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Surgical palliation or primary transplantation for aortic valve atresia

Open ArchivePublished:September 25, 2019DOI:https://doi.org/10.1016/j.jtcvs.2019.08.104

      Abstract

      Objective

      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.

      Methods

      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.

      Results

      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).

      Conclusions

      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.

      Key Words

      Abbreviations and Acronyms:

      CHSS (Congenital Heart Surgeons' Society), CI (confidence interval)
      Figure thumbnail fx1
      Survival of an aortic atresia inception cohort (1994-2000) by initial management strategy.
      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.
      See Commentaries on pages 1462 and 1463.
      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.
      • Donnellan A.
      • Justice L.
      Preoperative stabilization of infants with hypoplastic left heart syndrome before stage I palliation.
      • Ohye R.G.
      • Schranz D.
      • D'Udekem Y.
      Current therapy for hypoplastic left heart syndrome and related single ventricle lesions.
      • Dabal R.J.
      • Kirklin J.K.
      • Kukreja M.
      • Brown R.N.
      • Cleveland D.C.
      • Eddins M.C.
      • et al.
      The modern Fontan operation shows no increase in mortality out to 20 years: a new paradigm.
      • Poh C.L.
      • d'Udekem Y.
      Life after surviving Fontan surgery: a meta-analysis of the incidence and predictors of late death.
      • John M.
      • Bailey L.L.
      Neonatal heart transplantation.
      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.
      • Jacobs M.L.
      • Blackstone E.H.
      • Bailey L.L.
      Intermediate survival in neonates with aortic atresia: a multi-institutional study. The Congenital Heart Surgeons Society.
      ,
      • Ashburn D.A.
      • McCrindle B.W.
      • Tchervenkov C.I.
      • Jacobs M.L.
      • Lofland G.K.
      • Bove E.L.
      • et al.
      Outcomes after the Norwood operation in neonates with critical aortic stenosis or aortic valve atresia.
      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

      Patients

      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.
      • Ashburn D.A.
      • McCrindle B.W.
      • Tchervenkov C.I.
      • Jacobs M.L.
      • Lofland G.K.
      • Bove E.L.
      • et al.
      Outcomes after the Norwood operation in neonates with critical aortic stenosis or aortic valve atresia.
      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.
      • Jacobs M.L.
      • Blackstone E.H.
      • Bailey L.L.
      Intermediate survival in neonates with aortic atresia: a multi-institutional study. The Congenital Heart Surgeons Society.
      ,
      • Ashburn D.A.
      • McCrindle B.W.
      • Tchervenkov C.I.
      • Jacobs M.L.
      • Lofland G.K.
      • Bove E.L.
      • et al.
      Outcomes after the Norwood operation in neonates with critical aortic stenosis or aortic valve atresia.
      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.

      Data Acquisition

      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.
      Table 1Patient characteristics
      CharacteristicOverall cohort

      (n = 565)
      Surgical palliation

      (n = 453)
      Primary transplant

      (n = 68)
      P
      n
      Patients with data available.
      No. (%) or Mean ± SDn
      Patients with data available.
      No. (%) or Mean ± SDn
      Patients with data available.
      No. (%) or Mean ± SD
      Demographics
       Female559201 (36)453173 (38)6815 (22).04
       Race32925551.0007
      White217 (66)175 (69)34 (67)
      Black48 (15)38 (15)2 (3.9)
      Other64 (19)42 (16)15 (29)
      Atria
       Atrial septal defect455430 (95)378355 (94)5252 (100).17
       Atrial septal defect jet width (mm)2895.6 ± 1.72285.7 ± 1.7395.5 ± 1.8.02
      Ventricles
       LV forms apex3107 (2.3)2423 (1.2)412 (4.9).06
       LV absent30653 (17)23941 (17)416 (15).7
      Ventricular septal defect
       Present24850 (20)17940 (22)517 (14)
       Small4121 (51)3418 (53)41 (25)
       Large4120 (49)3416 (47)43 (75)
       Multiple256 (24)205 (25)20 (0)
      RV dysfunction44036247.006
       None297 (68)252 (70)31 (66)
       Mild99 (23)78 (22)12 (26)
       Moderate34 (7.7)27 (7.5)1 (2.1)
       Severe10 (2.3)5 (1.4)3 (6.4)
      Mitral valve
       Mitral atresia378284 (75)314244 (78)4126 (63).04
      Tricuspid valve
       Tricuspid regurgitation grade45438241.03
      None199 (44)175 (46)11 (27)
      Mild162 (36)136 (36)15 (37)
      Mild/moderate54 (12)43 (11)10 (24)
      Moderate29 (6.4)20 (5.2)5 (12)
      Moderate/severe9 (2.0)7 (1.8)0 (0)
      Severe1 (0.22)1 (0.26)0 (0)
      Pulmonary valve
       Pulmonary regurgitation grade36030235.9
      None324 (90)270 (89)34 (97)
      Mild26 (7.2)23 (7.6)1 (2.9)
      Mild/moderate9 (2.5)8 (2.6)0 (0)
      Moderate1 (0.28)1 (0.33)0 (0)
      Aorta
       Ascending aorta diameter (mm)4912.4 ± 0.844112.3 ± 0.83512.6 ± 0.85.002
       PDA diameter (mm)2806.5 ± 1.32176.6 ± 1.3406.4 ± 1.3.7
      SD, Standard deviation; LV, left ventricle; RV, right ventricle; PDA, patent ductus arteriosus.
      Patients with data available.

      Follow-up

      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).
      • Varni J.W.
      The PedsQLTM measurement model for the Pediatric Quality of Life InventoryTM.
      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.

      Data Analysis

      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.

      Mortality

      All-cause mortality by initial management strategy was estimated nonparametrically by the Kaplan–Meier method and parametrically by a multiphase hazard model,
      • Blackstone E.H.
      • Naftel D.C.
      • Turner Jr., M.E.
      The decomposition of time-varying hazard into phases, each incorporating a separate stream of concomitant information.
      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.

      Competing risks

      Progression of patients from initial palliation through stages of surgical reconstruction used competing-risks analyses.
      • Andersen P.K.
      • Borgan O.
      • Gill R.D.
      • Keiding N.
      Statistical Models Based on Counting Processes.
      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
      • Andersen P.K.
      • Borgan O.
      • Gill R.D.
      • Keiding N.
      Statistical Models Based on Counting Processes.
      and parametrically.
      • Blackstone E.H.
      • Naftel D.C.
      • Turner Jr., M.E.
      The decomposition of time-varying hazard into phases, each incorporating a separate stream of concomitant information.

      Health-related quality of life

      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).
      • Varni J.W.
      The PedsQLTM measurement model for the Pediatric Quality of Life InventoryTM.
      The PedsQL Cardiac Module was scored in the same manner, with 3- or 5-point Likert scales reverse-scored and linearly transformed.

      Results

      Surgical Palliation

      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.
      Figure thumbnail gr1
      Figure 1Competing risks after Norwood operation in patients with aortic atresia: alive without event (black dots and lines), bidirectional Glenn (yellow triangles and lines), transplantation (red squares and lines), and death before any of these procedures (blue circles and lines). Solid lines represent parametric estimates of being in each category across time. These estimates are enclosed within dashed 68% confidence bands equivalent to ± 1 standard error. Symbols are nonparametric estimates with 68% confidence bars.

      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.
      Figure thumbnail gr2
      Figure 2Competing risks after listing for primary cardiac transplant in patients with aortic atresia: alive without transplant (black dots and lines), transplant (red squares and lines), and death on transplant wait-list (blue circles and lines). Solid lines represent parametric estimates of probability of occurrence of competing events, enclosed within dashed 68% confidence bands equivalent to ± 1 standard error. Symbols are nonparametric estimates with 68% confidence bars.

      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).
      Figure thumbnail gr3
      Figure 3Survival and instantaneous risk of death among patients with aortic atresia by treatment strategy. Wait-list deaths are included, as are deaths after any surgical palliation procedure. A, Instantaneous risk of death after surgical palliation compared with primary transplantation. Solid lines represent parametric estimates of instantaneous risk of death enclosed within dashed 68% confidence bands equivalent to ± 1 standard error. B, Survival. Solid lines represent parametric estimates of survival, enclosed within dashed 68% confidence bands equivalent to ± 1 standard error. Symbols are nonparametric Kaplan–Meier estimates with 68% confidence bars. CHSS, Congenital Heart Surgeons' Society.
      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).

      Secondary Transplantation

      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).
      Figure thumbnail gr4
      Figure 4Survival after primary transplantation compared with transplantation after failed surgical palliation. Note that wait-list deaths are not included. Format is as in .

      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.
      Figure thumbnail gr5
      Figure 5Distribution of quality of life scores in each PedsQL domain for patients who received a transplant versus those who underwent surgical palliation. Dots represent mean values. Bars at the top, middle, and bottom of the boxes depict 15th, 50th, and 85th percentiles, respectively; top and bottom of the whiskers are maximum and minimum values. A, Raw transformed scores (see “Methods”), where the general adolescent population has a mean value of 100. B, z-scores, where 0 represents the mean value for the general adolescent population, −1 represents 1 standard deviation below this, and so on.
      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.
      Figure thumbnail gr6
      Figure 6Distribution of quality of life scores in each PedsQL Cardiac Module domain for patients who received a transplant versus those who underwent surgical palliation. Format is as in .

      Discussion

      Principal Findings

      Survival

      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.
      • Varni J.W.
      • Limbers C.A.
      • Burwinkle T.M.
      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.
      ,
      • Ingerski L.M.
      • Modi A.C.
      • Hood K.K.
      • Pai A.L.
      • Zeller M.
      • Piazza-Waggoner C.
      • et al.
      Health-related quality of life across pediatric chronic conditions.
      Fewer symptoms were reported after transplantation than after surgical palliation, but otherwise these groups had similar health-related quality of life.

      Surgical Palliation

      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.
      • Jacobs M.L.
      • Blackstone E.H.
      • Bailey L.L.
      Intermediate survival in neonates with aortic atresia: a multi-institutional study. The Congenital Heart Surgeons Society.
      Even in this early era, mortality after surgical palliation was similar to that after primary transplantation in some institutions.
      • Jacobs M.L.
      • Blackstone E.H.
      • Bailey L.L.
      Intermediate survival in neonates with aortic atresia: a multi-institutional study. The Congenital Heart Surgeons Society.
      Today, principles of supportive care before and after surgical palliation are well understood and standardized.
      • Donnellan A.
      • Justice L.
      Preoperative stabilization of infants with hypoplastic left heart syndrome before stage I palliation.
      Thus, early mortality after the Norwood operation is substantially less than was observed in the mid-to-late 1990s, when patients entered our inception cohort.
      • Ohye R.G.
      • Schranz D.
      • D'Udekem Y.
      Current therapy for hypoplastic left heart syndrome and related single ventricle lesions.
      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.
      • Tabbutt S.
      • Ghanayem N.
      • Ravishankar C.
      • Sleeper L.A.
      • Cooper D.S.
      • Frank D.U.
      • et al.
      Risk factors for hospital morbidity and mortality after the Norwood procedure: a report from the Pediatric Heart Network Single Ventricle Reconstruction trial.
      The 10- and 20-year outcomes of the trial are being monitored. While we await these results, it is known already that risk out to 20 years after the Fontan operation is lower than in earlier eras,
      • Dabal R.J.
      • Kirklin J.K.
      • Kukreja M.
      • Brown R.N.
      • Cleveland D.C.
      • Eddins M.C.
      • et al.
      The modern Fontan operation shows no increase in mortality out to 20 years: a new paradigm.
      ,
      • Poh C.L.
      • d'Udekem Y.
      Life after surviving Fontan surgery: a meta-analysis of the incidence and predictors of late death.
      brought about in part by innovations in improving energy transfer from the inferior vena cava to the pulmonary artery.
      • de Leval M.R.
      • Kilner P.
      • Gewillig M.
      • Bull C.
      Total cavopulmonary connection: a logical alternative to atriopulmonary connection for complex Fontan operations. Experimental studies and early clinical experience.
      However, the constant hazard of 1.3%/year reported by Dabal and colleagues
      • Dabal R.J.
      • Kirklin J.K.
      • Kukreja M.
      • Brown R.N.
      • Cleveland D.C.
      • Eddins M.C.
      • et al.
      The modern Fontan operation shows no increase in mortality out to 20 years: a new paradigm.
      remains approximately 20 times higher than the 0.072%/year for 20-year-old patients in the US general population.

      Primary Heart Transplantation

      Improved survival for initial surgical palliation is paralleled by improved survival of neonates and infants undergoing primary transplantation.
      • John M.
      • Bailey L.L.
      Neonatal heart transplantation.
      Advantages of transplantation in infancy were suspected by Bailey and colleagues
      • Bailey L.L.
      • Nehlsen-Cannarella S.L.
      • Doroshow R.W.
      • Jacobson J.G.
      • Martin R.D.
      • Allard M.W.
      • et al.
      Cardiac allotransplantation in newborns as therapy for hypoplastic left heart syndrome.
      in the 1984 “Baby Fae” xenotransplant. Subsequently, several studies have identified superior survival among patients undergoing transplantation in early infancy,
      • John M.
      • Bailey L.L.
      Neonatal heart transplantation.
      ,
      • Chinnock R.E.
      • Bailey L.L.
      Heart transplantation for congenital heart disease in the first year of life.
      with 60% 25-year survival among neonatal heart transplant recipients,
      • Chinnock R.E.
      • Bailey L.L.
      Heart transplantation for congenital heart disease in the first year of life.
      substantially higher than that of infants undergoing transplantation between the ages 1 and 12 months. They documented even better outcomes in the recent era.
      Investigators have proposed an immunologic advantage for neonates undergoing transplantation, invoking relative tolerance that is likely multifactorial
      • Platt J.L.
      • Cascalho M.
      • West L.
      Lessons from cardiac transplantation in infancy.
      : potential impairment in presentation of major histocompatibility complex antigens,
      • White D.J.
      • Gilks W.
      The ontogeny of immune responses.
      potential induction of tolerance by exposure to certain foreign antigens such as isohemagglutinins determining blood groups,
      • Platt J.L.
      • Cascalho M.
      • West L.
      Lessons from cardiac transplantation in infancy.
      and diminished T-cell receptor diversity.
      • Ogle B.M.
      • West L.J.
      • Driscoll D.J.
      • Strome S.E.
      • Razonable R.R.
      • Paya C.V.
      • et al.
      Effacing of the T cell compartment by cardiac transplantation in infancy.
      However, primary transplantation for aortic atresia poses important issues related to the challenge of optimum use and allocation of a scarce resource: neonatal and infant donor hearts.
      • Kon A.A.
      Ethics of cardiac transplantation in hypoplastic left heart syndrome.
      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.
      • Daly K.P.
      Finding the correct role for heart transplant in the treatment of hypoplastic left heart syndrome.
      ,
      • Checchia P.A.
      • Larsen R.
      • Sehra R.
      • Daher N.
      • Gundry S.R.
      • Razzouk A.J.
      • et al.
      Effect of a selection and postoperative care protocol on survival of infants with hypoplastic left heart syndrome.
      The 13% pretransplant wait-list mortality in this study could be the result of early introduction of neonatal transplantation at a few centers.
      • Chinnock R.E.
      • Bailey L.L.
      Heart transplantation for congenital heart disease in the first year of life.
      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.
      • West L.J.
      • Karamlou T.
      • Dipchand A.I.
      • Pollock-BarZiv S.M.
      • Coles J.G.
      • McCrindle B.W.
      Impact on outcomes after listing and transplantation, of a strategy to accept ABO blood group-incompatible donor hearts for neonates and infants.
      ,
      • Urschel S.
      • West L.J.
      ABO-incompatible heart transplantation.
      Since changing their organ allocation practice, Canadian institutions have decreased their wait-list mortality from 58% to 7% in babies aged less than 6 months.
      • West L.J.
      • Karamlou T.
      • Dipchand A.I.
      • Pollock-BarZiv S.M.
      • Coles J.G.
      • McCrindle B.W.
      Impact on outcomes after listing and transplantation, of a strategy to accept ABO blood group-incompatible donor hearts for neonates and infants.
      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.
      • Kane J.M.
      • Canar J.
      • Kalinowski V.
      • Johnson T.J.
      • Hoehn K.S.
      Management options and outcomes for neonatal hypoplastic left heart syndrome in the early twenty-first century.
      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%.
      • Daly K.P.
      Finding the correct role for heart transplant in the treatment of hypoplastic left heart syndrome.
      ,
      • Checchia P.A.
      • Larsen R.
      • Sehra R.
      • Daher N.
      • Gundry S.R.
      • Razzouk A.J.
      • et al.
      Effect of a selection and postoperative care protocol on survival of infants with hypoplastic left heart syndrome.
      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
      • Kirklin J.K.
      • Pearce F.B.
      • Dabal R.J.
      • Carlo Jr., W.F.
      • Mauchley D.C.
      Challenges of cardiac transplantation following the Fontan procedure.
      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.
      • Kulkarni A.
      • Neugebauer R.
      • Lo Y.
      • Gao Q.
      • Lamour J.M.
      • Weinstein S.
      • et al.
      Outcomes and risk factors for listing for heart transplantation after the Norwood procedure: an analysis of the Single Ventricle Reconstruction Trial.
      Although the difference may be explained by long-standing organ congestion and dysfunction,
      • Kirklin J.K.
      • Pearce F.B.
      • Dabal R.J.
      • Carlo Jr., W.F.
      • Mauchley D.C.
      Challenges of cardiac transplantation following the Fontan procedure.
      age at transplant may also be a factor, as found in our study. In the Pediatric Heart Transplant Study, 1-year survival after listing for failed surgical palliation was 60%,
      • Alsoufi B.
      • Mahle W.T.
      • Manlhiot C.
      • Deshpande S.
      • Kogon B.
      • McCrindle B.W.
      • et al.
      Outcomes of heart transplantation in children with hypoplastic left heart syndrome previously palliated with the Norwood procedure.
      and if the patient was younger than age 6 years at listing, the risk was greater than in older patients.
      • Carlo W.F.
      • West S.C.
      • McCulloch M.
      • Naftel D.C.
      • Pruitt E.
      • Kirklin J.K.
      • et al.
      Impact of initial Norwood shunt type on young hypoplastic left heart syndrome patients listed for heart transplant: a multi-institutional study.
      A hybrid stage-1 palliation with ductal stenting and bilateral pulmonary artery banding has been proposed as a reasonable bridging strategy to transplantation.
      • Morray B.H.
      • Albers E.L.
      • Jones T.K.
      • Kemna M.S.
      • Permut L.C.
      • Law Y.M.
      Hybrid stage 1 palliation as a bridge to cardiac transplantation in patients with high-risk single ventricle physiology.

      Health-Related Quality of Life

      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
      • Manlhiot C.
      • Knezevich S.
      • Radojewski E.
      • Cullen-Dean G.
      • Williams W.G.
      • McCrindle B.W.
      Functional health status of adolescents after the Fontan procedure–comparison with their siblings.
      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.
      • Goldberg C.S.
      • Schwartz E.M.
      • Brunberg J.A.
      • Mosca R.S.
      • Bove E.L.
      • Schork M.A.
      • 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.
      ,
      • Mahle W.T.
      • Clancy R.R.
      • Moss E.M.
      • Gerdes M.
      • Jobes D.R.
      • Wernovsky G.
      Neurodevelopmental outcome and lifestyle assessment in school-aged and adolescent children with hypoplastic left heart syndrome.
      School-age survivors are more likely to require remedial services, including tutoring, special education, and physical, occupational, and speech therapy.
      These findings are in accord with findings from other studies of patients with single-ventricle physiology after surgical palliation.
      • Idorn L.
      • Jensen A.S.
      • Juul K.
      • Overgaard D.
      • Nielsen N.P.
      • Sorensen K.
      • et al.
      Quality of life and cognitive function in Fontan patients, a population-based study.
      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.
      • McCrindle B.W.
      • Williams R.V.
      • Mital S.
      • Clark B.J.
      • Russell J.L.
      • Klein G.
      • et al.
      Physical activity levels in children and adolescents are reduced after the Fontan procedure, independent of exercise capacity, and are associated with lower perceived general health.
      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).
      • Wray J.
      • Long T.
      • Radley-Smith R.
      • Yacoub M.
      Returning to school after heart or heart-lung transplantation: how well do children adjust?.
      However, DeMaso and colleagues
      • DeMaso D.R.
      • Douglas Kelley S.
      • Bastardi H.
      • O'Brien P.
      • Blume E.D.
      The longitudinal impact of psychological functioning, medical severity, and family functioning in pediatric heart transplantation.
      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
      • Sigfusson G.
      • Fricker F.J.
      • Bernstein D.
      • Addonizio L.J.
      • Baum D.
      • Hsu D.T.
      • et al.
      Long-term survivors of pediatric heart transplantation: a multicenter report of sixty-eight children who have survived longer than five years.
      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.

      Study Limitations

      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.
      • Manlhiot C.
      • Knezevich S.
      • Radojewski E.
      • Cullen-Dean G.
      • Williams W.G.
      • McCrindle B.W.
      Functional health status of adolescents after the Fontan procedure–comparison with their siblings.
      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.
      • Meza J.M.
      • Hickey E.
      • McCrindle B.
      • Blackstone E.
      • Anderson B.
      • Overman D.
      • et al.
      The optimal timing of stage-2-palliation after the Norwood operation.
      These data do not allow discussion of potential for more biventricular or 1-1/2 ventricle repairs in this patient cohort.

      Conclusions

      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.
      Cleveland Clinic
      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 .
      Figure thumbnail fx2
      Figure E1CONSORT-style diagram of surgical treatment of patients with aortic atresia. BV, Biventricular.
      Figure thumbnail fx3
      Figure E2Institutional volume of neonates with aortic atresia managed by surgical palliation (blue), primary transplantation (red), biventricular repair (mauve), and no treatment (black).
      Figure thumbnail fx4
      Figure E3Competing risks after bidirectional Glenn/hemi-Fontan in patients with aortic atresia: alive without event (black dots and lines), Fontan (yellow triangles and lines), transplantation (red squares and lines), and death before any of these procedures (blue circles and lines). Solid lines represent parametric estimates of being in each category across time. These estimates are enclosed within dashed 68% confidence bands equivalent to ± 1 standard error. Symbols are nonparametric estimates with 68% confidence bars.
      Figure thumbnail fx5
      Figure E4Instantaneous risk of death on the heart transplant wait-list. Format is as in , A.
      Figure thumbnail fx6
      Figure E5Hazard function for primary versus secondary heart transplantation, not including wait-list mortality, which was not documented for secondary transplant patients. Format is as in , B.
      Figure thumbnail fx7
      Figure E6Distribution of quality of life scores in each PedsQL domain for patients with aortic atresia, in green, compared with healthy patients and those with other pediatric chronic diseases. Dots depict mean values, with error bars equivalent to ± 1 standard deviation.
      • Varni J.W.
      • Limbers C.A.
      • Burwinkle T.M.
      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.
      Table E1Characteristics of patients who returned questionnaires (responders) compared with those who did not (nonresponders)
      CharacteristicNonresponders (n = 117)Responders (n = 80)P
      n
      Patients with data available.
      No. (%) or Mean ± SDn
      Patients with data available.
      No. (%) or Mean ± SD
      Demographics
       Age at admission (y)
      15th/50th/85th percentiles.
      1170/1/6800/1/7>.9
       Female11733 (28)8022 (28).9
       Race7649.008
      White48 (63)43 (88)
      Black5 (6.6)2 (4.1)
      Other23 (30)4 (8.2)
      Initial management group11780.13
       Surgical palliation86 (74)64 (80)
       Transplant29 (25)12 (15)
       Biventricular repair2 (1.7)804 (5.0)
      Morphology and function
       ASD10199 (98)7167 (94).2
       ASD size8759.7
      Small38 (44)5924 (41)
      Medium32 (37)20 (34)
      Large17 (20)15 (25)
       ASD flow direction: left to right6258 (94)5351 (96).5
       Multiple ASDs7840 (51)5622 (39).17
       Abnormal pulmonary venous drainage530 (0)511 (2.0).3
       Pulmonary regurgitation grade7360.3
      Normal68 (93)50 (83)
      Mild4 (5.5)7 (12)
      Mild-moderate1 (1.4)2 (3.3)
      Moderate0 (0)1 (1.7)
      Moderate-severe0 (0)0 (0)
      Severe0 (0)0 (0)
       Tricuspid regurgitation grade9975.01
      Normal44 (44)29 (39)
      Mild43 (43)24 (32)
      Mild-moderate10 (10)15 (20)
      Moderate0 (0)6 (8.0)
      Moderate-severe2 (2.0)1 (1.3)
      Severe0 (0)0 (0)
       Mitral atresia8260 (73)5642 (75).8
       LV forms apex663 (4.5)565 (8.9).3
       RV dysfunction9674.5
      Normal74 (77)7454 (73)
      Mild16 (17)16 (22)
      Moderate4 (4.2)4 (5.4)
      Severe2 (2.1)0 (0)
       LV absent668 (12)567 (13)>.9
       IVS pressure5848.9
      Bows to RV19 (33)16 (33)
      Flat25 (43)22 (46)
      Bows to LV14 (24)10 (21)
       Ascending aorta hypoplasia grade6347.5
      Mild1 (1.6)1 (2.1)
      Moderate10 (16)4 (8.5)
      Severe52 (83)42 (89)
       Right atrial area (cm2)644.0 ± 1.2563.7 ± 1.1.18
       Left atrial area (cm2)641.8 ± 0.81561.8 ± 0.68.8
       ASD jet width (mm)645.7 ± 1.8545.4 ± 1.5.3
       Cardiac end-diastolic length (cm)632.9 ± 0.40532.8 ± 0.30.4
       End-systolic long-axis RV endocardial length (mm)632.8 ± 0.34532.8 ± 0.30.3
       End-diastolic long-axis RV epicardial length (mm)633.3 ± 0.33513.3 ± 0.32.4
       End-systolic short-axis RV endocardial length (mm)633.3 ± 0.90483.4 ± 1.3>.9
       End-diastolic short-axis RV endocardial length (mm)635.2 ± 1.0495.2 ± 1.6.8
       Ascending aorta diameter (mm)1052.5 ± 0.92752.5 ± 0.99.6
       PDA diameter (mm)634.7/6.4/7.6
      15th/50th/85th percentiles.
      545.1/6.2/7.8
      15th/50th/85th percentiles.
      >.9
      SD, Standard deviation; ASD, atrial septal defect; LV, left ventricle; RV, right ventricle; IVS, interventricular septum; PDA, patent ductus arteriosus.
      Patients with data available.
      15th/50th/85th percentiles.
      Table E2Risk factors for death after heart transplantation
      Risk factorCoefficient ± SEP
      Early phase
       Secondary transplantation0.097 ± 1.2.9
       Older age at transplantation−0.66 ± 0.95.5
      Late phase
       Secondary transplantation0.83 ± 0.61.17
       Older age at transplantation0.39 ± 0.082<.0001
      SE, Standard error.

      References

        • Donnellan A.
        • Justice L.
        Preoperative stabilization of infants with hypoplastic left heart syndrome before stage I palliation.
        Crit Care Nurse. 2016; 36: 52-59
        • Ohye R.G.
        • Schranz D.
        • D'Udekem Y.
        Current therapy for hypoplastic left heart syndrome and related single ventricle lesions.
        Circulation. 2016; 134: 1265-1279
        • Dabal R.J.
        • Kirklin J.K.
        • Kukreja M.
        • Brown R.N.
        • Cleveland D.C.
        • Eddins M.C.
        • et al.
        The modern Fontan operation shows no increase in mortality out to 20 years: a new paradigm.
        J Thorac Cardiovasc Surg. 2014; 148: 2517-2523.e1
        • Poh C.L.
        • d'Udekem Y.
        Life after surviving Fontan surgery: a meta-analysis of the incidence and predictors of late death.
        Heart Lung Circ. 2018; 27: 552-559
        • John M.
        • Bailey L.L.
        Neonatal heart transplantation.
        Ann Cardiothorac Surg. 2018; 7: 118-125
        • Jacobs M.L.
        • Blackstone E.H.
        • Bailey L.L.
        Intermediate survival in neonates with aortic atresia: a multi-institutional study. The Congenital Heart Surgeons Society.
        J Thorac Cardiovasc Surg. 1998; 116: 417-431
        • Ashburn D.A.
        • McCrindle B.W.
        • Tchervenkov C.I.
        • Jacobs M.L.
        • Lofland G.K.
        • Bove E.L.
        • et al.
        Outcomes after the Norwood operation in neonates with critical aortic stenosis or aortic valve atresia.
        J Thorac Cardiovasc Surg. 2003; 125: 1070-1082
        • Varni J.W.
        The PedsQLTM measurement model for the Pediatric Quality of Life InventoryTM.
        (Available at:)
        http://www.pedsql.org/
        Date accessed: November 29, 2018
        • Blackstone E.H.
        • Naftel D.C.
        • Turner Jr., M.E.
        The decomposition of time-varying hazard into phases, each incorporating a separate stream of concomitant information.
        J Am Stat Assoc. 1986; 81: 615-624
        • Andersen P.K.
        • Borgan O.
        • Gill R.D.
        • Keiding N.
        Statistical Models Based on Counting Processes.
        Springer-Verlag, New York1995: 176-331
        • Varni J.W.
        • Limbers C.A.
        • Burwinkle T.M.
        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.
        Health Qual Life Outcomes. 2007; 5: 43
        • Ingerski L.M.
        • Modi A.C.
        • Hood K.K.
        • Pai A.L.
        • Zeller M.
        • Piazza-Waggoner C.
        • et al.
        Health-related quality of life across pediatric chronic conditions.
        J Pediatr. 2010; 156: 639-644
        • Tabbutt S.
        • Ghanayem N.
        • Ravishankar C.
        • Sleeper L.A.
        • Cooper D.S.
        • Frank D.U.
        • et al.
        Risk factors for hospital morbidity and mortality after the Norwood procedure: a report from the Pediatric Heart Network Single Ventricle Reconstruction trial.
        J Thorac Cardiovasc Surg. 2012; 144: 882-895
        • de Leval M.R.
        • Kilner P.
        • Gewillig M.
        • Bull C.
        Total cavopulmonary connection: a logical alternative to atriopulmonary connection for complex Fontan operations. Experimental studies and early clinical experience.
        J Thorac Cardiovasc Surg. 1988; 96: 682-695
        • Bailey L.L.
        • Nehlsen-Cannarella S.L.
        • Doroshow R.W.
        • Jacobson J.G.
        • Martin R.D.
        • Allard M.W.
        • et al.
        Cardiac allotransplantation in newborns as therapy for hypoplastic left heart syndrome.
        N Engl J Med. 1986; 315: 949-951
        • Chinnock R.E.
        • Bailey L.L.
        Heart transplantation for congenital heart disease in the first year of life.
        Curr Cardiol Rev. 2011; 7: 72-84
        • Platt J.L.
        • Cascalho M.
        • West L.
        Lessons from cardiac transplantation in infancy.
        Pediatr Transplant. 2009; 13: 814-819
        • White D.J.
        • Gilks W.
        The ontogeny of immune responses.
        J Heart Lung Transplant. 1993; 12: S301-S308
        • Ogle B.M.
        • West L.J.
        • Driscoll D.J.
        • Strome S.E.
        • Razonable R.R.
        • Paya C.V.
        • et al.
        Effacing of the T cell compartment by cardiac transplantation in infancy.
        J Immunol. 2006; 176: 1962-1967
        • Kon A.A.
        Ethics of cardiac transplantation in hypoplastic left heart syndrome.
        Pediatr Cardiol. 2009; 30: 725-728
        • Daly K.P.
        Finding the correct role for heart transplant in the treatment of hypoplastic left heart syndrome.
        J Heart Lung Transplant. 2016; 35: 299-300
        • Checchia P.A.
        • Larsen R.
        • Sehra R.
        • Daher N.
        • Gundry S.R.
        • Razzouk A.J.
        • et al.
        Effect of a selection and postoperative care protocol on survival of infants with hypoplastic left heart syndrome.
        Ann Thorac Surg. 2004; 77 (discussion 83): 477-483
        • West L.J.
        • Karamlou T.
        • Dipchand A.I.
        • Pollock-BarZiv S.M.
        • Coles J.G.
        • McCrindle B.W.
        Impact on outcomes after listing and transplantation, of a strategy to accept ABO blood group-incompatible donor hearts for neonates and infants.
        J Thorac Cardiovasc Surg. 2006; 131: 455-461
        • Urschel S.
        • West L.J.
        ABO-incompatible heart transplantation.
        Curr Opin Pediatr. 2016; 28: 613-619
        • Kane J.M.
        • Canar J.
        • Kalinowski V.
        • Johnson T.J.
        • Hoehn K.S.
        Management options and outcomes for neonatal hypoplastic left heart syndrome in the early twenty-first century.
        Pediatr Cardiol. 2016; 37: 419-425
        • Kirklin J.K.
        • Pearce F.B.
        • Dabal R.J.
        • Carlo Jr., W.F.
        • Mauchley D.C.
        Challenges of cardiac transplantation following the Fontan procedure.
        World J Pediatr Congenit Heart Surg. 2017; 8: 480-486
        • Kulkarni A.
        • Neugebauer R.
        • Lo Y.
        • Gao Q.
        • Lamour J.M.
        • Weinstein S.
        • et al.
        Outcomes and risk factors for listing for heart transplantation after the Norwood procedure: an analysis of the Single Ventricle Reconstruction Trial.
        J Heart Lung Transplant. 2016; 35: 306-311
        • Alsoufi B.
        • Mahle W.T.
        • Manlhiot C.
        • Deshpande S.
        • Kogon B.
        • McCrindle B.W.
        • et al.
        Outcomes of heart transplantation in children with hypoplastic left heart syndrome previously palliated with the Norwood procedure.
        J Thorac Cardiovasc Surg. 2016; 151 (75.e1-2): 167-174
        • Carlo W.F.
        • West S.C.
        • McCulloch M.
        • Naftel D.C.
        • Pruitt E.
        • Kirklin J.K.
        • et al.
        Impact of initial Norwood shunt type on young hypoplastic left heart syndrome patients listed for heart transplant: a multi-institutional study.
        J Heart Lung Transplant. 2016; 35: 301-305
        • Morray B.H.
        • Albers E.L.
        • Jones T.K.
        • Kemna M.S.
        • Permut L.C.
        • Law Y.M.
        Hybrid stage 1 palliation as a bridge to cardiac transplantation in patients with high-risk single ventricle physiology.
        Pediatr Transplant. 2018; 22: e13307
        • Manlhiot C.
        • Knezevich S.
        • Radojewski E.
        • Cullen-Dean G.
        • Williams W.G.
        • McCrindle B.W.
        Functional health status of adolescents after the Fontan procedure–comparison with their siblings.
        Can J Cardiol. 2009; 25: e294-e300
        • Goldberg C.S.
        • Schwartz E.M.
        • Brunberg J.A.
        • Mosca R.S.
        • Bove E.L.
        • Schork M.A.
        • 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: 646-652
        • Mahle W.T.
        • Clancy R.R.
        • Moss E.M.
        • Gerdes M.
        • Jobes D.R.
        • Wernovsky G.
        Neurodevelopmental outcome and lifestyle assessment in school-aged and adolescent children with hypoplastic left heart syndrome.
        Pediatrics. 2000; 105: 1082-1089
        • Idorn L.
        • Jensen A.S.
        • Juul K.
        • Overgaard D.
        • Nielsen N.P.
        • Sorensen K.
        • et al.
        Quality of life and cognitive function in Fontan patients, a population-based study.
        Int J Cardiol. 2013; 168: 3230-3235
        • McCrindle B.W.
        • Williams R.V.
        • Mital S.
        • Clark B.J.
        • Russell J.L.
        • Klein G.
        • et al.
        Physical activity levels in children and adolescents are reduced after the Fontan procedure, independent of exercise capacity, and are associated with lower perceived general health.
        Arch Dis Child. 2007; 92: 509-514
        • Wray J.
        • Long T.
        • Radley-Smith R.
        • Yacoub M.
        Returning to school after heart or heart-lung transplantation: how well do children adjust?.
        Transplantation. 2001; 72: 100-106
        • DeMaso D.R.
        • Douglas Kelley S.
        • Bastardi H.
        • O'Brien P.
        • Blume E.D.
        The longitudinal impact of psychological functioning, medical severity, and family functioning in pediatric heart transplantation.
        J Heart Lung Transplant. 2004; 23: 473-480
        • Sigfusson G.
        • Fricker F.J.
        • Bernstein D.
        • Addonizio L.J.
        • Baum D.
        • Hsu D.T.
        • et al.
        Long-term survivors of pediatric heart transplantation: a multicenter report of sixty-eight children who have survived longer than five years.
        J Pediatr. 1997; 130: 862-871
        • Meza J.M.
        • Hickey E.
        • McCrindle B.
        • Blackstone E.
        • Anderson B.
        • Overman D.
        • et al.
        The optimal timing of stage-2-palliation after the Norwood operation.
        Ann Thorac Surg. 2018; 105: 193-199

      Linked Article

      • Commentary: No justification for transplantation in place of standard surgical palliation
        The Journal of Thoracic and Cardiovascular SurgeryVol. 159Issue 4
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          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.
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      • Commentary: Unicorns and leprechauns
        The Journal of Thoracic and Cardiovascular SurgeryVol. 159Issue 4
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          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.
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