Health-related quality of life: a closer look at related research in patients who have undergone the Fontan operation over the last decade.

The advancements in surgical technique and perioperative care have significantly improved the survival of children with single ventricle (SV) congenital heart disease (CHD) over the past decade. The population who have undergone the Fontan operation are growing into adulthood and facing many unique challenges. Past research has focused on functional and neurodevelopmental outcomes with inferences made to health-related quality of life (HRQOL). With the population who have undergone the Fontan operation surviving into adulthood, little research has been directed toward the self-report of HRQOL in adolescents and young adults after surgical palliation. Questions still remain on how these patients will transition into adulthood and whether they will live normal productive lives. This article reviews the literature related to HRQOL in the SV subgroup of CHD. In addition, an overview of newly developed disease-specific HRQOL instruments is presented as well as limitations and future research in HRQOL of the SV Fontan population. (Heart Lung® 2007;36:3–15.)

H ealth-related quality of life represents the patients' assessment of the impact of illness on their ability to carry out activities or roles that are important to them. 1 Over the past decade, health-related quality of life (HRQOL) has emerged as an important outcome measurement. 2 This measurement is particularly relevant with the increase in the incidence of chronic disease and longevity of the general population. 3 The concept of HRQOL and quality of life (QOL) are important areas of research to explore in the population with single ventricle (SV) congenital heart disease (CHD). This population is now surviving to adulthood and facing challenges of an uncertain future. The uncertainty of progressive func-tional limitations, ability to maintain a job, health insurance, SV failure, possibility of heart transplantation, arrhythmias, and sudden death are concerns. Issues related to HRQOL and factors that affect it in this population are poorly understood. Past research in patients with SV CHD has focused on functional and neurodevelopmental outcomes producing a growing body of literature with documented deficits that seem to be multifactoral. [4][5][6][7][8][9][10] However, little is known about the other determinants of HRQOL such as social well-being and function. Moreover, earlier studies in this population had identified the perceptions of family members rather than the actual self-perceived HRQOL of the individual, who may not have been of sufficient age to participate in the evaluation. Therefore, additional research to examine HRQOL in the population with SV CHD will provide health care workers, patients, and their families more realistic expectations of outcomes. Such outcomes research can evaluate medical management and surgical approaches, provide information for prenatal counseling, and parent and adolescent transition counseling, and assist in the development of specific interventions tailored to improve HRQOL and overall QOL as this population transitions into adulthood.
This article presents a review of the literature related to HRQOL in the SV subgroup of CHD. In addition, an overview of newly developed diseasespecific HRQOL instruments is presented as well as a discussion on limitations and future research in HRQOL of the SV Fontan population.

SEARCH STRATEGIES
PubMed and CINAHL searches were performed for studies examining HRQOL in SV CHD after the Fontan procedure. Included in this search were all empirical studies published between 1994 and 2005; were published in English; that assessed children, adolescents, and adults; and evaluated both individual and parent proxy reports of HRQOL. The search terms were "health-related quality of life" combined with "single ventricle" and "Fontan." However, only a limited number of articles were identified. The search terms were expanded to include "quality of life," because HRQOL is a newer term, and "complex congenital heart disease" to fully capture all articles that may have separated CHD according to disease severity. Excluded in this search were editorials, case studies, opinion articles, textbooks, qualitative studies, and conference abstracts.

SINGLE VENTRICLE CONGENITAL HEART DISEASE: A GROWING POPULATION
Congenital Heart Disease affects 40,000 newborns each year in the United States. 11 According to the March of Dimes Prenatal Statistics (2000), CHD is the number one birth defect in the United States. 12 More than 35 types of congenital heart defects have been identified, 11 which represent a broad spectrum of severity ranging from minor defects that may spontaneously self-correct, to more severe, potentially life-threatening defects that require several surgical interventions. Some children born with complex CHD have only one functional ventricle, which pumps to both pulmonary and systemic circulations. Thus, the term "single ventricle" is used to describe a functional SV regardless of anatomic subtype. Various forms of SV CHD, primarily hypoplastic left heart syndrome (HLHS), were considered fatal before the 1980s. 4 In the last 30 years, advances in treatment of CHD have enabled approximately 1 million U.S. children with significant heart defects to survive into adulthood. 11 At the present time, there are as many adults with CHD as there are children with this disease. 13 Therefore, a new specialized adult population with chronic disease has emerged and is estimated to grow at a rate of 5% per year. 14 Adolescents and young adults with CHD represent a growing subspecialty in adult cardiology. The first specialized center in the United States to treat adults with CHD is the UCLA Adult Congenital Heart Disease Center, founded in 1978. 15 Specialized centers provide medical care focused on the natural sequelae or residual effects after surgery and long-term health care needs of patients with CHD. 15 Other issues that present challenges to this population and areas for future research are employability, insurability (medical/life), contraception/pregnancy, genetic transmission, and exercise. 15,16

FONTAN PROCEDURE
Over the past two decades, life expectancy for children with SV CHD has increased significantly. This is related to advancements in surgical technique and perioperative care. SV CHD generally requires three or more staged palliative heart surgeries at various developmental stages (neonatal, 6 months, and 2-5 years of age). The goal of surgical palliation is to improve hemodynamics through gradual separation of the pulmonary and systemic circulations, thereby relieving cyanosis and volume overload of the SV. The Fontan procedure is the final staged palliative surgery, which usually provides complete separation of the two circulations.
The Fontan operation was first described by Fontan and Baudet 17 for the repair of tricuspid atresia. The underlying principle of Fontan circulation is that the pulmonary circulation can be perfused without a ventricular pump. 18 The SV becomes the systemic pump for blood flow to the aorta and the body. The pulmonary circulation receives passive nonpulsatile blood directly from the superior and inferior vena cavae through direct anastamosis or the use of synthetic graft material (eg, Gore-Tex, W.L. Gou and Associates, Inc, Newark, DE). The original Fontan procedure has undergone various modifications and can be applied to all types of SV anatomy. Thus, completion of the Fontan while providing satisfactory palliation, still leaves the patient with a single right or left ventricle at risk for late cardiac failure, exercise intolerance, and arrhythmias. A portion of the population who have undergone the Fontan procedure may ultimately require heart transplantation related to long-term postoperative morbidities associated with SV failure. 6

DIFFERENTIATION BETWEEN HRQOL AND QOL
Quality of life defined by Padilla and colleagues 19 is a subjective, multidimensional experience that involves a summary evaluation of the positive and negative attributes that characterizes one's life. It is a dynamic concept affected by one's ability to adapt to discrepancies between expected verses experienced well-being, 19 as well as one's ability to maintain a level of functioning that allows the individual to pursue life goals. 20 HRQOL differs from QOL in that the summary evaluation of attributes that characterize one's life is made at a point in time when health, illness, or treatment conditions are relevant to the individual. 19 Patrick and Erikson 21 further defined HRQOL as a subjective outcome that reflects the person's perception of his or her health status and has been defined as the specific impact of an illness or injury, medical treatment, or health care policy on an individual's QOL. In addition, the Rand Medical Outcome Study defined HRQOL as the extent to which health impacts an individual's ability to function and his/her perceived wellbeing in physical, mental, and social domains of life. 22 In evaluating QOL, Moons and colleagues 23,24 recently defined QOL as the degree of overall life satisfaction that is positively or negatively influenced by individuals' perception of certain aspects of life important to them, including matters both related and unrelated to health. This definition argues the notion that health status, HRQOL, or functional status cannot be substituted for QOL. The definition also stresses the individual's perception of life satisfaction as the only direct indicator of QOL, whereas other variables, such as health, social function, or emotional function are all determinants of QOL. 23 In this respect, QOL is viewed as a unidimensional construct that is influenced by multiple factors (multifactorial). Although QOL experts view this construct as multidimensional, most are evaluating determinants of QOL and not direct indicators.
These definitions emphasize that the major difference between QOL and HRQOL is the impact of a disease, illness, or treatment on QOL. However, the literature still lacks a universally accepted definition of HRQOL and QOL. Yet, there are some areas of conceptual agreement. Namely, most would agree that HRQOL is a multidimensional, subjectively perceived concept, influenced by health, illness, or disease, and viewed as a continuous life evaluation or process that changes with aging. [19][20][21][22]

RELATED RESEARCH IN HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WHO HAVE UNDERGONE THE FONTAN OPERATION
The historical trajectory of related HRQOL research in the population who have undergone the Fontan operation has been summarized in chronologic order in Table I. Despite the medical and surgical advancements in the population who have undergone the Fontan operation, most conclude that SV CHD continues to affect the daily life of the growing child into adulthood. Therefore, research in HRQOL and QOL has amplified, resulting in an emerging field of investigation that addresses these concerns. Unfortunately, because most children who underwent the procedure during the last decade have not reached an appropriate age to contribute meaningful data on this phenomenon, most published data on HRQOL or QOL in SV CHD are by appraisals of proxy respondents, primarily parents. Furthermore, earlier studies of HRQOL focus more on specific functional determinants such as exercise ability and neurodevelopmental or cognitive outcomes. More recent research has focused on a more global conceptual measurement of HRQOL in the population with CHD. 4-10,24-30

Functional status outcomes
From the 1990s, the SV CHD research primarily addressed functional status and functional outcomes. The increased survival and parent-reported deficits in physical activity prompted functional status testing in this population. The functional status literature used a variety of objective measures such as New York Heart Association (NYHA) classification, SV ejection fraction, mortality and morbidity outcomes, visual motor testing, and exercise testing using aerobic capacity measurements of maximum VO2 to quantify functional status. 9,26 Furthermore, on the basis of these data, assumptions were made on HRQOL or QOL without confirmation. Subsequently, child and parent proxy report questionnaires were instituted to assess functional status either alone or in conjunction with objective measures. 6,25 The terms "functional status" and "HRQOL" or "QOL" are often used interchangeably. However, empirical studies have substantiated that these are related, but distinct concepts that should not be used interchangeably. 27 The functional status research in the population who have undergone the Fontan operation has reported that despite an apparent healthy appear-

Pike et al
Health-related quality of life  Scores were similar to those of healthy population. Cyanosis worse scores for physical (P ϭ .05) and perceived health status (P ϭ .02). Higher education had better score for physical (P ϭ .004), mental (P ϭ .01), and general health (P ϭ .02). Ortho problems worsened social score (P ϭ .05), and psychosocial worsened with pain score (P ϭ .02). Satisfactory QOL, which is similar to healthy population.
Cyanosis predicted a worse score for physical and perceived health status. New York University Children's Heart Health Survey and NYU Pediatric Heart Failure Index -disease-specific HRQOL measurement. Evaluation of new instruments psychometric properties.
Average internal consistency reliabilities were similar between group with heart disease (alpha ϭ .84) and healthy control (alpha ϭ .82), subscales (range ϭ .48 -.90). Validity assessed through differences between mean scores of subjects. Heart disease was associated with impairment on all subscales except psychologic function. Adolescent selfreport did not differ significantly between cardiac and non cardiac groups. SF-36, TACQOL, TAAQOL questionnaires, Physical Index, Summerville Index, and NYHA classification HRQOL was lower than general population in motor function and vitality (P Ͻ .01). Relation between HRQOL and physical status were poor. Patients had worse subjective health status than the general population in physical role function, vitality, and general health perception (P Ͻ .01). Relation was weak between subjective health status and physical indices. Adult survivors experienced only limitations in the physical dimensions of HRQOL and perceived health status.
ance, when challenged with exercise testing, functional limitations are evident. 6,9,28,29 Some studies showed a poor correlation between NYHA classification or ejection fraction and performance on exercise testing. 6,9,28,29 Of note, an average of 90% of patients who have undergone the Fontan operation reported an NYHA class I or II. 6,9 Patients who have undergone the Fontan operation with NYHA classification III or IV were associated with longer duration of follow-up, a prior atrial septectomy, and prior main pulmonary artery-ascending aorta anastomosis. 6 Overall, the patient who has undergone the Fontan procedure has a decreased aerobic exercise capacity that further declines with age and time from the Fontan procedure. The multiple factors that contribute to reduced functional outcomes are abnormal heart rate and rhythm, oxygen desaturation (especially with a fenestrated Fontan) during exercise testing, and the inability to improve stroke volume related to impaired SV function. 30 One study demonstrated no correlation between exercise capacity and the type of SV or type of Fontan procedure. 29

Neurodevelopmental and cognitive outcomes
In the late 1990s to early 2000s, several studies evaluated the neurodevelopmental and cognitive outcomes after the Fontan operation. The population who have undergone the Fontan operation has significant risk factors for neurodevelopmental deficits such as congenital brain abnormalities, heart failure, cyanosis, failure to thrive, sequelae from multiple staged surgical palliations with cardiopulmonary bypass and deep hypothermic circulatory arrest, hypoxic ischemic insult, thromboembolic event, seizure, acidosis, and cardiac arrest. The majority of authors identified similar neurodevelopmental outcomes, but variations were noted depending on the severity of the SV anatomy and sample selection. 4,5,7,8 Uzark et al 8 provided one of the first neurodevelopmental outcome studies in the population who have undergone the Fontan operation. Neurodevelopmental testing in patients 2 to 16 years of age found that the majority of children had intellectual function within the normal range. However, visual motor deficits were more prevalent in this group compared with population norms. Wernovsky et al 5 reached a similar conclusion with a larger sample size that demonstrated cognitive outcomes and academic performance within normal range, but the overall performance was lower when compared with the general population. Some neurodevelopmental studies separate the patients who have undergone the Fontan procedure into anatomic subgroups of SV CHD. The hypoplastic left heart syndrome (HLHS) group seemed to have more neurodevelopmental deficits compared with other SV defects. [4][5]7,8,10 In addition, the patients with HLHS who had deep hypothermic circulatory arrest during their first-stage surgical palliation were noted to have worse outcomes. 5,7,8 Mahle et al 4 evaluated outcomes in school-aged adolescents with HLHS and identified IQ scores within normal range with mean performance of the group lower than that of the general population. Of note, the majority of parents or guardians in this study described their child's health as good (34%) or excellent (45%) and their academic performance as average (42%) or above average (42%). However, one third of the children were receiving some form of special education and mental retardation was noted in 18% of patients. Goldberg et al 7 noted a similar decrease in overall performance scores in a group of patients with HLHS who underwent the Fontan operation compared with a non-HLHS group.
Currently, the research emphasis is changing to investigate more HRQOL and QOL outcomes in SV CHD. The impetus for change could be attributed to the functional limitations and neurodevelopmental deficits identified in the previous research.

HRQOL and QOL outcomes
Findings on the impact of CHD on determinants of HRQOL and QOL remain controversial. Some studies indicate deficits in physical function and role function domains, [31][32][33][34][35] whereas others show no significant difference compared with the general population. 24,32 Few studies have addressed HRQOL or QOL in only the SV Fontan patients. Most studies examine all subtypes of CHD, including the population with SV CHD, who usually represent a small portion of the study sample. In addition, this makes it difficult to draw conclusions for

Methods/measurements Results/conclusion
Evaluate the psychometric properties of the PedsQL Cardiac Module Scales -disease-specific HRQOL measurement Group comparison revealed significant differences (P Ͻ .001) except on the child self-report physical function scale (P ϭ .114). All internal consistency reliability coefficients exceeded minimum standards for group comparison (0.72-0.96) except for the child 5-7 years of age group. Results support feasibility, reliability, and validity of the PedsQL Generic Core Scales and Cardiac Module to assess HRQOL in children with CHD. Assessed psychometric Properties of TAAQOL-CHD -disease-specific HRQOL measurement Cronbach's alpha for the three scales symptoms, impact cardiac surveillance, and worries were .77, .78, and .82, respectively. Convergent validity with other instruments (TAAQOL, SF-36) showed satisfactory results. The TAAQOL-CHD module together with the TAAQOL supported satisfactory reliability and validity in assessing HRQOL in adolescents to adults with CHD.
the population who have undergone the Fontan operation unless the study stratifies according to CHD defect or disease severity. According to Williams and colleagues, 10 parent proxy reports in children with HLHS showed that physical and psychologic health was lower compared with the healthy population. However, selfreported HRQOL studies demonstrated a wide variation in responses related to severity of the study population. Results ranged from no difference from the general population to impairment in all subscales. [32][33][34] Saliba et al 32 evaluated QOL and perceived health status in adolescents and adults with both surgically corrected and shunt-palliated SV CHD. The subjects living with residual cyanosis had worse physical and perceived health status scores. Overall, scores were similar to those of the general population.
These two studies represent the only QOL studies specifically for the population with SV CHD. 10,32 Contradictory results are identified from parent proxy reports and studies from the European population with SV CHD. [32][33][34] This further identifies the need for HRQOL studies in the U.S. population with SV CHD.
In addition, there remain major conceptual and methodologic issues in HRQOL and QOL research in the general population with CHD. 23 Few studies identify operational definitions for HRQOL or QOL as well as conceptual or theoretical frameworks. Different people value different things, which make HRQOL and QOL hard to define and not readily defined in the literature. 25,26 Future HRQOL studies need to convey rigorous conceptualization, operational definition, and a sound HRQOL or QOL measurement that is congruent with the operational definition.

Disease-specific HRQOL instruments for CHD
The literature is filled with a plethora of generic HRQOL and QOL instruments for use in pediatrics and adults. However, generic HRQOL measures may lack specificity to assess unique differences encountered by specific conditions, but has the advantage of broad applicability across diagnoses. The use of generic and disease-specific HRQOL measurements in tandem provides complementary information and the strengths of both approaches. Disease-specific HRQOL and QOL instruments have been designed and tested extensively in populations with heart failure and acquired heart disease. 36 However, there is a lack of disease-specific instruments for use in pediatric and adult CHD. With continued growth of the population with CHD, appropriate disease-targeted tools will need to be designed and implemented to adequately measure change in HRQOL outcomes in this population overtime.
Recently, disease-specific measures were developed for HRQOL research in CHD (eg, New York University Child Heart Health Survey, Pediatric Quality of Life Inventory (PedsQL, Mapi Research, Frust, France) cardiac module, Congenital Heart Disease Quality of Life Questionnaire (ConQol), and TNO/AZL Adult Quality of Life Congenital Heart Disease Module [TAAQOL-CHD]). 31,33,35,37 The instruments are summarized in Table II. The PedsQL cardiac module and TAAQOL-CHD are designed as cardiac modules for an existing generic HRQOL tool. This provides a consistent format for the generic and disease-specific tools to be used in conjunction with one another. The NYU-CHHS and the PedsQL cardiac module have both parent proxy report and child self-report forms for various age groups, whereas the ConQol has two child self-report forms for ages 8 to 11 and 12 to 18 years. The NYU-CHHS and PedsQL cardiac module accommodates subjects up to 20 and 18 years of age, respectively. However, the TAAQOL-CHD is designed as a self-report form for adolescents to adults with CHD and accommodates subjects 16 years of age and older. The four instruments measure various disease-specific determinants of HRQOL such as symptoms, anxiety or worries, physical appearance, function, and social roles. Data on reliability and validity are limited because the instruments are relatively new. Further empirical testing of the instruments is required to evaluate psychometric properties and clinical application. The sensitivity to detect clinically important changes over time will be needed to evaluate the transition of the population with SV CHD into adulthood.

DISCUSSION
The literature review on HRQOL in the patient who has undergone the Fontan operation over the past decade has addressed functional status and neurodevelopmental outcomes with recent HRQOL studies and disease-specific tool development. The research demonstrates significant functional limitations with exercise testing, despite a healthy physical appearance. 6,9,28,29 Furthermore, the majority of HRQOL deficits were identified in physical function and role function domains. [31][32][33][34][35] The neurodevelopmental studies demonstrate normal IQ score but overall performance scores lower than that of the general population. The subgroup of those with HLHS were noted to have a higher risk for neurodevelopmental deficits associated with prolonged periods of DHCA, congenital brain abnormalities, or hypoxic-ischemic insult. 4,5,8,38,39 The majority of the studies reviewed sampled the population who underwent the Fontan operation in the late 1970s and early 1990s. Patient selection and surgical techniques, however, have advanced over the past decade. Therefore, the results can only be applied to previous surgical techniques and not the most current approach to SV CHD. 5 Of further note, the studies reviewed are mostly retrospective crosssectional designs and with small sample sizes. The small sample sizes were attributed to lack of subject participation or resources to access the study center. Future prospective longitudinal study designs are needed to assess this population throughout adulthood and include the impact of additional surgical procedures (eg, pacemakers, valve replacements, and heart transplantation).
The majority of the HRQOL research in CHD has been conducted at Canadian and European cen-ters. 24,28,31,32,34 The studies used a combination of European and U.S. instruments. However, the generalizability of the result to the population with SV CHD in the United States is questionable because of cultural, social, and economic influences. A high percentage of the CHD samples were composed of individuals with acyanotic heart disease who were surgically repaired with one operation. 28,31,32,34 Furthermore, a portion of the patients with SV CHD who were sampled in these studies did not undergo Fontan completion and are living with residual cyanosis. 28,32,34 Future HRQOL studies need to provide evidence for reliability and validity of diseasespecific instruments and describe HRQOL in the SV Fontan population in the United States.
Finally, the HRQOL and QOL literature in CHD is primarily based on parent proxy reports. Studies have shown inconsistencies in parent proxy reports with both over-and underestimations of health and performance abilities. 4,28 Adolescent self-report