Neonatal mortality and
encephalopathy
JEANIE CHEONG
N E O N A T O L OG I S T
ROYAL WOMEN’S HOSPITAL,
MELBOURNE, AUSTRALIA
Perinatal mortality related to HIE
 Worldwide (Lawn 2010)
 5th most common cause of death in children under 5 years
 23% per annum since 2000 (≈814,000 deaths in 2008)
 New Zealand 2007-2010
 14.8% of neonatal deaths attributed to HIE
Neonatal encephalopathy (NE)
 Neonatal neurological syndrome
 Depressed conscious level
 Abnormal tone and power
 Feeding difficulties
 Seizures
 Incidence: 1-6 per 1000 live births
 Aetiology: Hypoxia-ischaemia (HIE) in 30-50%
 Outcome:
 Death (15%)
 Severe neurological deficit (25%)
(Badawi 98, Cowan 03, Ferriero 04, Volpe 08)
Diagnostic & Prognostic tools in HIE
 Clinical evaluation
 Biochemistry
 Electrophysiology
 Neuroimaging
Clinical evaluation
Diagnosis: History suggestive of
intrapartum insult
 Evidence of fetal distress


Cord or early neonatal acidaemia
Deterioration of fetal heart rate pattern
 Sentinel intrapartum event

E.g. Uterine rupture, cord prolapse, placental abruption
 Depression at birth
 Overt early neonatal neurological syndrome




Depressed conscious level
Abnormal tone and power
Feeding difficulties
Seizures
(MacLennan 99, Volpe 08)
Prognosis: Resuscitation
 Duration of fetal acidaemia >1 hour
 Major resuscitation
 6.4 fold  in abnormal neurological outcome
 Positive pressure ventilation, intubation and CPR in infants
with severe fetal acidaemia
 Delayed onset breathing
Time to onset of breathing
Death or severe neurological deficit
9 minutes
42%
20 minutes
88%
(Low 84, Ambalavanan 06, Salhab 04)
Prognosis: Neurologic evaluation
 Severity of acute encephalopathy syndrome


Sensitive for mild or severe encephalopathy
Not so for moderate encephalopathy
 Seizures



40 fold  in adverse sequelae
Prognosis worse if early onset and difficult to control
? Greater injury to the brain

 seizure burden associated with Lac/Cho & NAA/Cho
independent of structural changes on MRI
 Duration of neurological abnormalities

Low risk if normalisation by 1-2 weeks
(Finer 83, Levene 86, Robertson 93, Dubowitz 98, Miller 02 & 04, Caravale 03)
Prognosis: Other clinical aspects
 “Traditional signs of recovery”
 Apgar scores

Signs of recovery e.g.
 Early establishment of suck feeds
 Visual responsiveness
 Head growth
have low sensitivity/specificity for predicting neurodisability
(Nelson 81, Mercuri 97, 99 & 00, Stark 06)
Biochemistry
Diagnosis
 Most biochemical markers have low
sensitivity & specificity for diagnosis of HIE
 Reflect severity of neurological syndrome
 E.g.
 Glucose, serum lactate, calcium, sodium, pH

Excitatory amino acids & creatine kinase-BB in CSF,
inflammatory markers, brain specific proteins
(research only)
(de Praeter 91, Volpe 08)
Prognosis
 Increased risk of death or severe disability

Hypoglycaemia
 If glucose <2.2mmol/L in the first 30 minutes
 OR ↑ by 18-fold for death or disability

 peripheral neutrophil counts in first 96 hrs

High % nucleated RBC/WBC

High lactate in cord blood
(Salhab 04, Morkos 07, Haiju 08)
Electrophysiology
Conventional EEG
 Patterns reflect pathological varieties of HIE
 Diffuse cortical & thalamic necrosis
 discontinuity, burst suppression, voltage
suppression, isoelectric EEG

Periventricular leukomalacia

excessive sharp waves positive vertex or rolandic
 Prognosis
 Severity & duration of abnormalities
 Normalisation within 1 week associated with
favourable outcome
(Wertheim 94, Biagioni 01, Okumura 02, Caravale 03, Murray 06)
Amplitude integrated EEG (aEEG)
 aEEG background pattern:

Reflect severity of HI insult

Prognostic in the first 6 hours

Normalisation within 24 hours in 10-50% of abnormal
aEEG

Rapid recovery - good outcome

 PPV if combined with clinical evaluation or MRI

Quantitative aEEG-based index (Cerebral health index/b)
 Research tool
(Eken 95, Hellstrom-Westas 95, Toet 99, van Rooij 05, de Vries 05, Shalak 03, Leijser 07, Hathi 09)
aEEG in severe HIE
Seizures
Burst suppression
Evoked potentials & NIRS
 Visual evoked potentials (VEP) &
somatosensory evoked potentials (SSEP)

Predictive if done within 6 hours
 Near infrared spectroscopy (NIRS)
 Direct measure of cerebral blood flow
 Predictive if done in the first few days
 Research tool only
(de Vries 91, Taylor 92, Eken 95, Meek 99)
Neuroimaging
Cranial ultrasound
 Abnormalities in HIE




Normal (in 50%)
Non-specific cerebral oedema
“Slit-like” ventricles not prognostic (60% controls)
Acute cortical lesions poorly demonstrated
 Basal ganglia & thalamic
echogenicity


Haemorrhagic necrosis
High PPV of poor outcome if
persistent
(Babcock 83, Siegel 84, Eken 94, Rutherford 94)
Cranial ultrasound: Doppler
 Pourcelot resistive index (RI)

Anterior cerebral artery RI<0.55




Reflects high cerebral blood flow velocity
Indicative of severity
Associated with poor outcome
Predictive within 24-48 hours
Systolic
Diastolic
Doppler: Low RI
(Levene 89, Ilves 04)
Computed tomography (CT)
 Patterns of injury in HIE
Diffuse cortical neuronal injury: “reversal sign”
 Basal ganglia & thalamic injury: ↓ attenuation
 Not sensitive in mild/moderate HI injury

“Reversal” sign
“Isoattenuation” of deep
nuclear grey matter
MR imaging and spectroscopy
 Most accurate diagnostic imaging modality
 Timing of injury “peripartum”

245 infants with acute NE & intrapartum HI

MRI findings:
 80% acute HI lesions
 4% antenatal lesions
 4% another disorder
 16% normal
(Rutherford 04, Cowan 03)
MRI patterns, nature of insult & outcome
MRI pattern of
injury
Nature of insult
Estimated
incidence
Outcome
Basal ganglia &
thalamus
Severe “prolonged” insult 40-80%
Severe cognitive
and motor deficits
Watershed white
matter & cortex
Prolonged “partial”
asphyxia
40-60%
Cognitive deficits
> motor
Basal ganglia,
thalamus,
brainstem
Severe abrupt “total”
asphyxia
10-20%
Mortality 35%
Long term feeding
problems
Cerebral white
matter
Hypoglycaemia, chronic
haemodynamic
instability
15%
Mild cognitive
deficits
(Rutherford 98, Barkovich 98, Cowan 00, Barnett 02, Martinez-Biarge 11, Volpe 12)
MRI: Severe HIE pattern of injury
Day 4 T2-weighted MRI
MRI: Watershed white matter injury
Day 3 Diffusion weighted MRI (DW-MRI)
Proton MRS
 Direct measure of brain metabolites
 Metabolite profiles not specific to HIE
 Reflect severity of insult
 Predictive of poor outcome
  Lac/Cr, Lac/NAA, Lac/Cho
  NAA/Cr
  myo-inositol/Cr
(Hanrahan 99, Cheong 06, Maneru 01, Miller 02, Robertson 01, Soul 01, Zarifi 02, Barkovich 06)
Importance of TIMING in interpretation
 Conventional T1-W/T2-W imaging
 Normal on Day 1, abnormal by 3-4 days
 Diffusion imaging
 Abnormalities apparent early
 “Pseudo-normalise”
 Proton MRS
 Abnormalities appear early
  lactate (tissue necrosis & cell death)
  NAA (neuronal & oligodendroglial injury)
Prognostic value of MR biomarkers in HIE
32 studies (n=860)
Sensitivity (95% CI)
Specificity (95% CI)
Conventional MRI
(Day 1-30)
0.91 (0.87-0.94)
0.51 (0.45-0.58)
1H
0.82 (0.74-0.89)
0.95 (0.88-0.99)
MRS in deep nuclear grey
matter (Day 1-30) Lac/NAA **
 Late MRI (days 8-30) high sensitivity, low specificity
compared with early MRI (days 1-7)
 Posterior limb of the internal capsule (PLIC) sign &
brain water ADC poor discriminatory powers
(Thayyil 10)
Hypothermia & MRI
Study
Day of MRI
Median (IQR)
MRI differences in Prognostic
hypothermia
utility
group
Rutherford 10
(TOBY)
8 (5-11)
•  basal ganglia,
thalamus, white
matter, PLIC
abnormalities
Predictive
accuracy 0.84
(cooled) vs 0.81
(normothermia)
6 (3-7)
•  white matter &
cortical gray
matter
abnormalities on
T1/T2
• No difference in
DWI
PPV 88% for
T1/T2 & DWI
64 cooled
67 normothermia
Cheong in press
(ICE)
66 cooled
61 normothermia
No effect on
prognostic utility
with hypothermia
MRI/DWI/MRS in HIE
Severe
HIE
Moderate
HIE
Conclusion
 Neonatal encephalopathy (esp HIE) is an important
cause of perinatal mortality
 Many modalities available in diagnosis & prognosis
of HIE
 MRI & MRS have greatly improved & refined our
ability to prognosticate
 However....
“No neurodiagnostic technique is
capable of diminishing the importance
of the clinical evaluation of the infant
in assessment of outcome in HIE.
Clinical and specialised diagnostic
approaches are of value only when
used in concert”
(Volpe 08)