Neuropsychol Rev (2006) 16:65–85DOI 10.1007/s11065-006-9005-7

ORIGINAL PAPER

Neurocognitive Consequences of Surgically CorrectedCongenital Heart Defects: A ReviewM. Miatton · D. De Wolf · K. Francois · E. Thiery ·G. Vingerhoets

Received: 22 March 2006 / Accepted: 31 March 2006 / Published online: 8 September 2006C© Springer Science+Business Media, Inc. 2006

Abstract With advances in surgical procedures, neuropsy-chological assessment after congenital heart defects and pre,peri- and/or postoperative predictors of adverse outcome hasbecome an important focus in research. We aim to sum-marize neuropsychological sequelae associated with differ-ent types of congenital heart defects, critically review themethodology used in more than 20 empirical studies thatwere retrieved from biomedical electronic search engines,and identify possible directions for future research. Despitethe lack of adequate control groups and long-term studies,there seem to be some cognitive deficits. The largest group ofchildren with isolated congenital heart defects present withnormal intellectual capacities. However, they tend to showlanguage deficits and motor dysfunction. Although perfor-mances on memory tasks are good, unambiguous conclu-sions concerning their attentional and executive function-ing are still lacking. Serious behavioral problems are not anissue. In addition to a detailed description of the (neuro)psychological consequences of pediatric cardiac surgery,

M. Miatton (�) · G. VingerhoetsLaboratory for Neuropsychology, Department of InternalMedicine, Ghent University,De Pintelaan 185, 4 K 3, B-9000 Ghent, Belgiume-mail: marijke.miatton@ugent.be

D. De WolfPediatric Cardiology, Department of Pediatrics, Ghent University,Ghent, Belgium

K. FrancoisPediatric Cardiac Surgery, Department of Pediatrics, GhentUniversity, Ghent, Belgium

E. ThieryReference Center for Refractory Epilepsy, Ghent University,Ghent, Belgium

an overview of the predictors of the cognitive defects isprovided.

Keywords Congenital heart disease . Cardiac surgery .

Neurocognitive function . Neuropsychology . Child

Congenital heart disease is described as a gross structuralabnormality of the heart or intrathoracic great vessels withactual or potential functional significance (Nuutinen et al.,1989).

The incidence of congenital heart disease has been thor-oughly studied (Hoffman & Kaplan, 2002). A great varietyin incidence exists, caused by the definition of congenitalheart disease used, time of diagnosis, and diagnostic tools.Worldwide, the incidence of moderate to severe congenitalheart disease is estimated to be about 6 per 1000 live births.This incidence increases to 75 per 1000 when tiny ventricleseptal defects (VSD) present at birth and other trivial lesionsare included. Congenital heart defects can be graded intothree groups (see Table 1). The first group is severe congen-ital heart disease, which includes most of the patients whopresent severely ill in the newborn period or early infancy.They will need expert cardiologic care and (perhaps multi-ple) surgical interventions. Defects such as transposition ofthe great arteries, tetralogy of Fallot, hypoplastic left heartsyndrome, and large VSD can be found in this group and ac-count for 2.5 to 3 per 1000 live births. Moderate congenitalheart disease forms a second group, which needs expert care,but less intensive than those mentioned in the first group. Thenumber of operations can often be minimized, and sometimesreduced to interventional catheterization. The incidence ofthese moderate congenital heart defects, as mild or moder-ate aortic stenosis, pulmonary stenosis, or large atrial sep-tal defects (ASD), is estimated at 3 per 1000 live births.The largest group consists of patients who are most often

Springer

66 Neuropsychol Rev (2006) 16:65–85

Tabl

e1

Deg

rees

ofco

ngen

italh

eart

dise

ase,

card

iac

path

olog

yan

dco

mm

ontr

eatm

ent

Con

geni

talH

eart

Def

ect

Car

diac

Path

olog

yC

omm

onT

reat

men

t

Seve

reco

ngen

ital

hear

tdi

seas

eT

rans

posi

tion

ofth

egr

eata

rter

ies

Con

nect

ion

betw

een

vent

ricl

esan

dgr

eata

rter

ies

isin

vers

edFi

rst:

keep

ing

duct

usar

teri

osus

open

thro

ugh

pros

tagl

andi

nsan

dop

enin

gth

eat

rial

sept

um(R

ashk

ind

proc

edur

e)N

ext:

Art

eria

lSw

itch

Ope

ratio

nTe

tral

ogy

ofFa

llot

VSD

and

over

ridi

ngao

rta

and

pulm

onic

sten

osis

<3

mon

ths:

shun

tor

ballo

ondi

lata

tion

ofth

epu

lmon

icva

lve

>3

mon

ths:

tota

lsur

gica

lcor

rect

ion

Lar

geV

SDA

com

mun

icat

ion

inth

eve

ntri

cula

rse

ptum

Surg

ery:

the

VSD

issu

rgic

ally

patc

hed

with

synt

hetic

mat

eria

lH

ypop

last

icle

fthe

arts

yndr

ome

The

left

vent

ricl

eis

mal

deve

lope

d,its

size

and

func

tiona

lab

ility

isin

suffi

cien

tto

sust

ain

life.

The

mitr

alva

lve,

aort

icva

lve

and

first

port

ion

ofth

eas

cend

ing

aort

aar

esm

all

Hea

rttr

ansp

lant

atio

nor

thre

est

aged

oper

atio

n:1.

Nor

woo

dpr

oced

ure;

2.G

lenn

orhe

mi-

Font

anpr

oced

ure;

3.Fo

ntan

proc

edur

eM

oder

ate

cong

enit

alhe

art

dise

ase

ASD

Aco

mm

unic

atio

nin

the

atri

alse

ptal

wal

lSu

rgic

alcl

osur

eor

clos

ure

thro

ugh

inte

rven

tiona

lca

thet

eriz

atio

nPu

lmon

ary

sten

osis

The

pulm

onar

yva

lve

isth

icke

ned

and

does

noto

pen

com

plet

ely

Bal

loon

dila

tatio

n

Aor

ticst

enos

isT

heao

rtic

valv

edo

esno

tope

nco

mpl

etel

ydu

eto

thic

keni

ngan

dco

mm

issu

ralf

usio

nIn

the

neon

ate:

ballo

ondi

lata

tion

orsu

rgic

alva

lvot

omy

Inch

ildre

n:us

ually

asym

ptom

atic

,firs

tbal

loon

dila

tatio

n,la

ter:

repl

acem

ento

fth

eva

lve

with

ahu

man

valv

e(h

omog

raft

),its

own

pulm

onar

yva

lve,

orw

itha

mec

hani

calv

alve

Mild

cong

enit

alhe

art

dise

ase

Pate

ntdu

ctus

arte

rios

usT

hedu

ctus

arte

rios

us(b

lood

vess

elcl

oses

soon

afte

rbi

rth

situ

ated

betw

een

the

aort

aan

dpu

lmon

ary

arte

ry)

does

not

clos

esp

onta

neou

sly

Clo

sure

ofth

eve

ssel

thro

ugh

cath

eter

izat

ion

Smal

lVSD

Som

etim

esas

ympt

omat

icSm

allA

SDSo

met

imes

spon

tane

ous

clos

ure

Mild

pulm

onar

yst

enos

isSo

met

imes

asym

ptom

atic

Not

es.A

SD:a

tria

lsep

tald

efec

t;V

SD:v

entr

icul

arse

ptal

defe

ct.O

bvio

usly

,thi

sta

ble

isno

tcom

plet

e;w

ech

ose

toad

dres

son

lyth

ose

cong

enita

lcar

diac

defe

cts

men

tione

din

the

revi

ew.

Springer

Neuropsychol Rev (2006) 16:65–85 67

asymptomatic, and often undergo early spontaneous resolu-tion of their lesion. Small VSD, small ASD, small patentductus arteriosus and mild pulmonary stenosis are part ofthis group (Hoffman & Kaplan, 2002). Obviously, this de-scription is not complete; we chose to mention the defectsdiscussed later in the review. Since a thorough descriptionof the pathology of congenital heart defects and the corre-sponding (surgical) treatment are not within the scope of thisreview, we refer the interested reader to May, 2001.

In western countries, an incidence of 0.3 to 1% has beennoted for children with congenital heart disease who requiresurgical treatment (Van Hoecke & Dhont, 2004). Due tomedical and technical improvements, the surgical morbidityof infants has dramatically declined over the years.

Although a normal life expectancy and quality of lifemight be assumed in patients with early normalization oftheir cardiopulmonary status, negative developmental out-come might not supervene until later in life. Indeed, follow-up studies have identified developmental and neurologicalabnormalities in as many as 25% of survivors (Bellingeret al., 1999). Early identification of these developmen-tal deficits and subsequent remedial interventions are ofparamount importance to guarantee optimal development inthese children. In contrast with neuropsychological evalua-tion following cardiac surgery in adults, investigation of theneurocognitive and behavioral deficits following congenitalheart disease was not triggered by subjective complaints ofeither the parents or the children. Instead, improvements insurgical techniques have made cardiologists wonder whetherthere would be corresponding improvements reflected in im-proved neurocognitive outcome. We expect that having asevere congenital heart defect, requiring (multiple) surgicalintervention(s) will have more impact on neuropsychologicalfunctioning than a mild congenital heart defect.

In this review, we describe the global cognitive function-ing and psychosocial behavior of children with surgicallycorrected congenital heart disease. In addition, we offera short overview of the medical and surgical parametersthat can predict developmental disabilities after open-heartsurgery in order to identify possible directions for futureresearch.

Search method

The Web of Science or Medline search engines identifiedstudies published from 1950 through 2004. Following termsor combinations of these terms were used: congenital heartdisease, child or children, neuropsychology, cognition, cog-nitive functioning, and neurodevelopment. The term ‘con-genital heart disease’ revealed 8481 articles on the Web ofScience and 9111 on Medline. In combination with ‘child’or ‘children’ Web of science identified 2860 articles. The

search with the terms ‘congenital heart disease’ and ‘cogni-tion’ revealed 57 articles on the Web of Science, and 40 onMedline. Combining ‘congenital heart disease’ with ‘neu-ropsychology’ revealed 14 articles on Web of Science and12 on Medline. Finally, ‘congenital heart disease and neu-rodevelopment’ resulted in 7 articles on the Web of Scienceand in 33 articles on Medline.

Additional references were retrieved from selected arti-cles. The premised selection criteria for the articles were:(1) the abstract clearly stated that developmental deficits inchildren with congenital heart disease were studied by meansof intellectual performances or developmental neuropsycho-logical assessment batteries or (2) the study was designedto study medical and/or surgical predictors of the observeddevelopmental shortcomings.

In total, 57 studies were included, of which 23 were inten-sively reviewed. Because of methodological reasons such asnot using a assessment battery to rate “neurodevelopment”but only a neurological opinion, or using adolescents insteadof children, 38 studies were excluded. Studies of specificneuropsychological domains were only available from 1991onwards. Table 2 lists an overview of studies on cognitivefunctioning from 1991 until 2005.

Most of the pediatric studies mentioned in this reviewsought to define the range of neurodevelopmental dysfunc-tions that parents and primary care providers can expect aftersurgery.

Cognitive and psychosocial behavioral functioning

Intellectual performance

Initially, investigators focused on the intellectual conse-quences of pediatric cardiac surgery. The median full scaleIQ of children with hypoplastic left heart syndrome who un-derwent at least two stages of surgical palliation was foundto be 88, indicating low average intelligence (Kern et al.,1998). When standardized testing was performed in 28 chil-dren with hypoplastic left heart syndrome who had under-gone palliative surgery (mean age at testing 8.6 years), theresults revealed lower performance IQ scores than verbalIQ scores, borderline low range scores for full scale IQ in35.7% of the survivors, and 17.8% IQ scores below 70 werereported (Sharma et al., 2000). A first study on 38 childrenwith various congenital heart defects who were assessed 22months to 6 years after open-heart surgery reported normalintellectual capacities (Dickinson & Sambrooks, 1979). Itbecame overall accepted that undergoing cardiac surgery didnot impair intellectual function (Haneda et al., 1996). Com-parative studies on pre- and postoperative developmental andcognitive functioning in three groups of children (childrenwith a congenital heart disease, children awaiting a bone

Springer

68 Neuropsychol Rev (2006) 16:65–85

Tabl

e2

An

over

view

ofne

urop

sych

olog

ical

stud

ies

onch

ildre

nw

ithco

ngen

italh

eart

defe

cts

Aut

hors

Car

diac

Def

ect,

n,A

geR

ange

Con

trol

Gro

upC

ogni

tive

Task

Res

ult

Seve

reC

HD

Bel

linge

ret

al.(

1991

)T

GA

,n=

28(7

–53

mon

ths)

Non

eB

ayle

ySc

ales

ofIn

fant

Dev

elop

men

t(<

30m

onth

s,n

=20

)

Nor

mal

rang

e

Men

talD

evel

opm

entI

ndex

,Ps

ycho

mot

orD

evel

opm

entI

ndex

McC

arth

ySc

ales

ofC

hild

ren’

sA

bilit

ies

(>30

mon

ths,

n=

11)

Nor

mal

rang

e

Gen

eral

Cog

nitiv

eIn

dex

5su

bsca

les:

Ver

bal,

Perc

eptu

al-P

erfo

rman

ce,

Qua

ntita

tive,

Mem

ory,

Mot

orW

righ

tand

Nol

an(1

994)

TG

A,n

=29

(7–1

2ye

ars)

36ch

ildre

nw

itha

card

iac

mur

mur

that

did

notr

equi

retr

eatm

ento

ra

smal

lven

tric

lese

ptum

defe

ctth

atcl

osed

spon

tane

ousl

yan

ddi

dno

tre

quir

etr

eatm

ent,

n=

36(7

y4

m–1

1y

2m

)

WIS

C-R

Sign

ifica

ntly

low

erFS

IQ,V

IQan

dPI

Q,s

imila

ritie

s,vo

cabu

lary

,blo

ckde

sign

,obj

ecta

ssem

bly

and

codi

ngW

RA

TSi

gnifi

cant

lylo

wer

scor

esfo

rar

ithm

etic

Ari

thm

etic

,rea

ding

,spe

lling

Cor

siB

lock

Span

nsR

eyA

udit

ory

verb

alle

arni

ngte

stns

Rey

Fig

ure

Vis

uall

earn

ing

test

Sign

ifica

ntdi

ffer

ence

for

copy

scor

e,no

tfor

reca

llB

ruin

inks

-Ose

rets

kyte

stof

mot

orpr

ofici

ency

Onl

ysi

gnifi

cant

diff

eren

cefo

rgr

oss

mot

orab

ilitie

sFi

nean

dgr

oss

mot

orab

ilitie

s,vi

suom

otor

perf

orm

ance

Self

perc

epti

onpr

ofile

for

child

ren

nsC

BC

Lns

Teac

her

repo

rtfo

rmns

Oat

eset

al.(

1995

b)T

GA

,n=

30,(

med

ian

age:

10y

1m

)T

OF,

n=

51,(

10y

9m

)V

SD,n

=33

,(10

y7

m)

heal

thy

scho

olch

ildre

nn

=51

,(si

mila

rag

era

nge)

WIS

C-R

nsR

ey-O

ster

reit

hC

ompl

exF

igur

ens

Con

trol

led

Ora

lWor

dA

ssoc

iati

onns

Stro

opco

lor

wor

dte

stns

Tra

ilm

akin

gte

stns

Sele

ctiv

ere

min

ding

test

ns

Springer

Neuropsychol Rev (2006) 16:65–85 69

Tabl

e2

Con

tinue

d

Aut

hors

Car

diac

Def

ect,

n,A

geR

ange

Con

trol

Gro

upC

ogni

tive

Task

Res

ult

Hov

els-

Gur

ich

etal

.(19

97)

TG

A(w

ithun

impo

rtan

tVSD

orV

SDcl

osed

duri

ngA

SO,a

nd5.

2%ha

dco

arct

atio

nof

the

aort

aco

rrec

ted

ata

late

rda

te),

n=

77,(

age

rang

e:3

y2

m–9

y4

m)

Non

eK

aufm

anA

sses

smen

tB

atte

ryfo

rC

hild

ren

Inte

llige

nce

Acq

uire

dab

ilitie

s(l

earn

ing,

know

ledg

e)V

ocab

ular

yte

st(o

nly

for

the

child

ren

2.6–

4.11

y)as

sess

espo

wer

ofm

emor

yan

dex

pres

sive

skill

s

74%

with

inth

eno

rmal

rang

eon

cogn

itive

and

mot

orde

velo

pmen

tsca

les

9.1%

redu

ced

inte

llige

nce

(5.2

%be

low

1SD

,3.

9%be

low

2SD

s)

Kip

hard

and

Shill

ing

Bod

yC

oord

inat

ion

Test

Sign

ifica

ntly

low

ersc

ores

inth

eca

rdia

cgr

oup

Mot

orqu

otie

ntD

enve

rD

evel

opm

enta

lScr

eeni

ngTe

st(u

pto

6ye

ars)

Sign

ifica

ntly

low

ered

for

the

tota

lgro

upbu

tnot

for

the

grou

pw

ithou

tneu

rolo

gica

ldam

age

Fine

and

gros

sm

otor

func

tions

Fro

stig

Dev

elop

men

talT

est

ofV

isua

lP

erce

ptio

nan

dfin

em

otor

func

tion

(4–1

0y)

22.1

%w

ithfin

em

otor

dysf

unct

ion,

23.4

%w

ithgr

oss

mot

ordy

sfun

ctio

nB

ellin

ger

etal

.(19

97)

TG

Aw

ithor

with

outV

SD;n

=17

1(a

gera

nge:

1y–

2y

5m

)N

one

Bay

ley

Scal

esof

Infa

ntD

evel

opm

ent

(1y)

Bot

hin

dice

s0.

5or

1SD

belo

wth

eno

rm

Men

talD

evel

opm

entI

ndex

Psyc

hom

otor

Dev

elop

men

tInd

exM

inne

sota

Chi

ldD

evel

opm

ent

Inve

ntor

y(2

.5y)

With

inno

rmal

rang

e

Gen

eral

deve

lopm

ent,

gros

san

dfin

em

otor

func

tion,

expr

essi

vela

ngua

ge,

com

preh

ensi

on-c

once

ptua

l,si

tuat

ion

com

preh

ensi

on,s

elf

help

,per

sona

l/soc

ial

VSD

grou

p:hi

gher

scor

esfo

rth

ech

ildre

nop

erat

edon

with

circ

ulat

ory

arre

stte

chni

que

Che

cklis

t:M

acA

rthu

rC

omm

unic

ativ

eD

evel

opm

ent

Inve

ntor

y/W

ords

and

Sent

ence

s(2

.5y)

Del

ayof

2–4

mon

ths

Voc

abul

ary

prod

uctio

n,w

ord

use,

wor

den

ding

s,ir

regu

lar

form

s,ov

erre

gula

tizat

ions

,sen

tenc

eco

mpl

exity

,mea

nle

ngth

ofm

orph

emes

CB

CL

Pare

nts

perc

eive

dsi

gnifi

cant

lyfe

wer

beha

vior

prob

lem

sSo

cial

with

draw

al,d

epre

ssed

,sle

eppr

oble

ms,

som

atic

prob

lem

s,ag

gres

sive

,des

truc

tive,

inte

rnal

izin

g,ex

tern

aliz

ing,

tota

lpro

blem

Chi

ldre

nin

the

circ

ulat

ory

arre

stgr

oup

had

sign

ifica

ntly

high

ersc

ores

onth

eIn

tern

aliz

ing

band

scal

e

Springer

70 Neuropsychol Rev (2006) 16:65–85

Tabl

e2

Con

tinue

d

Aut

hors

Car

diac

Def

ect,

n,A

geR

ange

Con

trol

Gro

upC

ogni

tive

Task

Res

ult

Ald

enet

al.(

1998

)T

GA

,n=

31(a

gera

nge:

7y–

21y

9m

)N

one

WIS

C-R

orW

AIS

With

inno

rmal

rang

eC

hild

Beh

avio

rP

robl

ems

Inte

rvie

w(l

isto

fsy

mpt

oms

com

mon

lyen

coun

tere

din

child

and

adol

esce

ntps

ychi

atri

cse

rvic

es)

Ith

ink

Iam

scal

e

74%

noor

mild

sym

ptom

sW

ithin

norm

alra

nge

Mac

hove

rD

raw

aP

erso

nTe

stF

amily

Clim

ate

Scal

eB

oys

rece

ived

low

ersc

ores

than

the

girl

sIn

fam

ilies

with

aca

rdia

cpa

tient

sth

ele

velo

fex

pres

sed

emot

ions

islo

wer

and

the

leve

loch

aos

ishi

gher

than

in“n

orm

alfa

mili

es”

Bel

linge

ret

al.(

1999

)In

fant

sw

itha

D-t

rans

posi

tion

ofth

egr

eat

arte

ries

with

aV

SDor

anIV

Sra

ndom

lyas

sign

edto

asu

ppor

tmet

hod

cons

istin

gpr

edom

inan

tlyof

circ

ulat

ory

arre

st

Non

eW

PP

SI-R

With

inth

eno

rmal

rang

ebu

tsig

nific

antly

low

erth

anth

epo

pula

tion

mea

n

IVS

and

CA

:n=

61,(

mea

nag

e:49

.5±

2.3

m);

VSD

and

CA

:n=

18,(

mea

nag

e:49

.9±

3.4

m);

Inte

llige

nce

PIQ

was

sign

ifica

ntly

low

erth

anV

IQ

IVS

and

low

flow

:n=

61,(

mea

nag

e:49

.8±

2.5

m);

VSD

and

low

flow

:n=

18,

(mea

nag

e:49

.2±

1.1

m)

Pea

body

Dev

elop

men

talM

otor

Scal

esG

roov

edP

egbo

ard

No

diff

eren

ces

betw

een

the

card

iac

grou

psM

ean

raw

gros

sm

otor

scor

eco

rres

pond

sto

the

9th

perc

entil

efo

rag

eM

otor

func

tion

Mea

nra

wfin

em

otor

scor

esco

rres

pond

sto

the

4th

perc

entil

efo

rag

eC

hild

ren

assi

gned

toC

Aha

dsi

gnifi

cant

lylo

wer

scor

eson

gros

san

dfin

em

otor

task

s.D

urat

ion

ofC

Aw

asin

vers

ely

rela

ted

togr

oss

butn

otto

fine

mot

orfu

nctio

nTe

stfo

rA

udit

ory

Com

preh

ensi

onof

Lan

guag

eA

llte

sts

butt

heG

ram

mar

clos

ure

test

wer

esi

gnifi

cant

lyR

ecep

tive

One

Wor

dP

ictu

reV

ocab

ular

ybe

low

popu

latio

nm

eans

Gra

mm

atic

Clo

sure

subt

est

(>Il

linoi

sTe

stof

Psyc

holin

guis

ticA

bilit

ies)

Lan

guag

eO

rala

ndSp

eech

Mot

orC

ontr

olTe

stM

ayo

Test

sof

Apr

axia

ofSp

eech

Ora

lApr

axia

-Chi

ldre

n’s

Bat

tery

Gol

dman

-Fri

stoe

Test

ofA

rtic

ulat

ion

spee

ch

ns Ass

ignm

entt

oC

Aw

asas

soci

ated

with

redu

ced

abili

tyto

imita

teor

alm

ovem

ents

and

spee

chso

unds

,the

seve

rity

ofab

norm

aliti

esof

volit

iona

lora

lmov

emen

tsw

asgr

eate

ram

ong

child

ren

assi

gned

toC

A,t

his

grou

pal

som

ade

mor

ear

ticul

atio

ner

rors

and

perf

orm

edle

ssw

ello

npo

lysy

balli

cre

petit

ions

inte

rms

ofra

tean

ddu

ratio

n,ap

raxi

aof

spee

chm

ore

prev

alen

tin

the

CA

grou

pan

dm

ore

seve

re

Springer

Neuropsychol Rev (2006) 16:65–85 71

Tabl

e2

Con

tinue

d

Aut

hors

Car

diac

Def

ect,

n,A

geR

ange

Con

trol

Gro

upC

ogni

tive

Task

Res

ult

Shar

ma

etal

.(20

00)

Infa

nts

who

unde

rwen

tint

raca

rdia

cre

pair

ofco

ngen

italh

eart

defe

cts

N=

100,

(age

rang

e:2

days

to6

m)

oper

ated

onus

ing

eith

erde

ephy

poth

erm

icby

pass

only

(n=

28)

orw

ithas

soci

ated

circ

ulat

ory

arre

st(n

=72

)

Fift

yag

ean

dge

nder

mat

ched

heal

thy

child

ren

Ges

ell’s

deve

lopm

ent

sche

dule

nsbu

tlow

ersc

ores

for

the

card

iac

grou

pin

com

pari

son

toth

ehe

alth

ygr

oup

Hov

els-

Gur

ich

etal

.(20

01)

Chi

ldre

nop

erat

edon

asne

onat

esw

ithde

ephy

poth

erm

icci

rcul

ator

yar

rest

and

low

flow

card

iopu

lmon

ary

bypa

ss,A

SOfo

rT

GA

,n=

31,(

age

rang

e:3

y–4

y6

m)

Hea

lthy

child

ren,

N=

32,(

age

rang

e:3

y0

m–4

y8

m)

Vie

nna

Dev

elop

men

tTe

stD

evel

opm

enta

lsco

re(7

–14

subs

cale

s)M

otor

scor

e(2

subs

cale

s)V

isua

lper

cept

ion

Vis

ualm

otor

inte

grat

ion

(2su

bsca

les)

Lea

rnin

gan

dm

emor

y(2

subs

cale

s)

Dev

elop

men

tals

core

norm

alin

87.9

%M

otor

scor

eno

rmal

in98

.7%

Vis

ualp

erce

ptio

nan

dvi

sual

mot

orin

tegr

atio

nw

asno

rmal

in89

.5%

Lea

rnin

gan

dm

emor

yno

rmal

in96

.7%

Cog

nitiv

esc

ore,

lang

uage

and

soci

oem

otio

nals

core

norm

alin

100%

Com

plet

ede

velo

pmen

tals

core

,co

gniti

vesc

ore

and

lang

uage

wer

esi

gnifi

cant

lyre

duce

din

patie

nts

com

pare

dto

cont

rols

Cog

nitiv

esc

ore

(4su

bsca

les)

Lan

guag

e(s

peec

han

dco

mpr

ehen

sion

,2su

bsca

les)

Soci

oem

otio

nals

core

(2su

bsca

les)

Hov

els-

Gur

ich

etal

.(20

02)

Uns

elec

ted

child

ren

oper

ated

onas

neon

ates

(TG

Aw

ithor

with

out

VSD

,coa

rcta

tion)

,n=

60,(

age

rang

e:7

y9

m–1

4y

3m

)

Non

eK

ipha

rdan

dSh

illin

gB

ody

Coo

rdin

atio

nTe

stG

ross

mot

orfu

nctio

nK

aufm

anA

sses

smen

tB

atte

ryfo

rC

hild

ren

Gro

ssm

otor

dysf

unct

ion

redu

ced

in26

.7%

(11.

7%be

low

1SD

,15%

belo

w2

SDs)

Gen

eral

inte

llige

nce,

lear

ning

,ac

adem

ickn

owle

dge,

expr

essi

vean

dre

cept

ive

lang

uage

Ora

land

Mot

orSp

eech

cont

rol

Test

Red

uced

form

alin

telli

genc

ein

18.3

%(1

5%be

low

1SD

,3.3

%be

low

two

SD),

dysf

unct

ion

inac

adem

ickn

owle

dge

in23

.3%

(18.

3%be

low

1SD

,5.0

%be

low

2SD

),ex

pres

sive

lang

uage

redu

ced

in18

.3%

(all

belo

w1

SD),

rece

ptiv

ela

ngua

gere

duce

din

21.6

%(1

8.3%

belo

won

eSD

,3.3

%be

low

2SD

s)

Springer

72 Neuropsychol Rev (2006) 16:65–85

Tabl

e2

Con

tinue

d

Aut

hors

Car

diac

Def

ect,

n,A

geR

ange

Con

trol

Gro

upC

ogni

tive

Task

Res

ult

Spee

chSe

lect

edit

ems

ofM

ayo’

sTe

stof

Spee

chan

dO

ralA

prax

ia

Dys

func

tion

ofsp

eech

in40

%

Spee

chA

udit

ory

Clo

sure

subt

est

ofth

eIl

linoi

sTe

stof

Psy

chol

ingu

isti

cA

bilit

ies

Inco

mpa

riso

nw

ithth

eno

rms,

the

card

iac

child

ren

with

outn

euro

logi

cals

ympt

oms

did

notd

iffe

rin

acqu

ired

abili

ties

and

expr

essi

vean

dre

cept

ive

lang

uage

;Sp

eech

Test

ofA

udit

ory

Ana

lysi

sSk

ills

Aud

itory

com

preh

ensi

onan

dph

onat

ion

Chi

ldre

nw

ithne

urol

ogic

aldy

sfun

ctio

nha

dsi

gnifi

cant

lypo

orer

perf

orm

ance

sin

all

dom

ains

Rog

ers

etal

.(19

95)

HL

HS,

n=

11(1

1–37

m)

Non

eC

AT-

CL

AM

S64

%va

ryin

gde

gree

sof

men

talr

etar

datio

nB

ayle

ySc

ales

ofIn

fant

Dev

elop

men

t45

%sh

ows

mot

orde

lays

McC

arth

y’s

Scal

esof

Chi

lren

’sA

bilit

ies

Wee

FIM

73%

subs

tant

ialf

unct

iona

ldis

abili

tyU

zark

etal

.(19

98)

Surv

ivor

sof

the

Font

anpr

oced

ure,

n=

32,

(ran

ge:2

5m

–16

y)N

one

Stan

ford

–B

inet

Inte

llige

nce

Scal

eW

ithin

the

norm

alra

nge

Ver

balr

easo

ning

,num

eric

reas

onin

g,ab

stra

ctvi

sual

reas

onin

g,sh

ortt

erm

mem

ory

(chi

ldre

nw

hoha

dun

derg

one

CA

befo

reth

eFo

ntan

proc

edur

ete

ndto

have

low

erm

ean

IQsc

ores

)T

heD

evel

opm

enta

lTes

tof

Vis

ualM

otor

Inte

grat

ion

Mild

wea

knes

sin

visu

alm

otor

inte

grat

ion

Vis

uals

patia

lint

egra

tion

abili

tyan

dvi

sual

mot

orin

tegr

atio

nab

ility

Ach

enba

chC

hild

Beh

avio

rC

heck

list

Scho

olpe

rfor

man

ceA

bove

aver

age:

45%

Ave

rage

:32%

Bel

owav

erag

e:23

%M

ahle

etal

.(20

00)

Scho

ol-a

ged

surv

ivor

sof

stag

edpa

lliat

ion

for

HL

HS,

n=

115,

(mea

nag

e:9.

0±

2.0

y)N

one

Psy

cho

educ

atio

nala

ndM

otor

Mea

sure

sPI

Q<

VIQ

35.7

%sc

ores

inth

ebo

rder

line

low

rang

efo

rfu

llsc

ale

IQ,1

7.8%

scor

ed<

70W

ISC

-III

Inte

llige

nce

Woo

dcoc

k-Jo

hnso

nP

sych

oed

ucat

iona

lB

atte

ryR

evis

edM

ean

scor

esfo

rth

egr

oup

belo

wth

eex

pect

edva

lues

Rea

ding

,mat

hC

linic

alE

valu

atio

nof

Lan

guag

eF

unda

men

tals

-R

evis

edSc

ores

wer

elo

wer

than

expe

cted

for

the

norm

alpo

pula

tion

Dev

elop

men

talT

est

ofV

isua

lMot

orIn

tegr

atio

nO

nth

elo

wer

ofth

eno

rmal

rang

e

Springer

Neuropsychol Rev (2006) 16:65–85 73

Tabl

e2

Con

tinue

d

Aut

hors

Car

diac

Def

ect,

n,A

geR

ange

Con

trol

Gro

upC

ogni

tive

Task

Res

ult

Vis

uals

patia

land

visu

alm

otor

inte

grat

ion

abili

tyA

chen

bach

Chi

ldB

ehav

ior

Che

cklis

t50

%of

the

child

ren

with

inth

eno

rmal

rang

eB

ehav

ior

ques

tion

nair

eco

mpl

eted

byth

epa

rent

s17

.8%

met

crite

ria

for

bord

erlin

eor

clin

ical

beha

vior

alpr

oble

ms

on2

orm

ore

subt

ests

Wer

novs

kyet

al.(

2000

)Pa

tient

sw

itha

sing

leve

ntri

cle

afte

rth

eFo

ntan

oper

atio

n,n

=13

3,(a

gera

nge:

3y

7m

–41

y)

Non

eW

PP

SI-R

WIS

C-I

IIM

ean

IQis

sign

ifica

ntly

low

erth

anth

eex

pect

edva

lues

ina

norm

alpo

pula

tion

WA

IS-R

7.8%

had

FSIQ

<70

Kau

fman

Ass

essm

ent

Bat

tery

for

child

ren

Ach

ieve

men

tSc

ale

Ach

ieve

men

tsco

res

wer

esi

gnifi

cant

lylo

wer

than

the

expe

cted

norm

alva

lues

Aca

dem

icA

chie

vem

entf

orch

ildre

n3–

5ye

ars

Wid

eR

ange

Ach

ieve

men

tTe

st-

Rev

ised

Aca

dem

icac

hiev

emen

tfo

rch

ildre

n>

5ye

ars

Ach

ieve

men

tsco

res

wer

esi

gnifi

cant

lylo

wer

than

the

expe

cted

norm

alva

lues

Mod

erat

eC

HD

Mill

eret

al.(

1996

)C

hild

ren

who

unde

rwen

tope

nhe

arts

urge

ry,

n=

104,

(age

2ye

ars

orm

ore,

atle

ast2

year

saf

ter

oper

atio

n)

Non

eB

ayle

ySc

ale

ofIn

fant

Dev

elop

men

t(<

30m

onth

s)St

anfo

rd-B

inet

Inte

llige

nce

(>30

mon

ths)

ns

Han

eda

etal

.(19

96)

Car

diac

defe

cts,

n=

161

(age

atop

erat

ion

rang

edfr

om3

mon

ths

to13

year

s)te

stin

g:1

wee

kpr

eope

rativ

e,2–

4w

eeks

post

oper

ativ

e

Non

eG

esel

l’sD

evel

opm

enta

lQuo

tien

t(i

nV

SD,

TG

A,S

hunt

case

s)ns

Ada

ptiv

e,gr

oss

and

fine

mot

or,l

angu

age,

pers

onal

/soc

ial

Thi

rtee

npa

tient

sw

ithC

Aof

>50

min

at13

◦ C–2

3◦ C:s

igni

fican

tdec

reas

eM

otor

func

tions

:sig

nific

antd

ecre

ase

post

oper

ativ

ein

the

VSD

grou

pB

inet

’sIn

telli

genc

eQ

uoti

ent(

inV

SD,T

OF,

TG

A,A

SD,A

VC

,DO

RV

,and

shun

tcas

es)

ns Post

oper

ativ

eth

esc

ores

seem

edto

incr

ease

Springer

74 Neuropsychol Rev (2006) 16:65–85

Tabl

e2

Con

tinue

d

Aut

hors

Car

diac

Def

ect,

n,A

geR

ange

Con

trol

Gro

upC

ogni

tive

Task

Res

ult

Wra

yan

dSe

nsky

(199

9)C

hild

ren

with

aC

HD

,n=

25(a

gera

nge:

0y–

3y

5m

)C

hild

ren

wer

ete

sted

the

day

befo

resu

rger

yan

d12

mon

ths

post

oper

ativ

ely

Chi

ldre

naw

aitin

ga

bone

mar

row

tran

spla

ntat

ion,

n=

14,(

age

rang

e:0

y–3

y5

m)

and

heal

thy

child

ren

n=

15,(

age

rang

e:0

y–3

y5

m)

Rut

hG

riffi

ths

Men

tal

Dev

elop

men

tSc

ales

<2

y:lo

com

otor

,per

sona

l/soc

ial,

hear

ing/

spee

ch,h

and-

eye

coor

dina

tion,

perf

orm

ance

≥3

y:lo

com

otor

,per

sona

l/soc

ial,

hear

ing/

spee

ch,h

and-

eye

coor

dina

tion,

perf

orm

ance

,pra

ctic

alre

ason

ing

Pre

oper

ativ

eW

ithin

norm

alra

nge

butc

ardi

acgr

oup

and

tran

spla

ntgr

oup

perf

orm

edsi

gnifi

cant

lylo

wer

onlo

com

otor

,per

sona

l/soc

ial,

spee

chan

dhe

arin

gan

dov

eral

lIQ

Post

oper

ativ

eW

ithin

norm

alra

nge

butt

heca

rdia

cgr

oup

cont

inue

dto

show

impa

ired

loco

mot

oran

dso

cial

func

tioni

ng,

over

alll

owIQ

,as

wel

las

poor

erha

nd-e

yeco

ordi

natio

nW

ray

and

Sens

ky(2

001)

Chi

ldre

nw

itha

cong

enita

lhea

rtdi

seas

e,n

=47

,(ag

era

nge:

3y

5m

–17

y)C

hild

ren

awai

ting

abo

nem

arro

wtr

ansp

lant

atio

n,n

=51

,(ag

era

nge:

3y

5m–1

7y)

Chi

ldre

nw

ere

test

edth

eda

ybe

fore

surg

ery

ortr

ansp

lant

atio

nan

d12

mon

ths

post

oper

ativ

ely

Hea

lthy

child

ren,

n=

51,(

age

rang

e:3

y5m

–17

y)B

riti

shA

bilit

ySc

ale

(sho

rtfo

rmIQ

)V

erba

land

nonv

erba

lrea

soni

ngab

ility

,sho

rtte

rmm

emor

y,sp

eed

ofin

form

atio

npr

oces

sing

,ret

riev

alof

know

ledg

eB

riti

shA

bilit

ySc

ale

(3.5

–14.

5y)

Ari

thm

etic

Bri

tish

Abi

lity

Scal

e(5

–14.

5y)

Wor

dR

eadi

ngSc

hone

llgr

aded

spel

ling

test

(5–1

4.5

y)

Mea

nsc

ores

with

inth

eno

rmal

rang

eon

each

mea

sure

Chi

ldre

nw

ithcy

anot

icle

sion

sha

dov

eral

llow

erIQ

scor

es,a

lso

low

erab

ility

for

arith

met

ic,r

eadi

ngan

dsp

ellin

gas

wel

las

high

erra

tes

ofun

dera

chie

vem

enti

nre

adin

gO

nfo

llow

–up

thes

ech

ildre

nal

lsc

ored

with

inth

eno

rmal

rang

eC

yano

ticgr

oup

cont

inue

dto

show

impa

ired

perf

orm

ance

:low

erov

eral

lIQ

scor

es,p

erfo

rmed

less

wel

lon

the

spee

dof

info

rmat

ion

proc

essi

ng,

poor

erpe

rfor

man

cein

read

ing

and

spel

ling

and

agr

eate

rfr

eque

ncy

ofre

adin

gpr

oble

ms

Forb

ess

etal

.(20

02b)

Chi

ldre

nw

hoha

dun

derg

one

abi

vent

ricu

lar

repa

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lock

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ign,

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ure

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plet

ion,

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mal

Pegs

)

Springer

Neuropsychol Rev (2006) 16:65–85 75

Tabl

e2

Con

tinue

d

Aut

hors

Car

diac

Def

ect,

n,A

geR

ange

Con

trol

Gro

upC

ogni

tive

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ult

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pero

poul

oset

al.(

2002

)C

hild

ren

requ

irin

gth

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ativ

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ed12

to18

mon

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post

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n=

98,

(age

rang

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3ye

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test

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rang

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Springer

76 Neuropsychol Rev (2006) 16:65–85

Tabl

e2

Con

tinue

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Aut

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Def

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Springer

Neuropsychol Rev (2006) 16:65–85 77

marrow transplantation, and healthy children) revealed IQ-scores within the normal range, both before and after surgery.However, both the cardiac and bone marrow transplant grouphad significantly lower IQ-scores compared to the healthygroup (Wray & Sensky, 1999). Most researchers concludethat IQ-scores of the majority of children with congenitalheart disease are within the normal range, although severalstudies report lower IQ scores in some specific groups withmore severe cardiac pathology.

School achievement

School performance was also studied. Children with trans-position of the great arteries showed lower overall scoreson arithmetic, learning, and general knowledge tests. Of60 children with transposition of the great arteries oper-ated as neonates, 23.3% performed worse than expected. Inthis lower performance group, 18.3% performed lower thanone standard deviation and 5% performed lower than twostandard deviations of the mean score (Hovels-Gurich et al.,2002). In general, children with cyanotic defects appeared tohave lower abilities for arithmetic, reading, and spelling. Val-ues lower than expected were also found in reading and mathin children with hypoplastic left heart syndrome, of whichone third received special education (Mahle et al., 2000). Al-though most children with a congenital heart disease seem toperform well at school, about 20% are considered to performbelow average. Later research isolated specific neurocogni-tive domains in order to define the contribution of a specificcognitive dysfunction to this underachievement.

Attention

Only a few studies specifically included attentional tasksin their neuropsychological protocol. Children with trans-position of the great arteries, tetralogy of Fallot, or VSDwere investigated 9 to 10 years after corrective surgery, andtheir performances on attentional tasks were compared tothose of healthy children. No significant differences betweenthe performances of both groups were found on the StroopColor Word Test and the Trail Making Test (Oates et al.,1995 a). Another study that included attentional measurescompared children with a secundum ASD that was eitherclosed surgically or with a transcatheter device (Viscontiet al., 1999). These researchers found that the group withdevices made more errors of commission suggesting impul-sivity and their scores on the attentiveness index were alsolower.

However, the initial aim of this study was the comparisonof surgical treatment versus endovascular, and not the inves-

tigation of attentional problems per se. Overall, the findingsconcerning attentional measures appear too fragmented andcontradictory to allow for a viable interpretation.

Memory

In 1994, a study compared 29 children with transposition ofthe great arteries, aged 7 to 12 years and 36 children whosuffered from either a benign cardiac murmur that did notrequire treatment or a small VSD closing spontaneously. Thechildren performed a number of neuropsychological tests in-cluding the Rey Auditory Verbal Learning Test and the Rey-Osterrieth Complex Figure Test. The children with trans-position of the great arteries did not display any problemson these tasks and their performances were rated equal tothose of the control group (Wright & Nolan, 1994). Con-firmation of these findings was offered by other studies ofchildren with transposition of the great arteries or tetralogyof Fallot. Compared to children with VSD and healthy schoolchildren, the group with congenital heart defects showed nodifferences on the Rey-Osterrieth Complex Figure Test andthe Selective Reminding test (Oates et al., 1995 a). Up to96.7% of the children who had an arterial switch operationfor transposition of the great arteries performed normallyon learning and memory tasks (Hovels-Gurich et al., 2001).The single ventricle group, however, displayed significantlylower scores for design memory at the age of 5 years (Forbesset al., 2002). Generally, studies on memory functioning re-vealed that children with transposition of the great arteriesor tetralogy of Fallot attain performances within the averagerange.

Language

Studies investigating the expressive language developmentof children aged 16 to 30 months with a transposition ofthe great arteries in combination with a VSD report a de-lay of two to four months in communicative development(Bellinger et al., 1997). Scores lower than expected on lan-guage tests were also found in survivors of staged palliationfor hypoplastic left heart syndrome (Sharma et al., 2000).Similarly, language deficits were observed in children withtransposition of the great arteries: 18.3% had reduced scoreson expressive language tasks (all below 1 standard devia-tion) and 21.6% on receptive language tasks (18.3% belowone standard deviation, 3.3% below 2 standard deviations)(Hovels-Gurich et al., 2002). We conclude that most studiesinvestigating language skills report substantial problems ona variety of linguistic tasks.

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78 Neuropsychol Rev (2006) 16:65–85

Psychomotor functions

In early research on neuropsychological deficits, reducedgross motor coordination in children with cyanotic heart dis-eases was frequently reported (Limperopoulos et al., 1999)and has been supported by most research to date (Wright &Nolan, 1994; Oates et al., 1995 a). Fine motor dysfunctionsalso occur in about 22.1% of children with transposition ofthe great arteries (Hovels-Gurich et al., 1997; Hovels-Gurichet al., 2002). Survivors of an operation for hypoplastic leftheart syndrome tend to have weaker visual motor integrationcapabilities (Uzark et al., 1998). Studying children withvarious congenital heart defects before and after cardiacsurgery revealed poor locomotor skills both before andafter the operation (Wray & Sensky, 1999). Gross and finemotor deficits are estimated to appear in 42% of the children(Limperopoulos et al., 2002). Clearly, a large percentage ofchildren with congenital heart disease display motor deficits.

Psychosocial behavior

Both behavior at home, measured by the Child BehaviorChecklist and behavior at school, measured by the TeacherReport Form, have been object of study. Based on ratings,parents, and teachers early reports on behavior in childrenwith transposition of the great arteries aged 7 to 12 yearsrevealed no significant differences compared to healthy chil-dren (Wright & Nolan, 1994; Alden et al., 1998). Moreover,parents of children with a transposition of the great arter-ies perceived significantly fewer behavioral problems thanexpected from normative data (Bellinger et al., 1997). Thebehavior of school-aged survivors of staged palliation forhypoplastic left heart syndrome has also been investigated,showing 50% to fall within the normal range. However, in17.8% criteria for borderline significant or clinically sig-nificant behavioral problems on two or more subtests weremet (Sharma et al., 2000). Children with a secundum ASDdisplay higher prevalence of problem behavior (accordingto their parents) and particularly the behavior classified as“internalizing” (Visconti et al., 1999). The findings on psy-chosocial behavior depend on the type of cardiac defect anddo not permit accurate conclusions for the whole group ofchildren with congenital heart disease.

Summary

Although the IQ scores of the larger part of children withcongenital heart disease fall within the normal range, sev-eral studies reported lower IQ scores in some specific groupswith more severe cardiac pathology. On memory tasks, chil-dren with transposition of the great arteries or tetralogy ofFallot demonstrate performances within the average range.

Reduced performance in school has been noted in some spe-cific patient groups. With regard to language, delays of 2 to4 months in communicative development in children withtransposition of the great arteries in combination with VSDhas been reported, which is supported by other studies show-ing language deficits. Studies on motor functions concludethat most children with congenital heart disease display grossand fine motor deficits. The lack of studies on attentional andexecutive tasks unfortunately do not allow for a viable inter-pretation. Early reports on psychosocial behavior in childrenwith transposition of the great arteries showed no signifi-cant differences with healthy children, although these studiesencompass patients with diverse etiologies, making conclu-sions difficult to reach.

Despite the high incidence of congenital heart disease,psychological and neuropsychological research in this pop-ulation remains scarce. The difficult medical circumstancesand methodological constraints for research in this popula-tion play an important part in this scarcity. The acute criticalstatus of the newborn often requires immediate medical in-tervention, reducing the importance of a neurodevelopmentaltesting at that stage. Further, both the functional testing thatcan be completed on neonates is extremely limited and theillness of the child reduces the predictive validity of a preop-erative functional assessment. Because of these limitationsin preoperative assessment, research focus shifted to quan-tifying the impact of the medical and surgical variables onneuropsychological functioning in order to cause refinementof the medical policy and/or surgical techniques.

Medical and surgical predictors of developmentaldisabilities after open-heart surgery

As noted above, the critical status of the newborn with a con-genital heart defect often requires immediate intervention.After the inventory of developmental disabilities in earlierstudies, research focus shifted to etiology. Initially, studiesattributed neurodevelopment sequelae in children withcongenital heart disease to surgical procedures but it soonbecame clear that the etiology had to be multifactorial withpreoperative, intraoperative, and postoperative factors allcontributing to the outcome. Preoperative factors include theprevalence of pre-existing neurobehavioral abnormalities be-fore surgery (Limperopoulos et al., 1999), age at operation,and severity of the disease. During the operation, differentcardiopulmonary bypass techniques such as continuous low-flow bypass or circulatory arrest are used, depending on thetype of cardiac defect. These techniques demand several al-terations in homeostasis: anesthesia, cooling and rewarming,reduction in pump flow or circulatory arrest, pH manage-ment, oxygenation by membrane oxygenator, hematocritof the prime and changes in blood gases (Kirkham, 1998).

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Neuropsychol Rev (2006) 16:65–85 79

Finally, important postoperative factors such as hemody-namic stability after the operation, length of stay in theintensive care unit, and possible need for multiple operationsare mentioned.

Preoperative factors

Prevalence of neurobehavioral abnormalitiesbefore surgery

Preoperative neurobehavioral assessments and neurologicalexamination in newborns with congenital heart defectsrevealed abnormalities in more than half of the cohort. Theseabnormalities included hypotonia, hypertonia, jitteriness,motor asymmetries, absent suck, and poorly modulatedbehavioral state organization profiles (to make smooth andorganized transitions between states, e.g., sleep to arousal,to alert, to crying). Feeding difficulties were also common,as well as seizures and micro- or macrocephaly. In thegenesis of brain injury in these children, prevalence ofneurobehavioral abnormalities before surgery is under-appreciated and needs greater attention (Limperopouloset al., 1999). However, preoperative neuropsychologicalfunctioning is very difficult to assess. Some forms ofcritical congenital heart defects must be repaired hours toweeks after birth, and the functional testing that can becompleted on even healthy full term neonates is severelylimited in terms of scope and predictive validity for lateroutcomes.

Genetics

Few studies report the genetic screening of the children in-cluded, although it is known that 5% to 8% of congenitalheart diseases result from chromosome abnormalities, mostcommonly Down syndrome and 22q11.2 deletions. Sinceapproximately 15% to 20% of all conotruncal cardiac mal-formations will have the 22q11.2 deletion, this genetic syn-drome is one of the most common etiologies of heart defectsin cardiology (Colemann, 2002). Because these genetic syn-dromes involve intellectual and neuropsychological deficitsas well, they are crucial in the study of causative factors.Polymorphisms of apolipoprotein E have been shown as arisk factor for a worse neurological outcome after central ner-vous system injury. When determining the APOE genotypeof children age 6 months of less with congenital heart diseaseoperated, results show a significant effect of the APOE ε2allele to predict a lower psychomotor developmental indexat the age of 1 year after cardiac surgery. This finding isindependent of race, socioeconomic status, cardiac defect,and deep hypothermic cardiac arrest use. The study foundno evidence for an APOE ε4 effect on neurodevelopmen-

tal outcome. This APOE genotype-environment interactiondemonstrates that genetic polymorphisms may explain someof the interindividual variation in developmental outcomeafter surgery for congenital heart disease. Broader neurode-velopmental evaluation of these children at an older age willclarify the impact of the APOE genotype on long-term out-come (Gaynor et al., 2003).

Prematurity

No exact incidence of low birth weight or prematurity withinthe group of children with congenital heart defects is re-ported in the studies reviewed. Studies on neurodevelop-mental outcome after surgery for congenital heart diseaseonly sporadically mention low birth weight (<2500 g) andlow gestational age (<32 weeks) as exclusion criteria. Pre-maturity and low birth weight are often associated with cog-nitive deficits, so they should be used as exclusion criteriaor should be entered in the study as a possible confoundingvariable.

Structured brain injury

On preoperative magnetic resonance imaging, 5 of 15 chil-dren with either cyanotic heart disease or congestive heartfailure showed brain abnormalities. All lesions (ventricu-lomegaly and cerebral atrophy) were subclinical (McConnellet al., 1990). Hemodynamic disturbances caused, for in-stance, by low cardiac output might also be associatedwith poor brain growth, embolic infarction, cerebrovascularthrombosis, and abscess formation (Miller & Vogel, 1999).In 2002, an MRI study was conducted before and after con-genital heart surgery. Preoperative examinations revealedperiventricular leukomalacia in 16% of the patients and in-farction was present in 2%. Postoperatively, new lesions orworsening of preoperative lesions were found in 67% of thesubjects (Mahle et al., 2002).

Severity of the disease

Differences in severity of various congenital heart defectsare difficult to rate because of the subjectivity in diagnos-tic parameters. Several proposals to quantify the degree ofheart failure have been offered. In 2001, the New York Uni-versity Pediatric Heart Failure Index, derived from signsand symptoms, medical regimen, and ventricular physiologywas evaluated and appeared to be a reliable instrument forthe evaluation of heart failure severity in children (Connollyet al., 2001). A second measure, the New York Heart As-sociation Class classifies the functional status of the child.Initially, the classification only existed for adults, but in 2001

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80 Neuropsychol Rev (2006) 16:65–85

a modification was made for the use in children (Brunset al., 2001). Unfortunately, these measures did not existwhen the studies in this review were conducted. The effectsof acyanotic versus cyanotic congenital heart defects hasbeen investigated. Several studies in the 1960s (Linde et al.,1967; Rosenthal, 1967; Rasof et al., 1967; Feldt et al., 1969;Silbert et al., 1969) found children with cyanotic congenitalheart defects to have lower IQ scores and to show inferiorperformance in gross motor skills, perceptual motor skills,and visual reaction time compared to children with acyanoticcongenital heart defects. However, other studies could notconfirm these findings (Wray & Sensky, 1999). A seconddistinction is frequently made between univentricular andbiventricular congenital heart defects. Overall, researchersagree that children with hypoplastic left heart syndrome (auniventricular group) perform more poorly on cognitive out-come than children with other congenital cardiac defects(Miller et al., 1996; Sharma et al., 2000; Forbess et al., 2002;Uzark et al., 1998). Unfortunately, these distinctions regard-ing disease severity are not standardized, and depending onthe definitions used by the researcher, different classifica-tions can emerge, making generalizations of study resultsdifficult. To achieve homogeneity in the study groups, theuse of validated and reliable indices for the severity of heartfailure (New York University pediatric heart failure index)or the functional status of children with congenital heart dis-ease (in the New York Heart Association Class) will becomeindispensable in future research.

Age at repair

The unstable cardiac status of the newborn often requires ur-gent treatment. Certain heart defects, however, are repairedlater in life, prolonging the hypoxic status. A significantnegative correlation between age of corrective surgery (forcyanotic heart defects) and IQ scores has been shown, sug-gesting that longer periods of chronic hypoxia may reduceintelligence (O’Dougherty, 1983; O’Dougherty, 1985). An-other advantage of surgery on neonates is the lower incidenceof postoperative seizures in neonates than in older infants(Newburger et al., 1993). The results of these kind of studieshave led surgeons to operate on the neonates as soon as pos-sible. In contrast, there is other evidence that delaying theoperation in children with transposition of the great arteriesor tetralogy of Fallot does not appear to adversely affect theirintellectual development (Oates et al., 1995 a).

Intraoperative factors

Results on the relation between bypass techniques and neuro-logical problems (Colemann, 2002) or brain injury (Scallan,2003) have been reviewed elsewhere. We will give an

overview of some techniques that have been investigatedin relation to neuropsychological consequences.

Deep hypothermic circulatory arrest versus continuouslow-flow cardiopulmonary bypass

With the introduction of circulatory arrest at deep hypother-mia, it became possible for the surgeon to work in a field freeof catheters and blood. In 1953, the successful closure of anASD in a 5-year-old child with the use of surface coolingfollowed by cessation of circulation for 5 min 30 sec reported(Lewis & Taufic, 1953). Later, the principle was extended byreducing the brain’s temperature to 20◦C or lower to permitextended periods of circulatory arrest. Animal studies show-ing no obvious signs of cerebral damage formed the basisfor the view that up to 60 min of circulatory arrest at 20◦Cappears safe. In later research on hamsters the “safe” periodfor circulatory arrest was limited to 30 min with a maximumof 45 min (Treasure et al., 1983). Finally, it was shownthat the “true” safe period might be as short as 20 min at18◦C (Scallan, 2003). However, evidence that the degree ofincrease in levels of creatine kinase isoenzyme BB, a specificmarker for ischemia, is directly related to duration of arresttime in the presence of hypothermia, has raised concern aboutthe safety of circulatory arrest (Rossi et al., 1986; Ekrothet al., 1989; Rossi et al., 1989). The use of circulatoryarrest BB use has also raised concerns because of thevagueness of the effects on the cerebral functioning andthe neurological and developmental status. The associationbetween cardiopulmonary bypass perfusion variables andlater cognitive function has often been examined (Bellingeret al., 1999; Wright & Nolan, 1994; Newburger et al., 1993).A cohort of children who had undergone circulatory arrestwere compared to their siblings and to a group of childrenthat had undergone corrective surgery with moderatehypothermia and continuous cardiopulmonary bypass. Thecirculatory arrest group had significantly lower IQ-scoresthan the siblings and the moderate hypothermia group, witha reduction of 0.53 IQ- points noted per minute of circulatoryarrest time (Wells et al., 1983). No association betweenthe duration of deep hypothermic circulatory arrest andcognitive performances was found, but results suggest thatfor core cooling periods of less than 20 min duration, shortercooling periods are associated with lower scores. Thesedata suggest that patients undergoing relatively long periodsof deep hypothermic circulatory arrest might require someminimum time of cardiopulmonary bypass cooling to avoidcentral nervous system injury (Bellinger et al., 1991). Intel-ligence has been shown to be significantly inversely relatedto the duration of bypass. In addition, intelligence tends tobe inversely related to the duration of circulatory arrest, butnot to core cooling time on bypass or degree of hypothermia.Combined circulatory arrest and low flow bypass in

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the neonatal arterial switch operation is associated withneurological as well as fine and gross motor impairment butappears to be well tolerated concerning cognitive functionsbased on a formal intelligence testing (Hovels-Gurich et al.,1997).

The perioperative neurological effects of hypothermic cir-culatory arrest versus low-flow cardiopulmonary bypass ininfant heart surgery has also been thoroughly investigated(Newburger et al., 1993). The use of circulatory arrest wasassociated with greater central nervous system perturbationin the early postoperative period than a strategy consistingpredominantly of low-flow cardiopulmonary bypass. The lat-ter has recently even been called superior to circulatory arrestbecause it does not impair cerebral perfusion (Scallan, 2003).This finding was not confirmed by a study on the associationbetween the children’s functioning at ages 7 to 12 years, andmedical and surgical parameters. No statistically significantassociation between the IQ scores, achievement tests, andsurgical variables could be noted. Periods of hypothermialonger than 45 min were strongly associated with an IQ ofless than 85 and later neurological abnormality, suggestingthat the use of circulatory arrest or low-flow bypass wasnot as important as the duration of hypothermia (Miller etal., 1996). A study on the effect of circulatory arrest as asupport technique in 158 children with transposition of thegreat arteries at 4 years of age revealed an association be-tween assignment to circulatory arrest and a reduced abilityto imitate oral movements and speech sounds, more severeabnormalities of volitional oral movements, more articula-tion errors, decreased performances on polysyballic repeti-tions, and more prevalent apraxia of speech (Bellinger et al.,1999).

pH management during core cooling: alphaversus ph-stat method

During cardiopulmonary bypass, pH and blood gases arefrequently measured. There has been long controversy aboutwhether the results should be reported at the temperature atwhich they are taken or corrected to the value at a tempera-ture of 37◦C. For the former, to maintain a normal pH, car-bon dioxide is added to the bypass circuit (pH-stat strategy),whereas for the latter the pH is allowed to become progres-sively alkaline (α-stat strategy) (Kirkham, 1998). Studies onthe developmental and neurological effects of pH manage-ment for deep hypothermic cardiopulmonary bypass haveshown that children randomized to the pH-stat and α- statmethod not to differ significantly at 1 year of age in theirscores on the Bayley Infant Scales of Development or intheir neurological examination. In addition, at the age of 2to 4 years both groups of children had similar developmentas assessed by parental responses (Bellinger et al., 2001).

Hemodilution

In the 1950s, hemodilution during cardiopulmonary bypasswas introduced to decrease homologous blood use and wasthought to improve microcirculatory flow. However, mag-netic resonance and near-infrared spectroscopy suggest thatcurrently recommended protocols for hemodilution duringcardiopulmonary bypass might cause brain injury in ani-mal models by hypoxic-ischemic injury. Further, hemod-ilution might reduce perfusion pressure, increase cerebralblood flow, and reduce the oxygen carrying capacity of theblood which increases the risk of an adverse neurologicaloutcome. This hypothesis was tested by randomly assign-ing children needing reparative cardiac surgery at less than9 months of age to undergo hemodilution to a hematocritlevel of approximately 20% versus 30%. Children 1 year ofage underwent a neurological examination and developmen-tal evaluation. Results showed that the children assigned tothe lower-hematocrit group had a poorer perioperative out-come and a lower psychomotor developmental index. A sig-nificantly greater proportion of these children showed Psy-chomotor Development Index (PDI) scores of more than twostandard deviations lower than the population mean. Deficitswere mostly found in motor function but other domains, forinstance language or visual-motor integration that cannot beeasily assessed in 1-year olds, might equally be affected. Fu-ture research needs to refine the optimum hematocrit levelduring infant cardiac surgery (Jonas et al., 2003).

Oxygenators and filters

Data from adult research suggest that micro emboli, mainlybubbles and small particulate matter, occur during cardiopul-monary bypass and lodge in retinal and cerebral microcircu-lation, in association with poor neuropsychological outcome.The effect of the use of membrane oxygenators and line fil-ters on neuropsychological outcome, however, remains con-troversial. The neurodevelopmental outcome of infants sup-ported with extracorporeal membrane oxygenation (ECMO)after cardiac surgery show normal neuromotor outcome in75% of the survivors, while 50% had a normal cognitiveoutcome (Hamrick et al., 2003).

Postoperative factors

Number of operations

Logically, the risk for neuropsychological consequences in-creases after successive operations. For many children withcomplex congenital heart defects (e.g., hypoplastic left heartsyndrome) the Fontan procedure has become the definitivesurgical treatment. These children usually undergo more than

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one cardiac surgical procedure. It has been shown that chil-dren who had deep hypothermic circulatory arrest during anoperation, had somewhat lower IQ-scores than expected be-fore the operation. However, it was not within the scope ofthis study to isolate the effect of additional palliative proce-dures on intellectual performance (Uzark et al., 1998).

Length of stay in cardiac intensive care unit

The postoperative healing process of the child is reflectedin the length of stay in the cardiac intensive care unit. Post-operative length of stay is a marker for various events suchas hypotension or hypoxia, which can culminate in adversecognitive outcome. Longer postoperative stay in cardiac in-tensive care unit was indeed associated with worse cognitivefunctioning in 8-year-old children (Newburger, 2003).

Clinical and EEG-seizures

Early transient postoperative clinical seizures are reported in4% to 10% of infants with critical congenital heart diseasewho need open heart surgery. An even higher incidence ofchildren with seizure activity is detected by using postopera-tive continuous EEG-monitoring. Postoperative clinical andEEG seizures are associated with worse neurodevelopmen-tal outcomes at ages 1 year and 2.5 years in children withtransposition of the great arteries (Rappaport et al., 1998).The predictive value of the measures used at these ages islimited, yet the impact of clinical and EEG-seizures shouldnot be underestimated.

Age at testing

Age at the moment of testing can play an important rolein studying neurodevelopment in children with congenitalheart disease. Differences in cognitive functioning betweenthe acyanotic group and the cyanotic group have been re-ported, with the latter performing worse. Remarkably, thisdifference only presented in older children suggesting thatin the cyanotic group, impairment of cognitive functioningincreases with age (Wray & Sensky, 2001).

Summary

Initially, most studies attributed neurodevelopmental seque-lae in children with congenital heart disease to surgical pro-cedures but it soon became clear that the etiology is multi-factorial, with preoperative, intraoperative, and postoperativefactors all contributing to the outcome. The preoperative sta-tus of the child is the first step under consideration. Presenceof neurobehavioral and brain abnormalities as well as pre-maturity should be investigated, including a genetic screen-ing and determining the APOE -genotype. Further, studies

should strive for homogeneity in the severity of congeni-tal heart disease in the study groups by using validated andreliable indices for the severity of heart failure (New YorkUniversity pediatric heart failure index) or the functionalstatus of children with congenital heart disease (in the NewYork Heart Association Class). There are demonstratable ef-fects of cardiopulmonary bypass and circulatory arrest, pHmanagement, hemodilution, oxygenators, and filters in thispopulation as well as by the severity of the disease, need formultiple operations, length of stay in cardiac intensive careunit, and clinical and EEG seizures.

Medical and surgical variables have been highlighted sep-arately in this part of the review, but obviously the nature ofcongenital heart disease is too diverse and complex to relateneurodevelopmental disabilities to isolated parameters.

Discussion and conclusions

In studies on children with congenital heart disease the greatvariety in both heart defects under study and test materialused to assess neuropsychological performance are striking.This obviously complicates generalization of the results. Be-cause of this existing variety in heart defects and the differ-ent treatment procedures they require, investigators prefer-entially studied one heart defect, often resulting in smallsample sizes. In addition, most studies reflect an underesti-mation of the neurodevelopmental problems in children withcongenital heart disease since investigators exclude childrenwith serious neurological injury. To date, most studies wereretrospective caused by difficult preoperative clinical circum-stances and the methodological constraints of psychologicaland neuropsychological research in this population. Specificcritical congenital heart defects demand urgent repair andthe functional testing that can be completed on neonates isextremely limited. Moreover, these children are acutely illbefore surgery, reducing the validity of a preoperative func-tional assessment. The predictive value of these early assess-ments for later cognitive outcomes is therefore limited.

Selecting an appropriate control group is also a method-ological challenge in this group. Including healthy childrenas a control group is methodologically incorrect becauseneither physical nor environmental factors are equivalent inthese groups. In children with congenital heart disease, devel-opmental shortcomings can be attributed to several factors,such as the surgical intervention or the emotional trauma ofhospitalization. However, healthy children do not experiencethese causative factors in any way. To solve this problem onecould include children who undergo a non-cardiac surgicalintervention, but non-cardiac diagnoses do not hold the samepotential risks of central nervous system damage as do con-genital heart defects. Another option is to compare childrenwith congenital heart disease that require open-heart surgery

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to children with congenital heart disease that require closedsurgical procedures (Haneda et al., 1996). In this case dif-ferences in disease severity and surgical invasiveness mayconstitute another confound when comparing both congeni-tal heart disease groups.

The need for follow-up studies is increasing. Inventoriesof preoperative neurological, genetic deficits, and possiblepreoperatively present structural brain lesions will becomeessential. Follow-up studies will also clarify the persistenceof developmental abnormalities.

In future research, preoperative, intraoperative, and post-operative factors should be included when studying causesof neurodevelopmental disabilities. The cognitive domainsof attention and executive functioning remain largely under-investigated. As mentioned above, research on the develop-mental sequelae of congenital heart disease has been directedby the medical team and not so much by subjective com-plaints on neurocognitive functioning by parents or children.As studies pointed out, a substantial number of children withcongenital heart disease perform within average range, yetanother group displays mild to moderate cognitive dysfunc-tion. Examination of the subjective complaints of parentsand children as well as self-perception of competence of thechildren with congenital heart disease should be included infuture research.

Studies should strive for homogeneity in the severity ofcongenital heart defects in the study groups by using val-idated and reliable indices for the severity of heart failure(New York University pediatric heart failure index) and thefunctional status of children with congenital heart disease(in the New York Heart Association Class). Only then canwe draw firm conclusion on the different congenital heartdefects and their respective neurodevelopmental sequelae.Recognition of the population at risk will lead to preventionof serious sequelae.

The overall aim of this research is providing modifica-tions in cardiac and surgical management that will improveneurological and neurodevelopmental outcome in childrenwith congenital heart disease.

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