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REVIEW ARTICLE OPEN
Neuroplacentology in congenital heart disease: placental
connections to neurodevelopmental outcomes
Rachel L. Leon
1
, Imran N. Mir
1
, Christina L. Herrera
2
, Kavita Sharma
1
, Catherine Y. Spong
2
, Diane M. Twickler
2,3
and Lina F. Chalak
1
Children with congenital heart disease (CHD) are living longer due to effective medical and surgical management. However, the
majority have neurodevelopmental delays or disorders. The role of the placenta in fetal brain development is unclear and is the
focus of an emerging field known as neuroplacentology. In this review, we summarize neurodevelopmental outcomes in CHD and
their brain imaging correlates both in utero and postnatally. We review differences in the structure and function of the placenta in
pregnancies complicated by fetal CHD and introduce the concept of a placental inefficiency phenotype that occurs in severe forms
of fetal CHD, characterized by a myriad of pathologies. We propose that in CHD placental dysfunction contributes to decreased fetal
cerebral oxygen delivery resulting in poor brain growth, brain abnormalities, and impaired neurodevelopment. We conclude the
review with key areas for future research in neuroplacentology in the fetal CHD population, including (1) differences in structure
and function of the CHD placenta, (2) modifiable and nonmodifiable factors that impact the hemodynamic balance between
placental and cerebral circulations, (3) interventions to improve placental function and protect brain development in utero, and (4)
the role of genetic and epigenetic influences on the placenta–heart–brain connection.
Pediatric Research _#####################_ ; https://doi.org/10.1038/s41390-021-01521-7
IMPACT:
●Neuroplacentology seeks to understand placental connections to fetal brain development.
●In fetuses with CHD, brain growth abnormalities begin in utero.
●Placental microstructure as well as perfusion and function are abnormal in fetal CHD.
INTRODUCTION
Congenital heart disease (CHD) affects an estimated 40,000
neonates annually in the United States, which is approximately
1% of all live births.
1,2
Many of the severe forms of CHD require
surgical repair during the neonatal period or later in infancy. These
types of CHD are associated with an increased risk of neurode-
velopmental delays and disorders.
3
Now that survival in neonates
and children with CHD has increased significantly with improving
surgical techniques as well as medical treatment options, there is a
new focus on optimizing neurodevelopmental outcomes.
4
Some preliminary studies suggest that the placenta in
pregnancies complicated by CHD has a higher rate of both
structural and functional abnormalities.
5–7
The growing field
known as neuroplacentology seeks to understand the influence
of this vital organ on fetal brain development.
8
Its impact involves
both de novo synthesis of key neurotransmitters
9
and hor-
mones,
10
as well as the maintenance of a vital hemodynamic
balance to ensure adequate blood flow and oxygen delivery to the
developing brain.
11
In fetuses with CHD, an imbalance in the
prenatal hemodynamic relationship may contribute to preopera-
tive brain abnormalities and to the neurodevelopmental impair-
ments in the CHD population, in addition to the impact of events
in the neonatal period and beyond. Those events vary by cardiac
lesion, but for many neonates include a period of postnatal
hypoxia, intubation and exposure to volatile anesthetic agents,
pain and analgesic medications, cardiac catheterization, cardiac
surgery that may include cardiopulmonary bypass, deep
hypothermic circulatory arrest, postoperative recovery, and
hospitalization.
Despite these risk factors and high rates of neurodevelopmental
delays and impairments in children with CHD, studies of school-
age children with cardiac interventions in the first year of life have
not found significant associations with perioperative factors and
developmental or educational outcomes.
12,13
The idea of a
prenatal origin of brain maldevelopment in children with CHD
warrants further exploration. The role of placental hemodynamics
in fetal brain development is unclear, and the currently available
non-invasive tools, such as Doppler ultrasound, advanced
magnetic resonance imaging (MRI) techniques, and placental
pathologic examination, to study the placenta are under-
utilized.
14,15
This article reviews the literature on neurodevelopmental
outcomes in CHD patients including data suggesting neurodeve-
lopmental impairments may arise from disruptions to brain
development prenatally. Specifically, we review brain imaging
abnormalities in those with CHD, including the increased
prevalence of abnormalities such as delayed maturation,
decreased global and regional brain volumes, and white matter
injury on fetal brain MRI. We examine the link between aberrant
fetal brain development and abnormalities in placental structure
Received: 11 December 2020 Revised: 2 March 2021 Accepted: 11 March 2021
1
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA;
2
Department of Obstetrics and Gynecology, University of Texas Southwestern
Medical Center, Dallas, TX, USA and
3
Department of Radiology, University of Texas Southwestern Medical Center, Parkland Health and Hospital Systems, Dallas, TX, USA
Correspondence: Rachel L. Leon (Rachel.Leon@UTSouthwestern.edu)
www.nature.com/pr
©The Author(s) 2021
1234567890();,:
and function. We hypothesize that disruptions in placental
hemodynamics may have subtle deleterious effects on fetal brain
development in those with CHD. We conclude this review with
future research directions and considerations for the clinical care
of the CHD population.
NEURODEVELOPMENT IN PATIENTS WITH CHD
Neurodevelopmental outcomes in childhood and beyond
Children with CHD are significantly more likely to experience
developmental delays and disorders compared to the general
population.
12,16
Prevalence and severity of developmental delays
and disorders in children with CHD are directly related to severity
of their heart disease,
3
and these delays and disorders span all
domains of development.
13,17–24
Neurodevelopmental delays and
disorders can be diagnosed as early as infancy and are particularly
common in neonates with CHD and comorbid conditions, such as
prematurity.
12,25
As many as 15% of preschool-age children with
CHD who require surgery score in the at-risk or clinically
significant range on scales of pervasive developmental pro-
blems.
26
In addition, they have higher rates of attention and
learning problems
27
and high rates of motor deficits.
28
Sequelae
of neurodevelopmental delays and disorders persist into school
age and beyond. In a subgroup of infants with transposition of the
great arteries (TGA), the Boston Circulatory Arrest Trial showed
that 19–22% of their cohort of 155 children had problem
behaviors at age 8 years according to parental and teacher
assessments.
29
In children who underwent staged palliation for
hypoplastic left heart syndrome (HLHS), as many as one-third
require remedial education services during elementary school and
cognitive testing in a small cohort demonstrated intellectual
disability in 18%.
20
Likewise, in adolescence, CHD patients have a significantly
higher rate of memory deficits compared to healthy peers,
30
as
well as an increased need for remedial education services.
22
In
adulthood, CHD survivors have lower educational and occupa-
tional levels compared to healthy control groups
22
and signifi-
cantly lower scores on validated assessments of quality of life.
31
Psychiatric morbidity occurs at a higher rate in these adults as
well, spanning from major depressive disorder and panic
disorder
32
to obsessive-compulsive symptoms and psychosis.
33
One leading expert in the field contends that neurodevelopmental
challenges remain the most prevalent long-term adverse con-
sequence of CHD and its treatment and are more common than all
cardiac sequelae of their condition.
34
The challenges that children
with CHD face have led to specific recommendations by the
American Heart Association in 2014 for the screening, diagnosis,
and management of neurodevelopmental delays in this popula-
tion that focus on risk stratification, enhanced screening into
adolescence, and interventional services.
3
Multifactorial etiology of neurodevelopmental impairments
The multifactorial influences on neurodevelopment in the CHD
populationareclear,yettherelativeimportanceofprenatal,
surgical, and post-surgical factors remains unknown. Although
some of the increased incidence of neurodevelopmental
disorders are related to underlying genetic conditions, only an
estimated 23% of CHD patients have aneuploidies and copy
number variations.
35–37
Nevertheless, severe forms of CHD—
particularly those that necessitate surgical intervention in the
neonatal period—impart multiple potential causative factors for
developmental problems and disrupted brain development.
These factors include prolonged postnatal hypoxia while
awaiting surgical repair,
38,39
volatile anesthetic exposure,
40,41
cardiopulmonary bypass,
42
postoperative recovery with its
complications,andprolongedhospitalization. In addition, new
data have demonstrated that exposure to plastics may also
contribute to impaired neurodevelopment in this population.
43
Other reports have found significant associations between
cardiopulmonary bypass with regional cerebral perfusion, lower
intraoperative cerebral hemoglobin oxygen saturation during
the period of myocardial ischemia, and postoperative brain
injury.
44
The duration on cardiopulmonary bypass, use of deep
hypothermic circulatory arrest, and elevated postoperative
lactate levels, as well as preoperative white matter injury, have
been correlated with postoperative white matter injury in a
multivariable model that prospectively enrolled 147 neonates
with CHD.
45
Many conflicting reports exist in the literature with most studies
confounded by heterogeneous CHD populations and/or small
sample sizes. In one study of 109 school-aged children with CHD
requiring surgery in the neonatal period, investigators found no
association between perioperative events including cardiac
diagnosis, cardiopulmonary bypass time, and incidence of post-
operative cardiac arrest or seizures, with the use of remedial
school services or diagnosis of ADHD.
13
Similar findings were
confirmed by Lawley et al. in a population-based linkage study of
school-age outcomes in 260 children with CHD in Australia.
12
Another study found correlation between Bayley Scales of Infant
Development III (BSIDIII) at 24 months and many factors of the
home environment, preoperative health, and operative factors,
among others. However, in their multivariable analysis, intrao-
perative factors were not found to be independently associated
with BSIDIII scores.
46
In a cohort of 328 children with single-
ventricle physiology from the Pediatric Heart Network, Wolfe et al.
found no relationship between peripheral oxygen saturations
following state I and stage II palliative surgeries and neurodeve-
lopmental outcomes at 14 months, even when controlling for
relevant covariates (any SpO
2
<80% relative risk 2.25 [95%
confidence interval (CI) −1.55, 6.06], p=0.247).
47
The impact of anesthetic exposure is impossible to study in
isolation; however, studies comparing neonates undergoing non-
cardiac surgery versus cardiac surgery indicate that neurodeve-
lopmental outcomes are worse for children with CHD.
48
This may
be confounded by the fact that many with CHD undergo multiple
surgeries in childhood, as the number of surgical procedures has
been associated with progressively deleterious impact on
neurodevelopment in a large birth cohort study in Japan.
49
Together, these data suggest that the etiology of neurodevelop-
mental outcomes in children with CHD are complex, and
multifactorial, depending upon factors both within and outside
the surgical and postoperative periods.
STRUCTURAL AND FUNCTIONAL BRAIN ABNORMALITIES
Postnatal brain imaging
As expected from their neurodevelopmental impairments, chil-
dren with CHD have an increased incidence of brain abnormalities
in imaging studies.
44,50–62
In a systematic review and meta-
analysis that included 221 cases of CHD, Khalil and colleagues
reported the prevalence of brain lesions on MRI in TGA to be 34%,
in left-sided heart lesions 49%, and in mixed/unspecified heart
lesions 46%.
63
White matter injury is currently thought to
contribute most to overall neurodevelopmental outcomes.
64
In a
prospective, longitudinal study of 104 infants with single-ventricle
physiology or TGA, Peyvandi and colleagues found a significant
association with moderate-to-severe white matter injury with
impaired neurodevelopment at 30 months of age.
65
The timing of
injury is difficult to discern with the incidence of postoperative
brain injury in infants undergoing open heart surgery estimated at
34%,
57
indicating a role for intraoperative factors.
However, neonates with complex CHD have abnormal brain
structure and maturation even prior to corrective heart surgeries.
Using MRI, MR spectroscopy, and diffusion tensor imaging in a
cohort of neonates with TGA and single-ventricle physiology
imaged between 4 and 9 days of life, Miller et al. demonstrated
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2
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significant alterations in MR spectroscopy including decreased N-
acetylaspartate-to-choline ratio and increased ratio of lactate to
choline indicative of a delay in brain maturation.
54
The estimated
delay in maturation in a small study of term neonates with HLHS
and TGA was reported as approximately 1 month based on a
maturation scoring system that evaluates myelination, cortical in
folding, involution of glial cell migration bands, and presence of
germinal matrix tissue.
66
White matter injury is thought to be one of the most common
brain abnormalities in newborns with severe forms of CHD,
52,54,61
but increasingly, attention is being placed on cortical gray matter
and functional connectivity.
60,62,67
In the cohort imaged by Miller
and colleagues, white matter injury was found in 30% to as much
as 69% of preoperative infants with CHD in the first week of life.
53,54
White matter injury in preoperative neonates with CHD has been
shown to have predilection for anterior and posterior locations,
rather than the central white matter injury seen in preterm
infants.
57
Supporting the evidence of highly affected anterior brain
regions, Ortinau et al. demonstrated significantly smaller frontal
lobe volumes in their series of 67 neonates with preoperative
complex CHD (defined as those requiring surgery in first 2 months
of life) imaged, on average, by the eighth postnatal day.
52
Fetal brain imaging
An increasing number of fetal imaging studies show specific
abnormalities in brain growth and maturation that begins in utero
for fetuses with CHD. In series ranging from 5 fetuses imaged
every 4 weeks during the second half of gestation
68
to cohorts of
73 fetuses with CHD imaged once,
50
several research groups have
reported that fetuses with CHD have a smaller brain volume
compared to healthy counterparts.
50,68–71
As demonstrated
postnatally, specific brain regions are more vulnerable to lagging
growth in fetuses with CHD, particularly in the third trimester, a
period of rapid cortical development and expansion of white
matter.
72
Paladini et al. recently reported impaired frontal lobe
growth that plateaus around 30 weeks gestation in a cohort of 101
fetuses with CHD compared to >400 healthy controls.
73
Others
have demonstrated that in single-ventricle physiology CHD
fetuses, poor brain growth in pregnancy is driven by reduced
growth of gray matter structures, including the cortical plate, deep
gray matter, and the cerebellum.
74
Those fetuses with antegrade
aortic flow compared to ductus arteriosus-dependent systemic
flow has not been shown to correlate with the lagging head
growth in fetuses with CHD;
75
rather, adaptive cerebral vasodila-
tion as measured by the cerebroplacental ratio of pulsatility
indices appears to be linked to smaller head size.
76
Pathophysiology of prenatal brain injury
Most neonates with CHD have lower oxygen saturations
postnatally and some experts have suspected a prenatal origin
of neonatal brain abnormalities.
11,77,78
Disrupted brain develop-
ment in fetal CHD mirrors the pathology described in animal
models of chronic hypoxia, specifically, white matter volume loss
and decreased brain growth.
79
Using phase-contrast MRI and T2
mapping, one imaging study showed significant decreases in fetal
cerebral oxygen consumption in complex CHD fetuses compared
to controls (2.7 ± 1.2 mL/min/kg in CHD group versus 4.0 ± 1.2 mL/
min/kg in healthy controls; p=0.0001).
11
These findings support
the hypothesis that adaptive cerebral vasodilation is inadequate
to ensure normal brain development, thus questioning the notion
of “brain sparing,”which has been used to describe the fetal
cerebral vasodilatory response to impaired cerebral blood flow
and oxygen delivery. In fact, in studies of fetuses with CHD,
vasodilatation of cerebral vasculature by Doppler ultrasound has
been demonstrated in multiple cerebral arteries
80,81
and is
described in multiples studies of fetuses with HLHS.
82–84
The effects of chronic hypoxia on brain development have been
shown to depend on timing of initiation of the insult. Earlier
initiation of hypoxia is associated with more widespread white
matter injury, as described in fetal sheep.
85
Sheep exposed to
hypoxia later in gestation show reduced myelin, neuronal
apoptosis in areas of cortex, and decreased numbers of mature
oligodendrocytes.
85
The suspected etiology of these injuries lies in
the effects of chronic hypoxia on the sensitive population of cells
known as the premyelinating oligodendrocytes, which arise from
the subventricular zone and serve to myelinate neuronal
axons.
86,87
Back and colleagues have demonstrated a key
developmental window of susceptibility for these cell populations
in an animal model of hypoxic–ischemic injury
86
correlating to
approximately 23–32 weeks gestation in human fetuses, which
coincides with emergence of lagging head growth and perfusion
disturbances in CHD fetuses.
50
ROLE OF THE PLACENTA
It should come as no surprise that the placenta plays an important
role in fetal brain development. At term, the placenta receives
~40% of fetal cardiac output and is the largest fetal organ.
Neonates with CHD and superimposed placental dysfunction
including gestational hypertension, pre-eclampsia, preterm birth,
and growth restriction demonstrate higher mortality and
increased hospital length of stay than their counterparts with a
healthy placenta.
88
There is growing evidence that the placenta in
pregnancies complicated by fetal CHD may have morphologic and
functional changes, but the pathophysiologic mechanisms linking
aberrant placental structure and function to fetal brain abnorm-
alities remains unknown. The fetal heart and placenta are both
vascular organs of fetal origin, indicating that placental vascu-
lature may also be disrupted in fetal CHD, although there is
conflicting evidence in the literature. In some imaging studies, the
placenta in fetal CHD has a larger volume than expected for the
fetal size
5,6
along with pathologic evidence of reduced arboriza-
tion of the fetal villi.
89
This data suggests a different structural
phenotype in CHD pregnancies that is distinct. We propose a new
framework in considering the role of the placenta in fetal CHD,
namely, that the placenta in these pregnancies is functionally
inefficient and structurally impaired (Fig. 1). We postulate that, in
some pregnancies complicated by fetal CHD, the fetus perfuses an
immature placental microvasculature that may be disrupted by
multiple pathologies, thus preventing maximal oxygenation of
fetal blood, leading to lower oxygen saturation of blood coming
from the placenta. In these fetuses, this ultimately results in lower
cerebral oxygen delivery, poor brain growth, and impaired
neurodevelopment. Functional imaging of the placenta as well
as many of the studies on histologic examination of the CHD
placenta support this new placental classification and will be
reviewed in the sections that follow.
Functional placental imaging
Functional placental imaging indicates a possible role for placental
malfunction in the brain abnormalities seen in fetuses with CHD.
Advanced MR imaging has expanded our understanding of the
placenta by allowing volumetric growth curves throughout
gestation,
90,91
quantification of placental blood flow from the
maternal compartment,
7
and textural analysis as the placenta
matures.
14
These techniques have provided insights into placental
function in a diverse range of pregnancy-related disease states,
including fetal CHD. In a cohort of women pregnant with fetuses
diagnosed with either biventricular or single-ventricle physiology
CHD, You et al. used blood oxygen-level-dependent MRI (BOLD
MRI) to show differential changes in the placental and fetal brain
BOLD signal with maternal hyperoxygenation.
92
Fetuses with
single-ventricle physiology CHD had a significantly greater
increase in BOLD signal in the placenta compared to controls
and compared to pregnancies of fetuses with biventricular CHD
(mean Delta R2* 1.9 s
−1
± 0.2 for single-ventricle CHD, 1.0 s
−1
± 0.3
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for biventricular CHD, and 1.3 s
−1
± 0.1 for controls; p< 0.01). The
fetal brain BOLD signal did not increase from baseline with
maternal hyperoxygenation in healthy controls or those with fetal
biventricular CHD, but in single-ventricle fetal CHD, fetal brain
BOLD signal increased quickly with maternal hyperoxygenation
and remained higher even after discontinuation of maternal
oxygen administration.
92
Corroborating evidence using Doppler ultrasound of middle
cerebral artery pulsatility index was demonstrated by Szwast et al.
where maternal hyperoxygenation increased middle cerebral
artery pulsatility index in those with fetal HLHS.
93
Although
suggestive of an oxygen response in cerebral vascular resistance,
this study lacked healthy control comparisons. Umbilical venous
volume flow has also been shown to be decreased in mid-
gestation in fetuses with single-ventricle CHD compared to
controls [96.5 ± 24.3 mL/min/kg in single-ventricle CHD (n=24)
versus 118.5 ± 30.5 mL/min/kg in controls (n=141); p=0.001] but
does not represent a statistically significantly smaller portion of
estimated total cardiac output (23.9 ± 9.3% in single-ventricle CHD
compared to 27.2 ± 8.8% in controls; p=0.125).
94
Using phase-
contrast MRI and T2 mapping, Sun et al. have shown that fetuses
with severe forms of CHD have a lower oxygen saturation in the
umbilical vein compared to controls and an overall 13% reduction
in brain volume in fetal CHD subjects.
11
In sophisticated studies of
30 late-gestation fetuses with severe forms of CHD and 30 healthy
controls, they mapped the decreased oxygen saturation from the
umbilical vein (73 ± 9% in CHD group versus 79 ± 5% in healthy
controls; p=0.004) to the ascending aorta and showed decreased
cerebral oxygen consumption in the CHD cohort as well as
reduced total brain volume.
11
This data suggests that, in severe
forms of CHD, the cerebral autoregulation plateau is exceeded and
cerebral oxygenation becomes compromised in some fetuses with
CHD. To compensate for this decreased oxygen delivery, one
would expect a physiologic adaptation allowing for greater
oxygen extraction, but there was no increase in cerebral oxygen
extraction in the CHD group (32 ± 20% in CHD group versus 34 ±
8% in healthy controls; p=0.53).
11
These values are most
pronounced in their fetuses with single-ventricle physiology,
highlighting the need for replication of these studies in a larger
cohort of specific CHD physiology. Particularly of interest would be
comparisons between fetuses with antegrade versus retrograde
flow in the aortic isthmus.
The interpretation of this data is complex but suggests the
potential of a dynamic relationship between the fetal brain, heart,
and placenta in the setting of severe CHD. In the BOLD
hyperoxygenation imaging study, the increase in placental
oxygenation signal in fetuses with single-ventricle CHD compared
to both fetuses with two-ventricle CHD and healthy controls
suggests an ability to increase oxygen saturation perhaps
secondary to structural or physiologic differences in the placenta
or a greater deficit in its oxygen reservoir. The greater deficit could
be explained by either decreased placental uptake from maternal
circulation or greater extraction by the fetal circulation. The
possibility of a baseline deficient placental uptake of oxygen from
maternal circulation driving the increase in placental BOLD signal
in the setting of maternal hyperoxygenation is supported by a
recent study showing uteroplacental malperfusion with signifi-
cantly higher uterine artery pulsatility indices in pregnancies
complicated by fetal CHD compared to healthy controls (0.90
multiples of the median (MoM), n=153 versus 0.83 MoM, n=658;
p=0.006).
95
This preliminary data requires further studies to
corroborate this evidence and determine a mechanistic explana-
tion. The finding by Sun et al. of decreased umbilical vein oxygen
saturation in fetal CHD suggests that the placenta may play a role
in decreased brain growth through impaired cerebral oxygen
delivery in some fetuses with CHD. Unfortunately, these studies
do not include histopathology of placental specimens after
delivery, thus it remains unknown whether changes in oxygena-
tion are related to structural and microvascular pathology of the
placenta.
Placental histopathology in fetal CHD
Histopathologic studies of the placenta from pregnancies
complicated by fetal CHD support the notion of placental
dysfunction, but these studies have significant limitations. Due
to the infrequency of some CHD diagnoses necessitating
heterogeneous grouping of CHD subtypes and the inconsistency
in performing placental pathologic examination in fetal CHD,
these studies lead to mixed conclusions. Rychik et al. reported on
placental pathology in 120 cases of CHD with groups of
similar heart lesions grouped for subset analysis. Their primary
findings in the total CHD group were thrombosis in 41% of
placentas, infarction in 17%, chorangiosis in 18%, and hypomature
villi in 15%.
96
Unfortunately, this study did not examine a control
group of placental pathology, thus leading to concerns about
relative frequency in that center of the above findings. Likewise,
maternal factors that impact placental pathology such as
the presence of diabetes and gravida status were not included.
Other reports have shown an increased incidence of abnormal
cord insertion in all forms of fetal CHD, and fetuses with TGA
have been shown to have the greatest number of placental
abnormalities.
5
There is mixed support from histopathologic studies for a
placental inefficiency phenotype, and likely this phenotype
pertains to the most severe forms of CHD. In a study of placentas
from fetuses with HLHS, Jones et al. found reduced placental
Normal placenta
Placental inefficiency phenotype of severe CHD
Closely matched placental
size, microvasculature, and
fetal needs
Adequate cerebral blood
flow
Abnormal placenta with
disrupted microvasculature
and impaired oxygen
extraction
Decreased cerebral oxygen
delivery beyond the
autoregulatory capacity
Small-to-normal size fetus
with impaired brain
development
Normal fetal growth with
normal brain development
Fig. 1 Normal placenta characterized by closely matched size and
function to fetal needs compared to the inefficiency phenotype of
fetal CHD. This placenta is characterized by an inefficient function
with vascular immaturity and a myriad of placental pathologic
lesions, which leads to decreased cerebral blood flow beyond the
autoregulatory capacity of the fetus with CHD, resulting in a small-
to-normal size fetus with impaired brain development. CHD
congenital heart disease.
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weight as well as reduced birth weight in most of the cohort.
89
Placental-to-birth weight ratios were not calculated, but histolo-
gically, the placentas from HLHS patients appeared immature.
Specifically, placentas showed increased syncytial nuclear aggre-
gates, indicating failed branching of the villous tree.
89
This was
supported by the finding of decreased terminal villi. Interestingly,
there was increased leptin expression in HLHS placenta, thought
to be an attempt to compensate for the vascular immaturity.
89
Leptin is produced by the placenta and serves as a pro-angiogenic
hormone with leptin levels directly correlating with placental
weight.
97
Further studies showed a similar vascular disturbance in
placentas from fetuses with TGA but without reduction in the birth
weight-to-placental weight ratio.
98
In the study by Albalawi et al.,
the placental-to-birth weight ratios were not different from
controls but were significantly higher than those reported by
Rychik et al., highlighting the imprecision of this metric due to
factors, such as placental drain time and membrane trimming.
However, in fetuses with CHD who were growth restricted,
Albalawi et al. have reported an increased placental-to-birth
weight ratio.
5
SHARED DEVELOPMENTAL PATHWAYS
The placenta, heart, and brain share several key developmental
pathways that, when disrupted, may explain some of the
coinciding pathology in these organ systems. Specific genes and
pathways that have been studied most include those involving
angiogenesis, folic acid, and Wnt/planar cell polarity signaling,
among others. These data have recently been reviewed
99–101
and
a full discussion is beyond the scope of this review. Studies have
shown mixed results regarding the impact of these shared
pathways, highlighting the fact that the multifactorial nature of
neurodevelopmental outcomes in CHD remains incompletely
understood.
Regarding angiogenic pathways, damaging variants in genes
associated with promotion of angiogenesis were recently found to
be present in 55% of a population of 133 neonates with complex
CHD; but in this well-controlled study, a similar degree of
damaging variants were also present in patients without
CHD.
102,103
Vascular endothelial growth factor (VEGF) has been
shown to play a significant role in both cardiovascular, placental,
and brain development. In animal models, VEGF is a major
regulator in heart formation and its haploinsufficiency
104
or
overexpression
105
both lead to embryonic lethality due to heart
defects. Placental growth factor shares significant amino acid
homology with VEGR and both bind the Flt-1 receptor to promote
both vasculogenesis and angiogenesis. In the brain, neuropilin
receptors bind VEGF and play a role in neural vascularization as
well as heart development.
106
Pathways utilizing folic acid have long been suspected to play a
role in CHD and a recent case–control study from China built on
the accumulating evidence from prior investigations supporting
the role of folic acid supplementation in reducing the risk of fetal
CHD.
107–111
Qu et al. showed that women taking at least 0.4 mg of
folic acid daily in the first trimester of pregnancy (with or without
concurrent multivitamin use) had a significant reduction in the
adjusted odds ratio (aOR) of any form of CHD [aOR 0.69; 95% CI
0.62–0.76 (n=928 CHD, n=949 Controls)], and lower aORs of
most of the specific subtypes of CHD examined, although the
sample sizes were likely inadequate for meaningful subgroup
analyses.
112
Most studies in folic acid supplementation are limited
by their retrospective nature, possible role of recall bias, and lack
of maternal blood folate levels to establish a causal relationship
between folic acid intake and risk of CHD. Investigations that
have examined maternal folate levels in relation to CHD risk have
not found correlations,
113–115
but this may be related to
differential regulation of folate uptake and metabolism. Specific
polymorphisms of multiple genes related to folate metabolism
have been shown to correlate with CHD risk.
116–119
The Wnt/planar cell polarity signaling pathway is recognized as
essential in the development of multiple organ systems, including
the heart from early tube formation to remodeling of outflow
tracts.
120–122
Wnt/planar cell polarity signaling has also been
linked to brain development and specifically plays a role in
neuronal migration, axonal sprouting, and disorders of these
processes.
123
This rapidly expanding field will undoubtedly
provide greater understanding of the placenta–heart–brain
connections and represents an important area for future
investigations.
FUTURE DIRECTIONS IN NEUROPLACENTOLOGY
The gaps in our understanding of placental effects on brain
development in patients with CHD involve several key areas:
(1) differences in structure and function of the CHD placenta,
(2) factors that impact the hemodynamic balance between the
low resistance placental vascular bed and the higher resistance
cerebral circulation, (3) interventions to improve placental
function and protect brain development in utero, and (4) the
role of genetic and epigenetic influences. These knowledge
gaps underscore the three key modifiers in the
placenta–heart–brain connection, which include genetics/epige-
netics, hemodynamics, and organ structure and microstructure
(Fig. 2). We propose future directions for both the clinical care
and research into perinatal origins of neurodevelopmental
impairments in those with CHD.
Our clinical protocol recommends obtaining a pathologic
examination of the placenta in all pregnancies complicated by
fetal CHD requiring interventions in the neonatal period. The yield
is upwards of 80% in identifying pathologic lesions in the CHD
placenta at our center (unpublished data), and strict adherence to
the accepted Amsterdam classification system of placental
pathology will allow direct comparisons between patients and
across centers.
124
Doppler ultrasound measures of umbilical artery
and middle cerebral artery pulsatility indices should be considered
in all pregnancies complicated by fetal CHD in order to risk-stratify
this population in terms of likelihood of neurodevelopmental
problems. Careful technique in measuring the pulsatility index of
the middle cerebral artery is required for reliable data analysis.
Postnatally, all neonates who will undergo surgical correction of
CHD should ideally receive preoperative brain MRI, as recom-
mended by experts in the field.
54,125
Neurodevelopmental follow-
Placenta–heart–brain connection
Brain
Heart
Placenta
Key modifiers:
Genetics
Hemodynamics
Structure
Fig. 2 The placenta–heart–brain connection is modified by
genetic/epigenetic, hemodynamic, and structural/microstructural
influences. These represent key areas for future investigations in the
field of neuroplacentology in CHD.
Neuroplacentology in congenital heart disease: placental connections to. . .
RL Leon et al.
5
Pediatric Research _#####################_
up is paramount for these children and should be a routine part of
their care, ideally in a setting familiar with their unique medical
challenges. Providers should recognize the role of socioeconomic
barriers to optimal neurodevelopment in children with CHD
126
and facilitate identification and access to resources that will
improve outcomes in vulnerable individuals.
From a research standpoint, future investigations will benefit
from further development and validation of noninvasive func-
tional placental imaging. Investigators should consider functional
placental imaging at multiple timepoints in pregnancy to follow
the trajectory of placental hemodynamics and its influence on
fetal brain maturation, as single measurements can be misleading
given the wide range of normal variation in most measures of
placental size and perfusion.
7,90,127
These longitudinal studies are
limited by the high cost of MRI but are necessary to understand
the timing of placental functional deficits and the specific effects
on fetal brain development. The timing of disrupted brain
development is essential to inform the optimal use of targeted
interventions in these pregnancies. In fact, multiple clinical trials
are currently underway treating fetuses with single-ventricle
physiology CHD with maternal hyperoxygenation from second
trimester to term (ClinicalTrials.gov NCT03136835, NCT02965638,
NCT03147014). In addition to evaluation at multiple timepoints,
research in CHD populations will benefit from multicenter
aggregate data to allow for analyses based on physiologic
groupings of CHD, like that being collected by the Cardiac
Neurodevelopmental Outcome Collaborative Clinical Registry.
128
Likewise, data from healthy control groups are paramount to
making strong unbiased conclusions, and controls are commonly
lacking in the CHD literature. Postpartum placental tissue
examination should be included in all placental imaging studies,
as tissue- and cellular-level data are required to explain the big
picture imaging results and will allow us to begin to understand
underlying mechanisms of perfusion abnormalities. Lastly, these
studies, and all placental and fetal brain imaging studies in CHD,
should include neurodevelopmental follow-up in order to
determine the clinical significance of experimental results and
interventions. This data is readily available at many centers where
neurodevelopmental follow-up for children with CHD is routinely
provided.
CONCLUSION
We have presented evidence of impaired brain development in
patients with CHD and outlined the potential for a prenatal
influence. We have also described differences in the placenta of
pregnancies complicated by CHD both in imaging studies and by
histopathology. Taken together, these data suggest the likely
contribution of the placenta to abnormal brain development in
the CHD fetus. Future efforts to improve neurodevelopmental
outcomes in CHD should focus on optimizing the intrauterine
environment. Key areas for future research and improved clinical
care in fetal CHD should focus on longitudinal assessments of
both the placenta and fetal brain.
AUTHOR CONTRIBUTIONS
R.L.L.: concept, drafting, revising, final approval. I.N.M., K.S., C.Y.S., D.M.T., and L.F.C.:
concept, revising, final approval. C.L.H.: drafting, revising, final approval.
ADDITIONAL INFORMATION
Competing interests: The authors declare no competing interests.
Patient consent: Not required.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims
in published maps and institutional affiliations.
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