Intubation and Lower Saturation in the Delivery Room are Associated with Balloon Atrial Septostomy in Neonates with Transposition of the Great Arteries.

OBJECTIVE: To identify delivery room (DR) characteristics of patients with transposition of the great arteries (TGA) who underwent preoperative balloon atrial septostomy (BAS). STUDY DESIGN: Retrospective cohort study of all patients with prenatally diagnosed TGA delivered at our center between 2013 and 2023 who underwent arterial switch operation during the newborn admission. RESULTS: A total of 168 patients were included (median gestational age 39.5 weeks, 64% male, 33% with ventricular septal defect, 8% with aortic arch hypoplasia). BAS was performed in 84 patients (50%). Patients who underwent BAS had higher proportion of intubation in the DR (87% vs 33%, P < .001), lower maximum oxygen saturation in the first 10 minutes (64% vs 74%, P < .001) and 20 minutes (71% vs 81%, P < .001) of life, and lower maximum oxygen saturation at any point in the DR (79% vs 87%, P < .001). Adjusting for confounders (ventricular septal defect, aortic arch anomaly, 5-minute Apgar, birth weight), intubation in the DR (aOR 9.5, 95% CI 3.9, 25.0) and lower maximum oxygen saturation in the DR (aOR 0.9, 95% CI 0.8, 0.9) were independently associated with BAS. By receiver operating characteristic analysis, a maximum oxygen saturation of less than 86% at any time point in the DR discriminated for BAS with a specificity of 0.88, sensitivity of 0.70, and area under the curve of 0.82. CONCLUSIONS: Intubation and lower oxygen saturation in the DR are independently associated with BAS in patients with TGA born at our center. A maximum DR saturation of less than 86% best discriminates patients who undergo BAS in our population.

The Placenta in Congenital Heart Disease: Form, Function and Outcomes.

The maternal-fetal environment, controlled and modulated by the placenta, plays a critical role in the development and well-being of the fetus, with long-term impact through programming of lifelong health. The fetal cardiovascular system and placenta emerge at the same time embryologically, and thus placental form and function are altered in the presence of congenital heart disease (CHD). In this review, we report on what is known about the placenta from a structural and functional perspective when there is CHD. We describe the various unique pathologic findings as well as the diagnostic imaging tools used to characterize placental function in utero. With growing interest in the placenta, a standardized approach to characterizing placental pathology has emerged. Furthermore, application of ultrasonography techniques and magnetic resonance imaging now allow for insights into placental blood flow and functionality in vivo. An improved understanding of the intriguing relationship between the placenta and the fetal cardiovascular system will provide opportunities to develop novel ways to optimize outcomes. Once better understood, therapeutic modulation of placental function offered during the vulnerable period of fetal plasticity may be one of the most impactful ways to alter the course of CHD and its complications.

Deficits in the Functional Muscle-Bone Unit in Youths with Fontan Physiology.

OBJECTIVE: To determine whether dual energy X-ray absorptiometry (DXA), a clinically available tool, mirrors the magnitude of deficits in trabecular and cortical bone mineral density (BMD) demonstrated on peripheral quantitative computed tomography in youth with Fontan physiology. STUDY DESIGN: We aimed to describe DXA-derived BMD at multiple sites and to investigate the relationship between BMD and leg lean mass, a surrogate for skeletal muscle loading. Subjects with Fontan (n = 46; aged 5-20 years) underwent DXA in a cross-sectional study of growth and bone and muscle health as described previously. Data from the Bone Mineral Density in Childhood Study were used to calculate age-, sex-, and race-specific BMD z-scores of the whole body, lumbar spine, hip, femoral neck, distal one-third radius, ultradistal radius, and leg lean mass z-score (LLMZ). RESULTS: Fontan BMD z-scores were significantly lower than reference at all sites-whole body, -0.34 ± 0.85 (P = .01); spine, -0.41 ± 0.96 (P = .008); hip, -0.75 ± 1.1 (P < .001); femoral neck, -0.73 ± 1.0 (P < .001); distal one-third radius, -0.87 ± 1.1 (P < .001); and ultradistal radius. -0.92 ± 1.03 (P < .001)-as was LLMZ (-0.93 ± 1.1; P < .001). Lower LLMZ was associated with lower BMD of the whole body (R2 = 0.40; P < .001), lumbar spine (R2 = 0.16; P = .005), total hip (R2 = 0.32; P < .001), femoral neck (R2 = 0.47; P < .001), and ultradistal radius (R2 = 0.35; P < .001). CONCLUSIONS: Patients with Fontan have marked deficits in both cortical (hip, distal one-third radius) and trabecular (lumbar spine, femoral neck, ultradistal radius) BMD. Lower LLMZ is associated with lower BMD and may reflect inadequate skeletal muscle loading. Interventions to increase muscle mass may improve bone accrual.

Growth in Children with a Fontan Circulation.

OBJECTIVE: To evaluate growth in a population of patients with Fontan circulation. STUDY DESIGN: We performed a cross-sectional evaluation of patients followed in our multidisciplinary Fontan clinic from January 2011 through August 2015. We reviewed the historical data, anthropometry, clinical, and laboratory studies and performed bivariate and multivariate analysis of factors associated with height z score. RESULTS: Patients (n = 210) were included in the study at median age 11.07 years (8.3, 14.73 years) (43% female); 138 (65%) had a dominant right systemic ventricle and 92 (44%) hypoplastic left heart syndrome. Median age at completion of Fontan circulation was 31 months (7.6, 135.8 months). Median height z score was -0.58 (-1.75, 0.26). Twenty-five (12%) had current or past history of protein-losing enteropathy (PLE). Median height z score for those with current or past history of PLE was -2.1 (-2.46, 1.24). Multivariate analysis revealed positive associations between height z score and body mass index z score, time since Fontan, mid-parental height, dominant systemic ventricle type, and serum alkaline phosphatase. Height correlated negatively with known genetic syndrome, PLE, use of stimulant or oral steroid medication. CONCLUSIONS: Children with Fontan circulation have mild deficits in height, with greater deficits in those with PLE. Height z score improves with time postsurgery. Improving weight, leading to improved body mass index, may be a modifiable factor that improves growth in those who are underweight. Biochemical markers may be helpful screening tests for high-risk groups in whom to intensify interventions.

Prenatal hypoxemia alters microglial morphology in fetal sheep.

OBJECTIVE: Neuroimmune cells, particularly microglia and astrocytes, play a critical role in neurodevelopment. Neurocognitive delays are common in children with congenital heart disease, but their etiology is poorly understood. Our objective was to determine whether prenatal hypoxemia, at levels common in congenital heart disease, induced neuroimmune activation to better understand the origins of neurobehavioral disorders in congenital heart disease. METHODS: Eight fetal sheep at gestational age 109 ± 3 days (term ∼145 days) were cannulated onto a pumpless extracorporeal oxygenator via the umbilical vessels and supported in a fluid environment for 22 ± 2 days under normoxic (n = 4) or hypoxic (n = 4) conditions. Control fetuses (n = 7) were harvested at gestational age 133 ± 4 days. At necropsy, brains were stained with ionized calcium-binding adaptor molecule 1 and glial fibrillary acidic protein antibodies to quantify microglia and astrocytes, respectively, in gray and white matter in frontotemporal and cerebellar sections. Microglia were classified into 4 morphologic types based on cell shape. Data were analyzed with 1-way analysis of variance or Fisher exact test, as appropriate. RESULTS: Oxygen delivery was significantly reduced in hypoxic fetuses (15.6 ± 1.8 mL/kg/min vs 24.3 ± 2.3 mL/kg/min; P < .01). Rates of apoptosis were similar in hypoxic, normoxic, and intrauterine control animals in all examined areas. There were also no differences between groups in area occupied by glial fibrillary acidic protein-labeled astrocytes or ionized calcium-binding adaptor molecule 1-labeled microglia in all examined areas. However, round microglia were significantly increased in hypoxic animals compared with normoxic animals (33% vs 6%; P < .01) and control animals (33% vs 11%; P < .01). CONCLUSIONS: Prenatal hypoxemia altered microglial morphology without significant gliosis. Additional studies characterizing these mechanisms may provide insight into the origins of neurobehavioral disabilities in children with congenital heart disease.

Damaging Variants in Proangiogenic Genes Impair Growth in Fetuses with Cardiac Defects.

OBJECTIVE: To determine the impact of damaging genetic variation in proangiogenic pathways on placental function, complications of pregnancy, fetal growth, and clinical outcomes in pregnancies with fetal congenital heart defect. STUDY DESIGN: Families delivering a baby with a congenital heart defect requiring surgical repair in infancy were recruited. The placenta and neonate were weighed and measured. Hemodynamic variables were recorded from a third trimester (36.4 ± 1.7 weeks) fetal echocardiogram. Exome sequencing was performed on the probands (N = 133) and consented parents (114 parent-child trios, and 15 parent-child duos) and the GeneVetter analysis tool used to identify damaging coding sequence variants in 163 genes associated with the positive regulation of angiogenesis (PRA) (GO:0045766). RESULTS: In total, 117 damaging variants were identified in PRA genes in 133 congenital heart defect probands with 73 subjects having at least 1 variant. Presence of a damaging PRA variant was associated with increased umbilical artery pulsatility index (mean 1.11 with variant vs 1.00 without; P = .01). The presence of a damaging PRA variant was also associated with lower neonatal length and head circumference for age z score at birth (mean -0.44 and -0.47 with variant vs 0.23 and -0.05 without; P = .01 and .04, respectively). During median 3.1 years (IQR 2.0-4.1 years) of follow-up, deaths occurred in 2 of 60 (3.3%) subjects with no PRA variant and in 9 of 73 (12.3%) subjects with 1 or more PRA variants (P = .06). CONCLUSIONS: Damaging variants in proangiogenic genes may impact placental function and are associated with impaired fetal growth in pregnancies involving a fetus with congenital heart defect.

Chronic intrauterine hypoxia alters neurodevelopment in fetal sheep.

OBJECTIVE: We tested the hypothesis that chronic fetal hypoxia, at a severity present in many types of congenital heart disease, would lead to abnormal neurodevelopment. METHODS: Eight mid-gestation fetal sheep were cannulated onto a pumpless extracorporeal oxygenator via the umbilical vessels and supported in a fluid-filled environment for 22 ± 2 days under normoxic or hypoxic conditions. Total parenteral nutrition was provided. Control fetuses (n = 7) were harvested at gestational age 133 ± 4 days. At necropsy, brains were fixed for histopathology. Neurons were quantified in white matter tracts, and the thickness of the external granular layer of the cerebellum was measured to assess neuronal migration. Capillary density and myelination were quantified in white matter. Data were analyzed with unpaired Student t tests or 1-way analysis of variance, as appropriate. RESULTS: Oxygen delivery was reduced in hypoxic fetuses (15.6 ± 1.8 mL/kg/min vs 24.3 ± 2.3 mL/kg/min, P < .01), but umbilical blood flow and caloric delivery were not different between the 2 groups. Compared with normoxic and control animals, hypoxic fetuses had reduced neuronal density and increased external granular layer thickness. Compared with normoxic and control animals, hypoxic fetuses had increased capillary density in white matter. Cortical myelin integrity score was lower in the hypoxic group compared with normoxic and control animals. There was a significant negative correlation between myelin integrity and capillary density. CONCLUSIONS: Chronic fetal hypoxia leads to white matter hyper-vascularity, decreased neuronal density, and impaired myelination, similar to the neuropathologic findings observed in children with congenital heart disease. These findings support the hypothesis that fetal hypoxia, even in the setting of normal caloric delivery, impairs neurodevelopment.

Hepatic Fibrosis Is Universal Following Fontan Operation, and Severity is Associated With Time From Surgery: A Liver Biopsy and Hemodynamic Study.

BACKGROUND: Congestive hepatopathy is a recognized complication of Fontan physiology. Data regarding the incidence of hepatopathy and risk factors are lacking. METHODS AND RESULTS: Liver biopsies and cardiac catherizations were performed as part of an evaluation offered to all patients ≥10 years after Fontan. Quantitative determination of hepatic fibrosis was performed using Sirius red staining with automated calculation of collagen deposition per slide (%CD). Biopsies from included subjects were compared to stained specimens from controls without known fibrotic liver disease. Patient characteristics, echocardiographic findings, and hemodynamic measures were evaluated as potential risk factors. The cohort consisted of 67 patients (31 female) at mean age of 17.3±4.5 years and mean time from Fontan of 14.9±4.5 years. Right ventricular morphology was present in 37 subjects. Median %CD by Sirius red staining was 21.6% (range 8.7% to 49.4%) compared to 2.6% (range 2.2% to 3.0%) in controls. There was a significant correlation between time from Fontan and degree of Sirius red staining (r=0.33, P<0.01). Serum liver enzymes and platelet count did not correlate with %CD. The median inferior vena cava pressure was 13 mm Hg (range 6-24 mm Hg) and did not correlate with %CD. There was no difference in %CD based on ventricular morphology or severity of atrioventricular valve insufficiency. CONCLUSIONS: In this cohort of predominantly asymptomatic children and adolescents electively evaluated after a Fontan operation, all exhibited evidence for hepatic fibrosis as measured by collagen deposition in the liver. Time from Fontan was the only factor significantly associated with collagen deposition. These findings demonstrate that liver fibrosis is an inherent feature of Fontan physiology and that the degree of fibrosis increases over time.

Long-term survival after the Fontan operation: Twenty years of experience at a single center.

OBJECTIVE: Existing studies of patients palliated with the Fontan operation are limited by heterogeneous patient populations and incomplete follow-up. This study aimed to describe long-term post-Fontan survival in a modern patient cohort. METHODS: All 773 patients who underwent a first Fontan operation at our institution between 1992 and 2009 were reviewed. The primary outcome was the composite endpoint of Fontan takedown, heart transplantation, or death before 2013. RESULTS: Follow-up rate was 99.2%. Survival with intact Fontan circulation was 94% at 1 year (95% confidence interval [95% CI], 92%-95%), 90% at 10 years (95% CI, 88%-92%), 85% at 15 years (95% CI, 82%-88%), and 74% at 20 years (95% CI, 67%-80%). Distinct risk factors were identified for early (≤1 year) and late composite outcomes. Independent risk factors for early outcome included prolonged pleural drainage (hazard ratio [HR], 4.4; P < .001), intensive care unit stay >1 week (HR, 2.4; P < .001), Fontan before 1997 (HR, 3.3; P < .001), preoperative atrioventricular valve regurgitation (HR, 2.0; P < .001), and longer crossclamp time (HR, 1.3 per 10 minutes; P < .001). Late outcome was predicted by atrioventricular valve regurgitation prior to Fontan (HR, 2.0; P ≤ .001), and post-Fontan ICU stay >1 week (HR, 2.4; P < .001). CONCLUSIONS: Long-term mortality after Fontan operation remains substantial. Risk factors for death or loss of Fontan circulation differ between the early and late postoperative periods. Long-term survival has not improved appreciably over the last decade, suggesting that alternatives to the Fontan are warranted.

Risk Factors and Clinical Significance of Lymphopenia in Survivors of the Fontan Procedure for Single-Ventricle Congenital Cardiac Disease.

BACKGROUND: Congenital cardiac anomalies are associated with immunologic perturbations. Surgical thymectomy, thoracic duct manipulation, and protein- losing enteropathy (PLE), a condition related to stressed Fontan hemodynamics, presumably contribute to low peripheral absolute lymphocyte counts (ALCs) and quantitative immunoglobulins. Clinical significance of lymphopenia and hypogammaglobulinemia in single-ventricle survivors requires additional study. OBJECTIVE: Although immunologic laboratory anomalies are common in this population, we hypothesize that clinically significant immunodeficiency requiring intervention is rarely required. METHODS: A retrospective chart review of the immunologic parameters of patients enrolled in the Single Ventricle Survivorship Program (SVSP) at the Children's Hospital of Philadelphia was performed. RESULTS: The age range of the 178 SVSP patients was 3 to 26 years, with a median of 10.8 years. Most of the SVSP patients had some degree of lymphopenia. In the non-PLE group, the range of ALCs varied from 530 to 5322 cells/µL, with 17 patients without PLE maintaining an ALC of less than 1000 cells/µL. Among those with PLE, the median ALC and the IgG level were lower (672 cells/µL and 200 mg/dL, respectively) than in those without (1610 cells/µL and 868 mg/dL, respectively). Despite lymphopenia in the majority, few were severely clinically affected: 24% had delayed clearance of cutaneous viral infections, 63% had atopy, and 1 died of EBV-associated Hodgkin lymphoma. Immunoglobulin replacement was clinically indicated for 3 patients, 1 of whom had common variable immunodeficiency. Four patients with normal splenic function were treated with daily antibiotic prophylaxis. CONCLUSIONS: Patients with repaired single-ventricle physiology often demonstrate T-cell lymphopenia and hypogammaglobulinemia. A significant portion of patients without PLE also have lymphopenia. The most common clinical manifestation was delayed clearance of cutaneous viral infections, but significant systemic opportunistic infections were not seen despite laboratory abnormalities and lack of antimicrobial prophylaxis.

Maternal psychological stress after prenatal diagnosis of congenital heart disease.

OBJECTIVE: To determine whether prenatal diagnosis of congenital heart disease (CHD) increases maternal stress. STUDY DESIGN: Self-report instruments were administered to mothers carrying a fetus with CHD. Domains included: (1) traumatic stress (Impact of Events Scale-Revised); (2) depression (Beck Depression Index II); and (3) anxiety (State-Trait Anxiety Index). Modifiers included: (1) coping skills (COPE Inventory); (2) partner satisfaction (Dyadic Adjustment Scale); and (3) demographics. Multivariate linear regression models were used to assess relationships between stress measures and modifiers. RESULTS: Fifty-nine mothers (gestational age 27 ± 3 weeks) completed all measures. Clinically important traumatic distress was seen in 39%, depression in 22%, and state anxiety in 31%. Lower partner satisfaction was associated with higher depression (P < .01) and higher anxiety (P < .01). After controlling for partner satisfaction and income, "denial" was most associated with increased traumatic stress, anxiety, and depression (P < .01). CONCLUSIONS: Posttraumatic stress, depression, and anxiety are common after prenatal diagnosis of CHD. Healthy partner relationships and positive coping mechanisms can act as buffers.

Impact of mode of delivery on markers of perinatal hemodynamics in infants with hypoplastic left heart syndrome.

OBJECTIVE: To determine whether the mode of delivery of infants prenatally diagnosed with hypoplastic left heart syndrome (HLHS) affects markers of perinatal hemodynamics. STUDY DESIGN: A retrospective review of patients diagnosed prenatally with HLHS and delivered within our institution was undertaken. Arterial blood gases, echocardiographic data, and markers of end organ function were compared based on route of delivery. RESULTS: A total of 79 infants with HLHS were enrolled between January 2002 and December 2008. The infants delivered by elective cesarian delivery (CD) had younger gestational age compared with those delivered by vaginal delivery (VD) or by urgent CD/operative VD. Those delivered by elective CD had lower pH and higher partial pressure of CO(2) on arterial cord blood gas analysis. There were no differences in partial pressure of O(2) and base deficit among the 3 study groups. One-minute and 5-minute Apgar scores, markers of end organ function, echocardiographic parameters, length of hospitalization, and survival to discharge were similar among the groups. CONCLUSIONS: Overall, newborns with a prenatal diagnosis of HLHS transitioned well to extrauterine life without significant acidosis regardless of the mode of delivery. Delivery of newborns with HLHS by elective CD did not demonstrate any hemodynamic advantage over VD in our cohort of patients.

Influence of congenital heart disease on survival in children with congenital diaphragmatic hernia.

OBJECTIVE: We sought to assess outcome in patients with CDH and HD to determine if LHR is also predictive of outcome in this subset of patients. STUDY DESIGN: We carried out a retrospective review (April 1996-October 2000) of patients with isolated CDH (n = 143, 82.2%) and patients with HD (n = 31, 17.8%) to determine the incidence of additional anomalies, survival to term, CDH repair, cardiac repair, and survival to discharge. Survival based on LHR was analyzed in a subset of fetuses. RESULTS: The risk of death from birth to last follow-up was 2.9 times higher for patients with CDH plus HD than for patients with CDH alone (P <.0001). Of 11 patients with CDH plus HD who had CDH repair (5 of whom also had HD repair), 5 survived. All 10 patients with an LHR <1.2 died; 3 of 6 with an LHR >1.2 survived (Fisher exact test, P =.04). CONCLUSION: Heart disease remains a significant risk factor for death in infants with CDH. The LHR helps predict survival in this high-risk group of patients.

The small left ventricle: How small is too small for biventricular repair?

Left ventricular hypoplasia is associated with a variety of congenital heart defects, including critical aortic stenosis, unbalanced atrioventricular canal, and total anomalous pulmonary venous connection, and is almost uniformly fatal without surgical or catheter-directed intervention. Accurately determining whether the left ventricle can adequately support the systemic circulation can be challenging and may be approached in a variety of ways, depending on the cardiac defect. The decision is more difficult in the present era of pediatric cardiology and cardiothoracic surgery because other options, such as the Norwood procedure and cardiac transplantation, are available to infants with left ventricular hypoplasia with improving survival. This report is a review of the present understanding of left ventricular hypoplasia and gives suggestions about how to stratify these complex patients to single versus two-ventricle repair. Copyright 1999 by W.B. Saunders Company

Management of protein-losing enteropathy after the Fontan procedure.

Enteric loss of protein with the sequelae of edema, immunodeficiency, and hypercoagulability is being diagnosed with increasing frequency after Fontan procedure. The precise pathophysiological mechanism is unknown; however, protein-losing enteropathy (PLE) after Fontan procedure is likely related to a hemodynamic derangement that is not easily detectable via standard hemodynamic measures presently obtainable in the cardiac catheterization laboratory. Treatment options include (1) symptomatic relief via diuretics, supplemental albumin infusion, and dietary change to high protein/high medium-chain triglyceride intake, (2) hemodynamic improvement via afterload reduction (angiotensin-converting enzyme inhibitors), repair of branch pulmonary artery stenoses, or coil embolization of aortopulmonary collaterals, (3) intestinal cell membrane stabilization via high-dose steroids or heparin infusion, and (4) attempt at alteration of the primary hemodynamic derangement via fenestration of the systemic venous baffle or via heart transplantation. Further understanding of the cause of PLE after Fontan procedure is needed before more effective treatment options can be used. Copyright 1998 by W.B. Saunders Company