Neonatal Depression Is Associated With 1-Year Mortality in Critical Congenital Heart Disease.

Background Low 5-minute Apgar scores (AS) are predictive of term and preterm neonatal mortality but have not been well studied in the critical congenital heart disease (CCHD) population. We analyzed US national vital statistics data to evaluate the association between neonatal depression (AS 0-3) and 1-year mortality in CCHD. Methods and Results We performed a retrospective cohort study using 2014 to 2018 Centers for Disease Control and Prevention cohort-linked birth certificate and infant death records. Five-minute AS were categorized as ≤3, 4 to 6, or ≥7. We calculated birth rates and associated mortality rates by AS group in infants with and without CCHD. Multivariable logistic regression analyzed neonatal, maternal, and pregnancy-related risk factors for neonatal depression and 1-year mortality. Of 11 642 neonates with CCHD (0.06% of all births), the 5.8% with AS 0 to 3 accounted for 23.3% of all 1-year CCHD mortality, with 69.9% of deaths occurring within 1 month of life. Gestational age at birth, growth restriction, extracardiac defects, race, and low maternal education were associated with an increased odds of AS 0 to 3 in neonates with CCHD relative to those with AS 7 to 10 on multivariable analysis. AS 0 to 3 was associated with 1-year CCHD mortality after adjusting for these factors, prenatal care, and delivery location (adjusted odds ratio, 14.57 [95% CI, 11.73-18.10]). Conclusions The AS is a routine clinical measure providing important prognostic information in CCHD. These findings suggest that prenatal and perinatal factors, beyond those included in current risk stratification tools, are important for CCHD outcomes. Multidisciplinary collaboration to understand the pathophysiology underlying neonatal depression may help identify interventions to improve CCHD mortality rates.

Utility of Screening Fetal Echocardiograms at a Single Institution Following Normal Obstetric Ultrasound in Fetuses with Down Syndrome.

Fetal echocardiograms (F-echo) are recommended in all pregnancies when the fetus has Down syndrome (DS) even if there was a prior obstetric scan (OB-scan) that was normal. The utility of a screening F-echo in this high-risk population when an OB-scan is normal is unknown. Goal of this study was to evaluate if any diagnosis of a critical congenital heart disease (CHD) was missed in a fetus with DS who had a normal OB-scan. Secondary goal was to determine if any CHD was missed postnatally when an OB-scan was read as normal. Retrospective chart review of all fetuses that had a F-echo whose indication was DS between 1/1/2010 to 6/30/2022 was performed. Fetuses were included if they had an OB-scan that was read as normal and had a F-echo. Postnatal transthoracic echocardiogram (pTTE) was reviewed when available. Critical CHD was defined as CHD requiring catheterization or surgical intervention < 1 month of age. One hundred twenty-two F-echo on fetuses with DS were evaluated, of which 48 met inclusion criteria. OB-scan was performed at 20.4 ± 4.5 weeks gestational age and F-echo was performed at 24.0 ± 4.6 weeks gestational age. No patient with a normal OB-scan had a diagnosis of a critical CHD by F-echo (n = 48, negative predictive value = 100%). Evaluating those patients that had an OB-scan and a pTTE (n = 38), 14 patients were diagnosed with CHD (muscular ventricular septal defect (VSD) n = 5, perimembraneous VSD n = 3, secundum atrial septal defect (ASD) n = 2, primum ASD n = 1, transitional atrioventricular septal defect (AVSD) n = 2, and aortic valve abnormality n = 1; negative predictive value = 63.2%). F-echo correctly diagnosed 4 of the 14 missed OB-scan CHD (perimembraneous VSD n = 2, muscular VSD n = 1, and transitional AVSD n = 1). Critical CHD was not missed with a normal OB-scan in this high-risk population. F-echo also missed the majority of CHD when an OB-scan was read as normal. The cost/benefit of screening F-echo in fetuses with DS should be evaluated if a normal OB-scan has been performed, considering all these patients would have a pTTE performed per guidelines.

Aortic root rotational position associates with aortic valvar incompetence and aortic dilation after arterial switch operation for transposition of the great arteries.

PURPOSE: Aortic dilation and valvar regurgitation can develop in transposition of the great arteries (TGA) after the arterial switch operation (ASO). Variation in aortic root rotational position affects flow dynamics in patients without congenital heart disease. The aim of this study was to assess neo-aortic root (neo-AoR) rotational position and its association with neo-AoR dilation, ascending aorta (AAo) dilation, and neo-aortic valvar regurgitation in TGA following ASO. METHODS: Patients with TGA repaired by ASO who underwent cardiac magnetic resonance (CMR) were reviewed. Neo-AoR rotational angle, neo-AoR and AAo dimensions indexed (to height), indexed left ventricular end diastolic volume (LVEDVI), and neo-aortic valvar regurgitant fraction (RF) were obtained from CMR. RESULTS: Among 36 patients, the median age at CMR was 17.1 years (12.3, 21.9). Neo-AoR rotational angle (range - 52 to + 78°) was clockwise ( ≥ + 15°) in 50%, counterclockwise (<-9°) in 25%, and central (-9 to + 14°) in 25% of patients. A quadratic term for neo-AoR rotational angle, indicating increasing extremes of counterclockwise and clockwise angles, was associated with neo-AoR dilation (R2 = 0.132, p = 0.03), AAo dilation (R2 = 0.160, p = 0.016), and LVEDVI (R2 = 0.20, p = 0.007). These associations remained statistically significant on multivariable analyses. Rotational angle was negatively associated with neo-aortic valvar RF on univariable (p < 0.05) and multivariable analyses (p < 0.02). Rotational angle was associated with smaller bilateral branch pulmonary arteries (p = 0.02). CONCLUSION: In patients with TGA after ASO, neo-AoR rotational position likely affects valvar function and hemodynamics, leading to a risk of neo-AoR and AAo dilation, aortic valvar incompetence, increasing left ventricular size, and smaller branch pulmonary arteries.

Altered white matter connectivity in children with congenital heart disease with single ventricle physiology.

Children born with congenital heart disease (CHD) have seen a dramatic decrease in mortality thanks to surgical innovations. However, there are numerous risk factors associated with CHD that can disrupt neurodevelopment. Recent studies have found that psychological deficits and structural brain abnormalities persist into adulthood. The goal of the current study was to investigate white matter connectivity in early school-age children (6-11 years), born with complex cyanotic CHD (single ventricle physiology), who have undergone Fontan palliation, compared to a group of heart-healthy, typically developing controls (TPC). Additionally, we investigated associations between white matter tract connectivity and measures on a comprehensive neuropsychological battery within each group. Our results suggest CHD patients exhibit widespread decreases in white matter connectivity, and the extent of these decreases is related to performance in several cognitive domains. Analysis of network topology showed that hub distribution was more extensive and bilateral in the TPC group. Our results are consistent with previous studies suggesting perinatal ischemia leads to white matter lesions and delayed maturation.

Patent Ductus Arteriosus Stent Versus Surgical Aortopulmonary Shunt for Initial Palliation of Cyanotic Congenital Heart Disease with Ductal-Dependent Pulmonary Blood Flow: A Systematic Review and Meta-Analysis.

Background In patients with ductal-dependent pulmonary blood flow, initial palliation includes catheter-based patent ductus arteriosus (PDA) stent or surgical aortopulmonary shunt (APS). This meta-analysis aimed to compare outcomes between PDA stent and APS. Methods and Results A comprehensive literature search yielded six retrospective observational studies. Pooled adjusted hazard ratios (HR) were included to control for covariates and assess time to event analysis. Of 757 patients, 243 (32.1%) underwent PDA stent and 514 (67.9%) underwent APS. Pulmonary atresia with intact ventricular septum and expected biventricular repair were more common with PDA stent compared with APS (39.6% versus 21.2%, P<0.001 and 57.9% versus 46.6%, P=0.007, respectively). There was no statistically significant difference in mortality between PDA stent and APS (HR, 0.71; [95% CI, 0.26-1.93]; P=0.50). PDA stent was associated with lower risk of postprocedural complications (odds ratio [OR], 0.45; [95% CI, 0.25-0.81]; P=0.008), mechanical circulatory support (OR, 0.27; [95% CI, 0.09-0.79]; P=0.02), and shorter intensive care unit length of stay (-4.03 days; [95% CI, -5.99 to -2.07]; P<0.001), hospital length of stay (-5.54 days; [95% CI, -9.20 to -1.88]; P=0.003), and duration of mechanical ventilation (-3.41 days; [95% CI, -5.29 to -1.52]; P<0.001). There was no difference in pulmonary artery growth or hazard of unplanned reintereventions. Conclusions PDA stent has a similar hazard of mortality compared with APS. Benefits to PDA stent include shorter duration of mechanical ventilation, shorter hospital length of stay, and fewer complications. Differences in patient characteristics exist with more patients with pulmonary atresia with intact ventricular septum and expected biventricular repair undergoing PDA stent.

Myocardial Parametric Mapping by Cardiac Magnetic Resonance Imaging in Pediatric Cardiology and Congenital Heart Disease.

Parametric mapping, that is, a pixel-wise map of magnetic relaxation parameters, expands the diagnostic potential of cardiac magnetic resonance by enabling quantification of myocardial tissue-specific magnetic relaxation on an absolute scale. Parametric mapping includes T1 mapping (native and postcontrast), T2 and T2* mapping, and extracellular volume measurements. The myocardial composition is altered in various disease states affecting its inherent magnetic properties and thus the myocardial relaxation times that can be directly quantified using parametric mapping. Parametric mapping helps in the diagnosis of nonfocal disease states and allows for longitudinal disease monitoring, evaluating therapeutic response (as in Thalassemia patients with iron overload undergoing chelation), and risk-stratification of certain diseases. In this review article, we describe various mapping techniques and their clinical utility in congenital heart disease. We will also review the available literature on normative values in children, the strengths, and weaknesses of these techniques. This review provides a starting point for pediatric cardiologists to understand and implement parametric mapping in their practice.

Altered erythropoiesis in newborns with congenital heart disease.

BACKGROUND: Fetal hypoxia has been implicated in fetal growth restriction in congenital heart disease (CHD) and leads to stress erythropoiesis in utero. The objective is to assess erythropoiesis and its association with growth in newborns with CHD. METHODS: Fetuses with prenatally diagnosed CHD from 2013 to 2018 were retrospectively reviewed. Pregnancies with multiple gestation, genetic abnormalities, major extra-cardiac anomalies, and placental abruption were excluded. Complete blood count tests at birth were compared to published normative values. Spearman correlation assessed associations of red blood cell (RBC) indices with birth anthropometrics and prenatal Doppler measures. RESULTS: A total of 160 newborns were included. Median gestational age was 38.3 (37.3, 39.0) weeks. Infants ≥37 weeks gestation had lower hemoglobin (Hgb), hematocrit, and elevated nucleated RBC (nRBC), mean corpuscular volume, and mean corpuscular hemoglobin compared to reference. No differences in RBC indices were observed in infants <34 and 34-37 weeks gestation. There was no difference in Hgb and nRBC between CHD subgroups. Neither Hgb nor nRBC were associated with birth anthropometrics or Doppler patterns. CONCLUSIONS: Term infants with CHD demonstrated multiple alterations in erythrocyte indices suggesting ineffective stress erythropoiesis in late gestation resulting in lower Hgb at birth. Altered erythropoiesis was not correlated to growth or Doppler patterns. IMPACT: Newborns with congenital heart disease (CHD) born at term gestation demonstrated altered erythropoiesis. Term newborns with CHD have decreased hemoglobin levels despite having red blood cell indices consistent with stress erythropoiesis, suggesting an incomplete compensatory response to in utero physiologic disturbances associated with CHD. The etiology is unknown; however, it may be influenced by multiple risk factors during pregnancy in the maternal-fetal dyad. Alterations in red blood cell indices were not associated with outcomes of fetal growth.

Severe Maternal Morbidity in Pregnancies Complicated by Fetal Congenital Heart Disease.

Background: Maternal risk factors for fetal congenital heart disease (CHD) may also be associated with delivery complications in the mother. Objectives: This study aimed to determine the prevalence of and risk factors for severe maternal morbidity (SMM) and maternal hospital transfer in pregnancies complicated by fetal CHD. Methods: A population-based retrospective cohort study utilizing linked Ohio birth certificates and birth defect data for all live births from 2011 to 2015 was performed. The primary outcome was composite SMM. Secondary outcome was maternal hospital transfer prior to delivery. Pregnancies with isolated fetal CHD were compared to pregnancies with no fetal anomalies and isolated fetal cleft lip/palate (CLP). Results: A total of 682,929 mothers with live births were included. Of these, 5,844 (0.85%) mothers had fetal CHD, and 963 (0.14%) had fetal CLP. SMM in pregnancies with fetal CHD was higher than that in those with no anomalies (3.6% vs 1.9%, P < 0.001) or CLP (3.6% vs 1.9%, P = 0.006). After adjusting for known risk factors, fetal CHD remained independently associated with SMM when compared to no fetal anomalies (adjusted relative risk [adjRR]: 1.81, 95% CI: 1.58-2.08) and CLP (adjRR: 1.81, 95% CI: 1.12-2.92). Maternal hospital transfer occurred more frequently in fetal CHD cases vs for those without fetal anomalies with an increased adjusted risk (adjRR: 3.65, 95% CI: 3.14-4.25). Conclusions: Pregnancies with isolated fetal CHD have increased risk of SMM and maternal hospital transfer after adjusting for known risk factors. This may inform delivery planning for mothers with fetal CHD. Understanding the biological mechanisms may provide insight into other adverse perinatal outcomes in this population.

Pattern of head circumference growth following bidirectional Glenn in infants with single ventricle heart disease.

BACKGROUND: Infants with single ventricle congenital heart disease demonstrate increasing head growth after bidirectional Glenn; however, the expected growth trajectory has not been well described. AIMS: 1) We will describe the pattern of head circumference growth in the first year after bidirectional Glenn. 2) We will determine if head growth correlates with motor developmental outcomes approximately 12 months after bidirectional Glenn. METHODS: Sixty-nine single ventricle patients underwent bidirectional Glenn between 2010 and 2016. Patients with structural brain abnormalities, grade III-IV intra-ventricular haemorrhage, significant stroke, or obstructive hydrocephalus were excluded. Head circumference and body weight measurements from clinical encounters were evaluated. Motor development was measured with Psychomotor Developmental Index of the Bayley Scales of Infant Development, Third Edition. Generalised estimating equations assessed change in head circumference z-scores from baseline (time of bidirectional Glenn) to 12 months post-surgery. RESULTS: Mean age at bidirectional Glenn was 4.7 (2.3) months and mean head circumference z-score based on population-normed data was -1.13 (95% CI -1.63, -0.63). Head circumference z-score increased to 0.35 (95% CI -0.20, 0.90) (p < 0.0001) 12 months post-surgery. Accelerated head growth, defined as an increase in z-score of >1 from baseline to 12 months post-surgery, was present in 46/69 (66.7%) patients. There was no difference in motor Psychomotor Developmental Index scores between patients with and without accelerated head growth. CONCLUSION: Single ventricle patients demonstrated a significant increase in head circumference after bidirectional Glenn until 10-12 months post-surgery, at which time growth stabilised. Accelerated head growth did not predict sub-sequent motor developmental outcomes.

Pediatric Myocardial T1 and T2 Value Associations with Age and Heart Rate at 1.5 T.

The objective of the study was to determine normal global left ventricular reference values for T1 and T2 in children. This is a retrospective study that included healthy subjects, age 5-19 years, who underwent CMR for the indication of pectus excavatum from 2018 to 2019. Linear regression models were used to determine associations of native T1 and T2 values to heart rate, age, and other CMR parameters. 102 patients with a mean age of 14.0 ± 2.4 years were included (range 5.4-18.8). 87 (85%) were males and 15 (15%) were females. The mean global T1 was 1018 ± 25 ms and the mean T2 was 53 ± 3 ms. T1 was negatively correlated with age (r = - 0.39, p < 0.001) and positively correlated with heart rate (r = 0.32, p < 0.001) by univariate analysis. Multivariable analysis showed that age and heart rate were independently associated with T1. T2 demonstrated a weak negative correlation with age (r = - 0.20, p = 0.047) and no correlation with heart rate. There was no difference in T1 (p = 0.23) or T2 (p = 0.52) between genders. This study reports normal pediatric T1 and T2 values at a 1.5 Tesla scanner. T1 was dependent on age and heart rate, while T2 was less dependent on age with no correlation with heart rate.

Atrioventricular Valve Regurgitation in Single Ventricle Heart Disease: A Common Problem Associated With Progressive Deterioration and Mortality.

The Fontan procedure has provided patients with single ventricle physiology extended survival into adulthood and in many cases has improved their quality of life. Atrioventricular valve regurgitation (AVVR) is common in single ventricle patients and is associated with increased risk of mortality. AVVR is more common in patients with a systemic tricuspid or common atrioventricular valve but is generally progressive irrespective of underlying valve morphology. AVVR can be attributable to diverse structural and functional abnormalities at multiple levels of the valvar apparatus, as well as ventricular dysfunction and dilation. Multiple imaging modalities including recent advances in 3-dimensional echocardiography and cross-sectional imaging have been used to further understand AVVR. Surgery to address AVVR must be tailored to the underlying mechanism and the timing of surgical repair should be chosen carefully. In this review, we discuss the etiologies, treatment options, surgical timing, and outcomes of valve repair or replacement for AVVR in patients with single ventricle congenital heart disease, with a focus on those with a Fontan circulation as AVVR is associated with increased risk for Fontan failure and mortality. In-depth understanding of the current literature will help guide clinicians in their approach and management of AVVR in this population.

Risk Factors for Mortality and Ventricular Tachycardia in Patients With Repaired Tetralogy of Fallot: A Systematic Review and Meta-analysis.

BACKGROUND: Patients with repaired tetralogy of Fallot (rTOF) have increased risk for mortality, sudden cardiac death, and ventricular tachycardia (VT). The aim of this systematic review and meta-analysis is to offer an updated analysis of risk factors following significant changes in surgical and perioperative management. METHODS: A meta-analysis based on the published literature between 2008 and 2018 was conducted. Endpoints were VT, cardiac mortality/VT, and all-cause mortality/VT. Studies with ≥100 patients and ≥10 events were included. RESULTS: Fifteen studies including 7218 patients (average age 27.5 years) were analyzed. Risk factors for VT included older age (per 1 year, odds ratio [OR]: 1.039; 95% confidence interval [CI]: 1.025-1.053), older age at corrective surgery (per 1 year, OR: 1.034; CI: 1.017-1.051), previous palliative shunt (OR: 3.063; CI: 1.525-6.151), number of thoracotomies (OR: 1.416; CI: 1.249-1.604), longer QRS duration (per 1 ms, OR: 1.031; CI: 1.008-1.055), and at least moderate right-ventricular dysfunction (OR: 2.160; CI_ 1.311-3.560). Additional risk factors for cardiac death/VT were previous ventriculotomy (OR: 2.269; CI: 1.226-4.198), lower left-ventricular ejection fraction (per 1%, OR: 1.049; CI: 1.029-1.071), and higher right-ventricular end diastolic volume (per 1 mL/m2, OR: 1.009; CI: 1.002-1.016). Supraventricular tachycardia/atrial fibrillation was an additional risk factor for all-cause mortality/VT (OR: 1.939; CI: 1.088-3.457). CONCLUSIONS: The study highlights the importance of preservation of biventricular systolic function on late outcomes. Ventricular function appears to have a greater impact on outcomes than the severity of pulmonary regurgitation alone in this patient population.

Tricuspid atresia with restrictive foramen ovale: A rare combination with implications on fetal growth.

Restrictive atrial communication is rarely reported in tricuspid atresia but when present it can lead to important morbidity. We describe two fetuses with tricuspid atresia with restrictive foramen ovale who were found to have fetal growth failure. Fetal echocardiography detected a restrictive atrial communication by flow acceleration on color Doppler and significant right atrial dilation in one patient; the atrial septum was not well interrogated in the other patient. Restrictive foramen ovale in tricuspid atresia may be associated with fetal growth failure. Color Doppler interrogation of the atrial septum on fetal echocardiogram may help identify this condition prenatally.

Hemodynamic adaptation to suboptimal fetal growth in patients with single ventricle physiology.

BACKGROUND: In fetuses with structurally normal heart and suboptimal fetal growth (SFG), umbilical artery vascular resistance increases as measured by umbilical artery pulsatility index (UA-PI). The objective of this study is to compare hemodynamic responses to SFG in fetuses with single ventricle (SV) and controls with structurally normal heart. METHODS: Fetal echocardiograms around 30 weeks of gestation were reviewed. UA-PI and middle cerebral artery pulsatility index (MCA-PI) were calculated. SFG was defined as a birth weight below 25th percentile for gestational age. RESULTS: Studies from 92 fetuses were reviewed-SV (n = 50) and controls (n = 42). The prevalence of SFG was higher in SV compared to controls (46% vs 21%, P = .02). In patients with normal heart and SFG, UAPI was significantly higher than normal controls (P = .003) suggesting increased placental vascular resistance. In SV with SFG there was no difference in UAPI compared to SV without SFG. There was no difference in MCA-PI between the groups. CONCLUSIONS: The hemodynamic response to SFG in SV varies from fetuses with structurally normal heart. The mechanism of SFG and the placental pathology may be distinct in SV.

Merkel cell polyomavirus in cutaneous squamous cell carcinoma of immunocompetent individuals.

Squamous cell carcinoma (SCC) is the second most frequently diagnosed skin cancer. It has a higher incidence in immunosuppressed individuals such as organ transplant recipients and human immunodeficiency virus (HIV) carriers. Recently, a newly described polyoma virus, Merkel cell polyomavirus (MCPyV), was found in Merkel cell carcinoma (MCC), a rare aggressive skin cancer also associated with immunosuppression. We hypothesized that MCPyV would be present in SCCs. To test for the presence of MCPyV in immunocompetent SCC patients, we used PCR primer sets directed against the large T (LT) antigen and VP1 gene of MCPyV. We detected MCPyV in 15% (26/177) of SCC DNA samples and 17% (11/63) of adjacent skin DNA samples from 21 of 58 (36%) individuals studied. We did not detect MCPyV in any matched normal blood DNA (0/57), but observed the presence of MCPyV DNA in 1 of 12 normal mouthwash DNAs. All sequenced SCC samples had a common mutation truncating the LT antigen that provides indirect evidence of viral integration. The presence of MCPyV in approximately 15% of SCCs from immunocompetent individuals warrants evaluation of MCPyV as an etiologic agent in the carcinogenesis of SCC.

Methylation not a frequent "second hit" in tumors with germline BRCA mutations.

Mutations in tumor suppressor genes BRCA1 and BRCA2 confer an increased lifetime risk of breast and ovarian cancer. Loss of heterozygosity (LOH) of the wildtype allele has been observed in approximately 80% of tumors from BRCA1 carriers and 70% of tumors from BRCA2 carriers and accounts for the majority of the "second-hits" occurring in BRCA-related tumors. Few sporadic tumors have been reported to have mutations in BRCA. Some sporadic tumors do show LOH of BRCA1 and BRCA2. BRCA1 promoter methylation has also been observed in sporadic ovarian and breast tumors; however, BRCA2 promoter methylation has not been reported in sporadic tumors. The relationship between BRCA LOH and BRCA promoter methylation has not been well characterized in tumors from BRCA germline mutation carriers. The goal of this study was to determine if BRCA1 and BRCA2 promoter hypermethylation serves as a "second-hit" in tumors from mutation carriers that do not show LOH. We studied 38 tumors from BRCA1 carriers and 23 tumors from BRCA2 carriers for LOH. To determine if BRCA1 and BRCA2 promoter hypermethylation serves as a "second-hit" in tumors with germline mutations, we tested 15 tumors lacking LOH and nine tumors with LOH for BRCA1 or BRCA2 promoter methylation. We identified seven BRCA1 tumors and nine BRCA2 tumors lacking LOH. Of these, only one tumor with a BRCA2 mutation showed promoter methylation. These data indicate that promoter methylation is a not a frequent "second-hit" in tumors from BRCA1 or BRCA2 carriers.

Linear porokeratosis with underlying bony abnormalities.

A 58-year-old woman with linear porokeratosis involving the right hand and arm had distal digital narrowing and nail dystrophy with radiographic changes. Whereas isolated cases of bone resorption and flexion deformities with porokeratosis of Mibelli are known to occur, to our knowledge, bony abnormalities in association with linear porokeratosis have not been reported.