Introduction
Hypoplastic left heart syndrome (HLHS) is one of the most severe forms of congenital
heart disease (CHD) diagnosed during pregnancy [1], [2]. The incidence of HLHS is estimated to be 0.16 to 0.36 per 1000 live births and
accounts for approximately 4.8 – 9% of all CHD [3], [4], [5]. HLHS involves cardiac anomalies with stenosis or atresia of the mitral and/or aortic
valve leading to hypoplasia of the left ventricle and the ascending aorta [6], [7]. Endocardial fibroelastosis (EFE) may be present, especially in cases with aortic
valve stenosis. Without adequate postnatal treatment the prognosis is always lethal
[7]. Postnatal therapeutic options include three staged surgical palliative procedures
culminating in a Fontan procedure, hybrid management (a combination of surgery and
cardiac catheterization), or heart transplantation. Although rare in this day and
age, conservative compassionate care is still offered in extreme cases with a low
probability of surviving interventions [8], [9], [10], [11], [12]. Other therapeutic approaches aim to address the causes of HLHS prenatally. One
such approach is intrauterine balloon dilation of the aortic stenosis to promote left
ventricular blood flow and prevent degeneration of the left ventricle [13]. Another, more recent, non-invasive prenatal approach is maternal hyperoxygenation
(MH). Maternal inhalation of oxygen seems to increase the return of blood flow from
fetal lungs towards the left atrium and consequently the left ventricle. In some cases,
MH could have the potential to promote the growth of the underdeveloped left heart
structures in fetuses with borderline left heart dimensions insufficient to support
systemic circulation after birth [14]. However, the therapeutic benefits of MH in HLHS need to be validated in prospective
studies.
Recent studies have shown changes in intrauterine cerebral perfusion, the intrauterine
development of the central nervous system, and the psychomotor development of HLHS
fetuses post partum, all of which affect the long-term neurological outcome [15], [16], [17], [18], [19]. The overall increase in the detection rates of CHD generally leads to an earlier
diagnosis, with the possibility of planning targeted prenatal treatment. Advances
in fetal echocardiography have contributed to a better understanding of the underlying
pathophysiology. In addition to sonomorphology and blood flow assessment, interest
has increasingly begun to focus on the study of cardiac function, in particular of
the right ventricle, in HLHS fetuses [20], [21], [22], [23], [24], [25]. Prenatal changes in right ventricular function may be crucial for the future functioning
of the single ventricle, as postnatal right ventricular dysfunction is an important
risk factor which affects the survival of HLHS children during multi-stage surgery
[26], [27]. Advances in perioperative care and the development of novel surgical techniques
have led to a reduction in HLHS mortality, improving the prognosis of affected children
[28], [29], [30], [31]. The purpose of this brief review is to present an overview of the existing literature,
especially with regard to novel prenatal diagnostic methods which offer better estimates
of prognosis and new pre- and postnatal therapeutic approaches.
Review
Novel aspects in the diagnosis of HLHS
In HLHS children, cardiac output depends on the right ventricle (RV). Postnatally,
single ventricle circulation using the RV can be achieved by different surgical procedures.
Intrauterine changes in RV function may have a decisive effect on diastolic and systolic
function of the future single ventricle. Postnatal RV dysfunction is consequently
an important risk factor affecting the survival of HLHS children [32]. The prenatal examination of RV function in HLHS is therefore a focus of scientific
interest.
In a retrospective study of 48 HLHS fetuses, Brooks et al. examined RV function in
these fetuses compared to normal control fetuses, using speckle tracking echocardiography.
Brooks and colleagues reported a decrease in longitudinal deformation in relation
to the deformation of the circumferential axis of the RV in HLHS fetuses. As the diameter
increased, the RV also increased and its shape became spherical, indicating that in
fetal HLHS, RV remodeling already occurs prenatally [21].
In a retrospective study of 84 HLHS fetuses using blood flow and tissue Doppler techniques,
Natarajan et al. observed significantly elevated values with regard to the RV Tei
index or myocardial performance index (MPI), a parameter of global ventricular function
[33], with the values pointing to RV dysfunction in HLHS fetuses [20]. Morevoer, the E/e′ ratio used in adult echocardiography to record ventricular filling
pressures showed elevated values in the HLHS group compared to healthy control fetuses
[20]. This ratio is the ratio of blood flow velocity during early diastolic passive filling
of the RV (E) and early diastolic myocardial relaxation rate in the region of the
RV ventricular wall (e′). The higher the E/e′ ratio ([Fig. 1]), the greater the blood flow velocity in relation to myocardial movement, which
in turn indicates an increased atrial pressure gradient and reduced relaxation capacity
or compliance of the fetal myocardium [34].
Fig. 1 Schematic illustration of the right ventricular (RV) E/e′ ratio in a healthy fetus.
E and A (red): blood flow Doppler (PW = pulsed wave)-derived peak velocity during
early (E) and late (A) diastole. The sample volume is shown over the tricuspid valve
(in red). e′ and a′ (blue): tissue Doppler (PW-TDI = pulsed wave tissue Doppler imaging)-derived
peak velocity during early (e′) and late (a′) diastole. The sample volume is shown
in the tricuspid annulus (in blue).
Our own work which analyzed RV function in HLHS fetuses revealed that HLHS fetuses
show detectable changes, particularly with regard to RV diastolic function [23], [24]. In line with the results of Natarajan et al., increased values were observed for
the E/e′ ratio of the HLHS group, indicating reduced compliance of the RV myocardium
[23]. Subgroup analysis additionally revealed that HLHS fetuses with additional left
ventricular EFE (which indicates endocardial thickening due to increased incorporation
of collagen and elastin fibers) showed signs of both systolic and diastolic dysfunction
[25]. The use of 2D speckle tracking echocardiography to analyze RV myocardial deformation
revealed significantly higher mean values for global longitudinal peak systolic strain
in HLHS fetuses compared to fetuses with normal-sized left ventricles (− 16.22% vs.
− 12.31%) ([Fig. 2]) [35]. This can be understood as a sign of RV remodeling in HLHS which leads to an adaptation
of myocardial function to left ventricular conditions.
Fig. 2 Apical four chamber view of a hypoplastic left heart syndrome (HLHS) fetus (mitral
atresia/aortic atresia) at 26 + 5 weeks of gestation. Left: Traced myocardial wall
of the right ventricle (RV) and interventricular septum for myocardial deformation
analysis (strain) using 2D speckle tracking echocardiography. Right: Curves for RV
and septal longitudinal peak systolic strain (%) of six segments of the myocardial
wall and global strain (%) for one fetal heart cycle. BL: basal lateral, ML: middle
lateral, AL: apical lateral, AS: apical septal, MS: middle septal, BS: basal septal.
High values for RV global strain can be interpreted as a sign of RV remodeling leading
to an adaptation of myocardial function to left ventricular conditions.
Postnatally, the RV function of HLHS infants was examined before and after surgery.
Petko et al. used speckle tracking techniques to record RV deformation data obtained
before and after a Norwood procedure performed in HLHS children. They reported a significant
decrease in strain and strain rates after surgery [36]. Altmann et al. aimed to determine the mortality rate of HLHS children based on
RV function. They demonstrated that RV function measured before surgery had no effect
on the survival rate after a Norwood procedure. However, a follow-up of survivors
after stage I revealed that infants with RV dysfunction before stage II had a significantly
higher mortality rate. Survival at 18 months after Norwood surgery was 93% for patients
with initially normal RV function compared to 47% for those with abnormal RV function.
The relative risk of later mortality was approximately 11 times higher in patients
with initial RV dysfunction [27]. In contrast, a recently published work showed a significant association between
RV function before and after stage I of the Norwood operation. Zaidi et al. observed
a significant reduction in echocardiographic functional parameters after surgery as
well as a correlation with the length of hospital stay, the need for extracorporeal
membrane oxygenation, and the mortality rate of HLHS children [37], [38].
Prenatal cardiac interventions and maternal hyperoxygenation in HLHS
As fetal aortic stenosis may progress to hypoplastic left heart syndrome before birth
and require univentricular palliation post partum, fetal valvuloplasty has been proposed
to improve left ventricular (LV) hemodynamics, possibly maintaining biventricular
circulation [39], [40], [41]. In a retrospective multicenter study, Kovacevic et al. compared 67 fetuses with
aortic stenosis who underwent fetal valvuloplasty between 2005 and 2012 with cases
sharing similar characteristics at presentation but who did not undergo prenatal cardiac
intervention. They reported a procedure-related mortality of 10%. Inverse probability
of treatment weighting demonstrated an improved survival of liveborn infants following
prenatal cardiac intervention (HR: 0.38; 95% CI, 0.23 – 0.64; p = 0.0001) after adjusting
for circulation and the postnatal surgical center. However, the figures for biventricular
circulation were similar (36% in the fetal valvuloplasty group and 38% in the group
without intervention), and survival was similar for final circulations. Cases of successful
fetal valvuloplasty showed an improved hemodynamic response with better preservation
of LV growth compared to fetuses without prenatal cardiac intervention [42]. The International Fetal Cardiac Intervention Registry (IFCIR) analyzed data on
fetal valvuloplasty from 18 participating institutions. In 86 fetuses operated on
between 2001 and 2014, 70 aortic valvuloplasty procedures (81%) were technically successful,
and of those, 24 (32%) had a biventricular circulation [41].
The impact of fetal valvuloplasty on fetal cardiac function and postnatal outcome
has also been studied [43], [44]. Ishii et al. evaluated LV strain rates after aortic valvuloplasty in fetuses with
aortic stenosis and incipient HLHS. Tissue deformation rates were analyzed both before
and after the procedure, and postnatal outcomes were investigated with regard to whether
valvuloplasty could induce biventricular circulation of the heart post partum. Out
of a total of 57 treated fetuses, 23 fetuses had biventricular and 34 fetuses had
univentricular circulation. Fetuses with a biventricular outcome showed higher values
of LV strain rate compared to fetuses with a univentricular outcome [44].
Between 6 – 11% of cases diagnosed prenatally with HLHS have a severely restricted
foramen ovale or an intact interatrial septum (IAS) [45], [46]. In these cases, HLHS is already often established and there is no potential for
biventricular circulation [47]. Detecting IAS is very important for the postnatal survival of HLHS infants. Among
other findings, the postnatal survival of HLHS infants relies on unimpeded pulmonary
vein flow across the atrial septum [45], [48], [49], [50]. Fetal atrial septoplasty, sometimes combined with stenting of the atrial septum,
is considered to offer multiple benefits [47]. The IFCIR reported on septoplasty in 37 HLHS fetuses with IAS. In 24 cases (65%),
septoplasty was technically successful. However, no differences with regard to overall
survival or hospital discharge were observed between the intervention group and fetuses
who did not have fetal cardiac intervention [41]. Marshall et al. described the outcome of 21 HLHS fetuses with IAS who underwent
atrial septoplasty in a single-center study. 19/21 interventions resulted in successful
atrial communication; in the group of successful interventions, an atrial communication
≥ 3 mm was found to be correlated with higher postnatal oxygen saturation and lower
rates of emergent atrial septoplasty. Finally, surgical survival rates were better
for infants who did not need emergent atrial septoplasty (86 vs. 42%) without statistical
significance [51].
Maternal hyperoxygenation (MH) therapy consists of providing supplemental oxygen to
the mother during pregnancy to improve the cardiovascular hemodynamics of the fetus.
The effect of MH is due to the increase in fetal pulmonary blood flow, which results
in increased venous return to the left heart. This effect becomes more apparent with
increasing gestational age [49], [52]. In a systematic review, Co-Vu et al. analyzed the efficacy, safety, outcomes, and
intrauterine complications following MH therapy in fetuses with congenital heart disease,
using nine articles out of a total of 96 which met the inclusion criteria [53]. Fetuses included in the study were predominantly diagnosed with LV structural hypoplasia.
There are a number of different MH protocols, and currently only studies or case series
with small sample sizes are available. Our group has published a study on the use
of MH. At the time of intervention, the fetuses had a gestational age of more than
26 weeks. The study investigated pulmonary vasoreactivity, using vascular Doppler
to assess 20 HLHS fetuses. We used 100% oxygen with a flow of 8 L for 10 minutes administered
through a non-rebreather face mask, resulting in a fraction of inspired oxygen (FiO2) of 60%. A pulmonary Doppler examination was also performed, with the mother breathing
room air for 10 minutes after MH [54]. In a recent pilot study, Lara et al. reported on the use of MH in 9 fetuses with
left heart hypoplasia and a mean gestational age of 29.6 weeks. The daily goal was
to administer ≥ 8 h oxygen at 8 – 9 L/min 100% FiO2 until delivery. Maternal arterial partial pressure of oxygen (PaO2) was measured after 1 h of 8 L/min O2. If PaO2 was less than 250 mmHg O2, flow was increased to 9 L/min. Mothers were sent home with an oxygen condenser and
non-rebreather mask and encouraged to continue with MH therapy as long as possible
every day [52]. A growth of hypoplastic left heart structures was observed after MH [14], [49], [55], [56]. MH has been shown to be a useful tool to improve risk stratification in HLHS fetuses
with IAS or atrial septal aneurysm [49], [57], [58], [59]. No significant adverse fetal, maternal and neonatal events have been reported,
especially with regard to any preterm constriction of the ductus arteriosus, postnatal
pulmonary hypertension or retinopathy [53]. However, to date, there are no data on the long-term outcome of affected HLHS fetuses
undergoing MH therapy, particularly with regard to possible detrimental effects on
fetal circulation in terms of fetal programming.
Established and novel postnatal therapies for HLHS
Surgical treatment of HLHS consists of three staged palliative procedures, culminating
in a Fontan circulation. In addition to a Norwood procedure requiring cardiopulmonary
bypass and sometimes deep hypothermic cerebral perfusion, Gibbs et al. introduced
a so-called hybrid procedure in 1993 [12], [60]. The rationale for the hybrid procedure was to avoid cardiopulmonary bypass in high-risk
patients such as infants with low birth weight or prematurity and to thereby reduce
the surgical morbidity and mortality rates [60]. Akintuerk et al. and Galantowicz et al. demonstrated the feasibility of the hybrid
technique [61], [62]. To prevent pulmonary flooding, blood flow into the lungs is restricted by narrowing
the pulmonary arteries (bilateral pulmonary artery banding) during the first days
of life. In a second step, interventional cardiac catheterization is used to place
a stent in the ductus arteriosus to keep it open. In addition to the fact that the
procedure is carried out under beating heart conditions, another advantage of this
strategy is that complex reconstruction of the aorta is not performed immediately
after birth but only at the age of 4 – 6 months. Single-center studies comparing both
procedures demonstrated no significant differences in surgical outcomes between the
two techniques [63], [64], [65], [66]. Due to the small cohort sizes, Cao et al. carried out a meta-analysis to compare
hybrid and Norwood procedures [67]. Fourteen studies comprising 263 hybrid and 426 Norwood patients met the inclusion
criteria for statistical analysis. Cao and colleagues reported significantly higher
early mortality rates in the hybrid procedure group (21 vs. 18%, RR = 1.54, p < 0.05,
95% CI: 1.02 – 2.34), although interstage mortality of the two groups was comparable
(26 vs. 29%, RR = 0.88, p > 0.05, 95% CI: 0.46 – 1.70). The six-month and one-year
transplant-free survival rate for the hybrid procedure group was also significantly
worse compared to the Norwood procedure group (hybrid: 72 and 64%, RR = 0.89, p < 0.05,
95% CI: 0.80 – 1.00; Norwood: 77 and 70%, RR = 0.88, p < 0.05, 95% CI: 0.78 – 1.00).
The rate of reinterventions following initial surgical palliation was higher in the
hybrid procedure group (RR = 1.48, p < 0.05, 95% CI: 1.09 – 2.01), although the duration
of hospital stay and the length of time spent in the intensive care unit after surgery
was comparable between the two groups. The authors concluded that the hybrid procedure
had inferior early survival rates compared to the Norwood procedure during the period
of initial palliative treatment of infants with HLHS. However, since the hybrid procedure
is performed primarily in high-risk patients, the significance of this difference
is limited. It is also worth pointing out that several of the 95% CIʼs include 1,
indicating they are probably not truly different. In a retrospective outcome study,
Schranz et al. reported on the 15-year experience of a single institution in a cohort
of 154 patients with hypoplastic left heart syndrome who underwent a “Giessen hybrid”
stage I procedure as initial palliation. The 15-year survival rate for HLHS and variants
was 77%, and a birth weight of less than 2.5 kg had no significant impact. This underlines
the fact that prematurity and low birth weight are well-known risk factors after Norwood
palliation but not after hybrid procedures [30], [68], [69]. Yerebakan et al. reported on the long-term results of patients (n = 40) who received
biventricular correction (BVC) after an initial Giessen hybrid stage I approach. Patients
were treated with direct BVC. Median survival time after BVC was 7.9 years (0.9 – 14.9).
Overall mortality was 10% (4 patients) at 4 weeks, 5 weeks, 6 weeks, and 4 months
after BVC, respectively. The authors concluded that BVC after hybrid stage I is feasible
with satisfactory long-term survival rates [69]. To evaluate potential differences in RV function and pulmonary artery dimensions
after Norwood (n = 42) or hybrid (n = 44) procedures, Latus et al. used cardiac magnetic
resonance imaging in survivors with HLHS. Both techniques had an equivalent preserved
global RV pump function (59 ± 9% vs. 59 ± 10%, p = 0.91), but development of the pulmonary
arteries (lower lobe index: 135 ± 74 vs. 161 ± 62 mm2/m2, p = 0.02) and the reintervention rate were better after the Norwood approach. RV
myocardial deformation (strain and strain rate) as a potential marker of early RV
dysfunction was observed in the hybrid group with a
potential impact on the long-term outcome in this cohort [70].
Even after successful completion of surgical palliation, significant morbidity occurs
due to progressive RV dysfunction [71]. HLHS patients with RV dysfunction after a Norwood procedure have an 18-month survival
rate of 35% compared with a 70% survival rate for patients with normal RV function
[27]. Moreover, one third of HLHS patients die by the age of 25 years from end-stage
RV failure [72]. The ultimate solution for heart failure is heart transplantation, but patients
must cope with long-term immunosuppression and the risk of transplant failure. Novel
therapies to manage RV dysfunction in HLHS patients are therefore needed. Stem cell
therapy has the potential to be an innovative therapeutic approach. Multiple pathways
play an important role in the development of RV dysfunction which can originate from
cardiomyocyte hypertrophy, increased angiogenesis with the production of antioxidative
enzymes, and a change in fetal gene expression [73], [74]. The RV of HLHS patients has a limited angiogenic response to pressure overload
[75]. This reduces the supply of oxygen and nutrients to cardiomyocytes, leading to myocardial
dysfunction [76]. Different stem cell types are used in cell therapy, especially in the regenerative
therapy of ischemic heart disease [77]. It is believed that stem cells are present in the perivascular regions of various
tissue types including the myocardium. Because of their intrinsic properties, they
are able to secrete different angiogenic factors [78] which can increase myocardial angiogenesis, replace injured myocardium and improve
myocardial function [79]. Clinical trials for stem cell therapy in CHD are mostly carried out in patients
with single ventricle circulation, as can occur with HLHS. Published ongoing studies
use different stem cell types, evaluate different patient populations, and differ
in the route of stem cell administration [71], [80], [81], [82], [83], [84]. However, all have the same goal, namely to improve RV performance [71]. Ishigami et al. reported on the first phase I clinical trial (TICAP trial: transcoronary
infusion of cardiac progenitor cells in patients with single ventricle physiology,
NCT01273857) [80]. The study population included 14 children with HLHS, of whom 7 underwent transcoronary
infusion of cardiosphere-derived cells (CDCs) 4 to 5 weeks after stage II or III palliative
surgery. The other 7 HLHS children received standard care only and served as the control
group. No adverse events from the procedure (including tumor formation) were reported,
with a follow-up of 36 months after CDC infusion. Furthermore, the CDC-treated patients
demonstrated an improvement in RV function. Echocardiography showed a significantly
greater improvement in RV ejection fraction in patients receiving CDCs than in controls
at 36 months (+ 8.0 ± 4.7% vs. + 2.2 ± 4.3%; p = 0.03). In addition, improvements
in RV function resulted in lower brain natriuretic peptide levels (p = 0.04), a lower
incidence of unplanned catheter interventions (p = 0.04), and a higher weight-for-age
z-score (p = 0.02) at 36 months relative to controls [81]. This demonstrates the therapeutic potential of stem cell therapy to improve cardiac
function in single ventricle patients.
In this context, the results from Boston Childrenʼs hospital on the prenatal inhibition
of EFE are worth mentioning. Prenatal EFE is known to be a compromising factor for
long-term ventricular function in HLHS patients [85], [86]. Xu et al. demonstrated that fibrogenic cells in EFE tissue originate from endocardial
endothelial cells via aberrant endothelial-to-mesenchymal transition (EndMT). This
aberrant EndMT involving endocardial endothelial cells is caused by dysregulated TGFβ/BMP
signaling [86]. Supplementation with exogenous recombinant BMP7 (bone morphogenetic protein 7)
ameliorated EndMT in an experimental EFE model [85], [86]. BMP7 activates the BMP pathway by binding to bone morphogenetic protein receptors
(BMPR). Activating SMAD1/5/8, the myogenic regulators of murine and human mesoangioblasts
[87], can block EndMT-inducing signals and help maintain endothelial cell characteristics
[86]. These promising new insights may provide useful pointers for pharmacological interventions
and prenatal therapies to prevent EFE in HLHS fetuses.
Cerebroplacental hemodynamics and neurological outcomes in HLHS
Fetuses with severe forms of CHD are at high risk of impaired neurodevelopmental outcomes
in later childhood [88], [89]. A significant proportion of CHD children are reported to have neurological abnormalities
even before undergoing postnatal surgery [90]. Masoller et al. reported that CHD fetuses had a reduced head circumference and
a higher rate of cerebral redistribution in the second trimester of pregnancy [91]. Our own work has revealed that the head circumference of fetuses with low placental
blood content and therefore low levels of oxygen delivery to the brain (as occurs
with severe left heart obstruction) decreases during gestation depending on the direction
of aortic arch flow [92]. Furthermore, a high percentage of CHD infants show cerebral abnormalities on magnetic
resonance imaging and have a smaller head size and brain volume [93], [94], [95], [96]. Kuhn et al. examined the impact of surgical and therapeutic risk factors on pre-
and postoperative brain MRI findings in 48 neonates with complex CHD (HLHS and dextro-transposition
of the great arteries) using a brain injury score. The preoperative brain MRI was
abnormal in 27 of 48 neonates (56%) with no significant differences between the two
groups with regard to the total injury score (p = 0.47) [97]. This led to a supposition that the pathological processes had a prenatal origin,
leading to poor later neurodevelopment in CHD patients. Changes in the cerebroplacental
hemodynamics of CHD fetuses may have an impact on neurodevelopmental abnormalities.
For example, lower values for the middle cerebral artery (MCA) pulsatility index (PI)
have been reported for HLHS fetuses [98], [99], [100], [101], [102], particularly in the third trimester [103]. Cerebral vasodilatation generally reflects fetal adaption to hypoxia, which suggests
that all of the differences observed in CHD patients may be secondary to reduced cerebral
oxygen delivery [104], [105]. As MH has been shown to increase fetal partial pressure of oxygen in the umbilical
artery and vein as well as umbilical arterial oxygen saturation [106], [107], [108], [109], Szwast et al. hypothesized that MH may have a neuroprotective function as it increases
cerebral oxygen delivery by increasing the partial pressure of oxygen in the fetus.
Szwast et al. observed a first increase of MCA-PI in response to MH at ≥ 28 weeks
of gestation in 43 HLHS fetuses. A baseline MCA-PI z-score of less than − 0.96 was
predictive of an increase in cerebrovascular resistance in response to MH [110]. However, Edwards et al. reported relatively diminished fetal biparietal diameter
growth and smaller infant head circumference z-scores at 6 months in fetuses with
left heart hypoplasia and in utero MH exposure. No differences between controls (left
heart hypoplasia without MH exposure in utero) and children exposed to MH in utero
were observed during neurodevelopmental testing at 6 and 12 months [111]. These results may provide an impetus to conduct more randomized clinical trials
with larger case series and postnatal follow-up to achieve a better understanding
of MH as a useful neuroprotective tool in HLHS fetuses. However, it should be mentioned
again that the potential negative effects of MH must be investigated in prospective
studies with large sample sizes to determine the value of MH to treat HLHS.
Main advances in the diagnosis, therapy and care of HLHS patients
Approximately one-third of live-born newborns with HLHS die before undergoing surgical
intervention [112]. This comparatively high mortality rate is due, in the main, to delayed postnatal
diagnosis and the associated hemodynamic instability. Prenatal diagnosis improves
planning, as infants can be delivered close to or in specialized pediatric heart centers
which reduces preoperative morbidity and mortality rates of HLHS neonates [112], [113], [114]. Prenatal diagnosis also has a positive impact on the preoperative state (lowest
pH value, need for vasoactive drugs etc.) [115]. Surgery-related mortality rates of HLHS neonates undergoing a Norwood procedure
continue to decline [116], [117]. Survival rates of more than 95% following HLHS stage 1 palliation have been reported
for selected centers [118]. Advances in surgical techniques in the last decades have resulted in four viable
options for the long-term survival of HLHS patients: the Norwood procedure, the “true”
hybrid approach, a hybrid bridge-to-Norwood approach, and cardiac transplantation
[119]. However, due to their single ventricle physiology, HLHS children have a high risk
of mortality in the interstage period, i.e., the period between their discharge home
after stage 1 palliation until stage 2 palliation at 4 to 6 months. Interstage mortality
rates reported for single centers are between 10 and 18.9% [120], [121], [122], [123]. Novel management strategies such as interstage home surveillance monitoring (HSM)
have been developed to cope with this problem. HSM models are multidisciplinary programs
which provide focused parental education before patients are discharged home after
palliation. HSM programs include home weight checks, oxygen saturation monitoring
and educating parents to recognize specific symptoms indicating potential cardiopulmonary
or nutritional decompensation [124]. Ghanayem and colleagues reported that interstage mortality dropped from 15.8 to
0% in 24 HLHS patients after an HSM model was implemented [125]. In their 10-year experience with interstage HSM, they reported a 98% interstage
survival rate [126]. HSM represents a promising approach for the care of HLHS patients.
