Introduction
Prenatal investigation of the fetal venous system is becoming an increasingly important
aspect of the examination of fetal circulation. This is because isolated venous anomalies
can be identified not only as a lethal disease but also as a part of complex heart
diseases or genetic syndromes. Among cyanotic heart diseases, total anomalous pulmonary
venous connection (TAPVC) is the only condition involving a venous system malformation
[1] and is easily misdiagnosed. The key characteristic of this uncommon congenital
heart disease (CHD) is that all four pulmonary veins (PVs) fail to form a direct connection
to the left atrium (LA); instead, they drain into the right heart through different
routes of systemic venous return. The incidence of this condition is approximately
7–9 per 100,000 live births [2,3], and it accounts for 0.7–1.5% of all CHDs [4]. Patients
with CHD who were born from 2000 to 2006 in Taiwan also exhibited a similar prevalence
of TAPVC (0.11/1000) [5].
Over the past decades, TAPVC has been challenging for obstetricians to recognize in
utero. According to a retrospective study of birth records from 1998 to 2004, only
1.9% of TAPVC (8 in 424) cases were prenatally diagnosed [6]. The diagnosis rate gradually
improved through both awareness regarding the importance of assessing the venous system
during routine screening and the application of new scanning technologies such as
spatiotemporal image correlation (STIC) and color flow Doppler imaging. A prospective
study identified 14 TAPVC fetuses before birth without missing single one (but one
false positive reported) through a step-by-step, careful examination of one major
and several minor sonographic features [7].
In addition to identifying echocardiographic marks related to a TAPVC diagnosis, understanding
the embryonic development of the venous system is fundamental and crucial. This helps
in recognizing abnormal features during anatomical screening and prenatal counseling.
Embryology
The fetal cardiovascular system is the first embryonically developed organ, which
begins to develop at the gesta-tional age of 6 weeks (fourth week of embryonic development).
The embryonic formation of the pulmonary venous system is not as complicated as that
of the systemic venous circulation, which involves the fusion and degeneration of
dual cardinal veins, umbilical veins, and vitelline veins. However, whether the PV
becomes connected to the LA directly [8] or through the tributaries of the sinus venosus
remains disputed [9].
The former theory prescribes that a single embryonic common PV evaginates from the
dorsal wall of the LA and develops as an outgrowth of the LA, adjacent to the septum
primum. Meanwhile, the lung buds that have arisen from the lung parenchyma canalize
as a vessel and gradually connect to the developing PV directly [10]. Other experts
have suggested that the pulmonary bud is initially enmeshed in the splanchnic plexus,
which drains into the cardinal and umbilicovitelline veins (systemic venous system)
[11]. By the gestational age of 4 weeks, the primordial common PV derived from the
posterior LA connects to the pulmonary portion of the splanchnic plexus and forms
the pulmonary plexus. Ultimately, the well-established pulmonary plexus loses its
connection with the splanchnic plexus; in other words, the pulmonary venous system
separates from the systemic veins [12]. The incorporated PV subsequently divides into
four branches, two left and two right tributaries, with each having an orifice at
the posterior LA.
Both theories are supported by different lines of evidence such as vascular markers
or animal embryological studies [13,14]. The latter theory can offer a better understanding
of the failure of PVs in emptying into the LA and for joining with the systemic venous
system instead.
Definition and classification system
The normal pulmonary venous system consists of right and left pairs of PVs delivering
the blood from both lungs to the LA. In patients with TAPVC, the anomalous veins either
directly empty into the right atrium (RA) of the heart or empty through other routes
of systemic venous return. Several classification systems based on anatomy, physiology,
or perinatal outcomes exist.
Darling’s classification
Darling’s classification, first introduced in 1957, is the most commonly used system.
TAPVC is classified into four categories according to the sites where the abnormal
connection occurs [15] (Fig. 1).
Figure 1
Darling classification of total anomalous pulmonary venous connection (TAPVC). Type
I: supracardiac type. Four pulmonary veins connect to a vertical vein which subsequently
drains into the left brachiocephalic vein and superior vena cava (curved arrow). Type
II: intracardiac type. The pulmonary veins empty into the coronary sinus or directly
into the right atrium. Type III: infracardiac type. The pulmonary veins connect to
a vertical vein passes through diaphragm. The pulmonary flow ultimately drains to
the systemic venous system, such as portal vein or inferior vena cava (curved arrow).
Type IV: mixed type. ASD, atrial septum defect; LV, left antrum; IVC, inferior vena
cava; PV, pulmonary vein; RA, right antrum; SVC, superior vena cava.
Type I: Supracardiac type, which is the most common type. The entrance of the pulmonary
blood flow into the systemic venous system is cranial to the RA. This accounts for
45–55% of TAPVC cases, in which the confluent vessel usually empties into the innominate
vein or the right or left superior vena cava (SVC) [16,17]. Type II: Cardiac type,
which is diagnosed when the PVs converge on a confluent vessel and then horizontally
connect to the RA through the coronary sinus (CS) or at the posterior wall of the
RA. Approximately 20–30% of TAPVC patients exhibit the cardiac type. Type III: Infracardiac
type. The PVs conjoin and form a vertical vessel that travels caudally into the portal
vein or its branches such as the ductus venosus, hepatic vein, and inferior vena cava
(IVC). This type accounts for 13–25% of cases. Type IV: Mixed type. Less than 10%
patients belong to this subtype, in which the right and left pulmonary tributaries
drain at two or more different levels. In Taiwan, the frequency of these four types
are 42.3% (Type I), 39.8% (Type II), 12.8% (Type III), and 5.1% (Type IV), according
to a 15-year cohort study [18].
Smith classification
TAPVC cases are simply subdivided into two groups, supradiaphragmatic without pulmonary
venous obstruction and infradiaphragmatic with pulmonary venous obstruction. The distinct
features of these two groups are how the abnormal drainage anastomosis is related
to the diaphragm and the presence of venous obstruction [19].
Although supradiaphragmatic TAPVC is mainly non-obstructive, obstructions have been
noted in some cases [20]. Nevertheless, the infradiaphragmatic type is almost always
obstructive.
Another classification system
Herlong and colleagues announced a more detailed classification system. This system
is fundamentally related to the anatomical and physiological changes in TAPVC, which
involve the following parameters: (1) the level of connections: supracardiac, cardiac,
infracardiac, and mixed; (2) presence or absence of obstruction; and (3) cause of
obstruction: extrinsic, intrinsic, or obstructive atrial septal communication [21].
Pathophysiology and presentation
The hemodynamic changes in TAPVC primarily result from the mixing of oxygen-rich blood
from the pulmonary system and deoxygenated blood from the systemic venous circulation.
This leads to cyanosis and hypoxia in neonates. Hence, TAPVC is the fifth common cause
of cyanotic heart disease.
Several essential factors have a considerable effect on the pathophysiology and presentation
of TAPVC. The presence or absence of obstruction at any level of the venous route
is the most critical factor. Obstructions may occur in different situations: (1) the
confluent vein passing through tissue, which causes extrinsic compression, similar
to that by intrathoracic structures (supracardiac type) or at the entry of the diaphragm
(infracardiac type); (2) intrinsic compression resulting from narrowing of the lumen;
and (3) at the site where the confluent blood enters the route of systemic venous
return.
The infracardiac type is almost always associated with obstruction, which usually
occurs when the confluent vein vertically enters the diaphragm through the esophageal
orifice. The intracardiac type is rarely associated with obstruction. However, obstruction
still can be detected at the CS or at the entry to the RA. Half of the supracardiac
TAPVC cases are associated with venous obstruction.
Furthermore, the lumen narrowing of the left innominate vein, SVC, or azygos vein
can lead to obstructive TAPVC. In addition, passing of the vertical vein between the
left pulmonary artery and left bronchus, leading to external compression, is a possible
cause of obstruction [17].
Among patients with unobstructed TAPVC, the size of interatrial communication plays
an important role. After birth, pulmonary resistance decreases and an adequate amount
of blood enters the pulmonary bed for adequate oxygen exchange. The mixture of saturated
and desatu-rated blood occurs at the RA. In cases of nonrestrictive interatrial communication
(such as a large atrial septal defect [ASD]), the blood enters the left heart and
supplies the systemic circulation of infants. In spite of the right-to-left shunt,
3–5 times more blood enters the pulmonary bed and increases the pulmonary artery pressure
gradually. Overcirculation leads to right ventricular hypertrophy, right heart failure,
and subsequent desaturation in neonates.
In the obstructed types, high pulmonary venous pressure leads to an increase of hydrostatic
pressure in the capillaries, leading to the development of pulmonary edema. Simultaneously,
the elevated pulmonary artery pressure results in insufficient pulmonary flow. Severe
desaturation occurs without immediate relief of the obstructed vessel.
The presentation of TAPVC varies widely and depends on the severity of the obstruction
and the resistance of the pulmonary vessels. If severe obstruction is present, acute
illness with tachypnea, tachycardia, dyspnea, hypoxemia, and metabolic acidosis manifests
as early as within the first 12 h of life. Early death occurs within the first few
days if surgical correction cannot be performed. At the other end of the spectrum,
patients without venous obstruction are usually asymptomatic at birth, followed by
the development of tachypnea, mild cyanosis, and feeding difficulties in the first
few weeks. Profound failure to thrive and recurrent respiratory tract infection are
noticed gradually, and only a small number of patients can survive up to late childhood
or adolescence without treatment [22].
Associated anomalies and genetic mechanism
Approximately 30% TAPVC cases are associated with het-erotaxy syndrome, according
to an analysis of patients receiving postnatal surgical repair at a hospital [23].
This is commonly observed in cases of right atrial isomerism (RAI), owing to the lack
of a functional LA for PV connection. In non-heterotaxy cases, TAPVC can be detected
as an isolated anomaly or with other complex heart/great vessel lesions such as atrioventricular
septal defect, transposition of the great arteries, pulmonary stenosis, double outlet
right ventricle, and coarctation of the aorta. When TAPVC is diagnosed through prenatal
echocardiography, a trend of more fetuses accompanied with heterotaxy syndrome or
complex CHD and less fetuses with isolated TAPVC has been noted [24]. TAPVC genetic
etiology is remaining vogue and previous study reported some possible disease-driven
genes (e.g., ACVRL1, SGCD, 4p13-q12, ANKRD1, etc.) by whole-exome sequencing and linkage
mapping with polymorphic microsatellite markers [25].
Perinatal outcomes
An increasing trend in TAPVC research has been observed in the last decade, and most
of these studies are related to the postnatal management, radiological diagnosis,
and surgical outcomes of TAPVC [26
27
28]. The surgical outcomes have considerably improved from a mortality rate of 42.1%
in 1970 to 7.4% after 2010 [29]. Despite the advances in perioperative cardiovascular
care, TAPVC remains one of the true surgical emergencies after diagnosis. The goal
of surgical repair is to establish the normal anastomosis of the PVs to the LA. Patients
with heterotaxy syndrome and a single functional ventricle have a poorer prognosis
[30]. Other nonpreferable factors are obstructed PVs, coexistent complex cardiac defects
[2], pulmonary atresia [23], and younger age at surgery [26].
Pearls in prenatal sonographic diagnosis
Postnatal ultrasound diagnosis has a sensitivity and specificity of >97% [28], whereas
prenatal diagnosis is more challenging. In a large (n = 424) TAPVC case series implemented
from 1998 to 2004, only 1.9% cases were identified in utero [6]. France reported a
10% prenatal diagnosis rate for 95 isolated TAPVC neonates born between 2001 and 2011
[31].
The prenatal diagnosis rate is believed to be increased through a systemic, step-by-step
ultrasound examination [7]. Here we describe the characteristics of TAPVC in prenatal
ultrasonography based on the International Society of Ultrasound in Obstetrics and
Gynecology guideline for cardiac screening in midgestation [32].
Step 1: Identifying the normal connection of the PV to the LA and inspecting for indirect
signs (Table 1).
Table 1
Indirect imaging features of prenatal echocardiography for TAPVC.
View
Description of the abnormal image
Comment
Sensitivity (from small case series)
Situs
Situs ambiguous
TAPVC is associated with heterotaxy syndrome, especially RAI
–
Four-chamber view
Atrium
Failure to visualize the normal PV connection to the LA
-First clue to suspect TAPVC-diagnostic triad
60-100% [7
24
31]
Smooth posterior wall of the LA
Additional feature
79% [7]
Ventricle
Ventricular disproportion or asymmetry (RV > LV)
Inconsistent feature for fetuses before 28 weeks of gestation; observed in a large
VSD and obstructive type of TAPVC
19–60% [24
31]
Retrocardiac space
Increased space between the LA and DAo
Post-LAspace index cut-off of 1.27Post-LASpace index cut-off of 1.27The cut-off value
of “post-LA space index” is 1.27 [32]
50–100% [7,35]
Three-vessel view
A fourth vessel adjacent to the pulmonary trunk
Supracardiac type
33%a [24]
SVC dilatation
Supracardiac type
72–100%a [7
24
31]
Abdominal view
An extra vessel between the IVC and aorta
Infracardiac type
100%b [24]
TAPVC, total anomalous pulmonary venous connection; RAI, right atrium isomerism; PV,
pulmonary vein; LA, left atrium; RV, right ventricle; LV, left ventricle; VSD, ventricular
septal defect; Dao, descending aorta; SVC, superior vena cava; IVC, inferior vena
cava.
a The sensitivity is solely calculated for the supracardiac type.
b The sensitivity is solely calculated for the infracardiac types.
A. General aspects: Situs
TAPVC is part of the heterotaxy syndrome in both RAI and left atrial isomerism (LAI)
subtypes. This abnormal venous return can be observed in 50% of fetuses with RAI and
5% of those with LAI. Therefore, careful attention should be paid to the examination
of PV connections when the situs is ambiguous.
B. Four-chamber view
(a) Demonstrate normal PV connections into the LA
The PVs can often be seen entering the LA in the axial four-chamber view (Fig. 2).
An inability to demonstrate this normal connection is an important sign for suspecting
TAPVC. Recent studies have described this as the first clue to suspect the disease
[7,24]. A smooth posterior wall of the LA can be viewed as an accessory feature to
this abnormal connection of PVs and is observed in some cases.
Figure 2
On an apical four-chamber view, right and left inferior pulmonary vein enters left
antrum posteriorly and forms a “horn-like” insertion. Note the posterior wall of left
antrum is not as round and smooth as right antrum.
(b) Ventricular disproportion: RV > LV
The discrepancy in bilateral ventricles is not always observed and tends to be recognized
after the gestational age of 7 months [24]. This is because the flow of pulmonary
circulation increases in the latter stage of fetal life. Therefore, the extra abnormal
flow from the PV appears to affect the size of the heart chambers in the late second
trimester. Furthermore, dilatation of the right ventricle is not obvious among cases
of prominent ASD or obstructive TAPVC [33]. A recent study recommended that this feature
should not be enrolled into the diagnostic criteria because routine second trimester
obstetric ultrasonography is executed at the gestational age of 18–22 weeks [7].
(c) Retrocardiac space examination: wide space behind the heart
Evaluation of the area behind the heart offers important information for diagnosing
a fetal CHD, including TAPVC [34]. The diagnostic marker is a longer-than-usual distance
between the LA and aorta [7]. A Japanese group introduced a post-LA space index to
objectively examine this area. This index, defined as the ratio of the LA-descending
aorta distance to the descending aorta diameter, was significantly higher in eight
TAPVC fetuses than in 101 non-TAPVC fetuses (mean, 1.51 versus 0.71 ± 0.23) [35].
C. Three-vessel view
(a) A fourth vessel adjacent to the pulmonary trunk (supracardiac type)
The three-vessel view is a section for surveying the alignment, position, and size
of the pulmonary artery, aorta, and SVC. In supracardiac TAPVC, the PV empties into
a common vertical vein, which then connects to the RA. In this view, the vertical
vein can be observed as a fourth vessel to the left or posterior left of the pulmonary
artery [36].
(b) SVC dilatation (supracardiac type)
In the three-vessel view, the SVC usually appears smaller than both the pulmonary
artery and aorta. In some cases of supracardiac TAPVC, the SVC is either as large
as or more prominent than the aorta [37]. In supracardiac TAPVC, SVC dilatation is
more frequently identified than is the extra vertical vein [24].
D. Abdominal view
(a) An extra vessel between the IVC and aorta (infra-cardiac type)
Similar to the fourth vessel in the supracardiac type, the descending vertical vein
in infracardiac TAPVC can be seen between the IVC and aorta in the transverse view
of abdominal images [36].
Step 2: Actively looking for the confluent vessel and vertical vein and identifying
the TAPVC type.
A. Confluent vein
When the four PVs fail to develop a normal connection with the LA, they usually drain
into a confluent vein before emptying into the RA. Carefully searching for the confluent
vein is important when a normal PV connection is not identified, and this can be achieved
in most cases [38]. This tubular vessel is usually located between the LA and aorta
in types I, II, and III TAPVC [24]. Among those with highly suspected TAPVC but without
a visible confluent vein, focus on the CS or mixed-type TAPVC should be emphasized
[36,24] (see description below).
B. Dilatation of the CS (intracardiac type)
The diameter of the CS is usually <3 mm in a normal fetal heart, and an enlarged CS
is associated with CHD, including left SVC and coarctation [39]. In intracardiac TAPVC,
the PV empties into the CS through PV confluence or direct drainage. Therefore, dilatation
of the CS raises the suspicion of this type of TAPVC [31].
C. Vertical vein (infracardiac and supracardiac types)
Following the recognition of the confluence vein, the sonographer can sweep the transducer
along the transverse axis or change to the coronal/sagittal view to identify the site
of PV confluence joining the vertical vein [38]. The ascending or descending vertical
vein can usually be visualized in both infracardiac and supracardiac cases through
two-dimensional ultrasound or Doppler flow examination [24] (see below).
D. Color flow Doppler and spectra Doppler
The application of color Doppler imaging is very useful to detect the aforementioned
direct and indirect signs, especially the (1) normal connection of the PVs to the
LA, (2) confluent vein, and (3) vertical vein [24,36]. The fetal heart should be placed
apically or transversely, and then the color box should be narrowed to the LA for
depiction of the PV entry. Using low pulse-repetition frequency and high sensitivity
settings, the PV can be rapidly identified in most pregnant woman [7] (Fig. 3). A
careful survey of the vertical vein through color flow mapping is essential for both
the diagnosis and outcomes. Color Doppler shows flow turbulence if an obstruction
is present at the connection site, which leads to a poor prognosis [38].
Figure 3
Four-chamber view of the right pulmonary vein empty into left antrum in color Doppler
image. Note the color box should be narrowed to the LA with low pulse-repetition frequency
(0.8–2.0 Hz) and high sensitivity setting.
The normal PV Doppler waveform is pulsatile and biphasic, with distinct systolic and
diastolic peaks, followed by little or no forward flow at the end of diastole [36]
(Fig. 4). Abnormal PV spectral Doppler findings include a continuous monophasic pattern
or abnormal pulsatility [24]. A low velocity monophasic waveform in the vertical vein
with a high velocity (>0.5 m/s) flow over the connection site indicates the presence
of obstruction [24,38].
Figure 4
Doppler waveform across the inferior pulmonary vein. This triphasic pattern is similar
to the waveform observed in the ductus venosus. Note the Doppler sample gate placed
on the pulmonary vein is within the lung parenchyma (s, systolic velocity; d, diastolic
velocity; a, atrial reversal flow).
E. Four-dimensional ultrasound
One study applied four-dimensional ultrasound with B-flow imaging and STIC to obtain
more information regarding abnormal venous connections. The advantage of this technique
is the demonstration of the entire route and anatomic correlation of the PV confluence,
vertical vein, and anomalous venous connection site, which sometimes cannot be clearly
identified through two-dimensional examination [37].
Conclusion
Over the past few years, an increasing number of studies on the prenatal diagnosis
and postnatal management of TAPVC have been published. Through awareness of this rare
disease and a good understanding of the embryology/anatomy of the venous system, the
recognition of anomalous venous return can be achieved in mid-trimester anatomical
screening examinations or through echocardiography. Failure to identify a normal PV
connection and a demonstration of the vertical vein and confluent vessel are essential
for a confirmation of the diagnosis. Advanced sonographic techniques offer further
detailed information for postnatal care and surgical preparation.