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© Translational Pediatrics. All rights reserved. Transl Pediatr 2023;12(4):768-786 | https://dx.doi.org/10.21037/tp-22-687
Review Article on Pediatric Heart
Biological and structural phenotypes associated with
neurodevelopmental outcomes in congenital heart disease
Charlotte E. Verrall1,2^, Shrujna Patel2^, Leksi Travitz3, Jason Tchieu3^, Russel C. Dale2,
Nadine A. Kasparian4,5^, David S. Winlaw6^, Gillian M. Blue1,2^
1Heart Centre for Children, The Children’s Hospital at Westmead, Sydney, Australia; 2Sydney Medical School, Faculty of Medicine and Health,
University of Sydney, Sydney, Australia; 3Division of Developmental Biology and the Center for Stem Cell and Organoid Medicine, Cincinnati
Children’s Hospital Medical Center, Cincinnati, OH, USA; 4Center for Heart Disease and Mental Health, Heart Institute and the Division of
Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 5Department of Pediatrics,
University of Cincinnati College of Medicine, OH, USA; 6Cardiothoracic Surgery, The Heart Institute, Cincinnati Children’s Hospital Medical
Center, Cincinnati, OH, USA
Contributions: (I) Conception and design: DS Winlaw, GM Blue, CE Verrall; (II) Administrative support: CE Verrall, GM Blue; (III) Provision of
study materials or patients: None; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: None; (VI) Manuscript
writing: All authors; (VII) Final approval of manuscript: All authors.
Correspondence to: Dr. Gillian M. Blue, PhD. Heart Centre for Children, The Children’s Hospital at Westmead, Hawkesbury Road, Westmead, Sydney,
NSW 2145, Australia; Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Parramatta Road, Camperdown, Sydney, NSW
2050, Australia. Email: gillian.blue@health.nsw.gov.au.
Abstract: Neurodevelopmental disability (NDD) is recognised as one of the most common comorbidities
in children with congenital heart disease (CHD) and is associated with altered brain structure and growth
throughout the life course. Causes and contributors underpinning the CHD and NDD paradigm are not
fully understood, and likely include innate patient factors, such as genetic and epigenetic factors, prenatal
haemodynamic consequences as a result of the heart defect, and factors affecting the fetal-placental-maternal
environment, such as placental pathology, maternal diet, psychological stress and autoimmune disease.
Additional postnatal factors, including the type and complexity of disease and other clinical factors such as
prematurity, peri-operative factors and socioeconomic factors are also expected to play a role in determining
the final presentation of the NDD. Despite significant advances in knowledge and strategies to optimise
outcomes, the extent to which adverse neurodevelopment can be modied remains unknown. Understanding
biological and structural phenotypes associated with NDD in CHD are vital for understanding disease
mechanisms, which in turn will advance the development of effective intervention strategies for those
at risk. This review article summarises our current knowledge surrounding biological, structural, and
genetic contributors to NDD in CHD and describes avenues for future research; highlighting the need for
translational studies that bridge the gap between basic science and clinical practice.
Keywords: Neurodevelopment; congenital heart disease (CHD); genetics; fetal; brain
Submitted Dec 24, 2022. Accepted for publication Apr 23, 2023. Published online Apr 27, 2023.
doi: 10.21037/tp-22-687
View this article at: https://dx.doi.org/10.21037/tp-22-687
786
^ ORCID: Charlotte E. Verrall, 0000-0003-4445-2124; Shrujna Patel, 0000-0003-4928-692X; Jason Tchieu, 0000-0002-9793-9836; Nadine
A. Kasparian, 0000-0001-8075-6817; David S. Winlaw, 0000-0001-8005-3361; Gillian M. Blue, 0000-0002-1480-9535.
Translational Pediatrics, Vol 12, No 4 April 2023 769
© Translational Pediatrics. All rights reserved. Transl Pediatr 2023;12(4):768-786 | https://dx.doi.org/10.21037/tp-22-687
Introduction
Congenital heart disease (CHD) is the most common birth
defect, affecting 0.6–1.3% of babies born each year (1). It is
associated with signicant mortality and morbidity (2) with
many individuals with CHD requiring lifelong medical care
and treatment (3). The cause of most CHD is unknown
and attributed to a combination of genetic, epigenetic and
environmental factors (4). Following advances in treatment
and care, >90% of affected children now survive to
adulthood (5), resulting in greater appreciation and interest
in longer-term health outcomes, such as neurodevelopment
and quality of life (6).
Overview of neurodevelopmental disability in
CHD and relevance at all ages
Neurodevelopmental delay and/or disability (NDD) is now
recognised as a lifespan issue for many children born with
CHD (7). Those with more complex forms of CHD, such
as those with single ventricles pathologies or transposition
of the great arteries who typically experience more severe
disease requiring neonatal bypass operations and on-going
monitoring and care, are at a greater risk of worse prognosis
(8,9). However, risk factors contributing to more severe or
persisting disability are not fully understood and appear
multifactorial and synergistic (10). A spectrum of outcomes
is observed, and many individuals with CHD demonstrate
no impairment and their level of functioning may exceed
population norms. However, as many as 50% demonstrate
mild to moderate NDD and later cognitive impairment,
and a small number demonstrate global cognitive or
intellectual disability (7,8,11-15). These challenges have
important implications throughout the life course, including
on academic achievement, employment opportunities,
psychological and social functioning, and overall quality
of life (16-19). Established guidelines document the need
for routine neurodevelopmental follow-up throughout
childhood (7), however, this has not yet translated to
standard clinical care in most paediatric centres. Importantly,
neuropsychological services for children and adults with
CHD are under-resourced in comparison to other clinical
paediatric populations, such as those born very preterm,
despite similar risk factors and adverse outcomes (11).
Understanding biological and structural phenotypes
associated with NDD in CHD are necessary to advance
clinical care and the development of effective intervention
strategies for those at risk. Interventions targeting the
earliest stages of development will be vital for optimising
developmental outcomes. An overview of the risk factors
contributing to NDD in CHD is outlined in Figure 1.
Early manifestations of NDD typically include poor
feeding, speech and language delay, challenges with gross
and fine motor movement, and early cognitive concerns
(20-22). Early speech and language delays more commonly
resolve over time (23), whereas motor impairments are
a persisting concern throughout childhood (24,25), and
the extent of cognitive challenges typically worsen over
time (14,21). In infants with more complex CHD, such as
those undergoing the single ventricle pathway, the early
developmental years are impacted by the need for multiple
cardiac surgeries and prolonged exposure to the restrictive
and articial hospital environment. Length of inpatient stay
is usually a surrogate marker of more complex diagnoses
and post-operative complications and is a strong predictor
of long-term neurodevelopmental outcomes (7).
At school age, intelligence quotients are generally
within population norms, although typically fall within
the low average range (26,27). In contrast, early NDD
typically manifests as specific cognitive challenges that
have important implications for academic performance
and achievement, often requiring additional school
provisions and support (19,28). Key challenges include
deficits in attention, processing speed, visuospatial skills,
memory, social cognition, and executive functioning—
that encompasses a range of higher order cognitive skills
including working memory, mental flexibility, problem-
solving, and inhibitory control (27,29-32). Many children
show challenges across multiple domains of functioning,
requiring greater intervention and support (21). Behavioural
and psychological disorders (e.g., anxiety, depression,
and poor behavioural or emotional regulation) are also
an important concern (33,34). The extent to which these
difficulties are associated with NDD has not yet been
established but are anticipated to be linked. In addition,
children with CHD are at an increased risk of developing
disorders of social functioning, including autism spectrum
disorder (35).
Higher-order executive skills continue to develop
throughout childhood in conjunction with the maturation
of key brain structures, notably the pre-frontal cortex (36),
and the full extent of these challenges may not be observed
until adolescence or early adulthood. Indeed, studies have
shown that executive functioning deficits are among the
most prevalent and severe impairments observed in older
children and young adults with CHD (8,28,37), which
Verrall et al. Phenotypes associated with NDD in CHD
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become an increasingly significant challenge alongside
greater cognitive demands and the need for increased
functional independence that occurs with maturation into
adulthood. Cognitive dysfunction persists throughout
adulthood (8,38-40), although longer-term outcomes have
been less extensively studied. Older adults with a Fontan
circulation (up to 50 years old) have been found to have
worse neurocognitive dysfunction compared to Fontan
adolescents after controlling for age (8), that may suggest
a possible worsening of cognitive challenges throughout
adulthood in those with highly complex forms of CHD.
Although the extent to which these outcomes may reect an
era effect relating to previous surgical strategies and medical
care are currently undetermined. Concerningly, adults with
all forms of CHD are at a significantly increased risk of
dementia, including early onset dementia (41). As the adult
CHD population continues to grow, so does the need for a
better understanding of the accumulating risk factors that
compound early NDD and contribute to worse long-term
cognitive outcomes.
Brain structure and function: insights from
neuroimaging
In individuals with CHD, NDD is paralleled by
abnormalities in brain structure and function across the
lifespan (42-44). Neuroimaging studies of the fetal CHD
brain have demonstrated that abnormal brain development
begins in utero. Altered cortical development and reduced
brain size are observed as early as the second trimester of
gestation in fetuses with complex cardiac lesions (45-47)
and precede anomalous growth patterns and reduced brain
volumes, that become progressively more pronounced
throughout the third trimester (45,48-51). Fetal brain
volume has been shown to predict neurodevelopmental
outcomes at 2 years of age in children with CHD (52),
suggesting prenatal brain parameters may have prognostic
value in identifying infants at risk of early NDD; however,
further studies are needed to replicate these findings,
and associations with longer-term neurodevelopmental
outcomes are yet to be determined.
Post-natal brain development continues to follow
an altered growth trajectory, with progressive growth
of both regional and global brain volumes occurring at
a slower rate compared to typically developing infants
(53,54). Consistently, widespread reductions in global
and regional brain volumes have been demonstrated pre-
operatively in various heterogenous CHD cohorts (54-59).
In infants with transposition of the great arteries, the rate
of brain growth has been found to significantly increase
after surgical correction and normalisation of the cardiac
circulation and there may be some ‘catch-up’ growth by
3 years of age (60). In contrast, reduced brain growth and
smaller brain volumes persist in infants with hypoplastic left
heart syndrome post-operatively (60,61), suggesting that
continued haemodynamic instability may have an important
contributory role in pervasive post-natal brain development.
In infants requiring cardiac surgery, peri-natal brain
immaturity is associated with a greater risk of pre- and post-
operative brain injury (62-65), that occurs in as many as
40% and 26–44%, respectively (53,65-68). Predominant
lesions include patterns of white matter injury and stroke;
Genetic factors; genetic
predisposition (syndromic
or non-syndromic)
Placental pathology;
abnormal placental structure,
function, and microvasculature
Epigenetics and
environmental factors;
inflammation, cellular
and biological stress
responses
Altered cerebral
blood flow and
perfusion;
cerebral hypoxia
Maternal factors; psychological
dysfunction and stress,
autoimmune disease, poor diet
and obesity, exposure to pollutants
Delayed brain
maturation and
growth
Acquired brain
injury: white matter
injury, stroke, altered
connectivity
Sociodemographic factors;
home environment, parent-child
interactions, parental education,
household income
Clinical factors;
CHD type/complexity,
prenatal diagnosis,
prematurity, prolonged
altered haemodynamics
Peri-operative factors;
extracorporeal membrane
oxygenation, deep hypothermic
circulatory arrest, cardiopulmonary
bypass, peri-operative
complications, hospital length of
stay
Neurodevelopmental
delay/disability
Birth
Figure 1 Contributors to neurodevelopmental delay and disability in CHD. CHD, congenital heart disease.
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the prevalence and severity of which are typically worse
in infants with univentricular lesions (65,68). Recently,
Peyvandi and colleagues found that moderate to severe peri-
operative injury is associated with subsequent reduced brain
growth (68), demonstrating a complex interplay between
brain development and acquired injury and a possible “two-
hit phenomena” (69).
Associations between peri-operative brain injury
and early neurodevelopmental outcomes are variable
(65,66,68,70,71). The current understanding is that altered
brain maturation may be more closely linked to NDD
(52,55,72-74). Consistently, signicant associations between
smaller brain volumes and worse cognitive outcomes are
observed throughout childhood and adulthood in various
CHD cohorts (8,56,75-79). Alterations in white matter
microstructure, that may reflect aberrant white matter
maturation, have also shown significant associations with
cognitive dysfunction in older children and adults with
CHD (80-84), with some variation reported in recent
findings (85). In contrast, associations with structural
brain injury continue to be broadly inconsistent, despite
adolescents and adults demonstrating an alarming rate of
injury in some studies (8,42).
Current research has advanced into the field of
“connectomics” in an effort to better understand the
impact of CHD on structural brain connectivity, which
may provide clearer insight into direct structure-function
relationships. Emerging studies have demonstrated reduced
maturation in the whole brain connectome (i.e., neural
connections or networks) and specific brain networks in
infants with CHD that is associated with peri-operative
white matter injury burden (86-88); however, studies
investigating associations with NDD are limited. Ramirez
and colleagues have demonstrated that global and regional
structural connectivity in infants with CHD predicts early
motor development and language outcomes (89). Similarly,
Panigraphy and colleagues have found that network
topology mediates the differences observed in cognitive
functioning in adolescents with CHD compared to healthy
controls (90).
While major advances have been made in our
understanding of brain development in CHD, much remains
unknown and longitudinal brain magnetic resonance imaging
(MRI) studies evaluating the developmental trajectory and
timing of injury in the CHD brain from gestation onwards
are needed to fully elucidate the impact of perinatal
brain abnormalities on NDD and longer-term cognitive
dysfunction.
Weighing causes and contributors including
placental insufficiency
Distinguishing the causes and consequences of acute brain
injury, such as stroke, from altered neurodevelopment,
which appears to be pre-programmed, will have important
implications for the development of targeted NDD
interventions. This is made difcult given the considerable
overlap between these two entities, particularly in neonates
undergoing cardiac surgery, and notably in those on
the single ventricle pathway (68). The need for cardio-
pulmonary resuscitation (CPR) or extracorporeal membrane
oxygenation (ECMO) via the heart-lung machine, more
common in the neonatal cardiac surgery population, may be
associated with acute brain injury.
Early assumptions that NDD was due to perinatal
neurological compromise or perioperative brain injury
are not correct (10,91). The use of deep hypothermic
circulatory arrest, a common operative strategy in complex
heart operations during which the body is cooled to
temperatures ranging from 20–25 ℃ thereby ceasing blood
circulation and brain function, was also for a long time,
implicated as a cause or contributor to NDD. However, it
is likely that deep hypothermic circulatory arrest is just one
of many contributors with small effect sizes, including the
generation of cerebral microemboli or blood clots by the
heart-lung machine and the consequences of the systemic
inflammatory response that occurs during surgery. These
may contribute to acute brain injury, and may worsen
neurodevelopmental trajectory but are not thought of as
the primary causes of NDD and best estimates indicate that
peri-operative factors explain only 5–8% of the variability in
neurodevelopmental outcomes (91-93). Importantly, NDD
may occur despite an optimal clinical course of cardiac care,
where no complications are observed.
Instead, current thinking implicates impaired fetal brain
development (94), placental dysfunction (95,96) and genetic
factors (4,97), both fetal and maternal, as predominant
causes of NDD. Two important ‘environmental’ stressors
affect human fetuses in the context of CHD. The rst is a
form of placental insufciency; the placenta may be smaller
and structurally abnormal leading to relative substrate
deficiency, slower than normal fetal growth, smaller brain
volumes, preterm birth, and lower birthweight (96,98)
The second is the relative hypoxia encountered by the
fetal brain in circumstances where the normal highly
oxygenated blood cannot reach the brain because of aortic
atresia (99,100), a fundamental component in many single
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ventricle patients. In this context, blood with a lower-than-
normal oxygenation reaches the brain retrograde via the
ductus arteriosus and possibly at a lower pressure. These
factors may explain lactate accumulation within the brain
of CHD fetuses (101), and the relative brain immaturity
of neonates with CHD (102). Other environmental factors
including maternal obesity, stress, autoimmune disease are
also associated with NDD in offspring (103). As well as
being implicated in the cause of the CHD (4,97), genetic
variants are likely implicated in the adaptive responses to
these environmental stresses.
These environmental factors may contribute to the
abnormal brain development observed throughout
gestation and we lack an understanding of which factors
are important at which specific time-points. We also
do not know the extent to which amelioration of these
factors—including maternal oxygen therapy (104)—might
improve developmental trajectories in the child, or whether
any of these pathways might be amenable to post-natal
intervention.
Genetic contributions and unknowns
NDD in syndromic CHD
That genetics may underpin both heart and brain
development is evidenced in the many established
genetic syndromes incorporating both heart defects and
neurodevelopmental issues as part of the disease spectrum.
While the exact cause and/or genetic contribution of
the neurodevelopmental phenotype in most established
syndromes remains unknown, several candidate genes
have been identified in some established syndromes.
In syndromes associated with chromosomal alterations
and copy number variations, where multiple genes may
be implicated, significant headway has been made to
understand which genes contribute towards specific
phenotypic components, including neurodevelopment.
For example, in 22q11.2 deletion syndrome, which
encompasses 32 genes all of which are candidates for CHD
and NDD, genes contributing towards both heart and brain
development [TBX1 (100) and HIRA (105) among others]
or solely towards the neurodevelopmental/neurological
phenotype (COMT and PRODH (106)), have been
identied. Similarly, in Williams syndrome, which typically
involves 25–27 genes, the ELN gene is thought to primarily
contribute towards the characteristic cardiovascular
phenotype, supravalvular aortic stenosis, and the GTF2I
and GTF2IRD1 genes towards the neurodevelopmental
phenotype (107).
In syndromes caused by variations in single genes,
the mechanism by which these genes likely affect two or
more organ systems such as the heart and brain among
others, is due to their ability to regulate or interact with
multiple genes and/or gene pathways. Indeed, chromatin
modifying genes KMT2D, CHD7 and CDK13 which cause
Kabuki and CHARGE syndrome (108) and CDK13-related
disorder (109) respectively, modulate gene expression by
altering access to the DNA and thereby disrupting multiple
developmental processes, including in the heart and brain.
Similarly, transcriptional regulators, including FOXP1 (110),
ZEB2 (111) among others, have been implicated in both
CHD and NDD.
While NDD is the most common co-morbidity
associated with CHD, other extra-cardiac anomalies, such
as those affecting the urogenital system (112), are often
seen in conjunction with CHD and/or NDD, suggesting
that genetic risk may extend beyond heart and brain
development to other organ systems.
NDD in non-syndromic CHD
With the exact cause and/or genetic contribution of the
neurodevelopmental phenotype in many established
syndromes unknown, it is not surprising that understanding
the genetic contribution of NDD in non-syndromic CHD
poses a significant challenge, not helped by the fact that
these represent most presenting cases. Over the last decade;
however, advances in genomic technologies combined
with large cohorts and sophisticated statistical analyses,
have provided important clues to the genetic architecture
underlying this patient group. Specifically, these studies
identied a 2-fold enrichment in damaging de novo variants
in genes highly expressed in the heart in patients with
CHD and NDD and a 4.7-fold enrichment in patients with
CHD, NDD and other congenital anomalies, suggestive of
an additive effect in heart-expressing genes with increasing
non-cardiac phenotypic complexity (97). Further, 69 genes
harbouring damaging de novo variants, were shared between
CHD patients and cohorts comprising patients with
isolated NDD, providing additional support for shared
genetic aetiologies to heart and brain development. Not
surprisingly many of these genes are chromatin modifying
genes and transcriptional regulators, likely exerting wide-
reaching phenotypic effects. Importantly, CHD patients
with damaging de novo variants in these 69 genes, were
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at significantly increased risk of NDD, providing a basis
for future downstream applications of precision medicine
approaches.
More recently, a significant overlap of genetic burden
has been identified in patients with CHD and patients
with autism (113). Enrichments in de novo variants in
genes involved in the connectome, have also recently been
implicated in patients with CHD (114).
While these studies have provided important insight
into disease mechanisms of NDD in CHD, specifically in
terms of shared genetic aetiologies, the findings are not
readily applicable to the individual patient. Studies assessing
the clinical relevance of this information have identified
important genetic burden associated with ‘neurotransmitters’,
‘axon guidance’ and ‘RASopathy’ pathways in patients with
CHD and NDD; however, no clinically actionable cause for
the NDD could be identied (115).
The contribution of common variants in both heart
and brain development is becoming increasingly relevant
(116,117) and will likely inform the development of polygenic
risk scores used to identify those CHD patients most at risk
of NDD.
So, while significant headway has been made to unravel
the genetic component of NDD in CHD, specifically
the contribution of rare and damaging de novo genetic
variant burden, which is often in chromatin modifying and
connectome genes; additional factors such as common genetic
variants, morphology, epigenetics and the environment, are
increasingly highlighted as important contributors in the
nal phenotypic presentation.
Inherited and epigenetic associations in other
forms of NDD
Increasing evidence suggests that inammation, cellular stress,
and epigenetic factors at the gene-environment interface
play a key role in the pathogenesis of NDDs (118-120).
Neurodevelopment begins in-utero and continues to 21 years
of age, through a constant process of synaptic pruning and
re-wiring (121). Gestation is a particularly sensitive time, as
key brain networks are being established in the developing
fetus (122). The maternal immune activation hypothesis
posits that fetal exposure to inammation and dysregulated
immune milieu adversely affects neurodevelopment
(122,123). Many environmental factors, such as poor diet,
low exercise, sleep, infection, stress, and pollutants can cause
maternal immune activation and have all been associated
with increased risk of NDDs in offspring (103,124).
Environmental risk factors experienced by the mother
during pregnancy are hypothesized to be ‘biologically
embedded’ in the cellular and epigenetic architecture of the
offspring (125). These inherited vulnerabilities can then
be modulated by post-natal risk factors, such as neonatal
infections, childhood trauma, or other early life stress (126).
Environmental insults can influence the transcription
of susceptibility genes via key inflammatory and cellular
stress signalling pathways, including the Toll-like receptor
pathway (103), and the integrated stress response (127).
These signalling cascades may then modulate the expression
of NDDs through nely tuned epigenetic, gene regulation,
and post-transcriptional processes (128-130). Epigenetic
modications are chemical or physical changes to chromatin
which can either increase or repress gene transcription (130).
The four main epigenetic modifying factors are DNA
methylation, histone modifications, chromatin modelling,
and microRNA. Controlled, yet dynamic, epigenetic
patterns are crucial for brain development and are highly
sensitive to environmental changes (130).
Preclinical evidence indicates that maternal inammation
during pregnancy can induce long-lasting changes in
DNA methylation, histone modifications, and microRNA
expression in the offspring brain (131-133). Importantly,
animal models have shown that prenatal environmental
insults can lead to epigenetic alterations and associated
behavioural abnormalities in second—and third-generation
offspring, suggesting transferability of epigenetic
programming (134,135). Human studies have linked
inflammatory risk factors affecting pregnancy, including
depression, anxiety, and smoking, to epigenetic changes
in the placenta, offspring umbilical cord blood, peripheral
blood, and buccal cells (128,136). Furthermore, maternal
obesity, gestational diabetes, depression, and asthma,
have been associated with epigenetic changes in immune,
metabolic, and oxidative stress pathways in offspring
umbilical cord blood (137-140). These findings highlight
the transgenerational effects and widespread, long-term
consequences of disturbances in prenatal programming.
At the post-transcriptional stage, maternal immune
activation has been shown to disrupt mRNA translation,
ribosome biogenesis, and protein synthesis in rodent
brains (127,141,142). These processes are tightly regulated
and fundamental to brain development and neural
function. Activation of the integrated stress response
has been implicated as one mechanism through which
these disturbances occur (127); however, this field is very
much in its infancy. Therefore, by increasing attention
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to environmental effects and their epigenetic or cellular
consequences, there may be significant opportunities for
prevention (e.g., public health measures in pregnancy) or
individualised treatments for people with neurodevelopmental
disorders.
Parental psychological stress, anxiety, and
depression
Many complex CHD diagnoses, such as those with single
ventricles or transposition of the great arteries, now occur
prenatally and coincide with the critical in utero period
of neurodevelopment. Severe maternal stress and anxiety
surrounding fetal CHD diagnosis is well-established
(143-146). Until recently, however, we have had little
understanding of the consequences of these maternal
symptoms for brain development in CHD.
Threats to the health of the fetus have long been
recognized as an important risk factor for maternal
psychological disturbance in the perinatal period (147).
Parents’ experiences of CHD diagnosis are often associated
with enduring psychological distress (2,148,149). Up to
80% of parents report severe psychological distress at some
point in their child’s medical trajectory and as many as 50%
report anxiety or depressive symptoms indicative of a need
for clinical intervention (2,143). These rates far exceed
norms for perinatal anxiety and depression in the general
population (149); yet the severity and consequences of these
symptoms are often under-recognized and under-treated
by healthcare professionals. Without timely intervention,
parents with higher distress also report poorer physical
health (150), greater parenting burden (151), higher health
service use (152), more suicidal ideation (153), and poorer
quality of life for both themselves and their child with CHD
(154,155) compared with parents of sick children with lower
distress.
Decades of research demonstrate an association between
parent mental health and child neurodevelopment (156-158).
Studies of children with CHD and their caregivers suggest
that parent psychological distress is one of the strongest
predictors of child emotional, behavioural, and developmental
outcomes (154,159-161). For example, parent post-traumatic
stress, referring to specific psychological and physiological
symptoms (e.g., flashbacks, avoidance, hyperarousal)
following exposure to a traumatic event (e.g., witnessing
their child go into cardiac arrest), is associated with lower
psychosocial functioning (160) and quality of life (155) for
children and adolescents with CHD. While the mechanisms
underlying these associations are not fully understood,
family environment and parent-child interactions likely
play an important role (148,162). There is also evidence
that high and persistent maternal psychological stress and
anxiety during pregnancy can alter fetal brain development
in both healthy fetuses and fetuses with CHD (147).
Animal studies have shown that stress-elicited perturbations
in maternal prenatal biology (e.g., hypothalamic-pituitary-
adrenal axis function) affect offspring development, including
stress reactivity (163). Studies of psychological stress in
pregnant women largely mirror these ndings, showing links
to long-term cognitive, behavioral, and emotional dysfunction
in children across development (164-168). High maternal
stress during the middle-second and third trimesters - a time
when the fetal brain is highly susceptible to modification
by environmental factors and when CHD diagnosis is
also most common—may be associated with the greatest
neurodevelopmental impact (169). These effects persist after
controlling for family socioeconomic status and maternal
postnatal mental health, indicating a window of opportunity
during fetal development when we may be able to intervene
to prevent or minimize adverse child neurodevelopmental
outcomes (170).
Maternal prenatal stress is linked to altered fetal brain
development
Maternal prenatal stress, anxiety or depression has
been linked with cortical thinning (171), altered brain
microstructure (172,173), altered amygdala (174) and
hippocampal (175) growth, and alterations in functional
neural networks (i.e., the connectome) (176-178) in
offspring with (179) and without CHD. Altered placental
function (180,181), including decreased perfusion (182)
and placental expression of neurotropic precursors, such as
11-beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2),
are potential mechanisms (183). Decreased 11β-HSD2
expression may increase fetal cortisol exposure (184,185),
affecting gene expression in fetal brain cells (186), such that
small changes to early developmental trajectories may have
life-altering consequences for neurodevelopment (55) and
mental health outcomes (174,181,187-189). These ndings
underscore the importance of targeted therapies aimed at
reducing prenatal stress to optimize both maternal and fetal
wellbeing.
If maternal distress elicited by prenatal cardiac diagnosis
negatively impacts fetal brain development, we are obliged
to understand these ‘off-target’ effects and initiate prenatal
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neuroprotective therapies to improve long-term outcomes.
Expectant mothers are especially motivated for self-care (190),
and studies in other populations show prenatal interventions,
including interpersonal psychotherapy (191-193), effectively
prevent or reduce maternal anxiety and depression
(191,192,194-197). In CHD, one postnatally-delivered
psychological intervention targeting mothers demonstrated
efficacy in improving infant mental development at age
6 months (198), but this benefit was not sustained (159).
Neurocognitive interventions delivered later in life, for
children or adolescents with CHD, have had only limited
success (199-201).
‘Brain in a dish’ and insights from related and unrelated
neurological disease
The ability to deconstruct the biological and molecular
complexities of human neurodevelopmental disease and
translate findings into the clinic is only made possible
through the multidisciplinary approach between basic
science researchers and clinicians. While animal models
have been instrumental in advancing our understanding of
the molecular mechanisms of several genetic or extrinsic
factors, extrapolating these findings to human disease are
largely ineffective (202-204). This underscores a critical
need for models that can leverage the disparities between
the human and non-human brain with specific regard to
early developmental processes that can broadly impact
NDD. Human pluripotent stem cells (hPSCs), including
both embryonic- and patient-derived induced pluripotent
stem cells, have been a widely utilized model to satisfy the
necessity for analysing human cells and methods to direct
hPSCs towards specic cell fates in-vitro has demonstrated
to be an excellent tool for studying human development
programs and disease etiology (205-209).
Several strategies for differentiation of hPSCs into
specific neuronal subtypes include transcriptional
programming, small molecule and growth factor directed
differentiation in both monolayer, and three-dimensional
mini-brain organoids. While all methods will generate the
neuronal cell types of interest, factors related to the speed
and efficiency of cell generation, developmental accuracy,
and reproducibility need to be considered for downstream
applications. Advantages of transcriptional programming
include the rapid differentiation (~5–10 days) from hPSCs
resulting in a near homogenous population of cells that
represent the final product for analysis such as excitatory
neurons and astrocytes (209). However, questions regarding
how development of the neuron or astrocyte differentiate are
limited as well as the study of specic subtypes of neurons
or astrocytes may be limited due to a largely generic cell
identity. The directed differentiation of hPSCs recapitulates
aspects of brain development such as corticogenesis and
spinal cord development which can illuminate the process
of differentiation which provides an additional layer of
analysis for neurodevelopmental disorders. Recently,
hPSCs have been differentiated as three-dimensional neural
spheroids or cerebral organoids to highlight the remarkable
self-organizing properties of cortical development (210,211).
Importantly, cerebral organoids are similar to traditional
monolayer differentiation where one can analyze cortical
differentiation; however, they can also recreate the cortical
architecture of the human brain, providing additional
insight into human development, albeit with increased
cellular heterogeneity and variability (205).
Brain models derived from hPSCs have been
extensively used for various disease modelling, including
neurodevelopmental disorders including autism and
schizophrenia (212) assessing early stages of neurogenesis
(213-216). In the CHD field, this approach has been used
to define molecular mechanisms of functional alterations
evident in two-dimensional (2D) cultures and organoids
derived from patients with 22q11.2 deletion syndrome (217).
This deletion is associated with cardiac outflow tract
malformations. Transcriptional profiling over 100 days
demonstrated predictable differentiation and alterations
in neuronal excitability genes, emulating cortical brain
regions. These changes were evident in both 2D and
organoid cultures and correction of haploinsufficient
gene dosage was able to correct the disease phenotype.
It is reassuring that a disease phenotype was evident and
correctable in patient iPSC cells, highlighting the value
of this approach in assessing mechanisms of disease. The
impact of a chromosomal deletion may exceed the impact
of one or several single nucleotide variants expected in
NDD, and the cellular phenotype may also be more subtle.
Nevertheless, expression profiling, functional testing and
correlation of cell phenotype with patient phenotype is
likely to discriminate and allow prioritization of individual
genes and gene pathways that can be related back to the
genomic sequence of the patients involved to corroborate
individual variants and burden testing in gene set pathways.
Using a hPSC model to study NDD is advantageous as
it accounts for the complexity of human brain development
and eliminates confounding differences between human and
rodent brain development (218). As a model to study NDD,
Verrall et al. Phenotypes associated with NDD in CHD
776
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the use of organoids permits the characterization of fetal
brain development in-vitro using patient derived hPSC in an
environment that is similar to what would be encountered
in-vivo. With advancement of existing technologies,
patient derived hPSC can be corrected using CRISPR-
Cas9 system, allowing for reversion of disease-causing gene
mutations (219). However, manipulating the progenitor
populations may prove to be a more effective strategy to
obtain clinical relevance. As autologous transplantation
becomes more widely studied, novel therapies based on
replacement of genetically corrected cell populations may
be utilized to treat genetic brain disease (220).
Conclusions
Clinical applications and future directions
While research into improving current diagnostic, prognostic
and treatment options for NDD in CHD is on-going, there
are a number of practical ways in which neurodevelopmental
outcomes can be maximised for the CHD patient (69).
The importance of prenatal diagnosis of CHD in
reducing the risk of NDD through optimisation of
perinatal care has been demonstrated (221) and presents
an important modifiable factor in improving long-term
neurodevelopmental outcomes for CHD patients (222).
Individualised inpatient developmental care implemented
in the intensive care unit have been associated with better
neurodevelopmental outcomes, family functioning,
and greater school attendance (223). The inclusion of
parent-focused psychoeducation in such programs have
demonstrated a positive impact on psychological, emotional
and social development in the child with CHD (223) and
extends to improved maternal psychological functioning
and coping (198).
Similarly, genetic testing may identify patients at high
risk of NDD, and enable early interventions aimed at
optimising NDD outcomes for patients—which may be
particularly important in centres where neurodevelopmental
follow-up for infants with CHD is not part of standardised
care. The distinction between syndromic and non-syndromic
forms of CHD can be subtle and may be viewed as a
continuum or spectrum of disease. The importance of a
genetic assessment to identify subtle extracardiac features and
possible genetic contributors to guide clinical management
should be considered by physicians involved in the care of
CHD patients. The European Society of Cardiology and
American Heart Associations have released recommendations
for genetic testing in patients with CHD (224,225). Notably,
they recommend that patients with CHD and extracardiac
anomalies, including significant neurodevelopmental
abnormalities, should have chromosomal microarray
testing, followed by trio exome or genome sequencing due
to the reported high diagnostic yield of 25–40% in this
patient group (226,227).
Further, they recommend that a prenatal diagnosis
of CHD, should be accompanied by fetal chromosomal
microarray testing and trio fetal exome and genome
sequencing should be considered in any patients with
complex CHD and/or extracardiac anomalies (224,225)
Early diagnosis of a genetic syndrome provides important
information in terms of managing associated NDD which is
present in up to 75% of children with a diagnosed genetic
syndrome (228).
It is important to note; however, that the absence
of a genetic diagnosis or an uninformative genetic test
result does not minimise the risk of NDD or preclude its
development; and regular neurodevelopmental follow-up
throughout childhood should be part of best care practice
for all patients with CHD (7) Not all children will develop
NDD; however, without regular neurodevelopmental
assessments, those with issues, particularly those with minor
issues, will be overlooked and opportunities for intervention
and/or additional support, missed (229).
Similarly, there is growing support for increased
monitoring for brain injury pre- and post-cardiac surgery
that may serve as a prognostic indicator for new or worsening
NDD (68). A high proportion of peri-operative brain injury is
‘silent’, evidenced by the disparity between the rate of brain
injury identified in clinical practice (230), whereby brain
imaging typically occurs in response to a clinical event,
compared to studies that have included neuroimaging in an
entire cohort of CHD patients (53,65-68). Routine pre- and
post-operative neuroimaging may be warranted in infants
with severe CHD (231). However, is generally limited by
available resources and typically includes head ultrasound—
that may miss up to 80% of lesions detected by MRI,
particularly white matter injury (232). Better understanding
of the sensitive interplay between brain injury and NDD
trajectories in CHD, may inform future clinical practice in
this regard.
Additional factors, including peri-operative course and
socio-economic status may be stronger predictors of long-
term NDD compared to conventional brain MRI (233) and
these data should also be considered when determining a
patient’s risk prole.
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Longer-term neurodevelopmental and cognitive
follow-up extending beyond the early childhood years
are recommended (7); however poor accessibility to
neuropsychological services for older children and adults with
CHD remains an important issue. Interventions to minimise
new and accumulating risk factors occurring throughout
the CHD life course are required to mitigate the persisting
impact of NDD beyond the early childhood years.
In summary, current understanding and treatment
options for NDD in CHD are still in their infancy and
the coming years will likely see significant advances in the
field. Clinical trials, prospective clinical studies using novel
and sophisticated imaging technologies, as well as large
genomic analyses and functional experiments will provide
important insight into disease mechanisms, development,
and progression as well as possible interventions and
treatment. Indeed, examples of how genetic information can
inform personalised therapies already exist in syndromes
with neurodevelopmental phenotypes such as Kabuki
syndrome (234). Simple dietary modifications, inducing
epigenetic changes, have been shown to significantly
improve cognitive function through more effective neuronal
development in these patients (235).
Further, networks such as the Cardiac Neurodevelopmental
Outcome Collaborative (cardiacneuro.org) are enabling large
multinational, multicentre collaborations to inform future
research efforts and provide important longitudinal data.
Clinically, the rapidly evolving field of fetal cardiac
interventions, may be an important avenue to optimise
neurodevelopmental outcomes, especially in fetuses with
single ventricle pathologies (236).
Finally, polygenic risk scores, may in time provide
important information to determine which CHD patients
are at increased risk of developing NDD. Using prenatal
genetic testing to determine individual polygenic risk
scores, would enable early and on-going interventions to
maximise neurodevelopmental outcomes in at risk patients.
Acknowledgments
Funding: This work was supported by the Office of the
Assistant Secretary of Defense for Health Affairs through
the Autism Research Program (Award No. W81XWH-21-
ARP-CDA to J Tchieu).
Footnote
Provenance and Peer Review: This article was commissioned
by the Guest Editors (Antonio F. Corno and Jorge D.
Salazar) for the column “Pediatric Heart” published in
Translational Pediatrics. The article has undergone external
peer review.
Conicts of Interest: All authors have completed the ICMJE
uniform disclosure form (available at https://tp.amegroups.
com/article/view/10.21037/tp-22-687/coif). The column
“Pediatric Heart” was commissioned by the editorial ofce
without any funding or sponsorship. JT was supported by
the Ofce of the Assistant Secretary of Defense for Health
Affairs through the Autism Research Program (Award No.
W81XWH-21-ARP-CDA). NAK receives funding from
the National Heart Foundation of Australia, Additional
Ventures and the National Health and Medical Research
Council of Australia (research grant only, payment made
to the institution). The authors have no other conicts of
interest to declare.
Ethical Statement: The authors are accountable for all
aspects of the work in ensuring that questions related
to the accuracy or integrity of any part of the work are
appropriately investigated and resolved.
Open Access Statement: This is an Open Access article
distributed in accordance with the Creative Commons
Attribution-NonCommercial-NoDerivs 4.0 International
License (CC BY-NC-ND 4.0), which permits the non-
commercial replication and distribution of the article with
the strict proviso that no changes or edits are made and the
original work is properly cited (including links to both the
formal publication through the relevant DOI and the license).
See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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Cite this article as: Verrall CE, Patel S, Travitz L, Tchieu J,
Dale RC, Kasparian NA, Winlaw DS, Blue GM. Biological
and structural phenotypes associated with neurodevelopmental
outcomes in congenital heart disease. Transl Pediatr
2023;12(4):768-786. doi: 10.21037/tp-22-687
