in vivo 38: 1984-1992 (2024)

doi:10.21873/invivo.13655

Survival and Risk Factors for Mortality in Infants

With Congenital Heart Disease in South Korea
JUE SEONG LEE1, JEHA KWON2, HANNAH CHO1, JU SUN HEO1, KEE SOO HA1,
GI YOUNG JANG1, O KYU NOH3,4,5 and JUN EUN PARK1

1Department
of Pediatrics, Korea University Medical Center,
Korea University College of Medicine, Seoul, Republic of Korea;
2Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, U.K.;
3Department of Radiation Oncology, Ajou University School of Medicine, Suwon, Republic of Korea;
4Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Republic of Korea;
5Office of Biostatistics, Ajou Research Institue for Innovative Medicine, Suwon, Republic of Korea

Abstract. Background/Aim: The survival of patients with mortality rate was associated with non-conotruncal defects
congenital heart disease (CHD) has dramatically improved (19.7%), followed by conotruncal defects (10.2%). The
over recent decades. However, a disparity exists depending on significant risk factors for childhood mortality were complex
the country and medical system. This study aimed to analyze CHD, pulmonary hypertension, birth asphyxia, small for
the survival of infants with CHD until the age of 18 years using gestational age, respiratory distress, pulmonary hemorrhage,
large-scale population data in South Korea and investigate the bronchopulmonary dysplasia, and convulsions. Conclusion:
effect of neonatal conditions at birth. Patients and Methods: The survival of infants with CHD has been favorable in South
We retrospectively extracted the Korean National Health Korea. Several neonatal conditions are risk factors for
Insurance Service claims data from January 2002 to December childhood mortality. Individualized risk assessment and optimal
2020. We included patients diagnosed with CHD who were less treatment strategies may help improve their survival rate.
than one year of age. The follow-up duration was until their
death or until they were censored before the age of 18 years. Congenital heart disease (CHD) is among the most common
The CHD lesions were classified hierarchically (conotruncal, congenital anomalies, occurring in approximately nine out of
severe non-conotruncal, coarctation of the aorta, ventricular 1000 live births (1, 2). The survival rates of patients with
septal defect, atrial septal defect, and others). Several neonatal CHD have dramatically improved over recent decades,
conditions were adopted as risk factors. Results: Overall, driven by advances in treatment, including cardiac
127,958 infants had been diagnosed with CHD and 2,275 died procedures and medical treatments (1, 2). Currently, more
before the age of 18 years. The survival rate of infants with than 97% of CHD patients survive to adulthood (2).
CHD during childhood was 97.9%. The highest childhood However, the mortality rate of patients with CHD is still
higher than that of the general population (2, 3). Mortality
in patients with CHD during childhood is the highest during
infancy and decreases progressively thereafter (4, 5). In
Correspondence to: Jun Eun Park, MD, Ph.D., Department of particular, CHD of greater severity correlated with a higher
Pediatrics, Anam Hospital, Korea University School of Medicine, probability of death during infancy, and neonatal conditions,
74, Koryeodae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea. such as prematurity and low birth weights, affect mortality
Tel: +82 29205090, Fax: +82 29227476, e-mail: and morbidity of patients with CHD (4, 6-8).
[email protected]; O Kyu Noh, MD, Ph.D., Department of
However, a disparity exists in the survival and prognosis
Radiation Oncology, Ajou University School of Medicine, 164
Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea. Tel:
of CHD patients depending on the country and medical
+82 312195884, Fax: +82 312195894, e-mail: [email protected] system (1, 9). Studies on the survival of patients with CHD
are mostly concentrated on data from well-developed
Key Words: Congenital heart disease, infant, survival, risk factors. countries in the West, and there are few reports from non-
Western countries, including Korea. The Republic of Korea
has a well-developed health insurance system where almost
This article is an open access article distributed under the terms and
conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 all citizens benefit from the national health insurance, and
international license (https://creativecommons.org/licenses/by-nc-nd/4.0). the survival rate of patients with CHD has improved rapidly

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 in vivo 38: 1984-1992 (2024)

Table I. ICD-10 codes of the included variables.

Hierarchical classification

Lesion 1 Common arterial trunk Q20.0

(Conotruncal) Aortopulmonary septum defect Q21.4
Double outlet right ventricle Q20.1
Double outlet left ventricle Q20.2
Transposition of great arteries Q20.3
Congenitally corrected transposition Q20.5
Tetralogy of fallot Q21.3
Lesion 2 Endocardial cushion defect Q21.2
(Severe Single ventricle Q20.4
non-conotruncal) Hypoplastic left heart syndrome Q23.4
Lesion 3 Coarctation of the aorta Q25.1
Lesion 4 Ventricular septal defect Q21.0
Lesion 5 Atrial septal defect Q21.1
Lesion 6 All other congenital heart disease diagnoses
that are not included in the above
five lesion groups
Figure 1. Study flow chart.

over recent decades (1, 10). In a study of patients with CHD studies (2, 3, 5, 11). Lesion 1, a conotruncal lesion, included the
of all ages, the mortality rate was 451.0 per 100,000 person- common arterial trunk, aortopulmonary septum defect, double outlet
years in Korea (10). However, no Asian study has reported right ventricle, double outlet left ventricle, transposition of the great
arteries, congenitally corrected transposition, and tetralogy of Fallot.
whether the prognosis for infants born with CHD to survive
Lesion 2, a severe non-conotruncal lesion, included an endocardial
into adulthood differs depending on CHD severity or cushion defect, a single ventricle, and hypoplastic left heart
neonatal conditions other than CHD. syndrome. Lesion 3 refers to the coarctation of the aorta, Lesion 4
Therefore, this study aimed to analyze the survival of a ventricular septal defect, lesion 5 an atrial septal defect, and
infants with CHD until the age of 18 years using large-scale Lesion 6 included all other congenital heart anomalies not included
population data in Korea and investigate the effect of in lesions 1-5. We considered Lesions 1 and 2 as complex lesions.
neonatal conditions at birth.
Neonatal risk factors. We used twins, preterm birth (<28 weeks, 28-
37 weeks), birth asphyxia, small for gestation age (SGA), large for
Patients and Methods gestational age (LGA), low birth weight (<2,500 g), respiratory
distress, pulmonary hemorrhage, bronchopulmonary dysplasia (BPD),
Study population. This study was conducted retrospectively by bacterial sepsis, intracranial hemorrhage, disseminated intravascular
extracting the Korean National Health Insurance Service (NHIS) coagulation, necrotizing enterocolitis, seizure, and pulmonary
claims data from January 2002 to December 2020. The Korean hypertension as variables based on the ICD-10 code for neonatal
NHIS serves almost all the citizens of the Republic of Korea, with condition. Moreover, we also analyzed differences based on birth year
approximately 50 million registered citizens. The Korean NHIS divided as 2002-2005, 2006-2010, 2011-2015, and 2016-2020.
includes diagnostic codes according to the International
Classification of Disease, Tenth Revision (ICD-10); demographic Statistical analysis. The continuous variables are summarized as
characteristics; and information on prescriptions, tests, and surgeries means±standard deviations or as medians and interquartile ranges,
performed during outpatient visits or hospitalizations. Among all while the categorical variables are presented as frequencies and
individuals diagnosed with CHD based on the ICD-10 codes, we proportions. For continuous variables, either the Student’s t-test or
included only those diagnosed with CHD at less than one year of Mann-Whitney U-test was applied, and for categorical variables, either
age. The follow-up duration was from the date they were first the chi-squared test or Fisher’s exact test was used. Survival rates were
diagnosed with CHD to the date they died or were censored before calculated using the Kaplan-Meier method and the Cox proportional
the age of 18 years. The flowchart of this study is presented in hazards regression model was used for univariate and multivariate
Figure 1. This study was approved by the Institutional Review analyses. Variables with p-values of less than 0.10 in univariate
Board of Korea University Anam Hospital (approval no. analysis were included in the multivariate analysis. All analyses were
2021AN0418). The requirement for informed consent was waived performed using R statistical software (www.R-project.org).
because of the retrospective study design.

Definition. CHD classification. CHD was diagnosed by assigning Results

the corresponding ICD-10 codes (Table I). We classified infants
diagnosed with CHD at less than 1 year of age according to the Between 2002 and 2020, 127,958 infants were diagnosed
modified hierarchical classification that had been used in previous with CHD. Among them, 2,275 died before the age of 18

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 Lee et al: Survival for Congenital Heart Disease Infants

Table II. Baseline characteristics.

Survival Death p-Value Survival Death p-Value

(n=125,683) (n=2,275) (n=125,683) (n=2,275)

Sex 0.020 Respiratory distress 0.003

Male 61,615 (49.0) 1,172 (51.5) Yes 11,326 (9.0) 164 (7.2)
Female 64,068 (51.0) 1,103 (48.5) No 114.357 (91.0) 2,111 (92.8)
CHD lesion <0.001 Pulmonary <0.001
Complex (Lesions 1-2) 6,625 (5.3) 987 (43.4) hemorrhage
Lesion 1 4,921 (3.9) 568 (25.0) Yes 17 (0.0) 3 (0.1)
Lesion 2 1,704 (1.4) 419 (18.4) No 125,666 (100.0) 2,272 (99.9)
Non-complex 119,058 (94.7) 1,288 (56.6) Bronchopulmonary 0.002
(Lesions 3-6) dysplasia
Lesion 3 1,452 (1.2) 115 (5.1) Yes 578 (0.5) 21 (0.9)
Lesion 4 32,862 (26.1) 325 (14.3) No 125,105 (99.5) 2,254 (99.1)
Lesion 5 63,692 (50.7) 325 (14.3) Bacterial sepsis 0.974
Lesion 6 21,053 (16.8) 618 (27.2) Yes 2,060 (1.6) 38 (1.7)
Cardiac surgery <0.001 No 123,623 (98.4) 2,237 (98.3)
Yes 30,331 (24.1) 2,049 (90.1) Intracranial 0.608
No 95,352 (75.9) 226 (9.9) nontraumatic
Twin 0.039 hemorrhage
Yes 1,913 (1.5) 22 (1.0) Yes 379 (0.3) 5 (0.2)
No 123,770 (98.5) 2,253 (99.0) No 125,304 (99.7) 2,270 (98.3)
Preterm (<28 wk) 0.503 Disseminated 1.000
Yes 570 (0.5) 13 (0.6) intravascular
No 125,113 (99.5) 2,262 (99.4) coagulation
Preterm (28-37 wk) <0.001 Yes 22 (0.0) 0 (0.0)
Yes 11,204 (8.9) 108 (4.7) No 125,661 (100.0) 2,275 (100.0)
No 114,479 (91.1) 2,167 (95.3) Necrotizing 0.320
Birth asphyxia 0.063 enterocolitis
Yes 407 (0.3) 13 (0.6) Yes 113 (0.1) 4 (0.2)
No 114,479 (91.1) 2,167 (95.3) No 125,570 (99.9) 2,271 (99.8)
Small for 0.152 Convulsions 0.110
gestational age Yes 353 (0.3) 11 (0.5)
Yes 658 (0.5) 18 (0.8) No 125,330 (99.7) 2,264 (99.5)
No 124,998 (99.5) 2,257 (99.2) Pulmonary <0.001
Large for 0.235 hypertension
gestational age Yes 318 (0.3) 40 (1.8)
Yes 289 (0.2) 2 (0.1) No 125,365 (99.7) 2,235 (98.2)
No 125,394 (99.8) 2,273 (99.9) Diagnosis year <0.001
Low birth weight 0.037 2002-2005 8,603 (6.8) 396 (17.4)
(<2,500 g) 2006-2010 24,367 (19.4) 741 (32.6)
Yes 5,160 (4.1) 73 (3.2) 2011-2015 39,775 (31.6) 704 (30.9)
No 120,523 (95.9) 2,202 (96.8) 2016-2020 52,938 (42.1) 434 (19.1)

CHD: Congenital heart disease.

years (Table II). In brief, 568 (25.0%) deaths occurred in the mortality groups. Moreover, based on the year of diagnosis,
Lesion 1 group, which was the highest number of deaths, the order of the highest number of deaths was 2006-2010,
followed by 419 (18.4%) in the Lesion 2 group, which was 2011-2015, 2015-2020, and 2002-2005.
the second highest number of deaths. The next highest
number of deaths occurred in the Lesion 6, 4-5, and 3 Characteristics according to CHD lesions. The differences
groups, in that order. The proportion of infants who had according to CHD lesions are presented in Table III. Lesion 5
undergone cardiac surgery was significantly higher in the was present in the highest number of patients, followed by
mortality group than in the survival group (90.1% vs. 24.1%, Lesions 4, 1, 6, 2, and 3. The highest proportion of patients who
p<0.001). Among the neonatal conditions, twins, preterm had undergone cardiac surgery was in Lesion 1, followed by
birth (28-37 weeks), low birth weight, respiratory distress, Lesion 3 and 2 groups. The highest proportion of deaths was
pulmonary hemorrhage, BPD, and pulmonary hypertension observed in the Lesion 2 group (19.7%), followed by Lesion 1
showed significant differences between the survival and (10.3%), 3 (7.3%), 6 (2.9%), 4 (1.0%), and 6 (0.4%) groups.

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 in vivo 38: 1984-1992 (2024)

Table III. Clinical characteristics according to the complexity of congenital heart disease.

Lesion 1 2 3 4 5 6 p-Value
(N=5,489) (N=2,123) (N=1,567) (N=33,186) (N=63,922) (N=21,671)

Sex <0.001
Male 3,233 (58.9) 1,046 (49.3) 899 (57.4) 15,507 (46.7) 31,540 (49.3) 10,562 (48.7)
Female 2,256 (41.1) 1,077 (50.7) 668 (42.6) 17,679 (53.3) 32,382 (50.7) 11,109 (51.3)
Cardiac surgery <0.001
Yes 5,115 (93.2) 1,692 (79.7) 1,282 (81.8) 9,814 (29.6) 7,768 (12.2) 6,709 (31.0)
No 374 (6.8) 431 (20.3) 285 (18.2) 23372 (70.4) 56154 (87.8) 14962 (69.0)
Twin <0.001
Yes 37 (0.7) 13 (0.6) 17 (1.1) 407 (1.2) 1,163 (1.8) 298 (1.4)
No 5,452 (99.3) 2,110 (99.4) 1,550 (98.9) 32,779 (98.8) 62,759 (98.2) 21,373 (98.6)
Preterm (<28 wk) <0.001
Yes 5 (0.1) 1 (0.0) 0 (0.0) 22 (0.1) 302 (0.5) 253 (1.2)
No 5,484 (99.9) 2,122 (100.0) 1,567 (100.0) 33,164 (99.9) 63,620 (99.5) 21,418 (98.8)
Preterm (28-37 wk) <0.001
Yes 168 (3.1) 76 (3.6) 80 (5.1) 1,176 (3.5) 7,745 (12.1) 2,067 (9.5)
No 5,321 (96.9) 2,047 (96.4) 1,487 (94.9) 32,010 (96.5) 56,177 (87.9) 19,604 (90.5)
Birth asphyxia <0.001
Yes 8 (0.1) 6 (0.3) 3 (0.2) 41 (0.1) 281 (0.4) 81 (0.4)
No 5,481 (99.9) 2,117 (99.7) 1,564 (99.8) 33,145 (99.9) 63,641 (99.6) 21,590 (99.6)
Small for gestational age <0.001
Yes 13 (0.2) 11 (0.5) 15 (1.0) 103 (0.3) 484 (0.8) 77 (0.4)
No 5,476 (99.8) 2,112 (99.5) 1,552 (99.0) 33,083 (99.7) 63,438 (99.2) 21,594 (99.6)
Large for gestational age <0.001
Yes 3 (0.1) 4 (0.2) 0 (0.0) 32 (0.1) 182 (0.3) 70 (0.3)
No 5,486 (99.9) 2,119 (99.8) 1,567 (100.0) 33,154 (99.9) 63,740 (99.7) 21,601 (99.7)
Low birth weight (<2,500 g) <0.001
Yes 112 (2.0) 31 (1.5) 57 (3.6) 616 (1.9) 3,302 (5.2) 1,115 (5.1)
No 5,377 (98.0) 2,092 (98.5) 1,510 (96.4) 32,570 (98.1) 60,620 (94.8) 20,556 (94.9)
Respiratory distress <0.001
Yes 144 (2.6) 68 (3.2) 85 (5.4) 1,189 (3.6) 7,399 (11.6) 2,605 (12.0)
No 53,45 (97.4) 2,055 (96.8) 1,482 (94.6) 31,997 (96.4) 56,523 (88.4) 19,066 (88.0)
Pulmonary hemorrhage 0.074
Yes 1 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 12 (0.0) 7 (0.0)
No 5,488 (100.0) 2,123 (100.0) 1,567 (100.0) 33,186 (100.0) 63,910 (100.0) 21,664 (100.0)
Bronchopulmonary dysplasia <0.001
Yes 11 (0.2) 2 (0.1) 6 (0.4) 37 (0.1) 297 (0.5) 246 (1.1)
No 5,478 (99.8) 2,121 (99.9) 1,561 (99.6) 33,149 (99.9) 63,625 (99.5) 21,425 (98.9)
Bacterial sepsis <0.001
Yes 57 (1.0) 45 (2.1) 28 (1.8) 446 (1.3) 1,233 (1.9) 289 (1.3)
No 5,432 (99.0) 2,078 (97.9) 1,539 (98.2) 32,740 (98.7) 62,689 (98.1) 21,382 (98.7)

Table III. Continued

Survival and risk factors for mortality during childhood for (28-37 weeks), and respiratory distress decreased the likelihood
infants with CHD. The survival rate during childhood for of mortality in infants with congenital heart disease.
infants with CHD was 97.9% (Figure 2). There was a sharp Additionally, the risk of mortality decreased with more recent
decline in the survival rates during the first year of life, diagnoses. Multivariable analysis revealed that complex CHD
followed by a gradual decline thereafter. The survival rates was the most powerful risk factor for childhood mortality,
according to each characteristic of patients with CHD are followed by pulmonary hypertension. Other risk factors for
presented in Figure 3, and the hazard ratios (HRs) for various mortality in infants with CHD were birth asphyxia, SGA,
factors related to childhood mortality in infants with CHD are respiratory distress, pulmonary hemorrhage, BPD, and
shown in Table IV. Univariable analysis revealed that male sex, convulsions. Preterm birth (28-37 weeks) was significantly
birth asphyxia, pulmonary hemorrhage, BPD, pulmonary associated with a decreased risk of mortality in multivariate
hypertension, and complex CHD (Lesions 1-2) increased the analysis. Moreover, the risk of mortality decreased significantly
likelihood of mortality. However, twin pregnancy, preterm birth with more recent diagnoses, even in multivariate analysis.

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 Lee et al: Survival for Congenital Heart Disease Infants

Table III. Continued

Lesion 1 2 3 4 5 6 p-Value
(N=5,489) (N=2,123) (N=1,567) (N=33,186) (N=63,922) (N=21,671)

Intracranial nontraumatic <0.001

hemorrhage
Yes 5 (0.1) 0 (0.0) 3 (0.2) 25 (0.1) 275 (0.4) 76 (0.4)
No 5,484 (99.9) 2,123 (100.0) 1,564 (99.8) 33,161 (99.9) 63,647 (99.6) 21,595 (99.6)
Disseminated intravascular 0.655
coagulation
Yes 1 (0.0) 0 (0.0) 1 (0.1) 4 (0.0) 11 (0.0) 5 (0.0)
No 5,488 (100.0) 2,123 (100.0) 1,566 (99.9) 33,182 (100.0) 63,911 (100.0) 21,666 (100.0)
Necrotizing enterocolitis 0.008
Yes 8 (0.1) 3 (0.1) 1 (0.1) 14 (0.0) 62 (0.1) 29 (0.1)
No 5,481 (99.9) 2,120 (99.9) 1,566 (99.9) 33,172 (100.0) 63,860 (99.9) 21,642 (99.9)
Convulsions <0.001
Yes 5 (0.1) 3 (0.1) 5 (0.3) 53 (0.2) 230 (0.4) 68 (0.3)
No 5,484 (99.9) 2,120 (99.9) 1,562 (99.7) 33,133 (99.8) 63,692 (99.6) 21,603 (99.7)
Pulmonary hypertension <0.001
Yes 15 (0.3) 18 (0.8) 16 (1.0) 130 (0.4) 95 (0.1) 84 (0.4)
No 5,474 (99.7) 2,105 (99.2) 1,551 (99.0) 33,056 (99.6) 63,827 (99.9) 21,587 (99.6)
Death <0.001
Yes 568 (10.3) 419 (19.7) 115 (7.3) 325 (1.0) 230 (0.4) 618 (2.9)
No 4,921 (89.7) 1,704 (80.3) 1,452 (92.7) 32,861 (99.0) 63,692 (99.6) 21,053 (97.1)
Diagnosis year <0.001
2002-2005 804 (14.6) 350 (16.5) 157 (10.0) 4,057 (12.2) 2,217 (3.5) 1,414 (6.5)
2006-2010 1,492 (27.2) 750 (35.3) 398 (25.4) 8,665 (26.1) 9,180 (14.4) 4,623 (21.3)
2011-2015 1,672 (30.5) 636 (30.0) 532 (34.0) 10,511 (31.7) 20,113 (31.5) 7,015 (32.4)
2016-2020 1,521 (27.7) 387 (18.2) 480 (30.6) 9,953 (30.0) 32,412 (50.7) 8,619 (39.8)

Figure 2. Survival rates of infants with congenital heart disease (CHD) during childhood.

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Figure 3. Cumulative incidence of childhood mortality according to neonatal conditions.

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 Lee et al: Survival for Congenital Heart Disease Infants

Table IV. Univariate and multivariate analyses for mortality.

Univariate Multivariate

Variable HR 95%CI p-Value HR 95%CI p-Value

Female 0.905 (0.833-0.982) 0.017 1.017 (0.936-1.104) 0.686

Twin 0.656 (0.431-0.998) 0.049 1.019 (0.669-1.553) 0.928
Preterm (<28 wk) 1.285 (0.745-2.216) 0.367
Preterm (28-37 wk) 0.524 (0.432-0.636) <0.001 0.732 (0.601-0.893) 0.002
Birth asphyxia 1.753 (1.016-3.025) 0.043 1.944 (1.123-3.365) 0.017
Small for gestational age 1.507 (0.947-2.397) 0.083 2.137 (1.342-3.404) 0.001
Large for gestational age 0.390 (0.097-1.563) 0.184
Low birth weight (<2,500 g) 0.798 (0.632-1.007) 0.058 1.111 (0.874-1.411) 0.388
Respiratory distress 0.814 (0.695-0.955) 0.012 1.256 (1.063-1.484) 0.007
Pulmonary hemorrhage 9.285 (2.992-28.813) <0.001 3.839 (1.204-12.245) 0.023
Bronchopulmonary dysplasia 1.972 (1.283-3.030) 0.002 2.175 (1.390-3.403) 0.001
Bacterial sepsis 0.998 (0.724-1.375) 0.991
Intracranial nontraumatic hemorrhage 0.754 (0.313-1.815) 0.530
Disseminated intravascular coagulation 1.67×10–5 0.977
Necrotizing enterocolitis 1.928 (0.723-5.142) 0.189
Convulsions 1.740 (0.962-3.147) 0.067 2.470 (1.362-4.481) 0.003
Pulmonary hypertension 6.297 (4.606-8.609) <0.001 4.184 (3.034-5.769) <0.001
Complex CHD 12.448 (11.457-13.526) <0.001 10.736 (9.849-11.703) <0.001
Diagnosis year
2002-2005 Ref.
2006-2010 0.683 (0.605-0.773) 0.805 (0.711-0.910) 0.001
2011-2015 0.418 (0.369-0.474) 0.589 (0.519-0.669) <0.001
2016-2020 0.215 (0.187-0.247) 0.348 (0.302-0.401) <0.001

HR: Hazard ratio; CI: confidence interval; CHD: congenital heart disease.

Discussion highest. In our study, the highest mortality rate was observed
during the first year of life, and the mortality rates for each
In this study, using Korean NHIS claims data, out of 127,958 variable showed a sharp decline before the age of 5 years.
infants diagnosed with CHD, 2,275 died before 18 years of The mortality rate of young children with CHD under 5
age. The survival rate for infants with CHD in South Korea years of age is still steep, emphasizing the importance of
was 97.9%. The survival rate declined sharply during the early intervention and management for infants born with
first year of life, followed by a gradual and stable decline CHD to improve their future survival rates.
thereafter. The highest childhood mortality rate was observed Although the survival rate of CHD patients has improved
in Lesion 2 group (non-conotruncal defect) at 19.7%, dramatically, the mortality rate in patients with CHD remains
followed by Lesion 1 group (conotruncal defect) at 10.2%. significantly higher than that of the general population. The
The mortality rates for Lesion 3 (coarctation of the aorta), 6 mortality risk is reported to be 17.7 times higher
(all other lesions), 4 (ventricular septal defect), and 5 (atrial (95%CI=16.8-18.6) than that of the general population,
septal defect) groups were 7.3%, 2.9%, 1.0%, and 0.4%, indicating a significant difference in survival rates between
respectively. According to multivariable analysis, the children with CHD and the general population (2, 4).
significant risk factors for childhood mortality in infants with According to a study in Sweden, the mortality rate of children
CHD were complex CHD, pulmonary hypertension, birth with non-conotruncal CHD lesions was associated with the
asphyxia, SGA, respiratory distress, pulmonary hemorrhage, highest hazard ratio (HR=97.2, 95%CI=80.4-117.4) compared
BPD, and convulsions. Additionally, the mortality rate during to that of the general population. Conversely, another study in
childhood significantly decreased in more recent birth years. Sweden focused on adults with CHD found that those with
The survival rate for children with CHD has significantly conotruncal defects had the highest mortality rate (HR=10.13,
improved compared to the past, particularly in those less 95%CI=8.78-11.69) compared to that of the general
than one year old (4, 5). Consequently, the mortality rate of population (2, 3). Another study in the United States reported
relatively older children (>5 years old) is reportedly higher that the mortality for single-ventricle physiology among CHDs
than that in the past (4). However, the mortality rate, was the highest across all age groups of children. Specifically,
especially in children aged four or younger, remains the the mortality rates in infants with single-ventricle defects had

1990
 in vivo 38: 1984-1992 (2024)

significantly decreased, but those in older children and of heart anomalies in full-term infants was higher than that in
adolescents had actually increased compared to those in premature infants with coincidentally detected heart anomalies,
previous years (4). The authors suggested several potential suggesting that the impact of the anomaly on survival was
reasons for the observed increase, including the early timing more significant in full-term infants than in premature infants.
of Fontan surgery, development of failing Fontan physiology, We investigated neonatal risk factors for childhood
and difficulties in accessing healthcare due to insurance issues. mortality in infants with CHD. Complex CHD and
The risk factors for mortality in children with CHD pulmonary hypertension were the most significant risk
purportedly include low birth weight, male sex, prematurity, factors of mortality in infants with CHD, and the presence
extracardiac defects, and genetic anomalies (4, 7). of other neonatal morbidities also contributed to a
To our knowledge, this study is the first large-scale significantly higher risk of childhood mortality. This study
investigation of survival and neonatal risk factors in infants suggests the possibility of a more detailed and precise risk
with CHD in an Asian country with a developed health stratification for infants with CHD based on certain
insurance system. In this study, as in previous Western studies, characteristics in the neonatal period, which may lead to
the highest infant mortality rate was associated with non- higher childhood mortality. Through sophisticated and
conotruncal defects, and complex CHD, including Lesions 1 individualized risk assessments for these neonatal risk factors
(conotruncal) and 2 (non-conotruncal), was the most important and the development of optimal treatment strategies, we may
risk factor for mortality in infants with CHD during childhood improve the survival of infants born with CHD in the future.
(HR=10.736, 95%CI=9.849-11.703). The second most
significant risk factor was pulmonary hypertension. The Study limitations. First, this was a retrospective observational
annual incidence of pulmonary arterial hypertension associated study, which entails a potential for information bias. Second, it
with CHD in children is reportedly 2.2 per million, which is was based on the Korean NHIS, which has the advantage of
higher than the prevalence in adult patients with CHD (12). being a large-scale dataset covering almost all Korean citizens
Pulmonary hypertension in pediatric patients with CHD is but may lack detailed information on some factors. Additionally,
further complicated by the complexity of CHD, prematurity, the NHIS data do not provide information on patients’ lifestyle
underlying lung diseases, such as BPD, chromosomal habits, such as dietary patterns and physical activity. Third, the
anomalies, and other comorbidities, making treatment more mortality of infants with CHD may be influenced not only by
challenging (13). Sildenafil and bosentan are reportedly infantile diseases, but also by new diseases during childhood.
helpful in improving symptoms of pulmonary hypertension in However, in this study, we did not consider concurrent diseases
Fontan patients (14, 15). While small-scale reports have after infancy. Several childhood diseases not included in this
suggested the effectiveness of riociguat and selexipag for study might have affected the mortality rate of infants with
pediatric pulmonary arterial hypertension, data on pediatric CHD. Finally, we classified CHD hierarchically; however, CHD
patients with CHD is lacking (16-20). Future assessment of is a heterogeneous disease, and the disease severity can vary
the efficacy and clinical use of these pulmonary hypertension greatly, even within each lesion. However, this aspect could not
medications in pediatric patients with CHD, as well as be assessed using the NHIS data.
individualized evaluation and appropriate treatment strategies
in patients with CHD, may contribute to improving the Conclusion
survival rates in pediatric patients with CHD. Moreover, the
mortality rate was higher in cases with other underlying The survival of infants with CHD has been favorable in South
conditions during the neonatal period, such as birth asphyxia, Korea, with a survival rate of over 97% over the past 20 years.
SGA, respiratory distress, pulmonary hemorrhage, BPD, and Complex CHD and pulmonary hypertension are the most
convulsions. Therefore, individualized and optimal evaluation significant risk factors for mortality in infants with CHD, and
and treatment strategies may be necessary for children with several other neonatal conditions are also significant risk
CHD and other comorbidities in the future. factors. Individualized risk assessment that considers these
Contrary to our initial expectations, premature infants born factors and optimal treatment strategies may contribute to
between 28-37 weeks had a lower likelihood of mortality. improving the survival rates of children with CHD.
While causal relationships could not be confirmed in this
observational study, premature infants may have a higher Funding
incidence of mild CHD incidentally detected during routine
This study was supported by a grant from the Korea University
echocardiography screenings performed during admission to (K2023101).
the neonatal intensive care unit, who may not require treatment.
We attempted to adjust for CHD severity by classifying Conflicts of Interest
Lesions 1-2 as complex CHD using multivariable analysis.
However, even within non-complex Lesions 2-6, the severity The Authors declare no conflicts of interest in relation to this study.

1991
 Lee et al: Survival for Congenital Heart Disease Infants

Authors’ Contributions Perinatal Surveillance System (Public Health Agency of

Canada): Effect of folic acid food fortification in Canada on
Conceptualization, J.S.L., O.K.N and J.E.P.; Methodology, O.K.N.; congenital heart disease subtypes. Circulation 134(9): 647-655,
Software, J.S.L. and O.K.N.; Validation, H.C, J.S.H., K.S.H. and 2016. DOI: 10.1161/CIRCULATIONAHA.116.022126
G.Y.J.; Formal Analysis, O.K.N.; Investigation, J.S.L., J.K. and 12 van Loon RL, Roofthooft MT, Hillege HL, ten Harkel AD, van
O.K.N.; Resources, J.E.P.; Data Curation, J.S.L. and O.K.N.; Osch-Gevers M, Delhaas T, Kapusta L, Strengers JL, Rammeloo
Writing – Original Draft Preparation, J.S.L. and O.K.N.; Writing – L, Clur SA, Mulder BJ, Berger RM: Pediatric pulmonary
Review & Editing, J.E.P.; Visualization, J.S.L., O.K.N and J.E.P.; hypertension in the Netherlands. Circulation 124(16): 1755-
Supervision, O.K.N and J.E.P.; Project Administration, J.S.L., 1764, 2011. DOI: 10.1161/CIRCULATIONAHA.110.969584
O.K.N and J.E.P.; Funding Acquisition, J.E.P. 13 Kozlik-Feldmann R, Hansmann G, Bonnet D, Schranz D, Apitz
C, Michel-Behnke I: Pulmonary hypertension in children with
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M, Evans J, Lim K, Little J, Sauve R, Kramer MS, Canadian Accepted March 12, 2024

1992