Inhaled Nitric Oxide and Higher Necrotizing Enterocolitis Rates in Congenital Heart Disease Patients.

INTRODUCTION: Certain congenital cardiac lesions are at increased risk for the development of necrotizing enterocolitis (NEC). These patients are often reliant on pulmonary and systemic vasomodulators to maintain adequate perfusion and oxygenation. This study sought to determine whether pulmonary or systemic vasodilator treatment is protective against the development of NEC in this population. METHODS: We utilized International Classification of Diseases (ICD) codes to identify high risk congenital cardiac disease patients ≤6 mo of age, cared for at a tertiary children's hospital between January 2011 and January 2021. Cardiac anomalies were stratified into ductal dependent (pulmonary DD-P or systemic DD-S) or independent lesions. The rate of NEC development in those who received vasodilators (inhaled nitric oxide [iNO], pulmonary vasodilators, systemic vasodilators) was compared to controls in a multivariate analysis. RESULTS: Of the 352 patients, who met inclusion criteria, 77.6% had ductal dependent lesions (DD-S 41.9%, DD-P 35.7%), 19.5% received iNO, and 37.5% received other vasodilatory drugs. The overall NEC rate was 15.1%. On univariate analysis, DD-S, iNO use, and systemic vasodilators was associated with a significantly higher risk of NEC, while DD-P was associated with lower NEC risk. On multivariate analysis, only iNO (odds ratio 2.725, confidence interval [1.36-5.44]) and DD-S (odds ratio 2.279, confidence interval [1.02-5.11]) were independent risk factors for NEC. CONCLUSIONS: In patients with at-risk congenital cardiac disease lesions, a ductus dependent systemic circulation or iNO treatment is associated with an increased risk of developing NEC. The presence of iNO or DD-S should be utilized as markers of increased risk both in the prevention and workup of suspected NEC.

Management of Hypertrophic Cardiomyopathy in a Newborn with Dextro-Transposition of the Great Arteries.

Impaired maternal glucose metabolism during pregnancy can have significant effects on the cardiovascular system of the developing fetus. Early in pregnancy the teratogenic effects may lead to structural heart defects, while later in gestation a form of hypertrophic cardiomyopathy can develop due to overgrowth driven by fetal hyperinsulinism. We describe an infant with the uncommon combination of both dextro-transposition of the great arteries and hypertrophic cardiomyopathy. We emphasize the importance of a longitudinal multi-disciplinary approach, from fetal diagnosis to post-operative management, that allowed for an excellent outcome in this rare combination of severe cardiac malformations.

Impact of Maternal-Fetal Environment on Outcomes Following the Hybrid Procedure in the Single Ventricle Population.

Treatment of infants with hypoplastic left heart syndrome (HLHS) remains challenging, and those affected remain with significant risks for mortality and morbidity throughout their lifetimes. The maternal-fetal environment (MFE) has been shown to affect outcomes for infants with HLHS after the Norwood procedure. The hybrid procedure, comprised of both catheterization and surgical components, is a less invasive option for initial intervention compared to the Norwood procedure. It is unknown how the MFE impacts outcomes following the hybrid procedure. This is a single-center, retrospective study of infants born with HLHS who underwent hybrid palliation from January 2009 to August 2021. Predictor variables analyzed included fetal, maternal, and postnatal factors. The primary outcome was mortality prior to Stage II palliation. We studied a 144-subject cohort. There was a statistically significant difference in mortality prior to stage II palliation in infants with prematurity, small for gestational age, and aortic atresia subtype (p < 0.001, p = 0.009, and p = 0.008, respectively). There was no difference in mortality associated with maternal diabetes, hypertension, obesity, smoking or illicit drug use, or advanced maternal age. State and national area deprivation index scores were associated with increased risk of mortality in the entire cohort, such that infants born in areas with higher deprivation had a higher incidence of mortality. Several markers of an impaired MFE, including prematurity, small for gestational age, and higher deprivation index scores, are associated with mortality following hybrid palliation. Individual maternal comorbidities were not associated with higher mortality. The MFE may be a target for prenatal counseling and future interventions to improve pregnancy and neonatal outcomes in this population.

Initial fetal to initial postnatal echocardiogram in uncomplicated atrioventricular septal defects: Do significant changes occur?

BACKGROUND: Yield of serial echocardiography in fetuses with atrioventricular septal defects (fAVSD) has not been well defined. The goal of this study was to document if any major changes occurred from initial fetal to initial postnatal echocardiogram in uncomplicated fAVSD. METHODS: fAVSD were excluded if initial fetal scan documented complex CHD or any concerns. Changes in ventricular function, valvular regurgitation, or diagnosis between first fetal and first postnatal echocardiogram were recorded. RESULTS: Fifty-seven fAVSD met criteria. Ninety-six fetal echocardiograms were done in 57 patients. Initial fetal scan was performed at 24.3 ± 3.7 weeks of estimated gestational age. All fAVSD had normal function, 38 had no atrioventricular valve regurgitation (AVVR), and 19 had mild AVVR. First postnatal echocardiogram was performed at 6.3 ± 15.3 days. Fifty-six patients had normal function, 1 patient had mild dysfunction, 16 patients had no AVVR, 36 had mild AVVR, and 5 had moderate AVVR. Three patients (5%) had an improvement in AVVR by one degree, 27 patients (47%) had no change in AVVR, 24 patients (42%) had an increase in AVVR by one degree, and 3 patients (5%) had an increase in AVVR by two degrees. There was no major missed anatomical diagnosis from first prenatal to first postnatal echocardiogram. CONCLUSION: In fAVSD that had no concerns on their initial fetal echocardiogram, the majority of patients had no major changes noted between their initial fetal echocardiogram and their first postnatal echocardiogram. Repeat fetal echocardiograms may not necessarily be needed in this cohort of patients.

Early Integration of Palliative Care in Families of Children with Single Ventricle Congenital Heart Defects: A Quality Improvement Project to Enhance Family Support.

Children with single ventricle congenital heart defects (SVCHD) experience a significant risk of early mortality throughout their lifespan, particularly during their first year of life. Due to the intense care needed for these children and families, pediatric palliative care (PPC) team consults should be routine; however, medical staff are often reluctant to broach the idea of PPC to families. The involvement of PPC for many carries with it an association to end-of-life (EOL) care. Setting the standard of PPC involvement from the time of admission for the first palliative surgery led to increased family support, decreased days to consult, improved acceptance and communication. The purpose of this article is to describe a quality improvement project of early integration of PPC with families of children with SVCHD. Lessons learned will be presented, including the resources needed and the barriers encountered in assimilating PPC into the standard of care for all patients with SVCHD. The single ventricle (SV) and PPC teams collaborated to enhance the support given to SV families. Education was initiated with cardiology and PPC providers to understand the goal of consistent PPC consults beginning after birth for patients with SVCHD. Parents were educated during fetal consultation regarding the involvement of the PPC team. The SV team ensured compliance with the PPC initiative by identifying eligible patients and requesting consult orders from the primary providers. PPC consultation increased significantly over the 40 month study period to nearly 100% compliance for children with SVCHD who are undergoing pre-Fontan surgery. In addition, mean days to consult decreased dramatically during the study to a current average of 3 days into the patient's hospitalization; the data likely suggest that more PPC consults were routinely ordered versus urgently placed for unexpected complications. Data indicate that patients are being followed by the PPC team at an earlier age and stage in their SV journey which allows for more opportunity to provide meaningful support to these patients and families. The early involvement of the PPC team for children with SV physiology was operationally feasible and was accepted by families, thus allowing PPC providers to establish a therapeutic relationship early in the disease trajectory with the family. It allowed more continuity throughout the SV journey in a proactive fashion rather than a reactive manner.

Pediatric Fontan Associated Liver Disease: Non-invasive Evaluation with Serologic Markers and Acoustic Radiation Force Impulse (ARFI) Elastography.

Hepatic fibrosis is a significant complication in adult Fontan patients suggesting development as a function of time since the surgery. Children with Fontan circulation are not routinely assessed for development of liver disease. We aimed to evaluate the effectiveness of serologic biomarkers and acoustic radiation force impulse (ARFI) elastography to detect liver disease in pediatric Fontan patients. Patients ≥ 1 year after Fontan operation prospectively had hepatic US with acoustic radiation force impulse and laboratory testing. Clinical cardiac data (echocardiograms, cardiac catheterizations) were reviewed. Statistical analysis was performed using Pearson's correlation coefficient, Wilcoxon rank-sum test and Kruskal-Wallis test. Forty patients were enrolled with median age of 11 years and median time since Fontan of 6.5 years. Platelet count negatively correlated with years since Fontan (p < 0.000). Thrombocytopenia was noted in 15% of patients with the lowest platelet count of 78 K/cu mm, in a patient >10 years from the Fontan (DORV) operation. Alanine transaminase (ALT, p = 0.034) and aspartate aminotransferase (AST, p = 0.009) were higher in patients with Extracardiac Conduit Fontan and not in other Fontan operations. Heterogeneous echotexture on liver ultrasound correlated with years since Fontan (p = 0.022), however all acoustic radiation force impulse values were elevated (> 1.34 m/s) and did not correlate with age, years since Fontan, labs or imaging. FibroSure values did not correlate with years since Fontan. This suggests that ARFI may be elevated due to passive hepatic congestion, limiting its value in this patient population. Additional testing is necessary to identify reliable noninvasive screening modalities for hepatic fibrosis in Fontan patients. Our study is the largest pediatric study to evaluate ARFI in patients after the Fontan operation and showed increased shear wave speed for all patients with no correlation with time since palliation. Decreasing platelet count may indicate the development of liver fibrosis.

Clinical and Virologic Characteristics May Aid Distinction of Acute Adenovirus Disease from Kawasaki Disease with Incidental Adenovirus Detection.

Incidental adenovirus detection in Kawasaki disease (KD) is important to differentiate from acute adenovirus disease. Twenty-four of 25 children with adenovirus disease and mimicking features of KD had <4 KD-like features, predominance of species B or E, and higher viral burden compared with those with KD and incidental adenovirus detection.

Diagnosis of systemic-onset juvenile idiopathic arthritis after treatment for presumed Kawasaki disease.

OBJECTIVES: To estimate the incidence of systemic-onset juvenile idiopathic arthritis (SoJIA) within 6 months after treatment for presumed Kawasaki disease (KD) (presumed patients with KD with subsequent diagnosis of SoJIA [pKD/SoJIA]) and describe presentation differences from sole KD. STUDY DESIGN: We identified patients treated for KD at Nationwide Children's Hospital and from the Pediatric Health Information System from 2009-2013. We then identified the subset of children, pKD/SoJIA, who received an International Classification of Diseases, Ninth Revision code for SoJIA and had it listed at least once 3 months after and within 6 months after KD diagnosis. Demographic characteristics, readmission rates, treatments, and complications were noted. A literature review was also performed to identify clinical, laboratory, and echocardiographic data of previously documented patients with KD later diagnosed with SoJIA. RESULTS: There were 6745 total treated patients with KD in the Pediatric Health Information System database during the study period; 10 patients were identified to have pKD/SoJIA (0.2% of cohort). Those with pKD/SoJIA were predominantly Caucasian compared with patients with KD (90% and 46.8%, respectively; P=.003). Macrophage activation syndrome was more common in patients with pKD/SoJIA than in sole patients with KD (30% and 0.30%, respectively; P<.001). Fifteen cases of pKD/SoJIA were identified by literature and chart review, 12 of whom were initially diagnosed with incomplete KD. CONCLUSIONS: We reported a 0.2% incidence of pKD/SoJIA, which was associated with Caucasian race, macrophage activation syndrome, and an incomplete KD phenotype.

Generation of iPSC line NCHi015-A from a patient with truncus arteriosus carrying heterozygous variants in KMT2D and NOTCH1.

Truncus arteriosus (TA) is a congenital heart defect where one main blood vessel emerges from the heart, instead of individual aorta and pulmonary artreries. Peripheral mononuclear cells (PBMCs) of a male infant with TA were reporogrammed using Sendai virus. The resultant iPSC line (NCHi015-A) displayed normal colony formation, expressed pluripotency markers, and differentiated into cells from three germ layers. NCHi015-A was matched to the patient's genetic profile, had normal karyotype, retained genetic variants in KMT2D and NOTCH1, and tested negative for reprogramming transgene. This iPSC line can be used for studying congenital heart defects associated with genetic variants in KMT2D and NOTCH1.

The Utility of Screening Fetal Echocardiograms Following Normal Level II Ultrasounds in Fetuses with Maternal Congenital Heart Disease.

INTRODUCTION: Fetal echocardiograms (F-echo) are recommended in all pregnancies when maternal congenital heart disease (CHD) is present, even if there was a prior level II ultrasound (LII-US) that was normal. The goal of this study was to evaluate if any diagnosis of a critical CHD was missed in a fetus with maternal CHD who had a normal LII-US. METHODS: A retrospective chart review of all F-echoes where the indication was maternal CHD between 1/1/2015 to 12/31/2022 was performed. Fetuses were included if they had a LII-US that was read as normal and had an F-echo. Critical CHD was defined as CHD requiring catheterization or surgical intervention < 1 month of age. RESULTS: A total of 296 F-echoes on fetuses with maternal CHD were evaluated, of which 175 met inclusion criteria. LII-US was performed at 19.8 ± 2.9 weeks gestational age and F-echo was performed at 24.2 ± 2.8 weeks gestational age. No patient with a normal LII-US had a diagnosis of a critical CHD by F-echo (negative predictive value = 100%). Evaluating those patients that had a negative LII-US, ten patients were diagnosed with non-critical CHD postnatally (negative predictive value = 94.3%). F-echo correctly diagnosed two of the ten missed LII-US CHD. CONCLUSIONS: Critical CHD was not missed with a normal LII-US in this at risk population. F-echo also missed the majority of CHD when a LII-US was read as normal. A cost-benefit analysis of screening F-echo in fetuses with maternal CHD should be conducted if a normal LII-US has been performed.

Establishing a Fetal Center in a Freestanding Pediatric Hospital.

Advances in antenatal imaging have allowed early and accurate diagnosis of many fetal anomalies. This, together with the increasing understanding of the natural history of many fetal diseases, has opened the door to the possibility of offering timely fetal interventions in progressive or life-threatening conditions with the intention of improving perinatal outcomes. These interventions can occur at an adult hospital with obstetrical services (with or without pediatric care) or at a freestanding pediatric hospital. In this article, we provide an overview of the approach to develop a comprehensive fetal care center in a freestanding pediatric hospital. Services included prenatal consultation, advanced diagnostics, innovative fetal therapy, research, and special delivery services. We also review the importance of continuous improvement in achieving this goal.

Creation of iPSC line NCHi004-A from a patient with down syndrome and congenital heart defects.

Down syndrome is a congenital disorder resulting from an extra full or partial chromosome 21, which is characterized by a spectrum of systemic developmental abnormalities, including those affecting the cardiovascular system. Here, we generated an iPSC line from peripheral blood mononuclear cells of a male adolescent with Down syndrome-associated congenital heart defects through Sendai virus-mediated transfection of 4 Yamanaka factors. This line exhibited normal morphology, expressed pluripotency markers, trisomy 21 karyotype, and could be differentiated into three germ layers. This iPSC line can be used for studying cellular and developmental etiologies of congenital heart defects induced by aneuploidy of chromosome 21.

Establishment of NCHi009-A, an iPSC line from a patient with hypoplastic left heart syndrome (HLHS) carrying a heterozygous NOTCH1 mutation.

Hypoplastic left heart syndrome (HLHS) is a congenital heart malformation clinically characterized by an underdeveloped left ventricle, mitral or aortic valve stenosis or atresia, and narrowed ascending aorta. Although genetic etiology of HLHS is heterogenous, recurrent NOTCH1 variants have been associated with this defect. We report generation of an iPSC line derived from a female with HLHS with a heterozygous missense NOTCH1 (c.2058G > A; p.Gly661Ser) mutation within the conserved EGF-like repeat 17. This iPSC line exhibited typical cellular morphology, normal karyotype, high expression of pluripotent markers, and trilineage differentiation potential; and can be leveraged to dissect the complex NOTCH1-mediated HLHS disease mechanism.

Preemptive stenting of the left pulmonary artery during comprehensive stage 2 procedure does not influence Fontan candidacy.

Objective: Pulmonary artery reconstruction during comprehensive stage 2 (CS2) procedure can be challenging. Since 2017, we have employed preemptive left pulmonary artery (LPA) stenting. We hypothesized that LPA stenting promotes adequate growth and without compromising Fontan candidacy. Herewith, we report our midterm results. Methods: From 2002 to 2020, 159 patients underwent CS2. Patients were divided as follows: no stent (n = 122; Group 1) and perioperative LPA stent (n = 37; Group 2). Group 2 was subdivided according to unplanned stent (n = 17; Group 2a) or preemptive stent (n = 20; Group 2b). Relevant perioperative data was reviewed. Nonparametric statistics were utilized. Results: Median age and weight at surgery and hospital length of stay after CS2 did not differ between groups. Median cardiopulmonary bypass and crossclamp times were significantly greater in Group 1 (265 vs 243 minutes [P = .021] and 46 vs 26 minutes [P = .008]). In-hospital mortality was similar between Groups 1 and 2 (9.0% vs 18.9%, respectively [P = .1348]). Group 2b demonstrated a superior survival compared to Group 2a (P = .0335) but not Group 1 (P > .9999). Preemptive stenting significantly increased median hilar LPA diameter at CS2 exit angiogram compared with no stenting (P < .0001). Groups 2a and 2b significantly increased the pre-Fontan diameter of the hilar LPA when compared with Group 1 (6.1 and 6.8 vs 5.7 mm, respectively [P < .0001]). A further 120 patients underwent Fontan operation (75%). Median follow-up for Groups 1 and 2 were 7.4 and 3.0 years, respectively. Conclusions: Perioperative LPA stenting during CS2 does not adversely affect pulmonary growth. Preemptive stenting seems advantageous for LPA growth in preparation for Fontan completion.

Structural Racism, Social Determinants of Health, and Provider Bias: Impact on Brain Development in Critical Congenital Heart Disease.

Critical congenital heart disease (cCHD) has neurodevelopmental sequelae that can carry into adulthood, which may be due to aberrant brain development or brain injury in the prenatal and perinatal/neonatal periods and beyond. Health disparities based on the intersection of sex, geography, race, and ethnicity have been identified for poorer pre- and postnatal outcomes in the general population, as well as those with cCHD. These disparities are likely driven by structural racism, disparities in social determinants of health, and provider bias, which further compound negative brain development outcomes. This review discusses how aberrant brain development in cCHD early in life is affected by reduced access to quality care (ie, prenatal care and testing, postnatal care) due to divestment in non-White neighbourhoods (eg, redlining) and food insecurity, differences in insurance status, location of residence, and perceived interpersonal racism and bias that disproportionately affects pregnant people of colour who have fewer economic resources. Suggestions are discussed for moving forward with implementing strategies in medical education, clinical care, research, and gaining insight into the communities served to combat disparities and bias while promoting cultural humility.

Probing single ventricle heart defects with patient-derived induced pluripotent stem cells and emerging technologies.

Single ventricle heart defects (SVHDs) are a severe type of congenital heart disease with poorly understood pathogenic mechanisms. New research using patient-specific induced pluripotent stem cells (iPSCs) as a cellular model is beginning to uncover genetic and cellular etiologies of SVHDs. Hypoplastic left heart syndrome (HLHS) is a type of SVHD that is characterized by an underdeveloped left ventricle and other malformations in the left side of the heart. Hypoplastic right heart syndrome (HRHS), the second type of SVHD, is characterized by an underdeveloped right heart, including malformed tricuspid and pulmonary valves. Despite a noticeable lack of research on SVHD, emerging technologies offer a promising future to further probe the genetic and cellular mechanisms of these diseases. Pediatric cardiovascular research is at the dawn of a new era in terms of what can be discovered with patient-specific iPSCs in conjunction with other technologies (e.g., organoids, single-cell genomics, CRISPR/Cas9 genome editing). In this review, we present recent approaches and findings utilizing patient-specific iPSCs to identify cellular mechanisms responsible for improper cardiac organogenesis in HLHS and HRHS.

Generation of an induced pluripotent stem cell line NCHi003-A from a 11-year-old male with pulmonary atresia with intact ventricular septum (PA-IVS).

Pulmonary atresia with intact ventricular septum (PA-IVS) is a rare congenital heart defect defined by membranous or muscular atresia of the right ventricular outflow tract where patients display varying degrees of hypoplasia of the right ventricle. This condition results in cyanosis due to an inability of blood to flow from the right ventricle to the pulmonary arteries, thus requiring immediate surgical intervention after birth. An iPSC line was generated from peripheral blood mononuclear cells of a 11-year-old male patient diagnosed with PA-IVS through Sendai virus-mediated reprogramming. This disease-specific iPSC line was characterized by immunocytochemistry, STR analysis, karyotype analysis, and mycoplasma testing.

Characterization of an iPSC line NCHi006-A from a patient with hypoplastic left heart syndrome (HLHS).

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect characterized by underdeveloped structures on the left side of the heart, including hypoplasia of the left ventricle and stenosis or atresia of the aortic and mitral valves. Here, we generated an iPSC line from the peripheral blood mononuclear cells of a male patient with HLHS through Sendai virus-mediated transfection of 4 Yamanaka factors. This iPSC line exhibited normal morphology, expressed pluripotency markers, had a normal karyotype, and could differentiate into cells of three germ layers. This iPSC line can be used for studying cellular and developmental etiologies of HLHS.