Neurodevelopmental outcomes in
Infants with prenatally diagnosed CHD
Helena Gardiner MD PhD
Fetal cardiovascular Fellowship Director
Recognition of previously under-recognized neuro-
developmental delay in children with CHD
1988 – Boston circulatory arrest study of 171 newborns with TGA
2002 – preliminary ND outcomes
School-Age Outcomes after Arterial Switch operation
Hövels-Gürich H et al. J Thorac
Cardiovasc Surg 2002:124; 448-458Hövels-Gürich H et al. J Thorac Cardiovasc Surg 2002:124;448-458
School-Age Outcomes after Arterial Switch operation
Hövels-Gürich H et al. J Thorac
Cardiovasc Surg 2002:124; 448-458
School-Age Outcomes after Arterial Switch operation
Hövels-Gürich H et al. J Thorac
Cardiovasc Surg 2002:124; 448-458
School-Age Outcomes after Arterial Switch operation
Hövels-Gürich H et al. J Thorac
Cardiovasc Surg 2002:124; 448-458
School-Age Outcomes after Arterial Switch operation
Hövels-Gürich H et al. J Thorac
Cardiovasc Surg 2002:124; 448-458
Performance on the Rey-Osterrieth figure and academic success
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10
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remedial services grade retention
I(worst) 2 3 4 5 (best)%
Boston Circulatory Arrest Study
Special Education and Rehabilitative Services in Fontan Survivors
(n=240)
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Speech
Therapist
Special
Educator
Occupational
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Physical
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Neurologist Psychiatrist Social Worker
Never Previous CurrentMitchell M et al
J Thorac Cardiovasc Surg 2006;131:172
Recognition of previously under-recognized neuro-
developmental delay in children with CHD
1988 – Boston circulatory arrest study of 171 newborns with TGA
2002 – preliminary ND outcomes
2011 - outcome aged 16 years:
17% grade retention
25% special education
25% psychotherapy/counselling
Surgical strategies did not result in any marked differences in outcome
Survivors of arterial switch procedure for TGA showed poorer academic
achievement and abnormality of fine motor function, visual spatial skills,
attention deficit and social cognition
Term
BirthConception
Neurulation
3-4 Wk
Migration
20 Wk
Vulnerable Periods of White Matter Development
23 Wk 32 Wk
WM precursors
vulnerability Myelination
Back J, Neurosci 2001
> 2 years
Open
operculumChen-Yu, Am J
Neuroradiol 1995
34 week Term
Closed
operculum
(a) (b) (c)
(d) (e) (f)
(g) (h) (i)
(j) (k) (l)
Jiang et al 2008
Snapshot Volume Reconstruction SVR
Jiang et al 2008
Dynamic scans
Combined Loops
Registered
(aligned) 3D fetal
2D postnatal data
Recognition of pre-surgical white matter injury
in children with CHD
2002 – MRI studies first reported about 20% infants with mixed CHD
had pre-surgical WMI, despite optimal management after delivery
and 50% after surgery
2009 - Petit, CHOP reported 38% in TGA – no post-op increase
2009 - Beca, Australasia 27% in TGA unrelated to BAS, no post-op
increase
HLHS showed post-operative increase in WMI – from 20% to 70%
potentially due to continued hemodynamic instability and lower
oxygen delivery to brain?
Evidence for pre-surgical white matter injury in the
fetus with CHD
2007 – diffusion tensor imaging and spectroscopy MRI studies
showed differences in white matter microstructure and biochemistry
2009 - MRI observational metric – Total Maturation Scale (TMS) demonstrated
delayed brain maturation at term = 35 weeks’ gest.
TMS was subsequently shown to predict 2 yrs Bailey Scales testing
2010 – reduced MRI brain volumes in CHD, from early 3rd trimester
spectroscopy showed markers (N-Acetyl Aspartate to Choline ratios) lagged behind
Worse in HLHS than for other lesions
Brain Growth is Impaired in
fetuses with
Congenital Heart Disease
Jowett V, Allsop J, Fox M, Kyriakopoulou V,
Rutherford M, Gardiner H
Imperial College London
Kings College London
Whole brain volume
P=0.029
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Bra
in t
issu
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olu
me m
m3
Gestation (weeks)
cases
controls
Linear (cases)
Linear (controls)
Longitudinal data
Longitudinal controls vs cross sectional
controls
Longitudinal cases vs cross sectional
controls
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Ventricular volumes in cases and controls
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Vo
lum
e m
m3
Gestation (weeks)
cases controls Linear (cases) Linear (controls)
P<0.005
The Journal of Thoracic and Cardiovascular Surgery 2018 155, 289-290DOI: (10.1016/j.jtcvs.2017.09.083)
Apparently, size matters…in congenital heart disease and brain injury
Paul J. Chai, MD
Fetal pathophysiology in the fetus with CHD
MRI technology using Metric Optimized Gating (MOG) allows phase
contrast measurements of blood flow and oximetry in large fetal
vessels
Sun et al’s case-control study of 30 CHD fetuses suggest UV return
is desaturated in CHD – implicating placental factors
Streaming to the brain is altered because of CHD – 10% reduction
The figures also suggest cerebral blood flow and oxygen extraction
were normal overall – but lesion dependent
15% reduction in cerebral oxygen delivery, 32% reduction in Vo2
and 13% reduction in fetal brain volume
Suggest using maternal oxygen therapy to rectify these differences
Sun et al. Circulation 2015;131:1313-1323
Does image abnormality = neurodevelopmental abnormality?
Thalamo-cortical and cortical to cortical connections develop in the second half
of pregnancy to produce greater functional connectivity
EEG – assess functional brain maturation and network connectivity
MRI – determines brain injury and structural development
diffusion tensor MRI – microstructural development (Fractional Anisotrophy
and Diffusivity)
Birca et al, 2016
EEG – neuronal network dysfunction
20 fetuses enrolled and studied postnatally
5/20 with MRI signs of brain injury
4 hour recordings of EEG background activity
Correlate pre-surgical brain injury on MRI with increased beta
and gamma EEG connectivity
Association with brain maturity:
Lower TMS score had higher beta frequency
High FA (mature) increased EEG connectivity
Low FA (immature) showed:
decr. EEG connectivity at low frequencies and
incr. EEG connectivity at high frequencies
White matter diffusivity not related to EEG connectivity
Spectral power density not associated with brain injury, TMS
score or microstructure scores (FA and Diffusivity)
Only brain injury was associated with background EEG pattern
spending more time in discontinuous patterns
Birca et al, 2016
Synopsis of fetal cerebral physiology
Oxygen delivery increases third trimester to meet synapse
development and myelination needs
Human Hb is higher than in lambs (16.5 g/dl vs 8 g/dl) so
blood volume increase is not as high as in lamb
Cerebral autoregulation maintains delivery at low BP <40
mmHg lamb and < 60 mmHg in human adult
Arterial pulsatility is important for delivery
Doppler measurements of MCA PI altered by:
vascular resistance; arterial compliance; ventricular
ejection (SV) and vascular obstructive lesions
Cerebral metabolism uses glucose – glucose metabolism
depends on oxygen delivery:
normal glucose + low O2 = lactate production
low glucose = no excess lactate produced
Interpretation of fetal MRI data
MRI - excess lactate in 5/19 HLHS and 2/13 TGA (Limperopoulos, 2010)
HLHS: reduced MCA PI
cerebral O2 sats 50 – 55%.
Can reduce to 35% and still get adaptive response
PAIVS: normal or increased MCA PI
similar admixture of flows as HLHS
ND outcomes appear more normal than for HLHS
WHY do MCA PI differ in these lesions?
Possibly transmission of pulse wave is altered by length and
direction of flow to brain
CoA frequent, reducing retrograde flow
cerebral arterial pressure, autoregulation and
volume blood flow
Aortic atresia
Pulmonary atresia
Interpretation of fetal MRI data
MRI - excess lactate in 5/19 HLHS and 2/13 TGA (Limperopoulos)
Glucose metabolism depends on oxygen delivery:
normal glucose + low O2 = lactate production
low glucose = no excess lactate produced
TGA: MCA PI should be low, but inconsistent results
AoA O2 sats 40 - 45%.
High PO2 to lungs reduced PVR and alters arch flow dynamics
Shorter distance flow from LV to lungs, than RV to body
Diastolic run-off of flow from AoA to lungs
diastolic pressure and cerebral perfusion
Glucose concentration increased in UV – LV – lungs – AoD
glucose delivery to brainTGA
Summary: surgical strategies and neuro-developmental outcome
2011 - Boston circulatory arrest study - outcome aged 16 years:
17% grade retention
25% special education
25% psychotherapy/counselling
Survivors of arterial switch procedure for TGA showed poorer academic
achievement and abnormality of fine motor function, visual spatial skills, attention
deficit and social cognition
Surgical strategies did not result in any marked differences in outcome in TGA
Dutch study: Arch lesions repaired comparing DCHA (19) vs right sided antegrade
cerebral perfusion (18)
right –sided infarcts in 6/18 vs 0/19 DCHA - 3/23 had CP at 2 years
Bailey scores within normal limits in most children
Later surgery was associated with poorer outcome – possible NICU stay and
continuing hemodynamic instability
Meta-analyses
Meta-analyses highlight some of the conflicting parameters
MCA PI confusing – studies do not deal with the physiological variables
affecting measurement
Assessment of brain anatomy likely requires MRI techniques, rather than US,
but inconsistent reporting of some lesions – subependymal cysts
Role of placental function in brain growth and genetic influences remain
uncertain as minor CHD may also be associated with low HC, BWt and
neurodevelopmental delay
Does Prenatal Diagnosis improve neuro-developmental
outcome?
Cohort of TGA and SV neonates (2001-2013)
Term newborns with pre and post-operative MRI
Outcome measures:
presence of brain injury before surgery
trajectory of postnatal brain microstructural development
96 newborns with TGA and 57 SV
Brain injury more prevalent - postnatal diagnosis:41/86 (48%) vs 16/67 (24%), p=0.03
Brain development was faster - prenatal diagnosis group:white matter fractional anisotropy increased
grey matter apparent diffusion coefficient decreased
Peyvandi at al. JAMA Pediatr. 2016
Benefits of prenatal diagnosis
Greater circulatory stability may protect the brain
Earlier surgery may minimize exposure to infection
Role of therapy pre-delivery should be explored, but is far from conclusive
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