Front. Cardiovasc. Med. Frontiers in Cardiovascular Medicine Front. Cardiovasc. Med. 2297-055X Frontiers Media S.A. 10.3389/fcvm.2023.1293210 Cardiovascular Medicine Original Research Noncardiac anomalies in children with congenital heart disease HuangXianghui 1 2 † GaoYuan 1 3 † ChenWeicheng 1 3 * ShengWei 1 3 4 * HuangGuoying 1 3 4 * Cardiovascular Center, Children’s Hospital of Fudan University, Shanghai, China Fujian Key Laboratory of Neonatal Diseases, Xiamen Children’s Hospital, Fujian, China Shanghai Key Laboratory of Birth Defects, Shanghai, China Unit of Early Intervention of Genetically Related Childhood Cardiovascular Diseases, Shanghai, China

Edited by: Liqun Sun, University of Toronto, Canada

Reviewed by: Mingfu Wu, University of Houston, United States Zhang Cheng, Chongqing Medical University, China Kui Hu, Guizhou Provincial People’s Hospital, China

 Correspondence: Weicheng Chen weicheng.chern@gmail.com Wei Sheng sheng_wei@fudan.edu.cn Guoying Huang gyhuang@shmu.edu.cn

These authors have contributed equally to this work and share first authorship

 20112023 2023 101293210 12092023 27102023 © 2023 Huang, Gao, Chen, Sheng and Huang. 2023Huang, Gao, Chen, Sheng and Huang

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

 Introduction

Noncardiac anomalies (NCAs) in patients with congenital heart defects (CHDs) are crucial for perioperative management and etiology studies. This study aimed to investigate NCAs in Chinese children with CHDs.

Methods

Medical records for CHD-diagnosed children hospitalized from 1 January 2015 to 31 December 2019 were collected and subjected to retrospective analyses to excavate potential association rules between CHDs and noncardiac malformations.

Results

A total of 3,788 CHD patients were included in this study. The main phenotypes of CHD were Ventricular Septal Defect (VSD, 33.69%), Atrial Septal Defect (ASD, 12.72%), and Tetralogy of Fallot (TOF, 5.54%). A total of 887 (23.42%) cases showed noncardiac anomalies, which were mainly associated with the central nervous system (34.61%), nose/ear/mandibular/face (19.39%), genitourinary system (15.78%), and musculoskeletal system (15.56%). Compared to other CHD subtypes, septal defects had a lower percentage of associated NCAs (P = 3.7 × 10−9) while AVSD had a higher percentage (P = 0.0018).

Disscussion

NCAs are prevalent among CHD-diagnosed children in China, and the spectrums of NCAs in different CHD subcategories were different.

 congenital heart defects noncardiac anomalies Chinese children retrospective analyses phenotype 2021YFC2701000, 2016YFC100050082270321, 81873482, 8187348320JC14183002019-I2M-5-002National Key Research and Development Program of ChinaNational Natural Science Foundation of ChinaShanghai Natural Science Foundation of Science and Technology Innovation Action PlanCAMS Innovation Fund for Medical Sciences section-at-acceptancePediatric Cardiology Introduction

Congenital heart defects (CHDs) are a leading cause of infant mortality and the most commonly diagnosed major congenital anomaly worldwide (1, 2) with a prevalence of 8.98 per 1,000 live births in China (3). Although diagnostic capabilities and surgical strategies have significantly advanced, CHD remains a costly and onerous disease burden in many countries (4, 5). CHDs manifest as diverse structural abnormalities of the heart and great vessels that arise during embryonic development. The complexity of structural anomalies, defect severity, and the presence of comorbidities are essential determinants of CHD outcomes (6).

It is important to identify whether a CHD presents as an isolated condition or has developed in combination with noncardiac anomalies, as is frequently the case. Multiple organs originate from a common germ layer and can be regulated by shared signaling pathways (7). Moreover, chromosomal aberrations, which represent a leading cause of CHDs, alter the activities of multiple genes that may have different functions in embryogenesis. CHD comorbidities affecting other systems have a significant impact on clinical course. Despite advances in cardiac surgery and perioperative management, Eskedal et al. (8) reported that survival has not improved for CHD-diagnosed children with extracardiac anomalies. A 15-year follow-up study showed that noncardiac anomalies (NCAs) had a more significant effect on mortality in patients with CHDs than potential heart disease (9). Indeed, some have recommended that prediction modeling of thoracic surgery mortality risk for CHD patients could be augmented by adding a covariate that represents noncardiac congenital anatomic abnormalities (10). NCAs can increase the risk of postoperative complications, such as respiratory complications with heterotaxy (11), and children with CHD undergoing noncardiac surgery can have an increased mortality risk (12). Consequently, to identify optimal perioperative and long-term management of patients with CHDs and to elucidate the etiology of congenital defects, a detailed description of coexisting NCAs in children with CHD is necessary.

Reported frequencies of NCAs in CHD-diagnosed patients range widely from 4.53% to 50% (13–15). Different types of CHD are associated with distinct incidences of extracardiac comorbidities. For example, the NCA risk has been reported to be elevated among CHD patients with a cardiac looping defect, conotunal defect (CTD), or atrial septal defect (ASD) and reduced among CHD patients with a ventricular septal defect (VSD) or Ebstein anomaly (16, 17). Moreover, specific associations have been identified between common truncus and limb reduction defects and between great vessel-transposition and situs inversus (18). Piran found a trend toward a higher prevalence of major congenital extracardiac anomalies involving the musculoskeletal and genitourinary systems in adults with tetralogy of Fallot (TOF) (19). Thus far, there are limited data in the literature regarding the occurrence of NCAs in CHD-diagnosed children in China, and this study aimed to describe the proportions and distributions of NCAs in Chinese children of Han ethnicity who have been diagnosed with a CHD.

 Materials and methods Study population

Children diagnosed with a CHD and hospitalized in the Department of Cardiac Surgery, Children's Hospital of Fudan University from 1 January 2015 to 31 December 2019 were eligible for inclusion. Data collection and analysis processes were conducted with the permission of and under the guidance of the ethics committee. Written informed consent to participate was obtained from the guardians. Medical histories, surgical records, imaging data, outpatient medical records, and genetic test results of enrolled patients were collected and examined retrospectively. CHD diagnoses were confirmed by clinical assessment, echocardiography, cardiac catheterization, and, if necessary, surgical observations. Patent foramen ovale, patent ductus arteriosus (PDA) in premature infants, and a PDA that resolved within 3 months after birth were excluded. The analyses did not include patients with cardiomyopathies, cardiac arrhythmias, or primary pulmonary hypertension.

 Phenotype classification

Individual patients' CHDs were classified based on anatomy and etiology (20–23) into the level 1 and 2 categories (Table 1), where the latter are subcategories of the former. Level 1 categories included the following: septal defects, atrioventricular canal defect (AVSD), conotruncal cardiac defect (CTD), left ventricular outflow tract obstruction (LVOTO), right ventricular outflow tract obstruction (RVOTO), abnormal cell growth, heterotaxy (HTX), others, and associations.

Distribution of CHD subtypes and corresponding number of NCAs.

CHD phenotypesa n (%)b Sex ratio (M/F) Number of noncardiac malformation, n (%)c
0 1 2 ≥3
Septal defect 2,155 (56.89) 1.11 1,727 (80.14) 277 (12.85) 115 (5.34) 36 (1.67)
VSD 1,276 (33.69) 1.34 1,056 (82.76) 146 (11.44) 54 (4.23) 20 (1.57)
ASD 482 (12.72) 0.88 361 (74.90) 76 (15.77) 37 (7.68) 8 (1.66)
VSD + ASD 397 (10.48) 0.83 310 (78.09) 55 (13.85) 24 (6.05) 8 (2.02)
AVSD 124 (3.27) 0.8 80 (64.52) 22 (17.74) 17 (13.71) 5 (4.03)
AVSD 108 (2.85) 0.83 70 (64.81) 18 (16.67) 17 (15.74) 3 (2.78)
AVSD + OTO 16 (0.42) 0.60 10 (62.50) 4 (25.00) 0 (0.00) 2 (12.50)
CTD 524 (13.83) 1.94 400 (76.34) 80 (15.27) 37 (7.06) 7 (1.34)
PTA 9 (0.24) 0.50 6 (66.67) 2 (22.22) 0 (0.00) 1 (11.11)
DTGA-IVS 48 (1.27) 3.36 43 (89.58) 4 (8.33) 1 (2.08) 0 (0.00)
DTGA-IVS + OTO 11 (0.29) F = 0 5 (45.45) 4 (36.36) 2 (18.18) 0 (0.00)
DTGA + VSD 65 (1.72) 2.61 56 (86.15) 8 (12.31) 1 (1.54) 0 (0.00)
TOF 210 (5.54) 1.76 163 (77.62) 28 (13.33) 14 (6.67) 5 (2.38)
PA-VSD 43 (1.14) 1.05 32 (74.42) 6 (13.95) 5 (11.63) 0 (0.00)
DORV 77 (2.03) 1.85 58 (75.32) 13 (16.88) 6 (7.79) 0 (0.00)
APW 7 (0.18) 1.33 3 (42.86) 2 (28.57) 2 (28.57) 0 (0.00)
IAA 26 (0.69) 1.89 19 (73.08) 5 (19.23) 2 (7.69) 0 (0.00)
Vasc ring malformations 28 (0.74) 3.00 15 (53.57) 8 (28.57) 4 (14.29) 1 (3.57)
LVOTO 66 (1.74) 1.64 46 (69.7) 16 (24.24) 1 (1.52) 3 (4.55)
HLH 3 (0.08) 2.00 2 (66.67) 1 (33.33) 0 (0.00) 0 (0.00)
Valvular/supravalvular aortic stenosis or other malformation of aorta or the aortic valve 63 (1.66) 1.63 44 (69.84) 15 (23.81) 1 (1.59) 3 (4.76)
RVOTO 242 (6.39) 1.00 192 (79.34) 37 (15.29) 11 (4.55) 2 (0.83)
Pulmonary artery/valve atresia or other malformations of pulmonary artery/valve 146 (3.85) 0.85 119 (81.51) 19 (13.01) 6 (4.11) 2 (1.37)
Eebstein 12 (0.32) 2.00 8 (66.67) 3 (25) 1 (8.33) 0 (0.00)
TA-VSD/TA + PA-IVS 6 (0.16) 1.00 3 (50.00) 2 (33.33) 1 (16.67) 0 (0.00)
DCRV 59 (1.56) 1.19 45 (76.27) 12 (20.34) 2 (3.39) 0 (0.00)
HRH 19 (0.50) 1.38 17 (89.47) 1 (5.26) 1 (5.26) 0 (0.00)
Abnormal cell growth 75 (1.98) 1.78 59 (78.67) 11 (14.67) 4 (5.33) 1 (1.33)
APVD 56 (1.48) 2.73 46 (82.14) 6 (10.71) 3 (5.36) 1 (1.79)
Cor triatriatum 19 (0.50) 0.58 13 (68.42) 5 (26.32) 1 (5.26) 0 (0.00)
Others 151 (3.99) 0.61 108 (71.52) 30 (19.87) 10 (6.62) 3 (1.99)
CCTGA 6 (0.16) 2.00 4 (66.67) 2 (33.33) 0 (0.00) 0 (0.00)
SV 7 (0.18) 2.50 6 (85.71) 1 (14.29) 0 (0.00) 0 (0.00)
Isolated malformations of great arteries 3 (0.08) 2.00 1 (33.33) 2 (66.67) 0 (0.00) 0 (0.00)
Isolated malformation of the coronary arteries 15 (0.40) 0.36 12 (80.00) 2 (13.33) 0 (0.00) 1 (6.67)
Isolated malformations of heart valve 38 (1.00) 0.46 28 (73.68) 7 (18.42) 3 (7.89) 0 (0.00)
Isolated PDA 82 (2.16) 0.58 57 (69.51) 16 (19.51) 7 (8.54) 2 (2.44)
HTX 87 (2.30) 1.35 8 (9.2) 62 (71.26) 13 (14.94) 4 (4.6)
HTX + no CVM 5 (0.13) F = 0 4 (80.00) 0 (0.00) 0 (0.00) 1 (20.00)
HTX + simple CVM 37 (0.98) 0.76 2 (5.41) 26 (70.27) 7 (18.92) 2 (5.41)
HTX + complex CVM 45 (1.19) 1.81 2 (4.44) 36 (80.00) 6 (13.33) 1 (2.22)
Associations 364 (9.61) 1.38 281 (77.2) 52 (14.29) 20 (5.49) 11 (3.02)
AVSD + CTD 10 (0.26) 1.00 2 (20.00) 5 (50.00) 1 (10.00) 2 (20.00)
Septal defects + APVD 104 (2.75) 1.48 87 (83.65) 10 (9.62) 6 (5.77) 1 (0.96)
Septal defects + RVOTO 95 (2.51) 1.07 73 (76.84) 14 (14.74) 7 (7.37) 1 (1.05)
Septal defects + LVOTO 123 (3.25) 1.51 95 (77.24) 19 (15.45) 5 (4.07) 4 (3.25)
RVOTO + LVOTO 9 (0.24) 2.00 6 (66.67) 1 (11.11) 1 (11.11) 1 (11.11)
CTD + LVOTO 17 (0.45) 2.40 15 (88.24) 1 (5.88) 0 (0.00) 1 (5.88)
CTD + APVD 6 (0.16) 1.00 3 (50.00) 2 (33.33) 0 (0.00) 1 (16.67)
TOTAL 3,788 (100) 1.20 2,901 (76.58) 587 (15.50) 228 (6.02) 72 (1.90)

VSD, ventricular septal defect; ASD, atrial septa defect; AVSD, atrioventricular septal defect; OTO, outflow tract obstruction, including LVOTO (left ventricular outflow tract obstruction) and RVOTO (right ventricular outflow tract obstruction); CTD: conotruncal defect; PTA, persistent truncus arteriosus; D-TGA, dextro-transposition of the great arteries; IVS, intact ventricular septum; TOF, tetralogy of fallot; PA, pulmonary atresia; DORV, double outlet right ventricle; APW, aortopulmonary window; IAA, interruption of aortic arch, including type A/B/C; vasc ring malformations, including right arch and sling; HLH, hypoplastic left ventricle; TA, tricuspid atresia; DCRV, double-chambered right ventricle; HRH, hypoplastic right ventricle; APVD, anomalous pulmonary venous drainage; CCTGA, congenitally corrected transposition of the great arteries; SV, single ventricle; PDA, patent ductus arteriosus; HTX, heterotaxy or situs inversus totalis; CVM, refer to above structural cardiovascular malformations, and complex CVM refers to more than one above cardiovascular malformations.

CHD level 1 subcategories are represented in bold font centered on the center, and the level 2 subcategories included in each level 1 subcategories are aligned to the left below each other.

Percentage denominator was total N of 3,788.

Percentage denominator was total number of each CHD subcategories.

Diagnosed NCAs were summarized and aggregated according to affected systems. All developmental delays, including growth retardation, intellectual disability, mental delays, learning difficulties, and language/motor deficits, were classified as central nervous system (CNS) anomalies (24). We ignored syndrome diagnoses to focus on phenotypes. Syndrome-associated noncardiac phenotypes were disassociated and classified according to their respective affected systems. Anomalies within the same affected system were counted as one. CHD cases with and without NCAs are referred to as associated CHD cases and isolated CHD cases, respectively.

 Statistical analysis

R (version 4.1.2), R Studio (version 1.4.1717), and SPSS (IBM version 20) were used for statistical analysis. Analysis of description was used to provide the whole picture of CHD and NCAs; Pearson's χ2 test or Fisher's exact test was applied to compare the proportions of isolated CHD between different genders and different CHD subtypes. The apriori principle (25) was used to analyze CHD diagnosis-to-NCA association, setting thresholds for support and confidence at 0.01 and 0.1, respectively. Rules with a lift ≥ 3 were considered of value.

 Results Proportions of congenital heart defects

A total of 3,788 CHD-diagnosed children were identified retrospectively, of which 2,065 (54.51%) were male and 1,723 were female (45.49%) with a median age of 3.96 years (IQR, 2.56–5.39). The proportions of level 1 and level 2 diagnostic classifications are reported in Table 1 with sex ratios and the number of co-occurring anomalies. The most common level 1 diagnoses were septal defect (56.89%), CTD (13.83%), and RVOTO (6.39%); besides different septal defects TOF (5.54%), pulmonary artery/valve atresia or other malformations of the pulmonary artery/valve (3.85%), DORV (2.03%), valvular/supravalvular aortic stenosis or other malformation of the aorta or the aortic valve (1.66%), and dextro-transposition of the great arteries (D-TGA, 1.27%) were common level 2 diagnoses. Furthermore, 3.25% children had both septal defects and LVOTO and 2.75% children had septal defects and RVOTO.

 Noncardiac malformations in children with CHDs

A total of 887 (23.42%) cases of CHD were associated with noncardiac malformations, comprising 587 (15.50%) with one malformation, 228 (6.02%) with two malformations, and 72 (1.90%) with three or more malformations (Table 1).There were 1,284 noncardiac malformations among the 887 children, including 307 (34.61%) in the nervous system, 172 (19.39%) in the nose/ear/mandibular/face, and 140 (15.78%) in the musculoskeletal system (Table 2). The most common discrete NCA phenotype by far was developmental delay (n = 262, 29.54%), inguinal hernia (n = 83, 9.36%), and cryptorchidism and hydrocele (n = 77, 8.68%).

Distribution of NCAs in 887 children with associated CHD.

Noncardiac anomaly i (%)a
Central nervous system anomalies 307 (34.61)
 Archinencephaly 69 (7.78)
 Spina bifida 5 (0.56)
 Hydrocephaly 9 (1.01)
 Development delay, intellectual disability, mental delay, learning difficulties, language and motor deficit 262 (29.54)
Nose, ear, mandibular, and face anomalies 172 (19.39)
Genitourinary system anomalies 140 (15.78)
 Renal or bladder dysplasia and hydronephrosis 20 (2.25)
 Hypospadias and urethral valve 35 (3.95)
 Abnormal genitalia 23 (2.59)
 Cryptorchidism and hydrocele 77 (8.68)
Musculoskeletal anomalies 138 (15.56)
 Polydactyly, syndactyly, and trigger finger 52 (5.86)
 Developmental dysplasia of hip and other malformations of limbs 30 (3.38)
 Spine anomalies 21 (2.37)
 Skull deformity 4 (0.45)
 Chest wall deformity and rib dysplasia 21 (2.37)
 Torticollis and hypotonia 20 (2.25)
Heterotaxy 108 (12.18)
Abdominal wall deformity 98 (11.05)
 Inguinal hernia 83 (9.36)
 Umbilical hernia and omphalocele 15 (1.69)
Digestive system anomalies 56 (6.31)
 Esophageal stricture/atresia and tracheoesopahgeal fistula 9 (1.01)
 Biliary atresia and cholestasis 21 (2.37)
 Hirschsprung's disease, stenosis/atresia of digestive tract, malrotation, and fistula 13 (1.47)
 Annular pancreas and ectopic pancreas 5 (0.56)
 Anal atresia and cloacal malformations 16 (1.80)
Respiratory system anomalies 55 (6.20)
 Upper/lower airway stenosis or dysplasia 46 (5.19)
 Pulmonary sequestration and other lung aplasia 9 (1.01)
Congenital hypothyroidism and other endocrine and metabolic disease 47 (5.30)
Hemangioma and lymphangioma 47 (5.30)
Cleft lip and/or palate 25 (2.82)
Absence of thymus and other immunodeficiency 19 (2.14)
Eye anomalies 19 (2.14)
 Cataract, glaucoma and other abnormal structure of cornea, sclera, iris, and retina 13 (1.47)
 Visual impairment 6 (0.68)
Hearing impairment 15 (1.69)
Miscellaneous/Othersb 38 (4.28)
Totalc 1,284

Percentage denominator was 887 patients with associated CHD.

Includes aplastic anemia, idiopathic thrombocytopenic purpura, thalassemia, vitiligo, alopecia areata, lipoma, skin growth, etc

“TOTAL” represents the sum of noncardiac anomalies in 887 children with associated CHD, and anomalies within the same affected system were counted as one.

 NCA spectra for CHD subcategories

The level 1 diagnoses with the highest percentages of isolated CHDs were septal defects, wherein about four fifths of each were isolated (Table 1). Conversely, besides heterotaxy, the diagnosis with the greatest percentage of associated CHDs was AVSD, wherein almost two fifths of the patients have associated CHDs (Table 1). Statistical analysis proved that septal defects, especially VSD (P = 3.7 × 10−9) and D-TGA with an intact ventricular septum (D-TGA + IVS, P = 0.038), are less likely to associated with NCAs. Furthermore, there were a higher probability of combined NCAs in children with AVSD (P = 0.002) and vasc ring malformations (P = 0.007).

Although NCAs involving the CNS, nose/ear/mandibular/face, genitourinary system, and musculoskeletal system were common for most CHD subtypes, the distribution of NCAs differed slightly (Table 3). NCAs affecting the CNS were most frequently observed in AVSD and RVOTO cases, wherein approximately one third of patients were affected. Nose/ear/mandibular/face anomalies were observed in more than one fifth of AVSD cases. Children in groups of septal defects or groups of associations showed relatively larger proportions of combined musculoskeletal anomalies (12.16% and 12.00%) and abdominal wall deficiency (9.48% and 8.80%). Genitourinary malformations were less prevalent in LVOTO-diagnosed children whereas respiratory system NCAs and digestive system NCAs were apparently common in children with CTD and LVOTO, respectively. Laterality defects were notably common in heterotaxy cases and, albeit to a lesser extent, CTD cases (Table 3). Furthermore, taking gender into account, among children with septal defects, especially those with VSD, PA-VSD, pulmonary artery/valve atresia, or other malformation of the pulmonary artery/valve and double-chambered right ventricule (DCRV), males were more likely to have associated CHD than females (P < 0.05), whereas the situation is opposite in LVOTO and RVOTO diagnostic groups.

Distribution of NCAs associated with each CHD subcategorya.

CHDs NCAs Septal defect AVSD CTD LVOTO RVOTO Abnormal cell growth Others HTX Associations
Central nervous system anomalies 160 (25.28) 22 (30.56) 36 (20.57) 9 (31.03) 21 (31.82) 9 (40.91) 9 (15.25) 9 (8.74) 32 (25.60)
Nose, ear, mandibular, face anomaly 88 (13.90) 16 (22.22) 27 (15.43) 3 (10.34) 9 (13.64) 3 (13.64) 8 (13.56) 4 (3.88) 14 (11.20)
Genitourinary 72 (11.37) 7 (9.72) 21 (12.00) 2 (6.90) 10 (15.15) 4 (18.18) 10 (16.95) 1 (0.97) 13 (10.40)
Musculoskeletal 77 (12.16) 7 (9.72) 16 (9.14) 3 (10.34) 6 (9.09) 0 (0.00) 8 (13.56) 6 (5.83) 15 (12.00)
Laterality defects 8 (1.26) 3 (4.17) 12 (6.86) 0 (0.00) 3 (4.55) 0 (0.00) 3 (5.08) 72 (69.9) 7 (5.60)
Respiratory system 23 (3.63) 1 (1.39) 15 (8.57) 1 (3.45) 0 (0.00) 1 (4.55) 4 (6.78) 3 (2.91) 7 (5.60)
Digestive system 31 (4.90) 3 (4.17) 8 (4.57) 4 (13.79) 1 (1.52) 0 (0.00) 0 (0.00) 3 (2.91) 6 (4.80)
Abdominal wall 60 (9.48) 3 (4.17) 8 (4.57) 2 (6.90) 5 (7.58) 2 (9.09) 5 (8.47) 2 (1.94) 11 (8.80)
Endocrine and metabolic 25 (3.95) 3 (4.17) 4 (2.29) 3 (10.34) 3 (4.55) 0 (0.00) 3 (5.08) 0 (0.00) 6 (4.80)
Hemangioma, lymphangioma 25 (3.95) 1 (1.39) 10 (5.71) 1 (3.45) 1 (1.52) 2 (9.09) 2 (3.39) 0 (0.00) 5 (4.00)
Cleft lip and/or palate 18 (2.84) 1 (1.39) 0 (0.00) 0 (0.00) 2 (3.03) 0 (0.00) 0 (0.00) 2 (1.94) 2 (1.60)
Immunodeficiency 7 (1.11) 2 (2.78) 8 (4.57) 0 (0.00) 1 (1.52) 0 (0.00) 0 (0.00) 0 (0.00) 1 (0.80)
Eye 5 (0.79) 2 (2.78) 4 (2.29) 0 (0.00) 1 (1.52) 0 (0.00) 5 (8.47) 0 (0.00) 2 (1.60)
Hearing impairment 8 (1.26) 1 (1.39) 2 (1.14) 0 (0.00) 1 (1.52) 0 (0.00) 1 (1.69) 0 (0.00) 2 (1.60)
Others 26 (4.11) 0 (0.00) 4 (2.29) 1 (3.45) 2 (3.03) 1(4.55) 1(1.69) 1(0.97) 2(1.60)
Total: NCAs/associated CHDsb 633/428 70/44 175/124 29/20 66/50 22/16 59/43 103/79 125/83

Number of subjects with the certain CHD subcategories and NCAs are indicated; percentages in parentheses indicate the portion of specified NCA among all NCAs of children with each CHD phenotype in the header.

NCAs refers to the total number of NCAs within the population with specific CHD subcategories while associated CHDs refers to the total number of patients with combined NCAs.

 Co-occurrence of CHDs and NCAs

With support and confidence levels set to 0.01 and 0.1, respectively, we attained 213 rules between CHD subtypes and NCAs. After filtering out low-value rules (lift < 3), 11 rules were retained (Table 4), showing the reliability or value of the rule which indicated the following potential CHD–NCA co-occurrence relationships: CCTGA-SV–laterality defect (lift = 13.02); CTD, RVOTO–laterality defect NCA (lift = 9.01); heterotaxy–laterality defect NCA (lift = 6.93); vasc ring malformations–respiratory system NCA (lift = 5.19); VSD, PDA, and CNS anomalies-LVOTO (lift = 3.66).

Valuable rules with association analysisa.

Typeb lhsc rhsc Count Supportd Confidenced Liftd Coveraged Liftd Convictiond FishersExactTestV
NCA CNS, Miscellaneous Face 13 0.0156 0.6842 3.3370 0.0228 3.3370 2.5174 6.4871 × 10−6
NCA Face, CNS Miscellaneous 13 0.0156 0.1512 3.3176 0.1031 3.3176 1.1244 3.8934 × 10−5
CHD_NCA laterality defect (N)f CCTGA, SV 13 0.0156 0.2653 13.0156 0.0588 13.0156 1.3334 3.8326 × 10−14
CHD_NCA CCTGA, SV Laterality defect (N) 13 0.0156 0.7647 13.0156 0.0204 13.0156 4.0003 3.8326 × 10−14
CHD_NCA CTD, RVOTO Laterality defect (N) 9 0.0108 0.5294 9.0108 0.0204 9.0108 2.0001 6.7795 × 10−8
CHD_NCA HTX Laterality defect (N) 11 0.0132 0.4074 6.9342 0.0324 6.9342 1.5884 5.9480 × 10−8
CHD_NCA Laterality defect (N) HTX 11 0.0132 0.2245 6.9342 0.0588 6.9342 1.2477 5.9480 × 10−8
CHD_NCA Vasc ring Respiratory (N) 13 0.0156 0.3421 5.1876 0.0456 5.1876 1.4198 1.6641 × 10−7
CHD_NCA Respiratory (N) Vasc ring 13 0.0156 0.2364 5.1876 0.0659 5.1876 1.2499 1.6641 × 10−7
CHD_NCA RVOTO, laterality defect (N) CTD 9 0.0108 0.6923 4.8115 0.0156 4.8115 2.7824 8.6630 × 10−6
CHD_NCA CTD, laterality defect (N) RVOTO 9 0.0108 0.4286 4.1084 0.0252 4.1084 1.5674 1.0061 × 10−4
CHD_NCA VSD, PDA, CNS (N) LVOTO 10 0.0120 0.2326 3.6595 0.0516 3.6595 1.2202 1.7389 × 10−4
CHD_NCA VSD, LVOTO, CNS (N) PDA 10 0.0120 0.8333 3.4236 0.0144 3.4236 4.5396 2.5161 × 10−5

Association analysis performed with the apriori principle to find rules; rules with a lift >3 were considered valuable.

Association analyses for CHDs and NCAs involved 887 subjects with associated CHDs.

lhs, left-hand side; rhs, right-hand side. A rule can be written as lhsrhs, “lhs” and “rhs” are collections of phenotypes that lie at the end of the arrow.

Support = count (number of specific rule)/total subjects observed, represents rule frequency, and the numerator of the formula can be “lhs” or “rhs” as well; confidence = support(lhs∪rhs)/support(lhs), represents the probability “rhs” coexistence in subjects with “lhs”; lift = support(lhs∪rhs)/(support(lhs)*support(rhs)), measure of independence of “lhs” and “rhs”.

Quality measurement: Fisher's Exact Test inspects rule authenticity (rule valid at P < 0.05).

When inspecting “CHD-NCA” rules, phenotypes with “(N)” refer to NCAs, and others represent CHDs.

 Discussion

In the present study sample, 23.42% of CHD diagnosed children had coexisting NCAs, a value about midway between the wide range of percentages reported in the literature (4.53%–50%) (13–15) and somewhat similar to percentages obtained in extensive studies conducted in the city of Atlanta, GA in the USA (28.7%), the province of Alberta in Canada (25%), and Croatia (14.5%) (16, 26, 27). The wide range of findings reported in this regard may be attributed to different classifications, inclusion/exclusion criteria, and screening strategies. Stoll and colleagues reported that the incidence of NCAs co-occurring with CHDs was 24.2% in live births, 66.3% in stillbirths, and 69.4% in abnormal pregnancy terminations (21). The subjects in our study were all live births. The definition of associated CHD differs between studies as well. Some defined an associated CHD as an extracardiac or genetic abnormality (16, 21). In our study, we included anomalies affecting other organs but not genetic abnormalities. Consequently, the data are not fully comparable across different studies due to different methodologies. Nevertheless, the proportion of congenital defects was dramatically more significant than the prevalence of congenital defects for China's population as a whole (191.84/10,000) (28), which suggests that CHDs may be a risk factor for other defects and that a considerable number of children with CHDs have NCAs.

Our findings indicating that the most common NCAs observed were CNS anomalies, nose/ear/mandibular/face anomalies, genitourinary system anomalies, and musculoskeletal system anomalies are largely in agreement with previous reports (14, 21, 29–31). However, we observed relatively low percentages of gastrointestinal anomalies (6.31%) and respiratory system anomalies (6.20%), the ranges for which in the literature are 8%–35% and 2%–14%, respectively, but a relatively high percentage of nose/ear/mandibular/face anomalies (19.39%) (8, 14, 15, 18, 32–39). Divergences from prior reports may have several underlying causes. Firstly, we excluded stillbirths, fetal deaths, and pregnancy terminations, which are more likely to involve lethal and major anomalies than live births. Secondly, we included several minor NCAs that are often excluded in other literature (e.g., low set ears, atypical facial appearance, and high arched palate) because how little of an effect they have on prognoses. Lastly, we deconstructed phenotypes of known syndromes as discrete NCAs. Most syndromes that commonly present with CHDs—including Down syndrome, DiGeorge syndrome, and Turner syndrome—have clinically significant NCAs, such as development delays, atypical facial features, skeletal deformities, and genitourinary system anomalies (40); these syndromes explain in part the top four NCAs in our results. CNS anomalies, including development delays, account for a large portion of the NCAs observed in our study (Table 2). Because neurodevelopment is highly sensitive to oxygen, any cardiac defect that disturbs hemodynamics and oxygen transport has the potential to cause CNS anomalies. In addition, development delays continue to manifest with increasing child age; our study sample has a median age of 3.96 years (IQR, 2.56–5.39), providing recognition of NCAs with progressive symptoms that are not yet apparent in the fetal and infant stages. Furthermore, adverse neurodevelopmental outcomes after surgical repair of CHDs represent a clinically significant cause of morbidity. Indeed, neuropsychological deficits may occur in as many as 50% of children who undergo CHD repairs by the time they reach school age (41). Early diagnosis of CNS anomalies in this patient population would be of great benefit to perioperative management.

Regarding NCA risk among different CHD phenotypes, we found that AVSD, PTA, vasc ring malformations, LVOTO, and heterotaxy had relatively high incidences of associated NCAs, whereas VSD and APVD had relatively low incidences. It could be that CHDs that emerge in earlier stages of morphogenesis are more likely to be associated with multiple and complex defects (42). Boundaries between tissues are blurred in early development, and regulatory molecular signaling pathways affect the development of many organs simultaneously.

Our finding of a specific link between VSD/LVOTO/PDA presence and CNS anomalies should be explored. Interestingly, the impact of AVSDs on CNS anomalies and nose/ear/mandibular/face anomalies could potentially relate to the well-known correlation between AVSDs and Down syndrome (32, 43, 44). The finding that vasc ring anomalies (including right arch and sling) often co-occurred with malformations of the respiratory system was unsurprising given the oppression of the malformed arteries on the trachea. Theoretically, most CHD-associated NCAs should have an etiological explanation, such as a mesoderm differentiation event that causes CHD and musculoskeletal defects simultaneously (16). The detailed mechanisms underlying the breadth of co-occurring anomalies have yet to be delineated.

 Limitation

It was difficult to conduct a stratified analysis to correct for confounding factors as we did not obtain data related to risk factors for birth defects. We also did not capture associated CHD patterns in rural China, where there is a high prevalence of unrecognized CHDs (32). Thirdly, our sample included relatively few rare CHDs and NCAs, which may weaken the analyses.

 Conclusion

Han Chinese children with CHDs were found to have a high prevalence of NCAs, including CNS, nose/ear/mandibular/face, and musculoskeletal anomalies. Different CHD subtypes had different NCA probabilities and spectrums. Compared to other CHD subtypes, septal defects had a lower percentage of associated NCAs while AVSD had a higher percentage. Clinicians treating patients with CHDs should be attentive to the risk of NCAs, particularly for perioperative management but also for long-term prognosis determination.

 Data availability statement

The original contributions presented in the study are included in the article/Supplementary Materials, further inquiries can be directed to the corresponding authors.

 Ethics statement

The studies involving humans were approved by Fudan University Children's Hospita. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.

 Author contributions

XH: Data curation, Formal Analysis, Investigation, Writing – original draft. YG: Formal Analysis, Investigation, Methodology, Writing – original draft. WC: Project administration, Resources, Supervision, Writing – review & editing. WS: Formal Analysis, Project administration, Resources, Supervision, Writing – review & editing. GH: Conceptualization, Project administration, Resources, Supervision, Writing – review & editing.

 Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article.

This research was supported by the National Key Research and Development Program of China (grant no. 2021YFC2701000, 2016YFC1000500), the National Natural Science Foundation of China (grant no. 82270321, 81873482, 81873483), the Shanghai Natural Science Foundation of Science and Technology Innovation Action Plan (grant no. 20JC1418300), and the CAMS Innovation Fund for Medical Sciences (grant no. 2019-I2M-5-002).

 Acknowledgments

The authors thank for the support from National Key Research and Development Program of China and National Natural Science Foundation of China. We also thank all the patients and families for their understanding and support.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher's note

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