Factors Associated With Attendance for Cardiac Neurodevelopmental Evaluation.

BACKGROUND AND OBJECTIVES: Neurodevelopmental evaluation of toddlers with complex congenital heart disease is recommended but reported frequency is low. Data on barriers to attending neurodevelopmental follow-up are limited. This study aims to estimate the attendance rate for a toddler neurodevelopmental evaluation in a contemporary multicenter cohort and to assess patient and center level factors associated with attending this evaluation. METHODS: This is a retrospective cohort study of children born between September 2017 and September 2018 who underwent cardiopulmonary bypass in their first year of life at a center contributing data to the Cardiac Neurodevelopmental Outcome Collaborative and Pediatric Cardiac Critical Care Consortium clinical registries. The primary outcome was attendance for a neurodevelopmental evaluation between 11 and 30 months of age. Sociodemographic and medical characteristics and center factors specific to neurodevelopmental program design were considered as predictors for attendance. RESULTS: Among 2385 patients eligible from 16 cardiac centers, the attendance rate was 29.0% (692 of 2385), with a range of 7.8% to 54.3% across individual centers. In multivariable logistic regression models, hospital-initiated (versus family-initiated) scheduling for neurodevelopmental evaluation had the largest odds ratio in predicting attendance (odds ratio = 4.24, 95% confidence interval, 2.74-6.55). Other predictors of attendance included antenatal diagnosis, absence of Trisomy 21, higher Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery mortality category, longer postoperative length of stay, private insurance, and residing a shorter distance from the hospital. CONCLUSIONS: Attendance rates reflect some improvement but remain low. Changes to program infrastructure and design and minimizing barriers affecting access to care are essential components for improving neurodevelopmental care and outcomes for children with congenital heart disease.

Placental delayed villous maturation is associated with fetal congenital heart disease.

BACKGROUND: The placenta is crucial for the overall development and lifelong health of the fetus. Abnormal placental development and function occur in pregnancies with fetal congenital heart disease. However, studies that use standardized diagnostic criteria and incorporate control populations are lacking. This limits the generalizability of current research and the ability to determine the specific placental abnormalities associated with congenital heart disease. OBJECTIVE: This study applied consensus statement guidelines (known as the Amsterdam criteria) for placental pathology interpretation to compare the frequency and pattern of abnormalities in pregnancies with fetal congenital heart disease to demographically matched control pregnancies and evaluate for differences in placental abnormalities by cardiac physiology. STUDY DESIGN: A single-center retrospective cohort study was conducted from January 2013 to June 2019. Infants with a prenatal diagnosis of moderate-severe congenital heart disease who were born at ≥37 weeks of gestation were included. A control group born at ≥37 weeks of gestation but without fetal congenital heart disease or other major pregnancy complications was matched to the congenital heart disease group on maternal race and ethnicity and infant sex. Using the Amsterdam criteria, placental pathology findings were categorized as delayed villous maturation, maternal vascular malperfusion, fetal vascular malperfusion, and inflammatory lesions. The frequency of placental abnormalities was compared between groups, and logistic regression was performed to evaluate the association of clinical and sociodemographic factors with delayed villous maturation, maternal vascular malperfusion, and fetal vascular malperfusion. RESULTS: There were 194 pregnancies with fetal congenital heart disease and 105 controls included, of whom 83% in the congenital heart disease group and 82% in the control group were of non-Hispanic White race and ethnicity. Compared with controls, pregnancies with fetal congenital heart disease had higher rates of delayed villous maturation (6% vs 19%; P<.001) and maternal vascular malperfusion (19% vs 34%; P=.007) but not fetal vascular malperfusion (6% vs 10%; P=.23). Infants with congenital heart disease with 2-ventricle anatomy displayed the highest odds of delayed villous maturation compared with controls (odds ratio, 5.5; 95% confidence interval, 2.2-15.7; P<.01). Maternal vascular malperfusion was 2.2 times higher (P=.02) for infants with 2-ventricle anatomy and 2.9 times higher (P=.02) for infants with single-ventricle physiology with pulmonic obstruction. Within the congenital heart disease group, delayed villous maturation was associated with higher maternal body mass index, polyhydramnios, larger infant birth head circumference, and infant respiratory support in the delivery room, whereas maternal vascular malperfusion was associated with oligohydramnios. In multivariable models adjusting for cardiac diagnosis, associations of delayed villous maturation persisted for infant birth head circumference (odds ratio, 1.2; 95% confidence interval, 1.0-1.5; P=.02) and infant respiratory support in the delivery room (odds ratio, 3.0; 95% confidence interval, 1.3-6.5; P=.007). CONCLUSION: Pregnancies with fetal congenital heart disease displayed higher rates of delayed villous maturation and maternal vascular malperfusion than controls, suggesting that placental maldevelopment may relate to maternal factors. Future investigations are needed to determine the association of these abnormalities with postnatal infant outcomes.

Trajectories of Maternal and Paternal Psychological Distress After Fetal Diagnosis of Moderate-Severe Congenital Heart Disease.

OBJECTIVE: The aim of this study was to compare trajectories of maternal and paternal psychological distress after prenatal diagnosis of fetal moderate-severe congenital heart disease (CHD), from pregnancy through early-mid infancy. METHODS: Pregnant women who received a prenatal diagnosis of fetal moderate-severe CHD, and their partners, were enrolled in a prospective, longitudinal study. Symptoms of psychological distress were measured twice during pregnancy and twice after birth, using the Depression Anxiety Stress Scales (DASS-42). Patterns and predictors of psychological distress were examined using generalized hierarchical linear modeling. RESULTS: Psychological distress was present in 42% (18/43) of mothers and 22% (8/36) of fathers at least once during the study. The rates of distress did not differ between mothers and fathers. There was also no change in probability of distress over time or difference in distress trajectories between mothers and fathers. However, individual trajectories demonstrated considerable variability in symptoms for both mothers and fathers. Predictors of psychological distress included low social support for mothers and a history of mental health conditions for fathers. CONCLUSIONS: Parents who receive a prenatal diagnosis of fetal CHD commonly report symptoms of psychological distress from the time of diagnosis through early-mid infancy and display highly variable trajectories. These data suggest that early and repeated psychological screening is important once a fetal CHD diagnosis is made and that providing mental health and social support to parents may be an important component of their ongoing care.

Reproducibility of Left Ventricular Dimension Versus Area Versus Volume Measurements in Pediatric Patients With Dilated Cardiomyopathy.

BACKGROUND: Multiple echocardiographic methods are used to measure left ventricular size and function. Clinical management is based on individual evaluations and longitudinal trends. The Pediatric Heart Network VVV study (Ventricular Volume Variability) in pediatric patients with dilated cardiomyopathy has reported reproducibility of several of these measures, and how disease state and number of beats impact their reproducibility. In this study, we investigated the impact of observer and sonographer variation on reproducibility of dimension, area, and volume methods to determine the best method for both individual and sequential evaluations. METHODS AND RESULTS: In 8 centers, echocardiograms were obtained on 169 patients prospectively. During the same visit, 2 different sonographers acquired the same imaging protocol on each patient. Each acquisition was analyzed by 2 different observers; first observer analyzed the first acquisition twice. Intraobserver, interobserver, interacquisition, and interobserver-acquisition (different observers and different acquisition) reproducibility were assessed on measurements of left ventricular end-diastolic dimension, area, and volume. Left ventricular shortening fraction, ejection fraction, mass, and fractional area change were calculated. Percent difference was calculated as (interobservation difference/mean)×100. Interobserver reproducibility for both acquisitions was better for both volume and dimension measurements (P≤0.002) compared with area measurements, whereas intraobserver, interacquisition (for both observers), and interobserver-acquisition reproducibilities (for both observer-acquisition sets) were best for volume measurements (P≤0.01). Overall, interobserver-acquisition percent differences were significantly higher than interobserver and interacquisition percent differences (P<0.001). CONCLUSIONS: In pediatric patients with dilated cardiomyopathy, compared with dimension and area methods, left ventricular measurements by volume method have the best reproducibility in settings where assessment is not performed by the same personnel. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00123071.

Prenatal Counseling of Fetal Congenital Heart Disease.

OPINION STATEMENT: The field of fetal cardiology has advanced greatly over the last two decades and congenital heart defects can now be identified in utero with a high level of accuracy. Prenatal counseling of parents given the news of a fetal cardiac defect is an important role of the fetal cardiologist. Prenatal counseling is a complex task that requires skill to perform and interpret fetal echocardiograms, an understanding of fetal and postnatal cardiovascular physiology, knowledge of therapeutic and surgical options, and of long-term outcomes including quality of life. Just as important is the manner in which the information is conveyed and the support offered to the parents as these affect parental understanding, influence decision-making, and may impact the parents' emotional and psychological coping.

Autoimmunity Against the Heart and Cardiac Myosin in Children With Myocarditis.

BACKGROUND: Host autoimmune activity in myocarditis has been proposed to play a role in development of cardiac disease, but evidence of autoimmunity and relationship to outcomes have not been evaluated in pediatric myocarditis. METHODS: We performed a multi-institutional study of children with clinical myocarditis. Newly diagnosed patients were followed for up to 12 months and previously diagnosed patients at a single follow-up for serum levels of autoantibodies to human cardiac myosin, beta-adrenergic receptors 1 and 2, muscarinic-2 receptors, and antibody-mediated protein kinase A (PKA) activation in heart cells in culture. Results were compared with those of healthy control children. RESULTS: Both previously diagnosed patient at follow-up (P = .0061) and newly diagnosed patients at presentation (P = .0127) had elevated cardiac myosin antibodies compared with control subjects. Antibody levels were not associated with recovery status at follow-up in either group. PKA activation was higher at presentation in the newly diagnosed patients who did not recovery normal function (P = .042). CONCLUSIONS: Children with myocarditis have evidence of autoantibodies against human cardiac myosin at diagnosis and follow-up compared with control subjects. Differences in antibody-mediated cell signaling may contribute to differences in patient outcomes, as suggested by elevated antibody-mediated PKA activation in heart cells by the serum from nonrecovered patients.

High Frequency of Detection by PCR of Viral Nucleic Acid in The Blood of Infants Presenting with Clinical Myocarditis.

Specific viruses are associated with pediatric myocarditis, but the prevalence of viral DNAemia detected by blood polymerase chain reaction (PCR) is unknown. We evaluated the prevalence of known cardiotropic viruses (enterovirus, adenovirus, human herpesvirus 6, and parvovirus B19) in children with clinical myocarditis (n = 21). Results were compared to pediatric controls with similar viral PCR testing. The majority of positive PCR (89 %) was noted in children ≤12 months of age at diagnosis compared to older children. Infant myocarditis patients (8/10) had increased the prevalence of PCR positivity compared to infant pediatric controls (4/114) (p < 0.0001). Other than age, patient characteristics at diagnosis were similar between PCR-positive and PCR-negative patients. Both PCR-negative myocarditis infants had clinical recovery at follow-up. Of the PCR-positive myocarditis infants, 4 had clinical recovery, 2 developed chronic cardiomyopathy, 1 underwent heart transplant, and 1 died. Infants with clinical myocarditis have a high rate of blood viral positivity, which is higher compared to older children with myocarditis and healthy infant controls. Age-related differences in PCR positivity may be due to differences in host and/or virus characteristics. Our findings suggest that viral blood PCR may be a useful diagnostic tool and identify patients who would potentially benefit from virus-specific therapy.

Right ventricular function in preterm and term neonates: reference values for right ventricle areas and fractional area of change.

BACKGROUND: Right ventricular (RV) fractional area of change (FAC) is a quantitative two-dimensional echocardiographic measurement of RV function. RV FAC expresses the percentage change in the RV chamber area between end-diastole (RV end-diastolic area [RVEDA]) to end-systole (RV end-systolic area [RVESA]). The objectives of this study were to determine the maturational (age- and weight-related) changes in RV FAC and RV areas and to establish reference values in healthy preterm and term neonates. METHODS: A prospective longitudinal study was conducted in 115 preterm infants (23-28 weeks' gestational age at birth, 500-1,500 g). RV FAC was measured at 24 hours of age, 72 hours of age, and 32 and 36 weeks' postmenstrual age (PMA). The maturational patterns of RVEDA, RVESA, and RV FAC were compared with those in 60 healthy full-term infants in a cross-sectional study (≥37 weeks, 3.5 ± 1 kg), who underwent echocardiography at birth (n = 25) and 1 month of age (n = 35). RVEDA and RVESA were traced in the RV-focused apical four-chamber view, and FAC was calculated using the formula 100 × [(RVEDA - RVESA)/RVEDA)]. Premature infants who developed chronic lung disease or had clinically and hemodynamically significant patent ductus arteriosus were excluded (n = 55) from the reference values. Intra- and interobserver reproducibility analysis was performed. RESULTS: RV FAC ranged from 26% at birth to 35% by 36 weeks' PMA in preterm infants (n = 60) and increased almost 2 times faster in the first month of age compared with healthy term infants (n = 60). Similarly, RVEDA and RVESA increased throughout maturation in both term and preterm infants. RV FAC and RV areas were correlated with weight (r = 0.81, P < .001) but were independent of gestational age at birth (r = 0.3, P = .45). RVEDA and RVESA were correlated with PMA in weeks (r = 0.81, P < .001). RV FAC trended lower in preterm infants with bronchopulmonary dysplasia (P = .04) but was not correlated with size of patent ductus arteriosus (P = .56). There was no difference in RV FAC based on gender or need for mechanical ventilation. CONCLUSIONS: This study establishes reference values of RV areas (RVEDA and RVESA) and RV FAC in healthy term and preterm infants and tracks their maturational changes during postnatal development. These measures increase from birth to 36 weeks' PMA, and this is reflective of the postnatal cardiac growth as a contributor to the maturation of cardiac function These measures are also linearly associated with increasing weight throughout maturation. This study suggests that two-dimensional RV FAC can be used as a complementary modality to assess global RV systolic function in neonates and facilitates its incorporation into clinical pediatric and neonatal guidelines.

De novo 9q gain in an infant with tetralogy of Fallot with absent pulmonary valve: Patient report and review of congenital heart disease in 9q duplication syndrome.

Genomic disruptions, altered epigenetic mechanisms, and environmental factors contribute to the heterogeneity of congenital heart defects (CHD). In recent years, chromosomal microarray analysis (CMA) has led to the identification of numerous copy number variations (CNV) in patients with CHD. Genes disrupted by and within these CNVs thus represent excellent candidate genes for CHD. Microduplications of 9q (9q+) have been described in patients with CHD, however, the critical gene locus remains undetermined. Here we discuss an infant with tetralogy of Fallot with absent pulmonary valve, fetal hydrops, and a 3.76 Mb de novo contiguous gain of 9q34.2-q34.3 detected by CMA, and confirmed by karyotype and FISH studies. This duplicated interval disrupted RXRA (retinoid X receptor alpha; OMIM #180245) at intron 1. We also review CHD findings among previously reported patients with 9q (9q+) duplication syndrome. This is the first report implicating RXRA in CHD with 9q duplication, providing additional data in understanding the genetic etiology of tetralogy of Fallot, CHD, and disorders linked to 9q microduplication syndrome. This report also highlights the significance of CMA in the clinical diagnosis and genetic counseling of patients and families with complex CHD.

Variability of M-mode versus two-dimensional echocardiography measurements in children with dilated cardiomyopathy.

M-mode and 2-dimensional (2D) echocardiographic imaging are routinely used to quantify left-ventricular (LV) size and function in pediatric patients with dilated cardiomyopathy (DCM). The reproducibility of and correlation between these techniques are unknown. This analysis sought to compare interreader, intrareader, and interacquisition reproducibility of M-mode versus 2D measurements in pediatric DCM patients. The Ventricular Volume Variability study of the Pediatric Heart Network is a multicenter, prospective, observational study assessing the course of chronic DCM in children. Two sonographers performed baseline image acquisitions locally, and two readers performed measurements at the echocardiographic core laboratory. One reader repeated measurements 1 month later. These data were used to assess reproducibility and agreement between M-mode and 2D measurements. One hundred sixty-nine subjects were enrolled. M-mode had similar or greater reproducibility in both intrareader and interreader settings for LV dimensions, shortening fraction (SF), and most wall thicknesses. In contrast, 2D reproducibility was similar or better for nearly all variables in the interacquisition setting but not for SF. Interacquisition variability was approximately twice the intrareader variability. LV dimensions by either modality consistently had high reproducibility and had the highest agreement between modalities. In pediatric DCM patients, variability of linear echocardiographic assessment could be minimized by relying on a single reader and using a consistent method (M-mode or 2D) for serial measurements, preferably M-mode when SF is the primary variable of interest. Except for LV dimensions, M-mode and 2D values should not be used interchangeably due to poor agreement.

Spontaneous echocardiographic contrast associated with portosystemic shunt due to persistent patent ductus venosus.

We describe a case of an infant with a single ventricle physiology, who presented with spontaneous microbubbles originating from her inferior vena cava. Imaging revealed a persistent patent ductus venosus, leading to a portosystemic shunt, streaming the microbubbles into the heart. We discuss the possible mechanisms for this rare phenomenon in a child.

Pre-transplant risk factors for chronic renal dysfunction after pediatric heart transplantation: a 10-year national cohort study.

BACKGROUND: Chronic renal dysfunction may develop after pediatric heart transplantation (PHTx). We examined the incidence of end-stage renal disease (ESRD) and chronic renal insufficiency (CRI) after PHTx, the associated pre-transplant patient characteristics, and impact of renal disease on survival. METHODS: Data sources included the Scientific Registry of Transplant Recipients, Centers for Medicare and Medicaid Services and the Social Security Death Master File. All PHTx recipients (age <18 years) in the USA from 1990 to 1999 who survived >1 year were included. ESRD was defined as long-term dialysis and/or kidney transplant. CRI was defined as creatinine >2.5 mg/dl, including those with ESRD. Relationships between pre-transplant characteristics and time to ESRD and CRI were analyzed using Cox proportional hazards models. The effect of renal disease on survival was analyzed using time-dependent Cox models. RESULTS: During the mean follow-up of 7 years (range 1 to 14 years), 61 of 2,032 (3%) PHTxs developed ESRD. Ten-year actuarial risks for ESRD and CRI were 4.3% and 11.8%, respectively. In a multivariate analysis, significant risk factors for ESRD were: hypertrophic cardiomyopathy; African-American race; intensive care unit (ICU) stay or extracorporeal membrane oxygenation (ECMO) at time of transplant; and pre-transplant diabetes. Risk factors for CRI were: pre-transplant dialysis; hypertrophic cardiomyopathy; African-American race; and previous transplant. Adjusted risk of death in those who developed CRI was 9-fold higher than in those who did not (p < 0.0001). CONCLUSIONS: After PHTx there is an increasing risk for CRI and ESRD over time. Recipients with the characteristics identified in this study may be at greater risk. Development of renal disease significantly increases the risk of post-transplant mortality.