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Original Articles: Cardiovascular

Hypoplastic Left Heart Syndrome With Atrial Level Restriction in the Era of Prenatal Diagnosis

^a Department of Pediatrics, Children’s Hospital of Philadelphia and the University Hospital of Pennsylvania, Philadelphia, Pennsylvania
^b Department of Cardiothoracic Surgery, Children’s Hospital of Philadelphia and the University Hospital of Pennsylvania, Philadelphia, Pennsylvania
^c Department of Anesthesiology, Children’s Hospital of Philadelphia and the University Hospital of Pennsylvania, Philadelphia, Pennsylvania

Accepted for publication June 21, 2007.

^_* Address correspondence to Dr Rychik, Children’s Hospital of Philadelphia, Division of Cardiology, 34th and Civic Center Blvd, Philadelphia, PA 19104 (Email: rychik{at}email.chop.edu).

	Abstract

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Background: Despite recent improvements in survival of patients with hypoplastic left heart syndrome, those with severe atrial level restriction continue to face higher rates of mortality. We sought to assess the impact of prenatal diagnosis and immediate intervention on the outcome of this high-risk population.

Methods: We performed a retrospective review of patients with hypoplastic left heart syndrome and restriction at the atrial level born between 1997 and 2006. Patients with an intact atrial septum or an interatrial communication less than 2 mm by color Doppler flow mapping on initial postnatal study, or evidence of obstruction to left atrial egress on fetal echocardiogram, were included. Patients were subdivided into two groups based on severity of obstruction.

Results: Thirty-eight patients met inclusion criteria; 16 had the most severe form of anatomic obstruction (group 1), and 22 had a lesser degree of obstruction (group 2). Thirty-day cumulative survival for all was 68%: 38% for group 1 and 94% for group 2 (p = 0.001). Twenty-six of the 38 patients (68%) were prenatally diagnosed. Prenatal diagnosis did not improve initial hospital survival or cumulative survival for either group. Eight patients had progression of atrial level restriction from the first fetal study to the first postnatal study. Seven patients prenatally diagnosed with severe restriction underwent planned cesarean section followed by immediate surgical or catheter-based intervention, with only 2 survivors (28%).

Conclusions: Hypoplastic left heart syndrome with an intact atrial septum is a highly lethal condition despite prenatal diagnosis and immediate intervention at birth. Fetal intervention should be considered for these high-risk fetuses.

	Introduction

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Hypoplastic left heart syndrome (HLHS) refers to a spectrum of cardiac malformations with various degrees of hypoplasia of left-sided structures leaving the left ventricle unable to support systemic perfusion [1]. With prostaglandin therapy, a majority of these patients maintain adequate oxygenation and hemodynamic stability during the days preceding a palliative procedure or transplantation. Recent improvements in surgical technique and medical management have contributed to substantial improvement in outcome for neonates with HLHS [2, 3]. However, patients born with an intact atrial septum (HLHS-IAS) or highly restrictive interatrial communication can exhibit significant hypoxemia and hemodynamic instability within the first hours of life [4]. Once separation from the placental circulation occurs, the lungs expand with an increase in pulmonary blood flow. If the left-sided structures are inadequate, pulmonary venous return must obligatorily shunt across the atrial septum. A severely restrictive or intact interatrial communication therefore results in marked hypoxemia and pulmonary venous congestion [5]. Histologic changes of the lung vasculature including pulmonary venous thickening, "arterialization," and lymphatic dilation have been identified in these infants, suggesting the presence of a developmental abnormality associated with the degree of interatrial restriction [6]. All of these features make patients with HLHS-IAS extremely difficult to manage and stabilize in the early postnatal period.

A variety of interventions to improve survival of these patients have focused on relieving the obstruction by creating a larger interatrial communication. Several studies have shown that mortality rates continue to be high despite technically successful catheter-based atrial septostomy at birth [7–11]. Recently, fetal interventions to open the atrial septum have been performed in an effort to improve the postnatal course; however, the number of patients who have undergone this experimental procedure is yet too small to demonstrate any benefit [12–14].

Fetal echocardiography permits detection of high-risk fetuses while stable in utero, which allows for development of a strategy for immediate intervention at birth. Intervention at the earliest possible time after birth theoretically may improve outcome for HLHS-IAS patients. Prenatal diagnosis has been demonstrated to improve outcome overall in HLHS [15, 16]. The objective of our study was to review our recent experience with HLHS and severe atrial level restriction and to investigate the impact of prenatal diagnosis and immediate intervention on outcome in this high-risk population.

	Material and Methods

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Subjects
We searched the Cardiac Center databases at the Children’s Hospital of Philadelphia to identify all patients born between January 1997 and September 2006 with HLHS. A further chart review identified those patients with a highly restrictive or intact atrial septum as reported on either prenatal or postnatal echocardiogram. All echocardiograms were reviewed by a single reviewer for confirmation of anatomy and atrial level obstruction. An intact atrial septum was defined as no interatrial communication on echocardiographic two-dimensional imaging or color Doppler flow mapping. We defined a highly restrictive atrial septum as one in which egress of pulmonary venous return from the left atrium was through a single interatrial communication measuring less than 2 mm on echocardiographic color Doppler flow mapping. Foramen ovale size by two-dimensional imaging and peak Doppler gradient were not used to determine atrial level restriction as these are highly variable measures. Based on our experience, a communication of less than 2 mm by color Doppler flow mapping is a suitable indicator of a restricted atrial septum. Patients with a highly restrictive, and not just intact, atrial septum were intentionally included in this study in an effort to capture all patients with possible clinical manifestations of the disease.

Patients were subdivided into two groups on the basis of anatomic features suggestive of the severity of disease as identified on postnatal echocardiogram. The presence of a decompressing vessel was documented; however, because of the difficulty in reliably identifying their presence and in assessing the degree of obstruction, they were not used as an anatomic feature of disease severity characterization. Patients with an intact atrial septum and either mitral atresia or aortic atresia were considered the most severe form of anatomic restriction to left atrial egress and were designated group 1. Patients with an intact atrial septum and evidence of potential antegrade decompression across the mitral and aortic valves, partial anomalous pulmonary vein, or a restrictive atrial septum as defined above were considered less severe and were designated group 2. Patients who received fetal intervention were included in group 2 owing to the potential for altering the natural progression of the disease to a less severe form.

After identifying the study groups, chart review was performed to identify patient characteristics including birth weight, gestational age, comorbid conditions, and genetic syndromes; interventional and surgical history including the timing and type of interventions; and hospital course including length of stay. When prenatal echocardiograms were available, each study was reviewed to verify diagnosis and assess the degree of atrial level restriction by visualization of the atrial septum as well as analysis of pulmonary venous Doppler waveforms [17–19]. Prenatal studies were compared with postnatal echocardiograms. Patient follow-up was obtained through the Cardiac Center database at the Children’s Hospital of Philadelphia.

Data Analysis
Outcome was assessed as in-hospital survival after initial intervention as well as survival to 3 years of age. Kaplan–Meier survival curves were generated for the overall group, for the two anatomic groups, and for prenatally and postnatally diagnosed groups. Log-rank testing was used to identify differences in survival between anatomic groups and between those with prenatal versus postnatal diagnosis. Group characteristics including mean birth weight, gestational age, mean age at intervention, presence of decompressing vessels, and prenatal diagnosis were compared using Fisher’s exact test for categorical variables and a two-tailed Student’s t test for continuous variables. Variables including presence of decompressing vessels and prenatal diagnosis were assessed for association with survival using Fisher’s exact test. The degree of atrial septal restriction noted on the first fetal echocardiogram was compared with that found on the first postnatal echocardiogram. For purposes of this comparison, atrial septal restriction was graded as open, restrictive, or intact. The study was approved by the Institutional Review Board at the Children’s Hospital of Philadelphia. Statistical analysis was performed using SPSS version 14.0 Windows software (SPSS, Inc, Chicago, IL). A probability value of less than 0.05 was considered significant.

	Results

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Patient Characteristics
Thirty-eight patients were identified: 16 (42%) in group 1 with the most severe form of anatomic obstruction and 22 (58%) in group 2 with a lesser degree of anatomic obstruction. The anatomic findings are listed in Table 1. The mean birth weight for all patients was 3,165 ± 580 g; 18 patients (47%) were female and 20 patients (53%) were male. The average gestational age at birth was 38 ± 2 weeks. Five patients (13%) were born prematurely at a range of 32 to 36 weeks. Five patients (13%) had genetic or dysmorphic syndromes including Turner’s syndrome (n = 3), deletion of chromosome 11q, and one undefined syndrome consisting of marked facial dysmorphia and vertebral anomalies. There was no difference in percentage of patients with low birth weight (<2,500 g), prematurity, or genetic syndromes between group 1 and group 2 (p = 1.0, 0.3, 0.37, respectively). Additional cardiac defects identified included small ventricular septal defects (n = 2), aberrant right subclavian artery (n = 1), aberrant left subclavian artery (n = 1), cor triatriatum (n = 2), partial anomalous pulmonary venous return (n = 1), and obstructed total anomalous pulmonary venous return (n = 1). Only 1 patient had clinically significant tricuspid regurgitation. Five patients (group 1, n = 3; group 2, n = 2; p = 0.6) were noted to have double-outlet right ventricle with mitral atresia.

View larger version (15K): [in this window] [in a new window]   Fig 1. Flow diagram depicting initial intervention and in-hospital survival for all patients. Late death indicates those patients who died after initial hospital discharge.

View larger version (17K): [in this window] [in a new window]   Fig 2. Kaplan–Meier survival curve demonstrating estimated 3-year cumulative survival as a function of time for all patients. Number of patients remaining at various times is annotated.

View larger version (18K): [in this window] [in a new window]   Fig 3. Kaplan–Meier survival curve demonstrating estimated cumulative survival for group 1 and group 2 patients. Number of patients remaining at 30, 200, 800, and 1,100 days is annotated.

Of the patients who survived initial hospitalization, 19 subsequently underwent stage 2 superior cavopulmonary operation (3 from group 1) and 15 underwent Fontan completion (3 from group 1). The mean age for stage 2 palliation was 5.4 months (no significant difference between group 1 and group 2; p = 0.7); mean age for Fontan completion was 2.1 years. One patient from group 1 is awaiting stage 2 palliation, and 3 patients from group 2 are awaiting Fontan completion. Two patients died during hospitalization for stage 2 palliation (one group 1 patient), and 3 patients died during hospitalization for Fontan completion (all group 2 patients). Three patients (all group 2) were lost to follow-up, one after each of the three stages.

Prenatal Diagnosis
Twenty-six of the 38 patients (68%) were diagnosed prenatally. There was no difference in the frequency of patients diagnosed prenatally between group 1 versus group 2. There was no difference in initial hospital survival between those with or without prenatal diagnosis (17 of 26, 65% versus 9 of 12, 75%, respectively; p = 0.7). There was no difference in 3-year cumulative survival between those diagnosed prenatally or postnatally (p = 0.7; Fig 4).

View larger version (21K): [in this window] [in a new window]   Fig 4. Kaplan–Meier survival curve demonstrating estimated 3-year cumulative survival for patients with a prenatal versus postnatal diagnosis. Number of patients remaining at 30, 200, 800, and 1,100 days is annotated.

Prenatal Diagnosis and Strategy of Immediate Intervention
Seven patients were prenatally diagnosed and underwent a unique strategy of planned cesarean section in a cardiac operating room at the Children’s Hospital of Philadelphia with immediate intervention in an adjacent operating room or catheterization laboratory. Decision for undertaking this strategy was based on visualization of the atrial septum as well as evidence for severe restriction by presence of marked reversal of flow during atrial contraction on pulmonary venous Doppler interrogation [16–18]. Five of the 7 patients had a surgical approach (2 atrial septectomy, 2 stage 1 Norwood palliation, 1 total anomalous pulmonary vein repair and atrial septectomy), and 2 underwent catheter-based procedure (1 decompressing vein stent, 1 atrial septal stent). Only 2 patients survived: 1 underwent a stage 1 palliation and had a difficult postoperative course with a long initial hospitalization (48 days); the other had an atrial septal stent placed after birth and has survived to date. The overall survival for patients with immediate intervention at birth was 2 of 7 (28%).

Fetal Intervention
Two patients were diagnosed in utero with severe atrial septal restriction on the basis of visualization of the atrial septum as well as marked reversal of flow during atrial contraction on Doppler interrogation of the pulmonary veins and were referred for fetal intervention to another institution. One fetus had balloon atrial septoplasty at 32 weeks gestation and survived to Fontan completion but died at 34 months of age from pulmonary vein stenosis. The second patient had an atrial septal stent placed at 30 weeks gestation and survived the initial hospitalization including a stage 1 Norwood procedure. Sudden death occurred at home at 21 days of age.

	Comment

Top Abstract Introduction Material and Methods Results Comment References

 
During the past decade, advances in management for HLHS have resulted in marked improvement in survival [3]. Nevertheless, those with an intact or highly restrictive atrial septum have continued to present significant challenges. We previously described our experience with HLHS-IAS during the years 1990 through 1997 and reported only 33% early survival [5]. In a more recent report, Vlahos and colleagues [7] reported nearly 50% mortality in neonates managed by means of urgent catheter technique to enlarge or create an interatrial communication, with no improvement in outcome associated with presence of a prenatal diagnosis. In our present study, we sought to determine the current outcome for HLHS-IAS at our center in an era in which prenatal diagnostics can reliably predict the birth of these infants, and in which a prospective anticipatory strategy can be implemented immediately after birth to potentially maximize outcome. We found that despite the presence of prenatal diagnosis, and even if intervention occurs within the first few minutes of life, outcome remains poor.

In our study, patients were divided into two groups on the basis of anatomic severity to degree of obstruction of pulmonary venous egress. In the most severely obstructed group, early survival is only 38% and is not affected by the presence of prenatal diagnosis. This outcome is essentially unchanged from our previous experience a decade ago. Interestingly, early outcome was comparatively better for our patients with a lesser degree of anatomic obstruction; however, there was substantial late mortality at the time of cavopulmonary connection operations. Of 19 early survivors of both anatomic subgroups, 2 died after superior cavopulmonary operation and 3 after Fontan operation, this in an era during which mortality rates for each of these operations have plummeted to well below 5% for low-risk forms of single-ventricle anomalies [20]. It is unclear why these patients have an increased late mortality; however, it may be related to the presence of persistent abnormalities of the pulmonary vasculature that may inhibit the capacity for successful passive receipt of systemic venous flow. In essence, current advancements in management for the infant with HLHS have added an incremental benefit in outcome for those with a moderate degree of atrial level obstruction but not in those with severe atrial level obstruction, and there may be ongoing incremental risk in the former group at the subsequent cavopulmonary palliations.

All of the infants included in this study were cared for with the intention to treat, and the majority underwent surgery as their initial intervention. Of our 7 patients identified before birth and delivered by cesarean section in our cardiac operating room during the study timeframe, 5 had immediate surgical intervention and 2 had immediate catheter-based intervention. In 2, a surgical atrial septectomy was performed in the hopes of quickly and effectively creating an interatrial communication, thereby allowing for some period of pulmonary venous decompression before completion of a stage 1 Norwood operation. Unfortunately, both of these patients died—1 after stage 1 Norwood operation and the other as a result of an acute pulmonary hypertensive event while awaiting surgery. One of the patients initially treated by catheter survived. Because of small numbers, we could not compare outcomes between those who had immediate surgical and catheter-based intervention. Although surgical atrial septectomy after cesarean section in the cardiac operating room may be the fastest way to decompress the left atrium, the potential negative effects of cardiopulmonary bypass on lung mechanics may be a more important determinant of outcome. Since this initial series, we performed cesarean section delivery of 2 additional fetuses with HLHS-IAS with successful creation of an interatrial communication by use of a radiofrequency energy catheter to create a defect and deployment of a stent across the atrial septum.

The finding of progression of the degree of atrial restriction in our fetuses with HLHS is of great importance. In 6 patients, there was progression of restriction from a septum that was deemed to be fully open as a fetus at a mean of 34 weeks gestation to one in which there was significant obstruction at birth, either restrictive (n = 3) or intact (n = 3). This finding has great implications in terms of family counseling. Realizing that the outcome is so poor, parents may wish to have as much predictive information concerning outcome as early as possible in gestation. In all 8 of our fetuses with progression, the severity of degree of atrial septal restriction was ultimately recognized before birth. However, because some were cared for at other institutions between the period of initial evaluation and delivery at our center, the time course for progression could not be delineated in all. Our findings highlight the importance of regular interval surveillance with fetal echocardiography. The degree of reversal of pulmonary venous flow with atrial contraction as measured by Doppler echocardiography has been demonstrated to be a reliable marker for the degree of pulmonary venous obstruction and has been correlated with postnatal clinical outcome [17–19]. Our current protocol for any fetus with HLHS is for evaluation by means of fetal echocardiography every 4 weeks after initial diagnosis, with attention focused on the assessment of the nature of the interatrial communication as well as Doppler evaluation of pulmonary venous flow patterns in a serial manner.

Limitations to this study include the small number of patients available with this condition and the retrospective nature of the investigation. We have likely underestimated the number of mortalities in those patients with a postnatal diagnosis who died before coming to our attention. Hence, our postnatally diagnosed population has the bias of a self-selected group. Nevertheless, there was no significant advantage noted in those diagnosed either before or after birth.

Outcome in the current era for infants with HLHS-IAS remains poor despite fetal diagnosis, a planned delivery, and immediate intervention at birth. These findings further support the notion of the presence of a fixed, developmental abnormality of the pulmonary vasculature, which may not be readily amenable to any form of postnatal care. Although the 2 patients who underwent fetal intervention at another institution died, the experience with this approach is still early and holds promise. In our view, considering the continued poor outcome, patients with the most severe form of atrial level obstruction as we have described should be considered as candidates for fetal intervention. Techniques for safe and effective opening of the atrial septum in the fetus are currently being explored at our center and at other institutions [12–14]. Questions relating to the most effective method for opening the fetal atrial septum and the optimal timing for such an intervention at the moment remain unanswered.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Sarah Tabbutt J. William Gaynor Thomas L. Spray Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Glatz, J. A. Articles by Rychik, J. Search for Related Content PubMed PubMed Citation Articles by Glatz, J. A. Articles by Rychik, J. Related Collections Congenital - acyanotic Related Article