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Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. We report the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a fetus with CRIM (cross-reactive immunologic material)-negative infantile-onset Pompe's disease. The family history was positive for infantile-onset Pompe's disease with cardiomyopathy in two previously affected deceased siblings. After receiving in utero ERT and standard postnatal therapy, the current patient had normal cardiac and age-appropriate motor function postnatally, was meeting developmental milestones, had normal biomarker levels, and was feeding and growing well at 13 months of age.
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Enfermedad del Almacenamiento de Glucógeno Tipo II , Humanos , Lactante , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológicoRESUMEN
PURPOSE: This study evaluated screening tasks able to identify children with medical conditions or disabilities who may benefit from physical literacy. METHOD: Children completed ≤20 screening tasks during their clinic visit and then the Canadian Assessment of Physical Literacy (2nd edition) at a separate visit. Total Canadian Assessment of Physical Literacy scores <30th percentile were categorized as potentially needing physical literacy support. Receiver operator characteristic curves identified assessment cut points with 80% sensitivity and 40% specificity relative to total physical literacy scores. RESULTS: 223 children (97 girls; 10.1 [2.6] y) participated. Physical activity adequacy, predilection, and physical competence achieved ≥80% sensitivity and ≥40% specificity in both data sets. Adequacy ≤ 6.5 had 86% to 100% sensitivity and 48% to 49% specificity. Daily screen time >4.9 hours combined with Adequacy ≤6.15 had 88% to 10% sensitivity and 53% to 56% specificity. CONCLUSIONS: Activity adequacy, alone or with screen time, most effectively identified children likely to benefit from physical literacy support. Adequacy and screen time questionnaires are suitable for clinical use. Similar results regardless of diagnosis suggest physical competence deficits are not primary determinants of active lifestyles. Research to enhance screening specificity is required.
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BACKGROUND: Physical literacy is a concept used to describe the combined physical, affective and cognitive capacities facilitating an active lifestyle. Physical activity participation is essential for children living with chronic medical conditions, but knowledge of physical literacy among this group is scarce. METHODS: An explanatory, sequential mixed methods design was used to comprehensively describe the physical literacies of children with chronic medical conditions (CMCs). Participants were recruited from paediatric cardiology, respirology/cystic fibrosis, neurology, haematology and endocrinology outpatient clinics. All participants completed the Canadian Assessment of Physical Literacy (2nd Edition), and those with higher and lower scores were invited to a semi-structured interview. A deductive-inductive thematic analysis was applied using Margaret Whitehead's conceptualization of physical literacy. RESULTS: Using normative strata, 80.0% of the 99 children assessed (mean age = 9.97 ± 1.3 years, 48% girls) were considered beginning or progressing in their overall physical literacy (mean score = 56.5 ± 13.8/100). Meanwhile, physical literacy informed participants' approach to new, active experiences and may have contributed to a strong sense of self. There was a significant difference between endocrinology and haematology patients on total physical literacy score (p = 0.03) but not domain scores. Participants scored high on motivation/confidence (mean = 22.9 ± 5.0/30) but obtained low physical competence (mean = 11.8 ± 5.6/30) and daily behaviour scores (n = 72, mean = 15.5 ± 7.1/30). Main themes represent salient experiences of children with CMCs within the domains of physical literacy, including their need to evaluate active contexts, self-regulate activity intensity and manage physical limitations. CONCLUSIONS: Children with CMCs can achieve recommended levels of physical literacy without meeting normative standards for physical competence. Participants would benefit from a physical literacy intervention that targets the development of bodily self-regulation skills and risk evaluation in active settings.
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Ejercicio Físico , Alfabetización en Salud , Humanos , Niño , Femenino , Masculino , Enfermedad Crónica , Ejercicio Físico/psicología , Canadá , Desarrollo Infantil/fisiología , Investigación CualitativaRESUMEN
BACKGROUND: This study aims to evaluate the impact of socioeconomic status (SES) on the risk of congenital heart disease (CHD) since previous studies have yielded inconsistent results. METHODS: We conducted a population-based retrospective cohort study, including all singleton live and still births in Ontario hospitals from April 1, 2012, to March 31, 2018. We used linked records from the Better Outcomes Registry & Network Information System, the Canadian Institute for Health Information databases, and the Ontario Marginalization Index (ON_Marg). ON_Marg was estimated at a dissemination area level using Canadian Census 2016 data and categorized into quintiles. Multivariable logistic regression models were performed to examine the relationships between four ON_Marg indices (material deprivation, dependency, ethnic concentration, residential instability), as proxies for maternal SES and the risk of infant CHD. We adjusted for maternal age at birth, assisted reproductive technology, obesity, pre-existing health conditions, substance use during pregnancy, mental health conditions before and during pregnancy, rural residence, and infant's sex in the analysis. RESULTS: Among the cohort of 776,799 singletons, 9,359 infants had a diagnosis of CHD. Of those, 3,069 were severe CHD and 493 cases were single ventricle CHD. The prevalence of all infant CHD types was higher for males relative to females. Compared to mothers living in neighbourhoods with the lowest material deprivation, mothers with highest material deprivation had a 27% (adjusted OR = 1.27; 95% CI: 1.18-1.37) higher odds of having an infant diagnosed with CHD. Mothers living in neighbourhoods with the highest minority ethnic and immigrant concentration tend to have infants with 11% lower odds of CHD (adjusted OR = 0.89; 95% CI: 0.82-0.97) as compared to those living in the least ethnically diverse communities. Maternal dependency and residential stability quintiles were not significantly associated with the risk of CHD. CONCLUSION: Higher maternal material deprivation was associated with increasing odds of infant CHD, whereas neighbourhood minority ethnic concentration was inversely associated with the odds of infant CHD. Our study further confirms that poverty is associated with CHD development. Future investigations might focus on the causal pathways between social deprivation, immigrant status, ethnicity, and the risk of infant CHD.
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Cardiopatías Congénitas , Clase Social , Embarazo , Masculino , Recién Nacido , Femenino , Lactante , Humanos , Ontario/epidemiología , Estudios Retrospectivos , Madres , Cardiopatías Congénitas/epidemiologíaRESUMEN
BACKGROUND: The risk of congenital heart disease (CHD) has been found to vary by maternal socioeconomic status (SES) and rural-urban residence. In this study, we examined associations of CHD with two maternal SES indicators and stratified the analysis by maternal rural-urban residence. METHODS: This was a population-based retrospective cohort study. We included all singleton stillbirths and live hospital births from April 1, 2012 to March 31, 2018 in Ontario, Canada. We linked the BORN Information System and Canadian Institute for Health Information databases. Multivariable logistic regression models were used to examine associations of CHD with material deprivation index (MDI), social deprivation index (SDI), and maternal residence while adjusting for maternal age at birth, assisted reproductive technology, obesity, pre-pregnancy maternal health conditions, mental health illness before and during pregnancy, substance use during pregnancy, and infant's sex. MDI and SDI were estimated at a dissemination area level in Ontario and were categorized into quintiles (Q1-Q5). RESULTS: This cohort study included 798,173 singletons. In maternal urban residence, the p trend (Cochran-Armitage test) was less than 0.0001 for both MDI and SDI; while for rural residence, it was 0.002 and 0.98, respectively. Infants living in the most materially deprived neighbourhoods (MDI Q5) had higher odds of CHD (aOR: 1.21, 95% CI: 1.12-1.29) compared to Q1. Similarly, infants living in the most socially deprived neighbourhoods (SDI Q5) had an 18% increase in the odds of CHD (aOR: 1.18, 95% CI: 1.1-1.26) compared to Q1. Rural infants had a 13% increase in the odds of CHD compared to their urban counterparts. After stratifying by maternal rural-urban residence, we still detected higher odds of CHD with two indices in urban residence but only MDI in rural residence. CONCLUSION: Higher material and social deprivation and rural residence were associated with higher odds of CHD. Health interventions and policies should reinforce the need for optimal care for all families, particularly underprivileged families in both rural and urban regions. Future studies should further investigate the effect of social deprivation on the risk of CHD development.
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Cardiopatías Congénitas , Población Rural , Estudios de Cohortes , Femenino , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/etiología , Humanos , Lactante , Recién Nacido , Ontario/epidemiología , Embarazo , Características de la Residencia , Estudios Retrospectivos , Factores Socioeconómicos , Población UrbanaRESUMEN
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.
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Disparidades en el Estado de Salud , Cardiopatías Congénitas/epidemiología , Pobreza/estadística & datos numéricos , Adulto , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Madres , Ontario/epidemiología , Características de la Residencia , Estudios Retrospectivos , Factores de Riesgo , Factores Socioeconómicos , Adulto JovenRESUMEN
BACKGROUND: Participation in physical activity is essential to the long-term health and development of all children. However, children living with cardiac conditions are typically not active enough to sustain positive health outcomes. Understanding the experiences of children living with congenital heart disease in community-based settings could help inform the physical activity counselling practices of clinicians. The current study explored the perceptions of 7- to 10-year-old children with moderate or complex congenital heart disease as they participated in a 10-week multisport programme. METHODS: Detailed field notes recorded the discussions and behaviours of 11 participants (45% female participants) each week during the programme sessions. Among those, four participants (50% female participants) were purposively selected to participate in preprogramme and postprogramme focus groups to gather more detailed accounts of their experiences. RESULTS: Four main themes surrounding physical activity were identified: (a) motivation, (b) self-efficacy, (c) peer influences, and (d) family influences. Although feelings of excitement and enjoyment towards physical activity were prevalent throughout the data ("I'm really excited because I really like those sports"), participants also often felt frustrated, nervous, and fatigued ("I'm not very good at the skills"). Social inclusion with peers and family influences were meaningful reasons to engage in physical activity ("I really like playing games together"). Following the completion of the programme, participants emphasized their enjoyment of physical activity as a primary source of motivation, demonstrating an important shift from recognizing positive health outcomes ( " it's good for you") towards more intrinsic sources of motivation (" because it's fun"). CONCLUSION: Opportunities for physical activity that enhance positive experiences and build intrinsic motivation should be identified and promoted to children with congenital heart disease. Community-based programmes may also be an appropriate context for children with cardiac conditions to engage and maintain participation in physical activity through adolescence.
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Ejercicio Físico/psicología , Cardiopatías Congénitas/psicología , Motivación , Juego e Implementos de Juego/psicología , Deportes/psicología , Niño , Relaciones Familiares , Femenino , Grupos Focales , Cardiopatías Congénitas/fisiopatología , Humanos , Masculino , Ontario , Grupo Paritario , Autoeficacia , Inclusión SocialRESUMEN
PURPOSE: The genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of nonsyndromic individuals with AVSD. METHODS: Whole-exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD. RESULTS: A significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls (odds ratio (OR): 1.52; 95% confidence interval (CI): 1.35-1.71; P = 4.8 × 10(-11)). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR: 2.25; 95% CI: 1.84-2.76; P = 2.2 × 10(-16)). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2, and MDM4) were enriched for rare variants in AVSD compared with controls, including three syndrome-associated genes (NIPBL, CHD7, and CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands. CONCLUSION: Mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD, even in those with isolated heart disease. The identification of a gene set associated with AVSD will facilitate targeted genetic screening in this cohort.
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Exoma , Variación Genética , Defectos de los Tabiques Cardíacos/genética , Adolescente , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Masculino , Mutación , Fenotipo , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Cardiomyopathy is a clinically and genetically heterogeneous heart condition that can lead to heart failure and sudden cardiac death in childhood. While it has a strong genetic basis, the genetic aetiology for over 50% of cardiomyopathy cases remains unknown. METHODS: In this study, we analyse the characteristics of tandem repeats from genome sequence data of unrelated individuals diagnosed with cardiomyopathy from Canada and the United Kingdom (n = 1216) and compare them to those found in the general population. We perform burden analysis to identify genomic and epigenomic features that are impacted by rare tandem repeat expansions (TREs), and enrichment analysis to identify functional pathways that are involved in the TRE-associated genes in cardiomyopathy. We use Oxford Nanopore targeted long-read sequencing to validate repeat size and methylation status of one of the most recurrent TREs. We also compare the TRE-associated genes to those that are dysregulated in the heart tissues of individuals with cardiomyopathy. FINDINGS: We demonstrate that tandem repeats that are rarely expanded in the general population are predominantly expanded in cardiomyopathy. We find that rare TREs are disproportionately present in constrained genes near transcriptional start sites, have high GC content, and frequently overlap active enhancer H3K27ac marks, where expansion-related DNA methylation may reduce gene expression. We demonstrate the gene silencing effect of expanded CGG tandem repeats in DIP2B through promoter hypermethylation. We show that the enhancer-associated loci are found in genes that are highly expressed in human cardiomyocytes and are differentially expressed in the left ventricle of the heart in individuals with cardiomyopathy. INTERPRETATION: Our findings highlight the underrecognized contribution of rare tandem repeat expansions to the risk of cardiomyopathy and suggest that rare TREs contribute to â¼4% of cardiomyopathy risk. FUNDING: Government of Ontario (RKCY), The Canadian Institutes of Health Research PJT 175329 (RKCY), The Azrieli Foundation (RKCY), SickKids Catalyst Scholar in Genetics (RKCY), The University of Toronto McLaughlin Centre (RKCY, SM), Ted Rogers Centre for Heart Research (SM), Data Sciences Institute at the University of Toronto (SM), The Canadian Institutes of Health Research PJT 175034 (SM), The Canadian Institutes of Health Research ENP 161429 under the frame of ERA PerMed (SM, RL), Heart and Stroke Foundation of Ontario & Robert M Freedom Chair in Cardiovascular Science (SM), Bitove Family Professorship of Adult Congenital Heart Disease (EO), Canada Foundation for Innovation (SWS, JR), Canada Research Chair (PS), Genome Canada (PS, JR), The Canadian Institutes of Health Research (PS).
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Cardiomiopatías , Cardiopatías Congénitas , Humanos , Adulto , Cardiopatías Congénitas/genética , Secuencias Repetidas en Tándem/genética , Metilación de ADN , Cardiomiopatías/genética , Ontario , Proteínas del Tejido Nervioso/genéticaRESUMEN
BACKGROUND: Physical activity is essential to the long-term health of children living with cardiac disease. The simplicity and cost of pedometers make them an attractive alternative to accelerometers for monitoring the physical activity behaviors of these children. This study compared measures obtained from commercial-grade pedometers and accelerometers. METHODS: Pediatric cardiology outpatients (n = 41, mean age = 8.4 [3.7] y, 61% female) wore a pedometer and accelerometer daily for 1 week. Step counts and minutes of moderate to vigorous physical activity were compared between devices, accounting for age group, sex, and diagnostic severity, using univariate analysis of variance. RESULTS: While pedometer data were significantly correlated with accelerometers (r > .74, P < .001), measurements obtained were significantly different between devices. Overall, pedometers overestimated physical activity data. The overestimation of moderate to vigorous physical activity was significantly less among adolescents than younger age groups (P < .01, ηp2=.38). For step counts, there was a significant age by sex interaction observed where preschool and adolescent males tended to have greater differences between accelerometer and step count data than females (P < .01, ηp2=.33). Differences between devices were not associated with severity of diagnosis. CONCLUSIONS: The distribution of pedometers in a pediatric outpatient clinic was feasible, yet the data collected significantly overestimated physical activity, especially among younger children. Practitioners who want to introduce objective measurements as part of their physical activity counseling practice should use pedometers to monitor individual changes in physical activity and consider patient age before administering these devices for clinical care.
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Cardiología , Cardiopatías , Masculino , Niño , Adolescente , Humanos , Femenino , Preescolar , Ejercicio Físico , Actigrafía , Actividad Motora , Caminata/psicologíaRESUMEN
Cardiomyopathy has variable penetrance. We analyzed age and sex-related genetic differences in 1,397 cardiomyopathy patients (Ontario, UK) with whole genome sequencing. Pediatric cases (n = 471) harbored more deleterious protein-coding variants in Tier 1 cardiomyopathy genes compared to adults (n = 926) (34.6% vs 25.9% respectively, p = 0.0015), with variant enrichment in constrained coding regions. Pediatric patients had a higher burden of sarcomere and lower burden of channelopathy gene variants compared to adults. Specifically, pediatric patients had more MYH7 and MYL3 variants in hypertrophic cardiomyopathy, and fewer TTN truncating variants in dilated cardiomyopathy. MYH7 variants clustered in the myosin head and neck domains in children. OBSCN was a top mutated gene in adults, enriched for protein-truncating variants. In dilated cardiomyopathy, female patients had a higher burden of z-disc gene variants compared to males. Genetic differences may explain age and sex-related variability in cardiomyopathy penetrance. Genotype-guided predictions of age of onset can inform pre-test genetic counseling. Pediatric cardiomyopathy patients were more likely to be genotype-positive than adults with a higher burden of variants in MYH7, MYL3, TNNT2, VCL. Adults had a higher burden of OBSCN and TTN variants. Females with dilated cardiomyopathy (DCM) had a higher burden of z-disc gene variants compared to males.
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Cardiomiopatías , Cardiomiopatía Dilatada , Cardiomiopatía Hipertrófica , Adulto , Humanos , Masculino , Femenino , Niño , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/genética , Mutación , Caracteres Sexuales , Cardiomiopatías/genética , GenotipoRESUMEN
BACKGROUND: Hypoxia-inducible factor (HIF1A) regulates the myocardial response to hypoxia and hemodynamic load. We investigated the association of HIF1A variants with right-ventricular (RV) remodeling after tetralogy of Fallot (TOF) repair. METHODS: Children with TOF were genotyped for three single-nucleotide polymorphisms in HIF1A. Genotypes were analyzed for association with RV myocardial protein expression and fibrosis at complete repair (n = 42) and RV dilation, fractional area change, and freedom from pulmonary valve/conduit replacement on follow-up. RESULTS: In 180 TOF patients, mean age at repair was 1.0 ± 0.8 y with follow-up at 9.0 ± 3.5 y; 82% had moderate to severe pulmonary insufficiency. Freedom from RV reinterventions at 5, 10, and 15 y was 92, 84, and 67%, respectively. Patients with more functioning HIF1A alleles had higher transforming growth factor ß1 expression and more fibrosis at initial repair as compared with controls (P < 0.05). During follow-up, patients with more functioning HIF1A alleles showed less RV dilation, better preservation of RV function, and greater freedom from RV reinterventions (P < 0.05). This was confirmed in a replication cohort of 69 patients. CONCLUSION: In children who have had TOF repair, a lower number of functioning HIF1A alleles was associated with RV dilation and dysfunction, suggesting that hypoxia adaptation in unrepaired TOF may influence RV phenotype after repair.
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Procedimientos Quirúrgicos Cardíacos , Ventrículos Cardíacos/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Polimorfismo de Nucleótido Simple , Tetralogía de Fallot/cirugía , Remodelación Ventricular/genética , Adaptación Fisiológica , Proteínas Angiogénicas/genética , Proteínas Angiogénicas/metabolismo , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Preescolar , Fibrosis , Estudios de Seguimiento , Frecuencia de los Genes , Genotipo , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Humanos , Hipertrofia Ventricular Derecha/genética , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/cirugía , Hipoxia/genética , Hipoxia/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Lactante , Estimación de Kaplan-Meier , Modelos Lineales , Modelos Logísticos , Fenotipo , Estudios Prospectivos , Sistema de Registros , Reoperación , Tetralogía de Fallot/genética , Tetralogía de Fallot/metabolismo , Tetralogía de Fallot/patología , Tetralogía de Fallot/fisiopatología , Factores de Tiempo , Factor de Crecimiento Transformador beta1/metabolismo , Resultado del Tratamiento , Disfunción Ventricular Derecha/genética , Disfunción Ventricular Derecha/patología , Disfunción Ventricular Derecha/cirugíaRESUMEN
Background Transplacental fetal treatment of immune-mediated fetal heart disease, including third-degree atrioventricular block (AVB III) and endocardial fibroelastosis, is controversial. Methods and Results To study the impact of routine transplacental fetal treatment, we reviewed 130 consecutive cases, including 108 with AVB III and 22 with other diagnoses (first-degree/second-degree atrioventricular block [n=10]; isolated endocardial fibroelastosis [n=9]; atrial bradycardia [n=3]). Dexamethasone was started at a median of 22.4 gestational weeks. Additional treatment for AVB III included the use of a ß-agonist (n=47) and intravenous immune globulin (n=34). Fetal, neonatal, and 1-year survival rates with AVB III were 95%, 93%, and 89%, respectively. Variables present at diagnosis that were associated with perinatal death included an atrial rate <90 beats per minute (odds ratio [OR], 258.4; 95% CI, 11.5-5798.9; P<0.001), endocardial fibroelastosis (OR, 28.9; 95% CI, 1.6-521.7; P<0.001), fetal hydrops (OR, 25.5; 95% CI, 4.4-145.3; P<0.001), ventricular dysfunction (OR, 7.6; 95% CI, 1.5-39.4; P=0.03), and a ventricular rate <45 beats per minute (OR, 12.9; 95% CI, 1.75-95.8; P=0.034). At a median follow-up of 5.9 years, 85 of 100 neonatal survivors were paced, and 1 required a heart transplant for dilated cardiomyopathy. Cotreatment with intravenous immune globulin was used in 16 of 22 fetuses with diagnoses other than AVB III. Neonatal and 1-year survival rates of this cohort were 100% and 95%, respectively. At a median age of 3.1 years, 5 of 21 children were paced, and all had normal ventricular function. Conclusions Our findings reveal a low risk of perinatal mortality and postnatal cardiomyopathy in fetuses that received transplacental dexamethasone±other treatment from the time of a new diagnosis of immune-mediated heart disease.
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Bloqueo Atrioventricular , Fibroelastosis Endocárdica , Enfermedades Fetales , Antiinflamatorios/uso terapéutico , Anticuerpos , Niño , Preescolar , Dexametasona/uso terapéutico , Femenino , Enfermedades Fetales/diagnóstico , Enfermedades Fetales/tratamiento farmacológico , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Recién Nacido , EmbarazoRESUMEN
OBJECTIVE: To investigate the interrelationships between maternal socioeconomic status (SES), race and congenital heart diseases (CHD) among infants. DESIGN: Retrospective cohort study. STUDY SETTING: Ontario, Canada. STUDY POPULATION: All singleton stillbirths and live births born in hospitals between 1 April 2012 and 31 March 2018 in Ontario, Canada (n=804 292). OUTCOME: CHD. ANALYSIS: Multivariable logistic regression models were performed to assess associations between maternal neighbourhood household income, education level, race and CHD while adjusting for maternal age at birth, assisted reproductive technology, obesity, pre-existing health conditions, substance use during pregnancy, maternal rural residence and infant's sex. RESULTS: Compared with infants whose mothers lived in the highest median household income neighbourhoods, infants whose mothers lived in the lowest median income neighbourhoods had a higher likelihood of having CHD (adjusted OR 1.15, 95% CI 1.06 to 1.24). Compared with infants whose mothers lived in neighbourhoods with more people with a university or higher degree, those infants whose mothers lived in neighbourhoods with less people with a university or higher degree had a higher chance of developing CHD (adjusted OR 1.26, 95% CI 1.16 to 1.36). Compared with white mothers, black mothers had a higher odds of giving birth to a child with CHD (adjusted OR 1.40, 95% CI 1.27 to 1.54). No association was detected between White and Asian mothers and CHD among infants. CONCLUSIONS: Our study indicates that there are inequities in CHD burden by maternal SES and race in Ontario, Canada. Further investigation is needed to examine racial variation in CHD using more detailed ethnic data.
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Cardiopatías Congénitas , Clase Social , Estudios de Cohortes , Femenino , Cardiopatías Congénitas/epidemiología , Humanos , Lactante , Recién Nacido , Madres , Ontario/epidemiología , Embarazo , Estudios RetrospectivosRESUMEN
Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole-genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine percent of cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen percent harbored high-risk regulatory variants in promoters and enhancers of CMP genes (odds ratio 2.25, p = 6.70 × 10-7 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (odds ratio 6.7-58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early onset CMP.
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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.
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Enfermedad Crónica/psicología , Ejercicio Físico , Conocimientos, Actitudes y Práctica en Salud , Estilo de Vida Saludable , Canadá , Estudios de Casos y Controles , Niño , Estudios Transversales , Femenino , Conductas Relacionadas con la Salud , Humanos , Masculino , Motivación , Aptitud Física , AutoimagenRESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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, P < 0.001), prostaglandin therapy (0.1 vs 5.3 hours; P < 0.001), balloon atrial septostomy (5.3 vs 14.9 hours; P <0.001), 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). CONCLUSIONS: 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.
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Transposición de los Grandes Vasos , Ultrasonografía Prenatal , Operación de Switch Arterial/estadística & datos numéricos , Diagnóstico Tardío/efectos adversos , Diagnóstico Tardío/prevención & control , Diagnóstico Tardío/estadística & datos numéricos , Femenino , Humanos , Lactante , Mortalidad Infantil , Recién Nacido , Masculino , Ontario/epidemiología , Evaluación de Procesos y Resultados en Atención de Salud , Atención Perinatal/métodos , Embarazo , Respiración Artificial/métodos , Respiración Artificial/estadística & datos numéricos , Análisis de Supervivencia , Centros de Atención Terciaria/estadística & datos numéricos , Transposición de los Grandes Vasos/diagnóstico , Transposición de los Grandes Vasos/mortalidad , Transposición de los Grandes Vasos/terapia , Ultrasonografía Prenatal/métodos , Ultrasonografía Prenatal/estadística & datos numéricosRESUMEN
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.
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Instituciones Cardiológicas/organización & administración , Consejo/organización & administración , Ejercicio Físico , Cardiopatías Congénitas/terapia , Motivación , Actigrafía , Adolescente , Canadá , Niño , Preescolar , Femenino , Humanos , Masculino , Calidad de Vida , Proyectos de InvestigaciónRESUMEN
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 507â¯390 singleton or twin pregnancies (10â¯149 assisted pregnancies and 497â¯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 507â¯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.
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Cardiopatías Congénitas/epidemiología , Técnicas Reproductivas Asistidas , Adulto , Femenino , Humanos , Ontario/epidemiología , Embarazo , Embarazo Gemelar , Prevalencia , Estudios Retrospectivos , Factores de RiesgoRESUMEN
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.