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Background Overall one-year non-mortality outcomes for surgically palliated hypoplastic left heart syndrome (HLHS) patients remain understudied. Using the metric Days Alive and Outside of Hospital (DAOH), the present study sought to characterize expectations for surgically palliated patients’ first year of life. Methods The Pediatric Health Information System database was used to identify by ICD-10 code all HLHS patients who underwent surgical palliation (Norwood/hybrid and/or heart transplantation [HTx]) during their index neonatal admission and were successfully discharged alive (n = 2227) and for whom one-year DAOH could be calculated. DAOH quartiles were used to group patients for analysis. Results Median one-year DAOH was 304 (interquartile range [IQR] 250-327), including a median index admission length of stay of 43 days (IQR 28-77). Patients required a median 2 (IQR 1-3) readmissions, each spanning 9 days (IQR 4-20). One-year readmission mortality or hospice discharge occurred in 6% of patients. Patients with lower-quartile DAOH had a median DAOH of 187 (IQR 124-226), whereas upper-quartile DAOH patients had a median DAOH of 335 (IQR 331-340) ( P 7 days at surgery (1.50 [1.14-1.99]), and non-white race/ethnicity (1.33 [1.01-1.75]). Conclusions In the current era, surgically palliated HLHS infants spend approximately 10 months alive and outside of the hospital, although outcomes are highly variable. Knowledge of the factors associated with lower DAOH can inform expectations and guide management decisions.

This study describes the evolving in-hospital management strategies for neonates who are diagnosed with tetralogy of Fallot (ToF).The Pediatric Health Information System (PHIS) database was used to identify admitted patients aged 0 to 1 month old with ToF from 2010 through 2019; era 1, 2010 through 2014; and era 2, 2015 through 2019. International Classification of Diseases codes were used to identify related interventions that occurred during this admission but not necessarily as a neonate: full repair, systemic-to-pulmonary shunt, and percutaneous stent in the right ventricular outflow tract and/or patent ductus arteriosus.Among 6021 neonates diagnosed with ToF, 2030 (34%) underwent an intervention: 60% had total repair, 31% systemic-to-pulmonary shunt, and 9% percutaneous stent. In the no-intervention cohort, in-hospital mortality was 9%. In-hospital mortality between repair (6%), shunt (6%), and stent (3%) patients (P = .446) did not differ. Regarding regional practices, no intervention was most frequently used in the Midwest (69% vs 65% average for all other regions [avg], P = .075) while interventions overall were performed most frequently in the West (36% vs 33.5% avg, P = .075). Among the interventions, full repair was most frequent in the Northeast (76% vs 57% avg, P.001), shunt was most frequent in the Midwest (39% vs 28% avg, P.001), and stent was most frequent in the South (11% vs 7% avg, P = .083). Between eras 1 and 2, the type of intervention changed: full repair (52% vs 69%, P.001) and stent (1% vs 16%, P.001) increased, while shunt decreased (47% vs 15%, P.001).Although most neonates admitted with ToF are discharged with no intervention, more than one-third undergo some intervention with a 3% to 6% mortality. The proportion of these patients who undergo an intervention is unchanged during the past decade, but the types of intervention have changed, and significant regional differences exist.

Background: Congenital heart disease (CHD) is the most common major congenital anomaly and causes significant morbidity and mortality. Epidemiologic evidence supports a role of genetics in the development of CHD. Genetic diagnoses can inform prognosis and clinical management. However, genetic testing is not standardized among individuals with CHD. We sought to develop a list of validated CHD genes using established methods and to evaluate the process of returning genetic results to research participants in a large genomic study. Methods: Two-hundred ninety-five candidate CHD genes were evaluated using a ClinGen framework. Sequence and copy number variants involving genes in the CHD gene list were analyzed in Pediatric Cardiac Genomics Consortium participants. Pathogenic/likely pathogenic results were confirmed on a new sample in a clinical laboratory improvement amendments-certified laboratory and disclosed to eligible participants. Adult probands and parents of probands who received results were asked to complete a post-disclosure survey. Results: A total of 99 genes had a strong or definitive clinical validity classification. Diagnostic yields for copy number variants and exome sequencing were 1.8% and 3.8%, respectively. Thirty-one probands completed clinical laboratory improvement amendments-confirmation and received results. Participants who completed postdisclosure surveys reported high personal utility and no decision regret after receiving genetic results. Conclusions: The application of ClinGen criteria to CHD candidate genes yielded a list that can be used to interpret clinical genetic testing for CHD. Applying this gene list to one of the largest research cohorts of CHD participants provides a lower bound for the yield of genetic testing in CHD.

Recent large-scale sequencing efforts have shed light on the genetic contribution to the etiology of congenital heart defects (CHD); however, the relative impact of genetics on clinical outcomes remains less understood. Outcomes analyses using genetic data are complicated by the intrinsic severity of the CHD lesion and by interactions with conditionally dependent clinical variables. Here we apply Bayesian Networks, an explainable Artificial Intelligence solution, to describe the intertwined relationships between clinical variables, demography, and genetics in a cohort of children with single ventricle CHD. As isolated variables, a damaging genetic variant in a gene related to abnormal heart morphology and prolonged ventilator support following stage I palliative surgery increased the probability of having a low Mental Developmental Index (MDI) score at 14 months of age by 1.9- and 5.8-fold, respectively. However, in combination, these variables acted synergistically to further increase the probability of a low MDI score by 10-fold. Likewise, genetic information was predictive of a favorable neurodevelopmental outcome. For example, the absence of a damaging variant in a known syndromic CHD gene and a shorter post-operative ventilator support increased the probability of a normal MDI score 1.7- and 2.4-fold, respectively, but in combination increased the probability of a good outcome by 59-fold. Our analyses suggest a modest genetic contribution to neurodevelopmental and growth outcomes as isolated variables, similar to known clinical predictors. By contrast, genetic, demographic, and clinical variables interact synergistically to markedly impact clinical outcomes. These findings underscore the importance of capturing and quantifying the impact of damaging genomic variants in the context of multiple, conditionally dependent variables, such as pre- and post-operative factors, and demography.

Background: Valvar pulmonary stenosis (vPS) accounts for 8% to 12% of congenital heart disease cases. Multiple genetic syndromes are associated with vPS, most commonly Noonan syndrome, but the cause is unknown in most cases. We analyzed genomic data from a large cohort with vPS to determine the prevalence of genetic diagnosis. Methods: The Pediatric Cardiac Genomics Consortium database was queried to identify probands with vPS without complex congenital heart disease or aneuploidy and with existing whole exome or genome sequencing. A custom analysis workflow was used to identify likely pathogenic or pathogenic variants in disease-associated genes. Demographic and phenotypic characteristics were compared between groups with and without molecular diagnoses. Results: Data from 119 probands (105 trios) were included. A molecular diagnosis was identified in 22 (18%); 17 (14%) had Noonan syndrome or a related disorder. Extracardiac and neurodevelopmental comorbidities were seen in 67/119 (56%) of probands. Molecular diagnosis was more common in those with extracardiac and neurodevelopmental phenotypes than those without (18/67 versus 4/52, P =0.0086). Conclusions: Clinicians should have high suspicion for a genetic diagnosis in individuals with vPS, particularly if additional phenotypes are present. Our results suggest that clinicians should consider offering sequencing of at least the known congenital heart disease and RASopathy genes to all individuals with vPS, regardless of whether that individual has extracardiac or neurodevelopmental phenotypes present.

* Abbreviations: CICU: : cardiac intensive care unit d-TGA: : dextro-transposition of the great arteries FIO2: : fraction of inspired oxygen A 20-year-old gravida 2, para 1 pregnant woman was referred to our fetal care center because of a diagnosis of structural heart disease in the fetus. The woman’s medical history included asthma, seasonal allergies, and depression, with no surgical history. She had 1 prior term vaginal delivery. This pregnancy had been complicated by late presentation to prenatal care at 20 weeks’ gestation. Her medications included asthma maintenance medications and prenatal vitamins. Pertinent family history included her partner who had a ventricular septal defect and a paternal male first cousin with transposition of the great arteries. Prenatal laboratory test results were unremarkable and genetic screening was declined. Imaging at the referring obstetrician’s office was significant for transposition of the great arteries with an intact ventricular septum and normal fetal biometry. She was referred to our center at 21 1/7 weeks’ gestation, with imaging and consultation with fetal cardiology at 21 6/7 weeks’ gestation. The following tests were performed: Figure 1. Four-chamber view of the heart at 21 weeks’ gestation, swept to the outflow tracts showing parallel arrangement of the great arteries with the pulmonary artery (PA) located posteriorly and arising from the left ventricle (LV) and the aorta (Ao) arising from the right ventricle (RV). Fetal position: right (R), left (L), anterior (A), posterior (P). At …

Normalizing cardiovascular measurements for body size allows for comparison among children of different ages and for distinguishing pathologic changes from normal physiologic growth. Because of growing interest to use height for normalization, the aim of this study was to develop height-based normalization models and compare them to body surface area (BSA)-based normalization for aortic and left ventricular (LV) measurements. The study population consisted of healthy, non-obese children between 2 and 18 years of age enrolled in the Pediatric Heart Network Echo Z-Score Project. The echocardiographic study parameters included proximal aortic diameters at 3 locations, LV end-diastolic volume, and LV mass. Using the statistical methodology described in the original project, Z-scores based on height and BSA were determined for the study parameters and tested for any clinically significant relationships with age, sex, race, ethnicity, and body mass index (BMI). Normalization models based on height versus BSA were compared among underweight, normal weight, and overweight (but not obese) children in the study population. Z-scores based on height and BSA were calculated for the 5 study parameters and revealed no clinically significant relationships with age, sex, race, and ethnicity. Normalization based on height resulted in lower Z-scores in the underweight group compared to the overweight group, whereas normalization based on BSA resulted in higher Z-scores in the underweight group compared to the overweight group. In other words, increasing BMI had an opposite effect on height-based Z-scores compared to BSA-based Z-scores. Allometric normalization based on height and BSA for aortic and LV sizes is feasible. However, height-based normalization results in higher cardiovascular Z-scores in heavier children, and BSA-based normalization results in higher cardiovascular Z-scores in lighter children. Further studies are needed to assess the performance of these approaches in obese children with or without cardiac 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

Background Birthweight is a critical predictor of congenital heart disease (CHD) surgical outcomes. Hypoplastic left heart syndrome (HLHS) is cyanotic CHD with known fetal growth restriction and placental abnormalities. Transposition of the great arteries (TGA) is cyanotic CHD with normal fetal growth. Comparison of the placenta in these diagnoses may provide insights on the fetal growth abnormality of CHD. Methods Clinical data and placental histology from placentas associated with Transposition of the Great Arteries (TGA) were analyzed for gross pathology, morphology, maturity and vascularity and compared to both control and previously analyzed HLHS placentas [1]. RNA was isolated from HLHS, TGA and control placentas and sequenced by Illumina HiSeq.Transcriptome analysis was performed using AltAnalyze. Immunohistochemistry was utilized to assess placental nutrient transporter expression in all three groups. Results Placental weight was reduced in TGA cases, and demonstrated reduced villous vasculature, immature terminal villi in the parenchyma compared to controls and reflected our previous data from HLHS placentas. However, birth weight was not reduced in TGA cases compared to controls in contrast to the HLHS cohort and birthweight:placental weight ratio was significantly increased in TGA cases but not HLHS compared to control. Transcriptomic and histologic analysis demonstrates reduced cell activity and nutrient transport capability in HLHS but not TGA placentas which appear to increase/maintain these mechanisms. Conclusions Despite common vascular disturbances in placentas from HLHAs and TGA, these do not account for the disparities in birthweights frequently seen between these CHD subtypes, in contrast our transcriptomic and histologic analyses reveal differentially regulated mechanisms between the subtypes that may explain these disparities.

Objective To compare length of stay of the initial neonatal hospitalization and mortality across multiple stages of surgical palliation for infants with left-sided obstructive lesions and severely restrictive or intact atrial septum (I/RAS). Methods Retrospective cohort study of patients prenatally diagnosed with left-sided obstructive lesions and I/RAS, defined by fetal pulmonary venous Dopplers. Results We identified 76 fetal patients with 59 live born intending to pursue intervention. Those with I/RAS had longer durations of mechanical ventilation (P = .031) but no difference in intensive care unit or total length of stay. Survival to discharge from neonatal hospitalization was 41.7% in the I/RAS group and 80.7% in the unrestrictive group (P = .001). There was a higher proportion of deaths between stage 1 and stage 2 in the I/RAS group - 5/9 (55.6%) vs 9/50 (18%) in the unrestrictive group (P = .027). Beyond stage 2 palliation there was trend toward a difference in overall mortality (66.7% in I/RAS vs 35.7% in unrestrictive, P = .05) but no statistically significant difference in transplant-free survival (33.3% in I/RAS vs 53.5% in unrestrictive, P = .11). Conclusion The survival disadvantage conferred by prenatally diagnosed severe atrial septal restriction is most pronounced in the neonatal and early infancy period, with no detectable difference in late midterm transplant-free survival in our cohort.

ImportanceNeurodevelopmental disabilities are commonly associated with congenital heart disease (CHD), but medical and sociodemographic factors explain only one-third of the variance in outcomes.ObjectiveTo examine whether potentially damaging de novo variants (dDNVs) in genes not previously linked to neurodevelopmental disability are associated with neurologic outcomes in CHD and, post hoc, whether some dDNVs or rare putative loss-of-function variants (pLOFs) in specific gene categories are associated with outcomes.Design, Setting, and ParticipantsThis cross-sectional study was conducted from September 2017 to June 2020 in 8 US centers. Inclusion criteria were CHD, age 8 years or older, and available exome sequencing data. Individuals with pathogenic gene variants in known CHD- or neurodevelopment-related genes were excluded. Cases and controls were frequency-matched for CHD class, age group, and sex.ExposuresHeterozygous for (cases) or lacking (controls) dDNVs in genes not previously associated with neurodevelopmental disability. Participants were separately stratified as heterozygous or not heterozygous for dDNVs and/or pLOFs in 4 gene categories: chromatin modifying, constrained, high level of brain expression, and neurodevelopmental risk.Main Outcomes and MeasuresMain outcomes were neurodevelopmental assessments of academic achievement, intelligence, fine motor skills, executive function, attention, memory, social cognition, language, adaptive functioning, and anxiety and depression, as well as 7 structural, diffusion, and functional brain magnetic resonance imaging metrics.ResultsThe study cohort included 221 participants in the post hoc analysis and 219 in the case-control analysis (109 cases [49.8%] and 110 controls [50.2%]). Of those 219 participants (median age, 15.0 years [IQR, 10.0-21.2 years]), 120 (54.8%) were male. Cases and controls had similar primary outcomes (reading composite, spelling, and math computation on the Wide Range Achievement Test, Fourth Edition) and secondary outcomes. dDNVs and/or pLOFs in chromatin-modifying genes were associated with lower mean (SD) verbal comprehension index scores (91.4 [20.4] vs 103.4 [17.8]; P = .01), Social Responsiveness Scale, Second Edition, scores (57.3 [17.2] vs 49.4 [11.2]; P = .03), and Wechsler Adult Intelligence Scale, Fourth Edition, working memory scores (73.8 [16.4] vs 97.2 [15.7]; P = .03), as well as higher likelihood of autism spectrum disorder (28.6% vs 5.2%; P = .01). dDNVs and/or pLOFs in constrained genes were associated with lower mean (SD) scores on the Wide Range Assessment of Memory and Learning, Second Edition (immediate story memory: 9.7 [3.7] vs 10.7 [3.0]; P = .03; immediate picture memory: 7.8 [3.1] vs 9.0 [2.9]; P = .008). Adults with dDNVs and/or pLOFs in genes with a high level of brain expression had greater Conners adult attention-deficit hyperactivity disorder rating scale scores (mean [SD], 55.5 [15.4] vs 46.6 [12.3]; P = .007).Conclusions and RelevanceThe study findings suggest neurodevelopmental outcomes are not associated with dDNVs as a group but may be worse in individuals with dDNVs and/or pLOFs in some gene sets, such as chromatin-modifying genes. Future studies should confirm the importance of specific gene variants to brain function and structure.

Objective To determine uptake of cardiac screening and recurrence of bicuspid aortic valve (BAV) and thoracic aortic aneurysm (TAA) in a population of at-risk siblings of pediatric probands. Study design A retrospective chart review of pediatric patients with known BAV and/or TAA was performed. Echocardiogram data from identified siblings were collected to determine screening uptake and recurrence of BAV and TAA. Statistical analyses were performed using Wilcoxon signed-rank test and chi-square. Results The cohort included 251 probands and 388 at-risk siblings. Among the siblings, 150 had at least 1 echocardiogram, giving an overall screening uptake of 38.7%. The only factor found to be associated with increased uptake was documented recommendation for screening of first-degree relatives in the proband’s initial cardiology note (P = .03). A total of 11 screened siblings (7.3%) had BAV and 19 had TAA (12.7%), with an overall combined recurrence of 15.3%. Siblings of probands who had both BAV and TAA had increased recurrence of TAA compared with siblings of probands with isolated BAV (16.1% vs 3.9%, respectively). Conclusions Given low uptake in at-risk siblings, the opportunity exists to assess barriers for families in pursuing the recommended screening. Furthermore, the relatively high recurrence of BAV and TAA in at-risk siblings highlights the potential for improved health outcomes through increased screening and early detection. Developing standardized guidelines and promoting early cardiac screening in at-risk siblings while counseling families about hereditary risk for BAV and TAA may help improve uptake and optimize clinical management in at-risk pediatric patients.

OBJECTIVES: To determine if neurodevelopmental deficits in children with single-ventricle physiology change with age and early developmental scores predict 6-year outcomes. METHODS: In the Single Ventricle Reconstruction Trial, Bayley Scales of Infant Development, Second Edition, were administered at 14 months of age, and parents completed the Behavior Assessment System for Children, Second Edition (BASC-2) annually from the ages of 2 to 6 years. Scores were classified as average, at risk, or impaired. We calculated sensitivities, specificities, and positive and negative predictive values of earlier tests on 6-year outcomes. RESULTS: Of 291 eligible participants, 244 (84%) completed the BASC-2 at 6 years; more Single Ventricle Reconstruction participants than expected on the basis of normative data scored at risk or impaired on the BASC-2 Adaptive Skills Index at that evaluation (28.7% vs 15.9%; P < .001). Children with Adaptive Skills Composite scores CONCLUSIONS: Many children with hypoplastic left heart syndrome who have low adaptive skills at the age of 6 years will not be identified by screening at earlier ages. With our findings, we highlight the importance of serial evaluations for children with critical congenital heart disease throughout development.

Introduction: Ideal timing for elective delivery of infants with single ventricle heart disease, balancing benefits of fetal growth with risk of fetal demise, remains unclear. Improved understanding of fetal growth in late gestation and postnatal outcomes related to gestational age (GA) may improve insight. Hypothesis: Patients with single ventricle heart disease and aortic hypoplasia have decreased fetal growth velocity in late gestation, but longer gestation results in improved outcomes. Methods: This was a retrospective cohort analysis of patients in phase 2 of the National Pediatric Cardiology Quality Improvement Collaborative database from 2016-2019 who were anticipated to need stage 1 palliation (S1P) and had a GA of > 36 weeks. Birth weight (BW) and BW z-scores were compared across GA to normative values. Outcome measures of survival to stage 2 palliation (S2P), post-S1P length of stay, and duration of mechanical ventilation were compared by GA. Results: The cohort included 1290 infants. There was an increase in mean BW with increasing GA (2.83 kg at 36-37 weeks, 3.15 kg at 38 weeks, 3.33 kg at 39 weeks, 3.40 kg at > 40 weeks; p > 40 weeks; p > 40 weeks; p=0.0001). Among 1083 survivors to discharge or S2P if not discharged, there was no difference in post S1P length of hospitalization across GA (p=0.19). Infants who reached S2P readiness milestones were more likely to undergo S2P if born after longer gestation (p=0.0001). Conclusions: Infants with single ventricle heart disease and aortic hypoplasia have decreased growth velocity in late gestation, but growth continues. Infants born after longer gestation have improved outcomes with shorter duration of ventilation and greater likelihood of undergoing S2P.

Introduction: Obesity is associated with comorbidities that may be detrimental to single-ventricle patients who have had a Fontan procedure. We assessed the prevalence of obesity in adults with a Fontan circulation and evaluated the hypothesis that higher body mass index (BMI) in early childhood is associated with obesity in adulthood. Methods: Retrospective cohort study of patients with a Fontan circulation aged 18-32 years, seen 2011-2019. Those with an atriopulmonary Fontan or chromosomal abnormality known to affect growth were excluded. Historical height and weight measurements, results of recent cardiac testing, and body mass index (BMI) over time were recorded. Obesity was defined as BMI ≥30 kg/m 2 . The associations between childhood anthropometrics, adult BMI, and most recent cardiac testing were assessed. Results: The cohort included 113 adults with a Fontan circulation (median age 22.7 [IQR 20.2-26.4] years; 44% female). There were no significant differences in age, age at Fontan, Fontan type, or ventricular morphology between obese (n=21, 19%; 52% female) and non-obese (n=92, 81%; 41% female) patients. Compared to non-obese adults, obese patients had higher BMI percentiles at age 2 years (80 th [33-95] vs 43 rd [13-82] percentile, p=0.02), at age 4 years (90 th [73-93] vs 57 th [22-81] percentile, p=0.002), and at the time of the Fontan procedure (85 th [51-98] vs 20 th [5-57] percentile, p=0.002). Being overweight at time of Fontan (BMI percentile >85%) strongly predicted later obesity (OR=18.3, 95% CI 3.7-90.3, p2 (19.1±5.2 vs 25.5±6.6 mL/kg/min, p2 (59±13 vs 65±14% predicted, p=0.06), higher systolic blood pressure (121±17 vs 112±12 mmHg, p=0.007) and higher ventricular end-diastolic pressure (11±4 vs 9±3 mmHg, p= 0.03). Adult BMI weakly correlated with ventricular end-diastolic pressure (r=0.24, p=0.048). Conclusions: Higher BMI in early childhood is associated with obesity in adults with a Fontan circulation. Adult obesity is associated with worse exercise capacity, higher blood pressure, and higher ventricular end-diastolic pressure. Weight interventions in children with a Fontan circulation may help prevent later obesity and its adverse consequences.

IntroductionCongenital heart defects (CHD) affect approximately 1% of all live births, and often require complex surgeries at birth. Placental development and function is vital to ensure normal fetal development. We have previously demonstrated abnormal placental development and vascularization in human CHD placentas, and placental expression changes in genes important for heart development. Hand1 has roles in both heart and placental development and is implicated in CHDs including double right outlet, hypoplastic left heart syndrome, and septal defects; however, Hand1 involvement in placental vascularization and development is under-investigated. We utilized the Hand1A126fs/+murine model to investigate Hand1 in placentation and vascularization.MethodsHand1A126fs/+female mice were time-mated with Nkx2.5cre(placenta- and heart-specific) males to produce either Nkx2.5cre;Hand1+/+or Nkx2.5cre;Hand1A126fs/+fetuses. Feto-placental units were harvested at timepoints from E8.5 to E14.5 for histological analysis; vascular assessment by immunohistochemistry for Hand1, CD-31, and CK-7; and angiogenesis by qPCR.ResultsEmbryonic lethality occurs in Nkx2.5cre/Hand1A126fs/+by E14.5 due to a failure of placental labyrinth formation and vascularization. Chorionic trophoblasts did not form, although trophoblast giant cell subtypes were present. Fetal vessels failed to develop properly and were significantly lower in the labyrinth by day E12.5. Placental growth factor levels were significantly increased, and Angiopoietin2 expression trended higher in Nkx2.5cre/Hand1A126fs/+placental labyrinths compared to control littermates.ConclusionWe demonstrate that Hand1 expression in placental chorion and trophoblast is necessary for proper patterning of the labyrinth and vascularization within the labyrinth. Multiple angiogenic factors known to be expressed in trophoblast were disrupted in Nkx2.5cre/Hand1A126fs/+placental labyrinths compared to control littermates. Alterations in Hand1 expression represent a potential mechanism for abnormal placentation and early miscarriage in cases of CHD.

Background/Aims: The Pediatric Heart Network Marfan Trial was a randomized trial comparing atenolol versus losartan on aortic root dilation in 608 children and young adults with Marfan syndrome. Barriers to enrollment included a limited pool of eligible participants, restrictive entry criteria, and a diverse age range that required pediatric and adult expertise. Retention was complicated by a 3-year commitment to a complex study and medication regimen. The Network partnered with the Marfan Foundation, bridging the community with the research. The aims of this study are to report protocol and medication adherence and associated predictive factors, and to describe recruitment and retention strategies. Methods: Recruitment, retention, and adherence to protocol activities related to the primary outcome were measured. Retention was measured by percentage of enrolled participants with 3-year outcome data. Protocol adherence was calculated by completion rates of study visits, ambulatory electrocardiography (Holter monitoring), and quarterly calls. Medication adherence was assessed by the number of tablets or the amount of liquid in bottles returned. Centers were ranked according to adherence (high, medium, and low tertiles). Recruitment, retention, and adherence questionnaires were completed by sites. Descriptive statistics summarized recruitment, retention, and adherence, as well as questionnaire results. Regression modeling assessed predictors of adherence. Results: Completion rates for visits, Holter monitors, and quarterly calls were 99%, 94%, and 96%, respectively. Primary outcome data at 3 years were obtained for 88% of participants. The mean percentage of medication taken was estimated at 89%. Site and age were associated with all measures of adherence. Young adult and African American participants had lower levels of adherence. Higher adherence sites employed more strategies; had more staffing resources, less key staff turnover, and more collaboration with referring providers; utilized the Foundation’s resources; and used a greater number of strategies to recruit, retain, and promote protocol and medication adherence. Conclusion: Overall adherence was excellent for this trial conducted within a National Institutes of Health–funded clinical trial network. Strategies specifically targeted to young adults and African Americans may have been beneficial. Many strategies employed by higher adherence sites are ones that any site could easily use, such as greeting families at non-study hospital visits, asking for family feedback, providing calendars for tracking schedules, and recommending apps for medication reminders. Additional key learnings include adherence differences by age, race, and site, the value of collaborative learning, and the importance of partnerships with patient advocacy groups. These lessons could shape recruitment, retention, and adherence to improve the quality of future complex trials involving rare conditions.

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.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.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 infants34 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.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.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.

BACKGROUND: Low socioeconomic status (SES) has emerged as an important risk factor for higher short-term mortality and neurodevelopmental outcomes in children with hypoplastic left heart syndrome and related anomalies; yet little is known about how SES affects these outcomes over the long-term. METHODS: We linked data from the Single Ventricle Reconstruction trial to US Census Bureau data to analyze the relationship of neighborhood SES tertiles with mortality and transplantation, neurodevelopment, quality of life, and functional status at 5 and 6 years post–Norwood procedure (N = 525). Cox proportional hazards regression and linear regression were used to assess the association of SES with mortality and neurodevelopmental outcomes, respectively. RESULTS: Patients in the lowest SES tertile were more likely to be racial minorities, older at stage 2 and Fontan procedures, and to have more complications and fewer cardiac catheterizations over follow-up (all P < .05) compared with patients in higher SES tertiles. Unadjusted mortality was highest for patients in the lowest SES tertile and lowest in the highest tertile (41% vs 29%, respectively; log-rank P = .027). Adjustment for patient birth and Norwood factors attenuated these differences slightly (P = .055). Patients in the lowest SES tertile reported lower functional status and lower fine motor, problem-solving, adaptive behavior, and communication skills at 6 years (all P < .05). These differences persisted after adjustment for baseline and post-Norwood factors. Quality of life did not differ by SES. CONCLUSIONS: Among patients with hypoplastic left heart syndrome, those with low SES have worse neurodevelopmental and functional status outcomes at 6 years. These differences were not explained by other patient or clinical characteristics.

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Increased extracellular volume (ECV) by CMR is a marker of interstitial myocardial fibrosis and is associated with diastolic dysfunction in sickle cell anemia (SCA). Left atrial (LA) dysfunction and stiffness contribute to the development of diastolic heart failure in other settings. We aimed to evaluate LA function and stiffness associations with ECV, tricuspid regurgitation jet velocity (TRV) and exercise abnormalities in SCA. In a prospective study, individuals with SCA underwent CMR, echocardiography and exercise test. ECV was measured using MOLLI sequence. Atrial strain was studied in the 4- and 2-chamber views. LA stiffness was calculated as the ratio of echocardiographic E/e’-to-LA reservoir strain. Twenty-four participants with SCA were included (median age 20 years). ECV was increased in participant with SCA compared to our lab normal values (mean 0.44 ± 0.08 vs 0.26 ± 0.02, P

OBJECTIVE To evaluate the prevalence of Noonan spectrum disorders (NSD) in a pediatric population with valvar pulmonary stenosis (vPS) and identify the clinical characteristics that differentiate those with NSD from those without NSD. DESIGN A retrospective chart review of 204 patients diagnosed with vPS between 9/1/2012 and 12/1/2016 at a pediatric medical center was performed. The quantitative features of vPS, genetic diagnosis information, and phenotypic characteristics of Noonan syndrome were collected. Chi-square test, Fisher's exact test, t test, Wilcoxon rank-sum test, and ANOVA were used for comparisons among the groups. Logistic regression was used to test for the association between the clinical characteristics and the presence of NSD. RESULTS Syndromic diagnoses were made in 10% of the children with vPS, with NSD accounting for 6%. Hypertrophic cardiomyopathy (P

Congenital central hypoventilation syndrome (CCHS, OMIM 209880) is a rare autosomal dominant disorder caused by mutation in PHOX2B that manifests as a consequence of abnormal neural crest cell migration during embryogenesis. Unlike other neurocristopathies, however, its impact on the cardiovascular system has not been previously assessed. This study was an effort to characterize the association between congenital heart disease (CHD) and mutations in PHOX2B in patients with CCHS. A retrospective review of patients with CCHS in conjunction with functional analysis of PHOX2B mutations associated with CHD was performed. To substantiate functional implications of identified variants, we conducted protein structure analyses and in silico mutagenesis were conducted. The prevalence of CHD among patients with CCHS was significantly greater (30%; p

OBJECTIVE Maternal anti-Ro/SSA and anti-La/SSB antibodies can lead to fetal complete heart block (CHB). Current guidelines recommend weekly echocardiographic screening between 16 and 28 weeks gestation. Given the cost of screening and the rarity of conduction abnormalities in fetuses of mothers with low anti-Ro levels (

Introduction As birth weight is a critical predictor of neonatal congenital heart defect (CHD) outcomes, the common problem of poor fetal growth in this population is clinically important but not well understood. The impact of fetal hemodynamics on fetal growth and birth weight in CHD has not been assessed. Combined cardiac output (CCO) has been used to evaluate patients with structurally normal heart but rarely in CHD. Middle cerebral artery and umbilical artery pulsatility indices (PIs) have been used to evaluate the relative distribution of circulation in patients with CHD. In this study we sought to evaluate the impact of CCO and PIs on fetal growth in different subgroups of CHD and to study the effects of fetal hemodynamics on late gestation weight gain. We hypothesized that fetuses with CHD will have lower CCO and will be smaller at birth. Methods A retrospective review of fetal echocardiograms from 109 fetuses was performed. The diagnosis was hypoplastic left heart syndrome (HLHS, n=30), non-HLHS single ventricle (non-HLHS SV, n=20), transposition of the great arteries (D-TGA, n=17) and normal controls (n= 42). CCO was calculated using valvar area, velocity time integral and heart rate and indexed to estimated fetal weight. PIs were calculated using systolic, diastolic and mean velocities. Anthropometric measures were recorded. Regression models were used to study CCO, PIs and fetal anthropometric trends over gestational age. To evaluate fetal weight gain in late gestation, z-scores were compared between estimated fetal weight at 30 weeks and birth weight. Regression analysis was used to determine the association of CCO, indexed CCO and PIs at 30 weeks with birth weight, length and head circumference z-scores in addition to weight gain late in gestation. The 30 weeks gestational age was chosen based on previous studies that suggested an evidence of poor weight gain late in gestation in CHD starting around 30 weeks. Results CCO increased in all 4 groups through gestation but the rate slowed in HLHS and SV at the end of gestation. Middle cerebral artery PI values were lower in HLHS compared to non-HLHS SV through gestation suggesting a different cerebral blood distribution. At the end of gestation, fetal weight gain rate slowed in HLHS and SV (similar to CCO curves) and head circumference rate also slowed in all groups but controls. CCO, indexed CCO and PIs did not correlate with any of the birth measurements or with weight gain late in gestation in CHD. Conclusions We found no association of CCO or pulsatility indices with late gestation weight gain or birth anthropometrics in CHD. This does not support fetal hemodynamics as the primary driver of suboptimal fetal growth in SV. Future research may further explain genetic and placental abnormalities that may affect fetal growth in CHD.

Background The approach (lateral thoracotomy versus median sternotomy) to repair coarctation of the aorta is frequently based on arch dimensions from the preoperative echocardiogram. Few studies have assessed the relationship between preoperative arch dimensions and late postoperative outcome. This study aimed to define how preoperative arch dimensions relate to late outcomes and identify long-term predictors of a successful operation. Methods We performed a retrospective review of 102 neonates and infants undergoing isolated coarctation repair by lateral thoracotomy between 2003 and 2012. Long-term surgical success was defined based on the following five factors: corrected arch gradient below 20 mm Hg, blood pressure cuff gradient below 15 mm Hg, systolic blood pressure below the 95th percentile during the clinic visit, no antihypertensive medication use, and freedom from reintervention. Regression analysis was performed to identify factors that would predict the need for reintervention and long-term success. Results At a median of 6 years of follow-up, long-term success was achieved in 63% (56 of 89) of patients, and 94% (96 of 102) were free of reintervention. Bivariate analysis showed that patients requiring reintervention had smaller absolute isthmus dimension (p = 0.04). No significant predictors for reintervention or long-term success could be identified, although a larger distal transverse arch dimension may play a role in long-term success (hazard ratio, 0.7; 95% confidence interval, 0.05 to 1.0; p = 0.06). Conclusions Aortic arches of various dimensions were successfully repaired by lateral thoracotomy. No significant predictors for reintervention or long-term success could be identified, although the distal transverse arch dimension may play a role in long-term success.

Background: In the SVR trial (Single Ventricle Reconstruction), 1-year transplant-free survival was better for the Norwood procedure with right ventricle-to-pulmonary artery shunt (RVPAS) compared with a modified Blalock–Taussig shunt in patients with hypoplastic left heart and related syndromes. At 6 years, we compared transplant-free survival and other outcomes between the groups. Methods: Medical history was collected annually using medical record review, telephone interviews, and the death index. The cohort included 549 patients randomized and treated in the SVR trial. Results: Transplant-free survival for the RVPAS versus modified Blalock–Taussig shunt groups did not differ at 6 years (64% versus 59%, P =0.25) or with all available follow-up of 7.1±1.6 years (log-rank P =0.13). The RVPAS versus modified Blalock–Taussig shunt treatment effect had nonproportional hazards ( P =0.009); the hazard ratio (HR) for death or transplant favored the RVPAS before stage II surgery (HR, 0.66; 95% confidence interval, 0.48–0.92). The effect of shunt type on death or transplant was not statistically significant between stage II to Fontan surgery (HR, 1.36; 95% confidence interval, 0.86–2.17; P =0.17) or after the Fontan procedure (HR, 0.76; 95% confidence interval, 0.33–1.74; P =0.52). By 6 years, patients with RVPAS had a higher incidence of catheter interventions (0.38 versus 0.23/patient-year, P Conclusions: By 6 years, the hazards of death or transplant and catheter interventions were not different between the RVPAS versus modified Blalock–Taussig shunt groups. Children assigned to the RVPAS group had 5% higher transplant-free survival, but the difference did not reach statistical significance, and they required more catheter interventions. Both treatment groups have accrued important complications. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00115934.

Congenital heart defects (CHD) affect approximately 1% of all live births, and often require complex surgeries at birth. We have previously demonstrated abnormal placental vascularization in human placentas from fetuses diagnosed with CHD. Hand1 has roles in both heart and placental development and is implicated in CHD development. We utilized two conditionally activated Hand1A126fs/+ murine mutant models to investigate the importance of cell-specific Hand1 on placental development in early (Nkx2-5Cre) and late (Cdh5Cre) pregnancy. Embryonic lethality occurred in Nkx2-5Cre/Hand1A126fs/+ embryos with marked fetal demise occurring after E10.5 due to a failure in placental labyrinth formation and therefore the inability to switch to hemotrophic nutrition or maintain sufficient oxygen transfer to the fetus. Labyrinthine vessels failed to develop appropriately and vessel density was significantly lower by day E12.5. In late pregnancy, the occurrence of Cdh5Cre+, Hand1A126fs/+ fetuses was reduced from 29% at E12.5 to 20% at E18.5 and remaining fetuses exhibited reduced fetal and placental weights, labyrinth vessel density and placenta angiogenic factor mRNA expression. Our results demonstrate for the first time the necessity of Hand1 in both establishment and remodeling of the exchange area beyond early pregnancy and in patterning vascularization of the placental labyrinth crucial for maintaining pregnancy and successful fetal growth.

BackgroundThe growth trajectories of common measurements, including estimated fetal weight (EFW), head circumference (HC), and abdominal circumference (AC), in fetuses with congenital heart disease (CHD) have not been described for different cardiac lesions. We hypothesized that (i) fetuses with CHD have differential growth in utero, and (ii) different categories of CHD demonstrate different in utero growth curves.MethodsWe performed a retrospective observational cohort study of pregnancies with known fetal CHD seen from January 2000 to June 2013. For analysis, the infants were divided into single ventricle (SV), biventricular conotruncal, d-transposition of great arteries (d-TGA), biventricular septal defects (SD; including atrial, ventricular, and atrioventricular SD), and all others (Other).ResultsA total of 194 newborns met inclusion criteria. There was significant differential growth of EFW in all CHD types, except d-TGA, starting with low z-scores before 25 weeks gestation, improving toward normal around 30-32 weeks gestation, and then again differential growth with advancing gestation. SV and SD groups had significant differential growth of HC starting early in gestation and linearly progressing negative z-scores with advancing gestation.ConclusionWe observed differences in the fetal growth curves throughout gestation for the major categories of CHD, including significant differential growth in even "simple" CHD, such as SD.

BackgroundA few studies have evaluated the impact of clinical trial results on practice in paediatric cardiology. The Infant Single Ventricle (ISV) Trial results published in 2010 did not support routine use of the angiotensin-converting enzyme inhibitor enalapril in infants with single-ventricle physiology. We sought to assess the influence of these findings on clinical practice.MethodsA web-based survey was distributed via e-mail to over 2000 paediatric cardiologists, intensivists, cardiothoracic surgeons, and cardiac advance practice nurses during three distribution periods. The results were analysed using McNemar’s test for paired data and Fisher’s exact test.ResultsThe response rate was 31.5% (69% cardiologists and 65% with >10 years of experience). Among respondents familiar with trial results, 74% reported current practice consistent with trial findings versus 48% before trial publication (pConclusionsWithin 5 years of publication, the majority of respondents was familiar with the Infant Single Ventricle Trial results and reported less frequent use of angiotensin-converting enzyme inhibitor in single-ventricle infants; however, 28% reported not adjusting their clinical decisions based on the trial’s findings.

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.

BACKGROUND: Preterm delivery and low birth weight (LBW) are generally associated with worse outcomes in hypoplastic left heart syndrome (HLHS), but an individual preterm or small neonate may do well. We sought to explore the interactions between gestational age, birth weight, and birth weight for gestational age with intermediate outcomes in HLHS. METHODS: We analyzed survival, growth, neurodevelopment, length of stay, and complications to age 6 years in subjects with HLHS from the Single Ventricle Reconstruction trial. Univariate and multivariable survival and regression analyses examined the effects and interactions of LBW ( RESULTS: Early-term delivery (n = 234) was more common than term (n = 219) delivery. Small for gestational age (SGA) was present in 41% of subjects, but only 14% had LBW. Preterm, compared with term, delivery was associated with an increased risk of death or transplant at age 6 years (all: hazard ratio = 2.58, confidence interval = 1.43–4.67; Norwood survivors: hazard ratio = 1.96, confidence interval = 1.10–3.49) independent of LBW and weight for gestational age. Preterm delivery, early-term delivery, LBW, and SGA were each associated with lower weight at 6 years. Neurodevelopmental outcomes were worst in the LBW cohort. CONCLUSIONS: Preterm delivery in HLHS was associated with worse survival, even beyond Norwood hospitalization. LBW, SGA, and early-term delivery were associated with worse growth but not survival. LBW was associated with worse neurodevelopment, despite similar length of stay and complications. These data suggest that preterm birth and LBW (although often concomitant) are not equivalent, impacting clinical outcomes through mechanisms independent of perioperative course complexity.

BACKGROUND: The reliability of LV systolic functional indices calculated from blinded echocardiographic measurements of LV size has not been tested in a large cohort of healthy children. The objective of this study was to estimate interobserver variability in standard measurements of left ventricular (LV) size and systolic function in children with normal cardiac anatomy and qualitatively normal function. METHODS: The Pediatric Heart Network Normal Echocardiogram Database collected normal echocardiograms from healthy children ≤18 years old distributed equally by age, gender, and race. A core lab used 2-dimensional echocardiograms to measure LV dimensions from which a separate data coordinating center calculated LV volumes and systolic functional indices. To evaluate interobserver variability, two independent expert pediatric echocardiographic observers re-measured LV dimensions on a subset of studies, while blinded to calculated volumes and functional indices. RESULTS: Of 3215 subjects with measurable images, 552 (17%) had a calculated LV shortening fraction (SF)

Background Heart size and function in children with single right ventricle (RV) anomalies may be influenced by shunt type at the Norwood procedure. We sought to identify shunt-related differences during early childhood after staged surgical palliations using echocardiography. Methods We compared echocardiographic indices of RV, neoaortic, and tricuspid valve size and function at 14 months, pre-Fontan, and 6 years in 241 subjects randomized to a Norwood procedure using either the modified Blalock-Taussig shunt or RV-to-pulmonary-artery shunt. Results At 6 years, the shunt groups did not differ significantly in any measure except for increased indexed neoaortic area in the modified Blalock-Taussig shunt. RV ejection fraction improved between pre-Fontan and 6 years in the RV-to-pulmonary artery shunt group but was stable in the modified Blalock-Taussig shunt group. For the entire cohort, RV diastolic and systolic size and functional indices were improved at 6 years compared with earlier measurements, and indexed tricuspid and neoaortic annular area decreased from 14 months to 6 years. The prevalence of ≥moderate tricuspid and neoaortic regurgitation was uncommon and did not vary by group or time period. Diminished RV ejection fraction at the 14-month study was predictive of late death/transplant; the hazard of late death/transplant when RV ejection fraction was Conclusions By 6 years after staged palliation, shunt type has not impacted RV size and function, and RV and valvar size and function show beneficial remodeling. Poor RV systolic function at 14 months predicts worse late survival independent of the initial shunt type. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00115934.

OBJECTIVE To investigate the association of fetal growth and cerebrovascular resistance at different periods in gestation with neurodevelopment (ND) at 14 months in the univentricular subject. METHODS We reviewed serial prenatal ultrasound (US) examinations from 133 infants enrolled in the Pediatric Heart Network's Single Ventricle Reconstruction or Infants with Single Ventricle trials, including a subset of 82 infants in whom ND was assessed at 14 months using mental (MDI) and psychomotor (PDI) developmental indices. US examinations were assigned to one of four gestational time periods: (1) 20-23 weeks, (2) 24-29 weeks, (3) 30-33 weeks and (4) ≥ 34 weeks. Middle cerebral artery (MCA) flow velocity was measured and pulsatility index (PI), a measure of downstream resistance, was calculated. Data on fetal head circumference (HC), femur length, abdominal circumference (AC) and estimated fetal weight (EFW) were collected and their Z-scores were calculated. We evaluated the rate of change of these parameters over time within individuals, tested correlations between fetal growth and ND and assessed predictors of ND using linear regression. RESULTS The mean prenatal HC Z-score was < 0 at each gestational-age period and became more negative later in pregnancy. There was less growth in HC from time period 3 to period 4 compared with from period 2 to 3 (Δ HC Z-score, -0.07 ± 0.1 vs 0.11 ± 0.22, P = 0.03). Though ND did not correlate with HC, HC Z-score or MCA-PI Z-score, HC growth from period 2 to period 3 correlated with MDI (r = 0.45, P = 0.047). AC Z-score in period 4 predicted MDI (β = 4.02, P = 0.04). EFW Z-score and AC Z-score in period 2 predicted PDI (β = 10.6, P = 0.04 and β = 3.29, P = 0.047, respectively). Lower MCA-PI at initial US predicted higher PDI (β = -14.7, P = 0.03). CONCLUSION In univentricular fetuses, lower cerebrovascular resistance may be protective for ND. Decreased fetal somatic growth may predict developmental abnormalities. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.