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1
Verrall CE, etal. Open Heart 2019;6:e000998. doi:10.1136/openhrt-2018-000998
To cite: Verrall CE, Blue GM,
Loughran-Fowlds A, etal. ‘Big
issues’ in neurodevelopment for
children and adults with
congenital heart disease. Open
Heart 2019;6:e000998.
doi:10.1136/
openhrt-2018-000998
Received 18 December 2018
Revised 18 March 2019
Accepted 26 April 2019
For numbered afliations see
end of article.
Correspondence to
Dr David Winlaw; david.
winlaw@ health. nsw. gov. au
‘Big issues’ in neurodevelopment for
children and adults with congenital
heart disease
Charlotte E Verrall,1,2 Gillian M Blue,1,2 Alison Loughran-Fowlds,2,3
Nadine Kasparian,1,4 Jozef Gecz,5 Karen Walker,3 Sally L Dunwoodie,6,7
Rachael Cordina,8,9 Gary Sholler,1,2 Nadia Badawi,2,3 David Winlaw 1,2
Congenital heart disease
© Author(s) (or their
employer(s)) 2019. Re-use
permitted under CC BY-NC. No
commercial re-use. See rights
and permissions. Published
by BMJ.
AbstrAct
It is established that neurodevelopmental disability (NDD)
is common in neonates undergoing complex surgery for
congenital heart disease (CHD); however, the trajectory
of disability over the lifetime of individuals with CHD is
unknown. Several ‘big issues’ remain undetermined and
further research is needed in order to optimise patient care
and service delivery, to assess the efcacy of intervention
strategies and to promote best outcomes in individuals
of all ages with CHD. This review article discusses ‘gaps’
in our knowledge of NDD in CHD and proposes future
directions.
INTRODUCTION
Care of children with congenital heart
disease (CHD) is associated with a low risk of
periprocedural mortality and morbidity in all
but the most complex of conditions, which
constitute fewer than 10% of presentations.
A broad suite of outcomes is now evaluated,
including cardiovascular functional status
(how well the circulation works), educational
attainment and employment, social engage-
ment and psychological well-being, which,
when combined, are assessed as ‘quality
of life’ (QOL). An understanding of these
issues is important not only for those looking
forward after CHD is ‘fixed’ but also for those
contemplating long-term expectations after
a fetal diagnosis. This is a major issue in the
field as it is recognised that QOL is reduced
in children with CHD,1 which, in turn, may
have a detrimental effect on the QOL of
the parents and support networks of those
affected.
In this review, we articulate the undeter-
mined ‘big issues’ in neurodevelopment
affecting those who require treatment for
CHD. We bring together a description of the
problem, an overview of the aetiology, eval-
uation of the effectiveness of current inter-
ventions and considerations for the future.
For the purpose of the review, CHD patients
those require early cardiac intervention are
of primary interest, which make up a minority
of CHD as a whole. Findings may not be
relevant to individuals with minor lesions,
including minor pulmonary valve abnormal-
ities and small ventricular septal defects, that
do not require surgery.
Incidence and manifestations of
neurodevelopmental disability
Central to normal growth and learning is
brain development. Abnormal brain develop-
ment is a greater issue for children with CHD
(~20% of those requiring cardiac surgical
intervention in infancy) compared with those
without major illness (~5%). There is a spec-
trum of manifestations in what is termed
neurodevelopmental disability (NDD)
(figure 1). At one end, there are typical phys-
ical manifestations of developmental ‘delay’
which may resolve or be remediated over
time, through to persisting behavioural and
psychosocial syndromes, and major disability
at the severe end of the phenotype. The
pathophysiology of the subentities of NDD
may well differ but are grouped for clinical
convenience.
Depending on the definition, NDD may
be the most common adverse outcome in
children with CHD. Up to 50% of children
requiring cardiac intervention exhibit NDD,
including mild cognitive impairments, diffi-
culties with attention and hyperactivity, defi-
cits in motor functioning, social interaction,
language and communication skills, and
delayed executive function,2–7 which may
persist into school age and beyond.8–10 As
expected, NDD has a detrimental effect on
educational achievement and attainment,
which consequently affects later employ-
ability, independence and relationships, and
may heighten the burden of psychological
disturbance and reduce overall QOL11–13
(figure 1).
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2Verrall CE, etal. Open Heart 2019;6:e000998. doi:10.1136/openhrt-2018-000998
Figure 1 Potential manifestations of NDD in people with
CHD and associated long-term outcomes. ADHD, attention-
decit/hyperactivity disorder; CHD, congenital heart disease;
NDD, neurodevelopmental disability.
The extent to which these manifestations continue into
adolescence and adulthood remains unclear and the subject
of ongoing research. While many older CHD patients are
doing much better physically than was ever expected at the
time of their surgery, understanding the impact of NDD
in later life is essential. The adult health system is not
well equipped to support these issues, particularly given
widespread stigma and negative societal attitudes towards
disability, and a lack of adequate resourcing for dedicated
neurocognitive services in CHD; a particularly vulnerable
time is during the transition to adult health services.14
Advancing our understanding of the onset, causes and
long-term trajectory of NDD is important to advance effec-
tive intervention and management.
NEURODEVELOPMENTAL OUTCOMES IN CHD AT DIFFERENT
AGES
Children
It is well established that NDD in CHD is an issue, with its
origins in early gestation. Infants and children with CHD
requiring intervention display NDD across a multitude of
domains with outcomes comparable to those observed in
premature infants and other sick neonates.3 4 15 In our clin-
ical experience, up to 29% of children requiring cardiac
surgery during infancy displayed moderate-to-severe
impairment in at least one area of neurodevelopment at
age 12 months. While many individuals scored between
‘normative means’, up to 28% had scores ≥2 SD below
mean performance in at least one neurodevelopmental
scale indicative of ‘mildly’ reduced assessment scores. This
suggests that many infants requiring cardiac surgery will
have reduced abilities compared with the typical popula-
tion.3
Abnormalities noted in infancy may persist into early
childhood. Utilising the Australian ‘National Assessment
Program—Literacy and Numeracy’ data, we demon-
strated that 13.1% of children that underwent a cardiac
procedure within the first year of life were classified as
having ‘special needs’ at school age compared with 4.4%
of children that had not had a cardiac procedure, as well
as displayed a higher proportion of learning disabilities
and speech impairments.16
Standardised assessments, such as the Bayley Scales
of Infant and Toddler Development (BSITD)17 and the
Wechsler Scales of Intelligence,18 are routinely used at key
time points throughout childhood, starting with assessments
as early as 1 month of age (table 1). The BSITD assessments
have been found to underestimate developmental delay19 20
and newer assessments with a high sensitivity and specificity
for early detection of cerebral palsy are being introduced to
assess CHD infants, such as the Prechtl Qualitative Assess-
ment of General Movements and the Hammersmith Infant
Neurological Examination (HINE).21
Assessment frequency is often determined by risk
profile, those deemed ‘at-risk’ are routinely re-assessed
at specific intervals, with the acknowledgement that
risk profile can change over time.22 Scores are typi-
cally interpreted compared with normative data, and
scores determined to be ‘below average’ usually acti-
vate recommendations for intervention involving health
professionals from a range of disciplines, including devel-
opmental paediatrics, neurology, psychology and allied
healthcare providers, such as physiotherapists, occupa-
tional therapists, speech and language pathologists, and
child life therapy.
Extending existing guidelines published by the Amer-
ican Academy of Paediatrics (AAP), the American Heart
Association recommends universal screening and long-
term surveillance for NDD in all children with CHD.22
Clinical practice and current research is based on the
2006 AAP algorithm for developmental surveillance
and screening that emphasises the importance of early
identification and management of developmental disor-
ders, which suggests that earlier intervention improves
outcomes23; however, evidence to support this in the CHD
cohort is limited and much-needed to support necessary
expenditure in health systems.
Adolescents
NDD is reported in nearly twice as many adolescents with
CHD compared with population norms,24 with poorer
neurodevelopmental outcomes observed across various
domains, including full-scale IQ, perceptual reasoning,
working memory, visual perception, visuomotor integra-
tion, and executive and motor functioning.25 Attendance
at special schools and lack of final school examination
occurs in as many as 12% of adolescents with CHD,26 with
up to 65% receiving remedial academic or behavioural
services and up to 50% requiring therapeutic services,
including physiotherapy, speech therapy, occupational
therapy and psychotherapy or counselling.25 27 When
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Congenital heart disease
Table 1 Example neurodevelopmental assessment tools commonly used in CHD
Assessment Age range Scores
Bayley Scales of Development, Version III*
Cognition
Expressive language
Receptive language
Fine motor
Gross motor
1–42 months ≥8 normal
6–7 mild
2–6 moderate
1–2 severe
Wechsler Scales of Intelligence, Version IV*
Full-scale IQ
►Verbal IQ
►Performance IQ
Preschool and primary
2.5 years–7 years 7 months
Children
6–16 years
Adults
>16 years
≥130 superior or ‘gifted’
120–129 very high
110–119 bright normal
>90 average–low average
69–70 borderline mental functionality
<69 mental retardation
*These assessments are commonly used assessment tools in the CHD population but various other assessments have been used for
evaluation in children and adolescents with CHD including: Woodcock Johnson; Wide Range Achievement Test; Clinical Evaluation of
Language Fundamentals; Expressive Vocabulary Test; Neuropsychological Assessment; Peabody Picture Vocabulary Test; Rey-Osterrieth
Complex Figure Test; Visual-Motor Integration; Conners’ Continuous Performance Test; Children’s Memory Scale; Wide Range Assessment
of Memory and Learning; Behavior Rating Inventory of Executive Function; Delis-Kaplan Executive Function System; Bruininks-Oseretsky
Test of Motor Prociency; Peabody Developmental Motor Scales; Scales of Independent Behavior-Revised; Attention Decit/Hyperactivity
Disorder Rating Scale; Child Behavior Checklist; Youth Self-Report; Conners’ Rating Scale-Revised; Diagnostic Interview Schedule for
Children; Basic Assessment System for Children and Diagnostic Adaptive Behavior Scale.22
CHD, congenital heart disease.
compared with sibling controls, outcomes appear worse
than when compared with population norms, particu-
larly for full-scale IQ and processing speed28 and may be
a better overall assessment.
Understanding the onset and trajectory of NDD
throughout life is important for effective manage-
ment and optimal intervention; however, the extent
to which early childhood outcomes predict later
disability is uncertain. The Boston Circulatory Arrest
Study (BCAS) and the Aachen Study are the only
prospective longitudinal studies in this field. Both
explored neurodevelopment at multiple time points
throughout childhood and adolescence in individuals
with surgically corrected transposition of the great
arteries (TGA). The BCAS study found that outcomes
in those with TGA were below population norms across
various neurodevelopmental domains at different time
points throughout childhood,9 10 29 30 and below mean
average scores continued to be observed at age 16 years
when compared with ‘healthy’ controls, particularly in
academic achievement and social cognition. A substan-
tial proportion of TGA patients scored ≥1 SD below
the expected population mean across various neuro-
developmental domains, including memory (35%),
academic achievement (26%–27%) and visual-spatial
skills (54%), and frequencies of scores greater than the
cut-off for clinical concern were significantly higher in
executive functioning (13% self-reports, 23% parent
reports and 38% teacher reports) and attention (19%).
This was accompanied by a higher incidence of
brain abnormalities detected by MRI; however, these
tended to be acquired rather than developmental and
no significant association was identified between MRI
abnormality and neurodevelopmental test scores.27
Similar findings were also demonstrated in the Aachen
study, where significant motor dysfunction, poorer
acquired abilities (learning knowledge) and speech
impairment were found at age 5 years compared with
population norms,31 32 and assessment at age 10 years
showed that neurological and speech impairments were
more frequent and motor function, acquired abilities
and language were reduced compared with norms.8 33
When re-assessed during adolescence, IQ scores were
within the normal range; however, the frequency of
scores ≤2 SD below the expected mean for performance
IQ was 11%, suggesting a greater incidence of specific
cognitive deficits compared with the normal popula-
tion through adolescence.26
Evidence-based predictors of later NDD will aid in iden-
tifying those ‘at-risk’ of adverse outcomes and provide
opportunities for intervention. As expected, CHD
complexity is predictive of worse neurodevelopmental
outcomes in adolescence.34 35 Children with ‘simple’
CHD, such as atrial septal defects, have demonstrated
some impairment compared with population norms,36
while others have found no differences in outcomes based
on CHD complexity.25 Most neonatal indices, including
birth weight and length, and 1 and 5 min Apgar score,
are not predictive of adolescent NDD, with the exception
of head circumference.35 Head circumference continues
to be smaller than average in adolescents with CHD, and
neuroimaging studies have demonstrated smaller total
brain volumes, total white matter (WM), and cortical and
deep grey matter volumes compared with controls, with
those with cyanotic CHD being more notably affected
compared with acyanotic CHD.37 Smaller brain volumes
have been found to correlate with functional outcomes
in adolescents with CHD but not control subjects,
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highlighting the importance of quantitative imaging
measurements in this population.37
In time and with more research, these findings may
provide a diagnostic tool in the identification and inter-
vention of NDD in CHD; however, the generalisability
of findings is currently limited due to the studies being
small sample, single time point observations. To fully
understand the reliability and clinical significance of
these findings, longitudinal studies are needed.
Adults
Adults living with CHD now outnumber children,
accounting for up to 66% of the CHD population.38
The limited research to date shows that adults with
CHD (ACHD) display NDD across various domains,
including reduced abilities in executive functioning,39
information processing speed, psychomotor speed and
reaction time,40 overall and divided attention,39 40 fine
motor function,39 working memory41 and visuospatial
skills,41 with those with more complex CHD being more
notably affected compared with adults with simpler
CHD.39 40 42 A high frequency of MRI abnormalities and
reduced brain volumes in adults with cyanotic CHD has
also been observed.43 Adults with more complex CHD
have been found to have a higher frequency of neuro-
logical comorbidities, such as stroke and seizures, and
are more likely to be unemployed and receiving disa-
bility benefits despite educational attainment being no
different to those with simpler CHD.41
The rate of unemployment across all ACHD is esti-
mated at 18%–50%,11 44 and the incidence of comorbid
psychiatric disorders (eg, anxiety and depression),
pragmatic language impairment and delayed transi-
tion to independent living is increased.45 Understand-
ably, the overall QOL in ACHD is reduced compared
with population norms,46 and the accumulative effects
of neurological disability pose great demands on the
person affected, their support networks and societal
resources. Furthermore, the burden of neurocognitive
disability is likely to impact the rate of loss of follow-up
in this population, which has implications for the risk
of complications and consequentially, a higher cost
burden on resources. ACHD patients often require
additional nursing/allied health support to maintain
engagement, which also impacts the costs of care.
As the growing ACHD population ages, new concerns
are emerging regarding an increased risk of neurocog-
nitive decline and dementia, particularly early-onset
dementia, compared with population norms.38 47 This
may be evident earlier in life than typically expected and
associated with tachycardia, atrial fibrillation, hyperten-
sion, stroke, disordered glucose metabolism, coronary
artery disease and heart failure.47 48 Other risk factors for
dementia are also more common in the CHD population,
including genetic disorders and the impact of reduced
exercise capacity. Adults with severe CHD are considered
to have a greater risk of dementia, particularly those with
single ventricle morphology.47
AETIOLOGY OF THE CHD+NDD PHENOTYPE—WHAT CAN WE
MODIFY?
While we are starting to build a clearer picture of the inci-
dence of NDD over the course of a lifetime, the underlying
causes of the CHD+NDD paradigm are not fully under-
stood and the extent to which NDD can be prevented or
modified is unknown. Early research focused on intraop-
erative factors as the cause of adverse neurodevelopmental
outcomes in CHD.29 30 49–51 Use of prolonged deep hypo-
thermic circulatory arrest and extracorporeal membrane
oxygenation are still considered to be contributory risk
factors for adverse outcomes,2 51 and surgical techniques
have been adapted, where possible, to minimise potential
detrimental burden. Somewhat surprisingly, perioperative
factors have been found to explain only 5%–8% of varia-
bility in NDD outcomes following cardiac surgery.2 52 53
The fact that modification and improvements in surgical
techniques have not been accompanied by improvement in
neurodevelopmental outcomes supports this view.27 54 The
current understanding is that patient-specific and many
preoperative and antenatal factors are likely to contribute
to the majority of neurodevelopmental impairment in
people with CHD.
Development of the heart and brain are intimately
related and fetal neuroimaging demonstrates abnormal-
ities that are present from early gestation that are likely
to impact brain structure and growth in utero as a result
of altered perfusion and substrate delivery.55 56 Some
changes are dependent on the CHD anatomy, such as
retrograde perfusion of the aortic arch via the ductus in
fetuses with aortic atresia, and perfusion of the brain with
relatively hypoxic blood in fetuses with TGA.57 In support
of this concept, dysregulation of some angiogenic genes in
the brain of human fetuses with CHD has been observed,
possibly as a result of chronic hypoxia contributing to
abnormal brain development.58 59 Measurement of fetal
cerebral oxygenation by MRI demonstrates a reduction
in oxygen levels with increasing gestational age in fetuses
with CHD, which is considered to be significantly below
typical at as early as 32 weeks gestation; impaired perfu-
sion also correlates with smaller brain size.60 Sun et al61
demonstrated that a 15% reduction in cerebral oxygen
delivery and 32% reduction in cerebral VO2 in CHD
fetuses were associated with a 13% reduction in fetal
brain volume, supporting a direct link between reduced
cerebral oxygenation and impaired brain growth.
Disruption in fetal brain perfusion is thought to
contribute to greater susceptibility to brain injury in the
term neonate with CHD.62 63 Most commonly reported
is WM injury (WMI; up to 50% preoperatively and ≥62%
postoperatively64 65), which is comparable to the incidence
of periventricular leukomalacia identified in preterm
infants.63 66 The extent to which WMI worsens with surgery
is unclear, but WMI detected both preoperatively and
postoperatively is associated with NDD reported at various
points throughout childhood,65 67 and adolescents with
TGA have demonstrated reduced WM microstructure and
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Congenital heart disease
globally altered WM topology which correlates with worse
neurocognitive functioning across multiple domains.68 69
These data support the notion that the CHD brain may be
smaller and relatively underdeveloped at birth. Catch-up
growth may be possible as has been demonstrated in
infants after the arterial switch procedure for simple trans-
position,70 noting that persisting WM abnormalities have
been reported in other studies.69 71
Several strategies have been suggested to improve fetal
brain development. Maternal oxygen therapy is consid-
ered as one possible method and has also been used to
promote growth of small left ventricle morphology by
increasing fetal pulmonary blood flow and left atrial
return.59 While this is considered a diagnostic and ther-
apeutic tool in fetuses with some CHD subtypes, this
strategy is rarely used in clinical practice.59 72 Transla-
tional research in lambs offering an ‘artificial womb’,
where ‘normal’ substrate and oxygenation are provided
by extracorporeal support have allowed testing of the
concept that correction of flow and oxygenation abnor-
malities can improve brain development73 74 and may
eventually form the basis of care for preterm infants
with CHD, delaying the time to definitive cardiac care
to allow for brain maturation. The fetal brain in CHD
may also be affected by more generalised placental insuf-
ficiency, which may be difficult to detect using conven-
tional means.57 75 The placenta and fetal heart develop
in parallel and share a common vulnerability to genetic
defects, suggesting that deleterious defects in these
gene pathways could likely result in abnormality in the
morphology of both, with placental insufficiency further
exacerbating the development of key organs, including
both the heart and the brain.57 76–78 Chronic placental
insufficiency has been recognised to have serious conse-
quences on fetal growth, known as intrauterine growth
restriction (IUGR), which has been associated with
CHD79; however, the exact cause and effect mechanisms
of this relationship are unknown. Other factors, such as
folate metabolism, are also believed to compound the
issue of placental insufficiency and IUGR by impacting
the underlying mechanisms of cell growth and func-
tion.80 To add further ‘insult to injury’, fetal development
and growth may also be impacted by external environ-
mental factors, including developmental neurotoxicity
due to toxins, such as alcohol, drugs and environmental
organophosphates. Certain environmental chemicals
have been associated with cognitive and neurological
impairment, including diminished intellectual func-
tioning, learning disabilities, attention problems, hyper-
activity, attention-deficit/hyperactivity disorder (ADHD)
and autism, and are thought to disrupt the development
of the vulnerable fetal brain.81–83
Some very fundamental and readily accessible strategies
are known to optimise neurodevelopmental outcome.
Fetal cardiac diagnosis is important as it allows for coordi-
nation of perinatal care, and also provides an opportunity
for detailed antenatal counselling. Antenatal diagnosis
is associated with reduced risk of preoperative brain
injury, improved postnatal brain development and better
neurodevelopmental outcomes in infants with complex
CHD.73 74 Fetal diagnosis also allows planning of delivery
with current guidelines suggesting delivery between 39
and 40 weeks gestation.84 Early-premature and late-pre-
mature birth in the CHD population have been associ-
ated with greater neurodevelopmental impairment85 and
fetuses with CHD should not be delivered early for the
convenience of the treating teams.
Information provided during antenatal counsel-
ling should include discussion of neurodevelopmental
outcomes. For those requiring neonatal cardiac surgery,
our own practice is to outline the broad scope of neuro-
developmental impairment at a risk of 2–3 times the rate
observed in the population without CHD. We describe
a spectrum from motor delay to behavioural issues
(including autism and ADHD) and major disability.
Anticipated surgical complexity, as well as the risk of
acquired brain injury (eg, stroke), must also be consid-
ered.2 Thresholds for decisions regarding continuation
of pregnancy are individual and not necessarily based
on estimates of lesion severity or anticipated neuro-
developmental outcomes. Multidisciplinary support
and input into these decisions are required. Genomic
sequencing and fetal brain MRI have an emerging but, as
yet, unproven role in understanding mechanisms86 and
quantification of risk.61
There is considerable but, as yet, unwarranted opti-
mism that genetic variants explain much of the NDD
in CHD, possibly as a result of difficulty in identifying
other causes of the CHD+NDD phenotype. Nevertheless,
there is a growing body of evidence that genetic factors
are indeed contributing to altered fetal brain develop-
ment and often represent the key determinants of NDD
outcomes in patients with CHD.45 87 88 Of course, there are
several genetic syndromes in which both CHD and NDD
co-occur, such as Williams syndrome, Alagille syndrome,
Noonan syndrome or 22q11 deletion syndrome, among
others89; however, our principal interest remains the
much larger number of non-syndromic patients with a
largely sporadic mode of presentation.
Homsy et al studied 1213 CHD parent–offspring trios
and identified supporting evidence for the long-hy-
pothesised shared genetic origin of at least a propor-
tion of CHD with NDD.88 They found that genes highly
expressed in the heart were enriched for high expres-
sion in the developing brain and overlapped with
genes found to contain damaging de novo variants in
a number of NDD cohorts, comprising individuals with
isolated NDD. Jin et al90 extended this analysis to 2871
CHD probands, including 2645 parent–offspring trios,
and confirmed these findings and additionally identi-
fied an overlap between CHD and autism genes with
the suggestion that chromatin modifier genes have a
specific role. As CHD/NDD gene lists start to emerge,
genotype–phenotype correlations require large and
well-characterised patient cohorts necessitating multi-
centre collaboration.
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While these studies mark a significant milestone in our
understanding of the genetic underpinning of NDD in
CHD, the approach is not ready for clinical application.
The ability to predict the development of NDD at an early
time point on the basis of DNA sequencing is an attractive
prospect. Early work in this field using known CHD and
NDD genes86 demonstrates substantial genetic variation in
CHD+NDD patients in both the ‘heart’ and ‘brain’ genes.
More than 1000 genes may be implicated in CHD+NDD
patients, with the likelihood that computational assess-
ment of variant burden may be more useful than anal-
ysis of specific variants and genes. This is in contrast to
the identification of causal variants in CHD (without
NDD), which can nowadays be effectively achieved using
massively parallel sequencing approaches.91–93 A unifying
developmental model for NDD in CHD is yet to be estab-
lished. Whole-genome sequencing approaches in larger
well-defined patient cohorts, including prenatal and post-
natal clinical data and outcomes, will be required.
While contemporary research is predominantly focused
on perinatal and genetic contributions to altered brain
maturation and neurodevelopment, we should again
consider whether we are underestimating the role of
perioperative factors and chronic circulatory abnormal-
ities, including hypoxia. The key study by Gaynor et al in
200753 introduced the now common understanding that
innate patient factors have a greater part to play in deter-
mining neurodevelopmental outcomes compared with
the perioperative factors previously understood. This
study was based on the neurodevelopmental outcomes
of 188 neonates and infants who underwent cardiac
surgery utilising cardiopulmonary bypass. Perioperative
risk factors still have important associations with reduced
neurodevelopmental ability.2 94 Acquired perioperative
brain injury remains common in CHD, and is correlated
with NDD,2 64 and postoperative factors are believed to
still have a significant role in outcomes.95
EFFECTIVENESS OF NEW ASSESSMENTS AND INTERVENTION
The multitude of complex and often non-modifiable
mechanisms contributing to CHD+NDD make it hard
to determine optimal methods of intervention. The
extent to which we can minimise or even prevent adverse
outcomes is uncertain. Optimal management for those
at-risk should include a multidisciplinary approach
with early identification, vigorous intervention and
routine assessments at various time points throughout
life,22 96 97 and many hospital-based Cardiac Neurodevel-
opment Programs now exist to provide this service.98 99
However, research focusing on the efficacy of neurode-
velopmental intervention and treatment strategies in the
CHD population is scarce.
Advances in the early detection and treatment of cere-
bral palsy, unrelated to CHD, are likely to be relevant
to CHD patients with milder forms of NDD. Evaluation
of newer assessments, such as the General Movements
(GMs) assessment, is occurring and has shown that this
test is highly sensitive and specific to detect cerebral
palsy in cardiac infants at 3 months of age and should
be incorporated into routine standardised follow-up for
these infants; however, further research is needed into
the precise prediction of long-term outcomes using this
test.100 Combinations of the GMs and the HINE together
with standard assessments, such as MRI and BSITD, can
provide accurate and early diagnosis of infants at high
risk of cerebral palsy as early as 3 months of age, and can,
thus, provide strong impetus for linkage into early inter-
vention programmes to take advantage of the stage of
neuroplasticity.21 100 101
The Congenital Heart disease Intervention Program102
is one of the limited intervention trials in CHD which
examined the influence of family, particularly maternal,
factors on infant neurodevelopment. Parents assigned
to the intervention received tailored psychoeducation,
narrative therapy, problem-solving techniques and
parenting skills training, delivered in six sessions (each of
1–2 hours duration) by a clinical psychologist and paedi-
atric cardiac nurse specialist.
The intervention was initiated when infants were 3 months
of age and at 6-month follow-up, infants in the intervention
group had significantly higher mental development scores
compared with infants in the control group, as well as
higher rates of breastfeeding, lower maternal worry scores
and greater positive appraisals. Psychomotor scores did not
differ between intervention and control infants at 6-month
follow-up, with mean scores for both groups indicative of
psychomotor delay. While the results of this study provide
preliminary evidence that early parental psychological
intervention may bolster mental developmental outcomes
for infants with CHD, evidence of the longer-term efficacy
of this intervention strategy is much-needed, and integrated
mental health interventions tailored to support neurobio-
logical health in children with CHD are currently being
trialled.103 Psychological and socioeconomic factors and
a nurturing family environment are no doubt important
for maximising neurodevelopmental potential; however,
adequately powered randomised controlled trials which
provide data on the long-term effects of structured psycho-
logical interventions are needed to determine efficacy in
reducing the neurodevelopmental burden associated with
CHD.
Calderon and Bellinger104 have described avenues for
intervention and treatment of NDD found to be successful
in other cohorts, such as the use of psychostimulant
medications commonly used in the treatment of atten-
tion-deficit disorder to improve working memory and
attention performance, intensive computerised training,
such as the use of the widely successful Cogmed training
programme,105 as well as other non-pharmacological tech-
niques, such as specialised assistance and support within
the school classroom. While it is theorised that these tech-
niques could improve neurodevelopmental functioning in
affected individuals, controlled trials implementing these
strategies in a CHD cohort are lacking, and thus their
viability is unclear.
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Verrall CE, etal. Open Heart 2019;6:e000998. doi:10.1136/openhrt-2018-000998
Congenital heart disease
If, as yet undetermined, genetic and epigenetic influ-
ences are considered key to the development of NDD, is it
reasonable to expect that we can actually modify outcomes?
Early evidence would suggest that despite potential genetic
causes, early and intensive intervention can improve
outcomes in those affected. There is a dynamic interplay
between genes and environment that is understood to form
the basis of typical neurobehavioural maturation, and it is
believed that these principles can be applied to neurodevel-
opmental disorders, even in the context of a strong genetic
component.38 Synaptic development and neural plasticity
in the newborn period are highly sensitive to modification
and continue to be influenced by environment-dependent
factors throughout the first months and years of life. After
birth, the brain increases over 100% in volume in the first
year and another 15% by the end of the second year of
life39 and these key developmental windows are considered
crucial in laying the foundations for neurodevelopmental
outcomes.40
Cost-effectiveness of intervention is another key concern.
Neurodevelopmental interventions are complex, may be
life-long, and require a multidisciplinary approach with
input from an extensive list of primary health services not
necessarily directly linked to CHD, such as psychologists,
developmental paediatricians, behavioural neurologists,
physiotherapists and occupational therapists, as well as
non-health resources relating to education performance,
employability and social participation.106 It is estimated
that interventions to improve neurodevelopment have
a high economic return if implemented during preg-
nancy and early childhood107; however tangible evidence
to support this is limited due to the infancy of evidence-
based intervention trials in CHD. As our understanding
of NDD outcomes in response to new intervention strate-
gies progresses, the cost-benefit of these services should,
in turn, be estimated in order to guide the direction of
future clinical programmes and care.
CONCLUSIONS
CHD+NDD remains a cause for concern across the lifespan
of the individual with CHD and the adverse outcomes
observed in childhood extend into adolescence and adult-
hood, potentially increasing the risk of early neurocogni-
tive decline. The aetiology is complex, multifactorial and
often speculative, involving many currently non-modifi-
able factors. Contemporary research efforts are focused
on improving intervention strategies to minimise burden
and maximise healthy outcomes; however, these strategies
are still in their infancy. Controlled intervention trials and
extended periods of follow-up are needed to assess the effi-
cacy and cost-effectiveness of these techniques and to opti-
mise patient care, resource planning and service delivery
for people of all ages with CHD.
Author afliations
1Heart Centre for Children, The Children’s Hospital at Westmead, Sydney, New
South Wales, Australia
2Discipline of Child and Adolescent Health, Sydney Medical School, Faculty of
Health and Medicine, University of Sydney, Sydney, NSW, Australia
3Grace Centre for Newborn Care, The Children’s Hospital at Westmead, Sydney,
New South Wales, Australia
4Discipline of Paediatrics, School of Women’s and Children’s Health, UNSW
Medicine, University of New South Wales, Sydney, NSW, Australia
5Faculty of Health and Medical Sciences, University of Adelaide School of Medicine,
Adelaide, South Australia, Australia
6Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research
Institute, Darlinghurst, New South Wales, Australia
7Faculties of Medicine and Science, University of New South Wales, Sydney, NSW,
Australia
8Cardiology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
9Discipline of Medicine, Sydney Medical School, Faculty of Health and Medicine,
University of Sydney, Sydney, NSW, Australia
Contributors All the authors have contributed signicantly to the content of the
article.
Funding NK is the recipient of a National Heart Foundation of Australia Future
Leader Fellowship (101229), and a 2018–2019 Harkness Fellowship in Health Care
Policy and Practice from the Commonwealth Fund.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement There are no data in this work.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non-commercial. See:http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.
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