Original Investigation | Cardiology

Risk of Cancer Among Children and Young Adults With Congenital

Heart Disease Compared With Healthy Controls
Zacharias Mandalenakis, MD, PhD, FESC; Christina Karazisi, MD; Kristofer Skoglund, PhD; Annika Rosengren, PhD; Georgios Lappas, MSc;
Peter Eriksson, PhD; Mikael Dellborg, PhD

Abstract Key Points

Question What is the risk of developing
IMPORTANCE Adult patients with congenital heart disease (CHD) have an increased incidence of
cancer among children and young adults
cancer, presumably owing to repeated radiation exposure, genetic predisposition, or repeated stress
with and without congenital
factors during heart interventions. However, there are limited data on the risk of cancer in children
heart disease?
and young adults with CHD compared with the general population.
Findings In this nationwide registry-
OBJECTIVE To determine the risk of developing cancer from birth to age 41 years among patients based cohort study of 21 982 children
with CHD compared with healthy matched controls. and young adults with congenital heart
disease and 219 816 healthy matched
DESIGN, SETTING, AND PARTICIPANTS This registry-based, matched, prospective cohort study in controls in Sweden, the risk of cancer
Sweden used data from the Patient and Cause of Death Registers. Successive cohorts of patients was more than 2-fold higher among
with CHD born from 1970 to 1979, 1980 to 1989, and 1990 to 1993 were identified. Each patient patients with congenital heart disease
(n = 21 982) was matched for birth year, sex, and county with 10 controls without CHD from the than among controls.
general population (n = 219 816). Follow-up and comorbidity data were collected from 1970 until
Meaning The findings suggest that
2011. Data analysis began in September 2018 and concluded in February 2019.
children and young adults with
congenital heart disease have an
MAIN OUTCOMES AND MEASURES Risk of cancer among children and young adults with CHD and
increased risk of cancer, and a
among healthy controls.
systematic screening for cancer could be
considered for this at-risk group of
RESULTS Among 21 982 individuals with CHD and 219 816 healthy matched controls, 428 patients
patients.
with CHD (2.0%) and 2072 controls (0.9%) developed cancer. Among patients with CHD, the mean
(SD) age at follow-up was 26.6 (8.4) years, and 11 332 participants (51.6%) were men. Among healthy
controls, the mean (SD) age at follow-up was 28.5 (9.1) years, and 113 319 participants (51.6%) were + Invited Commentary
men. By the age of 41 years, 1 of 50 patients with CHD developed cancer. The overall hazard ratio
(HR) for cancer was 2.24 (95% CI, 2.01-2.48) in children and young adults with CHD compared with
+ Supplemental content
Author affiliations and article information are
controls. Risk increased by each successive birth cohort to an HR of 3.37 (95% CI, 2.60-4.35) among
listed at the end of this article.
those born from 1990 to 1993. The risk of cancer was similar in men and women with CHD (men: HR,
2.41; 95% CI, 2.08-2.79; women: HR, 2.08; 95% CI, 1.80-2.41). The HR for cancer among patients
with CHD who underwent surgery was 1.95 (95% CI, 1.58-2.33) compared with controls; for patients
with CHD who had not undergone surgery, the HR was 2.43 (95% CI, 2.12-2.76). According to a
hierarchical classification, a significantly increased risk of cancer was found among patients with
complex heart lesions, such as conotruncal defects (HR, 2.29; 95% CI, 1.62-3.25), compared with
healthy controls.

CONCLUSIONS AND RELEVANCE Children and young adult patients with CHD had an increased risk
of developing cancer compared with healthy matched controls, and the risk was significantly higher
among patients with CHD from the most recent birth cohort. An increased risk of cancer in all CHD

(continued)

Open Access. This is an open access article distributed under the terms of the CC-BY License.

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Abstract (continued)

lesion groups was found, and a systematic screening for cancer could be considered for this at-risk
group of patients.

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Introduction
Congenital heart disease (CHD) is the most common major congenital disorder, with a prevalence of
almost 1% in live births.1,2 With the evolution of pediatric care during the last decades, more than
95% of patients with CHD survive into adulthood.3 In parallel with increasing survival among patients
with CHD, lifetime secondary morbidities might be expected to increase in this group.
Previous studies have shown that the risk of acquired cardiovascular comorbidities is markedly
higher among young patients with CHD compared with matched controls from the general
population.4-6 Furthermore, noncardiovascular diseases, and particularly cancer, are associated with
CHD. The cause of this association is likely multifactorial, but radiation exposure is probably a
factor.7-12 However, genetic predisposition, socioeconomic status, other comorbidities, and lifestyle
factors (eg, a more sedentary lifestyle) are also associated with the development of cancer.13-17 In
contrast to many other cardiovascular disorders, CHD is present from birth. However, to our
knowledge, no study has observed patients with CHD from birth and compared their cancer
outcomes with matched controls. Therefore, we aimed to investigate the risk of developing cancer
in children and in young adults with CHD compared with matched controls without CHD from birth
up to age 41 years.

Methods
Study Population and Design
The study population has been described previously.3,4,6,18 Through the Swedish Patient Register, we
identified patients who were born between January 1970 and December 1993 and were diagnosed
as having CHD at any age. Each patient was matched by birth year, sex, and county with 10 controls
from the Total Population Register in Sweden. The patients were observed from birth until the
occurrence of cancer, death, or the end of the study on December 31, 2011, with a maximum
follow-up time of 41 years.
The study was approved by the Gothenburg Regional Research Ethics Board and complied with
the Declaration of Helsinki.19 In the data set provided by the Swedish National Board of Health and
Welfare, every individual’s social security number was replaced with a unique code. Therefore,
written informed consent was not required. This report follows the Strengthening the Reporting of
Observational Studies in Epidemiology (STROBE) reporting guideline.

Definitions
Congenital heart disease was defined as present in any patient with at least 1 outpatient visit, hospital
discharge, or death certificate with at least 1 registered diagnosis of CHD according to the
International Classification of Diseases, Eighth Revision (ICD-8), ICD-9, or ICD-10 (eTable 1 in the
Supplement). Cancer was defined by ICD codes (eTable 2 in the Supplement). Surgical procedures on
the cardiovascular system were classified as codes 30 to 32 in Classification of Operations20 or F
codes in Classification of Surgical Procedures.21 A hierarchical CHD classification was used to
categorize diagnosis of CHD.22

Statistical Analysis
We analyzed the survival of patients and controls born from 1970 to 1993 to determine the
association of CHD with the risk of developing cancer. The incidence rates and cause-specific hazard

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ratios (HRs) for cancer were estimated with 95% CIs to compare patients with CHD with healthy
controls who were matched by birth year, sex, and county. Two-sided P values were used, and P <.05
was considered statistically significant. We used SAS software version 9.4 (SAS Institute) and R
software version 3.2 (The R Foundation) to perform all statistical analyses.

Results
We identified 21 982 patients with CHD and 219 816 healthy controls who were matched by birth
year, sex, and county. Overall, 11 332 patients with CHD (51.6%) and 113 319 healthy controls (51.6%)
were men. The characteristics of the study population are shown in Table 1. Most participants (20 135
patients with CHD [91.6%] and 202 230 healthy controls [91.6%]) were born in Sweden. The mean
(SD) age at follow-up was 26.6 (8.4) years (median, 26.2 years; interquartile range, 19.8-32.6 years)
for patients with CHD and 28.5 (9.1) years (median 27.5 years; interquartile range, 21.1-33.9 years)
for controls. By the age of 41 years, 1 of 50 patients with CHD developed cancer. The cumulative
incidence of cancer exponentially increased during adulthood. This increase was higher among
patients with CHD than in controls, with up to 4.5% cumulative incidence among patients with CHD
and 2.5% cumulative incidence among healthy controls at a maximum age of 41 years (Figure 1).
Table 2 shows the risk of developing cancer in the study population by sex and birth cohort. The
overall HR for cancer was 2.24 (95% CI, 2.01-2.48) among patients with CHD compared with healthy
controls. The risk of cancer in men and women with CHD was similar, with HRs of 2.41 (95% CI,

Table 1. Characteristics of the Study Population

No. (%)
Characteristic Patients With CHD Controls
All participants, No. 21 982 219 816
Men 11 332 (51.6) 113 319 (51.6)
Birth cohort
1970-1979 7535 (34.3) 75 350 (34.3)
1980-1989 9126 (41.5) 91 266 (41.5)
1990-1993 5321 (24.2) 53 200 (24.2)
Born in Sweden 20 135 (91.6) 202 230 (91.6)
Age at follow-up, y
Mean (SD) 26.6 (8.4) 28.5 (9.1)
Median (IQR) 26.2 (19.8-32.6) 27.5 (21.1-33.9)

Abbreviations: CHD, congenital heart disease; IQR, interquartile range.

Figure 1. Cumulative Incidence of Cancer in the Study Population

Healthy controls
5
Patients with CHD
Cumulative Incidence, %

0
0 10 20 30 40
Age, y
No. at risk
Healthy controls 219 812 219 444 191 618 88 627 14 577
Patients with CHD 21 982 20 882 17 879 8012 1291 CHD indicates congenital heart disease.

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2.08-2.79) for men and 2.08 (95% CI, 1.80-2.41) for women. The cumulative incidence of cancer
exponentially increased in men and women with CHD until the age of 41 years, with a cumulative
incidence of cancer of 4.0% and 5.0%, respectively (eFigure 1 in the Supplement). For comparison of
successive birth cohorts, the highest relative risk of developing cancer was found among patients
with CHD born from 1990 to 1993 (HR, 3.37; 95% CI, 2.60-4.35). The cumulative incidence of cancer
among patients with CHD and in healthy controls exponentially increased by birth cohort. At age 18
years, patients with CHD from the 1990 to 1993 birth cohort had the highest cumulative incidence
rate of cancer (1.5%) (Figure 2).
The risk of cancer in different lesion groups was estimated and compared with controls
(Table 3). Numerically, the relative risk of cancer was higher among patients with CHD compared
with controls for all lesion groups, but one of the highest risks for cancer was found among patients
with conotruncal defects (HR, 2.29; 95% CI, 1.62-3.25). However, patients with simple defects, such
as coarctation of the aorta (HR, 2.00; 95% CI, 1.27-3.16) or ventricular septal defect (HR, 2.00; 95%
CI, 1.57-2.56), had a significantly increased risk of developing cancer. The cumulative incidence of
cancer among patients with conotruncal defect, coarctation of the aorta, ventricular septal defect,
and other heart and circulatory system anomalies (including isolated congenital valvulopathies) was
higher compared with healthy controls (eFigure 2 in the Supplement).
The incidence rates according to the type of cancer diagnosis are shown in eTable 3 in the
Supplement. A higher incidence of cancer among patients with CHD was observed in all types of

Table 2. Risk of Cancer Among Patients With CHD Compared With Matched Controls According
to Sex and Birth Period

No. (%)
Patients With CHD
Characteristic and Cancer Controls With Cancer Hazard Ratio (95% CI) P Value
All patients 428 (1.9) 2072 (0.9) 2.24 (2.01-2.48) <.001
Men 215 (1.9) 969 (0.9) 2.41 (2.08-2.79) <.001
Women 213 (2.0) 1103 (1.0) 2.08 (1.80-2.41) <.001
Birth cohort
1970-1979 209 (2.8) 1150 (1.5) 2.01 (1.73-2.33) <.001
1980-1989 142 (1.6) 686 (0.8) 2.21 (1.84-2.64) <.001
1990-1993 77 (1.4) 236 (0.4) 3.37 (2.60-4.35) <.001
Abbreviation: CHD, congenital heart disease.

Figure 2. Cumulative Incidence of Cancer in the Study Population by Birth Cohort

A Cumulative incidence of cancer among healthy controls B Cumulative incidence of cancer among patients with CHD
6 6

5 Born 1970 to 1979 5

Born 1980 to 1989
Cumulative Incidence, %

Cumulative Incidence, %

4 Born 1990 to 1993 4

3 3

2 2

1 1

0 0
0 10 20 30 40 0 10 20 30 40
Age, y Age, y
No. at risk No. at risk
Born 1970 to 1979 75 346 75 247 75 078 74 243 14 517 Born 1970 to 1979 7535 7074 6933 6707 1291
Born 1980 to 1989 91 265 91 117 90 816 14 384 Born 1980 to 1989 9126 8648 8502 1304
Born 1990 to 1993 53 199 53 081 25 724 Born 1990 to 1993 5321 5160 2445

CHD indicates congenital heart disease.

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cancer. Some of the most predominant types of cancer among patients with CHD were lymphoma or
leukemia and carcinoma.
The incidence rates and rate ratio of cancer among patients with CHD compared with controls
by cancer diagnosis are shown in eTable 4 in the Supplement. Malignant neoplasms of the digestive
system had the highest incidence rate ratio (3.58; 95% CI, 2.58-4.98). In contrast, the incidence rate
ratios of melanoma and other skin cancers were not significantly increased among patients with CHD.
The incidence rates of cancer by age and different lesion groups are shown in eTable 5 in the
Supplement. The highest incidence rates were observed during the first 4 years of life and during
adulthood, particularly among patients with conotruncal defects and ventricular septal defect.
A total of 8044 patients with CHD (36.6%) underwent at least 1 cardiac surgical procedure
before age 41 years. The HR for cancer among patients with CHD who underwent surgery was 1.95
(95% CI, 1.58-2.33), and the HR for patients with CHD who did not undergo surgery was 2.43 (95%
CI, 2.12-2.76) compared with healthy controls. We also found that the risk of cancer among patients
with surgically corrected ventricular septal defect increased (HR, 2.25; 95% CI, 1.69-3.04) compared
with healthy controls. Patients with ventricular septal defect who did not undergo surgery had an
HR of 1.93 (95% CI, 1.33-2.90) compared with healthy controls. Furthermore, we found that the HR
of benign tumors among patients with CHD was 1.38 (95% CI, 1.32-1.44) compared with healthy
controls.

Discussion
To our knowledge, this is the first study to investigate the long-term incidence of cancer from birth to
a maximum age of 41 years among patients with all types of CHD, with or without surgery. We found
an increased risk of cancer compared with healthy matched controls that was already present in
childhood. The absolute risk of developing cancer among patients with CHD increased for each
10-year birth cohort. Consequently, 1.5% of patients with CHD in the cohort who were born from
1990 to 1993 had developed cancer by age 18 years or younger.
We found a more than 2-fold higher risk among patients with CHD of developing cancer
compared with controls, which is marginally higher compared with previous studies.8,11 However, the
study by Gurvitz et al11 only included adult patients with CHD and only compared the prevalence rate
of cancer among patients with CHD with that in the general population, not with matched controls.
Therefore, these authors had potentially lower precision of estimates. Lee et al8 reported a median
follow-up of only 5.2 years, whereas follow-up started at birth in our study. We also had a
substantially longer follow-up, with median (interquartile range) follow-up of 26.2 (19.8-32.6) years
and a mean (SD) follow-up of 26.6 (8.4) years among patients with CHD.
We found that the relative risk of cancer was high, regardless of whether patients had
undergone surgical procedures. Our study findings add to the ongoing discussion on whether there
is an association of the use of cardiac procedures with the risk of malignancy, potentially mediated by
exposure to low-dose ionizing radiation, as suggested by Cohen et al.7 However, the radiation dose
from cardiac catheterization might not be the only contributor to the increased risk of cancer

Table 3. Risk of Cancer Among Patients With CHD Compared With Matched Controls According to Lesion Group

No./Total No. (%)

Cancer in Patients with Cancer in Controls With Hazard Ratio
Lesion Group CHD and Lesion Lesion (95% CI) P Value
Conotruncal defects 38/2022 (1.9) 226/20 230 (1.1) 2.29 (1.62-3.25) <.001
Severe nonconotruncal defects 15/1087 (1.4) 100/10 870 (0.9) 1.94 (1.12-3.35) .03
Coarctation of the aorta 22/1306 (1.7) 119/13 060 (0.9) 2.00 (1.27-3.16) .006
Ventricular septal defect 76/4369 (1.7) 402/43 689 (0.9) 2.00 (1.57-2.56) <.001
Atrial septal defect 44/2405 (1.8) 243/24 049 (1.0) 1.87 (1.36-2.58) <.001
Other heart and circulatory 233/10 793 (2.2) 982/107 918 (0.9) 2.49 (2.16-2.88) <.001
system anomalies Abbreviation: CHD, congenital heart disease.

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observed in our study population. Harbron et al9,23 reported that the standardized incidence ratio of
cancer was 0.90 for children undergoing cardiac catheterizations in childhood when patients who
underwent a transplant were censored. Our data would support that the increased risk of cancer in
children and young adults with CHD is not a simple function of radiation exposure.
According to the guidelines of the American Cancer Society, a major mechanism for reducing
the risk of cancer, and even preventing the occurrence of cancer, is performing physical activity and
eating healthy food.17 Patients with CHD have lower isotonic muscle function, reduced oxygen
uptake, and higher exercise intolerance compared with those without CHD.24,25 This further suggests
an increased risk of cancer in this group of patients. Furthermore, Keum et al14 described the
association of physical inactivity with an increased risk of cancer of the digestive system.
Interestingly, we found that cancer of the digestive system was the most prevalent among patients
with CHD, with an incidence rate ratio of 3.58 compared with any other cancer diagnostic group.
The incidence of cancer continuously increased by birth cohort among patients with CHD and
among healthy controls but to a lesser extent between those born from 1980 to 1989 and those born
from 1990 to 1993. This observation may reflect a change in the incidence of cancer in general, but
it may also reflect an increase in survival. Among patients born from 1970 to 1979, a significant
proportion of patients with complex CHD may not have survived long enough to develop cancer.
We previously reported that patients with CHD who were born in the early 1990s showed a high
survival into adulthood (96%).3 However, in the present analysis, we found that the cumulative
incidence of cancer was 1.5% when adulthood was reached. Preventive measures are important for
limiting the risk of cancer in the long term. However, with minimizing the risk of cancer in general,
particularly among patients with CHD, the value of such measures in young patients is less clear. The
importance of limiting radiation dose, potent antibiotics, and general biological stress in young
patients with CHD is largely unknown but requires further study. We also found no significant
increase in benign tumors among patients with CHD compared with controls, indicating that the
overreporting and increased awareness associated with more frequent medical contact is not a likely
explanation for our findings.

Strengths and Limitations

Our study has several strengths, but it also has some limitations. One strength of our study is that
follow-up started at birth and included all cancer forms. This minimized selection bias compared with
previous studies with follow-up that started at the time of CHD diagnosis or studies that only
included an adult population. Another strength is that our study used registry-based data from a
nationwide cohort that included all patients with CHD, and it was performed in a country with
universal health coverage. Although the hospital registry has been nationwide since 1987, hospitals
managing children with these conditions, particularly those providing heart surgery, have reported
diagnoses since 1970. The hospitals have been mandated by law to register and deliver each
diagnosis to the Ministry of Health and Welfare since 1964. Furthermore, each patient with CHD was
matched by the year of birth, sex, and county with 10 controls from the general population. This
provided additional strength to the comparison between patients and controls.
Our study has limitations. A major limitation of our study is that it was based only on
administrative data. Therefore, clinical data or further information on radiation exposure were not
available. Additionally, data from outpatient clinics before 2000 were not available. Another
limitation is that we were not able to perform any validation of the CHD diagnosis. However, patients
with CHD are generally managed in centers that specialize in CHD. Furthermore, external validation
of other cardiovascular diseases in these registries has shown an overall positive predictive value of
85% to 95%,26 which is likely also applicable to misclassification of CHD.

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Conclusions
In conclusion, this study found that the overall risk of cancer in children and young adult patients with
CHD in Sweden was more than twice that of healthy matched controls. The rates of cancer have
increased in cancer rates of patients with CHD and, less strikingly, in controls between the 1970s and
the early 1990s. Patients with complex heart lesions, such as conotruncal defects, had a particularly
high risk of cancer. This finding suggests that particular attention should be paid to early warning
signs of cancer and promotion of a healthy lifestyle. Further research on the mechanisms of cancer in
this young patient group is warranted.

ARTICLE INFORMATION
Accepted for Publication: May 16, 2019.
Published: July 5, 2019. doi:10.1001/jamanetworkopen.2019.6762
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Mandalenakis
Z et al. JAMA Network Open.
Corresponding Author: Zacharias Mandalenakis, MD, PhD, FESC, Institute of Medicine, Department of Molecular
and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg Hospital/Östra, Diagnosvägen 11,
Gothenburg SE-416 50, Sweden (zacharias.mandalenakis@gu.se).
Author Affiliations: Institute of Medicine, Department of Molecular and Clinical Medicine, Sahlgrenska Academy,
University of Gothenburg, Gothenburg, Sweden.
Author Contributions: Drs Mandalenakis and Dellborg had full access to all of the data in the study and take
responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Mandalenakis, Karazisi, Skoglund, Rosengren, Eriksson, Dellborg.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Mandalenakis, Eriksson.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Mandalenakis, Karazisi, Lappas.
Obtained funding: Mandalenakis, Rosengren, Dellborg.
Administrative, technical, or material support: Mandalenakis, Skoglund, Rosengren, Dellborg.
Supervision: Mandalenakis, Karazisi, Rosengren, Dellborg.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by grants ALFGBG-682561 and ALFGBG-427301 from the Swedish
state under the agreement concerning research and education of physicians, grants from the Swedish Heart and
Lung Foundation, and grants 2013-5187 and 2013-4236 from the Swedish Research Council.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and
decision to submit the manuscript for publication.
Additional Information: The raw data for our estimates are potentially identifiable, and access to those data is
restricted. Researchers wishing to access the individual-level data must apply for permission through a research
ethics board and from the primary data owners, the Swedish National Board of Health and Welfare and
Statistics Sweden.

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 JAMA Network Open | Cardiology Risk of Cancer Among Children and Young Adults With Congenital Heart Disease

SUPPLEMENT.
eTable 1. Congenital Heart Disease Diagnosis According to the International Classification of Diseases and Related
Health Problems
eTable 2. Cancer Diagnosis According to the International Classification of Diseases and Related Health Problems
eTable 3. Incidence Rate of Cancer in Patients With Congenital Heart Disease and Controls According to Type of
Cancer
eTable 4. Incidence Rate of Cancer in Patients With Congenital Heart Disease and Controls According to Cancer
Diagnosis
eTable 5. Incidence Rate of Cancer in Patients With Congenital Heart Disease and Controls According to Age and
Lesion Group
eFigure 1. Cumulative Incidence of Cancer in Patients With Congenital Heart Disease and Controls According to Sex
eFigure 2. Cumulative Incidence of Cancer in Patients With Congenital Heart Disease and Controls According to a
Hierarchic Classification

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