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Background Tetralogy of Fallot with absent pulmonary valve is associated with high mortality, but it remains difficult to predict outcomes prenatally. We aimed to identify risk factors for mortality in a large multicenter cohort. Methods and Results Fetal echocardiograms and clinical data from 19 centers over a 10-year period were collected. Primary outcome measures included fetal demise and overall mortality. Of 100 fetuses, pregnancy termination/postnatal nonintervention was elected in 22. Of 78 with intention to treat, 7 (9%) died in utero and 21 (27%) died postnatally. With median follow-up of 32.9 months, no deaths occurred after 13 months. Of 80 fetuses with genetic testing, 46% had chromosomal abnormalities, with 22q11.2 deletion in 35%. On last fetal echocardiogram, at a median of 34.6 weeks, left ventricular dysfunction independently predicted fetal demise (odds ratio [OR], 7.4; 95% CI 1.3, 43.0; P =0.026). Right ventricular dysfunction independently predicted overall mortality in multivariate analysis (OR, 7.9; 95% CI 2.1-30.0; P =0.002). Earlier gestational age at delivery, mediastinal shift, left ventricular/right ventricular dilation, left ventricular dysfunction, tricuspid regurgitation, and Doppler abnormalities were associated with fetal and postnatal mortality, although few tended to progress throughout gestation on serial evaluation. Pulmonary artery diameters did not correlate with outcomes. Conclusions Perinatal mortality in tetralogy of Fallot with absent pulmonary valve remains high, with overall survival of 64% in fetuses with intention to treat. Right ventricular dysfunction independently predicts overall mortality. Left ventricular dysfunction predicts fetal mortality and may influence prenatal management and delivery planning. Mediastinal shift may reflect secondary effects of airway obstruction and abnormal lung development and is associated with increased mortality.

Background In a recent multicenter study of perinatal outcome in fetuses with Ebstein anomaly or tricuspid valve dysplasia, we found that one third of live-born patients died before hospital discharge. We sought to further describe postnatal management strategies and to define risk factors for neonatal mortality and circulatory outcome at discharge. Methods and Results This 23-center, retrospective study from 2005 to 2011 included 243 fetuses with Ebstein anomaly or tricuspid valve dysplasia. Among live-born patients, clinical and echocardiographic factors were evaluated for association with neonatal mortality and palliated versus biventricular circulation at discharge. Of 176 live-born patients, 7 received comfort care, 11 died <24 hours after birth, and 4 had insufficient data. Among 154 remaining patients, 38 (25%) did not survive to discharge. Nearly half (46%) underwent intervention. Mortality differed by procedure; no deaths occurred in patients who underwent right ventricular exclusion. At discharge, 56% of the cohort had a biventricular circulation (13% following intervention) and 19% were palliated. Lower tricuspid regurgitation jet velocity (odds ratio [OR], 2.3 [1.1-5.0], 95% CI, per m/s; P =0.025) and lack of antegrade flow across the pulmonary valve (OR, 4.5 [1.3-14.2]; P =0.015) were associated with neonatal mortality by multivariable logistic regression. These variables, along with smaller pulmonary valve dimension, were also associated with a palliated outcome. Conclusions Among neonates with Ebstein anomaly or tricuspid valve dysplasia diagnosed in utero, a variety of management strategies were used across centers, with poor outcomes overall. High-risk patients with low tricuspid regurgitation jet velocity and no antegrade pulmonary blood flow should be considered for right ventricular exclusion to optimize their chance of survival.

In fetuses with Ebstein anomaly or tricuspid valve dysplasia (EA/TVD), poor hemodynamic status is associated with worse neonatal outcome. It is not known whether EA/TVD fetuses with more favorable physiology earlier in gestation progress to more severe disease in the third trimester. We evaluated if echocardiographic indexes in EA/TVD fetuses presenting <24 weeks of gestation are reliable indicators of physiologic status later in pregnancy. This multicenter, retrospective study included 51 fetuses presenting at <24 weeks of gestation with EA/TVD and serial fetal echocardiograms ≥4 weeks apart. We designated the following as markers of poor outcome: absence of anterograde flow across the pulmonary valve, pulmonary valve regurgitation, cardiothoracic area ratio >0.48, left ventricular (LV) dysfunction, or tricuspid valve (TV) annulus Z-score >5.6. Median gestational age at diagnosis was 21 weeks (range, 18 to 24). Eighteen fetuses (35%) had no markers for poor hemodynamic status initially, whereas only 7 of these continued to have no markers of poor outcome in the third trimester. Nine of 27 fetuses (33%) with anterograde pulmonary blood flow on the first echocardiogram developed pulmonary atresia; 7 of 39 (18%) developed new pulmonary valve regurgitation. LV dysfunction was present in 2 (4%) patients at <24 weeks but in 14 (37%) later (p <0.001). The TV annulus Z-score and cardiothoracic area both increased from diagnosis to follow-up. In conclusion, progressive hemodynamic compromise was common in this cohort. Our study highlights that care must be taken in counseling before 24 weeks, as the absence of factors associated with poor outcome early in pregnancy may be falsely reassuring., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Pulmonary valve (PV) incompetence following transannular patch (TAP) repair of tetralogy of Fallot (TOF) results in long-term morbidity and mortality. Valve-sparing repairs have recently gained recognition; however, they may be associated with residual pulmonary stenosis (PS) in patients with small PV z scores. We sought to determine whether a repair that increases the PV annulus and augments the valve leaflet with a biomaterial would result in annular growth and in longer duration of valve competence compared with TAP. Eighty patients (median age 136 days, range 4-350) who underwent surgical repair of TOF between 2010 and 2014 were included in the study. Patients were divided into three groups based on the PV intervention: balloon dilation/valvotomy (n = 29), valve-sparing transannular repair (VSTAR) (n = 19) and TAP (n = 32). Intraoperative, early postoperative and midterm follow-up echocardiographic data (median 19 months, range 1-59) were obtained. The primary outcomes were the presence and severity of pulmonary regurgitation and/or PS. Compared with TAP, VSTAR patients demonstrated significantly less severe PR with 100 % freedom of severe PR immediately post-op (vs. 0 % in TAP), 60 % at 6 months and 20 % at 20 months. There were no differences in PS between VSTAR and TAP at follow-up. A subgroup analysis of the VSTAR group was performed. PV z scores were calculated and fit to a random effects model. Patient data fit the model closely, predicting a reproducible increase in valve annulus size over time. With better short-term and comparable midterm results, VSTAR may be appropriate for TOF repair in patients with small PV that would conventionally require a TAP.

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 <32 weeks (odds ratio, 8.6; 95% confidence interval, 3.5-21.0; P<0.001), tricuspid valve annulus diameter z-score (odds ratio, 1.3; 95% confidence interval, 1.1-1.5; P<0.001), pulmonary regurgitation (odds ratio, 2.9; 95% confidence interval, 1.4-6.2; P<0.001), and a pericardial effusion (odds ratio, 2.5; 95% confidence interval, 1.1-6.0; P=0.04). Nonsurvivors were more likely to have pulmonary regurgitation at any gestational age (61% versus 34%; P<0.001), and lower gestational age and weight at birth (35 versus 37 weeks; 2.5 versus 3.0 kg; both P<0.001)., 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., (© 2015 American Heart Association, Inc.)

Background: This study aimed to evaluate fetal echocardiographic measurements at the time of the first fetal echocardiogram as predictors of neonatal outcome for tetralogy of Fallot (TOF)., Methods: The study reviewed all infants with a prenatal diagnosis of TOF from January 2004 to June 2011. Aortic valve (AoV), pulmonary valve (PV), main pulmonary artery (MPA), left and right pulmonary artery diameters, and ductus arteriosus flow were evaluated on fetal echocardiograms, and associations between the fetal echocardiogram and the neonatal echocardiogram measurements and outcomes were assessed., Results: The study identified 67 TOF patients who had an initial fetal echocardiogram at a mean gestational age of 25.0 ± 5.2 weeks. Patients with absent PV syndrome or major aortopulmonary collaterals were excluded from the study, as were those without anterograde pulmonary blood flow at the first fetal echocardiogram. Of the remaining 44 patients, 10 were ductal dependent and required neonatal surgery. Infants who were ductal dependent had lower fetal PV (-5.38 ± 2.95 vs. -3.51 ± 1.66; p < 0.05) and MPA (-3.94 ± 1.66 vs. -2.87 ± 1.04; p < 0.05) z-scores. A fetal PV z-score of -5 predicted ductal dependence with 78 % sensitivity and 87 % specificity, and a PV z-score of -3 showed 100 % sensitivity and 34 % specificity (p < 0.001). Fetuses with a reversed left-to-right flow across the ductus arteriosus (DA) were more likely to be ductal dependent (odds ratio, 25; p < 0.001) than those who had normal ductal flow., Conclusions: In TOF, fetal PV and MPA z-scores and direction of the DA blood flow predict neonatal ductal dependence. Patients with fetal PV z-scores lower than -3 or any left-to-right flow at the level of the DA should be admitted to a center where prostaglandin is available.

This study was undertaken to examine the impact that prenatal diagnosis of congenital heart disease (CHD) has on birth and early neonatal outcomes. The prevalence of prenatally diagnosed CHD has risen over the past decade, but the effect that prenatal diagnosis of CHD has on peripartum decisions remains unclear. No consensus exists on the effect of prenatal diagnosis on neonatal outcomes. Between January 2004 and July 2009, a retrospective chart review of all neonates with CHD admitted to our institution's neonatal intensive care unit was conducted. Obstetric and postnatal variables were collected. Among the 993 subjects, 678 (68.3%) had a prenatal diagnosis. A prenatal diagnosis increased the odds of a scheduled delivery [odds ratio (OR) 4.1, 95% confidence interval (CI) 3.0-5.6] and induction of labor (OR 11.5, 95% CI 6.6-20.1). Prenatal diagnosis was not significantly associated with cesarean delivery when control was used for maternal age, multiple gestation, and presence of extracardiac anomaly. Mean gestational age had no impact on prenatal diagnosis, but prenatal diagnosis was associated with increased odds of delivery before a gestational age of 39 weeks (OR 1.5, 95% CI 1.1-1.9) and decreased odds of preoperative intubation (OR 0.5, 95% CI 0.3-0.6). Prenatal diagnosis did not have an impact on preoperative or predischarge mortality. Prenatal diagnosis was associated with increased odds of a scheduled delivery, birth before a gestational age of 39 weeks, and a decreased need for invasive respiratory support. Prenatal diagnosis of CHD was not associated with preoperative or predischarge mortality.

Objectives: To determine whether pediatric cardiologists and parents of older children with congenital heart disease (CHD) share similar expectations regarding the education and counseling that should be provided to parents of children with CHD in both the prenatal and neonatal period., Design: Consenting parents of older children with CHD (age >3 years) and cardiologists ranked the importance of education topics on a scale of 1 (unimportant) to 10 (very important). The rankings of parents and cardiologists were compared using Student's t-test., Results: We had 38 cardiologists and 41 parents complete the questionnaire. There was a statistically significant difference in rankings between cardiologist and parents of children with CHD (P<0.03). Parents consistently ranked topics as more important than cardiologists with a mean difference in rank score of 0.85 ±0.3. In the prenatal period, the most significant differences between parents and cardiologists were noted for information related to the child's quality of life. For neonatal counseling, the most significant differences were noted for information regarding follow-up care and the parent's ability to describe the child's CHD to medical personnel., Conclusion: Parents of older children with CHD would prefer to receive more counseling and education in the prenatal and newborn period than cardiologists perceive is wanted., (© 2012 Wiley Periodicals, Inc.)

This study sought to determine whether improvements in the care of children with congenital heart disease (CHD) have changed the epidemiology of infective endocarditis (IE). A retrospective study of patients 18 years of age and younger treated for IE from 1992 to 2004 (era 3) was conducted at the authors' children's hospital in New York City. This study was compared with two previous studies conducted at the same hospital from 1930 to 1959 (era 1) and from 1977 to 1992 (era 2). During the three eras, IE was diagnosed for 205 children with a median age of 8 years during eras 1 and 2, which decreased to 1.5 years during era 3, partly because of IE after cardiac surgery for young infants. In era 3, nonstreptococcal and nonstaphylococcal pathogens associated with hospital-acquired IE increased. Complications from IE declined during era 3, but after the widespread availability of antibiotics in 1944, crude mortality rates were similar in eras 1 (32%), 2 (21%), and 3 (24%). However, in era 3, mortality occurred only among subjects with hospital-acquired IE. The epidemiology of pediatric IE has changed in the modern era. Currently, IE is most likely to occur among young children with complex congenital heart disease. Pediatric IE remains associated with high crude mortality rates when it is acquired in the hospital.

Prenatal diagnosis of congenital heart disease (CHD) is increasingly common. However, the current impact of prenatal diagnosis on neonatal outcomes is unclear. Between January 2004 and January 2008, a retrospective chart review of infants who underwent surgical repair of CHD before discharge at our institution was conducted. Obstetric and perioperative variables were recorded. Of 439 neonates, 294 (67%) were diagnosed prenatally (PREdx). Infants with PREdx had a lower mean birth weight (3.0 +/- 0.6 vs. 3.1 +/- 0.6 kg, p = 0.002) and gestational age (37.9 +/- 2.1 vs. 38.6 +/- 2.4 wk, p < 0.001) than those with postnatal diagnosis (POSTdx). Severe lesions were more likely to be PREdx: Neonates with single-ventricle (SV) physiology (n = 130 patients [31.2%]) had increased odds of PREdx (n = 113/130, odds ratio [OR] 4.7; 95% confidence interval [CI] 2.7-8.2, p < 0.001). PREdx was associated with decreased preoperative intubation (OR 0.62; 95% CI 0.42-0.95, p = 0.033), administration of antibiotics (OR 0.23; 95% CI 0.15-0.36, p < 0.001), cardiac catheterization (OR 0.54; 95% CI 0.34-0.85, p = 0.01), and emergency surgery (OR 0.18; 95% CI 0.06-0.5, p < 0.001) compared with POSTdx infants. There was no difference in APGAR scores, preoperative pH, day of life of surgery, operative complications, hospital length of stay, or overall mortality in the PREdx versus POSTdx groups, even when controlling for lesion severity. PREdx was not independently associated with neonatal mortality, despite having included more severe cardiac lesions. PREdx was significantly associated with decreased neonatal morbidity in terms of decreased use of preoperative ventilator, administration of antibiotics, cardiac catheterization, and emergency surgery.

Background: Referral for fetal echocardiography (fECHO) is an acute stressor that may induce significant maternal anxiety. To promote good clinical management of expectant mothers in this situation, including adequate screening for possible psychiatric interventions, data are needed regarding the psychosocial functioning of women scheduled for fECHO procedures., Objective: To investigate the association between fECHO and maternal anxiety., Methods: Pregnant women answered two questionnaires before first fECHO. The Spielberger State-Trait Anxiety Inventory (STAI) assessed how subjects feel "now" (state) versus how they "usually feel" (trait). Separate state and trait anxiety scores were calculated; scores were compared between the study cohort and a gestational age-matched historical cohort of 31 pregnant women who did not undergo fECHO. A second questionnaire developed by the investigators ascertained pregnancy specific concerns and characteristics., Results: Forty subjects were enrolled. The mean state score of the fECHO cohort (42.1 +/- 15.1) differed from the historical cohort (32.8 +/- 11.3; p = 0.006); however there was no difference between trait scores (34.7 +/- 10.8 vs. 35.4 +/- 12.8; p = 0.8). A multivariate linear regression model controlling for race and maternal age demonstrated that fECHO was a strong independent predictor of maternal state anxiety score (p = 0.004, beta = 10.4)., Conclusions: Pregnant women presenting for fECHO report high anxiety levels compared with women not presenting for fECHO. Clinician awareness and sensitivity are recommended and further investigation of modifiers of anxiety in this high risk group should be explored.

Background: This study aimed to evaluate the impact of prenatal diagnosis on parental understanding of congenital heart disease (CHD) in newborns., Methods: Consenting parents of newborns with CHD answered questions about the cardiac lesion, surgical repair, follow-up management, risk for CHD in future children, and maternal education before neonatal intensive care unit (NICU) discharge. A total understanding score was calculated (0-10) as the sum of five subscores: physician score, CHD score, surgery score, follow-up score, and reproduction score. Each category was scored as 0 (none correct), 1 (some correct), or 2 (all correct). The prenatal and postnatal diagnoses scores were compared., Results: From June 2006 to November 2006, 50 families completed the questionnaire. Of these 50 families, 26 reported a prenatal diagnosis. The mean infant age when the parents were approached was 17.3 +/- 13.3 days. The summary understanding score for the entire group was 6.3 +/- 2.4 of 10. Multivariate regression analysis demonstrated a difference in scores between prenatal and postnatal diagnosis groups (p = 0.02) when control was used for maternal education. Prenatal diagnosis and maternal education (p < 0.01) had independent effects on the score., Conclusion: Prenatal diagnosis increases parental understanding of neonatal CHD. Nevertheless, parental understanding remains suboptimal.

Postinhibitory rebound (PIR) is defined as membrane depolarization occurring at the offset of a hyperpolarizing stimulus and is one of several intrinsic properties that may promote rhythmic electrical activity. PIR can be produced by several mechanisms including hyperpolarization-activated cation current (I(h)) or de-inactivation of depolarization-activated inward currents. Excitatory swim motor neurons in the leech exhibit PIR in response to injected current pulses or inhibitory synaptic input. Serotonin, a potent modulator of leech swimming behavior, increases the peak amplitude of PIR and decreases its duration, effects consistent with supporting rhythmic activity. In this study, we performed current clamp experiments on dorsal excitatory cell 3 (DE-3) and ventral excitatory cell 4 (VE-4). We found a significant difference in the shape of PIR responses expressed by these two cell types in normal saline, with DE-3 exhibiting a larger prolonged component. Exposing motor neurons to serotonin eliminated this difference. Cs+ had no effect on PIR, suggesting that I(h) plays no role. PIR was suppressed completely when low Na+ solution was combined with Ca2+-channel blockers. Our data support the hypothesis that PIR in swim motor neurons is produced by a combination of low-threshold Na+ and Ca2+ currents that begin to activate near -60 mV.

To understand the molecular basis of nervous system function in the leech, Hirudo medicinalis, we have isolated four novel cDNAs encoding putative voltage-gated sodium (Na) channel alpha subunits, and have analyzed the expression of these genes in individual neurons of known function. To begin, degenerate oligonucleotide primers were used in combination with pre-existing cDNA libraries and reverse transcriptase-coupled polymerase chain reactions (RT-PCR). The putative leech Na channel cDNAs (LeNas) exhibit a higher degree of sequence homology to Na channel genes in other species than to voltage-gated calcium or potassium channel genes, including those expressed in leech. All LeNa cDNAs contain sequences corresponding to regions of functional importance in Na channel alpha subunits, including the "S4 region" involved in activation, the "pore loops" responsible for ion selectivity, and the "inactivation loop" between the third and fourth domains, though the latter lacks the highly conserved "IFM" motif critical for mammalian Na channel inactivation. Sequences corresponding to important determinants of tetrodotoxin sensitivity are found in some, but not all, LeNa cDNAs, consistent with prior electrophysiological evidence of Na channel heterogeneity in the leech with respect to this toxin. Subsequently, two different sets of isoform-specific primers and methods of RT-PCR, including a sensitive, fluorescence-based "real time" RT-PCR, were used to analyze LeNa isoform expression in functionally distinct neurons. The results from both approaches were consistent, and not only demonstrated that individual neurons often express more than one LeNa isoform, but also revealed cell-specific patterns of Na channel isoform expression in the leech nervous system., (Copyright 2003 Wiley Periodicals, Inc. J Neurobiol 55: 355-371, 2003)