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Coronary artery abnormalities (CA) occur in patients with hypoplastic left heart syndrome (HLHS) and may be associated with higher mortality and heart transplantation (HT). We aimed to determine whether fetuses with HLHS and prenatal CA have a higher risk of death or HT.We performed a retrospective review of fetal echocardiograms with HLHS from 2011 to 2018. We excluded fetuses with ventricular septal defects, elective termination, death in utero, planned postnatal non-intervention, or absent follow-up data. Presence or absence of CA was determined by review of serial fetal echocardiograms. Survival analysis was used to evaluate the relationship between prenatal CA and death or HT.Of 86 patients with fetal HLHS, 11 had prenatal diagnosis of CA. Of these, six required HT and five died (one after undergoing HT); only one remains alive without HT. Of those without prenatal CA (n = 75), 25 died and 7 underwent HT. Patients with prenatal diagnosis of HLHS and CA had a significantly increased likelihood of death or HT (p-value0.05).Prenatal diagnosis of CA in our cohort of patients with HLHS was associated with increased risk of death or HT. These data have significance for prenatal counseling and postnatal management.

Background: Prenatal detection (PND) has benefits for infants with hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA), but associations between sociodemographic and geographic factors with PND have not been sufficiently explored. This study evaluated whether socioeconomic quartile (SEQ), public insurance, race and ethnicity, rural residence, and distance of residence (distance and driving time from a cardiac surgical center) are associated with the PND or timing of PND, with a secondary aim to analyze differences between the United States and Canada. Methods: In this retrospective cohort study, fetuses and infants z score using the neighborhood summary score or Canadian Chan index and separated into quartiles. Insurance type and self-reported race and ethnicity were obtained from medical charts. We evaluated associations among SEQ, insurance type, race and ethnicity, rural residence, and distance of residence with PND of HLHS and TGA (aggregate and individually) using bivariate analysis with adjusted associations for confounding variables and cluster analysis for centers. Results: Data on 1862 subjects (HLHS: n=1171, 92% PND; TGA: n=691, 58% PND) were submitted by 21 centers (19 in the United States). In the United States, lower SEQ was associated with lower PND in HLHS and TGA, with the strongest association in the lower SEQ of pregnancies with fetal TGA (quartile 1, 0.78 [95% CI, 0.64–0.85], quartile 2, 0.77 [95% CI, 0.64–0.93], quartile 3, 0.83 [95% CI, 0.69–1.00], quartile 4, reference). Hispanic ethnicity (relative risk, 0.85 [95% CI, 0.72–0.99]) and rural residence (relative risk, 0.78 [95% CI, 0.64–0.95]) were also associated with lower PND in TGA. Lower SEQ was associated with later PND overall; in the United States, rural residence and public insurance were also associated with later PND. Conclusions: We demonstrate that lower SEQ, Hispanic ethnicity, and rural residence are associated with decreased PND for TGA, with lower SEQ also being associated with decreased PND for HLHS. Future work to increase PND should be considered in these specific populations.

OBJECTIVES Ebstein anomaly and tricuspid valve dysplasia (EA/TVD) carry high perinatal mortality. Past studies have focused on cardiac predictors of mortality; we sought to describe the fetal echo (FE) extracardiac Dopplers in this cohort and determine their association with perinatal mortality. METHOD Fetuses with EA/TVD at 23 centers from 2005-2011 were included for retrospective study. Doppler pattern and velocity of the umbilical artery (UA), umbilical vein (UV), ductus venosus (DV), and middle cerebral artery (MCA) were collected. Bivariate and multivariate analyzes were performed. The primary outcome measure was perinatal mortality, defined as fetal demise or neonatal death. RESULTS Of 190 cases that met eligibility criteria, alterations were seen in 50% of UA, 16% of UV, 48% of DV, and 8% of MCA Doppler indices on the last FE (median 27.4 weeks). Independent predictors of perinatal mortality included abnormal UA Doppler pattern of absence or reversed end diastolic flow (OR 9.7) and UV velocity z score

Importance Parents who receive a prenatal diagnosis of congenital heart disease may experience more short- and long-term stress than those who receive a postnatal diagnosis. To identify potential interventions to ameliorate that stress, the longitudinal emotional experience of parents must first be understood. Objective To better understand parents’ accounts of their own prenatal experience, particularly aspects they found to be stressful or challenging, and to identify strategies to improve support. Design, Setting, and Participants This qualitative study included analysis of transcripts of audio recorded telephone interviews with pregnant mothers and their support persons, as applicable, who were referred to and seen at the Fetal Cardiology Clinic at Vanderbilt Children’s Hospital from May 2019 to August 2019 with an initial likely diagnosis of complex congenital heart disease at any gestational age. Data analysis was conducted from August 2019 to November 2019. Main Outcomes and Measures An applied thematic analysis approach was used to code and analyze professionally transcribed interviews. Coding and codebook revisions occurred iteratively; intercoder reliability was assessed and confirmed routinely. One author coded all transcripts; a second author independently reviewed one-fifth of the transcripts at fixed intervals to ensure that interrater reliability remained greater than 80%. Results Twenty-seven individuals from 17 families participated in 42 phone interviews during pregnancy, 27 conducted at the first time point after the initial prenatal cardiology consultation and 15 at the second time point after a follow-up prenatal cardiology visit. Most interviewees were mothers (16 interviewees [59%]; median [interquartile range] age, 30.0 [27.3-34.8] years) or fathers (8 interviewees [30%)], with a few support individuals (3 interviewees [11%]) (median [interquartile range] age of family member or support individual, 30.0 [26.0-42.0] years). Initial fetal diagnoses included a range of severe congenital heart disease. Uncertainty was identified as a pervasive central theme and was related both to concrete questions on scheduling, logistics, or next steps, and long-term unknown variables concerning the definitiveness of the diagnosis or overall prognosis. Practitioners helped families through their framing of uncertainty at various time points including before, during, and after the clinic visit. Conclusions and Relevance Families walk an uncertain path following a fetal diagnosis of severe congenital heart disease. The challenges faced by the cardiologists caring for them overlap in many ways with those experienced by pediatric palliative care practitioners. Potential future interventions to improve parental support were identified in the areas of expectation setting before the referral visit, communication in clinic, and identity formation after the new diagnosis.

Congenital ventricular outpouchings (CVOs) are rare congenital heart defects with limited data regarding prognosis and outcomes. We aimed to describe the characteristics, outcomes and factors associated with morbidity and mortality of prenatally diagnosed CVOs using our institutional experience and a review of published cases. A total of 86 cases of prenatally diagnosed CVOs were identified, including 3 from our institution and 83 cases identified from a review of the literature. Fetal and postnatal outcomes were analyzed for each case. Pericardial effusions (44%) and ventricular dysfunction (17%) were the most common associated findings. Excluding cases that resulted in pregnancy termination, mortality was 17%, with the majority (11/13) occurring in the prenatal period. Factors associated with mortality included an outpouching located on the left ventricle, a diagnosis of hydrops fetalis, the presence of a pericardial effusion, and an earlier gestational age at diagnosis. Of those that survived to delivery, 57% remained asymptomatic without the need for intervention, and the outpouching regressed or resolved in an additional 15%. Prenatally diagnosed congenital ventricular outpouchings are a dynamic form of congenital heart disease with a high fetal mortality rate. The outcomes associated with the outpouchings appear to be the most variable in the prenatal period and the first year after birth. Serial prenatal and postnatal evaluations should be performed to evaluate for a change in the characteristics of the outpouching.

Objective Fetal tachyarrhythmias complicate 0.5% of pregnancies, with high morbidity and mortality. We hypothesized that maternal factors may predispose to fetal supraventricular tachycardia (SVT). Study Design We reviewed medical records of all 124 mothers who presented to the Vanderbilt Fetal Cardiology Clinic from 2004 to 2010 for fetal arrhythmias, excluding heart block. Maternal factors were compared between 28 fetuses with SVT and a control group of 112 fetuses screened for noncardiac conditions. The proportions were analyzed using chi-square or Fisher exact test for categorical variables and Wilcoxon rank sum test for continuous variables. Results Of maternal factors, thyroid disease was statistically significant compared with controls. Among mothers whose fetuses had SVT, 21% had thyroid disease (83% hypothyroidism) compared with 3% of controls ( p Conclusion In this cohort, the maternal thyroid disease was more common in fetuses with SVT compared with controls (odds ratio = 9.8, 95% confidence interval 2.3–42.3), suggesting closer screening for fetal arrhythmias and SVT in mothers with thyroid disease. Also, routine screening of thyroid functions and thyroid autoantibodies may be warranted in mothers of fetuses with SVT.

Fetal cardiology is a rapidly evolving field. Imaging technology continues to advance as do approaches to in-utero interventions and care of the critically ill neonate, with even greater demand for improvement in prenatal diagnosis of congenital heart disease (CHD) and arrhythmias.Reviewing the advances in prenatal diagnosis of CHD in such a rapidly developing field is a broad topic. Therefore, we have chosen to focus this review of recent literature on challenges in prenatal detection of CHD, challenges in prenatal counseling, advances in fetal arrhythmia diagnosis, and potential benefits to patients with CHD who are identified prenatally.As methods and tools to diagnose and manage CHD and arrhythmias in utero continue to improve, future generations will hopefully see a reduction in both prenatal and neonatal morbidity and mortality. Prenatal diagnosis can and should be used to optimize location and timing of delivery and postnatal interventions.

We report a 4-month-old girl who presented with poor ventricular function and was found to have occlusion of the left main coronary artery os by a tethered aortic cusp. The patient underwent surgical delamination of the aortic valve leaflet, revealing a normal left coronary os. After operative repair, her left ventricular function improved significantly. This diagnosis should be included in the differential in all children presenting with cardiac dysfunction.

Objective Pulmonary hypertension may complicate surgical correction of congenital heart defects, resulting in increased morbidity and mortality. We have previously shown that plasma levels of the nitric oxide precursors citrulline and arginine drop precipitously after congenital cardiac surgery and that oral citrulline supplementation may be protective against the development of pulmonary hypertension. In this study, we assessed the safety and pharmacokinetic profile of intravenous citrulline as a potential therapy for postoperative pulmonary hypertension. Methods The initial phase of this investigation was a dose-escalation study of intravenously administered citrulline in infants and children undergoing one of five congenital cardiac surgical procedures (phase 1). The primary safety outcome was a 20% drop in mean arterial blood pressure from the baseline pressure recorded after admission to the intensive care unit. Based on our previous work, the target circulating plasma citrulline trough was 80 to 100 μmol/L. Each patient was given two separate doses of citrulline: the first in the operating room immediately after initiation of cardiopulmonary bypass and the second 4 hours later in the pediatric intensive care unit. Stepwise dose escalations included 50 mg/kg, 100 mg/kg, and 150 mg/kg. After model-dependent pharmacokinetic analysis, we enrolled an additional 9 patients (phase 2) in an optimized dosing protocol that replaced the postoperative dose with a continuous infusion of citrulline at 9 mg/(kg·h) for 48 hours postoperatively. Results The initial stepwise escalation protocol (phase 1) revealed that an intravenous citrulline dose of 150 mg/kg given after initiation of cardiopulmonary bypass yielded a trough level of in the target range of approximately 80 to 100 μmol/L 4 hours later. The postoperative dose revealed that the clearance of intravenously administered citrulline was 0.6 L/(h·kg), with a volume of distribution of 0.9 L/kg and estimated half-life of 60 minutes. Because of the short half-life, we altered the protocol to replace the postoperative dose with a continuous infusion of 9 mg/(kg·h). An additional 9 patients were studied with this continuous infusion protocol (phase 2). Mean plasma citrulline levels were maintained at approximately 125 μmol/L, with a calculated clearance of 0.52 L/(h·kg). None of the 17 patients studied had a 20% drop in mean arterial blood pressure from baseline. Conclusions In this first report of the use of intravenous citrulline in humans, we found citrulline to be both safe and well tolerated in infants and young children undergoing congenital cardiac surgery. Because of the rapid clearance, the optimal dosing regimen was identified as an initial bolus of 150 mg/kg given at the initiation of cardiopulmonary bypass, followed 4 hours later by a postoperative infusion of 9 mg/(kg·h) continued up to 48 hours. Using this regimen, plasma arginine, citrulline, and nitric oxide metabolite levels were well maintained. Intravenous citrulline needs to be studied further as a potential therapy for postoperative pulmonary hypertension.

Background— Ebstein anomaly and tricuspid valve dysplasia are rare congenital tricuspid valve malformations associated with high perinatal mortality. The literature consists of small, single-center case series spanning several decades. We performed a multicenter study to assess the outcomes and factors associated with mortality after fetal diagnosis in the current era. Methods and Results— Fetuses diagnosed with Ebstein anomaly and tricuspid valve dysplasia from 2005 to 2011 were included from 23 centers. The primary outcome was perinatal mortality, defined as fetal demise or death before neonatal discharge. Of 243 fetuses diagnosed at a mean gestational age of 27±6 weeks, there were 11 lost to follow-up (5%), 15 terminations (6%), and 41 demises (17%). In the live-born cohort of 176 live-born patients, 56 (32%) died before discharge, yielding an overall perinatal mortality of 45%. Independent predictors of mortality at the time of diagnosis were gestational age P P P P =0.04). Nonsurvivors were more likely to have pulmonary regurgitation at any gestational age (61% versus 34%; P P Conclusion— In this large, contemporary series of fetuses with Ebstein anomaly and tricuspid valve dysplasia, perinatal mortality remained high. Fetuses with pulmonary regurgitation, indicating circular shunt physiology, are a high-risk cohort and may benefit from more innovative therapeutic approaches to improve survival.

Pericardial effusion and cardiac tamponade is a rarely reported complication following stem cell transplant (SCT). The incidence among pediatric SCT recipients is not well defined. To assess the frequency of clinically significant pericardial effusions, we retrospectively examined clinically significant cardiac effusions at our center. Between January of 1993 and August 2004, clinically significant pericardial effusions were identified in nine of 205 patients (4.4%). The median age at the time of transplant was 9 years (range 0.6-18 years) and seven received an allogeneic transplant. All nine had normal cardiac function prior to transplant. The effusion developed at a median of 30 days (range 18-210 days). All allogeneic recipients had acute or clinically extensive graft-versus-host disease (GVHD) at the time the effusion was diagnosed. Seven patients (78%) required pericardiocentesis or surgical creation of a pericardial window. No patient died as a complication of the effusion or the therapeutic procedures. Clinically significant pericardial effusions are more common than previously reported in pediatric SCT recipients. Acute and chronic GVHD is an associated factor.

Diagnosing coarctation of the aorta (CoA) in the presence of a patent ductus arteriosus (PDA) may require observation until PDA closure. The aim of this study was to create a model incorporating previously published indices to estimate the probability of neonatal CoA in the presence of a PDA.A retrospective "investigation" cohort of 80 neonates was divided into two groups: (1) neonates with PDA and suspicion for CoA requiring observation to confirm the presence or absence of CoA and (2) neonates with PDA and confirmed diagnosis of either CoA or unobstructed aortic arch. Multivariate logistic regression was used to create the coarctation probability model (CPM), which was used to calculate a neonate's probability of CoA. The CPM was validated internally using bootstrapping and subsequently validated prospectively using a "validation" cohort of 74 neonates with PDA.The CPM had an area under the receiver operating characteristic curve of 0.96 and demonstrated good clinical significance in the risk stratification of neonates with PDA and CoA. No neonate with a CPM probability of15% had CoA after PDA closure. Neonates with CPM probability15% were classified at low risk, between 15% and 60% at moderate risk, and60% at high risk for CoA.On the basis of these results, the authors recommend measurement of the CPM in all neonates with PDA. Those with CPM probability15% no longer require observation, which could decrease observation in as many as half of neonates with unobstructed aortic arches; those with CPM probabilities between 15% and 60% require follow-up imaging, while those with CPM probabilities60% should be observed as inpatients until PDA closure.

Hypoplastic left heart syndrome is the most common lethal cardiac defect in neonates. Options for treatment include cardiac transplantation and surgical palliation. When cardiac transplantation is chosen as the preferred option, a considerable delay may occur until a suitable donor is available. During this time, anesthetic care may be required for various surgical procedures. Associated anomalies seen in these infants and the anesthetic implications imposed by the abnormal cardiac anatomy are discussed.

An infant with a diagnosis of acute infantile cardiomyopathy was subsequently shown to have mucopolysaccharidosis VI. The mucopolysaccharidoses should be included in the differential diagnosis of infantile cardiomyopathy.

Autoimmune-mediated congenital complete heart block (CCHB) is associated with significant perinatal morbidity and mortality, and prenatal monitoring of these fetuses is a significant challenge. The cerebroplacental Doppler ratio (CPR), defined as the ratio of the middle cerebral artery pulsatility index (MCA-PI) to the umbilical artery pulsatility index (UA-PI), is predictive of perinatal outcome in growth-restricted fetuses. This study tests the hypothesis that the CPR would be useful in monitoring fetal well-being in fetuses with CCHB.We reviewed data on all patients diagnosed prenatally with autoimmune-mediated CCHB at our institution over the past 2 years. The fetal echocardiograms from each patient were analyzed for: CPR, UA-PI, MCA-PI, cardiothoracic ratio, degree of tricuspid regurgitation, ventricular function and presence of effusions. We compared hemodynamic data from the fetal echocardiogram before delivery in patients who required urgent pacemaker placement postnatally to those patients that did not require an urgent pacemaker.Five patients with autoimmune-mediated CCHB were identified, and two patients required urgent pacemaker placement. The CPR before delivery was significantly lower in the patients who required urgent pacemaker placement (0.97+/-0.06 versus 1.45+/-0.03; P=0.003), but there was no difference in other fetal echocardiographic markers between groups. Both patients requiring urgent pacemaker placement had a CPR less than 1.08.The CPR is predictive of postnatal outcome in fetuses with CCHB and is useful in prenatal monitoring of these patients.

A 3-month-old infant presented in extremis with a flail tricuspid valve. The authors theorized that the genesis of her papillary muscle rupture was perinatal ischemia compounded by worsening pulmonary valvular stenosis leading to excessive fiber tension. Her underlying diagnosis of autoimmune-mediated heart block with endocardial fibroelastosis and prenatal glucocorticoid steroid treatment represents potentiating factors.

Increased pulmonary artery pressure (PAP) can complicate the postoperative care of children undergoing surgical repair of congenital heart defects. Endogenous NO regulates PAP and is derived from arginine supplied by the urea cycle. The rate-limiting step in the urea cycle is catalyzed by a mitochondrial enzyme, carbamoyl-phosphate synthetase I (CPSI). A well-characterized polymorphism in the gene encoding CPSI (T1405N) has previously been implicated in neonatal pulmonary hypertension. A consecutive modeling cohort of children (N=131) with congenital heart defects requiring surgery was prospectively evaluated to determine key factors associated with increased postoperative PAP, defined as a mean PAP > 20mmHg for at least one hour during the 48 hours following surgery measured by an indwelling pulmonary artery catheter. Multiple Dimensionality Reduction (MDR) was used to both internally validate observations and develop optimal two-variable through five-variable models that were tested prospectively in a validation cohort (N= 41). Unconditional logistic regression analysis of the modeling cohort revealed that age (OR= 0.92, p=0.01), CPSI T1405N genotype (AC vs. AA: OR=4.08, p=0.04, CC vs. AA: OR=5.96, p=0.01), and Down syndrome (OR=5.25, p=0.04) were independent predictors of this complex phenotype. MDR predicted that the best two-variable model consisted of age and CPSI T1405N genotype (p

Isolated infundibuloarterial inversion is a rare conotruncal cardiac anomaly characterized by a leftward and posterior aortic valve in the face of ventriculoarterial concordance. It has previously been described only in cases associated with severe additional defects of substantial hemodynamic significance. We present a case of isolated infundibuloarterial inversion with a small, hemodynamically insignificant ventricular septal defect. The nature of this lesion, diagnostic methods of imaging, and features aiding its discrimination from the more commonly recognized anatomically corrected malposition of the great arteries are discussed.

We examined early results in infants with hypoplastic left heart syndrome undergoing the Norwood operation with perioperative use of inhaled nitric oxide and application of extracorporeal membrane oxygenation.Medical records were reviewed retrospectively.Between April 1997 and March 2001, 50 infants underwent a modified Norwood operation for hypoplastic left heart syndrome. Mean age at operation was 7.5 +/- 5.7 days, and mean weight was 3.1 +/- 0.5 kg. Five infants had a delayed operation because of sepsis. The mean diameter of the ascending aorta by echocardiography was 3.6 +/- 1.8 mm. Ductal cannulation was used to establish cardiopulmonary bypass in all patients. Mean circulatory arrest time was 39.4 +/- 4.8 minutes. The size of the pulmonary-systemic shunt was 3.0 mm in 6 infants, 3.5 mm in 37, and 4.0 mm in 7. Infants with persistent hypoxia (partial pressure of oxygen30 mm Hg) received nitric oxide after they were weaned from cardiopulmonary bypass. Extracorporeal membrane oxygenation was initiated in 8 infants in the pediatric intensive care unit primarily for low cardiac output and in 8 in the operating room because of the inability to separate them from cardiopulmonary bypass. The 30-day mortality rate was 22% (11 of 50 patients), and the hospital mortality rate was 32% (16 of 50 patients). Mean follow-up was 17 months. Ten patients (20%) underwent stage-two repair, with one operative death. One survivor had a Fontan procedure, and 2 underwent heart transplantation, with one death.Early application of extracorporeal membrane oxygenation for hemodynamic instability and selective use of nitric oxide for persistent hypoxia in the immediate postoperative period may improve survival of patients with hypoplastic left heart syndrome. Renal failure requiring hemofiltration during extracorporeal membrane oxygenation (p0.05) and cardiopulmonary arrest in the pediatric intensive care unit (p0.05) were predictors of hospital mortality.

Heterozygous mutations in NKX2.5, a homeobox transcription factor, were reported to cause secundum atrial septal defects and result in atrioventricular (AV) conduction block during postnatal life. To further characterize the role of NKX2.5 in cardiac morphogenesis, we sought additional mutations in groups of probands with cardiac anomalies and first-degree AV block, idiopathic AV block, or tetralogy of Fallot. We identified 7 novel mutations by sequence analysis of the NKX2.5-coding region in 26 individuals. Associated phenotypes included AV block, which was the primary manifestation of cardiac disease in nearly a quarter of affected individuals, as well as atrial septal defect and ventricular septal defect. Ventricular septal defect was associated with tetralogy of Fallot or double-outlet right ventricle in 3 individuals. Ebstein’s anomaly and other tricuspid valve abnormalities were also present. Mutations in human NKX2.5 cause a variety of cardiac anomalies and may account for a clinically significant portion of tetralogy of Fallot and idiopathic AV block. The coinheritance of NKX2.5 mutations with various congenital heart defects suggests that this transcription factor contributes to diverse cardiac developmental pathways. J. Clin. Invest. 104:1567–1573 (1999).

The incidence of significant valvar insufficiency at late (6 month) follow-up was retrospectively evaluated in 27 young patients (age 4. 0-18.0 years) undergoing 29 ablation procedures via the retrograde aortic approach for left-sided accessory connections in whom pre-ablation and post-ablation echocardiograms were available for review. Valvar insufficiency was graded using color flow techniques as absent, trivial, mild, moderate, or severe by blinded reviewers. Ablation was acutely successful via the retrograde approach in 25 of 29 procedures among these 27 patients. Successful ablation was ultimately achieved in all 27 patients. At baseline, 7 patients had evidence of trivial or mild mitral insufficiency, and no patient had aortic insufficiency. Three patients had evidence of impaired left ventricular systolic performance in the presence of manifest pre-excitation. At follow-up, pre-existing mitral insufficiency resolved in 5/7 patients, and persisted in 2 patients. New mitral insufficiency was evident in 3 patients, and new aortic insufficiency was transiently evident in 1 patient following ablation (all trivial). Institutional experience (mean rank 10 cases vs. 33 cases, p.0005), and lower patient weight (29.7 vs. 56.3 kilograms, p =.01) were the only factors associated with the development of new valvar insufficiency. Valvar insufficiency could not be detected by careful auscultation in any patient and was deemed clinically insignificant in all patients. We conclude that ablation of left-sided accessory connections can be performed via the retrograde aortic approach without creating clinically significant valvar insufficiency.