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Seminars in Fetal & Neonatal Medicine (2005) 10, 553e566
www.elsevierhealth.com/journals/siny
Hypoplastic left heart syndrome: From in-utero
diagnosis to school age
Jack Rychik a,b,*
a
b
Fetal Heart Program, The Cardiac Center at The Children’s Hospital of Philadelphia, PA, USA
University of Pennsylvania School of Medicine, Philadelphia, PA, USA
KEYWORDS
Hypoplastic left heart
syndrome;
Congenital heart
disease;
Fetal diagnosis
Summary HLHS can be treated with successful survival outcome. Prenatal diagnosis of the anomaly is now quite common. Our understanding of the developmental aspects of HLHS during the second and third trimesters of gestation is advancing.
Survivors of surgery are being closely followed and studied as they proceed forwards
in time. A number of morbidities are identified. Many questions concerning the pathophysiological mechanisms of these morbidities exist. New therapies and treatments
will certainly arise to meet the challenges these children face as they enter into
adulthood, and as our understanding of this unique cardiovascular state progresses.
ª 2005 Elsevier Ltd. All rights reserved.
Introduction
In the current era, nearly all forms of congenital
heart disease are amenable to highly successful
reparative strategies. However, one of the most
persistently difficult malformations to treat is when
there is underdevelopment, or hypoplasia, of a ventricle. One such anomaly, the hypoplastic left heart
syndrome (HLHS), is defined as an anatomical
constellation in which the left-sided structures
(mitral valve, left ventricle, aortic valve, aorta)
are inadequate and non-viable for support of the
systemic circulation. Without early neonatal surgical
intervention, this anomaly is uniformly fatal. Since
* Fetal Heart Program, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA
19104, USA. Tel.: C1 215 590 2192; fax: C1 267 426 5082.
E-mail address: [email protected]
the early 1980s, a series of surgical interventions
have been developed, and have subsequently
evolved, that allow for reconstruction of the circulation and survival.1e3 However, despite major
strides in improving survival, surgical mortality remains at least 5e10% in the best of series with ongoing life-long morbidity.
This article will review the advances made in
diagnosis and management of HLHS in the past two
decades, with emphasis on the progress made in
understanding the fetal aspects of this anomaly,
recent advances in surgical strategy, and some of
the long-term complications that these children
face as they grow into adulthood.
Prenatal diagnosis and perinatal course
HLHS occurs in approximately 200e300 per million
livebirths.4 The anatomy typically consists of
1744-165X/$ - see front matter ª 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.siny.2005.08.006
554
hypoplasia of the left ventricle with mitral atresia
or stenosis, aortic atresia or stenosis, and hypoplasia of the ascending aorta. As fetal ultrasound techniques and obstetric ultrasound operator skill have
improved over the past decade, prenatal detection
rates for HLHS have increased substantially. The diagnosis is now commonly made prior to birth as it
can be determined from simple absence of the normal ‘four-chamber’ heart. HLHS can be associated
with chromosomal anomalies, most commonly
Turner’s syndrome (45, XO),5 although the majority
of patients do not have any identifiable chromosomal or genetic association. Extracardiac anomalies can also be associated and have been
described in up to 28% of cases.6 The recurrence
rate for bearing another child with left-sided heart
disease (e.g. bicuspid aortic valve, coarctation of
the aorta) after having one child with HLHS is quite
high compared with the recurrence rate for other
forms of heart disease. Recurrence of left-sided
congenital heart disease (CHD) is reported to be
anywhere from 2% to 13%.7 This lends credence to
the notion of a strong genetic component or familial
predisposition to the disease. Specific gene loci
have, however, not yet been identified. Multiple genotypic configurations are likely to contribute to the
heterogeneous group of phenotypic anatomical
configurations called ‘HLHS’.
Features of in-utero diagnosis
HLHS is perceived to be a clinically silent disease
while in utero. Absence of a viable left ventricle
leads to dilation and hypertrophy of the right
ventricle. The right ventricle experiences an increase in volume load, as blood is diverted away
from the underdeveloped left side. Both the pulmonary and systemic vasculatures are perfused via
the right ventricle and pulmonary artery, with
patency of the ductus arteriosus assuring blood
supply to the systemic circulation. Most fetuses
with HLHS are asymptomatic prior to birth and come
to gestational term without difficulty. Hydrops
fetalis or fetal demise is unusual; when present, it
is commonly due to causes other than heart failure.
This suggests little physiological disturbance of the
cardiovascular system while in utero, but a more
careful analysis reveals otherwise.
Fetuses with HLHS are typically small for gestational age.8 Whether this is a genetically associated finding or acquired during development,
perhaps related to abnormal blood flow patterns,
is unclear. Although the absence of hydrops in
the typical case suggests adequate cardiac output,
evidence has recently been found for diminished
total cardiac output in the fetus with HLHS
J. Rychik
compared with control normal subjects with two
ventricles (A. Szwast, unpublished data). In a series
of 40 normal fetuses, combined cardiac output of
both ventricles as measured by Doppler echocardiography was 508 G 88 ml/min/kg compared with
cardiac output in an HLHS group of 18 fetuses of
419 G 122 ml/min/kg (P ! 0.05). This suggests incomplete right ventricular compensation for absence of the left ventricle in fetal HLHS, with
approximately 20% diminution in total combined
cardiac output as measured by Doppler techniques.
The decrement in cardiac output may explain the
limitations in somatic growth seen in these fetuses.
As we shall see, additional flow disturbances distinguish the cardiovascular system of a fetus with HLHS
from a fetus with a normal two-ventricle heart.
Assessment of a fetus with HLHS via fetal
echocardiography reveals normal umbilical arterial
flow patterns, suggesting healthy placental function. When performing fetal echocardiography, diagnostic features to focus on include morphometric
assessment of the left ventricle, mitral valve,
aortic valve and ascending aorta. In cases of mitral
atresia, the left ventricle may be completely
absent. In cases of mitral stenosis, a small hypertrophied left ventricle can be seen. Echocardiographic
brightness of the left ventricular endocardium suggests the presence of endocardial fibro-elastosis;
a fibrotic change in the endocardial portion of the
myocardium found in subjects with left-sided
obstructive disease. Colour Doppler flow mapping
may demonstrate a small amount of antegrade
flow in cases of stenosis, or absence of flow across
the mitral or aortic valves in cases of atresia. In
the presence of aortic atresia, the ascending aorta
may be quite miniscule, functioning as a common
coronary artery with retrograde perfusion via the
transverse aorta from the ductus arteriosus. The
tricuspid valve may be abnormal in a fetus with
HLHS, and may be incompetent. A mild degree of
tricuspid regurgitation is common, but severe regurgitation can also be seen. In such cases,
hydrops may develop as a consequence of diminished forward flow and elevated central venous
pressure.9 Tricuspid regurgitation may progress
during gestation; when severe, it may result in
right ventricular dysfunction.10 In those that survive to term, severe tricuspid regurgitation is
a risk factor for successful staged reconstruction.
Fetal blood flow patterns in HLHS:
pulmonary vasculature and restrictive
atrial septum
Doppler echocardiography has allowed in situ
observation of blood flow patterns of fetuses
Hypoplastic left heart syndrome
with HLHS. Investigation of these blood flow
patterns has resulted in a much clearer understanding of this complex and unique physiology.
In fetal HLHS, placental and systemic venous
return drains to the right atrium. Blood flows
across the tricuspid valve into the right ventricle
and is ejected into the pulmonary artery. The
majority of blood volume is then delivered across
the ductus arteriosus to the descending aorta, with
retrograde perfusion of the transverse aorta, head
vessels, ascending aorta and coronary arteries,
depending upon the degree of competitive antegrade flow from the underdeveloped left ventricle.
A portion of the blood volume delivered to the
main pulmonary artery also perfuses the branch
pulmonary arteries and the pulmonary vasculature. Elevated pulmonary vascular resistance limits the amount of pulmonary blood flow in the
fetus. The precise fraction of pulmonary blood
flow varies with gestational age, with an increasingly greater amount occurring later in gestation (up
to 25% of the total cardiac output).11 Although the
amount of pulmonary blood flow as a fraction of
the total cardiac output in the fetus is relatively
small, it is believed to be an important variable in
promoting normal pulmonary vascular development.
In a fetus with HLHS, pulmonary venous return is to
a left atrium that may have no other egress except
across the atrial septum, as the mitral valve and
left ventricle are underdeveloped and may not allow
for adequate left atrial decompression. Hence, the
size of the interatrial communication is critical to determining the degree of left atrial decompression,
and will determine the amount of forward pulmonary
blood flow that will take place. In the presence of
a large patent foramen ovale, or atria septal defect,
left atrial decompression takes place and forward
pulmonary blood flow will be normal. However, in
conditions of a very restrictive or intact atrial septum, left atrial and pulmonary venous pressure will
be elevated, and forward flow into the pulmonary arteries will be limited (Fig. 1). Blood will be preferentially shunted away from the lungs towards the
ductus arteriosus and systemic circulation. Persistent pulmonary venous hypertension and limited pulmonary arterial blood flow can result in
developmental and histological changes within the
lung vasculature.
While in utero, fetuses suffer no clinical symptoms in relation to a restrictive atrial septum as
the lungs are not inflated and do not provide for
oxygenation. However, at birth, with expansion of
the lungs at the first breath, pulmonary venous
return is immediately impaired leading to pulmonary venous congestion and severe hypoxaemia.
Infants born with HLHS and an intact or restrictive
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atrial septum constitute an urgent situation, and
require procedures to open the atrial septum
immediately. The outcome for these infants, despite timely and adequate opening of the atrial
septum, is extremely poor.12 Prenatal identification of this phenomenon is possible by observation
of the appearance of the atrial septum on twodimensional echocardiography, but also by analysis
of pulmonary venous flow patterns obtained using
Doppler echocardiography (Fig. 2).13
In a review of experience at The Children’s
Hospital of Philadelphia, only 17% of newborns
with intact atrial septum survived surgical reconstruction. Death is typically related to respiratory
insufficiency and hypoxaemia. Autopsy analysis of
the pulmonary vasculature in infants with HLHS
and intact atrial septa reveals marked histological
changes in the pulmonary veins with severe thickening and ‘arterialization’ (Fig. 3). These histological findings suggest the presence of a fixed
pulmonary vascular anomaly in addition to the
structural cardiac abnormality of HLHS.12
The advent of fetal echocardiography has allowed for reliable identification of HLHS with an
intact atrial septum prior to birth. In order to
reduce the amount of time after placental separation in which there is severe hypoxaemia, and in
order to most effectively open the atrial septum,
the author’s group has undertaken a strategy of
Caesarean section delivery at term with immediate
surgical resection of the atrial septum within the
first hour of life. Two operating rooms are prepared
adjacent to each other with a dedicated multidisciplinary team involved in the care of the mother
and infant. In a series of four such cases, despite
successful fetal delivery and atrial septal resection,
none of the infants survived beyond 30 days of life
(unpublished data). Other centres have reported
some improvement in results with catheter-driven
interventions performed immediately after birth;
however, outcome is still poor in comparison with
those with a naturally open atrial septum.14
Despite proper identification of the disease with
prompt and immediate postnatal intervention,
outcome remains extremely poor. Pulmonary vascular development has been deleteriously affected
while in utero; as such, creating an open atrial
septal communication after birth is too late to
affect the process. The ability to identify patients
with the disease reliably and the extremely poor
postnatal outcome makes HLHS with intact/restrictive atrial septum an ideal lesion on which to
attempt prenatal intervention. These techniques
are currently being explored at a number of
centres around the world.15 Beyond the technical
challenge of performing an adequate prenatal
556
J. Rychik
Figure 1 (A) Patterns of blood flow in the normal fetal heart. The left ventricle fills predominantly from the right to
left shunting across the foramen ovale, but also with a small amount returning to the left atrium via the pulmonary
veins. (B) Blood flow patterns in a fetus with hypoplastic left heart syndrome and an open atrial septum. Blood returning to the left atrium via the pulmonary veins cannot drain into the hypoplastic left ventricle, but finds its way across
the atrial septum to the right atrium. The right atrium and right ventricle therefore receive the entire complement of
venous return, both systemic and pulmonic. (C) Blood flow pattern in a fetus with an intact atrial septum. Pulmonary
venous return enters the left atrium but has no egress. Left atrial hypertension and pulmonary venous hypertension
ensues. Occasionally, blood will find its way out of the left atrium via primitive venous collaterals such as a levo-atrial
cardinal vein. Ao, aorta; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PA, pulmonary artery; PDA, patent
ductus arteriosus; RA, right atrium; RV, right ventricle; SVC, superior vena cava.
opening of the atrial septum is the dilemma of timing and potential reversibility of the process.
These questions are to be addressed via ongoing
investigations in the near future.
Cerebrovascular flow: the heartebrain
interaction
There is concern about the adequacy of blood
volume delivered to the brain in a developing fetus
with HLHS. In the normal fetus, flow is antegrade
via the left ventricle and ascending aorta to the
carotid arteries. The ascending aorta is a relatively
large vessel, carrying approximately 40% of the
combined cardiac output in the normal twoventricle state. However, in a fetus with HLHS,
antegrade flow in the ascending aorta is very
limited, or non-existent, and the ascending aorta
is variably small. The cerebral circulation is
supplied by the transverse aorta, which is perfused
retrograde from the ductus arteriosus. Hence the
blood volume delivered across the transverse aorta
is only a small fraction of that which is ejected
from the right ventricle.
Although precise measures of cerebrovascular
flow can be difficult, a measure of relative cerebrovascular resistance is possible. The pulsatility
index (PI) is a Doppler-derived measure of downstream vascular resistance and can be calculated
easily by analysis of the Doppler spectral waveform
(Fig. 4). Cerebrovascular resistance, as measured
by applying Doppler echocardiography in the middle cerebral artery, can be compared with placental vascular resistance, as measured in the
umbilical artery. In the normal healthy state, placental vascular resistance is very low due to its
highly vascular nature, while cerebrovascular resistance is relatively high. The PI ratio of middle cerebral artery to umbilical artery is high (O1). Under
Hypoplastic left heart syndrome
557
Figure 2 Spectral display of fetal pulmonary vein Doppler flow patterns. In the top panel is an example of a fetus
with hypoplastic left heart syndrome (HLHS) and an open atrial septum. The predominance of flow is forward out of
the vein as designated by flow above the baseline. There is only a small amount of reversal of flow (below the baseline) with atrial contraction, designated by the line and cross-hair. In the bottom panel is an example of a fetus with
HLHS and an intact atrial septum. Note the limited amount of forward flow (above the baseline) compared with the
panel above. Also note the prominent reversal of flow (below the baseline) designated by the line and cross-hair. The
peak velocity of reversed flow is equal to that of forward flow. This suggests physiological impairment to left atrial
egress and is a marker for severe pulmonary vascular disease and the resulting clinical sequelae after birth.
pathological conditions such as placental insufficiency or fetal distress (e.g. infection, hypovolaemia, heart failure), autoregulatory mechanisms
come into play. This results in diminution of cerebrovascular resistance in order to preserve the volume of blood flow to the brain (Fig. 5). Hence, in
a fetus in distress, the ratio of middle cerebral
artery PI to umbilical artery PI reaches 1 or even
!1. This phenomenon is called ‘cephalization’ in
which blood volume, in response to regional
changes in vascular resistance, is redistributed towards a vital organ, the brain.
In HLHS, investigators have found a shift in
resistance ratios compared with normal, with
‘cephalization’ a common finding.16 Kaltman et al.
investigated the middle cerebral artery PIs of a large
Figure 3 Histological stain of pulmonary veins in hypoplastic left heart syndrome. The panel on the left is an example of a pulmonary vein in a newborn with an open atrial septum. The panel on the right is an example of a pulmonary
vein in a newborn with an intact atrial septum. Note the thickened vessel wall and the presence of multiple darkly
stained elastic laminae, or ‘arterialization’ of the pulmonary vein.
558
J. Rychik
Figure 4 Method used for calculation of the pulsatility index (PI). Doppler spectral example of a normal umbilical
artery tracing.
series of fetuses with both right- and left-sided obstructive lesions.17 Fetuses with right-sided obstructive disease had relatively high PIs compared
with normal fetuses, suggesting elevated cerebrovascular resistance, while those with HLHS had relatively low PIs compared with normal fetuses and
markedly lower PIs than fetuses with right-sided
anomalies (Fig. 6). These findings can be logically
explained as follows. In a fetus with a hypoplastic
right ventricle or pulmonary atresia, blood flow is
shunted towards the left side with an increased
amount of blood volume filling the aorta and a concomitant increase in blood volume potentially being
delivered to the brain. In an attempt to limit this
increase in flow, autoregulatory mechanisms result
in an increase in cerebrovascular resistance. In
Figure 5 Doppler spectral display of flow in the middle cerebral artery. The top panel shows an example of normal
high vascular resistance. This is suggested by the relatively low diastolic velocity (D) compared with the systolic velocity (S). The bottom panel is an example of abnormal low vascular resistance. This is suggested by the elevated diastolic velocity.
Hypoplastic left heart syndrome
559
impaired head and brain growth. Further research
in this area will lead to an improved understanding
of the possible developmental links between HLHS
and brain dysfunction, now commonly identified
in this form of congenital heart disease (see below).
Surgical concepts and results
Figure 6 Pulsatility index (PI) z scores for gestational
age for different groups of fetuses sampled. One hundred and twenty-five normal fetuses with two ventricles
and no CHD were studied as controls, with a mean PI z
score of nearly zero. Twenty-one fetuses with left-sided
heart disease (LSOL), but with two ventricles and normal
left ventricular output, also had normal PI z scores.
However, 23 fetuses with right-sided heart disease
(RSOL) had significantly higher mean PI z scores
(P ! 0.05) and 34 fetuses with hypoplastic left heart
syndrome (HLHS) had significantly lower mean PI z
scores (P ! 0.05) than normal. In other words, fetuses
with right-sided disease had higher middle cerebral artery vascular resistance than normal, and fetuses with
HLHS had lower middle cerebral artery vascular resistance than normal.
contradistinction, in a fetus with HLHS, blood flow is
shunted away from the left side and is delivered to
the transverse aorta in a retrograde fashion. A decreased complement of blood volume is delivered
to the brain. Hence, in an attempt to increase cerebral blood flow, autoregulatory mechanisms
promote cerebrovascular vasodilation, with a decrease in vascular resistance. These data suggest
a very fundamental phenomenon not previously appreciated in fetuses with CHD. A dynamic interaction exists between the heart and the peripheral
vascular beds. Type of CHD and the subsequent alterations in flow patterns as a consequence may result in changes in the peripheral vascular beds, with
potential ramifications for organ perfusion.
The implications of this phenomenon are profound as the presence of structural CHD may, in
fact, exert the degree to which blood volume is
delivered to the developing fetal organs. In particular, the relationship between fetal cerebral blood
flow and neurocognitive outcome in children with
HLHS is of great interest. Shillingford et al. investigated the relationship between newborn head
circumference and size of ascending aorta in
infants with HLHS.18 They found a striking relationship between small head circumference and small
ascending aortic size, suggesting that early diminished forward flow in the aorta may lead to
The surgical approach to reconstruction for HLHS is
well established and performed regularly in many
centres in North America and Europe. Initially
conceived by William Norwood in the late
1970s,19 the approach has undergone modification
and evolution resulting in dramatically improved
survival statistics.2 Currently, the strategy consists
of three operations (Table 1). The overall objective is to ultimately assign the right ventricle to
the task of propelling blood into the systemic circulation, and for systemic venous return to passively flow into the pulmonary circulation in the
absence of a ventricular pumping chamber.
Although the strategy is not considered a repair
or a ‘cure,’ it does allow for normalization of blood
flow and creation of a system for sufficient oxygen
delivery for survival.
An alternative management strategy for HLHS is
infant cardiac transplantation. A number of centres
have excellent results with transplantation20; however, in the author’s view, the limited number of organs and the growing improvement in outcome for
reconstruction makes the latter the more logical
choice. Recently, an innovative technique has
been described in which stenting of the ductus arteriosus in the cardiac catheterization laboratory and
pulmonary artery banding has been performed,
with a more traditional pulmonary arteryeaorta
anastomosis and arch reconstruction performed at
a later point in time in conjunction with a bidirectional Glenn. This has been labelled the ‘hybrid procedure’ in that therapy consists of both catheterdriven intervention and surgery.21 The theoretical
benefits of this approach include elimination of
the first-stage operation in infancy, with a potential
reduction in early mortality. The initial experience
with this approach is still developing and will have
to demonstrate superior outcomes to the more traditional strategy of classic reconstruction in infancy
before becoming widely accepted.22
The author’s preferred strategy for HLHS is the
staged surgical reconstruction. Following stabilization with initiation of prostaglandin E1 infusion
for maintenance of patency of the ductus arteriosus, the first stage, or Norwood operation, is
undertaken. The goals of this procedure are to
more permanently redirect pulmonary venous
560
Table 1
Reconstructive strategy for hypoplastic left heart syndrome
Operation
Age
Objective
Procedure
Physiological impact
Stage I
(Norwood operation)
Newborn
Unimpaired mixing of systemic
and pulmonary venous return
Reliable, unobstructed
flow from right ventricle
into patent, newly
constructed aorta
Right ventricle as the
systemic and pulmonic
ventricle
Right ventricle volume
overload
Peripheral oxygen
saturation 75e85%
Stage II (superior
cavopulmonary
connection)
4e6 months
Incorporation of superior
systemic venous return
to the lungs as the source
for oxygenation
Stable, more reliable source
of pulmonary blood flow
Stage III
(Fontan operation)
18 monthse3 years
Incorporation of inferior
systemic venous return
into the lungs
Atrial septectomy
Proximal pulmonary artery
to aorta anastomosis
Reconstruction of the aortic
arch arising from the right ventricle
Creation of a reliable
source for pulmonary blood
flow (aorto-pulmonary shunt,
or right ventricle to
pulmonary artery conduit)
Elimination of shunt or conduit
Anastomosis of superior vena
cava to the branch pulmonary
arteries (bidirectional
Glenn, or hemi-Fontan)
Augmentation of branch
pulmonary arteries as necessary
Inferior vena cava flow channelled
to the pulmonary arteries (Fontan
operation, many modifications)
Volume unloading
of the right ventricle
Peripheral oxygen
saturation 80e85%
Increased pulmonary
blood flow
Peripheral oxygen
saturation O90%
J. Rychik
Hypoplastic left heart syndrome
return to the right atrium and assign the right
ventricle to the task of ejecting both systemic and
pulmonic venous return into a reconstructed aorta.
The ‘neo’-aorta is composed of the transected
native proximal pulmonary artery which is anastomosed to the diminutive native ascending aorta. In
order to fill out the full calibre of this ‘neo’-aorta,
a gusset of pulmonary homograft is used to create
an open and smooth transition in the vessel down
to the descending aorta distal to the insertion site
of the ductus arteriosus. An alternative approach
is described in which natural aortic and pulmonic
tissue alone is used to completely refashion the
aorta.23 Once an open pathway has been created
from the right ventricle to the descending aorta,
a source for pulmonary blood flow is established.
In the classic Norwood operation, a tube graft is inserted from the base of the innominate artery or
directly from the reconstructed aorta to the
branch right pulmonary artery (aorto-pulmonary
shunt, modified BlalockeTaussig shunt). Recently,
interest has been generated in the use of a small
tube conduit from an incision in the body of the
right ventricle to the central pulmonary arteries
as a source of pulmonary blood flow (Sano modification).24 This modification may have some advantages in that, unlike the aorto-pulmonary shunt,
there is no potential for competitive steal of blood
flow away from the ascending aorta and coronary
circulation. Preliminary data suggest an improved
early survival for infants utilizing the Sano-modified approach.25 However, concerns about the
long-term effects on right ventricular function of
an incision in the body of the right ventricle should
lead to caution in the widespread use of this approach. A randomized study sponsored by the National Institutes of Health looking at these two
approaches is currently underway in the USA.
The first stage of reconstruction is a technical
challenge to the surgeon and a physiological challenge to the infant. Reconstruction of the aortic
arch without proximal obstruction to coronary
perfusion or distal obstruction to descending aortic
flow is the goal. Physiologically, the right ventricle
must carry the burden of support for both the
systemic and pulmonic circulations. Experience in
postoperative care by dedicated teams of physicians and nurses has dramatically improved outcomes during the fragile period immediately
following surgery. Current survival outcomes for
stage I are greater than 90% in many centres
worldwide. Risk factors for poor outcome have
been identified,3 and include prematurity, the
presence of additional extracardiac anomalies or
chromosomal anomalies, and the anatomical findings of an abnormal tricuspid valve with severe
561
regurgitation or an intact atrial septum. In the author’s experience, other structural factors such as
the size of the ascending aorta or the subtype of
anatomical HLHS have not influenced outcome.
With improved stage I survival has come the identification of a growing interstage mortality, with
approximately 5% out-of-hospital mortality after
stage I but before stage II.26 The factors contributing to this mortality are unclear; however, its presence prompts the need to proceed with the stage II
operation at the earliest possible point in time
since mortality after stage II is limited.
The stage II superior cavopulmonary anastomosis operation can be performed as soon as passive
blood flow can be accommodated into the pulmonary vasculature. Pulmonary vascular resistance
decreases progressively after birth, and reaches
a point at which passive superior vena caval return
can be directed into the pulmonary arteries at
approximately 4e6 months of age. Two techniques
currently exist: (1) the bidirectional Glenn, in
which the superior vena cava is detached from
the roof of the right atrium and connected end-toside to the right pulmonary artery; and (2) the
hemi-Fontan, in which the superior vena cava is
left in situ, a side-to-side anastomosis is created
between it and the right pulmonary artery, and
a patch of pulmonary homograft is used to create
a dam to close the orifice of the superior vena cava
into the right atrium. Outcomes for both techniques are excellent, with 99% survival in a number
of series.27
The stage III operation, or Fontan operation,
can be performed electively anywhere from 18
months to 3 years of age. A variety of modifications
have evolved, with institutional-specific preferences dictating the style of operation. Common to all
is the channelling of inferior vena caval flow into
the pulmonary circulation. This can be achieved
via an intra-atrial baffle or lateral tunnel technique, in which a patch of material is sewn around
the orifice of the inferior vena cava with flow
baffled towards the junction between the superior
vena cava and the right pulmonary artery. Alternatively, a tube graft can be attached to the
inferior vena cava at its entry into the right atrium,
and then connected distally to the right pulmonary
artery outside of the confines of the right atrium.
This technique is known as the ‘extracardiac
conduit’ type of Fontan operation. The potential
benefit of this technique is the avoidance of atrial
incision and atrial hypertension, which may reduce
the incidence of late atrial arrhythmias commonly
seen in the atrial lateral tunnel technique.28
An important modification to the Fontan operation is the creation of a fenestration or
562
J. Rychik
communication between the systemic venous
pathway and the pulmonary venous chamber. In
the author’s experience, a 4e5-mm fenestration
created at the time of the Fontan operation results
in excellent postoperative outcome and a smooth
postoperative course.29 The fenestration results in
oxygen saturation that is slightly diminished due to
right to left shunting, but ventricular filling and
cardiac output are markedly enhanced; hence,
such patients have improved oxygen delivery.30
While early peripheral oxygen saturations are in
the mid-80% range, the fenestration commonly
undergoes spontaneous closure over time. In the
author’s experience, over three-quarters of fenestrations close spontaneously or are insignificantly
small within 1 year of surgery.31 Thereafter, oxygen saturation levels are O90%. Survival following
Fontan operation in the current era is excellent
with 99% survival.
School age: how are these children
doing?
The overall success of the strategy for reconstructive surgery for HLHS has resulted in a large
number of children who are survivors; the majority
are now at middle school. Most of the mortality
following reconstruction of HLHS takes place soon
after stage I or as an interstage death prior to the
superior cavopulmonary connection. Late mortality after reconstruction is relatively uncommon.
However, with an increasing number of children
surviving the rigors of surgery, a number of morbidities have been identified (Table 2).
Exercise limitation is a common finding in children with HLHS after Fontan operation. The ability
to increase cardiac output in response to the
demands of exercise is limited.32 The absence of
a pulmonary pumping chamber to deliver a normal
complement of blood to the lungs and the presence
of a morphological right ventricle as the systemic
ventricle contribute to an inability to appropriately
increase stroke volume to match needs to the same
degree seen in the normal two-ventricle heart. In
Table 2
addition, the heart rate response to exercise is typically blunted after Fontan operation due to sinus
node dysfunction. Many children with HLHS enjoy
a number of sports activities, but they frequently
tire easily and rarely enter high-level competition.
Each child is encouraged to participate in sports
and to seek out their own level of comfort, with
no strict restrictions imposed.
Atrial arrhythmias are common after Fontan
operation and are likely to be related to the
multiple incisions and suture lines present. Sinus
node dysfunction with sinus bradycardia or junctional rhythm can be present as a consequence of
the stage II or stage III operations, as these
operations require manipulation near the sinus
node with potential trauma to it or interruption of
the arterial supply of the sinus node.33 Atrial flutter
can be seen as a consequence of scarred atrial tissue and may sometimes be difficult to treat.
Children after Fontan operation have a predilection towards thrombus formation.34 The cause of
this phenomenon is multifactorial. A generalized
low cardiac output state with stasis of blood and
low flow velocity within the atria are contributing
factors. Synthetic patch material is used for the
lateral tunnel or conduit systemic venous pathway,
which may act as a thrombogenic source. Atrial arrhythmias may predispose to clot formation. A
number of investigators have documented abnormalities in coagulation proteins after Fontan operation.35 Recently, coagulation abnormalities have
been discovered in infants with single-ventricle
anatomy prior to Fontan operation, raising the possibility that these abnormalities are primary and
associated, but not secondarily caused by the
physiology of the Fontan circulation.36 Nonetheless, these children are at increased risk for stroke
and pulmonary embolism. Recommendations for
antiplatelet or anticoagulative therapies are controversial, with varying viewpoints on the correct
management style and efficacy of these agents.37
Prophylactic treatment strategies range from daily
aspirin (as an antiplatelet agent) to warfarin. Studies investigating the efficacy of these treatments
are currently underway.
Morbidities in children with hypoplastic left heart syndrome after Fontan operation
Morbidity
Frequency
Exercise intolerance
Arrhythmia
Thrombo-embolic disease (e.g. pulmonary embolism, stroke)
Protein-losing enteropathy
Neurocognitive disabilities (e.g. learning differences, attention deficit/
hyperactivity disorder)
Majority, to varying degrees
25e50%, to varying degrees
Approximately 10%
!5%
10e70%, to varying degrees
Hypoplastic left heart syndrome
Another enigmatic morbidity seen after Fontan
operation is protein-losing enteropathy. Abnormal
enteric protein loss can occur spontaneously, months
or years after Fontan surgery, resulting in marked
hypoproteinaemia. Clinically, these patients present
with diarrhoea, abdominal discomfort, and peripheral oedema with ascites as a consequence of low
serum protein levels.38 The disease occurs in 3e13%
of cases, with nearly 50% mortality 5 years after diagnosis.39 The precise pathophysiological mechanism is
unknown. Interventions that improve and maximize
cardiac output, such as creation of a fenestration,
have resulted in successful management of the disease, suggesting that the physiology of low cardiac
output and high central venous pressure unique to
the Fontan circulation may predispose to the ailment.40 However, questions remain regarding why
certain patients suffer from protein-losing enteropathy and others with similar haemodynamics do not,
raising the possibility of a predisposition to the disease in select patients, but only after the haemodynamics of the Fontan circulation are imposed.
Of great interest has been the identification of
neurocognitive difficulties in many of the children
with HLHS now entering school age.41 A number of
studies have demonstrated that these children
face a variety of neurodevelopmental difficulties.
In one series, mean scores on standardized psychometric tests for a group of HLHS children were significantly lower than the normal population, with 18%
scoring less than 70 on intelligence quotient testing.
Of note, nearly 70% met criteria for attention deficit/hyperactivity disorder based on neurological examination.42 In another study, children with HLHS
after Fontan operation were compared with other
children with a single ventricle after Fontan operation. Test scores for the HLHS group were found to
be lower than those for the non-HLHS group, but
were in the low-average range.43 Most interestingly,
similar deficiencies have been identified in children
with HLHS undergoing a strategy of heart transplantation,44 suggesting that these deficits may not necessarily be related to the style of treatment but are
directly associated with HLHS.
Children who undergo the reconstructive approach for HLHS are required to have three operations with consequential courses of deep
hypothermic circulatory arrest; a variable that can
impact negatively on neurocognitive outcome. However, emerging data indicate that the deficiencies
seen in HLHS may be influenced by other factors. The
duration of deep hypothermic circulatory arrest does
not appear to correlate with the neurodevelopmental deficits found. Structural abnormalities of the
brain have been identified in HLHS prior to surgery,
including holoprosencephaly and agenesis of the
563
corpus callosum.45 A more subtle abnormality of
brain dysgenesis noted is that of an underdeveloped
operculum, the region of the cortical mantle at the
juncture of the frontal, parietal and temporal lobes.
Deficiencies in this region are associated with feeding and swallowing difficulties, and this is of interest
as many infants exhibit problems with feeding after
stage I surgery.46 Periventricular leukomalacia,
a non-specific sign of cerebral white matter injury
as seen on magnetic resonance imaging, is present
in up to 16% of neonates with complex congenital
heart disease prior to surgery, but in over 50% after
surgery.47,48 This raises the possibility that neonates
with HLHS have a fragile central nervous system,
with inherent deficiencies present that may be further impacted upon by the potential neurological ‘injury’ of the procedures required for heart surgery.
Recent data on the response to brain injury after cardiopulmonary bypass demonstrate a relationship
with a gene polymorphism of the apo-lipoprotein E,
a molecule that plays an important role in neuronal
repair. Following heart surgery, infants with apo-lipoprotein E epsilon 2 allele are at greater risk of having significantly lower psychomotor development
indices at 1 year of age than infants with the other
genotypes for this protein.49 These data further support the notion of certain patients being at risk for
neurodevelopmental dysfunction with a predilection
towards poor response to nervous system injury, such
as cardiopulmonary bypass. Whether infants with
HLHS are at such an increased risk is speculative at
this point. Linking the data on fetal cerebrovascular
flow patterns and cerebrovascular resistance in the
fetus with HLHS with the subtle structural findings
and genetic predisposition to injury that exists may
ultimately result in stratification of the infant at
most significant risk for neurological injury. Specific
changes in neuroprotective strategy may then be
implemented for these high-risk patients.
Putting it all into perspective:
counselling a family carrying
a fetus with HLHS
Considering the outcome data on morbidity and
mortality as we know it today, how should one
counsel the family of a fetus with HLHS? Geographic, cultural and religious factors influence
the response when a family is faced with the news
of carrying a fetus with HLHS. Unfortunately,
because of the history related to poor outcome in
the past, many practitioners are unaware of the
current survival statistics for HLHS. National or
regional experiences may also impact either
564
positively or negatively on the statistics and data
transmitted to the family. Not all centres are
uniformly able to offer the same survival statistics
based on their own experiences. This raises the
question of regionalization of care and referral to
centres of excellence specifically identified as able
to treat this anomaly. The facts support the notion
that survival is possible for the majority when the
procedure and postoperative care are performed
by experienced hands. Lack of knowledge by
primary obstetricians and maternalefetal medicine
experts concerning these recent statistics can result in inaccurate transfer of information to families. While excellent operative statistics can now be
quoted, counselling sessions should focus more
extensively on the issues of long-term morbidity
and the risks of unknown beyond the second decade
of life, for which few data are available. In the
author’s view, counselling must be offered by
knowledgeable physicians/nurses in a non-biased
factual manner, providing as much objective information as possible. Family support should be
offered regardless of the decisions made.
Development of a multidisciplinary approach to
counselling these families is helpful. The author’s
group has constructed a Fetal Heart Program that
includes cardiologists, nurses, cardiac surgeons and
maternalefetal medicine specialists, all of whom
contribute to the evaluation and assistance of these
families as they make their way forward in gestation. Bringing potential parents into contact with
other families those have gone through the decision
process can be helpful. For those families who
choose to continue the pregnancy, delivery can be
safely performed vaginally with prostaglandin initiated after birth. The author’s group routinely
perform serial fetal echocardiographic studies for
fetuses with HLHS at 4-week intervals after initial
prenatal diagnosis to survey for any changes in
tricuspid valve regurgitation, or restriction in the
atrial septum. These serial sessions also offer the
opportunity for further educational and psychological support for the parents and other family
members. A dedicated nurse co-ordinator in our
programme assists with shepherding the families
through the prenatal process, creating a smooth
transition to the environment of the intensive care
unit. Recent data suggest that such a process can
alleviate some of the stress related to carrying
a fetus with HLHS.50 Prenatal diagnosis of HLHS has
also been shown to result in improved physiological
state prior to surgery51 and improved surgical outcome.52 The potential impact of prenatal diagnosis
of HLHS on some of the long-term morbidities listed
above, particularly neurocognitve outcome, is unknown; however, a positive influence is expected.
J. Rychik
Practice points
1) Currently multiple techniques for palliation of HLHS with relatively good survival
2) Neurocognitive testing and surveillance is
indicated in children with HLHS
Research directions
1) Improved understanding of the development of HLHS during fetal life
2) Long-term follow up and adult outcome of
survivors of HLHS
References
1. Spray TL. Stage I reconstruction. In: Rychik J, Wernovsky G,
editors. Hypoplastic left heart syndrome. Boston/
Dordrecht/London: Kluwer Academic Publishers; 2003.
p. 89e105.
2. Mahle WT, Spray TL, Wernovsky G, Gaynor JW, Clark 3rd BJ.
Survival after reconstructive surgery for hypoplastic left
heart syndrome: a 15-year experience from a single institution. Circulation 2000;102(Suppl. 3):III136e41.
3. Gaynor JW, Mahle WT, Cohen MI, Ittenbach RF,
DeCampli WM, Steven JM, et al. Risk factors for mortality
after the Norwood procedure. Eur J Cardiothorac Surg
2002;22:82e9.
4. Hoffman JI, Kaplan S, Liberthson RR. Prevalence of congenital heart disease. Am Heart J 2004;147:425e39.
5. Natowicz M, Kelley RI. Association of Turner’s syndrome
with hypoplastic left heart syndrome. Am J Dis Child
1987;141:218e20.
6. Natowicz M, Chatten J, Clancy R, Conard K, Glauser T,
Huff D, et al. Genetic disorders and major extra-cardiac
anomalies associated with the hypoplastic left heart syndrome. Pediatrics 1988;82:698e706.
7. Boughman JA, Berg KA, Astemborski JA, Clark EB,
McCarter RJ, Rubin JD, et al. Familial risks of congenital
heart defects assessed in a population based epidemiologic
study. Am J Med Genet 1987;26:839e49.
8. Rosenthal GL. Patterns of prenatal growth among infants
with cardiovascular malformations: possible fetal hemodynamic effects. Am J Epidemiol 1996;143:505e13.
9. Hornberger LK, Sahn DJ, Kleinman CS, Copel JA, Reed KL.
Tricuspid valve disease with significant tricuspid insufficiency
in the fetus: diagnosis and outcome. J Am Coll Cardiol 1991;
17:167e73.
10. Levin MD, Gaynor JW, Tian Z, Cohen MS, Donaghue DD,
Spray TL, et al. Prevalence of perinatal atrioventricular
valve regurgitation in the single ventricle: from the fetus,
through birth, and initial palliative surgery. J Am Soc Echocardiogr 2004;17:495 [abstract].
11. Rasanen J, Wood DC, Weiner S, Ludomirski A, Huhta JC.
Role of the pulmonary circulation in the distribution of
human fetal cardiac output during the second half of pregnancy. Circulation 1996;94:1068e73.
Hypoplastic left heart syndrome
12. Rychik J, Rome JJ, Collins MH, DeCampli WM, Spray TL. The
hypoplastic left heart syndrome with intact atrial septum:
atrial morphology, pulmonary vascular histopathology and
outcome. J Am Coll Cardiol 1999;34:554e60.
13. Chintala K, Tian Z, Donaghue DD, Thomas RL, Rychik J.
Fetal pulmonary venous Doppler patterns in hypoplastic
left heart syndrome: relationship to atrial septal restriction. J Am Coll Cardiol 2004;43(Suppl. A):381A [abstract].
14. Vlahos AP, Lock JE, McElhinney DB, van der Velde ME. Hypoplastic left heart syndrome with intact or highly restrictive
atrial septum: outcome after neonatal transcatheter atrial
septostomy. Circulation 2004;109:2326e30.
15. Marshall AC, van der Velde ME, Tworetzky W, Gomez CA,
Wilkins-Haug L, Benson CB, et al. Creation of an atrial septal defect in utero for fetuses with hypoplastic left heart
syndrome and intact or highly restrictive atrial septum. Circulation 2004;110:253e8.
16. Donofrio MT, Bremer YA, Schieken RM, Gennings C, Morton LD,
Eidem BW, et al. Autoregulation of cerebral blood flow in fetuses with congenital heart disease: the brain sparing effect.
Pediatr Cardiol 2003;24:436e43.
17. Kaltman JR, Di H, Tian Z, Rychik J. Impact of congenital
heart disease on cerebrovascular blood flow dynamics in
the fetus. Ultrasound Obstet Gynecol 2005;25:32e6.
18. Shillingford AJ, Marino BS, Ittenbach RF, Fedec A, Rychik J,
Clancy RR, et al. Microcephaly is common in neonates with hypoplastic left heart syndrome. Pediatr Cardiol 2005;25:581A.
19. Norwood WI, Lang P, Hansen DD. Physiologic repair of aortic
atresia e hypoplastic left heart syndrome. N Engl J Med
1983;308:23e6.
20. Chrisant MR, Naftel DC, Drummond-Webb J, Chinnock R,
Canter CE, Boucek MM, et al. Fate of infants with hypoplastic
left heart syndrome listed for cardiac transplantation: a multicenter study. J Heart Lung Transplant 2005;24:576e82.
21. Akintuerk H, Michel-Behnke I, Valeske K, Mueller M, Thul J,
Bauer J, et al. Stenting of the arterial duct and banding of
the pulmonary arteries: basis for combined Norwood stage I
and II repair in hypoplastic left heart. Circulation 2002;105:
1099e103.
22. Galantowicz M, Cheatham JP. Lessons learned from the development of a new hybrid strategy for the management of
hypoplastic left heart syndrome. Pediatr Cardiol 2005;26:
190e9.
23. Ishino K, Stumper O, De Giovanni JJ, Silove ED, Wright JG,
Sethia B, et al. The modified Norwood procedure for hypoplastic left heart syndrome: early to intermediate results of
120 patients with particular reference to aortic arch repair.
J Thorac Cardiovasc Surg 1999;117:920e30.
24. Sano S, Ishino K, Kado H, Shiokawa Y, Sakamoto K, Yokota M,
et al. Outcome of right ventricle-to-pulmonary artery shunt in
first-stage palliation of hypoplastic left heart syndrome:
a multi-institutional study. Ann Thorac Surg 2004;78:1951e7.
25. Pizarro C, Mroczek T, Malec E, Norwood WI. Right ventricle
to pulmonary artery conduit reduces interim mortality after
stage 1 Norwood for hypoplastic left heart syndrome. Ann
Thorac Surg 2004;78:1959e63.
26. Mahle WT, Spray TL, Gaynor JW, Clark 3rd BJ. Unexpected
death after reconstructive surgery for hypoplastic left heart
syndrome. Ann Thorac Surg 2001;71:61e5.
27. Karl TR. The bidirectional cavopulmonary shunt. In:
Rychik J, Wernovsky G, editors. Hypoplastic left heart syndrome. Boston/Dordrecht/London: Kluwer Academic Publishers; 2003. p. 129e49.
28. Nurnberg JH, Ovroutski S, Alexi-Meskishvili V, Ewert P,
Hetzer R, Lange PE. New onset arrhythmias after the extracardiac conduit Fontan operation compared with the
565
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
intraatrial lateral tunnel procedure: early and midterm results. Ann Thorac Surg 2004;78:1979e88.
Gaynor JW, Bridges ND, Cohen MI, Mahle WT, DeCampli WM,
Steven JM, et al. Predictors of outcome after the Fontan operation: is hypoplastic left heart syndrome still a risk factor?
J Thorac Cardiovasc Surg 2002;123:237e45.
Hijazi ZM, Fahey JT, Kleinman CS, Kopf GS,
Hellenbrand WE. Hemodynamic evaluation before and after
closure of fenestrated Fontan. An acute study of changes in
oxygen delivery. Circulation 1992;86:196e202.
Yang SG, Clark BJ, Gaynor JW, Spray TL, Rychik J. Rate of
spontaneous closure of fenestration in the modified Fontan
operation. Circulation 1999;100(Suppl. 1):I-399.
Joshi VM, Carey A, Simpson P, Paridon SM. Exercise performance following repair of hypoplastic left heart syndrome:
a comparison with other types of Fontan patients. Pediatr
Cardiol 1997;18:357e60.
Cohen MI, Rhodes LA. Sinus node dysfunction and atrial
tachycardia after the Fontan procedure: the scope of the
problem. Semin Thorac Cardiovasc Surg Pediatr Card Surg
Annu 1998;1:41e52.
Coon PD, Rychik J, Novello RT, Ro PS, Gaynor JW, Spray TL.
Thrombus formation after the Fontan operation. Ann
Thorac Surg 2001;71:1990e4.
Odegard KC, McGowan Jr FX, Zurakowski D, Dinardo JA,
Castro RA, del Nido PJ, et al. Procoagulant and anticoagulant factor abnormalities following the Fontan procedure:
increased factor VIII may predispose to thrombosis. J
Thorac Cardiovasc Surg 2003;125:1260e7.
Odegard KC, McGowan Jr FX, Zurakowski D, DiNardo JA,
Castro RA, del Nido PJ, et al. Coagulation factor abnormalities in patients with single-ventricle physiology immediately prior to the Fontan procedure. Ann Thorac Surg
2002;73:1770e7.
Jacobs ML, Pourmoghadam KK, Geary EM, Reyes AT,
Madan N, McGrath LB, et al. Fontan’s operation: is aspirin
enough? Is coumadin too much? Ann Thorac Surg 2002;73:
64e8.
Rychik J, Spray TL. Strategies to treat protein-losing enteropathy. Semin Thorac Cardiovasc Surg Pediatr Card Surg
Annu 2002;5:3e11.
Mertens L, Hagler DJ, Sauer U, Somerville J, Gewillig M. Protein-losing enteropathy after the Fontan operation: an international multicenter study. J Thorac Cardiovasc Surg
1998;115:1063e73.
Rychik J, Rome JJ, Jacobs ML. Late surgical fenestration for
complications after the Fontan operation. Circulation 1997;
96:33e6.
Wernovsky G, Shillingford AJ, Gaynor JW. Central nervous
system outcomes in children with complex congenital heart
disease. Curr Opin Cardiol 2005;20:94e9.
Mahle WT, Clancy RR, Moss EM, Gerdes M, Jobes DR,
Wernovsky G. Neurodevelopmental outcome and lifestyle assessment in school-aged and adolescent children with
hypoplastic left heart syndrome. Pediatrics 2000;105:1082e9.
Goldberg CS, Schwartz EM, Brunberg JA, Mosca RS, Bove EL,
Schork MA, et al. Neurodevelopmental outcome of patients
after the fontan operation: a comparison between children
with hypoplastic left heart syndrome and other functional
single ventricle lesions. J Pediatr 2000;137:646e52.
Ikle L, Hale K, Fashaw L, Boucek M, Rosenberg AA. Developmental outcome of patients with hypoplastic left heart syndrome
treated with heart transplantation. J Pediatr 2003;142:20e5.
Glauser TA, Rorke LB, Weinberg PM, Clancy RR. Congenital
brain anomalies associated with the hypoplastic left heart
syndrome. Pediatrics 1990;85:984e90.
566
46. Clancy R. Neurological issues. In: Rychik J, Wernovsky G,
editors. Hypoplastic left heart syndrome. Boston/Dordrecht/
London: Kluwer Academic Publishers; 2003. p. 251e73.
47. Mahle WT, Tavani F, Zimmerman RA, Nicolson SC, Galli KK,
Gaynor JW, et al. An MRI study of neurological injury before
and after congenital heart surgery. Circulation 2002;
106(Suppl. 1):I109e14.
48. Galli KK, Zimmerman RA, Jarvik GP, Wernovsky G,
Kuypers MK, Clancy RR, et al. Periventricular leukomalacia
is common after neonatal cardiac surgery. J Thorac Cardiovasc Surg 2004;127:692e704.
49. Gaynor JW, Gerdes M, Zackai EH, Bernbaum J,
Wernovsky G, Clancy RR, et al. Apolipoprotein E genotype
J. Rychik
and neurodevelopmental sequelae of infant cardiac surgery. J Thorac Cardiovasc Surg 2003;126:1736e45.
50. Sklansky M, Tang A, Levy D, Grossfeld P, Kashani I,
Shaughnessy R, et al. Maternal psychological impact of fetal
echocardiography. J Am Soc Echocardiogr 2002;15:159e66.
51. Verheijen PM, Lisowski LA, Stoutenbeek P, Hitchcock JF,
Brenner JI, Copel JA, et al. Prenatal diagnosis of congenital
heart disease affects preoperative acidosis in the newborn
patient. J Thorac Cardiovasc Surg 2001;121:798e803.
52. Tworetzky W, McElhinney DB, Reddy VM, Brook MM,
Hanley FL, Silverman NH. Improved surgical outcome after
fetal diagnosis of hypoplastic left heart syndrome. Circulation 2001;103:1269e73.