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. Author manuscript; available in PMC: 2017 Nov 1.
Published in final edited form as: Ann Thorac Surg. 2016 Jun 17;102(5):1607–1614. doi: 10.1016/j.athoracsur.2016.04.008

Prevalence of Non-cardiac and Genetic abnormalities in Neonates Undergoing Cardiac Surgery: Analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database

Angira Patel 1, John M Costello 1, Carl L Backer 2, Sara K Pasquali 3, Kevin D Hill 4, Amelia S Wallace 4, Jeffrey P Jacobs 5, Marshall L Jacobs 6
PMCID: PMC5077694  NIHMSID: NIHMS776855  PMID: 27319986

Abstract

Background

Among congenital heart disease (CHD) patients, the coexistence of non-cardiac congenital anatomic abnormalities (NC), genetic abnormalities (GA), and syndromes (S) may influence therapeutic strategies and outcomes. The appreciated prevalence of these abnormalities has risen, as increased screening and improved diagnostic precision enable identification of these comorbidities in a larger fraction of neonates with CHD. We examined the contemporary prevalence and distribution of NC/GA/S across diagnostic groups among neonates undergoing cardiac surgery using a large, nationally representative clinical registry.

Methods

The Society of Thoracic Surgeons-Congenital Heart Surgery Database (STS-CHSD) was queried to identify neonates (≤ 30 days) who underwent index cardiac operations from 2010–2013. The fundamental cardiac diagnosis was used to identify 10 diagnostic groups. The prevalence of NC/GA/S was reported across each group.

Results

The cohort included 15,376 index neonatal operations from 112 centers. Overall 18.8% (2,894/15,376) of operations were performed on neonates with NC/GA/S. Patients with atrioventricular septal defect (212/357, 59.4%), interrupted aortic arch (248/567, 43.7%), truncus arteriosus (204/554, 36.8%), tetralogy of Fallot (417/1383, 30.2%) had the highest prevalence of NC/GA/S abnormalities, whereas those with transposition (111/2778, 4.0%) had the lowest prevalence. The most commonly identified NC/GA/S included: heterotaxy (597/15,376, 3.9%), DiGeorge/22q11 deletion (550/15,376, 3.6%), Down syndrome/trisomy 21 (318/15, 376, 2.1%), intestinal malrotation (220/15,376, 1.4%), and Turner syndrome/45XO (189/15,376, 1.2%).

Conclusions

The prevalence of NC/GA/S varies widely across CHD diagnostic groups. This information may be useful for patient counseling, recommendations for screening for anomalies and genetic disorders, and perioperative management.

Keywords: Congenital heart disease, genetic syndrome, database, neonates, surgery

Neonates and infants with congenital heart disease (CHD) have experienced substantial reductions in mortality and morbidity over the last half-century. Improvements have been due in part to the advent and rapid evolution of surgical techniques and interventions, advances in diagnostic and imaging capabilities, and better perioperative management. The presence of non-cardiac congenital anatomic abnormalities (NC), genetic abnormalities (GA), and syndromes (S) and their potential impact on outcomes has been noted in patients with CHD [1–7]. Prior studies have evaluated overall prevalence of extracardiac abnormalities in CHD, with reported estimates in the range of 25–30% [8–12]. More recent meta-analyses and population-based studies have found a prevalence of associated anomalies in the range of 17–28% [13–19].

As screening practices change, the appreciated prevalence of important genetic and non-cardiac abnormalities associated with CHD will continue to rise. Increased screening and advances in diagnostic precision enable identification of genetic abnormalities in a larger fraction of neonates with CHD. Although single center studies have shown that prevalence of NC/GA/S varies by type of CHD, there are no large multicenter studies describing the prevalence of specific abnormalities across specific diagnostic groups. Understanding which specific abnormalities coexist with types of CHD has been challenging and is an important area of emerging research. The aim of this study is to examine the prevalence and distribution of NC/GA/S across specific diagnostic groups among neonates undergoing cardiac surgery in the first 30 days of life in North America.

Material and Methods

Data Source

The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) was used for this study. The STS-CHSD includes detailed information on more than 360,000 surgeries conducted at 127 centers in North America. It is estimated that the database currently collects data from 96% of all U.S. centers performing congenital heart surgery, including 98% of all operations [20]. Preoperative, operative, and outcomes data are collected on all patients undergoing pediatric and congenital heart surgery at participating centers. Coding for this database is accomplished by clinicians and ancillary support staff using the International Pediatric and Congenital Cardiac Code [21]. The Duke Clinical Research Institute serves as the data warehouse and analysis center for all of the STS National Databases. Evaluation of data quality includes the intrinsic verification of data, along with a formal process of in-person site visits and data audits conducted by a panel of independent data quality personnel and pediatric cardiac surgeons at approximately 10% of participating institutions each year [22]. This study was approved by the STS-CHSD Access and Publications Committee and the Duke University Institutional Review Board and was not considered human subjects research in accordance with the Common Rule (45 CFR 46.102(f)).

Patient population

Neonates (≤ 30 days) within ten specific diagnostic groups undergoing an index cardiovascular procedure from January 1, 2010 to December 31, 2013 were eligible for inclusion. The patient population was limited to the first 30 days of life so as to evaluate NC/GA/S abnormalities in a unique patient population and prevent double counting in cases of the same patient with multiple surgeries; this would lead to erroneously skewing our data. Categorization was based upon the patient’s fundamental diagnosis defined as the most complex cardiac anomaly or condition (or primary diagnosis in instances where the fundamental diagnosis was missing). The diagnostic groups were therefore mutually exclusive and included: hypoplastic left heart syndrome (HLHS), single ventricle non-HLHS (SV Non-HLHS), coarctation of aorta/aortic arch hypoplasia (COA), transposition of the great arteries (TGA), double outlet right ventricle (DORV), tetralogy of Fallot (TOF), interrupted aortic arch (IAA), truncus arteriosus (TA), atrioventricular septal defect (AVSD), and total anomalous pulmonary venous connections (TAPVC). For this analysis, patients coded in STS-CHSD as ‘Single Ventricle-Heterotaxy syndrome’ were included in the ‘Single Ventricle Non-HLHS’ diagnostic category. In addition, all patients with fundamental diagnosis of ‘single ventricle-heterotaxy’ were determined to have a syndrome (S); specifically ‘heterotaxy syndrome.’

Data Collection

Fundamental diagnosis and three data elements in the database were collected: non-cardiac congenital anatomic abnormalities, chromosomal abnormalities, and syndromes [23].

Analysis

Prevalence of NC/GA/S were described overall and by diagnostic group using standard summary statistics. In patients coded as having a syndrome that is known to be associated with a genetic abnormality (e.g. Down syndrome and trisomy 21), the syndrome and/or the genetic abnormality were combined into a single category and analyzed so as to not double count an abnormality. Two separate groups of closely related syndromes were also combined into single categories, e.g., VACTERL-H was included in the VACTERL group and all of the variants of heterotaxy (asplenia/polysplenia/no splenic involvement) were combined into a single heterotaxy group. NC were analyzed separately. All analyses were done using SAS (version 9.4; SAS Institute, Inc., Cary, NC).

Results

The cohort included 15,376 index neonatal operations at 112 centers, representing 71.8% of all neonatal index operations during the specified time frame. Figure 1 describes the prevalence of NC/GA/S across the ten diagnostic groups in neonates who underwent cardiac surgery. The overall prevalence of any NC/GA/S in this population selected on the basis of cardiac diagnoses was 18.8% (2,894/15,376). The overall prevalence of NC/S/GA within the ten CHD diagnostic groups ranged highest for AVSD (212/357, 59.4%), IAA (248/567, 43.7%), TA (204/554, 36.8%), TOF (417/1383, 30.2%) and lowest for TGA (111/2778, 4.0%).

Figure 1.

Figure 1

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Prevalence of non-cardiac congenital anatomic abnormalities (NC), genetic abnormalities (GA), and syndromes (S) in neonates undergoing cardiac surgery by diagnosis.

AVSD, atrioventricular septal defects; COA, coarctation of aorta/aortic arch hypoplasia; DORV, double outlet right ventricle; HLHS, hypoplastic left heart syndrome; IAA, interrupted aortic arch; SV/Non-HLHS, single ventricle non-HLHS; TA, truncus arteriosus; TAPVC, total anomalous pulmonary venous connection; TGA, Transposition of the Great Arteries TOF, tetralogy of Fallot

Figure 2 describes the prevalence of the specific NC abnormalities across the 10 CHD diagnostic groups. The prevalence of any NC ranges from 0.5% to 7.8%, with highest prevalence in AVSD (28/357, 7.8% and SV Non-HLHS (151/2147, 7.0%). Intestinal malrotation was the most commonly identified NC abnormality (220/15,376, 1.4%).

Figure 2.

Figure 2

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Prevalence of non-cardiac (NC) abnormalities in neonates undergoing cardiac surgery by diagnosis.

*Represents total N for each diagnosis further divided into N (%) for each NC abnormality.

**Represents unique neonates with any NC abnormality

AVSD, atrioventricular septal defects; CDH, congenital diaphragmatic hernia; COA, coarctation of aorta/aortic arch hypoplasia; DORV, double outlet right ventricle; HLHS, hypoplastic left heart syndrome; IAA, interrupted aortic arch; SV/Non-HLHS, single ventricle non-HLHS; TA, truncus arteriosus; TAPVC, total anomalous pulmonary venous connection; TEF, tracheoesophageal fistula; TGA, Transposition of the Great Arteries TOF, tetralogy of Fallot

Figure 3 describes the prevalence of the specific GA/S abnormalities across the 10 CHD diagnostic groups. The prevalence of any GA/S alone ranges from 3.6% to 58.0%. The most commonly identified GA/S across all diagnostic groups were: heterotaxy (597/15,376, 3.9%), DiGeorge/22q11 deletion (550/15,376, 3.6%), Down syndrome/trisomy 21 (318/15, 376, 2.1%), and Turner syndrome/45XO (189/15,376, 1.2%). The most prevalent GA/S abnormality for the AVSD group was Down syndrome/trisomy 21 (120/357, 33.3%), followed by heterotaxy syndrome (47/357, 13.2%). DiGeorge/22q11 deletion was highly prevalent in those with IAA (205/567, 36.2%), TA (137/554, 24.7%), and TOF (145/1,383, 10.5%). Of those with SV-Non-HLHS diagnosis, 18.2% (391/2,147) had heterotaxy syndrome. In the COA diagnostic group, 4.0% (137/3,454) had Turner syndrome.

Figure 3.

Figure 3

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Prevalence of genetic and syndromic abnormalities (GA/S) in neonates undergoing cardiac surgery by diagnosis.

*Represents total N for each diagnosis further divided into N (%) for each NC abnormality.

** GA/S is specified, but total prevalence is n <7 (0.0% for the specific GA/S

***GA/S not specified, “other” box in database checked

****Represents unique neonates with any GA/S abnormality

AVSD, Atrioventricular Septal Defects; CHARGE, coloboma, heart defect, atresia choanae, retarded growth and development, genital abnormality, and ear abnormality; COA, Coarctation of Aorta/Aortic Arch Hypoplasia; DORV, Double Outlet Right Ventricle; HLHS, Hypoplastic Left Heart syndrome; IAA: Interrupted Aortic Arch; SV/Non-HLHS, Single Ventricle Non-HLHS, TA, Truncus arteriosus; TAPVC, Total Anomalous Pulmonary Venous Connection; TGA: Transposition of the Great Arteries; TOF, Tetralogy of Fallot; VACTERL, Vertebral anomalies, Anal atresia, Cardiac defects, Tracheoesophageal fistula and/or Esophageal atresia, Renal & Radial anomalies and Limb defects, WPW, Wolf-Parkinson-White syndrome.

Comment

Awareness of the presence of NC/GA/S in neonates with CHD can have important implications for risk-stratification, screening tests, medical treatment, prognosis, and counseling of parents. Understanding the prevalence of these abnormalities, particularly with respect to their associations with specific congenital cardiac anomalies may help focus research efforts that will eventually contribute to more efficient evaluation of individual patients and improved outcomes. This analysis was undertaken to provide empirically derived data, based on multi-institutional experiences to further the understanding of the prevalence of NC/GA/S abnormalities in patients presenting for surgical repair in the first 30 days of life. We found that the existence of NC/GA/S varies widely across the CHD diagnostic groups with an overall prevalence of 18.8%.

Comparisons of our findings to existing studies are difficult for a number of reasons. The retrospective nature and lack of uniformity of most published studies results in different populations being studied and methodology being employed compared to the current era of increasing availability and granularity of genetic screening. In addition, many known associations are reported based on evaluating the prevalence of a CHD within a specific NC/GA/S abnormality. In contrast, we evaluated the prevalence of NC/GA/S within specific CHD diagnostic groups. Our overall prevalence of 18.8% is lower than the 25–30% range found in classic studies. This finding likely reflects the fact that our study only included patients in 10 diagnostic groups who underwent surgery in the first 30 days of life, and may not capture any NC/GA/S diagnoses made following neonatal hospitalization discharge which may not be captured by the STS database encounter.

COA is noted to have associated abnormalities prevalence in the range of 20–30% of which Turner and Noonan syndrome were noted to be common occurrences [12, 19, 24]. However, in our analysis, the overall prevalence of NC/GA/S in neonates with COA was 15.6%, with 4% having a diagnosis of Turner syndrome. The association between 22q11deletion/DiGeorge syndrome and conotruncal abnormalities is widely appreciated. In a single-institution study, Peyvandi et al obtained genetic testing in 1,610 consecutive infants with cardiac disease, and found that 22q11 deletion was present in 13.2% of patients with TOF, 35.5% with TA, and 56.2% in IAA [25]; the higher prevalence in this study likely reflects universal genetic testing for this population. Marino and colleagues reviewed a cohort of patients presenting with TOF and found that 25.3% had extracardiac abnormality, including 13% with trisomy 21 and 1.2% with DiGeorge syndrome [26]. This study included patients from an earlier era when less genetic testing was performed, which likely explains the lower prevalence of DiGeorge syndrome compared to our study as well as the one by Peyvandi et al. In addition, presence of DiGeorge syndrome has been associated with increased length of hospital stay and increased resource utilization in infants undergoing surgery for truncus arteriosus and interrupted aortic arch [27,28].

In our population, neonates undergoing AVC surgery have a 33% prevalence of trisomy 21, which is less than the 78.4% prevalence noted by St. Louis and colleagues for all patients with AVSD [29]. However, our study focuses specifically on neonates; among those with AVSD having neonatal repair, trisomy 21 seems to be half as prevalent versus prior studies that include all age groups, likely due to differences in study populations in time to presentation for surgery. Heterotaxy has a prevalence of 18.2% in SV-non-HLHS, 6.1% in DORV, and 5.1% in TAPVC; this finding reflects commonly known associations and unbalanced AVC may be encompassed in the SV-non-HLHS category [30,31].

A multifactorial hypothesis for etiology of CHD including genetic factors has long been recognized. Significant progress has been made in understanding the genetics of CHD, including identification of specific gene abnormalities associated with some types of malformations [32, 33]. Recent scientific statements provide recommendations for genetic screening [34, 35] which have led to an increase in genetic testing as well as increased recognition of associated anomalies [21]. The American Heart Association and American Academy of Pediatrics have outlined several important reasons to determine genetic causes of CHD: identify other organ systems requiring surveillance, determine and better define prognosis, inform families about recurrence risk, and identify at risk family members and provide necessary screening, including genetic testing [34]. Early diagnosis of a genetic syndrome allows for genetic counseling and early implementation of comprehensive care and recommended health supervision. Some have argued that genetic screening in CHD should be more rigorous [36, 37], but this practice has not uniformly been adapted and screening rates continue to be low [38–40]. Genetic screening practices continue to evolve, providing a growing body of information to clinicians and patients and the issue of who to screen and what to do with the information will become more pressing. Advocates for universal genetic screening for all patients with CHD will likely increase. However, given that genetic screening can produce non-clinically significant results, further work is likely needed prior to advocating for universal screening. The availability of on-site genetics experts seems prudent for active heart centers.

Limitations of this analysis include inherent limitations of the STS-CHSD. Importantly, these data represent prevalence in those neonates presenting for surgical repair. Our findings may differ from other studies that evaluated prevalence from autopsy studies, fetal studies, or postnatal studies later in life. For the AVSD and TOF groups, our study only included those patients who underwent cardiac surgery in the first 30 days of life, and thus the prevalence may differ if older infants and children were also included. In addition, this analysis does not include other common types of CHD which are generally repaired after 30 days of life such as atrial septal defects and ventricular septal defects. Variability across institutions with regard to genetic testing practices is a limitation of this study. But with respect to data reporting, data completion for the relevant fields was >98% in the STS-CHSD. We were only able to analyze data for NC/GA/S abnormalities that are specifically coded, as uncommon abnormalities are included in the “other” category. Finally, some patients may have been diagnosed with a noncardiac anomaly and/or genetic syndrome following discharge from the neonatal cardiac surgical hospitalization or may have had dysmorphic features or deformities but no identifiable noncardiac anomaly or genetic syndrome; such abnormalities would not have been coded in the STS-CHSD.

Conclusions

There is a large variation across diagnostic groups for the prevalence of NC/GA/S. This finding has important implications for patient counseling and screening recommendations. Given the results of this study, we advocate for a heightened focus on some diagnostic groups for genetic screening including: 22q11 deletion screening for those with IAA, TA, and TOF; heterotaxy screening in those with SV-non-HLHS; trisomy 21 in AVSD and TOF; and Turner syndrome in females with COA. All children with CHD should be considered potential candidates for genetic screening. We suggest that the chance of a positive screening may be guided by the information found in this review which in turn may influence the decision to obtain genetic testing.

In 2014, NC/GA/S were included as covariates in the newly developed STS-CHSD Mortality Risk Model [41,42]. They are currently considered in the context of “any one of those specified in the database codes” as a binary presence or absence of any NC/GA/S. However, our analysis demonstrates significant heterogeneity in the type and prevalence of various NC/GA/S across CHD diagnostic groups, and the possibility of a variable impact on outcomes must be considered. There are presently ongoing STS-CHSD analyses specifically evaluating outcomes including mortality and morbidity for the following: Williams syndrome, heterotaxy, 22q11 deletion syndrome, trisomy 13, and trisomy 18 [43]. Future investigations should include individual consideration of some of the more prevalent NC/GA/S, in order to refine the STS-CHSD Mortality Risk Model by including coefficients that correspond specifically to differential impact of the existence of specific abnormalities.

Acknowledgments

Dr. Costello was supported in part by a generous gift to the Division of Cardiology at Ann & Robert H. Lurie Children’s Hospital of Chicago by Mr. Warren Batts. Dr. Pasquali receives support from the Janette Ferrantino Professorship. Dr. Hill receives support from the National Center for Advancing Translational Sciences of the National Institutes of Health under award UL1TR001117 and from the Gilead Cardiovascular Scholars Program.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Presented at the Fifty-second Annual Meeting of the Society of Thoracic Surgeons, Phoenix, AZ, Jan 23–27, 2016. Winner of the Richard E. Clark Award for Congenital Heart Disease.

References

  • 1.Anaclerio S, Di Ciommo V, Michielon G, et al. Conotruncal heart defects: impact of genetic syndromes on immediate operative mortality. Ital Heart J. 2004;5:624–628. [PubMed] [Google Scholar]
  • 2.Michielon G, Marino B, Oricchio G, et al. Impact of DEL22q11, trisomy 21, and other genetic syndromes on surgical outcome of conotruncal heart defects. J Thorac Cardiovasc Surg. 2009;138:565–570. doi: 10.1016/j.jtcvs.2009.03.009. [DOI] [PubMed] [Google Scholar]
  • 3.Patel A, Hickey E, Mavroudis C, et al. Impact of noncardiac congenital and genetic abnormalities on outcomes in hypoplastic left heart syndrome. Ann Thorac Surg. 2010;89:1805–1813. doi: 10.1016/j.athoracsur.2010.02.004. [DOI] [PubMed] [Google Scholar]
  • 4.Atz AM, Travison TG, Williams IA, et al. Prenatal diagnosis and risk factors for preoperative death in neonates with single right ventricle and systemic outflow obstruction: screening data from the Pediatric Heart Network Single Ventricle Reconstruction Trial(*) J Thorac Cardiovasc Surg. 2010;140:1245–1250. doi: 10.1016/j.jtcvs.2010.05.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Mahle WT, Crisalli J, Coleman K, et al. Deletion of chromosome 22q11.2 and outcome in patients with pulmonary atresia and ventricular septal defect. Ann Thorac Surg. 2003;76:567–571. doi: 10.1016/s0003-4975(03)00516-2. [DOI] [PubMed] [Google Scholar]
  • 6.Chen MY, Chiu SN, Wang JK, et al. Genetic syndromes and outcome after surgical repair of pulmonary atresia and ventricular septal defect. Ann Thorac Surg. 2012;94:1627–1633. doi: 10.1016/j.athoracsur.2012.06.063. [DOI] [PubMed] [Google Scholar]
  • 7.Tabbutt S, Ghanayem N, Ravishankar C, et al. Risk factors for hospital morbidity and mortality after the Norwood procedure: A report from the Pediatric Heart Network Single Ventricle Reconstruction trial. J Thorac Cardiovasc Surg. 2012;144:882–895. doi: 10.1016/j.jtcvs.2012.05.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Nora JJ. Multifactorial inheritance hypothesis for the etiology of congenital heart diseases. The genetic-environmental interaction. Circulation. 1968;38:604–617. doi: 10.1161/01.cir.38.3.604. [DOI] [PubMed] [Google Scholar]
  • 9.Nora JJ, Nora AH. The evolution of specific genetic and environmental counseling in congenital heart diseases. Circulation. 1978;57:205–213. doi: 10.1161/01.cir.57.2.205. [DOI] [PubMed] [Google Scholar]
  • 10.Ferencz C, Correa-Vellasenor A, Loffredo CA, Wilson PD, editors. Perspective in Pediatric Cardiology. Vol. 5. Armonk, NY: Futura Publishing Co; 1998. Genetic and Environmental Risk Factors of Major Cardiovascular Malformations. The Baltimore-Washington Infant Study 1981–1989; p. 463. [Google Scholar]
  • 11.Hoffman JI, Christianson R. Congenital heart disease in a cohort of 19,502 births with long-term follow-up. Am J Cardiol. 1978;42:641–647. doi: 10.1016/0002-9149(78)90635-5. [DOI] [PubMed] [Google Scholar]
  • 12.Greenwood RD, Rosenthal A, Parisi L, Fyler DC, Nadas AS. Extracardiac abnormalities in infants with congenital heart disease. Pediatrics. 1975;55:485–492. [PubMed] [Google Scholar]
  • 13.Meberg A, Hals J, Thaulow E. Congenital heart defects--chromosomal anomalies, syndromes and extracardiac malformations. Acta Paediatr. 2007;96:1142–1145. doi: 10.1111/j.1651-2227.2007.00381.x. [DOI] [PubMed] [Google Scholar]
  • 14.Alabdulgader AA. Extra cardiac anomalies associated with congenital cardiac malformations in Saudi Arabian population. Research Journal of Cardiology. 2012;5:12–19. [Google Scholar]
  • 15.Karande S, Patil V, Kher A, Muranjan M. Extracardiac birth defects in children with congenital heart defects. Indian Pediatr. 2014;51:389–391. doi: 10.1007/s13312-014-0415-y. [DOI] [PubMed] [Google Scholar]
  • 16.Rosa RC, Rosa RF, Zen PR, Paskulin GA. Congenital heart defects and extracardiac malformations. Rev Paul Pediatr. 2013;31:243–251. doi: 10.1590/s0103-05822013000200017. [DOI] [PubMed] [Google Scholar]
  • 17.Grech V, Gatt M. Syndromes and malformations associated with congenital heart disease in a population-based study. Int J Cardiol. 1999;68:151–156. doi: 10.1016/s0167-5273(98)00354-4. [DOI] [PubMed] [Google Scholar]
  • 18.Eskedal L, Hagemo P, Eskild A, Aamodt G, Seiler KS, Thaulow E. A population-based study of extra-cardiac anomalies in children with congenital cardiac malformations. Cardiol Young. 2004;14:600–607. doi: 10.1017/S1047951104006043. [DOI] [PubMed] [Google Scholar]
  • 19.Trevisan P, Rosa RF, Koshiyama DB, Zen TD, Paskulin GA, Zen PR. Congenital heart disease and chromossomopathies detected by the karyotype. Rev Paul Pediatr. 2014;32:262–271. doi: 10.1590/0103-0582201432213213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Jacobs ML, Mavroudis C, Jacobs JP, Tchervenkov CI, Pelletier GJ. Report of the 2005 STS Congenital Heart Surgery Practice and Manpower Survey. Ann Thorac Surg. 2006;82:1152–1158. doi: 10.1016/j.athoracsur.2006.04.022. [DOI] [PubMed] [Google Scholar]
  • 21.Fahed AC, Gelb BD, Seidman JG, Seidman CE. Genetics of congenital heart disease: the glass half empty. Circ Res. 2013;112:707–720. doi: 10.1161/CIRCRESAHA.112.300853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Clarke DR, Breen LS, Jacobs ML, et al. Verification of data in congenital cardiac surgery. Cardiol Young. 2008;18(Suppl 2):177–187. doi: 10.1017/S1047951108002862. [DOI] [PubMed] [Google Scholar]
  • 23. [Accessed December 30, 2013];STS Congenital Heart Surgery Database v3.0. Available at http:/www.sts.org/sites/defaultfiles/pdf/congenitaldataspecificationsv3_0_20090904.pdf.
  • 24.Talner CN. Report of the New England Regional Infant Cardiac Program. Donald C, Fyler MD, editors. Pediatrics. 1998;102(1 Pt 2):258–259. [PubMed] [Google Scholar]
  • 25.Peyvandi S, Lupo PJ, Garbarini J, et al. 22q11.2 deletions in patients with conotruncal defects: data from 1,610 consecutive cases. Pediatr Cardiol. 2013;34:1687–1694. doi: 10.1007/s00246-013-0694-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Marino B, Digilio MC, Grazioli S, et al. Associated cardiac anomalies in isolated and syndromic patients with tetralogy of Fallot. Am J Cardiol. 1996;77:505–508. doi: 10.1016/s0002-9149(97)89345-9. [DOI] [PubMed] [Google Scholar]
  • 27.O’Byrne ML, Yang W, Mercer-Rosa L, et al. 22q11.2 Deletion syndrome is associated with increased perioperative events and more complicated postoperative course in infants undergoing infant operative correction of truncus arteriosus communis or interrupted aortic arch. J Thorac Cardiovasc Surg. 2014;148:1597–1605. doi: 10.1016/j.jtcvs.2014.02.011. Epub 2014 Feb 10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Liu M, Druschel CM, Hannan EL. Risk-adjusted prolonged length of stay as an alternative outcome measure for pediatric congenital cardiac surgery. Ann Thorac Surg. 2014;97:2154–2159. doi: 10.1016/j.athoracsur.2013.11.008. [DOI] [PubMed] [Google Scholar]
  • 29.St. Louis JD, Jodhka U, Jacobs JP, et al. Contemporary outcomes of complete atrioventricular septal defect repair: Analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. J Thorac Cardiovasc Surg. 201;148:2526–2531. doi: 10.1016/j.jtcvs.2014.05.095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Takeuchi K, McGowan FX, Jr, Bacha EA, et al. Analysis of surgical outcome in complex double-outlet right ventricle with heterotaxy syndrome or complete atrioventricular canal defect. Ann Thorac Surg. 2006;82:146–152. doi: 10.1016/j.athoracsur.2006.02.007. [DOI] [PubMed] [Google Scholar]
  • 31.Burton EC, Olson M, Rooper L. Defects in laterality with emphasis on heterotaxy syndromes with asplenia and polysplenia: an autopsy case series at a single institution. Pediatr Dev Pathol. 2014;17:250–264. doi: 10.2350/13-11-1406-OA.1. [DOI] [PubMed] [Google Scholar]
  • 32.Nemer M. Genetic insights into normal and abnormal heart development. Cardiovasc Pathol. 2008;17:48–54. doi: 10.1016/j.carpath.2007.06.005. [DOI] [PubMed] [Google Scholar]
  • 33.Clark EB. Pathogenetic mechanisms of congenital cardiovascular malformations revisited. Semin Perinatol. 1996;20:465–472. doi: 10.1016/s0146-0005(96)80062-0. [DOI] [PubMed] [Google Scholar]
  • 34.Pierpont ME, Basson CT, Benson DW, Jr, et al. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation. 2007;115:3015–3038. doi: 10.1161/CIRCULATIONAHA.106.183056. [DOI] [PubMed] [Google Scholar]
  • 35.Jenkins KJ, Correa A, Feinstein JA, et al. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation. 2007;115:2995–3014. doi: 10.1161/CIRCULATIONAHA.106.183216. [DOI] [PubMed] [Google Scholar]
  • 36.Cowan JR, Ware SM. Genetics and genetic testing in congenital heart disease. Clin Perinatol. 2015;42:373–393. doi: 10.1016/j.clp.2015.02.009. [DOI] [PubMed] [Google Scholar]
  • 37.Ko JM. Genetic Syndromes associated with Congenital Heart Disease. Korean Circ J. 2015;45:357–361. doi: 10.4070/kcj.2015.45.5.357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Connor JA, Hinton RB, Miller EM, Sund KL, Ruschman JG, Ware SM. Genetic testing practices in infants with congenital heart disease. Congenit Heart Dis. 2014;9:158–167. doi: 10.1111/chd.12112. [DOI] [PubMed] [Google Scholar]
  • 39.Fung A, Manlhiot C, Naik S, et al. Impact of prenatal risk factors on congenital heart disease in the current era. [Accessed December 30, 2015];J Am Heart Assoc. 2013 :2. doi: 10.1161/JAHA.113.000064. http://jaha.ahajournals.org/content/2/3/e000064.long. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Baker K, Sanchez-de-Toledo J, Munoz R, et al. Critical congenital heart disease--utility of routine screening for chromosomal and other extracardiac malformations. Congenit Heart Dis. 2012;7:145–150. doi: 10.1111/j.1747-0803.2011.00585.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Jacobs JP, O’Brien SM, Pasquali SK, et al. The Society of Thoracic Surgeons Congenital Heart Surgery Database Mortality Risk Model: Part 2-Clinical Application. Ann Thorac Surg. 2015;100:1063–1068. doi: 10.1016/j.athoracsur.2015.07.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.O’Brien SM, Jacobs JP, Pasquali SK, et al. The Society of Thoracic Surgeons Congenital Heart Surgery Database Mortality Risk Model: Part 1-Statistical Methodology. Ann Thorac Surg. 2015;100:1054–1062. doi: 10.1016/j.athoracsur.2015.07.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Hornik CP, Collins RT, II, Jaquiss RD, et al. Adverse cardiac events in children with Williams syndrome undergoing cardiovascular surgery: an analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. J Thorac Cardiovasc Surg. 2015;149:1516–1522. doi: 10.1016/j.jtcvs.2015.02.016. [DOI] [PMC free article] [PubMed] [Google Scholar]

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