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\begin{document}

\title{A `holistic' sonographic view on congenital heart disease -- how
semiautomatic reconstruction eases the unveiling of abnormal cardiac
anatomy part I: right heart anomalies}



\author[1]{Jan Weichert}%
\author[2]{Alexander Weichert}%
\affil[1]{University Hospital of Schleswig-Holstein, Campus Luebeck}%
\affil[2]{Charité Universitätsmedizin Berlin Campus Charite Mitte}%


\vspace{-1em}



  
  \date{June 11, 2024}


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\selectlanguage{english}
\begin{abstract}
Attempting a comprehensive examination of the fetal heart remains
challenging for unexperienced operators as it emphasizes the acquisition
and documentation of sequential cross-sectional and sagittal views and
inevitably results in diminished detection rates of fetuses affected by
congenital heart disease. The introduction of three-/four-dimensional
spatial-temporal image correlation 3D/4D STIC technology facilitated a
volumetric approach for thorough cardiac anatomic evaluation by the
acquisition of cardiac 4D datasets by analyzing and correlating numerous
images from different heart cycles obtained during an automated sweep
and subsequently displaying them in an endless cine loop sequence.
However, postanalysis with manipulation and repeated slicing of the
volume usually requires experience and in-depth anatomic knowledge,
which limits the widespread application of this advanced technique in
clinical care and unfortunately leads to the underestimation of its
diagnostic value to date. Fetal intelligent navigation echocardiography
(FINE), a novel method that automatically generates and displays 9
standard fetal echocardiographic views in normal hearts, has shown to be
able to overcome these limitations. Very recent data on the detection of
congenital heart defects (CHDs) revealed a sensitivity and specificity
of 98 \% and 93 \%, respectively. In this two-part manuscript, we
focused on the performance of FINE in delineating abnormal anatomy of
typical right and left heart lesions and thereby emphasized the
educational potential of this technology for more than just teaching
purposes. We further discussed recent findings regarding these
morphological changes seen in a pathophysiological and/or functional
context.%
\end{abstract}%



\sloppy


\emph{}

Introduction

Introduced as a promising tool, volumetry of the fetal heart using
spatial-temporal image correlation (STIC) has been shown to enable
obtaining in-depth information retrieved from large volume data sets of
the fetal heart and proven to be of additional value in offline analysis
for multidisciplinary consultation, facilitating a more detailed
understanding of the complex fetal anatomy and reducing operator
dependency\textsuperscript{1,2}. Multiplanar navigation and the
application of a number of imaging algorithms are of particular value in
evaluation of cardiovascular integrity or function (in combination with
color Doppler or M-mode). Nevertheless, quite a number of publications
have stated that these techniques have rather poor reliability in
clinical practice and have consequently faced limited use despite their
widespread availability for more than 15 years\textsuperscript{3}. Thus,
the major disadvantages of STIC interrogation include the following:
professional experience has been shown to be the most limiting factor in
the image quality of acquired volumes, and orientation within the volume
is cumbersome and remains challenging for most operators, precluding its
use in a screening setting\textsuperscript{4}. This illustrates the
urgent need for a concept to standardize 4D echocardiography and aid
targeted navigation in STIC volume data sets.

In 2013, fetal intelligent navigation echocardiography (FINE) emerged as
a novel semiautomatic technique to dissect fetal cardiac anatomy after a
STIC volume has been acquired. This intelligent navigation technology is
based on manual selection of key anatomical landmarks, allowing the
system to automatically realign the volume, reorientate and standardize
the anatomical position to find, extract, and display specific
diagnostic cardiac planes\textsuperscript{5}. Recent studies have
demonstrated that the FINE method is able to successfully generate all
nine standard views for complete fetal echocardiography in 96--100 \% of
2nd and 3rd trimester fetuses. It has also been shown that detection of
an altered cardiac morphology in case of congenital heart defects (CHDs)
is feasible with high sensitivity (98 \%) and specificity (93
\%)\textsuperscript{6}.

In this two-part manuscript, we aimed to scrutinize the advantages of
workflow-based semiautomatic postprocessing of STIC volumes for detailed
prenatal assessment of cardiovascular anatomy in fetuses affected by
congenital heart disease (CHD). Despite the fact that from a
physiological perspective left and right ventricular performance are
strictly related to that of the other (ventricular interdependence), for
teaching purposes, we focused on predominantly right- and left-sided
anomalies separately. We highlight the educational value of standardized
reconstruction of both cross-sectional and longitudinal cardiac planes
in order to aid in establishing correct diagnoses in index cases of
normal and anomalous fetal hearts assessed during mid- and third
trimester targeted ultrasound.

Detection of congenital heart defects

A recent study on epidemiological data of the potential impact of
technology on the diagnosis of congenital malformations demonstrated
that mainly the diagnosis of cardiac malformations that were not
preferentially present with overt symptoms increased in a 14-year
period. The authors suggested that these findings might at least
partially be explained by increased screening uptake (and intensity),
resulting in improved diagnosis of milder cases of selected common
malformations\textsuperscript{7}. Although the detection rates of CHD
have reportedly increased in national or community-wide regional
programs in the last decade\textsuperscript{8-11}, the sensitivity still
ranges somewhat between 22.5 \% and 52.8 \%\textsuperscript{12}. Local
policies, parental sociodemographics, screening access, operator
expertise and the type of CHD most likely account for the wide
variability in the antenatal diagnosis of CHD\textsuperscript{13}.
However, the most striking issue is that the vast majority of CHDs
actually occur in the population deemed to be at low risk, and only 10
\% of fetal CHD cases occur in pregnancies with known risk factors, such
as increased nuchal translucency, family history, or fetal extracardiac
malformations\textsuperscript{14}. The diagnosis of CHD in this
collective clearly shows operator dependency and is directly correlated
with the capability of recognizing that the appearance of the heart
deviates from normal\textsuperscript{15}. This may be related to what
Sklansky \& De Vore wrote in their 2016 commentary; i.e., future
prenatal cardiac examination and ameliorated detection of altered
cardiac anatomy should not only be based on the recommended views and
imaging modalities but also on the quality of the clips and the angles
at which they are acquired\textsuperscript{16}.

A controversial debate exists on which set of cardiac scanning planes
should be obtained to screen for CHD. As very recently published, the
implementation of extended cardiac views beyond the four-chamber view
(4CV) (as shown in figure 1) recommended by the 2014 Consensus Report
guidelines for detailed anatomic ultrasound survey led to an increase in
examination time and the frequency of both incomplete scans and the rate
of repeat examinations\textsuperscript{17}. Moreover, the authors stated
that detection of CHDs did not improve in their cohort. Similar findings
were reported by Sun et al., who could not register any significant
change in both referrals and prenatal diagnoses of critical outflow
tract anomalies despite revised obstetrical imaging
guidelines\textsuperscript{18}.

According to a Dutch study addressing the reasons why congenital heart
defects are being missed during fetal life, the lack of adaptational
skills appears to play an important role in undetected
CHDs\textsuperscript{19}. It may also require a logical approach to
understanding congenital heart disease rather than an approach in which
the various lesions are memorized\textsuperscript{20}. A prerequisite
for this is a standardized display of all cardiac diagnostic planes to
capture crucial information on anatomical (spatial) arrangements that
will dictate later functional characteristics of the heart.

\emph{}

Physiology of the right heart

Neglected for many years and even referred to as `the forgotten
chamber', the right ventricle (RV) has proven to be the dominant
ventricle \emph{in utero} \textsuperscript{2\emph{1}} . Doppler
interrogation has revealed the fetal right ventricular stroke volume to
be one-third higher than that of the LV\textsuperscript{22}. There is
compelling evidence that right ventricular dysfunction is the major
contributor to perinatal mortality even in the setting of left-sided
lesions\textsuperscript{23}. Recent studies have consistently
demonstrated a central role for RV dysfunction in the prognosis and
outcomes for a wide variety of acquired and congenital cardiac
conditions\textsuperscript{24}. In adulthood, the RV differs from the
left ventricle in terms of its contraction characteristics at
significantly lower myocardial energy costs due to lower impedance of
the pulmonary vascular bed accompanied by a unique pressure-volume
relationship. In contrast, in the fetus, cardiovascular physiology is
characterized by a high-resistance pulmonary circulation; a
low-resistance systemic circulation; a large, nonrestrictive ductus
arteriosus; right-to-left flow across the foramen ovale; equal pulmonary
arterial and aortic pressure; and hypoxemia\textsuperscript{25}.

Sonographic imaging of the right ventricle as the most anteriorly
situated cardiac cavity in its entirety might be challenging because of
the very particular crescentic shape of the right ventricle that wraps
around the side\textsuperscript{26}. Nevertheless, the apical trabecular
architecture including the moderator band that is morphologically
maintained in all hearts allows anatomic distinction between right and
left ventricles irrespective of the location of the chamber within the
ventricular mass. From a physiological perspective, the right and left
ventricular free wall thickness and force development are equal
throughout fetal life and increase up to 20-fold with advancing
pregnancy\textsuperscript{27}. The interventricular septum is located on
the midline between the ventricular chambers and is flat throughout the
cardiac cycle\textsuperscript{28}. For comprehensive analysis of
congenitally malformed hearts, a tripartite concept of the RV has been
established; it is divided into the inlet, apical trabecular and outlet
(conus) components\textsuperscript{29}. In right-sided CHDs, one or more
of these components may be affected, and this will be discussed below.

Ebstein's anomaly

This right ventricular myopathy was first described by Wilhelm Ebstein
in 1866 and is characterized by a failure of tricuspid valve (TV)
delamination, annulus dilatation, and highly variable tricuspid valve
morphology that typically results in severe tricuspid regurgitation
(TR)\textsuperscript{30,31}. The frequency of this lesion varies between
1 in 10.000 to 50.000 live births\textsuperscript{32,33}. In fact,
tricuspid valve dysplasia is an essential part of Ebstein's anomaly
(EA). Morphologically, in contrast to isolated dysplasia, the apical
displacement of the hinge points of the tricuspid valve in EA is towards
the outflow tract with rotation of the valve apparatus along the axis of
the aorta, constituting an ``all-or-none'' criterion for the diagnosis
of EA\textsuperscript{34}. The value of the offset distance of the
tricuspid septal leaflet compared to that of the mitral valve leaflet
for estimation the severity of the disease has been questioned in the
past\textsuperscript{35,36}. Accordingly, this further highlights the
need for an attitudinally appropriate assessment of the deformed and
displaced valve. In EA, the aforementioned inlet component of the RV is
functionally integrated into the right atrium (atrialized) and may
become disproportionately dilated and dyskinetic, whereas the trabecular
and outlet portions are situated downstream from the displaced orifice
and show preserved contractility\textsuperscript{37}. This consequently
results in decreased forward blood flow through the right heart.

As has clearly been demonstrated and validated for adult cardiology,
fetal 3D echocardiography is able to offer novel insights into the
altered morphology and function of the right heart and allows
elucidation of all the features of EA (e.g., shape and derangement of
the valve leaflets, level of their attachment, and degree of
coaptation)\textsuperscript{38,39}. Figure 2 shows semiautomatic
reconstruction of cardiac diagnostic planes of a fetus at 32 completed
gestational weeks. Two-dimensional echocardiography revealed a
cardiomegaly, an apically displaced tricuspid valve with marked
insufficiency (\textgreater{} 3 m/s) and a left ventricular outflow
tract obstruction (LVOTO). Upon assessment of the semiautomatic
reconstructed planes, it could be noted that all nine views reflect
anatomic abnormalities corresponding to those frequently seen in EA.
Most strikingly, there is a dysplastic TV with displacement of the
proximal attachments of its inferior and septal leaflets within the
markedly enlarged and left-rotated heart. The atrialized right ventricle
(aRV) and its demarcation against the residual RV are clearly depicted
in right ventricular outflow tract (RVOT) and ductal arch views. In a
recent retrospective study, Gottschalk et al. stated that EA was
isolated in 54 \% of cases and accompanied by other cardiac anomalies in
46 \% of cases. Other obstructive lesions of the left ventricular
outflow tract were found in two fetuses in their
study\textsuperscript{40}. In the present case, a concomitant aortic
coarctation was noted, which is clearly seen in three cardiac planes
(5CV, LVOT and ductal arch views). An abnormal RA/heart index
(Celermajer index; \textgreater{} 0.7), cardiomegaly (cardiothoracic
circumference ratio \textgreater{} 0.5), TV annulus diameter, TR
severity and younger age at prenatal diagnosis and at birth have been
shown to be significantly associated with an unfavorable postnatal
outcome. Standardized plane reconstruction as shown in figure 2 can ease
offline assessment of cardiac dimensions. Absence of antegrade pulmonary
blood flow was identified as the most important hemodynamic marker with
regard to postnatal survival\textsuperscript{40-43}. In a recent
multicenter study, qualitative left ventricular dysfunction has been
identified as an important predictor of poor postnatal
outcome\textsuperscript{44}. This functional impairment with reduced
left ventricular output is likely secondary to compression by the aRV,
warranting close surveillance for LV dysfunction throughout
pregnancy\textsuperscript{44-46}.

Tricuspid atresia

Tricuspid atresia~is a rare congenital heart defect with an estimated
prevalence of 1 in 15.000 live births\textsuperscript{47}. This lesion
was first described~by Friedrich Ludwig Kreysig in 1817 and is
characterized by an absence of the tricuspid valve, resulting in
complete obstruction of blood flow between the right atrium and right
ventricle\textsuperscript{48}. From a pathophysiologic perspective, the
inflow portion of the RV (normally directly related to proper
development of the TV) is absent. Consequently, there is an obligatory
right-to-left shunt at the atrial level, and a communication between the
systemic and the pulmonary circulation is enabled by a perimembranous
(or rarely muscular) ventricular septal defect (VSD). In the presence of
a large VSD, cardiac remodeling of the trabecular portion is usually
less severe, resulting in a larger RV. In those rare cases of TA with an
intact ventricular septum, the corresponding ventriculoarterial
connection is atretic, and the RV is nonfunctioning and severely
hypoplastic\textsuperscript{49}. TA is frequently associated with other
intracardiac anomalies that dictate the clinical presentation pre- and
postnatally. According to the nature of the ventriculoarterial
connection, TA has been initially classified into three groups (type
I-III); these groups were subsequently modified taking into account the
presence and degree of right ventricular outflow tract
obstruction\textsuperscript{50,51}.

Prenatal diagnosis of TA is usually straightforward, with a high
accuracy. Berg et al. noted 46 \% discordant ventriculoarterial
connections in their cohort. Similar findings were reported in a
previous study conducted by Wald and colleagues\textsuperscript{52}.
Both cases reviewed herein had an atretic TV and ventricular asymmetry
but normally arranged great vessels (figure 3 a,b) on 2D ultrasound.
Doppler interrogation showed no blood flow velocities across the TV.
Volume acquisition and subsequent FINE application was performed at 22
gestational weeks in each case and showed an abnormal 4CV with a
thickened fibrous plate instead of a competent tricuspid valve. The RV
was reduced in size but contractile. The remaining axial planes
displayed fundamental differences between both cases. Whereas the
ascending aorta in the three-vessel-trachea (3VT) view was s-shaped, the
main pulmonary artery was stenotic (figure 3a). The left-sided
structures appeared otherwise normal. Pulmonary forward blood flow was
maintained through a perimembranous VSD (seen in the 4CV and LVOT views)
and a large interatrial communication. The RVOT plane showed a normal
branching of the main pulmonary artery. These anatomic changes are
referred to as TA type Ib. Notably, the fetus in figure 3b had a
completely different hemodynamic situation. In the 3VT view, there was
only one outlet vessel (ascending aorta), and the 4CV view showed a
rudimentary RV and an enlarged LA. In addition, the fetus had a
restrictive foramen ovale and no communication at the ventricular level.
The pulmonary artery was atretic (seen in the RVOT and ductal arch
views), corresponding to TA type Ia.

In both studies cited above, the overall survival of pregnancies
continued until term was approximately \textgreater{}80 \%. The
individual prognosis of TA diagnosed \emph{in utero} was likely to be
determined by the presence of associated chromosomal anomalies or
syndromes that accompany TA in significant proportion of
cases\textsuperscript{49,52}. Berg et al. highlighted the need for close
surveillance in the third trimester to rule out interatrial restriction
and stated that frequently seen DV changes in TA do not indicate cardiac
compromise and are rather related to the changes in hemodynamics in
affected fetuses\textsuperscript{49}. On the other hand, according to a
recent study, an increased peak velocity index of the DV can be used to
predict compromise in fetuses with obstructive right heart
lesions\textsuperscript{53}.

Pulmonary stenosis

The prevalence of pulmonary stenosis (PS) is estimated to be 6-8 in
10.000 live births, accounting for 8--10 \% of
CHDs\textsuperscript{54-56}. Stenosis of the RVOT was first introduced
in medical literature by Giovanni B. Morgagni in
1761\textsuperscript{57,58} and represents the most common cause of
congenital outflow tract obstruction and the second most common CHD
postnatally. PS causes a decrease of blood flow from the right ventricle
to the pulmonary arteries, subsequently resulting in elevations of right
ventricular and pulmonary arterial (proximal to the stenosis) systolic
pressure that depend on the severity and distribution of the stenotic
part. The level of stenosis may be infravalvular (infundibular),
supravalvular or, most frequently, valvular (in 80 \% to 90 \% of cases
due to fusion of the valve commissures). In moderate forms of pulmonary
stenosis, the RV morphology can be normal and might escape prenatal
diagnosis. In those cases, an increase in flow velocity across the valve
is usually the only diagnostic hint. Early diagnosis of PS might be
cumbersome because of the diverse spectrum and different course
throughout pregnancy\textsuperscript{54}. In the absence of RV
hypertrophy (decrease in ventricular diastolic compliance and
end-diastolic volume), the peak velocity is correlated with the severity
of RVOTO\textsuperscript{59}. The fetus in figure 3 had moderate
cardiomegaly on conventional two-dimensional ultrasound (2DUS), and
Doppler interrogation showed turbulent flow across the pulmonary valve
and a concomitant tricuspid insufficiency with \textgreater{} 3 m/s.
Standardized analysis using FINE clearly demonstrated moderate
cardiomegaly and a narrow RVOT with thickened doming valvular tissue.

A recent cohort study on neonatal outcomes and the need for postnatal
pulmonary valvuloplasty revealed that fetuses with mild-to-moderate PS
had increased right cardiac output and signs of diastolic dysfunction
with a higher ductus venosus pulsatility index. Fetuses that needed
cardiac intervention were found to have significantly smaller and more
hypertrophic RVs and pulmonary valve diameters and reduced tricuspid
annular-plane systolic excursion (TAPSE)\textsuperscript{56}.
Mild-to-moderate cases of PS carry a favorable prognosis. Nevertheless,
the thin wall of the RV makes it sensitive to alterations in the
pulmonary artery pressure. With ongoing pregnancy, PS may worsen and
result in severe PS (figure 4) that may even progress to pulmonary
atresia. Due to the chronic increase in afterload, the RV dilates and
develops muscular hypertrophy\textsuperscript{60}. The tricuspid annulus
might also dilate, causing severe tricuspid regurgitation (as shown in
figure 4), which may subsequently lead to severe right heart failure.

Pulmonary atresia with an intact ventricular septum

Pulmonary atresia with an intact ventricular septum (PAIVS) constitutes
a rare cardiac condition with a reported frequency of 1 in 22.000
pregnancies that accounts for approximately 2-3 \% of all CHDs
prenatally\textsuperscript{61}. Although progression of severe PS and
subsequent development of PAIVS during fetal life have been documented,
studies on cardiac morphogenesis have suggested that this anomaly might
occur shortly after cardiac septation. In contrast, pulmonary atresia
with a ventricular septal defect (PAVSD)---also classified as a complex
variant of tetralogy of Fallot---evolves shortly after partitioning of
the conotruncus before closure of the ventricular
septum\textsuperscript{62,63}. Nevertheless, the exact pathomechanisms
of PAIVS are not well understood to date. This may also be related to
the striking heterogeneity of the size and physiology of the RV, the
morphology of the tricuspid valve, the degree of valvular insufficiency
and the presence of ventriculocoronary connections (VCCs)/fistulae.
These morphological features dictate classification into Type I-III
PAIVS. The pulmonary valve is usually imperforate, the ventricular
septum is intact, and the pulmonary blood flow is maintained by a
retrograde filling via a patent ductus arteriosus. In the vast majority
of cases, the cardiac dimensions have changed into a massively enlarged
heart with a hugely dilated right atrium due to retrograde jet across
the insufficient TV, as displayed in figure 5 (wall-to-wall heart). This
condition can subsequently lead to relevant compression of the lungs.

For further delineation of the disease with regard to postnatal
outcomes, different scoring systems based on different predictive
echocardiographic markers have been introduced\textsuperscript{61,64}. A
very recent retrospective cohort study revealed that cardiac parameters
such as the RV-to-LV length ratio [?] 0.6, TR \textless{} 2 m/s, and the
presence of VCCs were significantly associated with a univentricular
postnatal outcome\textsuperscript{62}. The semiautomatic approach allows
exact alignment of the cardiac diagnostic planes and precise
calculation/assessment of predictive markers. The heart assessed in
figure 5 had severe tricuspid regurgitation and no signs of
ventriculoarterial circulation, which is in line with previous
reports\textsuperscript{65}.

Double outlet right ventricle

Double outlet right ventricle (DORV) refers to a complex diagnostic
entity that commonly occurs as part of a range of heterogeneous cardiac
defects. Although early reports date back to the 18th century, the first
detailed descriptions of the clinical appearance of a large range of
anatomical variations were written later\textsuperscript{66}. In 1949,
Taussig and Bing reported on a case of a transposed aorta and pulmonary
trunk that both originated from the right ventricle\textsuperscript{67}.
Subsequently, this anomaly and accompanying defects have been further
characterized with the spatial relationship of the VSD to the semilunar
valves of the great arteries and the presence and extension of the
outflow tract obstruction, building the morphological basis for the most
widely used clinical classification\textsuperscript{68-72}.
Embryologically, DORV is supposed to represent a relatively primitive
cardiac condition with failed conotruncal rotation and a leftward shift
of either the aortic or pulmonary conus. The precise mechanisms by which
specific genetic lesions or teratogenic exposures result in
maldevelopment from normal anatomy to DORV phenotypes remain unknown and
may underscore etiologic heterogeneity. Although DORV constitutes a
conotruncal anomaly estimated to occur in 0.03-0.07 of 1,000 live
births, this spectrum of anomalies is committed to the RV, and its
physiology and will be discussed below. Notably, the frequency of double
outlet left ventricle (DOLV) seems to be significantly lower than that
of DORV. As a conotruncal anomaly, it is described to have similar
anatomic features to those observed in DORV; these include features of a
variety of entities ranging from a simple large VSD to TOF and complete
TGA.

According to the consensus definition made by the Congenital Heart
Surgery Nomenclature and Database Project, four major anatomic types
have been proposed that merely rely on the relationship of the ascending
aorta to the pulmonary artery (PA) at the level of the semilunar
valves\textsuperscript{71}. These types include (1) right lateral aorta
to the PA as the most common condition in DORV (side-by-side
relationship); (2) right anterior aorta (d-transposition type); (3)
right posterior aorta (ToF type); and (4) left anterior aorta
(l-transposition type). With respect to the location of the VSD
(subaortic as the most frequent type followed by subpulmonary, doubly
committed or noncommitted) and given that there is AV concordance, up to
16 variations of DORV may be found. Even more variants of DORV are
possible in case of situs ambiguous and/or an intact interventricular
septum. However, from a surgical perspective, based on the clinical
presentation, a functional classification scheme has been introduced
that considers four general types of DORV -- \emph{VSD-type} (DORV with
normally arranged vessels and a subaortic or doubly committed
VSD);\emph{Fallot-type} (DORV with a subaortic or doubly committed VSD
and RVOTO); \emph{TGA-type} (Taussig-Bing, DORV with a subpulmonary VSD
but usually no RVOTO); and \emph{noncommitted VSD-type} (DORV with a
remote VSD and possible RVOTO). Recently, a fifth type referred to
as\emph{AVSD-type} (DORV with AVSD/heterotaxy) has been
proposed\textsuperscript{73}. In a recent series by Gottschalk et al.,
the accuracy of prenatal diagnosis taking into account all the anatomic
details of DORV was 92 \%, which was in line with previous
studies\textsuperscript{74-76}. In their study, all fetuses had
additional cardiac anomalies, including severe RVOTO and LVOTO, HLV,
partial or total anomalous pulmonary venous connection or coronary
anomalies, which, when present, may commonly lead to an abnormal 4CV
view, as exemplified in figure 5. The frequency of extracardiac
anomalies ranges between 19 and 73 \%, and additional chromosomal
defects are found in 12 to 45 \% of cases in current
literature\textsuperscript{70,74-78}.

A number of case series have stated that ascertaining an antenatal
diagnosis of DORV continues to be difficult given the pronounced
anatomic variability as this cardiac defect may share morphological
similarities with either tetralogy of Fallot (ToF) or transposition of
the great arteries, as stated below\textsuperscript{74,78}. Moreover,
during grayscale US, the four-chamber view is usually normal, and, on
the other hand, the exact position of the accompanying VSD defining the
subtypes of DORV may be hard to characterize. Detailed anatomic
evaluation tends to be more accurate in fetuses with biventricular
anatomy than in those with single-ventricle hearts \textsuperscript{74}.
The challenge of antenatal evaluation is to elaborate the exact course,
size and relation of both great arteries and to distinguish a genuine
double outlet situation from classical ToF and or TGA. Due to the
malposition of the great arteries, only a single vessel (typically the
aorta) may be noticed when imaging the 3VT view, while angling the US
probe can allow visualization of the parallel arrangement of both outlet
vessels (even when the aorta is right posterior to the PA). In this
regard, Zidere et al. reported on the enhancement of visualization of
cardiac anatomy using 3D reconstruction that led to the accurate
categorization of the morphological type and prediction of surgical
repair\textsuperscript{79}. As illustrated in figure 6 a-d, a
standardized reconstruction of both axial and sagittal views of fetal
hearts with DORV enables a more detailed assessment of the malpositioned
vessels and gives valid inferences regarding the most likely anatomic
subset of the disease.

Although the majority of cases of misdiagnosed DORV were shown to have a
final diagnosis within the same spectrum of disease, the morphologic
subtype, irrespective of pre- or postnatal diagnosis, is a major
determinant of the outcome\textsuperscript{74,80}. Notably, only a few
studies correlated their antenatal diagnostic accuracy with the
prediction of the expected postnatal surgical approach, namely, the need
for uni- or biventricular repair. According to Lacour-Gayet et al.,
intracardiac repair of DORV, in the case of two viable ventricles, can
currently be achieved in nearly all anatomical subtypes including
DORV-nc-VSD and DORV-AVSD-heterotaxy\textsuperscript{73}. Nevertheless,
DORV, even without heterotaxy, is associated with complex postnatal care
and a high risk of early demise.

Tetralogy of Fallot

Tetralogy of Fallot (ToF) is one of the most common cyanotic heart
defects with an incidence of 3-5 per 10,000 live births, accounting for
approximately 7-10 \% of congenital heart defects in liveborn
children\textsuperscript{81}. Historically, the underlying anatomic
condition was attributed to Etienne-Louis Fallot in 1888, who introduced
the term `La Maladie Bleue', the Blue Disease\textsuperscript{82,83}.
However, it was the merit of the Danish anatomist Niels Stenson, who
described this pathology during a necropsy of a malformed fetus with
ectopia cordis already in 1671\textsuperscript{84}. In 1924, Maude
Abbott coined the term `Tetralogy of Fallot', as Fallot was the first to
link the defining classical clinical features: RV outflow tract
obstruction (RVOTO), ventricular septal defect, overriding aorta, and
right ventricular hypertrophy.

Embryologically, anterocephalad deviation of the developing outlet
ventricular septum together with hypertrophy of septoparietal
trabeculations determine both the RV outflow tract obstruction and the
malaligned ventricular septal defect with an overriding
aorta\textsuperscript{81}. The exact cause of this combination of
lesions remains unknown, and its etiology is thought to be
multifactorial including both environmental and genetic factors. The
reported incidence of chromosomal anomalies in ToF is 29 \% (including
microdeletion of 22q11.2). According to a recent systematic review,
22q11.2 microdeletion is apparently three times more common in ToF with
PA. Notably, aneuploidies are more often in classical
ToF\textsuperscript{85}. Other concomitant cardiac anomalies comprise an
atrioventricular septal defect (AVSD), a right-sided aortic arch (RAA),
an anomalous origin of the coronary arteries, a left persistent superior
vena cava and total anomalous pulmonary venous return (TAPVR). In subset
of cases, ToF is complicated by a severely underdeveloped or even absent
pulmonary valve that is replaced by a thickened infundibulum and
rudimentary valve tissue at the level of the pulmonary valve annulus,
with usually massively dilatated pulmonary arteries, as stated below.

In clinical practice, there is a broad spectrum of this condition. The
most common variety of ToF consists of a mild-to-moderate RVOTO and
normally sized branch pulmonary arteries. \emph{In utero} , RV
hypertrophy is almost always absent as the pressure gradient between of
right and left ventricles is rather low, and the four-chamber cardiac
view appears to be normal. On the other hand, there may also be complete
obstruction of the RVOT, which is similar to pulmonary atresia with VSD.
The pulmonary blood flow in this case is maintained from the aorta
either retrogradely via the ductus arteriosus supplying the PAs or via
major aortopulmonary collateral arteries (MAPCAs). In figure 7, the
cardiac anatomic changes in a fetus with ToF/PS are illustrated.
Notably, the 3VT and 4CV views are normal including the cardiac axis,
and the DA is patent, as in 80-90 \% of all ToF cases. A perimembraneous
VSD is clearly seen in the 5CV and LVOT views with an overriding aorta.
The main pulmonary artery is slightly smaller (than the ascending aorta)
in the RVOT and ductal arch views. Additional color Doppler
interrogation revealed laminar, nonturbulent flow across the PV,
precluding a hemodynamically significant RVOTO. Yeo and Romero published
a report of a case of ToF/PA analyzed with the FINE method and clearly
demonstrated a narrow and atretic RVOT\textsuperscript{86}. It has
previously been shown that an abnormal cardiac axis in fetuses with ToF
is highly predictive of the presence of pulmonary atresia and a
right-sided aortic arch and is linked to postnatal
death\textsuperscript{87}. In this regard, a recent study on the
prevalence of genetic abnormalities supported the impact of cardiac
angle assessment as levorotation of the cardiac axis was noticed in
two-third of ToF cases with genetic anomalies (assessed by chromosomal
microarray analysis)\textsuperscript{88}. Lv et al. published on a big
data analysis for the differential diagnoses of ToF; based on their
results, the PA/Ao ratio constitutes the primary parameter to
distinguish ToF from large malalignment VSD, which is in line with
observations by Wu and colleagues, who calculated 11 different
cardiovascular dimensions applied on STIC volumes and were able to show
that all fetuses with ToF had abnormal Ao z-scores and reduced PA/Ao
ratios\textsuperscript{89,90}. A recent multicenter study confirmed
these parameters to be the most valid predictors of neonatal
intervention (PV:AoV ratio \textless{}0.6, PV:AoV z-score difference
[?]5)\textsuperscript{91}.

Absent pulmonary valve syndrome

Absent pulmonary valve syndrome (APVS) is characterized by the
combination of an absent or hypoplastic pulmonary valve, stenosis of the
pulmonary valve annulus, and aneurysmal dilatation of the pulmonary
trunk and its branches. APVS accounts for 10-20 \% of all ToF cases
prenatally, whereas the incidence in postnatal series is estimated to be
significantly lower, ranging between 3 to 6 \% of all ToF cases and 0.2
to 0.4 \% of all CHDs. It was first described by J. Crampton during an
autopsy of a 10-year-old boy who died from a severe heart failure in
1830\textsuperscript{92}. This case was further delineated by N. Chevers
in 1846\textsuperscript{93,94}.

According to current literature, this lesion is categorized into three
subtypes: (I) the predominant type with an absent pulmonary valve, a
ventricular septal defect and an overriding ascending aorta. It is
considered an extreme variant of tetralogy of Fallot (Fallot type APVS;
ToFAPV), also referred to as Miller-Lev-Paul syndrome in postnatal
series\textsuperscript{95}. In the vast majority of cases, the ductus
arteriosus (DA) is absent. In addition, two very rare variants including
(II) APVS with an intact ventricular septum (IVS) and a patent DA
(non-Fallot type APVS) and (III) APVS with an intact ventricular septum
and concomitant tricuspid atresia have been described to date. There is
a reported association of ToFAPV with a microdeletion of 22q11.2 (21-25
\%) and trisomy 13 and 18\textsuperscript{96,97}. In two recent larger
prenatal series that both included first trimester cases, the incidence
of ToFAPV was up to 6 times higher than that of APV and IVS (83.1-92.5
\% vs. 7.5-16.9 \%)\textsuperscript{98,99}. Notably, all fetuses
diagnosed in early pregnancy had a patent DA, and none of them survived
beyond 24 gestational weeks due to progressive hydrops or other lethal
conditions, which is in line with prior reports. Berg et al.
hypothesized that agenesis of the ductus arteriosus is essential for
primary fetal survival in fetuses with TOF and APVS; otherwise, the
enormous diastolic volume overload caused by the regurgitant flow from
the aorta through the patent arterial duct will subsequently lead to
early intrauterine demise\textsuperscript{100}. Dilated main and branch
pulmonary arteries might result from elevated pressure and volume
loading rather than from connective tissue defects and can exert
pressure on the surrounding respiratory system (potentially causing
obstructive emphysema, atelectasis and
tracheobronchomalacia\textsuperscript{101}). However, the real clinical
impact of these findings is not fully understood nor are there
significant predictors of neonatal respiratory distress as
quantification of echocardiographic variables, including the pulmonary
valve annulus, right pulmonary artery diameter and cardiomegaly, were
not linked with an unfavorable outcome\textsuperscript{99}.

Figure 8 shows the above discussed hallmarks of APVS in a fetus at 27
weeks as a marked leftward rotation of the cardiac axis, as recently
reported in the study by Axt-Fliedner et al. (88 \% abnormal cardiac
axis)\textsuperscript{98}. The DA is apparently absent, but, most
obviously, there is huge bulging of the main and branching pulmonary
arteries. The proximity to vascular and tracheal structures is clearly
depicted. The value of conventional 3D reconstruction with color doppler
interrogation has previously been shown\textsuperscript{102}. However,
to capture the entire pathology of APVS, a detailed reconstruction of
all 9 planes using FINE technology that gives an excellent overview of
the malformed anatomy is helpful.

\emph{}

Conclusions

The ongoing diagnostic dilemma of CHDs being the most common group of
malformations affecting fetuses and newborns and the varying detection
rates of CHDs in the general population merits consideration as the
prenatal screening for CHDs remains flawed\textsuperscript{16}. The
clinical relevance of this issue is obvious considering that an
estimated 60 \% of newborns with CHDs will require a corrective
intervention throughout their lives. Fifty percent of affected newborns
need an intervention in their first year of life, among whom two-thirds
are characterized as being critical regarding short-term morbidity and
mortality (20 \% of all CHDs)\textsuperscript{20}. Moreover, CHDs
diagnosed postnatally result in greater costs merely related to
emergency transportation of ill infants\textsuperscript{103}. Despite
the adoption of updated screening guidelines, the implementation of
series of diagnostic planes to visualize cardiac anatomy, 2-dimensional
echocardiography shows limitations related to image acquisition, angle
dependency and, most strikingly, operator experience.

The advantages of 3D/4D echocardiography (STIC) over conventional 2D
ultrasound in delineating cardiac anatomy have been clearly elaborated.
Being less operator-dependent, it allows for more reproducible and
objective echocardiographic assessment of the fetal cardiac morphology
and function of all chambers and valves. However, a number of
publications have argued that the additional value of 3D/4D US in the
prenatal diagnosis of CHDs is rather limited and has only been reported
in centers with high expertise as it requires extra time and
effort\textsuperscript{1,104-106}. Since the introduction of a
semiautomatic technology (FINE), a standardized volumetric approach for
cardiac anatomic assessment has become available to overcome the
limitations of effective performance of fetal cardiac examination. FINE
has recently been shown to enable cardiac evaluation in normal and
CHD-affected fetuses with both high specificity and
sensitivity\textsuperscript{6}.

We demonstrated the superior value of this approach to comprehensively
assess altered cardiac anatomy. It has previously been shown that the
acquisition plane and insonation angle are crucial for both 2D image
quality and proper volume computing\textsuperscript{107}. It is of note
and illustrated herein that the use of standardized procedures, namely,
automatically realigned cardiac planes facilitate a systematic
evaluation of the fetal heart virtually irrespective of fetal position.
FINE provides the opportunity for even unexperienced operators to become
familiar with the anatomy of the fetal heart and the spatial
relationships of the heart structures. From our perspective, it seems
logical as a next step that 4DUS with subsequent FINE application could
be incorporated in daily practice in the future. However, using such
technology to examine the fetal heart requires an important
prerequisite, i.e., structured training interventions and feedback for
sonologists to acquire high-quality volume data sets so that they are
informative\textsuperscript{15,108,109}.

Figures

Fig. 1: Four-chamber views of different fetal conditions. Panel a shows
normal fetal anatomy, whereas panels b to f depict cardiac anomalies,
which will be discussed and further delineated within the paper.

Fig. 2: Ebstein's anomaly at 32 completed weeks with STIC volume
reconstruction and automatic labeling using FINE method. All nine
diagnostic planes are clearly depicted. The 3-vessel-trachea view shows
a size discrepancy of the great vessels with a small transverse aorta.
The 4-chamber view is abnormal with a marked left rotation (63 degrees)
and ventricular asymmetry (LV\textless{}RV) and demonstrates apically
displaced tricuspid valve hinges (atrialization of the RV; aRV) with
somewhat thickened septal and lateral leaflets. In both the 5-chamber
view (5CV) and left ventricular outflow tract (LVOT) views, there is a
small ascending aorta corresponding to tubular aortic stenosis. The RVOT
view shows normal main and right branch pulmonary arteries and aRV.
There is no regularly filled stomach in the abdominal plane. The ductal
arch view depicts the rotated tricuspid valve and gives an impression of
the remaining genuine RV. In contrast, the aortic arch is rather
hypoplastic, which confirms the finding of an obstructed LVOT. In
addition, an enlarged RA can be seen. The vena cave view denotes similar
findings.

A - transverse aortic arch; Ao - aorta; Desc - descending; IVC -
inferior vena cava; LA - left atrium; LV - left ventricle; P - pulmonary
artery; PA - pulmonary artery; RA - right atrium; RV - right ventricle;
RVOT - right ventricular outflow tract; S - superior vena cava; SVC -
superior vena cava; Trans - transverse.

Fig. 3: Tricuspid atresia at 22 gestational weeks. FINE application on
STIC volumes in both cases showed hypoplastic right-sided cardiac
structures. While assessing the altered anatomy in detail, subtle but
functional important differences can be noted. Whereas the 3VT view in
the left panel (a) demonstrates an only slightly smaller main pulmonary
artery, there is a hardly a visible pulmonary arm in panel b,
corresponding to a severely hypoplastic or atretic RV outflow. The RV in
panel b is small and hypocontractile due to an obstructed inflow via the
atretic TV. The findings are referred to as hypoplastic right heart (in
contrast to the typical findings of tricuspid atresia shown in panel a).
A perimembranous VSD was seen in the 4CV, 5CV and LVOT views (panel a);
this interventricular communication could only be assumed in the 4CV
view (panel b). There was a normal interatrial communication via a
patent foramen ovale. The ductal arch view in panels a and b is
abnormally thin. The LVOT as well as the aortic arch in both cases are
normal.

Fig. 4: Severe pulmonary stenosis seen at 29 weeks. Diagnostic plane
reconstruction using FINE shows moderate cardiomegaly and a slight
left-rotated cardiac axis. The main pulmonary artery depicted in the 3VT
view is narrow due to a thickened pulmonary valve (PV). There is a
moderate asymmetry in ventricular and atrial size, and the tricuspid
valve leaflets appear to be thickened (related to marked regurgitation
confirmed by additional Doppler interrogation). The RV cavity is narrow
but shows myocardial hypertrophy. The LVOT is otherwise normal; on the
other hand, the RVOT shows an hourglass-like appearance with an echoic,
thickened PV corresponding to valvular stenosis. Both arch views as well
as the bicaval plane are normal.

Fig. 5: Fetus with critical pulmonary stenosis and an intact ventricular
septum at 33 weeks (panel a) and complex cardiac anomaly with pulmonary
atresia and an intact ventricular septum, tricuspid atresia, LVOTO and
pericardial effusion at 17 weeks (panel b). In both cases, there is a
marked cardiomegaly in late and early pregnancy caused by a significant
RVOT obstruction. The characterizing anatomic sequelae of RVOTO are
clearly depicted after reconstruction using FINE. The 3VT view in both
cases is abnormal. In panel a, both vessels are equal in size, and the
PV is thickened and domed through cardiac cycle. In panel b, the
pulmonary artery cannot be visualized, resulting in an `I'-shaped
appearance on the 3VT view. The entire cardiac morphology is distorted,
and the cardiac axis is left-rotated. In panel a, the massively enlarged
heart occupies more than half of the thorax (merely due to the dilated
RA) and extends from wall to wall. The RV is round, and the myocardium
shows marked hypertrophy. The TV leaflets appear dysplastic and
thickened (Doppler ultrasound revealed regurgitation of \textgreater{}2
m/s). In panel b, the TV is atretic, the LV is normal, and the MV is
patent. The RVOT plane confirms the narrow pulmonary trunk that
bifurcates into the pulmonary arteries (panel a), and no detectable
pulmonary artery is visible in panel b. The ductal arch in both cases is
narrow or hypoplastic. The bicaval plane shows the enlargement of the RA
and normal venoatrial arrangement.

Fig. 6: Antenatal cases with different types of DORV (a-d).
3D-reconstructed planes showing the complexity of malposition of both
great arteries. In all cases, the 3VT view shows an abnormal parallel
course of both outlet vessels arising from the anatomical RV. The
spatial arrangement of the aorta is right anterior in panel a (TGA type
at 20 gestational weeks), and it is considerably smaller than the main
pulmonary artery. This size discrepancy is confirmed in the LVOT and
aortic arch cut section views. There is a huge VSD displayed in the 5CV
and LVOT views (noncommitted). The 4CV view further shows a common
atrium and atretic mitral valve but normal cardiac axis. The latter also
applies to the cardiac specimens in panel b and c (compared to a marked
left rotation in panel d). Panels b-d show both vessels located in a
side-by-side position, representing the most common anatomic variant of
DORV. According to the accompanying VSD, panels b and d show a doubly
committed arrangement of both outlet vessels. Note the extremely small
LV with an atretic MV and the diminished size of the main pulmonary
artery (3VT, RVOT) in panel d (seen in the 4CV, 5CV, and LVOT views).

Fig. 7: Tetralogy of Fallot at 22 weeks of gestation. The 3VT view shows
both vessels nearly equal in size with a patent DA, and the 4CV view
appears to be normal (the cardiac axis is slightly left-rotated). There
is a perimembraneous VSD with an overriding medially shifted ascending
aorta seen in the 5CV and LVOT views. The RVOT and ductal arch views
basically show the main pulmonary artery to be smaller than expected.

Fig. 8: Fetus with ToFAPVS at 29 gestational weeks. The complex cardiac
anomaly can be depicted in its entirety in 8 of 9 diagnostic planes.
Nonrestrictive interventricular communication in the membranous septum.
The 3VT view is distorted with no arterial duct. The cardiac proportions
are altered, and the cardiac axis is left rotated, as seen in the 4CV,
5CV and LVOT views. There is an overriding aorta with a broad aortic
root, and, most strikingly, both the LVOT and RVOT planes show a marked
bulging of the main and branch pulmonary arteries and a tiny
hourglass-like narrowing at the level of the absent pulmonary valve. The
ductal arch cannot be properly reconstructed due the absent DA. The
aortic arch and the bicaval plane are otherwise normal.

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