Longitudinal Follow-Up of Children With HLHS and Association Between Norwood Shunt Type and Long-Term Outcomes: The SVR III Study.

OBJECTIVE: In the SVR trial (Single Ventricle Reconstruction), newborns with hypoplastic left heart syndrome were randomly assigned to receive a modified Blalock-Taussig-Thomas shunt (mBTTS) or a right ventricle-to-pulmonary artery shunt (RVPAS) at Norwood operation. Transplant-free survival was superior in the RVPAS group at 1 year, but no longer differed by treatment group at 6 years; both treatment groups had accumulated important morbidities. In the third follow-up of this cohort (SVRIII [Long-Term Outcomes of Children With Hypoplastic Left Heart Syndrome and the Impact of Norwood Shunt Type]), we measured longitudinal outcomes and their risk factors through 12 years of age. METHODS: Annual medical history was collected through record review and telephone interviews. Cardiac magnetic resonance imaging (CMR), echocardiogram, and cycle ergometry cardiopulmonary exercise tests were performed at 10 through 14 years of age among participants with Fontan physiology. Differences in transplant-free survival and complication rates (eg, arrhythmias or protein-losing enteropathy) were identified through 12 years of age. The primary study outcome was right ventricular ejection fraction (RVEF) by CMR, and primary analyses were according to shunt type received. Multivariable linear and Cox regression models were created for RVEF by CMR and post-Fontan transplant-free survival. RESULTS: Among 549 participants enrolled in SVR, 237 of 313 (76%; 60.7% male) transplant-free survivors (mBTTS, 105 of 147; RVPAS, 129 of 161; both, 3 of 5) participated in SVRIII. RVEF by CMR was similar in the shunt groups (RVPAS, 51±9.6 [n=90], and mBTTS, 52±7.4 [n=75]; P=0.43). The RVPAS and mBTTS groups did not differ in transplant-free survival by 12 years of age (163 of 277 [59%] versus 144 of 267 [54%], respectively; P=0.11), percentage predicted peak Vo2 for age and sex (74±18% [n=91] versus 72±18% [n=84]; P=0.71), or percentage predicted work rate for size and sex (65±20% versus 64±19%; P=0.65). The RVPAS versus mBTTS group had a higher cumulative incidence of protein-losing enteropathy (5% versus 2%; P=0.04) and of catheter interventions (14 versus 10 per 100 patient-years; P=0.01), but had similar rates of other complications. CONCLUSIONS: By 12 years after the Norwood operation, shunt type has minimal association with RVEF, peak Vo2, complication rates, and transplant-free survival. RVEF is preserved among the subgroup of survivors who underwent CMR assessment. Low transplant-free survival, poor exercise performance, and accruing morbidities highlight the need for innovative strategies to improve long-term outcomes in patients with hypoplastic left heart syndrome. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT0245531.

Identifying novel data-driven subgroups in congenital heart disease using multi-modal measures of brain structure.

Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental impairments. Given the hypothesized complexity linking genomics, atypical brain structure, cardiac diagnoses and their management, and neurodevelopmental outcomes, unsupervised methods may provide unique insight into neurodevelopmental variability in CHD. Using data from the Pediatric Cardiac Genomics Consortium Brain and Genes study, we identified data-driven subgroups of individuals with CHD from measures of brain structure. Using structural magnetic resonance imaging (MRI; N = 93; cortical thickness, cortical volume, and subcortical volume), we identified subgroups that differed primarily on cardiac anatomic lesion and language ability. In contrast, using diffusion MRI (N = 88; white matter connectivity strength), we identified subgroups that were characterized by differences in associations with rare genetic variants and visual-motor function. This work provides insight into the differential impacts of cardiac lesions and genomic variation on brain growth and architecture in patients with CHD, with potentially distinct effects on neurodevelopmental outcomes.

Association Between Seasonal Fontan Timing, Viral Infection Burden, and Post-Operative Length of Stay.

The Fontan procedure (FP) is typically a semi-elective surgery performed between 2 and 5 years of age to complete staged single ventricle palliation. Optimal timing for the FP, particularly in relation to seasonal infectious burden, remains unclear. We queried the Pediatric Health Information System (PHIS) database for all admissions for viral respiratory infections (VRI) from January 2006 to September 2015 and separately for all admissions with a primary procedure code of FP. The PHIS query generated 2,767,142 admissions for VRI and 6349 admissions for the FP from 45 children's hospitals. Of all FP, 2124 (33.5%) were performed from October through March. The median length of stay after Fontan procedure was 9 days (IQR 7-15). Median length of stay after FP was correlated with VRI burden (correlation coefficient = 0.3, p = 0.03). April through August (weeks 18 through 35) had the lowest VRI admission burden and FP length of stay was significantly shorter during this time (13.6 ± 14.8 days vs 14.9 ± 20.3 days, p = 0.03). The FP is frequently performed during the viral respiratory season. This timing is associated with an increased post-operative length of stay after the FP. For elective FP, ideal timing that avoids the viral respiratory season and minimizes post-operative LOS is April through August.

The pediatric heart network's study on long-term outcomes of children with HLHS and the impact of Norwood Shunt type in the single ventricle reconstruction trial cohort (SVRIII): Design and adaptations.

BACKGROUND: The Single Ventricle Reconstruction (SVR) Trial was the first randomized clinical trial of a surgical approach for treatment of congenital heart disease. Infants with hypoplastic left heart syndrome (HLHS) and other single right ventricle (RV) anomalies were randomized to a modified Blalock Taussig Thomas shunt (mBTTS) or a right-ventricular-to-pulmonary-artery shunt (RVPAS) at the time of the Norwood procedure. The aim of the Long-term Outcomes of Children with HLHS and the Impact of Norwood Shunt Type (SVR III) study is to compare early adolescent outcomes including measures of cardiac function, transplant-free survival, and neurodevelopment, between those who received a mBTTS and those who received an RVPAS. METHODS: Transplant-free survivors of the SVR cohort were enrolled at 10 to 15 years of age for multifaceted in-person evaluation of cardiac function (cardiac magnetic resonance [CMR], echocardiogram and exercise test) and neurodevelopmental evaluation. Right ventricular ejection fraction measured by CMR served as the primary outcome. Development of arrhythmias, protein losing enteropathy, and other comorbidities were assessed through annual medical history interview. Through the course of SVR III, protocol modifications to engage SVR trial participants were designed to enhance recruitment and retention. CONCLUSIONS: Evaluation of long-term outcomes will provide important data to inform decisions about the shunt type placed at the Norwood operation and will improve the understanding of cardiovascular and neurodevelopmental outcomes for early adolescents with HLHS.

Altered erythropoiesis in newborns with congenital heart disease.

BACKGROUND: Fetal hypoxia has been implicated in fetal growth restriction in congenital heart disease (CHD) and leads to stress erythropoiesis in utero. The objective is to assess erythropoiesis and its association with growth in newborns with CHD. METHODS: Fetuses with prenatally diagnosed CHD from 2013 to 2018 were retrospectively reviewed. Pregnancies with multiple gestation, genetic abnormalities, major extra-cardiac anomalies, and placental abruption were excluded. Complete blood count tests at birth were compared to published normative values. Spearman correlation assessed associations of red blood cell (RBC) indices with birth anthropometrics and prenatal Doppler measures. RESULTS: A total of 160 newborns were included. Median gestational age was 38.3 (37.3, 39.0) weeks. Infants ≥37 weeks gestation had lower hemoglobin (Hgb), hematocrit, and elevated nucleated RBC (nRBC), mean corpuscular volume, and mean corpuscular hemoglobin compared to reference. No differences in RBC indices were observed in infants <34 and 34-37 weeks gestation. There was no difference in Hgb and nRBC between CHD subgroups. Neither Hgb nor nRBC were associated with birth anthropometrics or Doppler patterns. CONCLUSIONS: Term infants with CHD demonstrated multiple alterations in erythrocyte indices suggesting ineffective stress erythropoiesis in late gestation resulting in lower Hgb at birth. Altered erythropoiesis was not correlated to growth or Doppler patterns. IMPACT: Newborns with congenital heart disease (CHD) born at term gestation demonstrated altered erythropoiesis. Term newborns with CHD have decreased hemoglobin levels despite having red blood cell indices consistent with stress erythropoiesis, suggesting an incomplete compensatory response to in utero physiologic disturbances associated with CHD. The etiology is unknown; however, it may be influenced by multiple risk factors during pregnancy in the maternal-fetal dyad. Alterations in red blood cell indices were not associated with outcomes of fetal growth.

Uptake of Screening and Recurrence of Bicuspid Aortic Valve and Thoracic Aortic Aneurysm Among At-Risk Siblings of Pediatric Probands.

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

Height Versus Body Surface Area to Normalize Cardiovascular Measurements in Children Using the Pediatric Heart Network Echocardiographic Z-Score Database.

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

Conditional Mutation of Hand1 in the Mouse Placenta Disrupts Placental Vascular Development Resulting in Fetal Loss in Both Early and Late Pregnancy.

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

Recruitment, retention, and adherence in a clinical trial: The Pediatric Heart Network's Marfan Trial experience.

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

Pulmonary venous Doppler patterns and midterm outcomes in fetuses with left-sided obstructive lesions and restrictive atrial septum.

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

Transplant-Free Survival and Interventions at 6 Years in the SVR Trial.

BACKGROUND: In the SVR trial (Single Ventricle Reconstruction), 1-year transplant-free survival was better for the Norwood procedure with right ventricle-to-pulmonary artery shunt (RVPAS) compared with a modified Blalock-Taussig shunt in patients with hypoplastic left heart and related syndromes. At 6 years, we compared transplant-free survival and other outcomes between the groups. METHODS: Medical history was collected annually using medical record review, telephone interviews, and the death index. The cohort included 549 patients randomized and treated in the SVR trial. RESULTS: Transplant-free survival for the RVPAS versus modified Blalock-Taussig shunt groups did not differ at 6 years (64% versus 59%, P=0.25) or with all available follow-up of 7.1±1.6 years (log-rank P=0.13). The RVPAS versus modified Blalock-Taussig shunt treatment effect had nonproportional hazards (P=0.009); the hazard ratio (HR) for death or transplant favored the RVPAS before stage II surgery (HR, 0.66; 95% confidence interval, 0.48-0.92). The effect of shunt type on death or transplant was not statistically significant between stage II to Fontan surgery (HR, 1.36; 95% confidence interval, 0.86-2.17; P=0.17) or after the Fontan procedure (HR, 0.76; 95% confidence interval, 0.33-1.74; P=0.52). By 6 years, patients with RVPAS had a higher incidence of catheter interventions (0.38 versus 0.23/patient-year, P<0.001), primarily because of more interventions between the stage II and Fontan procedures (HR, 1.72; 95% confidence interval, 1.00-3.03). Complications did not differ by shunt type; by 6 years, 1 in 5 patients had had a thrombotic event, and 1 in 6 had had seizures. CONCLUSIONS: By 6 years, the hazards of death or transplant and catheter interventions were not different between the RVPAS versus modified Blalock-Taussig shunt groups. Children assigned to the RVPAS group had 5% higher transplant-free survival, but the difference did not reach statistical significance, and they required more catheter interventions. Both treatment groups have accrued important complications. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00115934.

Tricuspid atresia with restrictive foramen ovale: A rare combination with implications on fetal growth.

Restrictive atrial communication is rarely reported in tricuspid atresia but when present it can lead to important morbidity. We describe two fetuses with tricuspid atresia with restrictive foramen ovale who were found to have fetal growth failure. Fetal echocardiography detected a restrictive atrial communication by flow acceleration on color Doppler and significant right atrial dilation in one patient; the atrial septum was not well interrogated in the other patient. Restrictive foramen ovale in tricuspid atresia may be associated with fetal growth failure. Color Doppler interrogation of the atrial septum on fetal echocardiogram may help identify this condition prenatally.

Congenital heart disease and aortic arch variants associated with mutation in PHOX2B.

PURPOSE: Congenital central hypoventilation syndrome (CCHS, OMIM 209880) is a rare autosomal dominant disorder caused by mutation in PHOX2B that manifests as a consequence of abnormal neural crest cell migration during embryogenesis. Unlike other neurocristopathies, however, its impact on the cardiovascular system has not been previously assessed. This study was an effort to characterize the association between congenital heart disease (CHD) and mutations in PHOX2B in patients with CCHS. METHODS: A retrospective review of patients with CCHS in conjunction with functional analysis of PHOX2B mutations associated with CHD was performed. To substantiate functional implications of identified variants, we conducted protein structure analyses and in silico mutagenesis were conducted. RESULTS: The prevalence of CHD among patients with CCHS was significantly greater (30%; p < 0.001) than that of the current estimated prevalence of CHD. The majority of patients had anomalies involving the proximal aortic arch and/or proximal coronary arteries. Variants associated with CHD in this cohort appear to disrupt DNA binding of PHOX2B via alteration of its homeobox domain. CONCLUSION: This is the first report of an association between CHD and mutation in PHOX2B. Results are highly suggestive that alteration or elimination of the homeobox domain conveys significant risk for associated CHD or aortic arch variation.

Fetal somatic growth trajectory differs by type of congenital heart disease.

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

Diastolic dysfunction is associated with exercise impairment in patients with sickle cell anemia.

BACKGROUND: Left ventricular diastolic dysfunction (DD) is an independent risk factor for mortality in sickle cell anemia (SCA) and is associated with increased extracellular volume (ECV) on cardiac MRI (CMR). Exercise impairment is common in SCA, but its causes and prognostic value are not well understood. OBJECTIVE: To study the effects of DD and ECV on cardiopulmonary exercise test (CPET) in patients with SCA. METHODS AND RESULTS: As part of a prospective study to characterize the cardiomyopathy of SCA (NCT02410811), 20 children and adults with SCA underwent CMR, echocardiography, and cycle ergometer CPET (age range 8-43 years). Maximum exercise was reached in 18 patients and 17 (94%) had reduced exercise capacity (%predicted VO2 less than 80%). Six patients had DD and none had systolic dysfunction. Patients with DD had lower exercise capacity compared to patients with normal diastolic function (%predicted VO2 48.2 ± 9.1% vs. 61.2 ± 11.7%; P = 0.01). The z-score of left ventricular lateral E/e' ratio, which is a marker of DD, was negatively associated with %predicted VO2 (r = -0.61, P = 0.01). All patients with moderate-to-severe exercise impairment (%predicted VO2  < 60%) had lateral E/e' z-score > 2. In a multivariate analysis, lateral E/e' z-score was independently associated with %predicted VO2 (P = 0.02). All participants had elevated ECV but the degree of elevation was not associated with exercise parameters. CONCLUSION: Left ventricular DD is associated with decreased exercise capacity in SCA. Interventions to prevent or delay DD could improve exercise capacity, quality of life, and long-term outcomes in SCA.

Hemodynamic adaptation to suboptimal fetal growth in patients with single ventricle physiology.

BACKGROUND: In fetuses with structurally normal heart and suboptimal fetal growth (SFG), umbilical artery vascular resistance increases as measured by umbilical artery pulsatility index (UA-PI). The objective of this study is to compare hemodynamic responses to SFG in fetuses with single ventricle (SV) and controls with structurally normal heart. METHODS: Fetal echocardiograms around 30 weeks of gestation were reviewed. UA-PI and middle cerebral artery pulsatility index (MCA-PI) were calculated. SFG was defined as a birth weight below 25th percentile for gestational age. RESULTS: Studies from 92 fetuses were reviewed-SV (n = 50) and controls (n = 42). The prevalence of SFG was higher in SV compared to controls (46% vs 21%, P = .02). In patients with normal heart and SFG, UAPI was significantly higher than normal controls (P = .003) suggesting increased placental vascular resistance. In SV with SFG there was no difference in UAPI compared to SV without SFG. There was no difference in MCA-PI between the groups. CONCLUSIONS: The hemodynamic response to SFG in SV varies from fetuses with structurally normal heart. The mechanism of SFG and the placental pathology may be distinct in SV.

Variable phenotype in a novel mutation in PHOX2B.

We evaluated a family with three siblings, two of whom ages 2 years and 19 months, had long segment colonic agangliosis and anisocoria. The mother also had anisocoria. All three affected family members were mildly dysmorphic with a flat facial profile, square appearance to the face, depressed nasal bridge, and anteverted nares. Genetic testing identified a novel heterozygous mutation, c.234C>G, resulting in a premature stop codon in exon 1 of the PHOX2B gene. Screening for neural crest tumors was performed in the siblings and to date has been negative. This family supports a strong association between non polyalanine tract mutations, autonomic dysfunction, and Hirschsprung disease, but suggests mutation outside of the polyalanine tract may not dictate severe phenotype with significant respiratory compromise. A unique finding in this family is the association of congenital heart disease in two of the affected patients. These malformations may be a sporadic isolated finding or the result of environmental factors or a modifying allele. Given the association between congenital heart disease and aberrant neural crest cell development, however, findings are suggestive that congenital heart disease may be a rare feature of PHOX2B mutation which has not been previously reported.

Translating clinical trials into clinical practice: a survey assessing the potential impact of the Pediatric Heart Network Infant Single Ventricle Trial.

BACKGROUND: A few studies have evaluated the impact of clinical trial results on practice in paediatric cardiology. The Infant Single Ventricle (ISV) Trial results published in 2010 did not support routine use of the angiotensin-converting enzyme inhibitor enalapril in infants with single-ventricle physiology. We sought to assess the influence of these findings on clinical practice. METHODS: A web-based survey was distributed via e-mail to over 2000 paediatric cardiologists, intensivists, cardiothoracic surgeons, and cardiac advance practice nurses during three distribution periods. The results were analysed using McNemar's test for paired data and Fisher's exact test. RESULTS: The response rate was 31.5% (69% cardiologists and 65% with >10 years of experience). Among respondents familiar with trial results, 74% reported current practice consistent with trial findings versus 48% before trial publication (p<0.001); 19% used angiotensin-converting enzyme inhibitor in this population "almost always" versus 36% in the past (p<0.001), and 72% reported a change in management or improved confidence in treatment decisions involving this therapy based on the trial results. Respondents familiar with trial results (78%) were marginally more likely to practise consistent with the trial results than those unfamiliar (74 versus 67%, p=0.16). Among all respondents, 28% reported less frequent use of angiotensin-converting enzyme inhibitor over the last 3 years. CONCLUSIONS: Within 5 years of publication, the majority of respondents was familiar with the Infant Single Ventricle Trial results and reported less frequent use of angiotensin-converting enzyme inhibitor in single-ventricle infants; however, 28% reported not adjusting their clinical decisions based on the trial's findings.

Growth Asymmetry, Head Circumference, and Neurodevelopmental Outcomes in Infants with Single Ventricles.

OBJECTIVE: To assess the variability in asymmetric growth and its association with neurodevelopment in infants with single ventricle (SV). STUDY DESIGN: We analyzed weight-for-age z-score minus head circumference-for-age z-score (HCAZ), relative head growth (cm/kg), along with individual growth variables in subjects prospectively enrolled in the Infant Single Ventricle Trial. Associations between growth indices and scores on the Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI) of the Bayley Scales of Infant Development-II (BSID-II) at 14 months were assessed. RESULTS: Of the 230 subjects enrolled in the Infant Single Ventricle trial, complete growth data and BSID-II scores were available in 168 (73%). Across the cohort, indices of asymmetric growth varied widely at enrollment and before superior cavopulmonary connection (SCPC) surgery. BSID-II scores were not associated with these asymmetry indices. In bivariate analyses, greater pre-SCPC HCAZ correlated with higher MDI (r = 0.21; P = .006) and PDI (r = 0.38; P < .001) and a greater HCAZ increase from enrollment to pre-SCPC with higher PDI (r = 0.15; P = .049). In multivariable modeling, pre-SCPC HCAZ was an independent predictor of PDI (P = .03), but not MDI. CONCLUSION: In infants with SV, growth asymmetry was not associated with neurodevelopment at 14 months, but pre-SCPC HCAZ was associated with PDI. Asymmetric growth, important in other high-risk infants, is not a brain-sparing adaptation in infants with SV. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00113087.

Intrauterine fetal demise after prenatal diagnosis of congenital heart disease: assessment of risk.

OBJECTIVES: Elective deliveries in fetal congenital heart disease (CHD) attempt to balance fetal and neonatal risk with the goal of optimizing overall outcome. However, the magnitude of the risk for intrauterine fetal demise (IUFD) is unclear. This study aimed to (1) determine the rate of IUFD and (2) identify fetal risk factors associated with IUFD. METHODS: Retrospective review of pregnancies complicated by CHD between 1998 and 2010. Data were collected regarding pregnancy outcome, extracardiac anomalies (ECA), genetic and cardiac diagnoses, severity of valve regurgitation, gestational age at birth and birth weight. Fisher's exact test and odds ratios were used to compare outcomes between groups. RESULTS: A total of 501 pregnancies analyzed resulted in 445 live births, 22 IUFD, 16 terminations and 18 unknown outcomes. Amongst IUFD, 27% had a genetic diagnosis, 50% had an ECA and 27% had severe valve regurgitation. IUFD odds increased threefold with ECA and sevenfold with severe valve regurgitation. IUFD occurred in 1.2% without risk factors. CONCLUSIONS: IUFD in fetuses with CHD is associated with ECA, genetic syndromes and severe valve regurgitation. In absence of these fetal characteristics, the occurrence of IUFD is low, although it remains higher than in fetuses without CHD.