Complement (C1q) Binding De Novo Donor-Specific Antibodies and Cardiac-Allograft Vasculopathy in Pediatric Heart Transplant Recipients.

BACKGROUND: We hypothesized C1q binding de novo donor-specific antibody (DSA) after heart transplant (HT) is a higher risk for development of coronary artery vasculopathy (CAV) in children. METHODS: A retrospective analysis of 127 pediatric HT recipients transplanted between January 2005 and December 2014 was used to determine complement (C1q)-binding de novo DSA on the outcomes of HT and the ability of the C1q assay to predict CAV development. RESULTS: Of 127 patients, 59 (46.4%) developed de novo DSA, 37 of those had C1q+ DSA. There was no difference in baseline characteristics except patients who developed C1q+ DSA more often received a donor heart from a female compared with C1q- DSA group (P = 0.034). The DSA median fluorescent intensity (MFI) value of 7000 or greater had 80% sensitivity and 80% specificity (C statistics 0.89, P <0.05) for predicting positive C1q binding. Multivariate analyses identified C1q binding DSA as an independent risk for CAV with a hazard ratio (HR) of 3.25 (95% confidence interval [CI], 1.33-7.93; P = 0.0095). In multivariable Cox proportional hazard models, the covariates associated with graft loss included: C1q+ DSA (HR, 3.2; 95% CI, 1.34-7.86; P < 0.009), pre-HT renal insufficiency (HR, 11.3; 95% CI, 3.71-34.29; P < 0.0001), and pre-HT ventilator support (HR, 3.3; 95% CI, 1.39-7.81; P = 0.007). CONCLUSIONS: The DSA strength in MFI correlates with positive C1q-binding activity and hence functional capabilities of DSA. Close monitoring of DSA strength in MFI and function (C1q assay) may be useful for identifying pediatric HT recipient at risk for development of CAV.

Prenatal diagnosis, hospital characteristics, and mortality in transposition of the great arteries.

BACKGROUND: The role of prenatal diagnosis in reducing neonatal mortality from transposition of the great arteries (TGA) is controversial. Factors affected by prenatal diagnosis such as proximity at birth to a cardiac surgical center (CSC) and CSC volume are associated with mortality in congenital heart disease. The purpose of the study was to determine the associations between prenatal diagnosis, distance from birthplace to a CSC, CSC TGA volume, and neonatal mortality in patients with TGA. METHODS: The Texas Birth Defects Registry was queried for all live born infants with TGA from 1999 to 2007. Four hundred sixty-eight cases of TGA were included. RESULTS: Forty-eight patients (10.3%) were prenatally diagnosed, and 20 patients died before age 28 days (4.3%). Neither prenatal diagnosis nor close proximity to a CSC at birth (p > 0.05) were associated with decreased mortality. Low CSC TGA volume was associated with increased mortality (p < 0.0002). Mortality at the CSCs with <5 patients per year was 9.6%; CSCs with 5 to 10 patients per year had 0% mortality, and those with >10 patients per year had 2.3% mortality. In multivariable logistic regression, only preterm birth (odds ratio, 7.05; 95% confidence interval, 4.13-12.05) and lower CSC volume (p < 0.001) were associated with neonatal mortality, although prenatal diagnosis attenuated the detrimental association of lower volume CSCs with higher mortality (p for interaction = 0.047). CONCLUSION: Lower CSC TGA patient volume was associated with higher neonatal mortality. Prenatal diagnosis may improve survival in lower volume CSCs. Birth Defects Research (Part A) 106:739-748, 2016. © 2016 Wiley Periodicals, Inc.

Donor-specific HLA alloantibodies: Impact on cardiac allograft vasculopathy, rejection, and survival after pediatric heart transplantation.

BACKGROUND: There is increasing evidence that donor-specific anti-HLA antibodies (DSA) are associated with poor outcomes after cardiac transplantation in adults, but data are limited in children. The objective of this study was to examine the development and consequences of de novo DSA in pediatric recipients of heart transplants. METHODS: We analyzed 105 pediatric patients who received heart transplants at our center from January 2002 to December 2012. All patients had negative T-cell and B-cell post-transplant crossmatches. Patients underwent HLA antibody screening at 1, 2, 3, 6, and 12 months post-transplant and annually thereafter unless there was suspicion for rejection. HLA class I and II antibodies were identified using Luminex assay. Coronary angiography was performed at 1 year and annually thereafter. Acute cellular rejection, antibody-mediated rejection, and treated clinical rejections were included together as rejection events. RESULTS: Of 105 patients, 45 (43%) developed de novo DSA. DSA-positive patients had significantly higher rates of coronary artery vasculopathy (CAV) compared with DSA-negative patients (36% vs 13%). CAV-free survival at 1 year and 5 years post-transplant for DSA-negative patients was 90% and 25%, respectively, compared with 70% and 0%, respectively, for DSA-positive patients (p < 0.01). DSA-positive patients had 2.5 times more rejection events per year than DSA-negative patients. The 5-year graft survival rate was 72.4% for DSA-negative patients and 21% for DSA-positive patients (p < 0.001). CONCLUSIONS: De novo DSA has a strong negative impact on CAV, rejection, and graft survival in pediatric recipients of heart transplants.

Persistent Epstein-Barr viral load in Epstein-Barr viral naïve pediatric heart transplant recipients: Risk of late-onset post-transplant lymphoproliferative disease.

AIM: To examine the risk of late-onset post-transplant lymphoproliferative disorder (PTLD) in the presence of persisting high Epstein-Barr virus (EBV) in EBV naïve pediatric heart transplant (HT) recipients. METHODS: A retrospective review of the medical records of the 145 pediatric HT recipients who had serial EBV viral load monitoring at our center was performed. We defined EBV naive patients whose EBV serology either IgM or IgG in the blood were negative at the time of HT and excluded passive transmission from mother to child in subjects less than 6 mo of age. RESULTS: PTLD was diagnosed in 8 out of 145 patients (5.5%); 6/91 (6.5%) in those who were EBV seropositive and 2/54 (3.7%) in the EBV naïve group at the time of HT (P = 0.71). We found 32/145 (22%) patients with persistently high EBV load during continuing follow-up; 20/91 (22%) in EBV seropositive group vs 12/54 (22%) in EBV naïve group (P = 0.97). There was no significant association between pre-HT serostatus and EBV load after transplant (P > 0.05). In the EBV seropositive group, PTLD was diagnosed in 15% (3/20) of patients with high EBV vs 4.2% (3/71) of patients with low or undetectable EBV load (P = 0.14) whereas in EBV naïve patients 8.3% (1/12) of those with high EBV load and 2.3% (1/42) with low or undetectable EBV load (P = 0.41). There was a highly significant association between occurrence of PTLD in those with high EBV load and duration of follow up (4.3 ± 3.9 years) after HT by Cochran-Armitage test for the entire cohort (P = 0.005). At least one episode of acute rejection occurred in 72% (23/32) of patients with high EBV vs 36% (41/113) patients with low or undetectable EBV after HT (P < 0.05). CONCLUSION: There is an association between persistently high EBV load during post-HT follow up and the occurrence of late-onset PTLD in pediatric HT recipients irrespective of serostatus at the time of transplant. The occurrence of allograft rejection increased in patients with high EBV load presumably due to reduction in immunosuppression.

Age at referral and mortality from critical congenital heart disease.

BACKGROUND AND OBJECTIVE: Newborn pulse oximetry screening is recommended to promote early referral of neonates with critical congenital heart disease (CCHD) and reduce mortality; however, the impact of late referral on mortality is not well defined. The purpose of this population-based study was to describe the association between timing of referral to a cardiac center and mortality in 2360 liveborn neonates with CCHD. METHODS: Neonates with CCHD born before pulse oximetry screening (1996-2007) were selected from the Texas Birth Defects Registry and linked to state birth and death records. Age at referral was ascertained from date of first cardiac procedure at a cardiac center. Logistic and Cox proportional hazards regression models were used to estimate factors associated with late referral and mortality; the Kaplan-Meier method was used to estimate 3-month survival. RESULTS: Median age at referral was 1 day (25th-75th percentile: 0-6 days). Overall, 27.5% (649 of 2360) were referred after age 4 days and 7.5% (178 of 2360) had no record of referral. Neonatal mortality was 18.1% (277 of 1533) for those referred at 0 to 4 days of age, 9.0% (34 of 379) for those referred at 5 to 27 days of age, and 38.8% (69 of 178) for those with no referral. No improvement in age at referral was found across the 2 eras within 1996-2007. CONCLUSIONS: A significant proportion of neonates with CCHD experienced late or no referral to cardiac specialty centers, accounting for a significant number of the deaths. Future population-based studies are needed to determine the benefit of pulse oximetry screening on mortality and morbidity.

Late detection of critical congenital heart disease among US infants: estimation of the potential impact of proposed universal screening using pulse oximetry.

IMPORTANCE: Critical congenital heart disease (CCHD) was added to the Recommended Uniform Screening Panel for Newborns in the United States in 2011. Many states have recently adopted or are considering requirements for universal CCHD screening through pulse oximetry in birth hospitals. Limited previous research is directly applicable to the question of how many US infants with CCHD might be identified through screening. OBJECTIVES: To estimate the proportion of US infants with late detection of CCHD (>3 days after birth) based on existing clinical practice and to investigate factors associated with late detection. DESIGN, SETTING, AND PARTICIPANTS: Descriptive and multivariable analysis. Data were obtained from a multisite population-based study of birth defects in the United States, the National Birth Defects Prevention Study (NBDPS). We included all live-born infants with estimated dates of delivery from January 1, 1998, through December 31, 2007, and nonsyndromic, clinically verified CCHD conditions potentially detectable through screening via pulse oximetry. MAIN OUTCOMES AND MEASURES: The main outcome measure was the proportion of infants with late detection of CCHD through echocardiography or at autopsy under the assumption that universal screening at birth hospitals might reduce the number of such late diagnoses. Secondary outcome measures included prevalence ratios for associations between selected demographic and clinical factors and late detection of CCHD. RESULTS: Of 3746 live-born infants with nonsyndromic CCHD, late detection occurred in 1106 (29.5% [95% CI, 28.1%-31.0%]), including 6 (0.2%) (0.1%-0.4%) first receiving a diagnosis at autopsy more than 3 days after birth. Late detection varied by CCHD type from 9 of 120 infants (7.5% [95% CI, 3.5%-13.8%]) with pulmonary atresia to 497 of 801 (62.0% [58.7%-65.4%]) with coarctation of the aorta. In multivariable analysis, late detection varied significantly by CCHD type and study site, and infants with extracardiac defects were significantly less likely to have late detection of CCHD (adjusted prevalence ratio, 0.58 [95% CI, 0.49-0.69]). CONCLUSIONS AND RELEVANCE: We estimate that 29.5% of live-born infants with nonsyndromic CCHD in the NBDPS received a diagnosis more than 3 days after birth and therefore might have benefited from routine CCHD screening at birth hospitals. The number of infants in whom CCHD was detected through screening likely varies by several factors, including CCHD type. Additional population-based studies of screening in practice are needed.

Prenatal diagnosis, birth location, surgical center, and neonatal mortality in infants with hypoplastic left heart syndrome.

BACKGROUND: Most studies have not demonstrated improved survival after prenatal diagnosis of critical congenital heart disease, including hypoplastic left heart syndrome (HLHS). However, the effect of delivery near a cardiac surgical center (CSC), the recommended action after prenatal diagnosis, on HLHS mortality has been poorly investigated. METHODS AND RESULTS: Using Texas Birth Defects Registry data, 1999 through 2007, which monitored >3.4 million births, we investigated the association between distance (calculated driving time) from birth center to CSC and neonatal mortality in 463 infants with HLHS. Infants with extracardiac birth defects or genetic disorders were excluded. The associations between prenatal diagnosis, CSC HLHS volume, and mortality were also examined. Neonatal mortality in infants born <10 minutes from a CSC was 21.0%, 10 to 90 minutes 25.2%, and >90 minutes 39.6% (P for trend <0.001). Prenatal diagnosis alone was not associated with improved survival (P=0.14). In multivariable analysis, birth >90 minutes from a CSC remained associated with increased mortality (odds ratio, 2.03; 95% confidence interval, 1.19-3.45), compared with <10 minutes. In subanalysis, birth >90 minutes from a CSC was associated with higher pretransport mortality (odds ratio, 6.69; 95% confidence interval, 2.52-17.74) and birth 10 to 90 minutes with higher presurgical mortality (odds ratio, 4.45; 95% confidence interval, 1.17-17.00). Higher surgical mortality was associated with lower CSC HLHS volume (odds ratio per 10 patients, 0.88; 95% confidence interval, 0.84-0.91). CONCLUSIONS: Infants with HLHS born far from a CSC have increased neonatal mortality, and most of this mortality is presurgical. Efforts to improve prenatal diagnosis of HLHS and subsequent delivery near a large volume CSC may significantly improve neonatal HLHS survival.

Racial/ethnic disparities in timing of death during childhood among children with congenital heart defects.

BACKGROUND: Infants with congenital heart defects (CHD) have increased risk of morbidity and mortality. Little is known about racial/ethnic differences in timing of death during childhood. Our intent was to investigate racial/ethnic differences in mortality for CHDs during specific time periods in childhood. METHODS: Texas Birth Defect Registry data were used for a retrospective cohort study with 30,015 singleton infants with a CHD, born January 1, 1999, to December 31, 2007, to non-Hispanic (NH) white, NH-black, or Hispanic women. Texas Birth Defect Registry data were linked to Texas death records to ascertain death. Kaplan-Meier survival probabilities and multivariable Cox-proportional hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. RESULTS: NH-blacks and Hispanics with specific CHDs had increased mortality during the postneonatal period and early childhood. NH-blacks had increased postneonatal mortality compared with NH-whites for transposition of the great arteries (HR = 2.4; 95% CI, 1.5-4.0), pulmonary valve atresia without ventricular septal defect (HR = 4.1; 95% CI, 1.7-9.7), Ebstein's anomaly (HR = 8.6; 95 CI, 1.2-61.1), hypoplastic left heart syndrome (HR = 2.1; 95% CI, 1.2-3.7), coarctation of the aorta (HR = 2.1; 95% CI, 1.2-3.5), ventricular septal defect (HR = 2.1; 95% CI, 1.6-2.8), and atrial septal defect (HR = 1.4; 95% CI, 1.1-1.8). Hispanics had increased postneonatal mortality risk for tetralogy of Fallot (HR = 2.0; 95% CI, 1.1-3.5). Racial/ethnic increases in mortality risk were also observed during infancy and childhood. CONCLUSION: Racial/ethnic differences in mortality were most notably observed during the postneonatal period and early childhood. Future studies should assess factors associated with this disparity in mortality risk for infants with CHDs.

The importance of the muscle and ventilatory blood pumps during exercise in patients without a subpulmonary ventricle (Fontan operation).

OBJECTIVES: The aim of this study was to determine the relative contribution of the muscle and ventilatory pumps to stroke volume in patients without a subpulmonic ventricle. BACKGROUND: In patients with Fontan circulation, it is unclear how venous return is augmented to increase stroke volume and cardiac output during exercise. METHODS: Cardiac output (acetylene rebreathing), heart rate (electrocardiography), oxygen uptake (Douglas bag technique), and ventilation were measured in 9 patients age 15.8 ± 6 years at 6.1 ± 1.8 years after Fontan operation and 8 matched controls. Data were obtained at rest, after 3 min of steady-state exercise (Ex) on a cycle ergometer at 50% of individual working capacity, during unloaded cycling at 0 W (muscle pump alone), during unloaded cycling with isocapnic hyperpnea (muscle and ventilatory pump), during Ex plus an inspiratory load of 12.8 ± 1.5 cm water, and during Ex plus an expiratory load of 12.8 ± 1.6 cm water. RESULTS: In Fontan patients, the largest increases in stroke volume and stroke volume index were during zero-resistance cycling. An additional increase with submaximal exercise occurred in controls only. During Ex plus expiratory load, stroke volume indexes were reduced to baseline, non-exercise levels in Fontan patients, without significant changes in controls. CONCLUSIONS: With Fontan circulation increases in cardiac output and stroke volume during Ex were due to the muscle pump, with a small additional contribution by the ventilatory pump. An increase in intrathoracic pressure played a deleterious role in Fontan circulation by decreasing systemic venous return and stroke volume.

Effect of acculturation and distance from cardiac center on congenital heart disease mortality.

BACKGROUND AND OBJECTIVE: Despite improvements in congenital heart disease (CHD) survival over the past 4 decades, ethnic disparities persist. Several studies have shown higher postoperative CHD adjusted mortality in black and Hispanic children. Others noted that non-English-speaking language at home was associated with appointment noncompliance, which the parents attributed to misunderstanding and living too far from a health center. The purpose of this study was to determine the effect of home distance to a cardiac center, or having a Latin American-born parent, on first-year mortality in infants with severe CHD. METHODS: Infants with severe CHD, having an estimated first-year mortality >25%, born 1996-2003, were identified from the Texas Birth Defects Registry and linked to state and national vital records. We examined the effects of defect type; birth weight; gestational age; extracardiac anomalies; infant gender; maternal race/ethnicity, marital status, and education; residence in a Texas county bordering Mexico; home distance to cardiac center; and parental birth country on first-year survival. RESULTS: Overall first-year survival was 59.9%, and no race/ethnic differences were noted; however, survival was significantly (P < .05) lower for Hispanic infants with hypoplastic left heart syndrome. Neither home distance to a cardiac center nor parental birth country was related to first-year survival; however, survival was noted to be lower in Texas counties bordering Mexico, counties that have high rates of poverty. CONCLUSIONS: Further studies are needed to determine if these disparities in survival of infants with severe CHD are attributable to delays in referral to a cardiac center.

Use of a highly sensitive assay for cardiac troponin T and N-terminal pro-brain natriuretic peptide to diagnose acute rejection in pediatric cardiac transplant recipients.

BACKGROUND: Biomarkers have been proposed to augment or replace endomyocardial biopsy (EMB) to diagnose acute transplant rejection (AR). A new, highly sensitive assay for troponin T detects levels of cardiac troponin T (cTnT) 10- to 100-fold lower than standard assays but has not been investigated in transplant patients. N-terminal pro-brain natriuretic peptide (NT-proBNP) has not been evaluated in pediatric transplant patients. The purpose of this pilot study was to evaluate the association of cTnT and NT-proBNP with AR in pediatric cardiac transplant patients. METHODS: Plasma was obtained at the time of EMB from pediatric patients ≥ 1 year old. N-terminal pro-brain natriuretic peptide was measured in fresh plasma at the time of biopsy, and cTnT was measured from frozen, stored samples using the highly sensitive assay for troponin T. Biomarker data were correlated with EMB results. Cellular AR was defined as an International Society for Heart and Lung Transplantation biopsy score of grade ≥ 2R. RESULTS: Fifty-three blood samples were obtained from 42 patients (mean age 11 years). Seven episodes of AR occurred in 5 patients. Biopsies with vs without AR were associated with higher cTnT (median [interquartile range {IQR}] 66 [45-139] vs 7 [2-13] pg/mL, P = .001) and NT-proBNP (median [IQR] 11,169 [280-23,317] vs 334 [160-650] pg/mL, P < .01). After successful treatment of AR in 5 patients, cTnT fell markedly (median [IQR] 53.5 [44.8-66.5] to 10.7 [1.5-16.4], P = .05). CONCLUSION: In this pilot study, we found marked elevation of cTnT and NT-proBNP among children with AR. Moreover, reduction in cTnT levels after treatment paralleled improvement in EMB results. If these findings are confirmed in larger prospective studies, monitoring with these biomarkers may obviate surveillance EMB.

Racial/Ethnic disparities in risk of early childhood mortality among children with congenital heart defects.

BACKGROUND: Infants with congenital heart defects (CHDs) have increased risk of childhood morbidity and mortality. However, little is known about racial/ethnic differences in early childhood mortality. PATIENTS AND METHODS: We conducted a retrospective cohort study with data from the Texas Birth Defect Registry on 19 530 singleton, live-born infants with a CHD and born January 1, 1996, to December 31, 2003, to non-Hispanic (NH) white, NH black, and Hispanic women. Texas Birth Defect Registry data were linked to Texas death records and the National Death Index to ascertain deaths between January 1, 1996, and December 31, 2005. Kaplan-Meier survival estimates were computed, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated from multivariable Cox-proportional hazard regression models to determine the effect of maternal race/ethnicity on mortality for selected CHD phenotypes. RESULTS: After adjusting for covariates, compared with NH white children, NH black children had increased early childhood mortality risk for transposition of the great arteries (HR: 2.04 [95% CI: 1.40-2.97]), tetralogy of Fallot (HR: 1.85 [95% CI: 1.09-3.12]), pulmonary valve atresia without ventricular septal defect (VSD) (HR: 2.60 [95% CI: 1.32-5.12]), VSD (HR: 1.56 [95% CI: 1.19-2.03]), and atrial septal defect (HR: 1.34 [95% CI: 1.08-1.66]). Hispanic children had higher mortality risk for pulmonary valve atresia without VSD (HR: 1.76 [95% CI: 1.06-2.91]) and hypoplastic left heart syndrome (HR: 1.51 [95% CI: 1.13-2.02]). CONCLUSIONS: We provide evidence that supports racial/ethnic disparities in early childhood mortality among infants with CHDs. Identifying infants with the greatest risk of early childhood mortality will facilitate development of interventions and policies to mitigate these risks.

Mortality resulting from congenital heart disease among children and adults in the United States, 1999 to 2006.

BACKGROUND: Previous reports suggest that mortality resulting from congenital heart disease (CHD) among infants and young children has been decreasing. There is little population-based information on CHD mortality trends and patterns among older children and adults. METHODS AND RESULTS: We used data from death certificates filed in the United States from 1999 to 2006 to calculate annual CHD mortality by age at death, race-ethnicity, and sex. To calculate mortality rates for individuals ≥1 year of age, population counts from the US Census were used in the denominator; for infant mortality, live birth counts were used. From 1999 to 2006, there were 41,494 CHD-related deaths and 27,960 deaths resulting from CHD (age-standardized mortality rates, 1.78 and 1.20 per 100,000, respectively). During this period, mortality resulting from CHD declined 24.1% overall. Mortality resulting from CHD significantly declined among all race-ethnicities studied. However, disparities persisted; overall and among infants, mortality resulting from CHD was consistently higher among non-Hispanic blacks compared with non-Hispanic whites. Infant mortality accounted for 48.1% of all mortality resulting from CHD; among those who survived the first year of life, 76.1% of deaths occurred during adulthood (≥18 years of age). CONCLUSIONS: CHD mortality continued to decline among both children and adults; however, differences between race-ethnicities persisted. A large proportion of CHD-related mortality occurred during infancy, although significant CHD mortality occurred during adulthood, indicating the need for adult CHD specialty management.

Mortality among infants with birth defects: Joint effects of size at birth, gestational age, and maternal race/ethnicity.

BACKGROUND: We examined the separate and joint effects of gestational age, size at birth and maternal race/ethnicity on early childhood survival among 48,391 singleton infants with major birth defects. METHODS: Texas Birth Defects Registry data were linked to death records and the National Death Index to ascertain deaths. Gestational age categories were preterm or term birth; size at birth included small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA). Kaplan-Meier survival estimates were calculated, and Cox-proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) to determine risk of death after adjusting for covariates. RESULTS: Overall, relative to non-Hispanic (NH) -whites, NH-blacks, and Hispanics had a 51 and 10% greater risk of death during early childhood, respectively. Compared to NH-whites born term and AGA (survival = 97%), Hispanic children born SGA and preterm had the greatest risk of death (HR(a) = 6.1; 95% CI, 5.2, 7.2) and the lowest early childhood survival (76%), followed by SGA preterm NH-blacks (HR(a) = 4.8; 95% CI, 3.6, 6.5; survival = 81%) and SGA preterm NH-whites (HR(a) = 4.5; 95% CI, 3.7, 5.6; survival = 83%). Children born LGA at term had no increased risk of mortality regardless of maternal race/ethnicity. CONCLUSIONS: The joint effect of gestational age and size at birth had greatest impact on childhood mortality. Additional population based studies are needed to better understand causes of racial/ethnic disparities in mortality among children with birth defects.

Mortality in first 5 years in infants with functional single ventricle born in Texas, 1996 to 2003.

BACKGROUND: Infants with functional single ventricle have a high risk of death during the early years of life. Studies have reported improvement in postoperative survival, but they do not include preoperative deaths or those occurring before transfer. The purpose of this population-based study was to estimate 5-year survival in infants with functional single ventricle, to define factors associated with survival, and to estimate improvement in outcome. METHODS AND RESULTS: Patients with hypoplastic left heart syndrome, pulmonary atresia intact ventricular septum, single ventricle, and tricuspid atresia born in 1996 to 2003 were identified from the Texas Birth Defects Registry and linked to state and national birth and death vital records. We examined the effects of defect type, birth era, birth weight, gestational age, maternal race/ethnicity, extracardiac anomalies, sex, and maternal age and education on survival. Five-year survival varied by defect type: hypoplastic left heart syndrome, 38.0% (95% confidence interval, 32.6 to 43.5); single ventricle, 56.1% (95% confidence interval, 49.9 to 61.7); pulmonary atresia intact ventricular septum, 55.7% (95% confidence interval, 45.8 to 64.4); and tricuspid atresia, 74.6% (95% confidence interval, 62.4 to 83.4). The presence of extracardiac defects increased the adjusted risk of death by 84%. Non-Hispanic blacks had an adjusted risk of death that was 41% higher than that for non-Hispanic whites, and Hispanics had a 26% higher risk. Patients born in 2001 to 2003 had a 47% lower risk than those born in 1996 to 2000. CONCLUSIONS: This population-based study demonstrates significant improvement in overall 5-year survival, particularly in cases of hypoplastic left heart syndrome and single ventricle. Additional studies are needed to determine the factors causing racial/ethnic and regional differences in outcome.

3-Acetyl-benzoic acid.

In the crystal structure of the title compound, C(9)H(8)O(3), essentially planar mol-ecules [the carboxyl group makes a dihedral angle of 4.53 (7)° with the plane of the ring, while the acid group forms a dihedral angle of 3.45 (8)° to the ring] aggregate by centrosymmetric hydrogen-bond pairing of ordered carboxyl groups. This yields dimers which have two orientations in a unit cell, creating a herringbone pattern. In addition, two close C-H⋯O inter-molecular contacts exist: one is between a methyl H atom and the ketone of a symmetry-related mol-ecule and the other involves a benzene H atom and the carboxyl group O atom of another mol-ecule. The crystal studied was a non-merohedral twin with twin law [100, 00, 0] and a domain ratio of 0.8104(14): 0.1896(14).

Pulse oximetry screening at 4 hours of age to detect critical congenital heart defects.

OBJECTIVE: The purpose of this prospective study was to assess the feasibility and reliability of pulse oximetry screening to detect critical congenital heart defects in a newborn nursery. METHODS: The study was performed in a large urban hospital with an exclusively inborn population. Stable neonates who had a gestational age of >or=35 weeks and birth weight of >or=2100 g and in whom a critical congenital heart defect was not suspected were admitted to the newborn nursery. When the 4-hour pulse oximetry reading was <96%, pulse oximetry was repeated at discharge, and when the pulse oximetry reading remained at persistently <96%, echocardiography was performed. RESULTS: Of 15299 admissions to newborn nursery during the 12-month study period, 15233 (99.6%) neonates were screened with 4-hour pulse oximetry. Pulse oximetry readings were >or=96% for 14374 (94.4%) neonates; 77 were subsequently evaluated before discharge for cardiac defects on the basis of clinical examination. Seventy-six were normal, and 1 had tetralogy of Fallot with discontinuous pulmonary arteries. Pulse oximetry readings at 4 hours were <96% in 859 (5.6%); 768 were rescreened at discharge, and 767 neonates had a pulse oximetry reading at >or=96%. One neonate had persistently low pulse oximetry at discharge; echocardiography was normal. Although 3 neonates with a critical congenital heart defect had a 4-hour pulse oximetry reading of <96%, all developed signs and/or symptoms of a cardiac defect and received a diagnosis on the basis of clinical findings, not screening results. CONCLUSIONS: All neonates with a critical congenital heart defect were detected clinically, and no cases of critical congenital heart defect were detected by pulse oximetry screening. These results indicate that pulse oximetry screening does not improve detection of critical congenital heart defects above and beyond clinical observation and assessment. Our findings do not support a recommendation for routine pulse oximetry screening in seemingly healthy neonates.

Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease.

OBJECTIVE: To investigate the safety, tolerability, and pharmacokinetics of the anti-tumor necrosis factor-alpha monoclonal antibody infliximab in subjects with intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD). STUDY DESIGN: We conducted a multicenter, randomized, prospective trial of second IVIG infusion (2 g/kg) versus infliximab (5 mg/kg) in 24 children with acute KD and fever after initial treatment with IVIG. Primary outcome measures were the safety, tolerability, and pharmacokinetics of infliximab. Secondary outcome measures were duration of fever and changes in markers of inflammation. RESULTS: Study drug infusions were associated with cessation of fever within 24 hours in 11 of 12 subjects treated with infliximab and in 8 of 12 subjects retreated with IVIG. No infusion reactions or serious adverse events were attributed to either study drug. No significant differences were observed between treatment groups in the change from baseline for laboratory variables, fever, or echocardiographic assessment of coronary arteries. CONCLUSIONS: Both infliximab and a second IVIG infusion were safe and well tolerated in the subjects with KD who were resistant to standard IVIG treatment. The optimal management of patients resistant to IVIG remains to be determined.

Aspirin resistance in children with heart disease at risk for thromboembolism: prevalence and possible mechanisms.

Aspirin is used to prevent thromboembolism in children with heart disease without evidence supporting its efficacy. Studies in adults report a 5%-51% prevalence of aspirin resistance, yet the mechanisms involved are poorly understood. Our aims were to determine its prevalence in these children and to explore its possible mechanisms. One hundred twenty-three cardiac patients routinely receiving aspirin were prospectively enrolled. Platelet function was measured by Platelet Function Analyzer (PFA)-100 using epinephrine and adenosine diphosphate (ADP) agonists. Aspirin resistance was defined as failure to prolong the epinephrine closure time following aspirin administration. Urine levels of 11-dehydro-thromboxane B(2) (11-dTXB(2)) were measured to determine inhibition of the cyclo-oxygenase pathway. The prevalence of aspirin resistance was 26%. Median ADP closure time was shorter for aspirin-resistant (79.60-115 s) than for aspirin-sensitive (100.60-240 s) patients (p < 0.01). 11-dTXB(2) levels did not correlate with aspirin resistance. Aspirin-resistant patients had higher 11-dTXB(2) levels before (7297 vs. 4160 pg/mg creatinine; p < 0.01) and after (2153 vs. 1412 pg/mg; p = 0.03) aspirin, with a similar percentage decrease in thromboxane (70.5% vs. 66.1%; p = 0.43). Our findings suggest that resistance is not entirely due to lack of inhibition of platelet thromboxane production. Alternative sources of thromboxane and thromboxane-independent mechanisms, such as ADP-induced platelet activation, may contribute to aspirin resistance.