NeuroImage xxx (2018) 1–7

Contents lists available at ScienceDirect

NeuroImage
journal homepage: www.elsevier.com/locate/neuroimage

The neonatal brain in critical congenital heart disease: Insights and

future directions
Shabnam Peyvandi a, *, Beatrice Latal b, Steven P. Miller c, Patrick S. McQuillen d
a
Division of Pediatric Cardiology, University of California San Francisco Benioff Children’s Hospital, USA
b
University Children's Hospital Zurich, Child Development Center and Children's Research Center, Zurich, Switzerland
c
University of Toronto, Hospital for Sick Children, Department of Neurology, Canada
d
Division of Critical Care, University of California San Francisco Benioff Children’s Hospital, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Neurodevelopmental outcomes are impaired in survivors of critical congenital heart disease (CHD) in several
Congenital heart disease developmental domains including motor, cognitive and sensory outcomes. These deficits can extend into the
Brain injury adolescent and early adulthood years. The cause of these neurodevelopmental impairments is multi-factorial and
Brain development includes patient specific risk factors, cardiac anatomy and physiology as well as brain changes seen on MRI.
Neurodevelopment Advances in imaging techniques have identified delayed brain development in the neonate with critical CHD as
well as acquired brain injury. These abnormalities are seen even before corrective neonatal cardiac surgery. This
review focuses on describing brain changes seen on MRI in neonates with CHD, risk factors for these changes and
the association with neurodevelopmental outcome. There is an emerging focus on the impact of cardiovascular
physiology on brain health and the complex heart-brain interplay that influences ultimate neurodevelopmental
outcome in these patients.

Introduction cardiac interventions. However, in the recent era with advances in

Severe congenital heart disease (CHD) requiring corrective surgery
occurs in 6–8 per 1000 live births with up to half of these cases requiring
an operation in the neonatal period to survive (Hoffman and Kaplan,
2002). With improved surgical techniques, mortality has steadily
declined with an increasing number of adults living with CHD (Marelli
et al., 2007, 2016). Given the changing epidemiology of CHD, much
effort has been devoted to describe and understand the neuro-
developmental outcomes and quality of life for survivors of CHD.
Although children with CHD rarely exhibit overt neurologic dysfunction,
many may face deficits in multiple developmental domains including
overall intellectual functioning, memory, executive function, speech and
language, gross and fine motor and visual-spatial skills (Newburger et al.,
2012; Sananes et al., 2012; Rhein von et al., 2012; Naef et al., 2017).
Long-term data suggests that these deficits continue into adolescence and
young adulthood with potential significant impact on societal contribu-
tion and ultimately long-term neurocognitive function (Marelli et al.,
2016; Bellinger et al., 2011; Schaefer et al., 2013).
A natural assumption was that the adverse outcomes in infants with
CHD were directly related to brain injuries sustained during neonatal
neonatal brain imaging, it has become apparent that brain abnormalities
are seen even before surgical repair and the relationship between the
brain and the heart is complex, occurring at many levels through fetal
and postnatal development. This review will focus on 1) neonatal brain
development in the context of CHD; 2) timing, appearance and mecha-
nism of acquired brain injuries and 3) current knowledge on the
relationship between neonatal brain changes in CHD and neuro-
developmental outcomes.
Brain development is delayed in CHD
Neonatal brain MRI studies have demonstrated evidence that brain
development is delayed in CHD prior to corrective surgery (Miller et al.,
2007). In fact, fetal brain MRI studies suggest that delayed brain devel-
opment begins in utero likely as a result of aberrations in fetal circulation
leading to abnormal oxygen and nutrient delivery to the brain (Limper-
opoulos et al., 2010; Sun et al., 2015). In contrast to human cardiac
development that is largely complete by gestational week seven (Sri-
vastava, 2006), brain development extends over a much longer period of
time that extends into the third trimester and postnatally. Brain

* Corresponding author.
E-mail address: shabnam.peyvandi@ucsf.edu (S. Peyvandi).

https://doi.org/10.1016/j.neuroimage.2018.05.045
Received 7 December 2017; Received in revised form 18 April 2018; Accepted 18 May 2018
Available online xxxx
1053-8119/© 2018 Published by Elsevier Inc.

Please cite this article in press as: Peyvandi, S., et al., The neonatal brain in critical congenital heart disease: Insights and future directions,
NeuroImage (2018), https://doi.org/10.1016/j.neuroimage.2018.05.045
S. Peyvandi et al.
maturation during the 3rd trimester of pregnancy is notable for a dra-
matic increase in connections and neuronal activity. Consequently, blood
flow to the developing brain increases and is estimated to be a quarter of
the combined ventricular output in the third trimester demonstrating the
unique interplay between the heart, circulation and the brain that is
critical for normal brain development (Rudolph, 2011, 2016). Fetal ce-
rebral oxygen consumption is almost half of all fetal oxygen consumption
(Reference Ranges of Blood, 2014). Not surprisingly then, chronic hyp-
oxia alters neuronal and glial protein expression in the fetal brain
(Pearce, 2006). In a preterm sheep model of the 3rd trimester of gesta-
tion, prenatal cerebral ischemia resulted in cortical maturation impair-
ments evident on diffusion tensor imaging, with widespread disturbance
of dendritic arbour development and synapse formation of cortical neu-
rons (Dean et al., 2013). Analogous changes in development of the ce-
rebral cortex are observed using DTI in preterm neonates (MRI obtained
at a median of 32 weeks gestation and at 40 weeks gestation) with
impaired postnatal growth (Vinall et al., 2013).
In the context of complex CHD, such as hypoplastic left heart syn-
drome (HLHS), left-sided cardiac structures are underdeveloped, leading
to decreased oxygenation and perfusion of the brain due to intracardiac
mixing and retrograde flow in the aortic arch. Similarly, in d-Trans-
position of the great arteries (TGA), although perfusion to the brain may
be normal, the aorta and pulmonary artery are transposed, thus the
higher oxygenated blood reaches the pulmonary vasculature as opposed
to the cerebral vasculature.
These physiologic aberrations continue into the transitional and
postnatal time period. With a precipitous drop in pulmonary vascular
resistance after birth, maintaining adequate cerebral blood flow can be
challenging in the context of critical CHD with an open ductus arteriosus,
thus perpetuating lack of adequate nutrient and oxygen delivery to the
brain. Newborns with unrepaired cyanotic CHD have decreased cerebral
oxygen delivery due to arterial desaturation as demonstrated using
phase-contrast magnetic resonance imaging and T2 mapping with MRI
brain volumetry (Lim et al., 2016). Although some of these critical car-
diac lesions (i.e. TGA) are anatomically and physiologically corrected
after the neonatal operation the effect of abnormal fetal and neonatal
cardiac physiology may have lasting effects on the vulnerable developing
brain. Furthermore, glucose and nutrient delivery to the fetal brain may
also be impaired in utero and undergoes rapid transitions with postnatal
physiologies (Rudolph, 2016). The impact of pre- and post-natal nutrition
on the developing brain in the context of the cardiovascular de-
rangements of CHD merits ongoing study.
Although physiologically different, different types of critical cardiac
lesions (e.g. HLHS and TGA) have demonstrated substantial delays in
brain development in the fetal and pre-operative time period measured
utilizing various MRI techniques including macroscopic, microscopic and
metabolic measures of brain development.
Macroscopic brain development
Measurements of simple metrics of brain growth on MRI have iden-
tified smaller total and regional brain size at birth and in infancy in CHD
as compared to controls (Ortinau et al., 2012, 2013). Cerebral MRI
volumetry is a quantitative measure of total and regional brain volume
providing an accurate means to assess brain volume and growth trajec-
tory (Gholipour et al., 2011; Matsuzawa et al., 2001; Weisenfeld and
Warfield, 2009). Sophisticated automated and manual volumetry tech-
niques can model brain tissue characteristics during neonatal develop-
ment and have identified decreased total and regional brain volumes in
neonates with complex CHD prior to any corrective operation as
compared to controls (Rhein von et al., 2015). All brain areas were
affected including cortical and deep grey matter, white matter and
cerebellar volumes. In addition, this has been noted in the third trimester
fetus (Limperopoulos et al., 2010). In particular, fetuses with HLHS and
lack of anterograde flow across the ascending aorta (aortic atresia) have
the smallest global brain volumes noted on MRI, providing more
2
NeuroImage xxx (2018) 1–7
evidence of the interplay between cardiac anatomy and physiology with
brain development. Emerging studies are focusing on growth trajectories
into childhood and adolescence utilizing these techniques, addressing
differences by cardiac lesion and the impact of somatic growth on brain
development.
The Total Maturation Score (TMS) is a semi-quantitative scoring
system developed and validated in healthy preterm infants and has been
used to assess macroscopic brain development in the neonate with CHD
(Childs et al., 2001). Using this score, which combines elements of
myelination, cortical folding, germinal matrix distribution and glial cell
migration, researchers found that neonates with d-TGA and HLHS have
evidence of lower TMS scores as compared to controls prior to any
corrective operation (Licht et al., 2009).
Microscopic and metabolic brain development
Other quantitative techniques such as Diffusion tensor imaging (DTI)
and spectroscopy have been applied to the newborn with CHD. DTI,
which is a sensitive measure of regional brain microstructural develop-
ment, has demonstrated evidence of higher apparent diffusion coefficient
(ADC) and lower fractional anisotropy (FA) in pre-operative CHD neo-
nates as compared to controls. Importantly, FA, increases in white matter
with maturation of the oligodendrocyte lineage and early myelination
(Drobyshevsky et al., 2005).
Similarly, metabolic compounds in the brain such as N-acetyl aspar-
tate (NAA), choline (cho), creatine (Cr) and lactate, are known to be
abnormal in the newborn with CHD (10% lower NAA/cho ratio as
compared to controls). Comparing these findings to those obtained in
premature newborns without CHD, full-term newborns with CHD appear
approximately one month delayed compared to term born healthy chil-
dren (Miller et al., 2007). These metabolites are also known to be
abnormal beginning in the third trimester fetus with CHD. By placing a
volume of interest within the cerebral hemisphere at the level of the
centrum ovale, metabolic information was obtained on the developing
white matter with evidence of lower NAA:Cho ratio as compared to
controls. Similar to the volumetric analysis, fetuses with HLHS and aortic
atresia had the lowest NAA:Cho ratios (Limperopoulos et al., 2010). In
line with these differences by cardiac anatomy, those with aortic atresia
have also been found to have a greater degree of impairment in micro-
structural brain development as compared to HLHS patients with anter-
ograde flow across the aorta (Sethi et al., 2013). In particular, those with
aortic atresia had lower white matter FA and higher ADC. Thus, single
ventricle anatomy and physiology appears to directly impact brain
development beginning in the third trimester of fetal life (Limperopoulos
et al., 2010). In addition to anatomy playing a role, physiology and he-
modynamic stability appear to impact neonatal brain development.
Prenatally diagnosed neonates with single ventricle physiology and
d-TGA had higher FA and lower ADC on pre-operative MRI's as compared
to those that were postnatally diagnosed (Peyvandi et al., 2016). This
likely reflects the relatively stable hemodynamic state of the prenatally
diagnosed patient as opposed to the instability during the immediate
neonatal period often seen in the postnatally diagnosed patients.
Fetuses with HLHS are now recognized to have a progressive fall-off
in cortical and subcortical gray matter, as well as white matter volumes,
through the third trimester (Clouchoux et al., 2012). These volumetric
changes were preceded by delays in cortical folding. In this context of
abnormal cortical development, the subventricular zone (SVZ) represents
the largest late gestation and postnatal niche of neural stem/progenitor
cells (NSPCs). Recent studies in humans have identified streams of
migrating neural progenitors that integrate into the frontal lobes after
birth (Paredes et al., 2016). Analyses of a piglet CHD model demonstrates
that postnatal hypoxia impairs the generation and migration of neural
progenitors destined to become forebrain interneurons and reduces
overall cortical growth (Morton et al., 2017). Consistent with earlier
neuropathology descriptions (Paredes et al., 2016), these data emphasize
the brain vulnerability in CHD is not limited to the white matter and
S. Peyvandi et al.
highlight the need to better define the mechanisms of delayed brain
development in the setting of CHD so that new therapeutic targets can be
identified.
These fetal and neonatal studies reflect developmental disturbances
of fetal origin. Although in some sub-types of CHD, the neonatal opera-
tion can be considered “corrective” (i.e. restoring normal cardiac physi-
ology), the long-term effects of fetal and neonatal physiologic aberrations
on brain development and neurodevelopmental outcomes are unclear.
However, given the evidence of continued brain MRI abnormalities and
neurodevelopmental impairments in adolescents with CHD, abnormal
fetal and pre-operative physiology likely have lasting effects. How these
changes in brain maturation are mitigated through improvements in pre-
or post-natal cerebral oxygen delivery or nutrient supply are questions in
pressing need of investigation with advanced brain and cardiovascular
imaging.
3
NeuroImage xxx (2018) 1–7
Acquired brain injury with CHD
Neonates with CHD are at increased risk of newly acquired brain
injury. Focal brain injury in the term newborn can be clearly and reliably
detected with conventional MRI, and with greater resolution than with
either ultrasound or computed tomography. The most common brain
injuries encountered in this patient population including focal white
matter injury (WMI) and small focal strokes (<1/3-2/3 of the arterial
distribution) (Fig. 1). These injures are largely clinically silent and can be
overlooked with routine clinical screening ultrasounds.
Similar to the premature newborn, WMI has specific imaging charac-
teristics defined by punctate periventricular lesions associated with T1
hyperintensity with or without restriction of water diffusion. The mech-
anism of WMI is thought to be secondary to hypoxic-ischemic and in-
flammatory injury to susceptible immature premyelinating
Fig. 1. MRI Patterns of Brain Injury in CHD. (A, B) Mod-
erate white matter injury in a newborn with hypoplastic
left heart syndrome is seen on sagittal T1 images in the
postoperative scan. White matter injuries appear as small,
focal areas of T1 hyperintensity (brightness). (C, D) Term
newborn with hypoplastic left heart syndrome imaged
postoperatively at day of life 17, after a modified Norwood
procedure. A small middle cerebral artery distribution
infarct is seen as cortical T2 hyperintensity (white arrows
in (C)) and corresponding reduced diffusion (white arrows
in (D)) in the right parietal-occipital lobe. (E, F) Term
newborn with transposition of the great arteries imaged
preoperatively after a balloon atrial septostomy. A single
focus of T1 hyperintensity is seen in the periatrial white
matter on the coronal SPGR sequence (E). This same focus
has reduced water diffusivity on the average diffusivity
(Dav) map (F, dark spot). This spot is larger than the
typical solitary white matter lesion and may represent a
small embolic stroke.
S. Peyvandi et al. NeuroImage xxx (2018) 1–7

oligodendrocytes similar to the mechanism seen in preterm infants (Miller
et al., 2005). In the preterm neonate, WMI occurs in a characteristic dis-
tribution in the periventricular white matter, predominantly centrally
(Guo et al., 2017). Several large prospective studies have been performed
using pre- and post-operative brain MRI to determine the frequency of
acquired brain injury and associated risk factors in newborns with CHD.
Risk factors for brain injury have been identified in the pre, intra- and
post-operative time periods. These are summarized in Table 1.
Approximately 40% of newborns with critical CHD are found to have
evidence of brain injury pre-operatively in the form of WMI or small focal
strokes (Mahle et al., 2002; Licht et al., 2004; Miller et al., 2004;
McQuillen et al., 2007). Risk factors for pre-operative brain injury
include hypoxemia and time to surgery (Petit et al., 2009), preoperative
base deficit, cardiac arrest and the need for balloon atrial septostomy
(McQuillen et al., 2006). Cardiac anatomy and physiology also play a role
in acquired brain injury. Neonates with HLHS and aortic atresia are at
increased risk of pre-operative WMI (Goff et al., 2013).
Risk factors for intraoperative brain injury relate primarily to the
methods of cardiopulmonary bypass and/or hypothermic total circula-
tory arrest. The Boston Circulatory Arrest Trial was a landmark trial that
compared two methods of vital organ support in infants undergoing
surgery to repair d-TGA with an arterial switch operation (Newburger
et al., 1993). Although deep hypothermic circulatory arrest, which pro-
vides the surgeon with an empty and relaxed heart, clearly allows intri-
cate surgeries to be performed, there was concern at the time regarding
later adverse neurologic outcomes. An alternative method (low-flow
bypass) was felt to maintain some amount of brain oxygen delivery, while
still allowing the surgeon a relatively bloodless field. This particular
study was a randomized clinical trial that compared these two methods
(Newburger et al., 1993). Although earlier outcomes suggested a benefit
to low-flow bypass (less post-operative seizures), longer-term studies
found no significant difference in cognitive outcomes between the two
groups. In particular, MRI studies at one year of age were no different
between the two groups. However, other studies have shown that cir-
culatory arrest is a risk factor for developing new post-operative WMI in
Table 1
Risk factors for neonatal brain injury in CHD.
Preoperative Intraoperative Postoperative
the subgroup of neonates with arch obstruction (Beca et al., 2013). Other
risk factors that have been examined include hypothermic blood pH
management, hemodilution/hematocrit and maintaining regional cere-
bral perfusion during arch reconstruction with variable results (Wypij
et al., 2008; Jonas et al., 2003). In an observational study, post-operative
stroke was most common in neonates undergoing surgical repair with
cardiopulmonary bypass with regional cerebral perfusion, a technique
introduced as theoretically brain-protective (McQuillen et al., 2007). The
variability in the literature for these intra-operative risk factors suggests
that the major burden of risk for acquired brain injury occurs outside of
the operative period. This has been demonstrated in a large sample of
pooled patient data with 1770 patients. The authors showed that the
relative contribution of surgical factors on neurodevelopmental outcome
in CHD patients was much smaller than innate patient and preoperative
factors (International Cardiac Col, 2016).
Risk factors for postoperative brain injury include hypotension and
hypoxemia related to low cardiac output syndrome. Multiple studies
have identified hypotension as a risk for new post-operative WMI
(McQuillen et al., 2007; Galli et al., 2004). In general, patients with single
ventricle anatomy carry a higher risk of new post-operative brain injury,
which correlates with the higher postoperative hemodynamic instability,
morbidity and mortality seen in these patients. More recently, timing of
surgery is thought to influence the risk of post-operative brain injury in
HLHS with a lower risk in those that undergo surgery earlier after birth
(Lynch et al., 2014).
The relationship between brain immaturity and brain injury has been
explored in the literature with variable results depending on the technique
used to measure brain development. Semi-quantitative methods (TMS)
have demonstrated an association between brain immaturity and the risk of
pre- and post-operative brain injury (Andropoulos et al., 2010). However,
quantitative methods (DTI and MRS), have shown an association between
immaturity and the risk of pre-operative brain injury but not post-operative
brain injury (Dimitropoulos et al., 2013). Both studies suggest that, in
general, brain immaturity is a risk factor for peri-operative brain injury. As
noted above, newborns with prenatal diagnosis of SVP and TGA demon-
strate less preoperative brain injury and more robust microstructural brain
development than those with postnatal diagnosis (Peyvandi et al., 2016).
These findings complement those relating cardiovascular physiology and
early brain development and suggest the potential of improved cardio-
vascular stability to promote optimal brain development.

Low arterial hemoglobin Prolonged total circulatory Low blood pressure Neonatal brain imaging in CHD and outcomes
saturation (Petit et al., arrest (Beca et al., 2013), (McQuillen et al., 2007;
2009) (Wypij et al., 2003), Galli et al., 2004)
(Andropoulos et al., 2013) Although much is known about the neonatal brain in the context of
Length of time to surgery Decreased cerebral oxygen Low arterial PaO2 (Galli CHD, there is limited data on the relationship between neonatal brain
(Petit et al., 2009; saturation (NIRS) et al., 2004) changes and neurodevelopmental outcome. In contrast, literature has
Lynch et al., 2014) (McQuillen et al., 2007; clearly identified an association between brain injury/development in
Andropoulos et al., 2012)
Catheter based procedure Cardiopulmonary bypass Prolonged cerebral
the premature neonate and neurodevelopmental outcome in infancy and
(e.g. balloon atrial strategy (regional cerebral regional oxygen childhood (Chau et al., 2013). Cross-sectional studies performed in in-
septostomy) perfusion) (McQuillen saturation (NIRS <45% fancy (12 months of age) and in adolescent years demonstrate a clear
(McQuillen et al., et al., 2007), (Goldberg for >3 h) (McQuillen association between measures of brain maturity, volume or connectivity
2006) et al., 2007) et al., 2007)
and neurodevelopment (Rollins et al., 2014; Rollins et al., 2017; Pani-
Cardiac Arrest Hematocrit < 24% (Wypij Morphologically
(Dimitropoulos et al., et al., 2008) immature brain grahy et al., 2015; Rhein von et al., 2014) in the patient with CHD;
2013), (Block et al., (Total Maturation Score) however, there are a paucity of longitudinal studies assessing the pre-
2010) (Beca et al., 2013; dictive abilities of neonatal brain imaging in CHD (Table 2).
Andropoulos et al., 2010; Among the few studies in the literature, the relationship between
Dimitropoulos et al.,
2013)
acquired neonatal brain injury and neurodevelopmental outcome is
Morphologically Single ventricle mixed. A prospective cohort study with a modest sample size of subjects
immature brain physiology (McQuillen with d-TGA demonstrated that pre-operative WMI, but not new post-
(Total Maturation Score) et al., 2007), (Beca et al., operative WMI, was associated with lower scores on motor and lan-
(Goff et al., 2013; 2013), (Forbess et al.,
guage development (Bayley Scales of Infant and Toddler Development-
Andropoulos et al., 2002)
2010; Dimitropoulos III) (Andropoulos et al., 2012). In a follow-up study the same group
et al., 2013) assessed a larger number of subjects with a mixed group of CHD lesions
Male sex (Goff et al., 2013) and found that new post-operative WMI, but not pre-operative WMI, was
Aortic Atresia (Goff et al., 2013) associated with lower cognitive scores at 12 months of age (Andropoulos
Postnatal diagnosis of CHD (Peyvandi et al., 2016)
et al., 2014). In contrast, Beca et al. failed to find any associations

4
S. Peyvandi et al. NeuroImage xxx (2018) 1–7

Table 2
The association between neonatal brain imaging and neurodevelopmental outcome in newborns with congenital heart disease.
Study Sample Size & CHD ND Instrument Brain MRI measure Findings

Andropoulos et al., 2012
(Andropoulos et al., 2012)
Beca et al., 2013 (Beca et al.,
2013)
Andropoulos et al., 2014
(Andropoulos et al., 2014)
Wong et al., 2017 (Wong et al.,
2017)
ND ¼ neurodevelopment; d-TGA ¼ d-transposition of the great arteries; BSID¼ Bayley's Scale of Infant Development; WMI ¼ white matter injury; TMS ¼ total matu-
ration score.
N ¼ 30 d-TGA BSID-III (12 months) Brain Injury: Pre-op injury associated with motor and
- WMI language deficits.
- Infarction
- Hemorrhage
Pre-op: 33%
New post-op: 43%
N ¼ 122 Mixed BSID-III (12 months) Pre-op Brain Injury: WMI not associated with outcome; TMS at 3
- Stroke (5%) months associated with deficits in all domains.
- WMI (20%- mild (70%),
moderate (27%), severe (3%)
- Hemorrhage (4%)
Post-op Brain Injury:
- Stroke (4%)
- WMI (42%- mild (67%),
moderate (21%), severe (12%)
- Hemorrhage (2%)
Brain Maturity:
- TMS
N ¼ 59 Mixed BSID- III (2 years) Pre- op brain injury: Post-op injury associated with cognitive
- WMI (31%: Mild 67%, Moderate deficits.
25%, Severe 8%)
- Infarction (23%)
- Hemorrhage (10%)
Post-op brain injury:
- WMI (36%: Mild 71%, Moderate
29%)
- Infarction (26%)
- Hemorrhage (26%)
Brain Maturity:
- TMS
N ¼ 11 CHD- Mixed Battelle Developmental Fetal and pre-operative MRI (simple Small cerebellar size associated with deficits in
N ¼ 51 Control Inventory-2nd Ed metrics): all domains.
- Operculum
- Cerebellum

between brain injury (pre- or post-op) and neurodevelopmental outcome Conclusions

at 2 years of age. However, they did find that relative brain immaturity
(as measured by the TMS) on brain MRI at 3 months of age was associated
with reduced performance in cognition, language and motor skills at 2
years of age (Beca et al., 2013). Although these studies were prospective
with relatively large sample sizes, brain injury was largely treated as a
dichotomous predictor, which may mask associations between different
subtypes of injury and outcome. In addition, the majority of subjects had
mild forms of injury that may not influence outcome.
Although the relationship between brain injury and outcome is un-
clear, emerging literature with newer imaging techniques may provide
clarity on this relationship. In particular, a recent study found that fetal
and neonatal smaller cerebellar size was associated with several deficits
in developmental domains in infancy (between 9 and 36 months of age,
Battelle Developmental Inventory, 2nd ed) (Wong et al., 2017). Simi-
larly, in a recent study, 20 neonates underwent continuous EEG moni-
toring and brain MRI with DTI to assess functional brain maturation,
network connectivity and brain microstructural development (Birca
et al., 2016). Neonates with delayed microstructural development
demonstrated significantly stronger high-frequency (beta and gamma
frequency band) connectivity and significantly weaker low-frequency
(delta, theta, alpha frequency band) connectivity. These data suggest
that delayed microstructural brain development has immediate func-
tional consequences manifested by altered neuronal network connec-
tivity. How these perturbations of developing neuronal networks
impacts longer-term brain maturation and neurocognitive function is a
key area for future study.
Neonates with complex CHD exhibit abnormalities in brain maturity
and are at risk for acquired brain injuries. While these changes impact the
white matter prominently, there is an increasing appreciation of abnor-
malities of cortical and subcortical gray matter development. These
changes can be apparent even before undergoing neonatal cardiac sur-
gery, suggesting that patient specific risk factors, cardiac physiology and
the interplay between cardiac and brain development plays a critical role
in overall brain health in CHD. The predictive ability of neonatal brain
imaging is a work in progress; however initial studies suggest that both
brain immaturity and brain injury may increase the risk of neuro-
developmental impairment in infancy and childhood. Incorporating
other measures of brain function in addition to MRI such as clinical exam,
or EEG monitoring may help better predict outcomes in this population of
patients.
References
Andropoulos, D.B., Hunter, J.V., Nelson, D.P., Stayer, S.A., Stark, A.R., McKenzie, E.D.,
et al., 2010 Mar. Brain immaturity is associated with brain injury before and after
neonatal cardiac surgery with high-flow bypass and cerebral oxygenation monitoring.
J. Thorac. Cardiovasc. Surg. 139 (3), 543–556.
Andropoulos, D.B., Easley, R.B., Brady, K., McKenzie, E.D., Heinle, J.S., Dickerson, H.A.,
et al., 2012 Oct. Changing expectations for neurological outcomes after the neonatal
arterial switch operation. Ann. Thorac. Surg. 94 (4), 1250–1255 discussion1255–6.
Andropoulos, D.B., Brady, K., Easley, R.B., Dickerson, H.A., Voigt, R.G.,
Shekerdemian, L.S., et al., 2013 Jul. Erythropoietin neuroprotection in neonatal
cardiac surgery: a phase I/II safety and efficacy trial. J. Thorac. Cardiovasc. Surg. 146
(1), 124–131.

5
S. Peyvandi et al.
Andropoulos, D.B., Ahmad, H.B., Haq, T., Brady, K., Stayer, S.A., Meador, M.R., et al.,
2014 Mar. The association between brain injury, perioperative anesthetic exposure,
and 12-month neurodevelopmental outcomes after neonatal cardiac surgery: a
retrospective cohort study. Pediatric Anesthesia 24 (3), 266–274.
Beca, J., Gunn, J.K., Coleman, L., Hope, A., Reed, P.W., Hunt, R.W., et al., 2013 Mar 5.
New white matter brain injury after infant heart surgery is associated with diagnostic
group and the use of circulatory arrest. Circulation 127 (9), 971–979.
Bellinger, D.C., Wypij, D., Rivkin, M.J., DeMaso, D.R., Robertson, R.L., Dunbar-
Masterson, C., et al., 2011 Sep 20. Adolescents with D-transposition of the Great
Arteries Corrected with the Arterial Switch Procedure: Neuropsychological
Assessment and Structural Brain Imaging. Circulation, 124. Lippincott Williams &
Wilkins (12):1361–9.
Birca, A., Vakorin, V.A., Porayette, P., Madathil, S., Chau, V., Seed, M., et al., 2016 Sep.
Interplay of brain structure and function in neonatal congenital heart disease. Ann
Clin Transl Neurol 3 (9), 708–722.
Block, A.J., McQuillen, P.S., Chau, V., Glass, H., Poskitt, K.J., Barkovich, A.J., et al., 2010
Sep. Clinically silent preoperative brain injuries do not worsen with surgery in
neonates with congenital heart disease. J. Thorac. Cardiovasc. Surg. 140 (3),
550–557.
Chau, V., Synnes, A., Grunau, R.E., Poskitt, K.J., Brant, R., Miller, S.P., 2013. Abnormal
Brain Maturation in Preterm Neonates Associated with Adverse Developmental
Outcomes. Neurology, 81. Lippincott Williams & Wilkins, pp. 2082–2089 (24).
Childs, A.M., Ramenghi, L.A., Cornette, L., Tanner, S.F., Arthur, R.J., Martinez, D., et al.,
2001 Sep. Cerebral maturation in premature infants: quantitative assessment using
MR imaging. AJNR Am J Neuroradiol 22 (8), 1577–1582.
Clouchoux, C., Plessis du, A.J., Bouyssi-Kobar, M., Tworetzky, W., McElhinney, D.B.,
Brown, D.W., et al., 2012 Sep 12. Delayed cortical development in fetuses with
complex congenital heart disease. Cerebr. Cortex.
Dean, J.M., McClendon, E., Hansen, K., Azimi-Zonooz, A., Chen, K., Riddle, A., et al., 2013
Jan 16. Prenatal cerebral ischemia disrupts MRI-defined cortical microstructure
through disturbances in neuronal arborization. Sci Transl Med. American Association
for the Advancement of Science 5 (168), 168ra7–168ra7.
Dimitropoulos, A., McQuillen, P.S., Sethi, V., Moosa, A., Chau, V., Xu, D., et al., 2013 Jul
16. Brain Injury and Development in Newborns with Critical Congenital Heart
Disease. Neurology, 81. Lippincott Williams & Wilkins, pp. 241–248 (3).
Drobyshevsky, A., Song, S.-K., Gamkrelidze, G., Wyrwicz, A.M., Derrick, M., Meng, F.,
et al., 2005 Jun 22. Developmental changes in diffusion anisotropy coincide with
immature oligodendrocyte progression and maturation of compound action potential.
J Neurosci. Society for Neuroscience 25 (25), 5988–5997.
Forbess, J.M., Visconti, K.J., Hancock-Friesen, C., Howe, R.C., Bellinger, D.C., Jonas, R.A.,
2002 Sep 24. Neurodevelopmental outcome after congenital heart surgery: results
from an institutional registry. Circulation 106 (12 Suppl 1). I95–102.
Galli, K.K., Zimmerman, R.A., Jarvik, G.P., Wernovsky, G., Kuypers, M.K., Clancy, R.R.,
et al., 2004 Mar. Periventricular leukomalacia is common after neonatal cardiac
surgery. J. Thorac. Cardiovasc. Surg. 127 (3), 692–704.
Gholipour, A., Estroff, J.A., Barnewolt, C.E., Connolly, S.A., Warfield, S.K., 2011 May.
Fetal Brain Volumetry through MRI Volumetric Reconstruction and Segmentation. Int
J Comput Assist Radiol Surg, 6. Springer-Verlag, pp. 329–339 (3).
Goff, D.A., Shera, D.M., Tang, S., Lavin, N.A., Durning, S.M., Nicolson, S.C., et al., 2013
Jul 20. Risk factors for preoperative periventricular leukomalacia in term neonates
with hypoplastic left heart syndrome are patient related. J. Thorac. Cardiovasc.
Surg.
Goldberg, C.S., Bove, E.L., Devaney, E.J., Mollen, E., Schwartz, E., Tindall, S., et al., 2007
Apr. A randomized clinical trial of regional cerebral perfusion versus deep
hypothermic circulatory arrest: outcomes for infants with functional single ventricle.
J. Thorac. Cardiovasc. Surg. 133 (4), 880–881.
Guo, T., Duerden, E.G., Adams, E., Chau, V., Branson, H.M., Chakravarty, M.M., et al.,
2017 Feb 14. Quantitative Assessment of white Matter Injury in Preterm Neonates:
Association with Outcomes. Neurology, 88. Lippincott Williams & Wilkins (7):
614–22.
Hoffman, J.I.E., Kaplan, S., 2002 Jun 19. The incidence of congenital heart disease. JAC
(J. Antimicrob. Chemother.) 39 (12), 1890–1900.
International cardiac collaborative on neurodevelopment (ICCON) investigators. Impact
of operative and postoperative factors on neurodevelopmental outcomes after cardiac
operations. Ann. Thorac. Surg. 102 (3), 2016 Sep, 843–849.
Jonas, R.A., Wypij, D., Roth, S.J., Bellinger, D.C., Visconti, K.J., Plessis du, A.J., et al.,
2003 Dec. The influence of hemodilution on outcome after hypothermic
cardiopulmonary bypass: results of a randomized trial in infants. J. Thorac.
Cardiovasc. Surg. 126 (6), 1765–1774.
Licht, D.J., Wang, J., Silvestre, D.W., Nicolson, S.C., Montenegro, L.M., Wernovsky, G.,
et al., 2004 Dec. Preoperative cerebral blood flow is diminished in neonates with
severe congenital heart defects. J. Thorac. Cardiovasc. Surg. 128 (6), 841–849.
Licht, D.J., Shera, D.M., Clancy, R.R., Wernovsky, G., Montenegro, L.M., Nicolson, S.C.,
et al., 2009 Mar. Brain maturation is delayed in infants with complex congenital heart
defects. J. Thorac. Cardiovasc. Surg. 137 (3), 529–536 discussion536–7.
Lim, J.M., Kingdom, T., Saini, B., Chau, V., Post, M., Blaser, S., et al., 2016 Oct. Cerebral
oxygen delivery is reduced in newborns with congenital heart disease. J. Thorac.
Cardiovasc. Surg. 152 (4), 1095–1103.
Limperopoulos, C., Tworetzky, W., McElhinney, D.B., Newburger, J.W., Brown, D.W.,
Robertson, R.L., et al., 2010 Jan 5. Brain Volume and Metabolism in Fetuses with
Congenital Heart Disease: Evaluation with Quantitative Magnetic Resonance Imaging
and Spectroscopy. Circulation, 121. Lippincott Williams & Wilkins, pp. 26–33 (1).
Lynch, J.M., Buckley, E.M., Schwab, P.J., McCarthy, A.L., Winters, M.E., Busch, D.R.,
et al., 2014 Jun 27. Time to surgery and preoperative cerebral hemodynamics predict
postoperative white matter injury in neonates with hypoplastic left heart syndrome.
J. Thorac. Cardiovasc. Surg.
6
NeuroImage xxx (2018) 1–7
Mahle, W.T., Tavani, F., Zimmerman, R.A., Nicolson, S.C., Galli, K.K., Gaynor, J.W., et al.,
2002 Sep 24. An MRI study of neurological injury before and after congenital heart
surgery. Circulation 106 (12 Suppl 1). I109–14.
Marelli, A.J., Mackie, A.S., Ionescu-Ittu, R., Rahme, E., Pilote, L., 2007 Jan 16. Congenital
Heart Disease in the General Population: Changing Prevalence and Age Distribution.
Circulation, 115. Lippincott Williams & Wilkins, pp. 163–172 (2).
Marelli, A., Miller, S.P., Marino, B.S., Jefferson, A.L., Newburger, J.W., 2016 May 17.
Brain in Congenital Heart Disease across the Lifespan: the Cumulative Burden of
Injury. Circulation, 133. Lippincott Williams & Wilkins, pp. 1951–1962 (20).
Matsuzawa, J., Matsui, M., Konishi, T., Noguchi, K., Gur, R.C., Bilker, W., et al., 2001 Apr.
Age-related volumetric changes of brain gray and white matter in healthy infants and
children. Cerebr. Cortex 11 (4), 335–342.
McQuillen, P.S., Hamrick, S.E.G., Perez, M.J., Barkovich, A.J., Glidden, D.V., Karl, T.R.,
et al., 2006 Jan 17. Balloon Atrial Septostomy Is Associated with Preoperative Stroke
in Neonates with Transposition of the Great Arteries. Circulation, 113. Lippincott
Williams & Wilkins, pp. 280–285 (2).
McQuillen, P.S., Barkovich, A.J., Hamrick, S.E.G., Perez, M., Ward, P., Glidden, D.V.,
et al., 2007 Feb. Temporal and Anatomic Risk Profile of Brain Injury with Neonatal
Repair of Congenital Heart Defects. Stroke, 38. Lippincott Williams & Wilkins,
pp. 736–741 (2 Suppl).
Miller, S.P., McQuillen, P.S., Vigneron, D.B., Glidden, D.V., Barkovich, A.J.,
Ferriero, D.M., et al., 2004 May. Preoperative brain injury in newborns with
transposition of the great arteries. Ann. Thorac. Surg. 77 (5), 1698–1706.
Miller, S.P., Ferriero, D.M., Leonard, C., Piecuch, R., Glidden, D.V., Partridge, J.C., et al.,
2005 Nov. Early brain injury in premature newborns detected with magnetic
resonance imaging is associated with adverse early neurodevelopmental outcome.
J. Pediatr. 147 (5), 609–16.
Miller, S.P., McQuillen, P.S., Hamrick, S., Xu, D., Glidden, D.V., Charlton, N., et al., 2007
Nov 8. Abnormal brain development in newborns with congenital heart disease.
N. Engl. J. Med. 357 (19), 1928–1938.
Morton, P.D., Korotcova, L., Lewis, B.K., Bhuvanendran, S., Ramachandra, S.D.,
Zurakowski, D., et al., 2017 Jan 25. Abnormal neurogenesis and cortical growth in
congenital heart disease. Sci Transl Med. American Association for the Advancement
of Science 9 (374) eaah7029.
Naef, N., Liamlahi, R., Beck, I., Bernet, V., Dave, H., Knirsch, W., et al., 2017 Sep.
Neurodevelopmental profiles of children with congenital heart disease at school age.
J. Pediatr. 188, 75–81.
Newburger, J.W., Jonas, R.A., Wernovsky, G., Wypij, D., Hickey, P.R., Kuban, K.C., et al.,
1993 Oct 7. A comparison of the perioperative neurologic effects of hypothermic
circulatory arrest versus low-flow cardiopulmonary bypass in infant heart surgery.
N. Engl. J. Med. 329 (15), 1057–1064.
Newburger, J.W., Sleeper, L.A., Bellinger, D.C., Goldberg, C.S., Tabbutt, S., Lu, M., et al.,
2012 May 1. Early Developmental Outcome in Children with Hypoplastic Left Heart
Syndrome and Related Anomalies: the Single Ventricle Reconstruction Trial.
Circulation, 125. Lippincott Williams & Wilkins, pp. 2081–2091 (17).
Ortinau, C., Inder, T., Lambeth, J., Wallendorf, M., Finucane, K., Beca, J., 2012 Oct.
Congenital Heart Disease Affects Cerebral Size but Not Brain Growth. Pediatric
Cardiology, 33. Springer-Verlag, pp. 1138–1146 (7).
Ortinau, C., Alexopoulos, D., Dierker, D., Van Essen, D., Beca, J., Inder, T., 2013 Nov.
Cortical folding is altered before surgery in infants with congenital heart disease.
J. Pediatr. 163 (5), 1507–1510.
Panigrahy, A., Schmithorst, V.J., Wisnowski, J.L., Watson, C.G., Bellinger, D.C.,
Newburger, J.W., et al., 2015. Relationship of white matter network topology and
cognitive outcome in adolescents with d-transposition of the great arteries.
Neuroimage Clin 7, 438–448.
Paredes, M.F., James, D., Gil-Perotin, S., Kim, H., Cotter, J.A., Ng, C., et al., 2016 Oct 7.
Extensive migration of young neurons into the infant human frontal lobe. Science.
American Association for the Advancement of Science 354 (6308) aaf7073.
Pearce, W., 2006 Feb. Hypoxic regulation of the fetal cerebral circulation. J Appl Physiol.
American Physiological Society 100 (2), 731–738.
Petit, C.J., Rome, J.J., Wernovsky, G., Mason, S.E., Shera, D.M., Nicolson, S.C., et al., 2009
Feb 10. Preoperative Brain Injury in Transposition of the Great Arteries Is Associated
with Oxygenation and Time to Surgery, Not Balloon Atrial Septostomy. Circulation,
119. Lippincott Williams & Wilkins, pp. 709–716 (5).
Peyvandi, S., De Santiago, V., Chakkarapani, E., Chau, V., Campbell, A., Poskitt, K.J.,
et al., 2016 Feb 22. Association of prenatal diagnosis of critical congenital heart
disease with postnatal brain development and the risk of brain injury. JAMA Pediatr.
Reference Ranges of Blood Flow in the Major Vessels of the Normal Human Fetal
Circulation at Term by Phase Contrast Magnetic Resonance Imaging, 2014 May 29.
Lippincott Williams & Wilkins. CIRCIMAGING.113.001859.
Rhein von, M., Dimitropoulos, A., Valsangiacomo Buechel, E.R., Landolt, M.A., Latal, B.,
2012 Sep. Risk factors for neurodevelopmental impairments in school-age children
after cardiac surgery with full-flow cardiopulmonary bypass. J. Thorac. Cardiovasc.
Surg. 144 (3), 577–583.
Rhein von, M., Buchmann, A., Hagmann, C., Huber, R., Klaver, P., Knirsch, W., et al.,
2014 Jan. Brain volumes predict neurodevelopment in adolescents after surgery for
congenital heart disease. Brain 137 (Pt 1), 268–276.
Rhein von, M., Buchmann, A., Hagmann, C., Dave, H., Bernet, V., Scheer, I., et al., 2015
Dec. Severe congenital heart defects are associated with global reduction of neonatal
brain volumes. J. Pediatr. 167 (6), 1259–1263 e1.
Rollins, C.K., Watson, C.G., Asaro, L.A., Wypij, D., Vajapeyam, S., Bellinger, D.C., et al.,
2014 Nov. White matter microstructure and cognition in adolescents with congenital
heart disease. J. Pediatr. 165 (5), 936–944 e1–2.
Rollins, C.K., Asaro, L.A., Akhondi-Asl, A., Kussman, B.D., Rivkin, M.J., Bellinger, D.C.,
et al., 2017 Feb. White matter volume predicts language development in congenital
heart disease. J. Pediatr. 181, 42–2.
S. Peyvandi et al.
Rudolph, A., 2011. Congenital Diseases of the Heart. John Wiley & Sons, p. 1.
Rudolph, A.M., 2016 Aug. Impaired Cerebral Development in Fetuses with Congenital
Cardiovascular Malformations: Is it the Result of Inadequate Glucose Supply? Pediatr
Res, 80. IOP Publishing, pp. 172–177 (2).
Sananes, R., Manlhiot, C., Kelly, E., Hornberger, L.K., Williams, W.G., MacGregor, D.,
et al., 2012 May. Neurodevelopmental outcomes after open heart operations before 3
months of age. Ann. Thorac. Surg. 93 (5), 1577–1583.
Schaefer, C., Rhein von, M., Knirsch, W., Huber, R., Natalucci, G., Caflisch, J., et al., 2013
Dec. Neurodevelopmental outcome, psychological adjustment, and quality of life in
adolescents with congenital heart disease. Dev. Med. Child Neurol. 55 (12), 1143–1149.
Sethi, V., Tabbutt, S., Dimitropoulos, A., Harris, K.C., Chau, V., Poskitt, K., et al., 2013
May. Single-ventricle anatomy predicts delayed microstructural brain development.
Pediatr. Res. 73 (5), 661–667.
Srivastava, D., 2006 Sep 22. Making or breaking the heart: from lineage determination to
morphogenesis. Cell 126 (6), 1037–1048.
Sun, L., Macgowan, C.K., Sled, J.G., Yoo, S.-J., Manlhiot, C., Porayette, P., et al., 2015 Apr
14. Reduced Fetal Cerebral Oxygen Consumption Is Associated with Smaller Brain
Size in Fetuses with Congenital Heart Disease. Circulation, 131. Lippincott Williams
& Wilkins, pp. 1313–1323 (15).
NeuroImage xxx (2018) 1–7
Vinall, J., Grunau, R.E., Brant, R., Chau, V., Poskitt, K.J., Synnes, A.R., et al., 2013 Jan 16.
Slower postnatal growth is associated with delayed cerebral cortical maturation in
preterm newborns. Sci Transl Med. American Association for the Advancement of
Science 5 (168), 168ra8–168ra8.
Weisenfeld, N.I., Warfield, S.K., 2009 Aug 15. Automatic segmentation of newborn brain
MRI. Neuroimage 47 (2), 564–572.
Wong, A., Chavez, T., O'Neil, S., Votava-Smith, J., Miller, D., delCastillo, S., et al., 2017
Jan. Synchronous Aberrant Cerebellar and Opercular Development in Fetuses and
Neonates with Congenital Heart Disease: Correlation with Early Communicative
Neurodevelopmental Outcomes, Initial Experience. AJP Rep, 7. Thieme Medical
Publishers, pp. e17–e27 (1).
Wypij, D., Newburger, J.W., Rappaport, L.A., duPlessis, A.J., Jonas, R.A., Wernovsky, G.,
et al., 2003 Nov. The effect of duration of deep hypothermic circulatory arrest in
infant heart surgery on late neurodevelopment: the Boston Circulatory Arrest Trial.
J. Thorac. Cardiovasc. Surg. 126 (5), 1397–1403.
Wypij, D., Jonas, R.A., Bellinger, D.C., del Nido, P.J., Mayer Jr., J.E., Bacha, E.A., et al.,
2008 Feb. The effect of hematocrit during hypothermic cardiopulmonary bypass in
infant heart surgery: results from the combined Boston hematocrit trials. J. Thorac.
Cardiovasc. Surg. 135 (2), 355–360.