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Background This study aimed to examine the relationships between various maternal socioeconomic status (SES) indicators and the risk of congenital heart disease (CHD). Methods This was a population-based retrospective cohort study, including all singleton stillbirths and live births in Ontario hospitals from April 1, 2012 to March 31, 2018. Multivariable logistic regression models were performed to examine the relationships between maternal neighbourhood household income, poverty, education level, employment and unemployment status, immigration and minority status, and population density and the risk of CHD. All SES variables were estimated at a dissemination area level and categorized into quintiles. Adjustments were made for maternal age at birth, assisted reproductive technology, obesity, pre-existing maternal health conditions, substance use during pregnancy, rural or urban residence, and infant’s sex. Results Of 804,292 singletons, 9731 (1.21%) infants with CHD were identified. Compared to infants whose mothers lived in the highest income neighbourhoods, infants whose mothers lived in the lowest income neighbourhoods had higher likelihood of developing CHD (adjusted OR: 1.29, 95% CI: 1.20–1.38). Compared to infants whose mothers lived in the neighbourhoods with the highest percentage of people with a university or higher degree, infants whose mothers lived in the neighbourhoods with the lowest percentage of people with university or higher degree had higher chance of CHD (adjusted OR: 1.34, 95% CI: 1.24–1.44). Compared to infants whose mothers lived in the neighbourhoods with the highest employment rate, the odds of infants whose mothers resided in areas with the lowest employment having CHD was 18% higher (adjusted OR: 1.18, 95% CI: 1.10–1.26). Compared to infants whose mothers lived in the neighbourhoods with the lowest proportion of immigrants or minorities, infants whose mothers resided in areas with the highest proportions of immigrants or minorities had 18% lower odds (adjusted OR: 0.82, 95% CI: 0.77–0.88) and 16% lower odds (adjusted OR: 0.84, 95% CI: 0.78–0.91) of CHD, respectively. Conclusion Lower maternal neighbourhood household income, poverty, lower educational level and unemployment status had positive associations with CHD, highlighting a significant social inequity in Ontario. The findings of lower CHD risk in immigrant and minority neighbourhoods require further investigation.

Background Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging. Objectives This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. Methods We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 case patients with reduced left ventricular ejection fraction despite low-dose doxorubicin (≤250 mg/m2), and 106 control patients with preserved left ventricular ejection fraction despite doxorubicin >250 mg/m2 were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between case patients and control patients. The expression levels of 5 top-ranked genes were evaluated in human induced pluripotent stem cell–derived cardiomyocytes, and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed. Results Thirty-one genes were differentially enriched for variants between case patients and control patients (p < 0.001). Only 42.6% case patients harbored a variant in these genes compared to 89.6% control patients (odds ratio: 0.09; 95% confidence interval: 0.04 to 0.17; p = 3.98 × 10–15). A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical-only model. In vitro inhibition of gene-associated pathways (PI3KR2, ZNF827) provided protection from cardiotoxicity in cardiomyocytes. Conclusions Our study identified variants in cardiac injury pathway genes that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and it also provided new targets in autophagy genes for the development of cardio-protective drugs. (Preventing Cardiac Sequelae in Pediatric Cancer Survivors [PCS2]; NCT01805778), Central Illustration

Transposition of the great arteries (TGA) may present as a life-threatening neonatal malformation. Although prenatal detection facilitates the perinatal management, the impact on outcome is controversial.This study reviewed the differences in prenatal diagnosis of TGA from 2009 to 2014 among the 5 geographic areas in Ontario and compared the management, morbidity, and mortality among neonates with a prenatal (prenatal cohort; n = 70) vs a postnatal (postnatal cohort; n = 76) anomaly diagnosis. Cases were identified from prospective databases of the provincial cardiac tertiary centres and the coroner's office.Prenatal TGA detection rates varied significantly among areas (median: 50%; range: 14% to 72%; P = 0.03). Compared with the postnatal cohort, time from birth to tertiary care admission (1.4 vs 10.4 hours, P0.001), prostaglandin therapy (0.1 vs 5.3 hours; P0.001), balloon atrial septostomy (5.3 vs 14.9 hours; P0.001), and arterial switch operation (6 vs 9 days, P = 0.002) was significantly shorter in the prenatal cohort. Although other preoperative variables-including the need of ventilation and mechanical support, morbidity score, and lowest pH and preductal oxygen saturations-were comparable, a prenatal diagnosis was associated with improved 1-year survival (odds ratio: 0.108; 95% confidence interval, 0.013-0.88; P = 0.0184).Prenatal diagnosis of TGA significantly shortened time intervals from birth to neonatal care and surgery and was associated with improved survival. The prenatal detection rate of TGA in Ontario was low (50% or less) outside of Metropolitan Toronto, suggesting the need for new strategies to further improve intraprovincial detection rates.

AimsCardiomyopathy is a clinically and genetically heterogeneous disorder with age and sex-related differences in severity and outcomes. The aim of our study was to identify age and sex-related differences in the genetic architecture of cardiomyopathy.Methods and ResultsWe analyzed whole genome sequence data from 471 pediatric and 926 adult cardiomyopathy patients from our Heart Centre Biobank and from the Genomics England cohort. Overall yield of rare deleterious coding variants was higher in pediatric compared to adult onset cardiomyopathy, but not different by sex.MYH7, TNNT2, MYL3, andVCLvariants were more frequent in pediatric patients;TTNandOBSCNvariants were more frequent in adult patients, withMYH7(Odds ratio 3.6; CI 2.1-6.3) andOBSCN(Odds ratio 5.5, CI 2.0-21.4) remaining significant after adjusting for multiple testing. Variants in early-onset cardiomyopathy clustered in highly constrained coding regions compared to those in adult patients (p=3.9×10−3). There were also differences between pediatric and adult patients in variant location withinMYH7andTTNgenes. When analyzed by sex, variants in female compared to male patients were in more highly constrained coding regions (p=0.002).ConclusionOur findings highlight under-appreciated genetic differences in early versus late onset cardiomyopathy. Variants in childhood cardiomyopathy and in female patients were in highly constrained coding regions of the genome suggesting greater deleterious effects and strong purifying selection in the general population. Knowledge of the affected gene, variant location within the gene, and variant constraint scores may be useful in predicting early versus late onset cardiomyopathy.

To determine the physical literacy, defined as the capability for a physically active lifestyle, of children with medical conditions compared with healthy peers, this multicenter cross-sectional study recruited children with medical conditions from cardiology, neurology (including concussion), rheumatology, mental health, respirology, oncology, hematology, and rehabilitation (including cerebral palsy) clinics. Participants aged 8–12 years (N = 130; mean age: 10.0 ± 1.44 years; 44% female) were randomly matched to 3 healthy peers from a normative database, based on age, gender, and month of testing. Total physical literacy was assessed by the Canadian Assessment of Physical Literacy, a validated assessment of physical literacy measuring physical competence, daily behaviour, knowledge/understanding, and motivation/confidence. Total physical literacy mean scores (/100) did not differ (t(498) = –0.67; p = 0.44) between participants (61.0 ± 14.2) and matched healthy peers (62.0 ± 10.7). Children with medical conditions had lower mean physical competence scores (/30; –6.5 [–7.44 to –5.51]; p < 0.001) but higher mean motivation/confidence scores (/30; 2.6 [1.67 to 3.63]; p < 0.001). Mean daily behaviour and knowledge/understanding scores did not differ from matches (/30; 1.8 [0.26 to 3.33]; p = 0.02;/10; –0.04 [–0.38 to 0.30]; p = 0.81; respectively). Children with medical conditions are motivated to be physically active but demonstrate impaired movement skills and fitness, suggesting the need for targeted interventions to improve their physical competence. Novelty: Physical literacy in children with diverse chronic medical conditions is similar to healthy peers. Children with medical conditions have lower physical competence than healthy peers, but higher motivation and confidence. Physical competence (motor skill, fitness) interventions, rather than motivation or education, are needed for these youth.

Background: Despite known clinical and genetic risk factors, predicting anthracycline cardiotoxicity remains challenging. Objective: To develop a risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. Methods: We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 cases with LV ejection fraction (LVEF) ≤55% despite low-dose doxorubicin (DOX) (≤250 mg/m2), and 106 controls with LVEF >55% despite DOX >250 mg/m2 were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between cases and controls. The top-ranked genes were functionally evaluated in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed. Results: Thirty-one genes were differentially enriched for variants between cases and controls (p-15 ] suggesting that absence of these variants may predispose to cardiotoxicity. A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical model. In vitro inhibition of gene-associated pathways ( PI3KR2, ZNF827 ) provided protection from cardiotoxicity in CMs. Conclusions: Our study identified variants that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and also provided new targets in autophagy genes for development of cardio-protective drugs.

Background The vast majority of children undergoing cardiac surgery have low vitamin D levels post-operative, which may contribute to greater illness severity and worse clinical outcomes. Prior to the initiation of a large phase III clinical trial focused on clinical outcomes, studies are required to evaluate the feasibility of the study protocol, including whether the proposed dosing regimen can safely prevent post-operative vitamin D deficiency in this high-risk population. Methods We conducted a two-arm, double-blind dose evaluation randomized controlled trial in children requiring cardiopulmonary bypass for congenital heart disease. Pre-operatively, participants were randomized to receive cholecalciferol representing usual care (< 1 year = 400 IU/day, > 1 year = 600 IU/day) or a higher dose approximating the Institute of Medicine tolerable upper intake level (< 1 year = 1600 IU/day, > 1 year = 2400 IU/day). The feasibility outcomes were post-operative vitamin D status (primary), vitamin D-related adverse events, accrual rate, study withdrawal rate, blinding, and protocol non-adherence. Results Forty-six children were randomized, and five withdrew prior to surgery, leaving 41 children (21 high dose, 20 usual care) in the final analysis. The high dose group had higher 25-hydroxyvitamin D concentrations both intraoperatively (mean difference + 25.9 nmol/L; 95% CI 8.3–43.5) and post-operatively (mean difference + 17.2 nmol/L; 95% CI 5.5–29.0). Fewer participants receiving high-dose supplementation had post-operative serum 25-hydroxyvitamin D concentrations under 50 nmol/L, compared with usual care (RR 0.31, 95% CI 0.11–0.87). Post-operative vitamin D status was associated with the treatment arm and the number of doses received. There were no cases of hypercalcemia, and no significant adverse events related to vitamin D. While only 75% of the target sample size was recruited (limited funding), the consent rate (83%), accrual rate (1.5 per site month), number of withdrawals (11%), and ability to maintain blinding support feasibility of a larger trial. Conclusions Pre-operative daily high-dose supplementation improved vitamin D status pre-operatively and at time of pediatric ICU admission. The protocol for a more definitive trial should limit enrollment of children with at least 30 days between randomization and surgery to allow adequate duration of supplementation or consider a loading dose. Trial registration ClinicalTrials.gov, NCT01838447. Registered on April 24, 2013

BackgroundAssess process, uptake, validity and resource needs for return of actionable research findings to biobank participants.MethodsParticipants were prospectively enrolled in a multicenter biorepository of childhood onset heart disease. Clinically actionable research findings were reviewed by a Return of Research Results Committee (RRR) and returned to the physician or disclosed directly to the participant through a research genetic counselor. Action taken following receipt of this information was reviewed.ResultsGenetic data was generated in 1963 of 7408 participants. Fifty-nine new findings were presented to the RRR committee; 20 (34%) were deemed reportable. Twelve were returned to the physician, of which 7 were disclosed to participants (median time to disclosure, 192 days). Seven findings were returned to the research genetic counselor; all have been disclosed (median time to disclosure, 19 days). Twelve families (86%) opted for referral to clinical genetics after disclosure of findings; 7 results have been validated, 5 results are pending. Average cost of return and disclosure per reportable finding incurred by the research program was $750 when utilizing a research genetic counselor; clinical costs associated with return were not included.ConclusionsReturn of actionable research findings was faster if disclosed directly to the participant by a research genetic counselor. There was a high acceptability amongst participants for receiving the findings, for referral to clinical genetics, and for clinical validation of research findings, with all referred cases being clinically confirmed.

Background Most (>90%) children with congenital health defects are not active enough for optimal health. Proactively promoting physical activity during every clinic visit is recommended, but rarely implemented due to a lack of appropriate resources. Methods This cluster randomized controlled trial will implement an evidence-based, multi-faceted physical activity intervention. All eligible patients at small (London, ON), medium (Ottawa, ON) and large (Edmonton, AB) pediatric cardiac clinics will be approached, with randomization to intervention/control by clinic and week. Intervention patients will be counselled with 5 key physical activity messages, have questions about physical activity answered, and have access to a custom web site with personalized activity suggestions and support from a Registered Kinesiologist. The primary outcome is daily physical activity (number of steps, minutes of moderate-to-vigorous activity) assessed via pedometer one week per month for 6-months. Standardized questionnaires assess activity motivation and quality of life at baseline and end of study. Healthcare outcomes will be clinic visit time and contacts for physical activity concerns. Repeated measures ANCOVA will compare control/intervention pedometer outcomes, adjusting for covariates (alpha=0.05). Conclusions This trial aims to determine whether providing resources and protocols enables clinicians to counsel about physical activity as part of every pediatric cardiology appointment. Evaluations of healthcare system impact and intervention delivery in small, medium and large clinics will assess applicability for implementation in all pediatric cardiac clinics. The impact on physical activity motivation and participation will evaluate the effectiveness of this standardized approach for increasing physical activity in children with congenital heart defects.

Objectives: Children with congenital heart disease (CHD) often lack confidence and demonstrate limited movement skills during physical activity. Community-based sport programs have been suggested to build their confidence and competence. This study examined the feasibility and physical literacy impact of an existing community-based sport program for children with moderate to complex CHD. Methods: This pilot study employed a parallel mixed method, single-case experimental design to evaluate the feasibility and impact of a weekly, community-based sport intervention (Sportball©). Intervention field notes and focus group transcripts were analysed deductively to inform feasibility. Physical literacy outcomes were measured using the Canadian Assessment of Physical Literacy. Paired t-tests examined changes in physical literacy scores, while qualitative data informed perceived changes in physical literacy tasks. Results: Participants (n=11, 45% female) were 8.2 ± 1.2 years. Nine children completed >80% of the 1-hour Sportball© sessions (10 lessons total). No adverse events occurred during or as a result of the intervention. Enabling participants to recognize the sensations of exercise and whether or not they needed to rest, designing activities and instructions to mitigate the risk of body contact, and accommodating the needs of participants with developmental/attentional limitations were important factors embedded into the design of the program, contributing to its feasibility. Participants reported perceived improvements in movement skill and torso endurance/strength, changes which were reflected in the objective physical literacy measures (movement skill: ∆ mean= 2.0 ± 0.98 points, p=0.07, r=0.57; torso endurance/strength: ∆ mean= 5.27 ± 7.20 seconds, p=0.44, r=0.26). Conclusions: The Sportball© intervention was feasible for children with CHD, including those with activity restrictions or developmental delays. Children enjoyed the program and wanted it to continue. Measurable improvements in movement skill and muscular endurance were recognized by participants. Future trials evaluating Sportball©’s impact with larger samples and multiple 10-week sessions are recommended.

Importance The extent to which assisted reproductive technology is associated with increased risk of congenital heart defects independent of its known association with twinning remains uncertain. Objective To assess the extent to which assisted pregnancy is associated with increased risk of congenital heart defects independent of its known association with twinning. Design, setting, and participants This retrospective cohort study linked records of congenital heart defect diagnoses with assisted reproductive technology cycles in 507 390 singleton or twin pregnancies (10 149 assisted pregnancies and 497 241 nonassisted pregnancies), including singleton and twin early pregnancy losses, stillbirths, and live births (follow-up to 1 year of age) in Ontario, Canada, between April 1, 2012, and October 31, 2015. Statistical analysis was performed from January 1, 2017, to September 9, 2019. Exposures Assisted reproductive technology and its 2 subtypes: intracytoplasmic sperm injection and in vitro fertilization without intracytoplasmic sperm injection. Main outcomes and measures The main outcome was congenital heart defects (prevalence and relative risk measured as odds ratios [ORs]). Mediation analysis was performed to assess the extent to which the association between assisted reproductive technology and congenital heart defects was mediated by twinning. Results Of 507 390 mother-infant pairs with singleton or twin pregnancies evaluated, the prevalence of congenital heart defects in assisted pregnancies (223 [2.2%]) was higher than that in nonassisted pregnancies (6057 [1.2%]; crude OR, 1.82; 95% CI, 1.59-2.09). The strength of the association between assisted pregnancy and congenital heart defects decreased after adjusting for several risk factors simultaneously (adjusted OR, 1.70; 95% CI, 1.48-1.95). Further mediation analysis indicated that most of the association between assisted pregnancy and congenital heart defects was mediated by twinning (adjusted OR, 1.68; 95% CI, 1.44-1.92), and the natural direct association of assisted pregnancy with congenital heart defects among singleton pregnancies was 1.09 (95% CI, 0.93-1.25). Mediation of twinning accounted for 87.3% of the association. Conclusions and relevance Our study results suggest that the association between assisted reproductive technology and congenital heart defects may be mediated by twinning.

The field of pediatric cardiology has changed significantly over the past decade. The epidemiology of congenital heart disease (CHD) is shifting, with increased prenatal diagnosis, improved survival, and improved imaging and intervention techniques. Long term issues including neurodevelopmental outcome, exercise capacity, quality of life and reproduction have become more important as children survive their heart disease into adulthood. Neonatal oximetry screening is becoming routine practice to ensure that the majority of critical CHD is diagnosed as early as possible, as this has a positive impact on outcome. Imaging techniques in pediatric cardiology are evolving rapidly. Echocardiography remains the mainstay of imaging, with new techniques of 3D imaging and advanced function assessment adding to its utility. Cardiac MRI and CT are becoming important adjunct imaging techniques, particularly due the 3D and spatial information obtained. Cardiac catheterization with angiography is utilized less as a solely diagnostic technique, but has a substantial and increasing role in non-surgical intervention for CHD. Genetic testing in pediatric cardiology is adding yet further information regarding diagnosis, treatment options and prognosis in CHD, cardiomyopathies and cardiac channelopathies.

BACKGROUND: Consenting minors for genetics research and biobanking involves ethical and social challenges. We examined factors influencing participation rates in a population-based biorepository for childhood heart disease. METHODS: Individuals were prospectively enrolled across 7 centers in Ontario by using a standardized consent form. Individuals were approached for consent for the donation of blood/saliva (DNA), tissue, and skin from the affected individual for future genomics and stem cell research. Consent rates were compared between pediatric and adult patients and factors affecting consent were analyzed by using multiple logistic regression analysis. RESULTS: From 2008 to 2011, 3637 patients were approached. A total of 2717 pediatric patients consented (90% consent rate); mean age was 8.5 ± 5.8 years (57% male; 76% white). A total of 561 adult patients consented (92% consent rate, P = .071 versus pediatric). Factors associated with lower pediatric consent rates included younger age, race, absence of complex defects, and location of consent; these were not associated with adult consent rates. Leading causes for refusal of consent were lack of interest in research (43%), overwhelmed clinically (14%), and discomfort with genetics (11%). Concerns related to privacy, insurability, indefinite storage, and ongoing access to medical records were not the leading causes for refusal. CONCLUSIONS: The high pediatric consent rate (90%) was comparable with that of adults. Ethical, social, or legal issues were not the leading reasons for refusal of consent.

Il est demontre que le traitement pharmacologique par des stimulants reduit les symptomes associes au trouble de deficit de l’attention avec hyperactivite (TDAH), et ce traitement fait partie des recommandations therapeutiques de l’American Academy of Pediatrics pour les enfants presentant ce trouble (1,2). Cependant, de recentes decisions en matiere de reglementation sur l’homologation et l’etiquetage des medicaments contre le TDAH (3,4), ainsi qu’un recent document de principes de l’American Heart Association (5), une correction et une reponse (clarification) de l’American Academy of Pediatrics (6,7), ont souleve des questions sur l’evaluation et la therapie du TDAH que preconisent les praticiens canadiens. La pratique canadienne actuelle dans le domaine de la pharmacotherapie du TDAH et du depistage cardiovasculaire est mixte, et il y a peu de consensus quant a l’evaluation pertinente des enfants avant d’instaurer la pharmacotherapie du TDAH (8). Les avis sont encore plus partages au sujet de l’innocuite du traitement des enfants ayant subi une refection ou une palliation de leur cardiopathie congenitale (CPC) et qui prennent des medicaments contre le TDAH (8). Afin d’orienter les medecins canadiens qui soignent les enfants ayant un TDAH et de clarifier la situation, la Societe canadienne de pediatrie, la Societe canadienne de cardiologie et l’Academie canadienne de psychiatrie de l’enfant et de l’adolescent ont prepare conjointement le present document de principes. Il contient des recommandations consensuelles sur l’evaluation du risque cardiaque chez les enfants ayant un TDAH a qui on envisage d’administrer des stimulants. Il ne s’attarde pas au diagnostic de TDAH, ni aux bienfaits therapeutiques des stimulants. De meme, il n’aborde pas le bien-fonde ou les risques relatifs d’un medicament par rapport a un autre au sein de cette population de patients. Enfin, les medicaments non stimulants utilises dans le traitement du TDAH, y compris l’atomoxetine, les antidepresseurs et les agonistes alpha-adrenergiques, ne font pas l’objet d’une analyse particuliere.

Background: An electrocardiogram has been proposed to screen for prolonged QT interval that may predispose infants to sudden death in the first year of life. Understanding the reliability of QT interval measurement will inform the design of a screening program. Methods: Three pediatric cardiologists measured the QT/RR intervals on 60 infant electrocardiograms (median age 46 days), from leads II, V5 and V6 on three separate occasions, 7 days apart, according to a standard protocol. The QTc was corrected by Bazett's (QTcB), Fridericia's (QTCFrid), and Hodges' (QTcH) formulae. Intraobserver and interobserver reliability were assessed by intraclass correlation coefficients (ICC), limits of agreement and repeatability coefficients for single, average of two and average of three measures. Agreement for QTc prolongation (> 440 msec) was assessed by kappa coefficients. Results: QT interval intraobserver ICC was 0.86 and repeatability coefficient was 25.9 msec; interobserver ICC increased from 0.88 for single observations to 0.94 for the average of 3 measurements and repeatability coefficients decreased from 22.5 to 16.7 msec. For QTcB, intraobserver ICC was 0.67, and repeatability was 39.6 msec. Best interobserver reliability for QTcB was for the average of three measurements (ICC 0.83, reproducibility coefficient 25.8 msec), with further improvement for QTcH (ICC 0.92, reproducibility coefficient 16.69 msec). Maximum interobserver kappa for prolonged QTc was 0.77. Misclassification around specific cut points occurs because of the repeatability coefficients. Conclusions: Uncorrected QT measures are more reliable than QTcB and QTCFrid. An average of three independent measures provides the most reliable QT and QTc measurements, with QTcH better than QTcB.

This study assessed the effects of repeated courses of antenatal corticosteroids on biometric characteristics, salivary cortisol, and heart function in children 6 to 10 years of age using a retrospective cohort study. Twenty-nine children whose mothers had received two or more courses of antenatal corticosteroids were identified from hospital charts. Eighty-seven children whose mothers did not receive antenatal corticosteroids were frequency matched with the exposed group by child's age, sex, and ethnicity. The body development, heart function, and salivary corticosteroid level were evaluated at 6 to 10 years of age. The percentiles of body measurements were calculated based on the 2000 Centers for Disease Control and Prevention growth charts. The general linear models were applied to assess the observed association. Decreased head circumference ( P = 0.017) and body mass index (BMI) ( P = 0.047) in children 6 to 10 years of age were associated with repeated courses of antenatal corticosteroids. Morning salivary cortisol level was lower in the exposed group than the unexposed group ( P = 0.048). No difference was found in height, weight, blood pressure, heart rate, and echocardiogram measurements between the two groups. Repeated courses of antenatal corticosteroid therapy are associated with decreased head circumference, BMI, and salivary cortisol level in children 6 to 10 years of age.

Because there is a paucity of information regarding the diagnosis and outcomes of fetal heterotaxy syndrome (HS), this study sought to determine the spectrum of cardiac pathology, accuracy of diagnosis, and outcome of fetal HS. All cases of fetal HS encountered in the investigators' institution over a 10-year period through 2002 were identified. Prenatal and postnatal echocardiograms and medical records were reviewed. Seventy-one fetuses were diagnosed with HS, including 48 with left atrial isomerism (LAI) and 23 with right atrial isomerism (RAI). For LAI and RAI, most intracardiac lesions, the pulmonary venous connections, and superior vena caval anatomy were correctly diagnosed in utero (93%, 86%, and 77% accuracy, respectively), whereas hepatic venous connections and inferior vena caval-atrial connections in RAI were difficult to define (65% and 56% accuracy, respectively). Of 32 continued and followed pregnancies with LAI, 22 are currently alive at 48 +/- 30 months. Heart block and associated major extracardiac pathology were significantly more common in nonsurvivors with fetal LAI (p = 0.007 and 0.024, respectively). Outcomes were even worse for prenatally diagnosed RAI: of 14 continued pregnancies, only 3 are currently alive. In conclusion, fetal HS is associated with a broad spectrum of cardiac pathology, which can be diagnosed accurately in utero. Fetal LAI is associated with a mortality of 31%, with heart block and extracardiac pathology as primary risk factors for perinatal mortality. The outcome of prenatally diagnosed RAI is poor.

OBJECTIVES The goal of this study was to determine the prevalence and evolution of acquired right ventricular outflow tract obstruction (RVOTO) in the recipient twin in twin-twin transfusion syndrome (TTTS). BACKGROUND Twin-twin transfusion syndrome complicates 4% to 26% of diamniotic monochorionic twin gestations and is associated with high fetal morbidity and mortality. Cardiac dysfunction and biventricular hypertrophy may develop in the recipient twin with the potential for RVOTO. METHODS This was a retrospective review of a two-center experience of TTTS to describe the prevalence and evolution of acquired RVOTO in the recipient twin. Right ventricular outflow tract obstruction was diagnosed or excluded by fetal or postnatal echocardiography or clinical assessment. RESULTS Of 73 twin pregnancies with TTTS identified between 1994 to 1998, a total of seven (9.6%) were complicated by RVOTO in the recipient twin: two subvalvar/muscular, four valvar and one combined. Of 44 pregnancies with fetal echo, six had in utero RVOTO with antegrade flow diagnosed at gestational ages ranging from 19 to 27 weeks. In utero progression occurred in four cases over a period of four to eight weeks, with the development of RVOT atresia by delivery. Postnatal progression of RVOTO occurred in two cases, one of which required pulmonary balloon valvuloplasty at age two years. Postnatal regression of subvalvar RVOTO occurred in two cases in early infancy. Death related directly or indirectly to the RVOTO occurred in all four patients who developed complete RVOT obliteration. CONCLUSIONS Right ventricular outflow tract obstruction may occur in the recipient twin of at least 9% of pregnancies complicated by TTTS. Right ventricular outflow tract obstruction progression is common in utero and may worsen neonatal outcome.

Background The healthcare burden related to congenital heart disease ( CHD ) is increasing with improving survival. We assessed changing trends in prenatal risk factors for CHD in the current era in a Canadian cohort. Methods and Results CHD patients ECA s), and antenatal risk factors were assessed. Temporal trends were analyzed and associations with CHD were measured using linear and logistic regression. Family history of CHD and frequency of major ECA s was higher in cases versus controls ( P CHD had a confirmed genetic diagnosis. Yield of genetic testing (ie, frequency of abnormal results) was higher in familial and syndromic cases. There was an increase in parental age at conception, maternal prepregnancy body mass index, maternal urinary tract infections, type 1 diabetes, and exposure to nonfertility medications during pregnancy from 1990–2011. Later year of birth, family history of CHD , presence of major ECA s, maternal smoking during pregnancy, and maternal medication exposure were associated with increased odds of CHD ( P CHD caused by genetic abnormalities. Conclusions The increase in prenatal risk factors for CHD highlights the need for more rigorous ascertainment of genetic and environmental factors including gene‐environment interactions that contribute to CHD .

Pediatric heart failure (HF) is an important cause of morbidity and mortality in childhood. This article presents guidelines for the recognition, diagnosis, and early medical management of HF in infancy, childhood, and adolescence. The guidelines are intended to assist practitioners in office-based or emergency room practice, who encounter children with undiagnosed heart disease and symptoms of possible HF, rather than those who have already received surgical palliation. The guidelines have been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and are accompanied by practical Recommendations for their application in the clinical setting, supplemented by online material. This work does not include Recommendations for advanced management involving ventricular assist devices, or other device therapies.

We describe a case of horseshoe lung in an infant with facio-auriculo-vertebral (FAV) sequence that included mild hemifacial microsomia, ear anomalies, a missing left rib, left hemivertebrae (T2-T4), and complex congenital heart disease. Of the approximately 40 cases of horseshoe lung described since 1962, most are reported in association with scimitar syndrome, and only four reported cases were associated with left lung hypoplasia. None of these cases included malformations consistent with a diagnosis of FAV sequence.

Large randomized trials have demonstrated the critical role of folic acid supplementation in the prevention of neural tube defects. Since 1992, a number of national and international professional societies have released guidelines recommending folic acid supplementation of at least 0. 4 mg/day for all women of childbearing age or women planning pregnancies, and 4 mg/day for women with a previous infant with a neural tube defect. Furthermore, a reduction in the incidence of congenital cardiac and urologie anomalies has been demonstrated in some studies following periconceptional folic acid supplementation. There is growing evidence of a possible role of folic acid supplementation in the prevention of other congenital anomalies, including cardiac defects. Since 1998, mandatory fortification of certain foods with folate has been associated with at least a 54% reduction in the incidence of open neural tube defects, yet rates of periconceptional folic acid use remain suboptimal, especially in minority women. Innovative strategies in educating women, health-care providers, and pharmacists on the benefits of folic acid supplementation need to be explored. Mandatory folate fortification of foods needs to be defined and monitored.

Regulatory decisions and scientific statements regarding the management of attention-deficit hyperactivity disorder (ADHD) raise questions about the safety of medications and the appropriate pretreatment evaluation to determine suitability for treatment with medication. This is particularly true in the setting of known structural or functional heart disease. The present paper reviews the available data, including peer-reviewed literature, data from the United States Food and Drug Administration Web site on reported adverse reactions in children using stimulant medication, and Health Canada data on the same problem. A consensus-based guideline on appropriate assessment is provided, based on input from members of the Canadian Paediatric Society, the Canadian Cardiovascular Society and the Canadian Academy of Child and Adolescent Psychiatry, with specific expertise and knowledge in the areas of both ADHD and pediatric cardiology. The present statement advocates a thorough history and physical examination before starting stimulant medications, with an emphasis on the identification of risk factors for sudden death, but does not routinely recommend electrocardiographic screening or cardiac subspecialist consultation unless indicated by history or physical examination findings. A checklist for identifying children who are potentially at risk of sudden death (independent of ADHD or medications used to treat it) is provided. Although recommendations are based on the best evidence currently available, the committee further agrees that more research on this subject is necessary to optimize the approach to this common clinical scenario.