Anatomic and physiologic classification of adults with congenital heart disease to predict adverse outcomes: Use of administrative codes compared to clinical staging.

BACKGROUND: The 2018 anatomic physiologic (AP) classification American Heart Association/American College of Cardiology (AHA/ACC) Guidelines for Adults with Congenital Heart Disease (ACHD) encompasses both native and post-operative anatomy and physiology to guide care management. As some physiologic conditions and post-operative states lack specific International Classification of Diseases (ICD) 9- Clinical Modification (CM) and 10-CM codes, an ICD code-based classification approximating the ACHD AP classification is needed for population-based studies. METHODS: A total of 232 individuals, aged ≥ 18 years at the time of a health encounter between January 1, 2010 and December 31, 2019 and identified with at least one of 87 ICD codes for a congenital heart defect were validated through medical chart review. Individuals were assigned one of 4 mutually exclusive modified AP classification categories: (1) severe AB, (2) severe CD, (3) non-severe AB, or (4) non-severe CD, based on native anatomy "severe" or "non-severe" and physiology AB ("none" or "mild") or CD ("moderate" or "severe") by two methods: (1) medical record review, and (2) ICD and Current Procedural Terminology (CPT) code-based classification. The composite outcome was defined as a combination of a death, emergency department (ED) visits, or any hospitalizations that occurred at least 6 months after the index date and was assessed by each modified AP classification method. RESULTS: Of 232 cases (52.2% male, 71.1% White), 28.4% experienced a composite outcome a median of 1.6 years after the index encounter. No difference in prediction of the composite outcome was seen based on modified AP classification between chart review and ICD code-based methodology. CONCLUSION: Modified AP classification by chart review and ICD codes are comparable in predicting the composite outcome at least 6 months after classification. Modified AP classification using ICD code-based classification of CHD native anatomy and physiology is an important tool for population-based ACHD surveillance using administrative data.

Automatic pediatric congenital heart disease classification based on heart sound signal.

Congenital heart diseases (CHD) are the most common birth defects, and the early diagnosis of CHD is crucial for CHD therapy. However, there are relatively few studies on intelligent auscultation for pediatric CHD, due to the fact that effective cooperation of the patient is required for the acquisition of useable heart sounds by electronic stethoscopes, yet the quality of heart sounds in pediatric is poor compared to adults due to the factors such as crying and breath sounds. This paper presents a novel pediatric CHD intelligent auscultation method based on electronic stethoscope. Firstly, a pediatric CHD heart sound database with a total of 941 PCG signal is established. Then a segment-based heart sound segmentation algorithm is proposed, which is based on PCG segment to achieve the segmentation of cardiac cycles, and therefore can reduce the influence of local noise to the global. Finally, the accurate classification of CHD is achieved using a majority voting classifier with Random Forest and Adaboost classifier based on 84 features containing time domain and frequency domain. Experimental results show that the performance of the proposed method is competitive, and the accuracy, sensitivity, specificity and f1-score of classification for CHD are 0.953, 0.946, 0.961 and 0.953 respectively.

Risk Stratification for Congenital Heart Surgery for ICD-10 Administrative Data (RACHS-2).

BACKGROUND: As the cardiac community strives to improve outcomes, accurate methods of risk stratification are imperative. Since adoption of International Classification of Disease-10th Revision (ICD-10) in 2015, there is no published method for congenital heart surgery risk stratification for administrative data. OBJECTIVES: This study sought to develop an empirically derived, publicly available Risk Stratification for Congenital Heart Surgery (RACHS-2) tool for ICD-10 administrative data. METHODS: The RACHS-2 stratification system was iteratively and empirically refined in a training dataset of Pediatric Health Information Systems claims to optimize sensitivity and specificity compared with corresponding locally held Society of Thoracic Surgeons-Congenital Heart Surgery (STS-CHS) clinical registry data. The tool was validated in a second administrative data source: New York State Medicaid claims. Logistic regression was used to compare the ability of RACHS-2 in administrative data to predict operative mortality vs STAT Mortality Categories in registry data. RESULTS: The RACHS-2 system captured 99.6% of total congenital heart surgery registry cases, with 1.0% false positives. RACHS-2 predicted operative mortality in both training and validation administrative datasets similarly to STAT Mortality Categories in registry data. C-statistics for models for operative mortality in training and validation administrative datasets-adjusted for RACHS-2-were 0.76 and 0.84 (95% CI: 0.72-0.80 and 0.80-0.89); C-statistics for models for operative mortality-adjusted for STAT Mortality Categories-in corresponding clinical registry data were 0.75 and 0.84 (95% CI: 0.71-0.79 and 0.79-0.89). CONCLUSIONS: RACHS-2 is a risk stratification system for pediatric cardiac surgery for ICD-10 administrative data, validated in 2 administrative-registry-linked datasets. Statistical code is publicly available upon request.

Hospitalizaciones por cardiopatías congénitas en la Unidad de Cardiología Pediátrica del Centro Hospitalario Pereira Rossell / Hospitalization due to congenital heart disease at the Pereira Rossell Pediatric Hospital's Cardiology Unit / Internações por cardiopatia cardíaca congênita na Unidade de Cardiologia Pediátrica do Centro Hospitalar Pereira Rossell

Introducción: las cardiopatías congénitas (CC) son patologías frecuentes en pediatría. Son causa de importante morbimortalidad en la infancia. Son pacientes complejos, que requieren abordaje integral, en equipo interdisciplinario. Objetivos: describir las características epidemiológicas, clínicas y evolutivas de niños portadores de CC asistidos en la Unidad de Cardiología del HP-CHPR durante el año 2015, así como su estado nutricional y los factores que pudieran influir en este. Material y método: estudio descriptivo, retrospectivo, a través de la revisión de historias clínicas de pacientes portadores de CC, hospitalizados en la Unidad de Cardiología del HP-CHPR en 2015. Se describieron características epidemiológicas y clínicas de los pacientes. Resultados: en el período evaluado egresaron 63 pacientes, que representaron una tasa de 6,58/1.000 egresos hospitalarios. Tenían un promedio de edad de 23,8 meses. Un total de 8 pacientes fueron diagnosticados en el período prenatal, 54 presentaban CC no cianóticas. Habían sido sometidos a tratamiento quirúrgico 24 niños, 13 con cirugía correctiva. Se diagnosticó desnutrición en 43%. Esta fue más prevalente en portadores de CC cianótica, de defectos complejos, y de cromosomopatías u otras malformaciones. Conclusión: los niños con CC representaron un pequeño porcentaje de quienes requirieron hospitalización en el HP-CHPR. El porcentaje de desnutrición fue elevado. Este estudio confirma la importante morbimortalidad de los niños pequeños portadores de CC. Es importante reconocer el mayor riesgo de estos pacientes y actuar en forma individualizada y oportuna.

Introduction: congenital heart disease (CHD) is a frequent pathology among children. It may cause significant morbidity and mortality during childhood. These are complex patients, who require a comprehensive approach and an interdisciplinary team. Objective: to describe the epidemiological, clinical and evolutionary characteristics of children with CHD assisted in the Cardiology Department of the Children Hospital-CHPR in 2015. Material and Methods: descriptive, retrospective study, review of clinical records of patients with CHD, hospitalized in the Cardiology Department of the Children's Hospital PRHC in 2015. Epidemiological and clinical characteristics of patients were described. Results: 63 patients were hospitalized during the evaluated period, a total rate of 6.58/1.000 discharges. They had an average age of 23.8 months. Eight patients were diagnosed in the prenatal period, 54 presented non-cyanotic CHD. Twenty-four children had undergone surgical treatment, 13 had had corrective surgery. Malnutrition was diagnosed in 43% and it was more prevalent in cyanotic CHD carriers, complex defects, and chromosomopathies or other malformations. Conclusion: CHD represented a small percentage of the children who required hospitalization at the PH-PRHC. The percentage of malnutrition was high. The study confirmed the significant morbidity and mortality of these patients. It is important to recognize the highest risk of these patients and act in a customized and timely fashion.

Introdução: as cardiopatias congênitas (CC) são patologias comuns em pediatria. Elas são uma causa significativa de morbidade e mortalidade na infância. Os pacientes são complexos e requerem uma abordagem integral e uma equipe interdisciplinar. Objetivos: descrever as características epidemiológicas, clínicas e evolutivas de crianças com CC atendidas na Unidade de Cardiologia do Hospital Pediátrico PHPR durante o ano de 2015, descrever seu estado nutricional e os fatores que poderiam influenciá-lo. Material e métodos: estudo descritivo, retrospectivo, feito por meio da revisão de prontuários de pacientes com CC, internados na Unidade de Cardiologia do HP-CHPR em 2015. Foram descritas as características epidemiológicas e clínicas dos pacientes. Resultados: no período avaliado, 63 pacientes receberam alta hospitalar, representando uma taxa de 6,5/1.000 altas hospitalares. Eles tinham uma idade média de 23,8 meses. Oito pacientes foram diagnosticados no período pré-natal, 54 apresentavam CC não cianótica. 24 crianças tinham sido submetidas a tratamento cirúrgico, 13 tinham recebido cirurgia corretiva. 43% foram diagnosticadas com desnutrição, a qual foi mais prevalente em portadores de CC cianótica, defeitos complexos e malformações cromossômicas ou outras. Conclusão: os CCs representaram um pequeno percentual de crianças que necessitaram de internação no HP-CHPR. O percentual de desnutrição foi alto. Este estudo confirma a morbidade e mortalidade significativas de crianças pequenas com CC. É importante reconhecer o risco aumentado desses pacientes e agir de forma individualizada e oportuna.

Cardiac and Pregnancy Outcomes of Pregnant Patients With Congenital Heart Disease According to Risk Classification System.

Pregnancy risk assessment for patients with adult congenital heart disease (ACHD) must include physiologic and anatomic impacts. We aimed to determine whether maternal cardiac and pregnancy outcomes vary by disease severity defined according to the following 3 different classifications: ACHD anatomic severity, ACHD physiologic class, and modified World Health Organization (mWHO) class. Cardiac outcomes included a composite of arrhythmia, heart failure, stroke, and thromboembolism. Pregnancy outcomes included a composite of intrauterine growth restriction, preterm birth, preeclampsia, or postpartum hemorrhage. We employed generalized estimating equations to account for multiple pregnancies. Of the 245 pregnancies, 17.1% were preterm and 45.7% were cesarean deliveries. Cardiac hospitalizations occurred in 22.0% and arrhythmias in 12.7%. Cardiac outcomes tended to be more prevalent in people with more severe heart disease. Pregnancy outcomes were U-shaped or less prevalent in people with more severe disease. There was a 2.9-fold increased risk for the composite cardiac outcome for complex anatomy (adjusted incidence rate ratio 2.90, 95% confidence interval 1.08 to 7.81, p = 0.04), a 9.4-fold increased risk for physiologic class C or D (9.37, 1.28 to 68.79, p = 0.03), and a fourfold increased risk for mWHO class III or IV (3.99, 1.53 to 10.40, p = 0.005). There was a lower risk for the composite pregnancy outcome for mWHO class II or II to III (0.54, 0.36 to 0.79, p = 0.002) but no association with anatomy or physiology. In conclusion, physiologic class may be most accurately associated with adverse outcomes and therefore efforts to optimize hemodynamics before pregnancy may help to mitigate the risk.

Associations Between Clinical Outcomes and a Recently Proposed Adult Congenital Heart Disease Anatomic and Physiological Classification System.

Background American Heart Association and American College of Cardiology consensus guidelines introduce an adult congenital heart disease anatomic and physiological (AP) classification system. We assessed the association between AP classification and clinical outcomes. Methods and Results Data were collected for 1000 outpatients with ACHD prospectively enrolled between 2012 and 2019. AP classification was assigned based on consensus definitions. Primary outcomes were (1) all-cause mortality and (2) a composite of all-cause mortality or nonelective cardiovascular hospitalization. Cox regression models were developed for AP classification, each component variable, and additional clinical models. Discrimination was assessed using the Harrell C statistic. Over a median follow-up of 2.5 years (1.4-3.9 years), the composite outcome occurred in 185 participants, including 49 deaths. Moderately or severely complex anatomic class (class II/III) and severe physiological stage (stage D) had increased risk of the composite outcome (AP class IID and IIID hazard ratio, 4.46 and 3.73, respectively, versus IIC). AP classification discriminated moderately between patients who did and did not suffer the composite outcome (C statistic, 0.69 [95% CI, 0.67-0.71]), similar to New York Heart Association functional class and NT-proBNP (N-terminal pro-B-type natriuretic peptide); it was more strongly associated with mortality (C statistic, 0.81 [95% CI, 0.78-0.84]), as were NT-proBNP and functional class. A model with AP class and NT-proBNP provided the strongest discrimination for the composite outcome (C statistic, 0.73 [95% CI, 0.71-0.75]) and mortality (C statistic, 0.85 [95% CI, 0.82-0.88]). Conclusions The addition of physiological stage modestly improves the discriminative ability of a purely anatomic classification, but simpler approaches offer equivalent prognostic information. The AP system may be improved by addition of key variables, such as circulating biomarkers, and by avoiding categorization of continuous variables.

Risk stratification of adults with congenital heart disease during the COVID-19 pandemic: insights from a multinational survey among European experts.

OBJECTIVE: Adults with congenital heart disease (ACHD) may be at a higher risk of a fatal outcome in case of COVID-19. Current risk stratification among these patients relies on personal experience and extrapolation from patients with acquired heart disease. We aimed to provide an expert view on risk stratification while awaiting results from observational studies. METHODS: This study was an initiative of the EPOCH (European Collaboration for Prospective Outcome Research in Congenital Heart disease). Among nine European countries (Austria, Belgium, Denmark, France, Germany, Italy, the Netherlands, Spain and Switzerland), 24 experts from 23 tertiary ACHD centres participated in the survey. ACHD experts were asked to identify ACHD-specific COVID-19 risk factors from a list of potential outcome predictors and to estimate the risk of adverse COVID-19 outcomes in seven commonly seen patient scenarios. RESULTS: 82% of participants did not consider all ACHD patients at risk of COVID-19 related complications. There was a consensus on pulmonary arterial hypertension, Fontan physiology and cyanotic heart disease as risk factors for adverse outcomes. Among different ACHD scenarios, a patient with Eisenmenger syndrome was considered to be at the highest risk. There was a marked variability in risk estimation among the other potential outcome predictors and ACHD scenarios. CONCLUSIONS: Pulmonary arterial hypertension, Fontan palliation and cyanotic heart disease were widely considered as risk factors for poor outcome in COVID-19. However, there was a marked disparity in risk estimation for other clinical scenarios. We are in urgent need of outcome studies in ACHD suffering from COVID-19.

COVID-19 in Adults With Congenital Heart Disease.

BACKGROUND: Adults with congenital heart disease (CHD) have been considered potentially high risk for novel coronavirus disease-19 (COVID-19) mortality or other complications. OBJECTIVES: This study sought to define the impact of COVID-19 in adults with CHD and to identify risk factors associated with adverse outcomes. METHODS: Adults (age 18 years or older) with CHD and with confirmed or clinically suspected COVID-19 were included from CHD centers worldwide. Data collection included anatomic diagnosis and subsequent interventions, comorbidities, medications, echocardiographic findings, presenting symptoms, course of illness, and outcomes. Predictors of death or severe infection were determined. RESULTS: From 58 adult CHD centers, the study included 1,044 infected patients (age: 35.1 ± 13.0 years; range 18 to 86 years; 51% women), 87% of whom had laboratory-confirmed coronavirus infection. The cohort included 118 (11%) patients with single ventricle and/or Fontan physiology, 87 (8%) patients with cyanosis, and 73 (7%) patients with pulmonary hypertension. There were 24 COVID-related deaths (case/fatality: 2.3%; 95% confidence interval: 1.4% to 3.2%). Factors associated with death included male sex, diabetes, cyanosis, pulmonary hypertension, renal insufficiency, and previous hospital admission for heart failure. Worse physiological stage was associated with mortality (p = 0.001), whereas anatomic complexity or defect group were not. CONCLUSIONS: COVID-19 mortality in adults with CHD is commensurate with the general population. The most vulnerable patients are those with worse physiological stage, such as cyanosis and pulmonary hypertension, whereas anatomic complexity does not appear to predict infection severity.

Physical Functioning, Mental Health, and Quality of Life in Different Congenital Heart Defects: Comparative Analysis in 3538 Patients From 15 Countries.

BACKGROUND: We compared physical functioning, mental health, and quality of life (QoL) of patients with different subtypes of congenital heart disease (CHD) in a large international sample and investigated the role of functional class in explaining the variance in outcomes across heart defects. METHODS: In the cross-sectional Assessment of Patterns of Patient-Reported Outcome in Adults with Congenital Heart Disease-International Study (APPROACH-IS), we enrolled 4028 adult patients with CHD from 15 countries. Diagnostic groups with at least 50 patients were included in these analyses, yielding a sample of 3538 patients (median age: 32 years; 52% women). Physical functioning, mental health, and QoL were measured with the SF-12 health status survey, Hospital Anxiety and Depression Scale (HADS), linear analog scale (LAS) and Satisfaction with Life Scale, respectively. Functional class was assessed using the patient-reported New York Heart Association (NYHA) class. Multivariable general linear mixed models were applied to assess the relationship between the type of CHD and patient-reported outcomes, adjusted for patient characteristics, and with country as random effect. RESULTS: Patients with coarctation of the aorta and those with isolated aortic valve disease reported the best physical functioning, mental health, and QoL. Patients with cyanotic heart disease or Eisenmenger syndrome had worst outcomes. The differences were statistically significant, above and beyond other patient characteristics. However, the explained variances were small (0.6% to 4.1%) and decreased further when functional status was added to the models (0.4% to 0.9%). CONCLUSIONS: Some types of CHD predict worse patient-reported outcomes. However, it appears that it is the functional status associated with the heart defect rather than the heart defect itself that shapes the outcomes.

Impact of Coronavirus Disease 2019 (COVID-19) on Patients With Congenital Heart Disease Across the Lifespan: The Experience of an Academic Congenital Heart Disease Center in New York City.

Background We sought to assess the impact and predictors of coronavirus disease 2019 (COVID-19) infection and severity in a cohort of patients with congenital heart disease (CHD) at a large CHD center in New York City. Methods and Results We performed a retrospective review of all individuals with CHD followed at Columbia University Irving Medical Center who were diagnosed with COVID-19 between March 1, 2020 and July 1, 2020. The primary end point was moderate/severe response to COVID-19 infection defined as (1) death during COVID-19 infection; or (2) need for hospitalization and/or respiratory support secondary to COVID-19 infection. Among 53 COVID-19-positive patients with CHD, 10 (19%) were <18 years of age (median age 34 years of age). Thirty-one (58%) had complex congenital anatomy including 10 (19%) with a Fontan repair. Eight (15%) had a genetic syndrome, 6 (11%) had pulmonary hypertension, and 9 (17%) were obese. Among adults, 18 (41%) were physiologic class C or D. For the entire cohort, 9 (17%) had a moderate/severe infection, including 3 deaths (6%). After correcting for multiple comparisons, the presence of a genetic syndrome (odds ratio [OR], 35.82; P=0.0002), and in adults, physiological Stage C or D (OR, 19.38; P=0.002) were significantly associated with moderate/severe infection. Conclusions At our CHD center, the number of symptomatic patients with COVID-19 was relatively low. Patients with CHD with a genetic syndrome and adults at advanced physiological stage were at highest risk for moderate/severe infection.

Interobserver agreement of the anatomic and physiological classification system for adult congenital heart disease.

The Anatomic and Physiological (AP) classification system proposed in the 2018 American College of Cardiology/American Heart Association adult congenital heart disease (ACHD) guidelines assigns 2 dimensions to each patient: anatomic class (AnatC) and physiological stage (PhyS). This approach has not been tested in practice; we assessed interrater reliability and identified sources of disagreement. METHODS: Consensus definitions for AP categories were developed with input from 4 experts. Research assistants (RAs) assigned AnatC/PhyS for patients in the Boston ACHD Biobank, a prospectively enrolled cohort of ambulatory ACHD patients ≥18 years old seen between 2012 and 2019. Two (of 4) expert reviewers then independently assigned AnatC/PhyS for 41 patients. Interrater reliability was assessed with linearly weighted kappa (κω) for agreement between (1) experts and (2) an RA and an expert. Experts examined disagreements and identified sources of variability and areas requiring clarification. RESULTS: Interexpert agreement for AnatC was excellent, with agreement on 38/41 (92.7%) cases and κω 0.88 [0.75, 1.01]. Agreement for PhyS was less robust, with consensus on 24/41 cases (59.5%), κω 0.57 [0.39, 0.75]. Expert-RA agreement was lower for AnatC (κω 0.77 [0.60, 0.95]), whereas PhyS was similar to interexpert agreement (κω 0.53 [0.34, 0.72]). There was ambiguity in the definitions of (1) arrhythmia status, (2) cyanotic CHD, and (3) valve disease. CONCLUSIONS: Although AnatC can be assessed reliably, that is not true for the PhyS part of the AP classification proposed in the 2018 American College of Cardiology/American Heart Association guidelines. Reliability of PhyS would be strengthened by more precise definitions readily interpretable in clinical practice.

The Adult Patient with a Fontan.

The authors summarize the most important anatomic and physiologic substrates of Fontan circulation. Common anatomic substrates include hypoplastic left heart syndrome, tricuspid atresia, double inlet left ventricle, and unbalanced atrioventricular septal defects. After the Fontan operation exercise capacity is limited and the key hemodynamic drivers is limited preload due to a relatively fixed pulmonary vascular resistance. The authors provide contemporary data on survival, morbidity, and need for reintervention. Operative morality is now expected to be less than 1% and 30 year survival approximately 89%. The authors delineate potential therapeutic approaches for the potential late complications.

Transcatheter Interventions in Adult Congenital Heart Disease.

This article provides a detailed review of the current practices and future directions of transcatheter interventions in adults with congenital heart disease. This includes indications for intervention, risks, and potential complications, as well as a review of available devices and their performance.

Triage and management of the ACHD patient with COVID-19: A single center approach.

With the recent emergence of SARS-CoV-2 and COVID-19, healthcare facilities and personnel are expected to rapidly triage and care for patients with even the most complex medical conditions. Adults with congenital heart disease (ACHD) represent an often-intimidating group of complex cardiovascular disorders. Given that general internists and general cardiologists will often be asked to evaluate this group during the pandemic, we propose here an abbreviated triage algorithm that will assist in identifying the patient's overarching ACHD phenotype and baseline cardiac status. The strategy outlined allows for rapid triage and groups various anatomic CHD variants into overarching phenotypes, permitting care teams to quickly review key points in the management of moderate to severely complex ACHD patients.

Adult congenital heart disease and the COVID-19 pandemic.

Adults with congenital heart disease (ACHD) may be at high risk in the case of COVID-19. Due to the heterogeneity of ACHD and secondary complications, risk profiles are, however, not uniform. This document aims to give an overview of relevant data and outline our pragmatic approach to disease prevention and management. Based on anatomy and additional physiological factors including symptoms, exercise capacity, heart failure, pulmonary hypertension and cyanosis, we propose a pragmatic approach to categorising patients into low-risk, intermediate-risk and high-risk groups. We regard especially patients with complex cyanotic conditions, those with palliated univentricular hearts, heart failure, severe valvular disease or pulmonary hypertension as high-risk patients. To avoid infection, we recommend self-isolation and exemption from work for these cohorts. Infected ACHD patients with low or moderate risk and without signs of deterioration may be remotely followed and cared for at home while in self isolation. High-risk patients or those with signs of respiratory or cardiovascular impairment require admission ideally at a tertiary ACHD centre. Especially patients with complex, cyanotic disease, heart failure and arrhythmias require particular attention. Treatment in patients with cyanotic heart disease should be guided by the relative degree of desaturation compared with baseline and lactate levels rather than absolute oxygen saturation levels. Patients with right heart dilatation or dysfunction are potentially at increased risk of right heart failure as mechanical ventilation and acute respiratory distress syndrome can lead to increase in pulmonary arterial pressures.

Incidence and mortality trend of congenital heart disease at the global, regional, and national level, 1990-2017.

Congenital heart disease (CHD) is the most commonly diagnosed congenital disorder in newborns. The incidence and mortality of CHD vary worldwide. A detailed understanding of the global, regional, and national distribution of CHD is critical for CHD prevention.We collected the incidence and mortality data of CHD from the Global Burden of Disease study 2017 database. Average annual percentage change was applied to quantify the temporal trends of CHD incidence and mortality at the global, regional, and national level, 1990-2017. A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility.The incidence of CHD was relatively high in developing countries located in Africa and Asia, while low in most developed countries. Between 1990 and 2017, the CHD incidence rate remained stable at the global level, whereas increased in certain developed countries, such as Germany and France. The age-standardized mortality rate of CHD declined substantially over the last 3 decades, regardless of sex, age, and SDI region. The decline was more prominent in developed countries. We also detected a significant positive correlation between CHD incidence and CHD mortality in both 1990 and 2017, by SDI.The incidence of CHD remained stable over the last 3 decades, suggesting little improvement in CHD prevention strategies and highlighting the importance of etiological studies. The mortality of CHD decreased worldwide, albeit the greatly geographical heterogeneity. Developing countries located in Africa and Asia deserve more attention and priority in the global CHD prevention program.

Prenatal exome sequencing in fetuses with congenital heart defects.

The genetic diagnosis of congenital heart defects (CHDs) is challenging because of genetic and phenotypic heterogeneity. The aim of our study was to evaluate the clinical value of whole exome sequencing (WES) in the prenatal diagnosis of CHDs in a large cohort. Trio-based WES was performed in 260 fetuses with CHDs negative for karyotype and chromosome microarray analysis results. WES produced a diagnostic yield of 10% (26/260) in the entire cohort. Relative high diagnostic rate was observed in cases with cardiac rhabdomyoma (60%), complex CHDs (16.7%), septal defect (14.0%), and conotruncal defect (9.9%). There was no significant difference between the diagnostic yields in simple and complex CHDs groups (9.9% vs 16.7%), and in non-isolated and isolated CHDs groups (15.7% vs 7.9%). The diagnostic yields in cases with CHDs with soft markers, CHDs with fetal growth restriction, and CHDs with other structural anomalies (syndromic CHDs) were 0 (0/13), 50% (1/2) and 18.2% (10/55), respectively. Variants of unknown significance were detected in 16 (6.2%) fetuses, and secondary findings in 7 (2.7%) cases. Variants in 14 candidate genes were identified. Our study demonstrates an incremental diagnostic yield by trio-based WES in the prenatal diagnosis of CHDs after routine tests, not as high as expected.