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The study objective was to describe the surgical pathway progression through adolescence of an inception cohort of neonates with aortic valve atresia managed initially with surgical palliation or primary transplantation, comparing survival and self-reported health-related quality of life.
From 1994 to 2000, 565 neonates with aortic atresia were admitted to 26 Congenital Heart Surgeons' Society hospitals and followed annually for vital status. Initial management included surgical palliation (n = 453) and primary cardiac transplantation (n = 68). PedsQL health-related quality of life questionnaires were sent cross-sectionally to a subgroup of 198 patients alive at previous follow-up, with 80 responses.
Risk of death was initially high for both treatment strategies. However, compared with initial surgical palliation, survival with primary transplantation, including wait-list mortality, was greater and persisted long-term (65% vs 40% at 15 years; P = .002). Survival after secondary transplantation (48% at 9 years) was lower than after primary transplantation (74%). Health-related quality of life total score was lower overall than that of the general adolescent population (71 ± 16 vs 84 ± 13; P = .0001; normal = 100), but similar to that of adolescents with chronic diseases. It was similar in the surgical palliation and primary transplantation groups (70 ± 16 vs 75 ± 15; P = .3). Patients who received surgical palliation reported more symptoms (76 ± 15 vs 63 ± 18; P = .02).
Patients receiving primary heart transplantation for aortic atresia in 1994 to 2000 experienced better survival, fewer symptoms, and equivalent quality of life compared with those undergoing initial surgical palliation. Notwithstanding the limited availability of neonatal and infant donor hearts, primary transplantation may be considered for those neonates with risk factors predictive of exceptionally poor survival after surgical palliation.
Notwithstanding the limited availability of donor hearts, primary transplantation may be considered for aortic atresia with risk factors predictive of exceptionally poor survival after surgical palliation.
Among patients born in 1994-2000 with aortic atresia, long-term survival in those managed with primary transplantation was better than in those managed with surgical palliation. For both groups, early-phase hazard was greater than a fairly constant late-phase hazard. Self-reported quality of life scores were similar for both groups and comparable to those of adolescents with chronic diseases.
Aortic atresia is lethal without neonatal treatment. Innovations in surgical palliation and primary heart transplantation, combined with advances in managing these patients over the past several decades, have led to greatly improved survival. Therefore, more of these patients are living into adulthood.
However, no large multi-institutional studies describe the sequence of treatments from birth through adolescence, and how survival varies according to initial neonatal treatment strategy. Further, with growing numbers of survivors reaching adulthood, caregivers must be prepared to deal with their medical and health-related quality of life issues.
The Congenital Heart Surgeons' Society (CHSS) enrolled an inception cohort of neonates with aortic atresia across North America between 1994 and 2000 and has followed them annually.
This unique cohort provides the opportunity to study survival and health-related quality of life through adolescence and explore possible associations between these outcomes and initial management strategies. Therefore, purposes of this investigation were to assess the effect of alternative management strategies on survival and health-related quality of life as these patients approach adulthood, with particular focus on surgical palliation versus primary cardiac transplantation.
Patients and Methods
From 1994 to 2000, 565 neonates born with aortic atresia and concordant atrioventricular and ventriculoarterial connections were admitted to 26 CHSS institutions (Appendix E1), 36% on the day of birth and 95% by day 10.
All had absence of blood flow across the aortic valve as determined by color Doppler echocardiography. During this era, institutional review boards waived the requirement for written parental consent; thus, the cohort is believed to comprise essentially consecutive patients.
The neonates were initially managed by 1 of 4 strategies: surgical palliation (n = 453), listing for primary cardiac transplantation (n = 68), biventricular repair (n = 6), or supportive care only (n = 38) (Figure E1). Management strategy was at the discretion of parents, based on guidance from individual institution's physicians. Early outcomes of the initial portion of this cohort have been reported.
In this historical cohort, primary transplantation was performed predominantly at 2 institutions (Figure E2). Characteristics of patients from these 2 institutions were similar to those at all other institutions, but only a few patients underwent surgical palliation at these institutions.
Admission, diagnostic, and surgical information were abstracted from institutional medical records and cardiac catheterization, echocardiogram, and surgical reports. Characteristics of patients undergoing surgical palliation and primary transplantation were similar, with the exception that those with associated mitral atresia were more often managed with surgical palliation than primary transplantation (Table 1). Eight patients with a large ventricular septal defect and functional mitral valve underwent primary (n = 6) or secondary (n = 2) biventricular repair after a Norwood procedure; they are all alive but not considered further, nor are the 38 patients managed with supportive care, all of whom died within 2 months. Data are housed at the CHSS Data Center, located in The Hospital for Sick Children in Toronto, Canada. The University of Toronto Research Ethics Board approved use of these data for research.
In the early 2000s, institutional review boards required that these patients be consented for continued follow-up. CHSS Data Center personnel contacted the institution and a parent or guardian of each patient annually to ascertain interim details of relevant clinical history, additional investigations, and interventions. Clinical data were complete for 70% of patients within 1 year of the 2013 annual follow-up. From the date of admission, 50% of patients were followed more than 11.8 years, 25% were followed more than 16 years, and 10% were followed more than 17.5 years.
At the 2013 follow-up, 249 patients were known to be alive, but 51 of these were not contacted because of lack of institutional review board approval. Two validated questionnaires related to general and disease-specific health-related quality of life were included in the 2014 follow-up inquiry: the PedsQL and PedsQL Cardiac Module (Appendix E2).
Of the 198 contactable patients, 80 (40%) completed and returned the follow-up packet. Responders versus nonresponders are compared in Table E1. For this portion of the study, an “as-treated” analysis was performed of 60 patients after surgical palliation and 15 after transplantation.
Analyses were performed using SAS version 9.2 software (SAS Institute, Inc, Cary, NC). Continuous variables are summarized as mean ± standard deviation or as equivalent 15th, 50th (median), and 85th percentiles when their distribution was skewed; comparisons were made using Wilcoxon rank-sum or Kruskal–Wallis tests. Categoric data are summarized by frequencies and percentages; comparisons were made using the chi-square test or Fisher's exact test when frequency was less than 5. Time-to-event estimates are presented with asymmetric 68% confidence intervals (CIs), comparable to ± 1 standard error.
All-cause mortality by initial management strategy was estimated nonparametrically by the Kaplan–Meier method and parametrically by a multiphase hazard model,
the latter used to resolve the phases of time-varying instantaneous risk of death (hazard function), which in most cases was 2. The first phase describes high, early postprocedure risk and the second subsequent ongoing risk.
Progression of patients from initial palliation through stages of surgical reconstruction used competing-risks analyses.
After first-stage palliation (Norwood), competing risks were superior cavopulmonary shunt (bidirectional Glenn), secondary heart transplantation, and death. After second-stage palliation (bidirectional Glenn and occasionally hemi-Fontan), competing risks were Fontan procedure, secondary heart transplantation, and death. Transition into each of these mutually exclusive states was estimated nonparametrically
The PedsQL was reverse-scored and linearly transformed to a 0 to 100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0), with higher scores representing better health-related quality of life. Domain scores were calculated as the sum of item scores divided by number of items answered, thereby adjusting for missing data. The Physical Health Summary Score is identical to the Physical Functioning Scale. The Psychosocial Health Summary Score is the mean of items comprising the Emotional, Social, and School Functioning Scales. Scores were standardized as z-values using norms for healthy adolescents (z = 0).
The PedsQL Cardiac Module was scored in the same manner, with 3- or 5-point Likert scales reverse-scored and linearly transformed.
After Norwood palliation and before a bidirectional Glenn, 2 patients underwent biventricular repair (combined Norwood-Rastelli) and 7 patients underwent a secondary heart transplant (Figure E1). Most patients transitioned to a bidirectional Glenn between the ages of 3 and 9 months (Figure 1). After bidirectional Glenn and before the Fontan, another 7 patients underwent secondary heart transplantation. Most patients transitioned from bidirectional Glenn to Fontan completion between the ages of 1 and 3 years (Figure E3). After the Fontan operation, 5 more patients underwent secondary heart transplantation.
Primary Heart Transplantation
Of 68 patients listed for primary heart transplantation, 59 received a heart and 9 died on the waiting list (Figure E1). The likelihood of transplantation within 6 months after listing was 86% (CI, 71-94), and likelihood of death on the waiting list was 13% (CI, 8-21) (Figure 2). The average age at primary transplant was 51 days. After primary transplantation, 1 patient underwent retransplantation.
Survival by Initial Management
Patients managed by initial surgical palliation experienced high instantaneous risk of mortality in the first weeks after the Norwood procedure, which then decreased to 1.5% to 2.0%/year by age 4 to 5 years, with an inflection point between ages 1 and 2 years (Figure 3, A). Fifteen-year survival was 42% (Figure 3, B).
For patients managed by primary transplantation, risk of death on the transplant wait-list averaged 0.25%/day (Figure E4). Including wait-list deaths, early mortality was not as high as for those initially managed by surgical palliation in this 1994 to 2000 era (Figure 3, B). Fifteen-year survival, including wait-list deaths, was 62%. Long-term risk of death remained constant after 5 years at 1%/year (CI, 0.8-1.8) (Figure 3, A, difference from surgical palliation P = .002).
Of 19 patients who underwent a transplant after a Norwood, bidirectional Glenn, or Fontan procedure, 9 died by the end of follow-up; intermediate-term risk of death was 7.3%/year (CI, 3.5-15) compared with 1%/year after primary transplant (Figure E5), and survival was 46% (CI, 35-58) at 9 years after transplantation (Figure 4). Confidence limits for primary versus secondary transplant separated after 5 years. However, older age at transplantation was a more reliable risk factor for death than the transplant being secondary (Table E2).
Health-Related Quality of Life
PedsQL scores in all domains were lower for both surgical palliation and transplant groups than those in the general adolescent population (Figure 5, B), but were similar to those for other chronic pediatric diseases, such as asthma and diabetes (Figure E6). Adolescents with aortic atresia had worse school functioning scores than adolescents with diabetes, asthma, and obesity, but scored similarly to adolescents with cerebral palsy, a group that scored lower than those with other chronic diseases in all domains.
There were no statistically significant differences between PedsQL scores of transplant recipients compared with those undergoing surgical palliation (Figure 5, A), although transplant recipients scored slightly higher in all domains. In both groups, highest scores were in the social domain (78 ± 19 vs 77 ± 20, P = .8) and lowest in the school domain (67 ± 24 vs 63 ± 22, P = .6). There was large variability among patients in all domains.
For the more specific PedsQL Cardiac Module, transplant recipients had fewer symptoms than those who underwent surgical palliation (Figure 6). Patients in both groups scored high in the compliance domain, with a smaller standard deviation than in other domains. The lowest scores for both groups were in the cognitive domain.
This longitudinal inception cohort study of patients with aortic atresia admitted as neonates to 26 North American institutions from 1994 to 2000 provides new descriptive information regarding their intermediate-term outcomes. In that era, survival was markedly reduced by high early risk of death, irrespective of initial treatment strategy. But survival for primary transplantation (predominantly at 2 institutions), including wait-list deaths, was better than after initial surgical palliation, primarily because of lower early mortality. Older age at transplantation, such as at secondary transplant after surgical palliation, was associated with lower survival than after primary transplantation in infancy
Quality of life
Self-reported health-related quality of life was worse in both surgical palliation and primary transplant groups than in the general adolescent population, but similar to that of individuals with other chronic diseases.
Impaired health-related quality of life in children and adolescents with chronic conditions: a comparative analysis of 10 disease clusters and 33 disease categories/severities utilizing the PedsQL 4.0 Generic Core Scales.
Fewer symptoms were reported after transplantation than after surgical palliation, but otherwise these groups had similar health-related quality of life.
This CHSS experience occurred in an era when management strategies to stabilize neonates presenting with hypoplastic left heart physiology were evolving to optimize their status before initial surgical intervention. Some strategies were based on lessons learned from transplant centers, where it was often necessary to extend supportive pretransplant care over many weeks.
The National Heart, Lung, and Blood Institute–sponsored Single Ventricle Reconstruction trial enrolled 549 patients from 15 centers during the years 2005 to 2008, and 30-day and hospital mortality were 11.5% and 16.0%, respectively.
For most of these patients, there is another option—surgical palliation—that may not be available for some other types of critical congenital heart disease. Even if outcomes of primary transplantation are superior to surgical palliation, this is only true if wait-list plus post-transplant mortality is lower than mortality after surgical palliation. If more patients were listed for transplantation, wait-list mortality would increase unless more hearts became available.
However, there is no reason not to maximize primary neonatal transplantation. For example, ABO-incompatible transplantation is not uniformly performed across US centers, where the current allocation system prioritizes donor hearts to recipients of identical blood group. In Canada, allocation of donor hearts is based on clinical status, not blood group compatibility.
Because the CHSS experience ended in 2000, discussion about when to recommend primary heart transplantation is confounded by improved survival after surgical palliation, particularly after the Norwood procedure.
If we were to assume hypothetically that early and late results after a primary transplant strategy have remained constant since 2000, we could use the lower 70% confidence limit of the transplant strategy survival curve as a reference point. At 5 years, the lower 70% confidence limit is between 60% and 65% (Figure 3, B). Many factors enter the decision to transplant other than just projected survival with an alternative therapy (in this case, first-stage palliation), but the patient care team could justify a discussion about primary transplantation if the upper 70% confidence limit of predicted 5-year survival after first-stage palliation were less than approximately 60%.
This might be particularly relevant for patients who have moderate or severe tricuspid regurgitation or moderate or severe right ventricular dysfunction prior to first-stage palliation, or have left ventricle to coronary artery fistulae.
The reality remains that there is a paucity of donor hearts compared with demand. Thus, a recent Society of Thoracic Surgeons Congenital Heart Surgery Database report to participants revealed that from 2014 to 2017, 2016 patients with hypoplastic left heart syndrome underwent a Norwood procedure; during the same period, 113 underwent transplantation, with timing of transplantation at median age 1775 days (Q1-Q3, 274-3970), suggesting that few were primary transplants (Society of Thoracic Surgeons, personal communication, 2018).
Transplantation After Surgical Palliation
We observed a difference in post-transplant outcomes between patients who received primary transplantation and those who underwent transplantation after 1 or more palliative surgical procedures. However, Kirklin and colleagues
report little difference in outcomes today between secondary transplantation and those for other forms of congenital heart disease. In contrast, 1-year mortality after listing for failed surgical palliation in the Single Ventricle Reconstruction trial was 47%, with 39% of listed patients dying on the wait-list.
Aortic valve atresia, whether treated with surgical palliation or primary transplantation, results in a challenging chronic condition with profound effects on health-related quality of life. What our questionnaires assessed was adolescents' own opinions of how their health was affecting their daily life. These self-reports depend on patients' expectations of how adolescents want to function. Manlhiot and colleagues
demonstrated that having a healthy sibling was associated with lower self-reported functional health status, suggesting a possible disconnect among true physical, social, and mental limitations and self-perception of limitations.
Adolescents in our study scored themselves lowest in school function, regardless of treatment strategy. Studies of patients with hypoplastic left heart physiology reveal a distinct pattern of neurodevelopmental and behavioral dysfunction characterized by mild cognitive impairment, impaired social interaction, and deficits in core communication skills, as well as inattention, impulsive behavior, and impaired executive function.
The findings may be related in part to the burden of repeat interventions rather than to the underlying cardiac diagnosis. It is also likely related to the fact that many patients who undergo a Fontan procedure have reduced physical activity levels independent of exercise capacity and perceived worse general health, but not a reduction in other aspects of functional status.
In transplant recipients, school performance is substantially lower than that of healthy children despite normal academic ability; a substantial number have behavioral problems (8% at age 6 months and >26% by age 2 to 5 years).
found better outcomes; 78% of their study population showed good psychologic outcomes at a mean of 2.1 years after transplant, a finding maintained at 10 years. In our study, transplant recipients also reported fewer cardiac symptoms than adolescents who underwent surgical palliation. Sigfusson and colleagues
found that children were active and generally returned to age-appropriate developmental, educational, social, and recreational activities after transplantation, with 89% to 100% capable of participating in normal activities for their age.
The most important aspect of this study is continued follow-up through adolescence of a large inception cohort of neonates with a single diagnosis of aortic atresia across the North American continent; it is also its most important weakness, because subsequent advances in treatment have improved outcomes. Additionally, in the era during which these neonatal procedures were performed, only a few centers offered neonatal transplantation. Therefore, results of our study should be extrapolated to other single-ventricle diagnoses with caution, because we suspect the hazard of death after palliation may differ for each morphologic entity.
Accurately characterizing patient status and health-related quality of life depends on the ability and permission to contact patients. Attempts to follow patients yearly were limited by wide geographic distribution and mobility, and requirements of many different institutional review boards with differing interpretations of the study design.
Self-reports of health-related quality of life depend for accuracy on an ability to contact these adolescents, their willingness to respond to questionnaires, and their honesty in answering; illness perception itself affects self-reported quality of life.
Nonwhite adolescents were less likely to return questionnaires than white adolescents. In addition, we presume that the most impaired adolescents could be underrepresented. We made no direct measurements of exercise capacity and did not conduct formal studies of neurodevelopmental and behavioral dysfunction.
This study assesses health-related quality of life in patients with a rather homogeneous form of congenital heart disease. Because of this homogeneity, we are unable to conduct a risk-factor analysis for surgical palliation or primary transplantation. Other left ventricular outflow obstruction neonatal cohorts of the CHSS have addressed risk factors, as have other investigators.
These data do not allow discussion of potential for more biventricular or 1-1/2 ventricle repairs in this patient cohort.
Compared with surgical palliation for aortic atresia in an era before year 2000, primary heart transplantation was associated with better survival that endured through adolescence, with no evidence of accelerating risk. We acknowledge that mortality of surgical palliation and both primary neonatal and secondary transplantation have improved substantially since year 2000. Self-reported health-related quality of life of adolescents managed by either strategy is lower than that of the general adolescent population, but similar to that of adolescents with other chronic diseases. Patients who underwent transplantation experienced fewer cardiac symptoms than those who completed surgical palliation, but no other differences in overall self-reported quality of life were observed between the groups.
Although a strategy of primary heart transplantation could be considered a preferred strategy over surgical palliation for patients who have sufficient risk factors to predict a high probability of exceptionally poor midterm survival with a strategy of surgical palliation, it is likely more important to make every effort to maximize primary neonatal transplantation for newborns with an otherwise lethal congenital heart defect. It will be essential to continue following this cohort of patients into adulthood to monitor their clinical and physiologic status, transition of care, and self-reported health-related quality of life.
Conflict of Interest Statement
Authors have nothing to disclose with regard to commercial support.
Appendix E1. Congenital Heart Surgeons' Society Institutions that participated in aortic atresia study
Children's Hospital of Philadelphia
Children's Hospital of Pittsburgh
Children's Hospital Los Angeles
Cincinnati Children's Hospital Medical Center
Children's Hospital of Michigan, Detroit
Children's Hospital of Buffalo
Children's Memorial Hospital, Chicago
Children's Mercy Hospital, Kansas City
Children's National Health System, Washington D.C.
Columbia Presbyterian Medical Center, New York
Duke University Medical Center, Durham
Loma Linda University Medical Center
Mayo Clinic, Rochester
Milton S. Hershey Medical Center, Hershey
Montreal Children's Hospital
C.S. Mott Children's Hospital, Ann Arbor
St. Christopher's Hospital for Children, Philadelphia
Boston Children's Hospital
Children's Hospital Colorado, Aurora
The Hospital for Sick Children, Toronto
University of Alabama at Birmingham
University of Chicago
University of Miami
University of Nebraska
Vanderbilt University Medical Center
Appendix E2. Health-related quality of life
PedsQL Generic and Cardiac Modules
The PedsQL generic form is a brief, practical, flexible, and developmentally appropriate questionnaire that uses a multidimensional modular approach to measure health-related quality of life in children and adolescents. It is age-specific and can include both a patient and parent version. It measures core dimensions of health as designated by the World Health Organization, as well as school functioning. The 4 multidimensional scales are physical functioning (8 items), emotional functioning (5 items), social functioning (5 items), and school functioning (5 items), and the summary scores include physical health summary, psychosocial health summary, and total score. The PedsQL Cardiac Module is similar, but includes questions specifically for adolescents with cardiac disease. Reported dimensions (or grouped categories of questions) include heart problems and treatment (7 items), treatment (3 items), perceived physical appearance (3 items), treatment anxiety (4 items), cognitive problems (5 items), and communication (3 items). Higher scores indicate fewer problems and better quality of life.
Comparison of responders and nonresponders
A total of 80 patients, ranging from 12 to 19 years of age (mean 15 ± 2.2), returned questionnaires. Clinical characteristics and cardiac morphology of patients who returned the questionnaires were generally similar to those of patients who did not (n = 117; Table E1). However, there was slightly more tricuspid regurgitation at neonatal baseline in patients who returned the questionnaires, and they were more likely to be white. Despite the statistical significance, these differences between groups are likely not clinically important .
Table E1Characteristics of patients who returned questionnaires (responders) compared with those who did not (nonresponders)
Impaired health-related quality of life in children and adolescents with chronic conditions: a comparative analysis of 10 disease clusters and 33 disease categories/severities utilizing the PedsQL 4.0 Generic Core Scales.
This study was supported in part by member institutions of the Congenital Heart Surgeons' Society, the Drs Sidney and Becca Fleischer Heart and Vascular Education Chair, and the Peter and Elizabeth C. Tower and Family Endowed Chair in Cardiothoracic Research.
In their review of CHSS data from 1994 to 2000, Stackhouse and colleagues1 make clear their point that a strategy of surgical palliation for treatment of aortic atresia during an earlier generation carried a greater early risk of death than primary transplantation. This observation led them to conclude that it may be reasonable to encourage full utilization of primary pediatric transplantation, including extension to more aggressive use of primary transplantation in patients with aortic atresia today.
Stackhouse and colleagues1 report on the cohort of patients with aortic atresia (read: hypoplastic left heart syndrome [HLHS]) enrolled from 1994 to 2000 in the Congenital Heart Surgeons' Society study comparing outcomes of different initial management strategies. The focus of this manuscript is on the 2 most common initial interventions—surgical palliation and listing for primary cardiac transplantation. The authors discovered that survival with primary transplantation, including waitlist mortality, was superior to surgical palliation.