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ORIGINAL CLINICAL SCIENCE

Outcomes in adult congenital heart disease

patients undergoing heart transplantation:
A systematic review and meta-analysis
Barbara Stella Doumouras, MD,a Ana Carolina Alba, MD, PhD,a Farid Foroutan,a
Luke James Burchill, MBBS, PhD,b Anne I. Dipchand, MD,c and
Heather Joan Ross, MDa
From the aHeart Failure and Transplant Program, Toronto General Hospital, University Health Network, University of
Toronto, Toronto, Ontario, Canada; bAdult Congenital Heart Disease Program, Knight Cardiovascular Institute, Oregon
Health Science University, Portland, Oregon, USA; and the cLabatt Family Heart Centre, The Hospital for Sick Children,
University of Toronto, Toronto, Ontario, Canada.

KEYWORDS:
congenital heart
disease;
adults;
transplantation;
outcomes;
mortality;
morbidity;
Fontan/Glenn

BACKGROUND: Studies assessing mortality and morbidity in adult transplant recipients with congenital
heart disease (CHD) are limited. We conducted a systematic review and meta-analysis comparing posttransplant outcomes in these 2 populations.
METHODS: After conducting an electronic database search, we selected studies evaluating mortality,
cause-specic mortality, and risk of reoperation and dialysis in adult CHD vs non-CHD patients. We
used random-effects models for the meta-analysis.
RESULTS: Thirty-day mortality was signicantly higher in CHD vs non-CHD patients (risk ratio [RR],
2.18; 95% condence interval [CI], 1.622.93; I2 41%). This was inuenced by increased mortality in
Fontan/Glenn patients compared with non-CHD patients (RR, 3.3; 95% CI, 1.895.77; I2 0%).
Mortality at 1 and 5 years was higher in the CHD population, although neither achieved statistical
signicance. Ten-year mortality was signicantly lower in CHD patients (RR, 0.75; 95% CI, 0.600.95,
I2 42%). Deaths caused by malignancy, infection, rejection, and cardiac allograft vasculopathy were
decreased in CHD patients, although only death from malignancy achieved signicance. Death
secondary to primary graft failure, stroke, and hemorrhage was signicantly higher in CHD patients.
Risk of reoperation and dialysis were not statistically different between the 2 groups.
CONCLUSIONS: Although adult CHD patients have higher early mortality, post-transplantation longterm survival is superior to non-CHD recipients. The challenge is to identify the CHD patients who will
benet from transplantation vs those who are higher risk.
J Heart Lung Transplant ]]]];]:]]]]]]
r 2016 International Society for Heart and Lung Transplantation. All rights reserved.

Congenital heart defects are the most common congenital

anomaly diagnosed at birth.1,2 With improvements in surgical
repair and palliation of congenital heart disease (CHD) during
infancy, an increasing number of patients are reaching
Reprint requests: Barbara Stella Doumouras, MD, UHN Toronto
General Hospital, 11 PMB 137, 585 University Avenue, Toronto, ON,
Canada, M5G2N2. Telephone: 416 340 3482. Fax: 416 340 4134.
E-mail address: barbara.doumouras@mail.utoronto.ca

adolescence and adulthood.3,4 Currently, up to 90% of

children with CHD are expected to attain adulthood, an
increase from prior eras.5
Persistent abnormalities in valvular and ventricular
function, coupled with residual shunts, anatomic lesions,
and arrhythmia burden, place CHD patients at risk of
complications, including heart failure.68 Increasingly, adult
CHD patients are undergoing transplantation. The International Society for Heart and Lung Transplantation (ISHLT)

1053-2498/$ - see front matter r 2016 International Society for Heart and Lung Transplantation. All rights reserved.
http://dx.doi.org/10.1016/j.healun.2016.06.003

The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]

2015 registry reported that 3.3% of adult heart transplants

between 2009 and 2014 were for CHD. Congenital patients
comprised 2.7% of recipients from 2004 to 2008 and 2.0%
of those from 1991 to 2003.9
Studies analyzing post-transplant outcomes in adult CHD
and non-CHD patients are limited. Single-center studies are
characterized by small cohort sizes, and registry studies
have incomplete data. Our aim was to perform a systematic
review and meta-analysis assessing post-transplant outcomes in adult CHD vs non-CHD recipients. A systematic
review summarizes all available evidence, minimizes bias,
and identies gaps in our knowledge.

Methods
Study sources
A systematic search of the MEDLINE, Embase, and CINAHL
databases ending October 2013 was performed, with additional
studies identied from references of included sources and expert
recommendations (Supplement 1, available on the jhltonline.org
Web site). Observational studies comparing post-transplant
outcomes in adult (age Z 18 years) CHD and non-CHD patients
were selected. Two independent reviewers conducted the title/
abstract and full-text assessments. Unless different clinical out
comes were evaluated, duplicate populations were excluded. For
multiple publications from an institution or registry, the study with
the greatest number of CHD patients was included for that
particular outcome. The weighted score for the full-text screen
was 0.91, indicating excellent reviewer agreement.

Data abstraction
Data abstraction was performed in duplicate (Table 1).10 The
Kaplan-Meier mortality outcomes at 30 days and at 1, 5, and 10
years post-transplantation were collected. Data tables were used
when Kaplan-Meier analysis was not performed or if the survival
curve included pediatric patients. All values were rounded to the
nearest integer. Cause-specic mortality and morbidity outcomes
during the overall study follow-up were collected. The causespecic mortality outcomes were infection, acute or chronic
rejection, malignancy, cardiac allograft vasculopathy (CAV),
primary graft failure, stroke, and hemorrhage. The morbidity
outcomes were reoperation (profuse bleeding signied by postoperative chest tube drainage requiring surgical intervention11 or
post-operative cardiac complications12) and dialysis.

Data synthesis
Results were summarized using overall risk ratio (RR) and 95%
condence interval (CI). The I2 statistic was used to analyze
heterogeneity based on the Cochrane guide: 0% to 40% may not be
important, 30% to 60% may represent moderate heterogeneity, 50% to
90% may represent substantial heterogeneity, and 75% to 100% may
represent considerable heterogeneity.13 Random-effects models were
used to conduct the meta-analysis, derived through Mantel-Haenszel
analysis. Three studies evaluated mortality using multivariable analysis
but at different times, including overlapping populations, thus preventing
the performance of a meta-analysis. These results were qualitatively
summarized. A sub-group analysis was performed dividing CHD singleventricle patients with a prior Fontan or Glenn procedure from those

who did not undergo either operation, and compared mortality with nonCHD patients using the test for sub-group interaction. A p-value of
o 0.05 was considered statistically signicant. We analyzed the data
and generated plots using Review Manager 5.3 (Cochrane).

Quality assessment (risk of bias within studies)

Quality assessment was conducted in duplicate by evaluating study
design, accuracy of outcome measures, control for confounding,
recruitment from the same population, length of follow-up, and
unselective reporting of results.

Condence in cumulative evidence

The Grades of Recommendation, Assessment, Development and
Evaluation approach14 was used for each outcome to assess the risk
of bias at the study level, inconsistency, indirectness, imprecision,
publication bias, and magnitude of effect. Our condence in the
evidence was rated as high, moderate, low, or very low.

Results
Study selection and characteristics
The search yielded 4,053 studies, with 13 studies fullling the
inclusion critieria,1112,1525 (Figure 1) all of which were
retrospective, unmatched cohort studies. Included were 9
single-center and 4 registry studies consisting of 899 CHD
and 43,452 non-CHD patients. The most frequent congenital
diagnoses were transposition of the great arteries (TGA; 22%,
including dextro-TGA and congenitally corrected TGA) and
tricuspid atresia (8%; Table 2), with comorbidities listed in
Supplement 2 (available on the jhltonline.org Web site).

Risk of bias within studies

Many factors showed evidence of risk of bias within studies
(Supplement 3, available on the jhltonline.org Web site). All
of the studies reported in an unadjusted manner, with 8 of
these through Kaplan-Meier analysis. The studies were
unclear about length of follow-up.

Mortality
Thirty-day mortality was analyzed in 9 studies of 855 CHD and
41,722 non-CHD patients. For CHD patients, 30-day mortality
was signicantly higher (RR, 2.18; 95% CI, 1.622.93; I2
41%) at 17.4% vs 7.4% in non-CHD patients (Figure 2A).
One-year mortality was assessed in 856 CHD and 42,515
non-CHD patients in 8 studies. The mortality difference was
not signicant, being 20.6% in the CHD population vs
15.4% in the non-CHD group (RR, 1.26; 95% CI, 0.95
1.66, I2 36%; Figure 2B).
Five-year mortality was evaluated in 9 studies with
861 CHD and 42,826 non-CHD patients. The difference in
5-year mortality between the 2 populations was 30.8% in the
CHD group and 29.5% in the non-CHD population, which is
not signicant (RR, 1.05; 95% CI, 0.831.33; I2 45%;
Figure 2C).

Doumouras et al.
Table 1

Outcomes in CHD transplant recipients

Characteristics of Included Studies

CHD patients

Non-CHD patients

Transplant
Age
Male
period
No. (years)a (%) No.

Age
Male
(years)a (%) Outcomes

Besik, 2016;
Single center
Czech Republic

19992014 25

38

68

634

NR

NR

Mortality: 30 days, 1 year, 5 years, 10 years

Bhama, 2013;
Single center
United States

20012011 19

39

63

428

55

75

Mortality: 30 days, 1 year, 5 years

Chen, 2004;
Single center
United States

19842004 39

4 18

NR

1,419

NR

NR

Mortality: 1 year, 5 years, 10 years

Coskun, 2007;
Single center
Germany

19892005 12

38

58

1,216b NR

NR

Mortality: 30 days, 1 year, 5 years, 10 years

Davies, 2011;
UNOS study
United States

19952009 558 35c

60c

25,497 52c

77c

Mortality: 30 days, 1 year, 5 years, 10 yearsd

Morbidity: reoperation, dialysis

Greutmann, 2009;
Single center
Switzerland

19852006 9

33

NR

309

48

86

Mortality: 30 days, 1 year, 5 years, 10 years

Cause-specic mortality: malignancy, CAV,
infection, rejection, stroke (ischemic)

Hsu, 2007;
Single center
Taiwan

19932005 1

39

43

83

Mortality: 30 days
Cause-specic mortality: infection,
hemorrhage
Morbidity: reoperation, dialysis

Irving, 2010;
Single center
United Kingdom

19882009 37

34

49

620e

NR

NR

Mortality: 30 days

Karamlou, 2010;
UNOS study
United States

19902008 575 28

63

7,921

35

69

Mortality: 1 year, 5 years, 10 yearsd

Cause-specic mortality: hemorrhage, malignancy

Paniagua Martin, 2012;

Spanish Heart Registry
study
Spain

19842009 55

62

3,111

NR

86

Mortality: 30 days, 1 year, 5 years, 10 years

Cause-specic mortality: primary graft failure,
rejection, infection, CAV SD, malignancy

Patel, 2009;
UNOS study
United States

19872006 689 417

63

34,645 417

78

Mortality: 30 days, 1 year, 5 years, 10 yearsd

Cause-specic mortality: primary graft failure,
rejection, infection, stroke

Pigula, 2001;
Single center
United States

19841999 8

35

38

753

NR

NR

Mortality: 30 days, 1 year, 5 years

Romero-Rodriguez, 2010; 19912010 5

Single center
Spain

NR

NR

311

50f

84f

Mortality: 5 years

Study

26

CAV, cardiac allograft vasculopathy; CHD, congenital heart disease; NR, not reported; SD, sudden death; UNOS, United Network for Organ Sharing.
a
Age is reported as a mean. If the mean is not stated, then the age restriction is listed or NR as applicable.
b

The non-CHD population is from another publication at the same institution. This was published by Minami et al10 (2005), and reported actuarial
survival rates in adults receiving heart transplantation for dilated and ischemic cardiomyopathy between 1989 and 2004.
c
These values are for patients listed for transplantation.
d
A UNOS study of the same population: Davies 2011, Karamlou 2010, and Patel 2009. The Patel 2009 study was used for the mortality outcomes because
a larger population was studied.
e
The non-CHD population was not specically evaluated in the study. However, the authors stated the 30-day mortality for non-CHD patients at their
institution during the time period and also provided the total number of heart transplants performed.
f
Values include CHD and non-CHD patients.

The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]

Figure 1

Study selection process.

Ten-year mortality was analyzed in 6 studies with 829 CHD

and 41,334 non-CHD patients. Mortality was signicantly
lower in CHD vs non-CHD transplant recipients (40.7% vs
49.0%; RR, 0.75; 95% CI, 0.600.95; I2 42%; Figure 2D).
Three studies using the United Network for Organ Sharing
(UNOS) database reported multivariable analyses assessing
CHD as an independent predictor of death12,15,16 (Supplement
4, available on the jhltonline.org Web site). Although the data
sets were likely similar, the inclusion criteria were different. In
Davies et al,12 CHD was associated with increased 30-day
mortality (odds ratio, 3.6; 95% CI, 2.84.7) but decreased
late-term mortality (hazard ratio [HR], 0.73; 95% CI, 0.560.94)
in patients surviving at least 1 year after transplantation. Patel
et al16 assessed patients aged older than 17 years, concluding
that CHD was associated with high overall mortality (HR, 1.25;
95%, CI, 1.021.52) but not with increased long-term mortality.
Karamlou et al15 restricted the analysis to patients aged 18 to 45
years and found that CHD patients had 1.96-fold increased
overall mortality risk (95% CI, 1.372.55).

Sub-group analyses of patients with and without

prior Fontan/Glenn
Within the CHD population, there was increased early
mortality risk in those with a prior Fontan or Glenn
operation. In the 3 studies that assessed Fontan/Glenn
patients, the 30-day mortality risk was signicantly higher
than in non-CHD patients (43.8% vs 14.4% respectively;
RR, 3.30; 95% CI, 1.895.77; I2 0%), whereas the risk at
the remaining times was non-signicant (Figure 3). The
CHD single-ventricle patients without previous Fontan/
Glenn procedures had similar mortality outcomes as nonCHD patients (RR, 0.99, 95% CI, 0.422.34; p 0.02 for
sub-group interaction test).

Cause-specic mortality
Mortality secondary to malignancy was assessed in 3 studies
(639 CHD and 11,341 non-CHD patients), with 1.1% mortality
in CHD vs 4.7% in non-CHD. There was a signicant 2.63times reduced risk of cancer-related mortality in CHD patients
(RR, 0.38; 95% CI, 0.180.79; I2 0%; Figure 4A).
Mortality secondary to primary graft failure was
evaluated in 2 studies (296 CHD and 17,376 non-CHD
patients). It was signicantly higher in the CHD (10.5%) vs
the non-CHD (4.7%) group (RR, 2.20; 95% CI, 1.493.23;
I2 21%; Figure 4B).
Mortality secondary to stroke was assessed in 2 studies
(252 CHD and 14,780 non-CHD patients). There was a
statistically signicant higher mortality in CHD patients
(RR, 2.29; 95% CI, 1.214.33; I2 0%) at 3.6% compared
with 1.7% in non-CHD patients (Figure 4C).
Finally, mortality secondary to hemorrhage (Days 146
post-transplant) was analyzed in 2 studies of 576 CHD and
7,927 non-CHD patients. Results showed a signicantly
higher mortality due to hemorrhage in CHD (2.8%) than in
non-CHD (1.0%) patients (RR, 2.86, 95% CI, 1.674.89;
I2 0%; Figure 4D).
Death due to infection, rejection, and CAV were all
decreased in the CHD population; however, none of these
outcomes achieved statistical signicance (Figure 4EG)

Morbidity
Reoperation and risk of dialysis were assessed in 2 studies
of 559 CHD and 25,503 non-CHD patients. Although more
CHD patients required reoperation (21.1% vs 10.5%) and
dialysis (21.5% vs 8.4%), neither outcome was statistically
signicant (Figure 5).

Doumouras et al.
Table 2

Outcomes in CHD transplant recipients

Congenital Heart Disease Diagnoses and Non-Congenital Heart Disease Cardiomyopathya

Study

Congenital diagnosis

Non-CHD cardiomyopathy

Besik, 2016

TGA: 8 (32%), tetralogy of Fallot: 4 (16%), DILV: 3

(12%), DORV: 3 (12%), Ebsteins anomaly: 2 (8%),
ALVT: 1 (4%), ccTGA: 1 (4%), DOLV: 1 (4%),
pulmonary atresia: 1 (4%), VSD: 1 (4%)

Not reported

Bhama, 2013

Single ventricle: 7 (37%), failed Fontan: 5 (26%), TGA: 5 Ischemic: 216 (51%), idiopathic: 164 (38%),
(26%), ASD/VSD: 3 (16%), tetralogy of Fallot: 1 (5%), other: 48 (11%)
other: 3 (16%)

Chen, 2004b

Not reported
Single ventricle: 65 (61%), single ventricle not
otherwise specied: 22 (21%), tricuspid atresia: 13
(12%), HLHS/Shones complex: 12 (11%), DILV: 10
(9%), pulmonary atresia/intact septum: 8 (8%),
Fontan: 29 (27%), Glenn: 8 (8%) d-TGA: 10 (9%),
tetralogy of Fallot (/ pulmonary atresia): 9 (8%),
ccTGA: 6 (6%), Ebsteins anomaly: 3 (3%), other: 13
(12%)

Coskun, 2007

d-TGA: 5 (42%), Ebsteins anomaly: 3 (25%), tetralogy of Not reported

Fallot: 1 (8%), DORV: 1 (8%), anomalous origin of the
left coronary artery from the pulmonary artery: 1
(8%), DILV: 1 (8%)

Davies, 2011c

Not reported

Ischemic: 20,170 (49%), dilated:

17,837 (44%), other: 2,807 (7%)

Greutmann, 2009

Single ventricle: 6 (67%) tricuspid atresia with

hypoplastic RV: 2 (22%), DORV: 1 (11%), Glenn: 2
(22%) d-TGA: 2 (22%), ccTGA: 1 (11%)

Not reported

Hsu, 2007

Tetralogy of Fallot: 1 (100%)

Rheumatic heart disease: 2 (33%),

ischemic: 2 (33%), dilated: 2 (33%)

Irving, 2010

Not reported
Single ventricle: 15 (41%) DILV: 6 (16%), tricuspid
atresia: 5 (14%), Fontan: 3 (8%), Glenn: 1 (3%)
d-TGA: 8 (22%), ccTGA: 3 (8%), tetralogy of Fallot: 2
(5%), Ebsteins anomaly: 1 (3%), other: 8 (22%)

Karamlou, 2010

Not reported

Dilated: 3,939 (46%), nondilated ischemic:

1,624 (19%), hypertrophic: 215 (3%),
valvular: 231 (3%), restrictive: 163 (2%)

Paniagua Martin, 2012

Single ventricle with pulmonary stenosis: 18 (33%),

single ventricle with Fontan/Glenn: 10 (18%), CHD
with RV overload: 17 (31%), ccTGA/TGA with atrial
switch: 10 (18%)

Ischemic: 1,888 (61%), idiopathic dilated:

1,223 (39%)

Patel, 2009

Not reported

Not reported

Pigula, 2001

Tricuspid atresia: 3 (38%) Fontan: 1 (13%) shunts: 2 Not reported

(25%) tetralogy of Fallot: 2 (25%), Ebsteins anomaly:
2 (25%), ccTGA: 1 (13%)

Romero-Rodriguez, 2010 Not reported

Ischemic: 175 (55%), dilated: 92 (29%), valvular:

17 (5%), alcoholic: 8 (3%), acute myocarditis:
5 (2%), hypertrophic: 5 (2%), endomyocardial
brosis: 4 (1%), anthracyclines-related
cardiomyopathy: 3 (1%)

ALVT, aortic-left ventricular tunnel; ASD, atrial septal defect; ccTGA, congenitally corrected transposition of the great arteries; CHD, congenital heart
disease; d-TGA, dextro-transposition of the great arteries; DILV, double inlet left ventricle; DOLV, double outlet left ventricle; DORV, double outlet right
ventricle; HLHS, hypoplastic left heart syndrome; RV, right ventricle; VSD, ventricular septal defect.
a
Values are expressed as the total number with the percentage in parentheses.
b
The study reports the diagnoses for both the adult and pediatric population.
c
The study reports the cardiomyopathies for patients listed for transplant.

The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]

Figure 2
Mortality outcomes in congenital heart disease (CHD) transplant recipients vs non-CHD transplant recipients at (A) 30 days,
(B) 1 year, (C) 5 years, and (D) 10 years after transplantation. The solid squares indicate the mean difference and are proportional to the
weights used in the meta-analysis. The solid vertical line indicates no effect. The horizontal lines represent the 95% condence interval (CI).
The diamond indicates the weighted mean difference, and the lateral tips of the diamond indicate the associated CI. M-H, Mantel-Haenszel.

Risk of bias across studies

Our condence in effect estimates was low to very low. For
all outcomes, the evidence was downgraded for risk of bias
due to univariable analysis and unclear follow-up. The use
of univariable analysis does not take into account potential

confounders. The 5-year mortality outcome was also

downgraded for inconsistency due to heterogeneity. Oneyear mortality, death secondary to rejection and CAV, and
both morbidity outcomes were downgraded for imprecision.
The risk of publication bias was dened by the Grades of
Recommendation, Assessment, Development and Evaluation

Doumouras et al.

Outcomes in CHD transplant recipients

Figure 3
Subgroup analysis of mortality outcomes in single-ventricle transplant recipients with and without Fontan/Glenn at (A) 30 days,
(B) 1 year, (C) 5 years, and (D) 10 years. Paniagua Martin et al22 included mortality outcomes for the following single ventricle patients:
(1) single-ventricle with different degrees of pulmonary stenosis (non-Fontan/non-Glenn), and (2) single-ventricle with tricuspid atresia with
Fontan/Glenn, The study also included congenital heart disease (CHD) patients with different degrees of right ventricle overload, including
double-outlet right ventricle (DORV). How many patients in this group had a diagnosis of DORV is unclear. These patients are not included
in this analysis. The solid squares indicate the mean difference and are proportional to the weights used in the meta-analysis. The solid
vertical line indicates no effect. The horizontal lines represent the 95% condence interval (CI). The diamond indicates the weighted mean
difference, and the lateral tips of the diamond indicate the associated CI. M-H, Mantel-Haenszel.

The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]

Figure 4
Cause-specic mortality secondary to (A) malignancy, (B) primary graft failure, (C) stroke, (D) hemorrhage, (E) infection,
(F) rejection (acute and chronic), and (G) cardiac allograft vasculopathy in transplant recipients with and without congenital heart disease
(CHD). The solid squares indicate the mean difference and are proportional to the weights used in the meta-analysis. The solid vertical line
indicates no effect. The horizontal lines represent the 95% condence interval (CI). The diamond indicates the weighted mean difference, and
the lateral tips of the diamond indicate the associated CI. M-H: Mantel-Haenszel.

Doumouras et al.

Outcomes in CHD transplant recipients

Figure 5
Morbidity outcomes in transplant recipients with and without congenital heart disease (CHD). (A) Reoperation requirement
after transplantation and (B) dialysis requirement. The solid squares indicate the mean difference and are proportional to the weights used in
the meta-analysis. The solid vertical line indicates no effect. The horizontal lines represent the 95% condence interval (CI). The diamond
indicates the weighted mean difference, and the lateral tips of the diamond indicate the associated CI. M-H: Mantel-Haenszel.

criteria14 and assessed via funnel plots. This was done for
the mortality outcomes (Supplement 5, available on the
jhltonline.org Web site) because the others consisted of a
small number of studies. Lastly, based on an RR value of
4 2 or o 0.5, 6 outcomes were upgraded for large effect.
The quality of evidence for each outcome was deemed low
or very low (Supplement 6, available on the jhltonline.org
Web site).

Discussion
This meta-analysis found that despite increased early
mortality after heart transplant, adult CHD patients have
improved long-term survival compared with non-CHD
recipients. The early increased mortality risk was observed
in Fontan/Glenn-CHD patients, with non-Fontan/non-Glenn
single-ventricle patients having outcomes similar to those of
non-CHD transplant recipients. In studies that performed
multivariable analysis taking into account time post-transplantation, CHD was an independent risk factor for early
death although associated with improved long-term survival. However, these studies did not adjust by type of CHD or
procedural history. In the ISHLT 2015 registry, 1-year
survival post-transplant was signicantly lower in CHD
patients (77%) vs patients with a pre-transplant diagnosis of
cardiomyopathy (83%) or coronary artery disease (CAD)
(81%).26 The median survival was 14.6 years for CHD
patients, 11.6 years for cardiomyopathy patients, and
9.4 years for CAD patients. Long-term median survival
conditional on survival to 1 year post-transplant was higher
in CHD patients (20.2 years) than in other cardiomyopathy
(14.1 years) and CAD (11.7 years) patients.26
In this meta-analysis, the Fontan/Glenn population
represented a high-risk population, with increased early
post-transplant mortality. In a combined adult and pediatric
registry study, prior Fontan operation was a risk factor
for early death.27 Although small in number, patients who
die early after transplant are often those with a prior
Fontan.17,22,28 Owing to the manner in which the studies

reported outcomes, the mortality risk of Fontan patients

could not be assessed separately from those with Glenn anatomy. Larger, multicenter studies are required to elucidate
the effect of a prior Fontan or Glenn procedure on mortality
in the adult transplant population because this presents a
signicant challenge in recipient selection.
CHD patients were less likely to die of malignancy,
infection, rejection, or CAV, although the latter 3 were nonsignicant. The lower risk of death secondary to malignancy
or CAV is likely due to their younger age and fewer
comorbidities (Supplement 2, available on the jhltonline.org
Web site). The ISHLT 2014 registry found that a diagnosis
of CHD was associated with a lower hazard for the
development of CAV vs a diagnosis of cardiomyopathy
(HR, 0.54; 95% CI, 0.360.81).29 These outcomes likely
contribute to the long-term survival benet seen in CHD
patients. In terms of rejection, 1 study found CHD patients
have higher pre-transplant panel reactive antibody levels,
with operative mortality being greater for a level above
10%,16 but panel reactive antibody levels were not an
independent risk factor for death in another analysis.17
Additional studies need to evaluate immunologic risk and
the consequent degree of rejection in CHD.
Mortality secondary to primary graft failure, stroke, and
hemorrhage was signicantly higher in CHD patients. Prior
sternotomies and longer donor ischemic times, frequent
characteristics of CHD patients, are risk factors for early
graft failure.30 Ischemic time is signicantly longer, because
reconstructive surgery can be required in more than 75% of
CHD patients undergoing heart transplantation.28 The
increased mortality associated with hemorrhage and longer
ischemic time16 is of particular relevance to adults with
single-ventricle anatomy.28 Many single-ventricle patients
have dense sternal adhesions arising from multiple sternotomies, leading to a high bleeding risk at the time of sternal
reentry. To mitigate this risk, groin bypass is often undertaken at the time of transplantation.31 Heart transplantation
in these patients often requires extensive reconstruction of
the aortic arch, vena cavae, or the pulmonary arteries,

10

The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]

leading to longer ischemic time and increased bleeding risk.

Others have reported signicantly longer cardiopulmonary
bypass and donor ischemic times in Fontan vs non-Fontan
single-ventricle patients.32
Comorbid liver disease is highly prevalent in adults with
CHD33 and associated with an increased risk of coagulopathy in the peri-operative phase. Post-operative hemorrhage
and shock is often treated with anti-brinolytics. These
factors may contribute to the higher incidence of stroke in
adult CHD patients undergoing heart transplantation.3436
The risk for reoperation after transplantation in CHD
patients was similar to non-CHD patients. Given the
increased mortality secondary to hemorrhage, this was
surprising. A concern was that the studies assessed different
postoperative complications in which the timing was not
dened. Risk of dialysis was also non-signicantly different
between groups. In the ISHLT 2012 registry, multivariable
analysis found that a diagnosis of CHD or ischemic
cardiomyopathy had a lower risk of severe renal dysfunction
(creatinine 4 2.5 mg/dL or dialysis) compared with nonischemic cardiomyopathy within 5 years after transplant.37
Patients with severe renal dysfunction at transplant were
excluded, as opposed to the meta-analysis studies which
included patients with pre-transplant renal failure and
dialysis, with similar rates between CHD and non-CHD
populations. Studies with well-dened criteria of preoperative status and timing of reoperation and dialysis are
necessary.
There was moderate to high risk of bias secondary to
limitations in study design (Supplement 6, available on the
jhltonline.org Web site). The quality of evidence for some
outcomes was downgraded because of imprecision,
resulting in low to very low condence in effect estimates.
The individual study quality was low given unclear
follow-up timelines and lack of control for confounders.
Although studies frequently report higher mortality risk
in adult CHD patients after heart transplant, the magnitude
is not quantiable due to limitations in study design. This
has implications in clinical practice because adult CHD
patients may be denied a transplant because of the reported
high mortality risk. Further well-designed, multicenter
studies are required that report early and long-term mortality
by the type of CHD diagnosis, including Fontan, Glenn, and
non-procedural patients.
A limitation of this study is the possibility of double
counting. All United States centers report to UNOS.
Assuming a constant recruitment rate, 50% of Bhama
et al,17 85% of Chen et al,18 and 80% of Pigula et al23
overlap with Patel et al16 in years. Furthermore, 95% of
Romero-Rodriguez et al24 overlaps with Paniagua Martin
et al.22 UNOS and the Spanish Heart Transplant Registry
both report to the ISHLT. We were able to contact 6 of the
9 authors of the studies, and most contributed to some
degree to registry data. The ISHLT registry study,38 which
was published after the database search was conducted, was
not included to minimize the extent of double counting.
Registry data are plagued by incomplete information, such
as mortality based on CHD diagnosis. We were able to
overcome this by using single-center data. Removing single-

center studies with possible double-counted registry patients

did not change mortality outcomes.
This study did not evaluate mortality in patients who
were listed but did not undergo transplant. Adult CHD
patients spend a longer time on the waiting list than nonCHD recipients.12,15,16 A recent multicenter study found no
waiting list mortality among adult CHD patients listed for
transplant.39 There is, however, evidence that patients at
higher risk, such as those with single-ventricle physiology,
are less likely to be listed for transplant, and mortality
among these patients is high after the onset of progressive
heart failure.39,40
In conclusion, although adult CHD patients experienced
higher early mortality after heart transplantation, with
improved long-term survival compared with non-CHD
recipients, we found an overall low to very low quality of
evidence. Therefore, the true effect of CHD on outcomes is
largely unknown. The high early mortality was evident in
Fontan/Glenn patients, a population that requires further
attention during transplant assessment. The lower mortality
secondary to malignancy in CHD patients contributes to
long-term survival benets, whereas the increased mortality
secondary to primary graft failure, stroke, and hemorrhage
inuences early post-transplant outcomes. These ndings
should be considered when identifying CHD patients for
transplantation, during the peri-operative period, and in
long-term management to minimize mortality.

Disclosure statement
None of the authors has a nancial relationship with a commercial
entity that has an interest in the subject of the presented manuscript
or other conicts of interest to disclose.
The authors thank Ani Orchanian-Cheff, Information Specialist,
who completed the database literature search.

Supplementary material
Supplementary data are available in the online version of
this article at www.jhltonline.org.

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