephalopathy in infants > 34 weeks gestation and;

3. Cerebral palsy is of the spastic quadriplegic or dyskinetic type.

ACOG/AAP

Criteria Required to Define an Acute Intrapartum Hypoxic Event as Sufficient to Cause Cerebral Palsy

Essential criteria (must meet all four)

1. Evidence of a metabolic acidosis in fetal, umbilical cord arterial blood obtained at delivery (pH 7.00 and base deficit >12 mmol/L).

2. Early onset of severe or moderate neonatal encephalopathy in infants of 34 or more weeks of gestation.

ACOG/AAP

3. Cerebral palsy of the spastic quadriplegic or dyskinetic type*.

4. Exclusion of other identifiable etiologies such as trauma, coagulation disorders, infectious conditions, or genetic disorders.

Criteria Required to Define an Acute Intrapartum Hypoxic Event as Sufficient to Cause Cerebral Palsy

International Consensus Conference

Criteria That Together Suggest an Intrapartum Timing but by Themselves Are Non-specific

1. A sentinel (signal) hypoxic event occurring immediately before or during labor.

2. A sudden, rapid and sustained deterioration of the fetal heart rate pattern usually following the hypoxic sentinel event where the pattern was previously normal.

3. Apgar scores of 0-6 for longer than 5 minutes.4. Early evidence of multi-system involvement.5. Early imaging evidence of acute cerebral

abnormality.

ACOG/AAP

Criteria That Collectively Suggest an Intrapartum Timing but Are Nonspecific to Asphyxial Insults

1. A sentinel (signal) hypoxic event occurring immediately before or during labor.

2. A sudden and sustained fetal bradycardia or the absence of fetal heart rate variability in the presence of persistent, late or variable decelerations, usually after an hypoxic sentinel event when the pattern was previously normal.

ACOG/AAP

3. Apgar scores of 0-3 beyond 5 minutes.

4. Evidence of multi-system involvement up to 72 hours.

5. Early imaging study showing evidence of acute nonfocal cerebral abnormality.

Criteria That Collectively Suggest an Intrapartum Timing but Are Nonspecific to Asphyxial Insults

Need to Educate

• Physicians

• Decision/policy makers

• Public

Conclusion

“This survey identified large knowledge gaps

in this area, suggesting a need to develop

educational projects to address these

deficits by both professional organizations

and individual teachers.”

1. In cases of intrapartum asphyxia sufficient to result in cerebral palsy, injury to organ systems other than the brain most likely to result from:

a) Loss of cerebral vascular autoregulation (15.7)

b) Redistribution of cardiac output (34.3)

c) Diminution in cardiac output (17.2)

d) Don’t know (32.8)

J Perinatol 2005 (34.9)

2. Using electronic fetal heart rate monitoring, it is

possible to prospectively recognize the precise

point in time at which cerebral injury becomes

irreversible following interruption of placental

blood flow.

a) Agree (0.3)

b) Disagree (97.7)

c) Don’t know (2.0)


3. Required criteria to define an acute intrapartum hypoxic event sufficient to result in cerebral palsy do not include:a) Umbilical arterial cord pH < 7.0 and base deficit

> 12 mmol/L (5.0)

b) Early onset of severe or moderate encephalopathy in infants > 34 wk EGA (16.0)

c) Exclusion of other identifiable etiologies (8.2)

d) Sentinal hypoxic event occurring prior/during labor (42.6)

e) Don’t know (28.3)


4. In your experience, the most common outcomes for the fetus exposed to an acute catastrophic hypoxic event, but who is born live, is:

a) Neonatal death (10.7)

b) Transient moderate or severe encephalopathy (18.6)

c) Cerebral palsy (4.3)

d) Normal neurologic outcome (65.1)


5. The most characteristic brain lesion after the death of a co-twin in a monochorionic twin pregnancy is multicystic encephalomalacia. To the best of your knowledge, this is most likely caused by:a) Infection (1.4)

b) Capacitance effect of the dead fetus and hypotension in the surviving twin (42.3)

c) High output cardiac failure of the surviving twin (14.0)

d) Chronic placental abruption (3.7)



6. Early imaging studies in the setting of a neonatal encephalopathy may assist in timing the event. Most imaging studies will be able to demonstrate the onset of diagnostic abnormality within…a) 6 h (1.2)b) 24 h (19.2)c) 48 h (14.9)d) 72 h (16.9)e) 7 d (6.1)f) Don’t know (41.7)

7. Randomized controlled clinical trials show

that antepartum fetal testing decreases the

rate of cerebral palsy.

a) Agree (2.0)

b) Disagree (92.6)

c) Don’t know (5.4)


8. In evaluation of neonatal encephalopathy, do you believe the EEG primarily:a) Is information as to the etiology of the lesion

(2.3)

b) Documents the presence of and severity of the injury (40.8)

c) Rules out an encephalopathy if it is normal (14.7)

d) Can accurately time the occurrence of the injury (1.2)



Origin & Timing of Brain Lesions in Term Infants with Neonatal Encephalopathy

• Time: 1 Jan 1992 – 31 Dec 1998• Location: Utrecht, Netherlands

London, England• Population: EGA ≥ 36 weeks

NE or seizures within 72h birth• Recruited: 351 infants

261 met NE criteria

90 seizures within 72h birthCowan, F., et. al., The Lancet, 2003;vol 361:736-742

• Group I – NE defined by abnormal tone pattern, feeding difficulties altered alertness & at least 3 of the following– Late decelerations or MSAF– Delayed onset respirations– Arterial cord blood ph < 7.1– Apgar <7 at 5 minutes– Multi organ failure

Cowan, F., et. al., The Lancet, 2003;vol 361:736-742

• Group II – Seizures within 72h birth but lack NE criteria

• Exclusions:– Major structural anomalies– Major chromosomal abnormalities– Hypothermia

“Proven bacterial or viral infection was not a reason for exclusion”


Group I

Acute Injury Pattern 197/245 (80%) Bilateral 189/197 Focal 8/197

Normal 40/245 (16%)

Findings not compatible with hypoxia 8/245 ( 3%)

Acute hypoxic damage with other disorders 9/245 ( 4%)


MRI Findings in Group I with Neonatal Encephalopathy

Group II

Acute ischemic or hemorrhagic lesions 62/90 (69%)

Concomitant evidence of antenatal injury 2/62 ( 3%)

Focal cerebral infarction 35/62 (56%)

Focal white matter hemorrhage 12/62 (19%)

Extensive parenchymal hemorrhage 8/62 (13%)

Posterior fossa hemorrhage (2), subarachnoid (3) and intraventricular (2) hemorrhage

7/62 (11%)


MRI Findings in Group II with Seizures within 72 Hours of Birth

Interpretation

Although our results cannot exclude the possibility that antenatal or genetic factors might predispose some infants to perinatal brain injury, our data strongly suggest that events in the immediate perinatal period are most important in neonatal brain injury.


Criticism of Cowan, PhDI. Criteria to define group I

i. Late decels 99% false positive for CPii. MSAF 14-20% of term gestations

II. Umbilical arterial pH <7 ּ1i. Pathologic acidemia agreed by most as <7ּ0ii. Significant number of normal babies can/will have this

level of acidemia. Respiratory versus metabolic?

III. Apgar <7 at 5 minutesWhat is the rate of any of these markers in their general population?

Origin & Timing of Brain Lesions in Term Infants with Neonatal Encephalopathy

• Design: 173 Term newborns with NE• Location: UCSF & Loma Linda

NE or a marker of perinatal depression:– UA pH <7 ּ1– UA base deficit > 10mEq/L– 5 minute Apgar ≤5

Miller, Steven P., Barkovich, James A., et. al., J Pediatr, April 2005; 453-460

MRI

• Median – 6 days of age

• Range – 1 - 24 days

• Injury Patterns –1) basal ganglia /thalamus, predominant

2) watershed predominant

3) normal


Table I. Clinical characteristics by magnetic resonance imaging pattern

Normal Watershed predominant

Basal ganglia/thalamus

predominant

P value

Number 51 78 44

Male sex 27 (54%) 51 (65%) 24 (56%)

Antenatal

Substance use 8 (16%) 11 (14%) 11 (25%) .3

Gestational diabetes 4 (8%) 9 (12%) 6 (14%) .6

Preeclampsia 2 (4%) 6 (8%) 3 (7%) .7

Prolonged rupture of membranes 6 (12%) 16 (21%) 8 (19%) .4

Intra-uterine growth restriction 0 4 (5%) 2 (5%) .3

Maternal inflammatory state 19 (37%) 35 (45%) 12 (28%) .2





predominant

P value

Perinatal

Fetal distress 33 (66%) 51 (66%) 23 (56%) .5

Complicated vaginal delivery 8 (16%) 17 (18%) 10 (23%) .7

Cesarean delivery 24 (47%) 42 (54%) 22 (50%) .7

Emergent Cesarean delivery 18 (75%) 29 (69%) 22 (100%) .006

Placenta/cord insult 16 (31%) 21 (27%) 15 (34%) .7





predominant

P value

Postnatal

Gestational age (weeks) 40 (36-42) 40 (36-42) 40 (36-42) .5

Birthweight (kg) 3.5 (2.2-5.2) 3.2 (2.0-5.4) 3.4 (1.6-4.9) .01

Head circumference (cm) 35 (32-38) 35 (31-44) 35 (29-39) .4

Length (cm) 51 (38-56) 51 (41-59) 51 (44-56) .9

Resuscitation score (1-6) 4 (1-6) 4 (2-6) 5 (1-6) .001

Five-minute Apgar score 6 (1-9) 5 (1-9) 4 (0-9) .0005

Meconium aspiration 14 (28%) 17 (22%) 10 (23%) .8

Encephalopathy score (0-6) 2 (0-6) 3 (1-6) 5 (1-6) .0001

Clinical seizures (yes/no) 14 (28%) 34 (44%) 36 (82%) .0001

Seizure score (0-10) 0 (0-6) 0 (0-8) 4.5 (0-9) .0001


Table III. Neurodevelopmental outcome of newborns observed to30 months of age by magnetic resonance imaging pattern



predominant

P value

Number 20 48 21

Died* 0 3 5 .01

30-month MDI 101 (77-121) 84 (50-116) 62.5 (50-104) .0007

12-month MDI 93 (53-109) 91.5 (50-120) 58 (50-109) .006

30-month NMS 0 (0-2) 1 (0-5) 5 (0-5) .0001

12-month NMS 0 (0-3) 1 (0-5) 5 (0-5) .0008

30-month head circumference 50 (47-57) 50 (41-53) 47 (39-51) .005

Data is presented as median (range) or number (%). P values refer to comparisons across the 3 groups.

NMS=Neuromotor score. *All infants died before 12 months of age.


Although many risk factors are clearly prenatal, recent evidence from prospective cohorts of neonatal encephalopathy using MRI demonstrate that the brain injury happens close to the time of birth. (Cowan).

“The MRI findings in our cohort were also consistent with recent rather that chronic brain injury, and the prenatal conditions measured were remarkably similar in newborns with normal & abnormal results”.


“Because of the frequent occurrence of cerebral watershed injury with the basal ganglia/ thalamus predominant pattern, cognitive deficits cannot be directly attributed to damage to the deep gray nuclei themselves”.

“In contrast, the watershed pattern had predominantly cognitive impairments at 30 months that were not detected at 12 months of age”


Conclusion

• Neuroimaging will continue to evolve until they become the gold standard on timing fetal/neonatal HIE.

• Final common pathway to injury of many insults will be the same – ie hypoxia; ischemia; hypoxia and ischemia, infection…

Neonatal Encephalopathy

Mary E. D’Alton, MDMary E. D’Alton, MDWillard C. Rappleye Professor of Obstetrics & GynecologyWillard C. Rappleye Professor of Obstetrics & Gynecology

New York Presbyterian HospitalNew York Presbyterian Hospital

Columbia University College of Physicians & SurgeonsColumbia University College of Physicians & Surgeons

Neonatal Encephalopathy Mary E. D’Alton, MD Willard C. Rappleye Professor of Obstetrics &...

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