neurodevelopmental outcomes in infants with prenatally ... · school-age outcomes after arterial...

Neurodevelopmental outcomes in

Infants with prenatally diagnosed CHD

Helena Gardiner MD PhD

Fetal cardiovascular Fellowship Director

Disclosure slide

• I have no disclosures

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

Newburger, PCCS 2001

Boston Circulatory Arrest Study

Performance on the Rey-Osterrieth figure and academic success

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remedial services grade retention

I(worst) 2 3 4 5 (best)%


Special Education and Rehabilitative Services in Fontan Survivors

(n=240)

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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

Fetal brain MRI

(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

Volumetric measurement

Manual segmentation to measure

brain and ventricles

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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controls

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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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lum

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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

Fetal pathophysiology in the fetus with CHD


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

Debate: interpretation of fetal evidence

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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