Does functional health status predict health-related quality of life in children after Fontan operation?

Abstract

Purpose It is important to identify those children with a Fontan circulation who are at risk for impaired health-related quality of life. We aimed to determine the predictive value of functional health status - medical history and present medical status - on both physical and psychosocial domains of health-related quality of life, as reported by patients themselves and their parents.
We carried out a prospective cross-sectional multi-centre study in Fontan patients aged between 8 and 15, who had undergone staged completion of total cavopulmonary connection according to a current technique before the age of 7 years. Functional health status was assessed as medical history - that is, age at Fontan, type of Fontan, ventricular dominance, and number of cardiac surgical procedures - and present medical status - assessed with magnetic resonance imaging, exercise testing, and rhythm assessment. Health-related quality of life was assessed with The TNO/AZL Child Questionnaire Child Form and Parent Form.
In multivariate prediction models, several medical history variables, such as more operations post-Fontan completion, lower age at Fontan completion, and dominant right ventricle, and present medical status variables, such as smaller end-diastolic volume, a higher score for ventilatory efficiency, and the presence of sinus node dysfunction, predicted worse outcomes on several parent-reported and self-reported physical as well as psychosocial health-related quality of life domains.
Medical history and worse present medical status not only predicted worse physical parent-reported and self-reported health-related quality of life but also worse psychosocial health-related quality of life and subjective cognitive functioning. These findings will help in identifying patients who are at risk for developing impaired health-related quality of life.

Full text

Original Article
Does functional health status predict health-related quality of
life in children after Fontan operation?
Karolijn Dulfer,
1,*
Sjoerd S. M. Bossers,
2,*
Elisabeth M. W. J. Utens,
1
Nienke Duppen,
2
Irene M. Kuipers,
3
Livia Kapusta,
4,5
Gabrielle van Iperen,
6
Michiel Schokking,
4
Arend D. J. ten Harkel,
7
Tim Takken,
8
Willem A. Helbing
2
1
Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Centre–Sophia Children’s Hospital;
2
Department of Paediatrics, Division of Cardiology, Erasmus Medical Centre –Sophia Children’s Hospital, Rotterdam;
3
Department of Paediatrics, Division of Cardiology, Academic Medical Centre, Amsterdam;
4
Department of Paediatrics,
Division of Cardiology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands;
5
Department of
Paediatrics, Pediatric Cardiology Unit, Tel-Aviv Sourasky Medical Centre, Tel Aviv, Israel;
6
Department of Paediatrics,
Division of Cardiology, University Medical Centre Utrecht –Wilhelmina Children’s Hospital, Utrecht;
7
Department of
Paediatrics, Division of Cardiology, Leiden University Medical Centre, Leiden;
8
Child Development and Exercise Centre,
University Medical Centre Utrecht –Wilhelmina Children’s Hospital, Utrecht, the Netherlands
Abstract Purpose: It is important to identify those children with a Fontan circulation who are at risk for impaired
health-related quality of life. We aimed to determine the predictive value of functional health status –medical
history and present medical status –on both physical and psychosocial domains of health-related quality of life, as
reported by patients themselves and their parents. Methods: We carried out a prospective cross-sectional multi-
centre study in Fontan patients aged between 8 and 15, who had undergone staged completion of total cavo-
pulmonary connection according to a current technique before the age of 7 years.
Functional health status was assessed as medical history –that is, age at Fontan, type of Fontan, ventricular
dominance, and number of cardiac surgical procedures –and present medical status –assessed with magnetic
resonance imaging, exercise testing, and rhythm assessment. Health-related quality of life was assessed with The
TNO/AZL Child Questionnaire Child Form and Parent Form. Results: In multivariate prediction models, several
medical history variables, such as more operations post-Fontan completion, lower age at Fontan completion, and
dominant right ventricle, and present medical status variables, such as smaller end-diastolic volume, a higher
score for ventilatory efficiency, and the presence of sinus node dysfunction, predicted worse outcomes on several
parent-reported and self-reported physical as well as psychosocial health-related quality of life domains. Conclusions:
Medical history and worse present medical status not only predicted worse physical parent-reported and self-
reported health-related quality of life but also worse psychosocial health-related quality of life and subjective
cognitive functioning. These findings will help in identifying patients who are at risk for developing impaired
health-related quality of life.
Keywords: Fontan circulation; congenital heart disease; quality of life
Received: 29 July 2014; Accepted: 4 March 2015
OVER THE LAST 40 YEARS,TREATMENT OF
children with univentricular heart defects
has changed considerably. The technique of
choice, the Fontan procedure, has evolved from
the initial atriopulmonary connection to the total
cavopulmonary connection. At present, the total
cavopulmonary connection is usually performed as a
Correspondence to: W. A. Helbing, Department of Pediatric Cardiology, Erasmus
Medical Centre –Sophia Children’s Hospital, Sp-2429, PO Box 2060, 3000 CB
Rotterdam, the Netherlands. Tel: +31 10 7036264; Fax: +31 10 7036772;
E-mail: w.a.helbing@erasmusmc.nl
*
Both authors contributed equally.
Cardiology in the Young 2015; Page 1 of 10 © Cambridge University Press, 2015
doi:10.1017/S1047951115000426

staged procedure using either the intra-atrial lateral
tunnel or the extra-cardiac conduit technique to
complete the total cavopulmonary connection.
Nowadays, the 10-year-survival after the Fontan
completion is more than 90%.
1,2
Fontan patients, however, remain a vulnerable
group; therefore, focus on long-term follow-up has
shifted from survival to functional parameters such as
ventricular performance and exercise capacity. More-
over, in evaluating the success of treatment, health-
related quality of life is considered a key outcome.
3
Children with congenital heart disease, specifically
those with a Fontan circulation, are at risk for
impaired health-related quality of life.
4,5
Several
studies have assessed associations between objective,
functional health status, and health-related quality of
life in children with a Fontan circulation.
6–8
Most of
these studies, however, have been performed retro-
spectively. Besides, the authors have not always use
standardised assessment of present medical status, or
have focused on subjective health status instead of
health-related quality of life. These studies found that
reduced exercise capacity was associated with a
reduced physical health-related quality of life; how-
ever, psychosocial domains of health-related quality of
life have hardly been studied in Fontan patients
treated according to current strategies. Determining
the predictive value of functional health status on
health-related quality of life is important to be able to
identify those children and adolescents who are at risk
for an impaired health-related quality of life.
The aim of this study was to determine associations
between functional health status –biographical sta-
tus, medical history, and present medical status –on
physical but also on psychosocial domains of health-
related quality of life, on both self-reports and parent-
reports, in a large cohort of children operated
according to current Fontan strategies.
Materials and methods
Inclusion
All consecutive patients, aged 8 years or older, who
had undergone completion of the total cavo-
pulmonary connection before the age of 7 years were
eligible for this prospective cross-sectional study. The
total cavopulmonary connection had an at least two-
staged approach according to a current technique –
that is, intra-atrial lateral tunnel or extracardiac
conduit. Patients had been treated at one of the five
participating centres in the Netherlands.
Exclusion
Patients with pacemakers and implantable cardioverter-
defibrillators were excluded from the study, as previous
studies have shown that the presence of a pacemaker or
an implantable cardioverter-defibrillator itself has a
large effect on health-related quality of life.
9
Patients
with mental retardation, as stated in their medical
records, were also excluded from this study.
Assessment procedure
The ethics committee review boards of all five med-
ical centres approved the research protocol. All eli-
gible patients and their parents were approached in a
standardised way through a patient information let-
ter. Written informed consent was obtained from all
patients and/or their parents. Patients underwent
medical and psychological assessment within 1 week.
The medical assessment comprised of functional
health status measures –that is, cardiac MRI, exercise
testing, and rhythm assessment. The psychological
assessment comprised a web-based health-related
quality of life questionnaire –or pencil-and-paper
form when families had no internet access –for
patients and one of their parents.
Predictor variables: functional health status
Biographical data and medical history
Biographical data comprised age and gender. The med-
ical records were checked to determine age at Fontan,
type of Fontan, ventricular dominance, and number
of cardiac surgical procedures. The number of surgi-
cal procedures in the course of the staged Fontan was
defined as all cardiac operations leading to the total
cavopulmonary connection, including the total
cavopulmonary connection; the number of operations
after Fontan was defined as all cardiac operations after
Fontan completion.
Present medical status
MRI. All patients underwent cardiac MRI. Ventricular
volumes were imaged using a multi-slice, multi-phase,
steady-state free precession sequence. Technical details of
the sequences and volume analysis have been reported
previously.
10,11
End-diastolic volume, ejection fraction,
and mass/end-diastolic volume ratio were assessed.
Ventricular volumes were corrected for body surface area.
Exercise testing. Exercise tests were performed on a
bicycle ergometer according to a previously described
protocol.
12
From these exercise tests, ventilatory
efficiency was assessed. To calculate the predicted
value, normal values from healthy children were
used.
13
Submaximal parameter ventilatory efficiency
was chosen over VO
2
peak, because it was available
2Cardiology in the Young 2015

for all patients. Particularly in younger children, it
can be difficult to achieve maximal exercise levels
with reliable VO
2
peak values. Moreover, sub-
maximal exercise is more likely to be in line with
daily exercise levels of these patients.
12
A higher score
for ventilator efficiency reflects a poorer exercise
performance.
Rhythm assessment. For each patient, a 12-lead ECG
was carried out during rest. In addition, patients
underwent 24-hour Holter-recording during normal
daily activity. From these data, the presence of sinus
node dysfunction was determined. Sinus node dys-
function was defined as having one or more of the
following symptoms: (1) minimal heart rate >2SD
below the mean value for age and gender, (2) pre-
dominant nodal rhythm, (3) sinus pause(s) >3 seconds
on Holter recording, and/or (4) (in maximally
performed exercise tests) peak heart rate <80% of the
predicted value for age and gender.
14–18
The presence
of sinus node dysfunction was chosen, because in
relatively young samples, the prevalence of (tachy-)
arrhythmiasislow.
2,19
Sinus node dysfunction is
relatively common in Fontan patients at medium-term
follow-up and can lead to chronotropic incompetence,
arrhythmias, and the need for pacemaker therapy at
longer follow-up.
20,21
Outcome measure
Health-related quality of life. The TNO/AZL
Child health-related quality of life Questionnaire
Child Form and Parent Form were used to assess the
generic aspects of health-related quality of life.
22
These questionnaires contained 63 items on the
occurrence of functional problems, and if such
problems occur the subsequent emotional reactions
to these problems. The questionnaire consisted of the
following six sub-scales: pain and physical symptoms,
motor functioning, cognitive functioning, social
functioning (score ranges 0–32), positive emotional
functioning, and negative emotional functioning
(score ranges 0–16). Higher scores indicate a better
health-related quality of life.
Verrips et al
23
described satisfactory psychometric
properties (sub-scale Cronbach’sαranged from 0.73
to 0.82) of the TNO/AZL Child health-related
quality of life Questionnaire. For the Child Form,
the normal group consisted of 593 girls and 660 boys
(n =1253). For the Form, no normal data were
available. Patients and their parents were instructed
to complete the questionnaires separately at home.
Statistical analysis
For statistical analysis, only participants with com-
plete data for medical history, present medical status,
and self-reported health-related quality of life were
included. The comparison of complete cases (n =79)
with non-complete cases (n =17) was carried out
using Mann–Whitney U tests for age and age at
Fontan completion. Pearson’sχ
2
-tests were used to
test differences in distributions of gender, type of
Fontan, dominant ventricle, number of operations in
the Fontan course, and number of operations after
Fontan completion. Comparison with normative data
was carried out using Students’t tests.
To determine the predictive power of functional
health status on health-related quality of life, a three-
stage strategy was followed for each TACQOL scale.
This was carried out separately for the Child Form
and for the Parent Form. Multiple linear regression
analysis was applied.
In phase 1, each functional health variable was asso-
ciated with each of the TNO/AZL Child health-related
quality of life Questionnaire scales (univariate analysis).
When their association was significant (p <0.05), they
were entered in a cluster analysis called phase 2: each
cluster (i.e. combination) of functional health variables –
that is, biographical status, medical history, and pre-
sent medical status –was associated with each of the
TNO/AZL Child health-related quality of life Ques-
tionnaire scales. As this second phase served as a selec-
tion of candidate functional health variables for the
final regression model, p-values were set to p <0.20
(backward elimination procedure). In phase 3,allthe
functional health variables remaining from phase 2
were forced simultaneously into the final model to test
their predictive value of health-related quality of life.
Functional health variables that were not significant
(p >0.050) in the final model were removed (backward
elimination procedure), and then the total explained
variance (R
2
) was calculated. To check multi-colli-
nearity, the variance inflation factor was calculated. For
each model, the average of the variance inflation factors
of the entered functional health variables was around 1,
which is expedient. The linearity assumption was
examined by scatter plots, with continuous functional
health variables on the x-axis and the TNO/AZL Child
health-related quality of life Questionnaire scales on the
y-axis. The scatter plots presented no other than linear
relationships for continuous variables. Statistics were
conducted using SPSS version 21.0.
Results
Baseline characteristics
Participants were recruited and examined between
January, 2010 and August, 2012.
In total, 144 Eligible children were contacted, of
whom 96 (67%) finally participated (see Fig 1 for
flowchart).
Dulfer et al: Does functional health status predict health-related quality of life in children? 3

Non-participating patients were comparable with
participants in demographic characteristics and
medical history –gender, age, and type of Fontan;
however, they had a slightly higher age at Fontan
completion: median 3.5 (2.7–4.2) versus median 2.9
(2.4–3.6) years, p =0.003.
Children with complete data for medical history,
present medical status, and self-reported health-rela-
ted quality of life were included in analyses; therefore,
the final sample contained 79 (81%) participants;
Table 1 shows demographic characteristics, medical
history, and present medical status. As two parents
did not fill in the health-related quality of life ques-
tionnaire, the sample size for parent-reported health-
related quality of life was n =77. No differences were
found between children with (n =79) and those
without (n =17) complete data regarding demo-
graphic characteristics and medical history.
Sinus node dysfunction was present in 28% of the
patients. These patients had significantly lower resting
heart rates compared with those without sinus node
dysfunction (59 ±13 versus 76 ±15 beats/minute,
p<0.001).
Table 2 presents health-related quality of life scores;
children themselves reported significantly lower scores
for motor functioning and social functioning compared
with normative data. For other health-related quality of
life scales, scores were comparable with normative data.
Overall, parent-reported health-related quality of life
scores were comparable with those of their children.
The predictive value of functional health status on health-
related quality of life
To determine the predictive power of functional
health status on health-related quality of life, a three-
stage strategy was followed for each health-related
quality of life questionnaire scale. Results of the first
phase, univariate associations between functional
health status and health-related quality of life, are
presented in Table 3. Since the second phase, multi-
variate cluster-analyses served to select the significant
functional health variables for the final model; these
results are only presented in supplemental Tables S1
and S2.
Phase 3: final prediction model of health-related
quality of life (see Table 4)
Self-reported health-related quality of life. More opera-
tions after Fontan completion and smaller
end-diastolic volume significantly predicted more
self-reported pain and physical symptoms, explaining
24% of its variance. A lower score for ventilatory
Figure 1.
Enrolment in study.
Table 1. Demographic characteristics and functional health status.
Biographical characteristics n =79
Age in years 11.6 (9.8–13.8)
Male 47 (60)
Medical history
Age at Fontan completion 2.9 (2.4–3.6)
Type of Fontan
Intra-atrial lateral tunnel 27 (34)
Extra-cardiac conduit 52 (66)
Dominant Ventricle
Left 47 (60)
Right 32 (40)
Operations Fontan course
2 11 (14)
3 53 (67)
4 or more 15 (19)
Operations post-Fontan
0 70 (89)
1 9 (11)
Present medical status
MRI
End-diastolic volume (ml/m
2
) 87.3 (18.9)
Ejection fraction (%) 53.0 (8.4)
Mass/volume ratio 0.66 (0.15)
Exercise testing
VE/VCO
2
-slope (% predicted) 127.9 (30.8)
Rhythm
Presence of sinus node dysfunction 22 (28)
Biographical status and medical history data are presented as number
(percentage), only age is presented as median (inter quartile range).
Present medical data are presented as mean (SD), only sinus node dys-
function is presented as number (percentage)
4Cardiology in the Young 2015

efficiency, indicating better exercise performance,
significantly predicted better motor functioning.
Both smaller end-diastolic volume and lower age
at Fontan completion significantly predicted worse
self-reported social functioning, explaining 12% of
its variance. Lower score for ventilatory efficiency and
higher age at Fontan completion significantly pre-
dicted better self-reported positive emotional func-
tioning, explaining 17% of its variance. Finally,
smaller end-diastolic volume also significantly pre-
dicted worse self-reported cognitive functioning.
Parent-reported health-related quality of life. More
operations after Fontan completion significantly
predicted lower scores for parent-reported pain and
physical symptoms. Both a lower (better) score for
ventilatory efficiency and a higher age at Fontan
completion significantly predicted higher scores for
parent-reported motor functioning, explaining 20%
of its variance.
The presence of sinus node dysfunction sig-
nificantly predicted lower parent-reported scores
for negative emotional functioning in the child.
Furthermore, both the presence of a dominant right
ventricle and the presence of sinus node dysfunction
significantly predicted lower parent-reported cogni-
tive-functioning; explaining 23% of its variance.
Discussion
The aim of this study was to investigate the
predictive value of functional health status –bio-
graphical status, medical history, and present medical
status –on self-reported and parent-reported health-
related quality of life. Furthermore, we identified those
variables that contributed most to the explained var-
iance of health-related quality of life. Medical history
and present medical status not only predict outcomes
on physical health-related quality of life but also on
psychosocial health-related quality of life, such as social
functioning, positive and negative emotional func-
tioning, and subjective cognitive functioning.
Psychosocial health-related quality of life
Remarkably, and in contrast with previous studies,
several functional health status variables in our
study predicted psychosocial health-related quality of
life scales: social functioning, positive emotional
functioning, and negative emotional functioning.
Children reported better social functioning and
positive emotional functioning when their age at the
Fontan completion was higher. An explanation may
be that children had better coping mechanisms with
Fontan completion at higher age. To our knowledge,
we are the first to describe this finding. At present,
the standard practice is to perform the completion of
the total cavopulmonary connection as early as pos-
sible, around the age of 2 years. These results indicate
that this possibly influences emotional functioning;
however, the Fontan completion is only the final step
in a series of multiple operations. The first operation
is often performed within the first few months of
life.
24
The observed relationship should, therefore, be
interpreted with caution.
The predictive value of smaller end-diastolic volume
onworsesocialfunctioningishardtoexplain.Inthis
study, we observed a wide range of end-diastolic
volumes in our patients, confirming observations in
other studies.
3,10
A smaller end-diastolic volume might
represent a worse diastolic ventricular filling in the
preload-dependent Fontan circulation, which might
contribute to worse overall ventricular performance,
resulting in worse social functioning. On the other
hand, a larger end-diastolic volume could also indicate
inadequate ventricular dilatation, which is unlikely to
contribute to improved ventricular performance. In a
recent study, we did not find a relation between exer-
cise capacity –as a marker of overall ventricular per-
formance –and end-diastolic volume. Exercise capacity
did, however, correlate with end-systolic volume and
ejection fraction.
12
In a study of 511 Fontan patients
with mixed surgical strategies, MRI-derived ven-
tricular measurements (available for 155 patients) were
not associated with parent-reported psychosocial health
Table 2. Health-related quality of life child form and parent form.
TACQOL* Child form (n =79) Parent form (n =77) Normative data child form (n =930)
Pain and physical symptoms 24.3 (5.1) 25.3 (4.8) 24.2 (5.1)
Motor functioning 26.9 (4.3)** 27.7 (3.6) 30.1 (2.8)
Cognitive functioning 26.9 (4.5) 26.2 (4.9) 27.8 (4.0)
Social functioning 29.6 (5.0)** 29.6 (4.6) 31.2 (2.7)
Positive emotional functioning 13.6 (2.4) 14.4 (2.2) 13.2 (2.7)
Negative emotional functioning 12.2 (2.5) 11.7 (2.5) 11.8 (2.5)
Data are presented as mean (SD). A higher score indicates a better quality of life
*TNO/AZL Child Quality of Life Questionnaire
**Significant different from normative data; p <0.01
Dulfer et al: Does functional health status predict health-related quality of life in children? 5

Table 3. Associations (β) between functional health status and health-related quality of life; standardised coefficients β.
TACQOL child form (n=79) TACQOL parent form (n=77)
Pain Motor Cognitive Social Positive Negative Pain Motor Cognitive Social Positive Negative
Biographical demographics
Age −0.20 −0.06 0.08 0.25* −0.09 0.06 −0.12 −0.22 0.14 0.16 −0.12 −0.11
Gender −0.17 0.05 0.03 <0.01 0.03 0.07 0.06 0.18 0.20 0.11 0.11 0.10
Medical history
Age at Fontan completion −0.05 −0.01 0.17 0.23* 0.28* 0.18 0.10 0.31** 0.24* 0.23 0.16 0.07
Type Fontan**** <0.01 0.17 0.03 0.03 0.18 0.03 0.18 0.32** 0.10 0.15 0.05 0.24*
Dominant ventricle***** 0.11 −0.12 −0.11 −0.11 −0.12 −0.11 0.07 −0.05 −0.34*** 0.09 −0.18 −0.16
Operations Fontan course <0.01 0.03 <−0.01 0.18 −0.16 −0.04 0.13 0.18 −0.07 0.09 −0.05 0.06
Operations postFontan −0.42*** −0.14 −0.12 −0.07 0.10 −0.20 −0.24* −0.13 0.02 −0.06 −0.03 −0.21
Present medical status
End-diastolic volume 0.22* 0.08 0.25* 0.24* 0.14 0.18 0.07 <0.01 0.10 0.11 <0.01 0.29*
Ejection fraction −0.11 −0.11 −0.06 −0.11 0.27* −0.06 <−0.01 −0.07 0.07 −0.13 −0.04 −0.08
Mass/volume ratio −0.04 <−0.01 −0.08 <−0.01 0.08 0.01 0.02 −0.07 −0.03 −0.15 <0.01 −0.25*
VE/VCO
2
-slope −0.03 −0.25* −0.13 <0.01 −0.32*** −0.02 −0.17 −0.34*** −0.23* −0.01 −0.10 −0.20
Sinus node dysfunction****** −0.07 0.04 −0.15 <0.01 −0.04 0.09 −0.05 0.02 −0.26* 0.03 0.01 0.34***
Cognitive=cognitive functioning; Motor=motor functioning; Negative=Negative emotional functioning; Pain=pain and physical symptom; Positive=positive emotional functioning; Social=social functioning.
A higher score indicates a better quality of life
****0=Intra-atrial lateral tunnel, 1=Extra-cardiac conduit
*****0=Left ventricle, 1=right ventricle
******0=No, 1=yes
*p<0.05, **p<0.01, ***p<0.005
6Cardiology in the Young 2015

status. When corrected for age at Fontan completion,
McCrindle et al found a weak negative correlation
between worse psychosocial health status and smaller
end-diastolic volumes, but only in those operated on at
an age below 2 years or over 4 years.
25
In our study, parents reported less negative emo-
tions in their child when the child had sinus node
dysfunction. This is surprising, as parents are not
necessarily aware of the presence of sinus node
dysfunction in their child. As sinus node dysfunction
and a lower heart rate are highly associated, it is
possible that the positive effect of sinus node dys-
function on parent-reported negative emotional
function is actually an effect of lower heart rate.
Possibly, the lower heart rate in children with
sinus node dysfunction contributes to less arousal.
26
Consequently, the parent may experience less nega-
tive emotions in their child. Most patients with sinus
node dysfunction did not have clinical symptoms;
however, close rhythm surveillance remains impor-
tant, as sinus node dysfunction could become symp-
tomatic over time and lead to rhythm disturbances
requiring intervention.
19
In a study among adult
Fontan survivors, Van den Bosch et al have shown
that arrhythmias were present in the majority of
patients, who had significantly reduced quality of
life.
27
Other studies have also shown high incidence
of arrhythmias in older Fontan patients.
19,28
Although the incidence of arrhythmia is relatively
low in young Fontan patients, McCrindle et al
showed that the presence of arrhythmias was asso-
ciated with reduced scores for physical quality of
life. This emphasises the need for adequate rhythm
surveillance in this population.
29
The discrepancy between our finding that func-
tional health status predicted psychosocial health-
related quality of life and the lack of predictive value
in previous studies could be explained by the differ-
ences in the definition of health-related quality of life
and the subsequent assessment instruments. Health-
related quality of life is an ambiguous concept and
consensus about its definition is lacking.
30
Most of
the previous studies assessed health status, instead of
health-related quality of life, with the Child Health
Questionnaire, a generic instrument. Some studies
have assessed health-related quality of life with a
disease-specific instrument,
8,31
the Congenital Heart
Adolescent and Teenage questionnaire. Both these
questionnaires focus on symptoms per se, whereas a
surplus value of the TNO/AZL Child health-related
quality of life Questionnaire is that it takes not only
into account symptoms but also the subjective eva-
luation of these symptoms. This may explain the
associations between psychosocial health-related quality
of life and functional health variables that we found.
Children may not report complaints when questioned
Table 4. Final model results of significant functional health status predictors of health-related quality of life.
Constant Unstandardised βSE Standardised βp-value Multiple R
2
TNO/AZL Child Quality of Life Questionnaire –Child Form (n =79)
Pain and physical symptoms
Operations post-Fontan 19.35 −6.82 1.59 −0.43 <0.001 0.24
End-diastolic volume 0.07 0.03 0.24 0.020
Motor functioning
VE/VCO
2
-slope 31.33 −0.04 0.02 −0.25 0.029 0.06
Cognitive functioning
End-diastolic volume 21.67 0.06 0.03 0.25 0.029 0.06
Social functioning
End-diastolic volume 20.15 0.07 0.03 0.25 0.024 0.12
Age at Fontan completion 1.21 0.54 0.25 0.027
Positive emotional functioning
VE/VCO
2
-slope 14.77 −0.02 0.01 −0.31 0.004 0.17
Age at Fontan completion 0.61 0.25 0.26 0.016
TNO/AZL Child Quality of Life Questionnaire –Parent Form (n =77)
Pain and physical symptoms
Operations post-Fontan 25.73 −3.51 1.66 −0.24 0.038 0.06
Motor functioning
VE/VCO
2
-slope 29.40 −0.04 0.01 −0.33 0.003 0.20
Age at Fontan completion 1.05 0.37 0.30 0.006
Cognitive functioning
Dominant ventricle 28.84 −4.00 1.04 −0.40 <0.001 0.23
Sinus node dysfunction* −3.61 1.13 −0.34 0.002
Negative emotional functioning
Sinus node dysfunction* 11.21 1.84 0.60 0.34 0.003 0.12
*0 =No, 1 =yes
Dulfer et al: Does functional health status predict health-related quality of life in children? 7

about generic symptoms; however, when questioned
about their subjective evaluation of these symptoms,
they may be more conscious regarding their sub-
jective feelings of limitations. Furthermore, we
assessed multi-informant health-related quality of life
(self-reports and parent-reports), whereas most of the
previous studies only assessed one informant.
In addition, the discrepancy could also be
explained by differences in patient selection between
our study and other studies. Although we only
included patients with a staged total cavopulmonary
connection, other studies included older Fontan
types, such as the atriopulmonary connection, as
well.
5,25
We included children aged between 8 and
15 only, which allowed us to use one single instru-
ment to assess health-related quality of life.
Subjective cognitive functioning
Children with complex congenital heart disease are at
risk for neurocognitive anomalies: lower intelligence
quotient, more attention problems, and executive
functioning problems.
32,33
In our study, a smaller
end-diastolic volume significantly predicted worse
self-reported cognitive functioning, a subscale of
health-related quality of life.
As discussed previously, the predictive value of end-
diastolic volume is difficult to interpret in this popu-
lation. Other MRI-derived ventricular parameters we
assessed, ejection fraction and mass/volume ratio, were
relatively well preserved in this population and did not
predict self-reported cognitive functioning.
Parents reported lower scores for cognitive func-
tioning in children with sinus node dysfunction. No
data exist on this subject; therefore, we can only
speculate on this association. Cardiac output is highly
heart rate-dependent in the Fontan circulation.
Whether the lower heart rate in patients with sinus
node dysfunction results in a lower cardiac output
and, as a result, lower cerebral perfusion is unknown.
Very little data exist on cerebral perfusion long-term
after the operation in Fontan patients. In a recent
study, carotid artery flow dynamics were assessed in
34 Fontan patients, comparable with our sample.
That study suggested that cerebral perfusion is
impaired in Fontan patients.
34
Further studies with
direct measurements of cerebral blood flow, includ-
ing the effects of heart rate are needed. Furthermore, a
lower heart rate in Fontan patients is not necessarily a
sign of decreased cardiac functioning.
35
Parents also
reported a lower cognitive functioning in children
with right dominant ventricles. This is possibly
explained by the fact that since the birth of a child
with a dominant right ventricle, parents were
informed that the child had a worse future pro-
spective than children with a left dominant ventricle.
Therefore, these parents may consider their child less
capable to develop cognitive functioning. The rela-
tionship between cardiac morphology, or ventricular
dominance, and objectively measured cognitive
functioning has hardly been studied. Sugimoto et al
did not find an association between ventricular
dominance and intelligence quotient, whereas Sar-
ajuuri et al showed that especially patients with a
hypoplastic left heart syndrome were at risk for neu-
rodevelopmental deficits.
36,37
In an older, small
cohort, Goldberg et al showed that, although neu-
rodevelopmental scores were significantly lower for
hypoplastic left heart syndrome patients compared
with non-hypoplastic left heart syndrome patients,
scores for all Fontan patients were within the normal
range.
38
In a study among 158 Fontan patients, Idorn
et al demonstrated impaired quality of life and cog-
nitive speed compared with healthy controls. They
did not find a difference in quality of life and cogni-
tive speed between patients with hypoplastic left
heart syndrome and those without.
5
Physical health-related quality of life
Several variables from medical history and present
medical status domains significantly predict physical
health-related quality of life: pain and physical
symptoms and motor functioning. This is in line
with previous studies that also found associations
between parent-reported health status and exercise
capacity
25,31,39–41
and MRI measures.
25
In a study among children and adolescents with
variouscongenitalheartdefects,Hageretalfoundsig-
nificant correlations between maximum oxygen uptake
and physical functioning and general heath perception,
but not with other subscales of quality of life.
42
McCrindle et al found a weak association between
functional health status and exercise capacity. Of 390
patients, 157 reached maximal effort. For that reason,
we chose a sub-maximal exercise parameter to assess
exercise capacity.
25
In the study of McCrindle et al,
MRI parameters, end-sytolic volume, and mass/
volume ratio were weakly associated with physical
health status. We found that end-diastolic volume
significantly predicted self-reported pain and physi-
cal symptoms. As stated earlier, in a recent study, we
found that end-systolic volume and ejection fraction
were significant predictors for exercise capacity as
assessed by peak oxygen uptake.
12
Recommendations for future research
As discussed, the influence of end-diastolic volume
on subjective cognitive functioning, but also on social
and emotional functioning, is difficult to explain.
Further research is necessary to identify mechanisms
8Cardiology in the Young 2015

behind the influence of medical parameters on
health-related quality of life.
Earlier studies in cohorts of Fontan patients,
operated mainly according to older techniques,
described failure of the Fontan circulation in patients
around their third decade of life. It is, therefore,
crucial to conduct longer follow-up and to repeat our
study at longer follow-up.
Strengths and limitations
As to strengths, the percentage of complete cases on
medical history, present medical status, and health-
related quality of life was high in this large multi-
centre prospective study with a heterogeneous group
of patients operated upon according to contemporary
strategies. Second, we assessed multi-informant
health-related quality of life as the presence of
symptoms, together with the subjective evaluations
of these symptoms. Third, only single functional
health predictor variables, instead of large clusters of
variables, were used in the analyses to explain var-
iance in health-related quality of life.
As to limitations, because not all patients agreed to
participate in the present study, the results of our
study may be influenced by selection bias.
Clinical implications
As functional health status predicted both physical
and psychosocial health-related quality of life in chil-
dren with total cavopulmonary connection, we
recommend screening for health-related quality of
life problems during outpatient consultations, espe-
cially in children after total cavopulmonary connec-
tion with medical status. Fontan patients with
impaired health-related quality of life might benefit
from further psychological screening and psychoso-
cial interventions to improve health-related quality of
life.
33
Conclusions
Health-related quality of life is impaired in the pre-
sent cohort of Fontan patients. Medical history and
present medical status significantly predicted physical
health-related quality of life, but also psychosocial
health-related quality of life in children with total
cavopulmonary connection. The knowledge of risk
factors may help in identifying patients at increased
risk for impaired health-related quality of life.
For clinical practice, it is recommended not only to
assess impairments in functional health status but
also to screen for impairments in health-related
quality of life.
Acknowledgements
The authors thank the children and their parents for
their participation in this study.
Financial Support
This work was supported by the Stichting Rotter-
dams Kinderrevalidatie Fonds Adriaanstichting and
the Dutch Heart Foundation (grant 2008T037).
Conflicts of Interest
None.
Supplementary material
To view supplementary material for this article, please
visit http://dx.doi.org/10.1017/S1047951115000426
References
1. d’Udekem Y, Iyengar AJ, Cochrane AD, et al. The Fontan proce-
dure: contemporary techniques have improved long-term out-
comes. Circulation 2007; 116: I157–I164.
2. Robbers-Visser D, Miedema M, Nijveld A, et al. Results of staged
total cavopulmonary connection for functionally univentricular
hearts; comparison of intra-atrial lateral tunnel and extracardiac
conduit. Eur J Cardiothorac Surg 2010; 37: 934–941.
3. Anderson PA, Sleeper LA, Mahony L et al. Contemporary outcomes
after the Fontan procedure: a Pediatric Heart Network
multicenter study. J Am Coll Cardiol 2008; 52: 85–98.
4. Marino BS, Shera D, Wernovsky G, et al. The development of the
pediatric cardiac quality of life inventory: a quality of life measure
for children and adolescents with heart disease. Qual Life Res 2008;
17: 613–626.
5. Idorn L, Jensen AS, Juul K, et al. Quality of life and cognitive
function in Fontan patients, a population-based study. Int J Cardiol
2013; 168: 3230–3235.
6. Dulfer K, Helbing WA, Duppen N, Utens EM. Associations
between exercise capacity, physical activity, and psychosocial
functioning in children with congenital heart disease: a
systematic review. Eur J Prev Cardiol 2014; 21: 1200–1215.
7. McCrindle BW, Zak V, Breitbart RE, et al. The Relationship of
patient medical and laboratory characteristics to changes in func-
tional health status in children and adolescents after the Fontan
procedure. Pediatr Cardiol 2014; 35: 632–640.
8. McCrindle BW, Zak V, Pemberton VL, et al. Functional health
status in children and adolescents after Fontan: comparison of
generic and disease-specific assessments. Cardiol Young 2013: 1–9.
9. Czosek RJ, Bonney WJ, Cassedy A, et al. Impact of cardiac devices
on the quality of life in pediatric patients. Circ Arrhythm Electro-
physiol 2012; 5: 1064–1072.
10. Robbers-Visser D, Jan Ten Harkel D, Kapusta L, et al. Usefulness
of cardiac magnetic resonance imaging combined with low-dose
dobutamine stress to detect an abnormal ventricular stress response
in children and young adults after Fontan operation at young age.
Am J Cardiol 2008; 101: 1657–1662.
11. Luijnenburg SE, Robbers-Visser D, Moelker A, Vliegen HW,
Mulder BJ, Helbing WA. Intra-observer and interobserver varia-
bility of biventricular function, volumes and mass in patients with
congenital heart disease measured by CMR imaging. Int J Cardi-
ovasc Imaging 2010; 26: 57–64.
12. Bossers SS, Helbing WA, Duppen N, et al. Exercise capacity in children
after total cavopulmonary connection: lateral tunnel versus extracardiac
conduit technique. J Thorac Cardiovasc Surg 2014; 148: 1490–1497.
Dulfer et al: Does functional health status predict health-related quality of life in children? 9

13. Ten Harkel AD, Takken T, Van Osch-Gevers M, Helbing WA.
Normal values for cardiopulmonary exercise testing in children.
Eur J Cardiovasc Prev Rehabil 2011; 18: 48–54.
14. Cohen MI, Bridges ND, Gaynor JW, et al. Modifications to the
cavopulmonary anastomosis do not eliminate early sinus node
dysfunction. J Thorac Cardiovasc Surg 2000; 120: 891–900.
15. Mason JW, Ramseth DJ, Chanter DO, Moon TE, Goodman DB,
Mendzelevski B. Electrocardiographic reference ranges derived from
79,743 ambulatory subjects. J Electrocardiol 2007; 40: 228–234.
16. Rijnbeek PR, Witsenburg M, Schrama E, Hess J, Kors JA. New
normal limits for the paediatric electrocardiogram. Eur Heart J
2001; 22: 702–711.
17. Salameh A, Gebauer RA, Grollmuss O, Vit P, Reich O, Janousek J.
Normal limits for heart rate as established using 24-hour ambula-
tory electrocardiography in children and adolescents. Cardiol
Young 2008; 18: 467–472.
18. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS
2008 Guidelines for device-based Therapy of Cardiac Rhythm
Abnormalities: a report of the American College of Cardiology/
American Heart Association Task Force on practice guidelines
(Writing Committee to Revise the ACC/AHA/NASPE 2002
Guideline Update for Implantation of Cardiac Pacemakers and
Antiarrhythmia Devices): developed in collaboration with the
American Association for Thoracic Surgery and Society of Thoracic
Surgeons. Circulation 2008; 117: e350–e408.
19. Deal BJ. Late arrhythmias following Fontan surgery. World J
Pediatr Congenit Heart Surg 2012; 3: 194–200.
20. Cohen MI, Wernovsky G, Vetter VL, et al. Sinus node function
after a systematically staged Fontan procedure. Circulation 1998;
98: II352–II358; discussion II358–II359.
21. Dilawar M, Bradley SM, Saul JP, Stroud MR, Balaji S. Sinus node
dysfunction after intraatrial lateral tunnel and extracardiac conduit
Fontan procedures. Pediatr Cardiol 2003; 24: 284–288.
22. Vogels T, Bruil J, Koopman H, Fekkes M, Verrips GHW. TAC-
QOL CF 12-15 Manual. Developed by Leiden Center for Child
Health and Pediatrics LUMC-TNO 2004.
23. Verrips GH, Vogels AG, den Ouden AL, Paneth N, Verloove-Vanhorick
SP. Measuring health-related quality of life in adolescents: agreement
between raters and between methods of administration. Child Care
Health Dev 2000; 26: 457–469.
24. Khairy P, Fernandes SM, Mayer JE Jr., et al. Long-term survival,
modes of death, and predictors of mortality in patients with Fontan
surgery. Circulation 2008; 117: 85–92.
25. McCrindle BW, Zak V, Sleeper LA, et al. Laboratory measures of
exercise capacity and ventricular characteristics and function are
weakly associated with functional health status after Fontan pro-
cedure. Circulation 2010; 121: 34–42.
26. Appelhans BM, Luecken LJ. Heart rate variability as an index of
regulated emotional responding. Rev General Psychol 2006; 10: 229.
27. van den Bosch AE, Roos-Hesselink JW, Van Domburg R, Bogers
AJ, Simoons ML, Meijboom FJ. Long-term outcome and quality of
life in adult patients after the Fontan operation. Am J Cardiol 2004;
93: 1141–1145.
28. Khairy P, Poirier N, Mercier LA. Univentricular heart. Circulation
2007; 115: 800–812.
29. McCrindle BW, Williams RV, Mitchell PD, et al. Relationship of
patient and medical characteristics to health status in children and
adolescents after the Fontan procedure. Circulation 2006; 113:
1123–1129.
30. Moons P, Van Deyk K, Budts W, De Geest S. Caliber of quality-of-
life assessments in congenital heart disease: a plea for more con-
ceptual and methodological rigor. Arch Pediatr Adolesc Med 2004;
158: 1062–1069.
31. McCrindle BW, Williams RV, Mital S, et al. Physical activity levels
in children and adolescents are reduced after the Fontan procedure,
independent of exercise capacity, and are associated with lower per-
ceived general health. Arch Dis Child 2007; 92: 509–514.
32. Snookes SH, Gunn JK, Eldridge BJ, et al. A systematic review of
motor and cognitive outcomes after early surgery for congenital
heart disease. Pediatrics 2010; 125: e818–e827.
33. Marino BS, Lipkin PH, Newburger JW, et al. Neurodevelopmental
outcomes in children with congenital heart disease: evaluation and
management: a scientific statement from the American Heart
Association. Circulation 2012; 126: 1143–1172.
34. Saiki H, Kurishima C, Masutani S, Senzaki H. Cerebral circulation in
patients with Fontan circulation: assessment by carotid arterial wave
intensity and stiffness. Ann Thorac Surg 2014; 97: 1394–1399.
35. Blaufox AD, Sleeper LA, Bradley DJ, et al. Functional status, heart
rate, and rhythm abnormalities in 521 Fontan patients 6 to 18
years of age. J Thorac Cardiovasc Surg 2008; 136: 100–107;
107 e101.
36. Sarajuuri A, Jokinen E, Mildh L, et al. Neurodevelopmental burden
at age 5 years in patients with univentricular heart. Pediatrics
2012; 130: e1636–e1646.
37. Sugimoto A, Ota N, Ibuki K, et al. Risk factors for adverse neu-
rocognitive outcomes in school-aged patients after the Fontan
operation. Eur J Cardiothorac Surg 2013; 44: 454–461.
38. Goldberg CS, Schwartz EM, Brunberg JA, 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.
39. Blaufox AD, Sleeper LA, Bradley DJ, et al. Functional status, heart
rate, and rhythm abnormalities in 521 Fontan patients 6 to 18
years of age. J Thorac Cardiovasc Surg 2008; 136: 100–107; e101.
40. Williams IA, Sleeper LA, Colan SD, et al. Functional state fol-
lowing the Fontan procedure. Cardiol Young 2009; 19: 320–330.
41. Jenkins PC, Chinnock RE, Jenkins KJ, et al. Decreased exercise
performance with age in children with hypoplastic left heart
syndrome. J Pediatr 2008; 152: 507–512.
42. Hager A, Hess J. Comparison of health related quality of life with
cardiopulmonary exercise testing in adolescents and adults with
congenital heart disease. Heart 2005; 91: 517–520.
10 Cardiology in the Young 2015