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BACKGROUND AND AIMS: A variety of maternal heart conditions are associated with abnormal placentation and reduced foetal growth. However, their impact on offspring's long-term cardiovascular health is poorly studied. This study aims to investigate the association between intrauterine exposure to pre-existing maternal cardiovascular disease (CVD) and offspring CVD occurring from infancy to early adulthood, using paternal CVD as a negative control. METHODS: This nationwide cohort study used register data of live singletons without major malformations or congenital heart disease born between 1992 and 2019 in Sweden. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusted for essential maternal characteristics. Paternal CVD served as a negative control for assessment of unmeasured genetic and environmental confounding. RESULTS: Of the 2 597 786 offspring analysed (49.1% female), 26 471 (1.0%) were born to mothers with pre-existing CVD. During a median follow-up of 14 years (range 1-29 years), 17 382 offspring were diagnosed with CVD. Offspring of mothers with CVD had 2.09 times higher adjusted HR of CVD (95% CI 1.83, 2.39) compared with offspring of mothers without CVD. Compared with maternal CVD, paternal CVD showed an association of smaller magnitude (HR 1.49, 95% CI 1.32, 1.68). Increased hazards of offspring CVD were also found when stratifying maternal CVD into maternal arrhythmia (HR 2.94, 95% CI 2.41, 3.58), vascular (HR 1.59, 95% CI 1.21, 2.10), and structural heart diseases (HR 1.48, 95% CI 1.08, 2.02). CONCLUSIONS: Maternal CVD was associated with an increased risk of CVD in offspring during childhood and young adulthood. Paternal comparison suggests that genetic or shared familial factors may not fully explain this association.
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The Nexilin F-Actin Binding Protein (Nexilin) encoded by NEXN is a cardiac Z-disc protein important for cardiac function and development in humans, zebrafish, and mice. Heterozygote variants in the human NEXN gene have been reported to cause dilated and hypertrophic cardiomyopathy. Homozygous variants in NEXN cause a lethal form of human fetal cardiomyopathy, only described in two patients before. In a Swedish, four-generation, non-consanguineous family comprising 42 individuals, one female had three consecutive pregnancies with intrauterine fetal deaths caused by a lethal form of dilated cardiomyopathy. Whole-exome sequencing and variant analysis revealed that the affected fetuses were homozygous for a NEXN variant (NM_144573:c.1302del;p.(Ile435Serfs*3)). Moreover, autopsy and histology staining declared that they presented with cardiomegaly and endocardial fibroelastosis. Immunohistochemistry staining for Nexilin in the affected fetuses revealed reduced antibody staining and loss of striation in the heart, supporting loss of Nexilin function. Clinical examination of seven heterozygote carriers confirmed dilated cardiomyopathy (two individuals), other cardiac findings (three individuals), or no cardiac deviations (two individuals), indicating incomplete penetrance or age-dependent expression of dilated cardiomyopathy. RNA sequencing spanning the variant in cDNA blood of heterozygote individuals revealed nonsense-mediated mRNA decay of the mutated transcripts. In the current study, we present the first natural course of the recessively inherited lethal form of human fetal cardiomyopathy caused by loss of Nexilin function. The affected family had uneventful pregnancies until week 23-24, followed by fetal death at week 24-30, characterized by cardiomegaly and endocardial fibroelastosis.
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Cardiomegalia , Fibroelastose Endocárdica , Proteínas dos Microfilamentos , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Fibroelastose Endocárdica/genética , Fibroelastose Endocárdica/metabolismo , Fibroelastose Endocárdica/patologia , Feminino , Humanos , Imuno-Histoquímica , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Sequenciamento do ExomaRESUMO
INTRODUCTION: Aorto-left ventricular tunnel (ALVT) accounts for <0.1% of congenital heart defects. Evidence on the prognosis from a fetal perspective is limited. With this retrospective international case series, we provide information on the outcome of fetuses with ALVT. METHODS: All members of the Association for European Pediatric and Congenital Cardiology's (AEPC) fetal working group and fetal medicine units worldwide were invited for participation. We observed antenatal parameters, neonatal outcome and postnatal follow-up. Additionally, a systematic search of the literature was performed. RESULTS: Twenty fetuses with ALVT were identified in 10 participating centers (2001-2019). Fetal echocardiographic characteristics of ALVT included an increased cardiac-thorax ratio (95%), left ventricular end-diastolic diameter (90%) and a dysplastic aortic valve (90%). Extracardiac malformations were rare (5%). Eight fetuses died at a median gestational age (GA) of 21 + 6 weeks (range, 19-24): all showed signs of hydrops prior to 24 weeks or at autopsy. All others (60%, 12/2) were live-born (median GA 38 + 4, range 37-40), underwent surgery and were alive at last follow up (median 3.2 years, range 0.1-17). The literature reported 22 ALVT fetuses with similar outcome. CONCLUSIONS: In the absence of fetal hydrops, ALVT carries a good prognosis. Fetuses who survive to 24 weeks without hydrops are likely to have a good outcome.
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Túnel Aorticoventricular , Túnel Aorticoventricular/diagnóstico , Túnel Aorticoventricular/embriologia , Túnel Aorticoventricular/mortalidade , Túnel Aorticoventricular/terapia , Feminino , Seguimentos , Humanos , Recém-Nascido , Masculino , Gravidez , Diagnóstico Pré-Natal , Prognóstico , Estudos RetrospectivosRESUMO
AIM: To study real-life experiences of drug treatment discontinuations and safety in a well-defined cohort of patients with juvenile idiopathic arthritis (JIA), over an eleven-year period in Uppsala County, Sweden. METHODS: Clinical charts of all incident and prevalent cases of juvenile arthritis were reviewed prospectively by an experienced paediatric rheumatologist. Each patient file was supplemented retrospectively regarding hereditary diseases, clinical data and aspects of pharmacological treatment. RESULTS: Severe adverse events from methotrexate or biological agents were rare, but 84 occasions of interrupted therapy due to adverse events or inefficacy were identified within 225 treatment periods (37.3%) in the 156 patients (108 girls and 48 boys) studied. The median observation period was 8.6 years after disease onset (minimum 1.33, maximum 17.5 years). Oral and subcutaneous methotrexate caused adverse events in 22.6% of the treatment periods and biological agents in 19.2% (p = 0.71). Discontinuation of treatment periods was equally common for methotrexate (38.7%) and biological agents (33.3%) (p = 0.53). CONCLUSION: Our study shows a high percentage of interrupted medical therapies, due to adverse events or inefficacy, in children with JIA. Adverse events from methotrexate and biological agents were seldom severe. The results highlight the need for better predictive factors to guide therapy.
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Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Suspensão de Tratamento/estatística & dados numéricos , Adolescente , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Estudos Retrospectivos , Falha de TratamentoRESUMO
OBJECTIVES: Early diagnosis of critical congenital heart defects (CCHD) improves survival. We evaluated the relative contributions of prenatal ultrasound, neonatal pulse oximetry screening (POS), and neonatal physical examination (NPE) to the early detection (before discharge) of CCHD in the context of increasing prenatal detection, and POS being a national standard since 2013. METHODS: Retrospective, nationwide population-based study. All full-term live-born infants with CCHD in Sweden between 2014 and 2019 were included. CCHD was defined as a congenital heart defect requiring surgery or catheter-based intervention or resulting in death within 28 days of birth. RESULTS: Of 630 infants, 89% were diagnosed before discharge or death, 42% prenatally, 11% from early symptoms, 23% by POS, and 14% from NPE after a negative POS. Four (0.6%) died undiagnosed before discharge and 64/630 (10%) were discharged undiagnosed, with 24/64 being readmitted with circulatory failure and causing 1 preoperative death. Coarctation was the most prevalent CCHD (N = 184), 25% of whom were detected prenatally (12% by POS and 29% by NPE). Two died undiagnosed before discharge and 30% were discharged undiagnosed. Transposition was the second most common defect (N = 150) and 43% were detected prenatally (33% by POS, 1 by NPE) and 2 died undiagnosed before POS. None was discharged undiagnosed. CONCLUSIONS: POS and NPE remain important for the early detection of CCHD complementing prenatal ultrasound screening. Nevertheless, 1 in 10 with CCHD leaves the hospital without a diagnosis, with coarctation being the predominant lesion. Future research on CCHD screening should have a particular focus on this cardiac defect.
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PURPOSE: Adolescents with congenital heart disease transition from childhood to adulthood and transfer from pediatric-oriented to adult-oriented care. High-level empirical evidence on the effectiveness of transitional care is scarce. This study investigated the empowering effect (primary outcome) of a structured person-centered transition program for adolescents with congenital heart disease and studied its effectiveness on transition readiness, patient-reported health, quality of life, health behaviors, disease-related knowledge, and parental outcomes e.g., parental uncertainty, readiness for transition as perceived by the parents (secondary outcomes). METHODS: The STEPSTONES-trial comprised a hybrid experimental design whereby a randomized controlled trial was embedded in a longitudinal observational study. The trial was conducted in seven centers in Sweden. Two centers were allocated to the randomized controlled trial-arm, randomizing participants to intervention or control group. The other five centers were intervention-naïve centers and served as contamination check control group. Outcomes were measured at the age of 16 years (baseline), 17 years, and 18.5 years. RESULTS: The change in empowerment from 16 years to 18.5 years differed significantly between the intervention group and control group (mean difference = 3.44; 95% confidence interval = 0.27-6.65; p = .036) in favor of intervention group. For the secondary outcomes, significant differences in change over time were found in parental involvement (p = .008), disease-related knowledge (p = .0002), and satisfaction with physical appearance (p = .039). No differences in primary or secondary outcomes were detected between the control group and contamination check control group, indicating that there was no contamination in the control group. DISCUSSION: The STEPSTONES transition program was effective in increasing patient empowerment, reducing parental involvement, improving satisfaction with physical appearance, and increasing disease-related knowledge.
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Cardiopatias Congênitas , Transição para Assistência do Adulto , Adulto , Humanos , Adolescente , Criança , Adulto Jovem , Qualidade de Vida , Cardiopatias Congênitas/terapia , Participação do Paciente , PaisRESUMO
BACKGROUND: Providing continuous follow-up care to patients with congenital heart disease (CHD) remains a challenge in many settings. Previous studies highlight that patients with CHD experience discontinuation of follow-up care, but mainly describe a single-centre perspective, neglecting inter-institutional variations. Hospital-related factors above and beyond patient-related factors are believed to affect continuity of care. The present multicentre study therefore investigated (i) proportion of "no follow-up care"; (ii) transfer destinations after leaving paediatric cardiology; (iii) variation in proportions of no follow-up between centres; (iv) the association between no follow-up and outpatient volumes, and (v) its relationship with staffing resources at outpatient clinics. METHODS: An observational, multicentre study was conducted in seven university hospitals. In total, 654 adolescents with CHD, born between 1991 and 1993, with paediatric outpatient visit at age 14-18â¯years were included. Transfer status was determined 5â¯years after the intended transfer to adult care (23y), based on medical files, self-reports and registries. RESULTS: Overall, 89.7% of patients were receiving adult follow-up care after transfer; 6.6% had no follow-up; and 3.7% were untraceable. Among patients in follow-up care, only one remained in paediatric care and the majority received specialist adult CHD care. Significant variability in proportions of no follow-up were identified across centres. Higher outpatient volumes at paediatric outpatient clinics were associated with better continued follow-up care after transfer (ORâ¯=â¯1.061; 95% CIâ¯=â¯1.001 - 1.124). Medical staffing resources were not found predictive. CONCLUSION: Our findings support the theory of hospital-related factors influencing continuity of care, above and beyond patient-related characteristics.