Congenital Heart Disease Subtypes Research Articles

Association between maternal exposure to indoor air pollution and offspring congenital heart disease: a case\u2013control study in East China

BackgroundPrevious research suggested an association between maternal exposure to ambient air pollutants and the risk of congenital heart disease (CHD). However, the effect of individual prenatal exposure to indoor air pollutants on CHD occurrence was not reported.MethodsWe performed a hospital-based case–control study to investigate the association between personal air pollution exposure during pregnancy and the risk of CHD in offspring. A total of 44 cases and 75 controls were included from two hospitals in East China. We investigated maternal and residential environmental characteristics using a questionnaire and obtained personal indoor air samples to assess particulate matter (PM) and volatile organic compounds (VOCs) from 22–30 gestational weeks. Formaldehyde, benzene, toluene, xylene, total volatile organic compounds (TVOCs), PM2.5, and PM10 were assessed. Logistic regression was performed to assess associations and interactions between individual indoor air pollutants and CHD after adjusting for confounders. The potential residential environmental factors affecting the risks of indoor air pollutants on CHD were also assessed.ResultsMedian TVOC (0.400 vs. 0.005 mg/m3, P < 0.001) exposure levels in cases were significantly higher than controls. A logistic regression model adjusted for confounders revealed that exposure to high levels of indoor TVOCs (AOR 7.09, 95% CI 2.10–23.88) during pregnancy was associated with risks for CHD and the occurrence of some major CHD subtype in offspring. These risk effects were enhanced in pregnant women living in a newly renovated house but were mitigated by household use of smoke ventilators when cooking. We observed a positive interaction of maternal exposure to TVOCs and PM2.5 and the risk for CHD.ConclusionsMaternal exposure to indoor VOCs and PMs may increase the risk of giving birth to foetuses with CHD.

Translational potential of hiPSCs in predictive modeling of heart development and disease.

Congenital heart disease (CHD) represents a major class of birth defects worldwide and is associated with cardiac malformations that often require surgical intervention immediately after birth. Despite the intense efforts from multicentric genome/exome sequencing studies that have identified several genetic variants, the etiology of CHD remains diverse and often unknown. Genetically modified animal models with candidate gene deficiencies continue to provide novel molecular insights that are responsible for fetal cardiac development. However, the past decade has seen remarkable advances in the field of human induced pluripotent stem cell (hiPSC)-based disease modeling approaches to better understand the development of CHD and discover novel preventative therapies. The iPSCs are derived from reprogramming of differentiated somatic cells to an embryonic-like pluripotent state via overexpression of key transcription factors. In this review, we describe how differentiation of hiPSCs to specialized cardiac cellular identities facilitates our understanding of the development and pathogenesis of CHD subtypes. We summarize the molecular and functional characterization of hiPSC-derived differentiated cells in support of normal cardiogenesis, those that go awry in CHD and other heart diseases. We illustrate how stem cell-based disease modeling enables scientists to dissect the molecular mechanisms of cell-cell interactions underlying CHD. We highlight the current state of hiPSC-based studies that are in the verge of translating into clinical trials. We also address limitations including hiPSC-model reproducibility and scalability and differentiation methods leading to cellular heterogeneity. Last, we provide future perspective on exploiting the potential of hiPSC technology as a predictive model for patient-specific CHD, screening pharmaceuticals, and provide a source for cell-based personalized medicine. In combination with existing clinical and animal model studies, data obtained from hiPSCs will yield further understanding of oligogenic, gene-environment interaction, pathophysiology, and management for CHD and other genetic cardiac disorders.

Maternal Viral Infection in Early Pregnancy and Risk of Congenital Heart Disease in Offspring: A Prospective Cohort Study in Central China.

PurposeTo examine the associations of maternal virus infection in early pregnancy with risk of offspring congenital heart disease (CHD) and its seven common subtypes including atrial septal defect, ventricular septal defect, atrioventricular septal defect, patent ductus arteriosus, Tetralogy of Tallot, pulmonary stenosis, and transposition of the great arteries.Patients and MethodsA prospective cohort study was conducted in Central China. A total of 44,048 pregnant women with singleton pregnancies at 8–14 gestational weeks were finally included and followed to 3 months postpartum. Serum was tested for virus infection including hepatitis B virus (HBV), coxsackievirus-B, human cytomegalovirus (HCMV), herpes simplex virus (HSV), and rubella virus. Multivariable modified Poisson regression models were used to estimate the relative risks (RRs) of all CHDs as well as seven common subtypes of CHD in offspring of pregnant women with different types of virus infection in early pregnancy, adjusting for confounders identified by directed acyclic graphs.ResultsAt the end of follow-up, 564 births were diagnosed with CHD. Multivariable analyses showed that the presence of maternal viral infection in early pregnancy was independently associated with increased risks of CHD in offspring, with an adjusted relative risk of 2.21 (95% CI: 1.66–2.95) for HBV infection, 2.21 (95% CI: 1.63–3.00) for coxsackievirus-B infection, 3.12 (95% CI: 2.44–3.98) for HCMV infection, and 2.62 (95% CI: 1.95–3.51) for rubella virus infection. More specifically, the offspring of pregnant women with HCMV infection had the highest increased risk of patent ductus arteriosus (RR=10.50, 95% CI: 6.24–17.66). These findings persisted in analyses that were further adjusted for the other virus of interest in this study.ConclusionOur study proposed evidence that maternal virus infection in early pregnancy, including HBV, coxsackievirus-B, HCMV, and rubella virus, was implicated in CHD, although more studies remain needed to verify the results, especially associations in specific CHD phenotypes.

MRI characterization of hemodynamic patterns of human fetuses with cyanotic congenital heart disease.

To characterize, using magnetic resonance imaging (MRI), the distribution of blood flow and oxygen transport in human fetuses with subtypes of congenital heart disease (CHD) that present with neonatal cyanosis. Blood flow was measured in the major vessels of 152 late-gestation human fetuses with CHD and 40 gestational-age-matched normal fetuses, using cine phase-contrast MRI. Oxygen saturation (SaO2 ) was measured in the major vessels of 57 fetuses with CHD and 40 controls. Compared with controls, we found lower combined ventricular output in fetuses with single-ventricle physiology, with the lowest being observed in fetuses with severe forms of Ebstein's anomaly. Obstructive lesions of the left or right heart were associated with increased flow across the contralateral side. Pulmonary blood flow was reduced in fetuses with Ebstein's anomaly, while those with Ebstein's anomaly and tricuspid atresia had reduced umbilical flow. Flow in the superior vena cava was elevated in fetuses with transposition of the great arteries, normal in fetuses with hypoplastic left heart, tetralogy of Fallot or tricuspid atresia and reduced in fetuses with Ebstein's anomaly. Umbilical vein SaO2 was reduced in fetuses with hypoplastic left heart or tetralogy of Fallot. Ascending aorta and superior vena cava SaO2 were reduced in nearly all CHD subtypes. Fetuses with cyanotic CHD exhibit profound changes in the distribution of blood flow and oxygen transport, which result in changes in cerebral, pulmonary and placental blood flow and oxygenation. These alterations of fetal circulatory physiology may influence the neonatal course and help account for abnormalities of prenatal growth and development that have been described in newborns with cyanotic CHD. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Interpregnancy interval and subsequent perinatal risk of congenital heart disease in Guangzhou, Southern China: a retrospective cohort study, 2014–2019

Background The association between maternal interpregnancy interval (IPI) and congenital heart disease (CHD) in neonates remains inconclusive. This study aimed to examine the effect of maternal IPI on birth risk of CHD. Methods Chinese women with two consecutive singleton deliveries in Guangzhou between January 2014 and December 2019 were selected as participants. Information on IPI and CHD was extracted from the Guangzhou Perinatal Health Care and Delivery Registry and the Guangzhou Birth Defects Surveillance Program. We stratified IPI into four categories: <24 months, 24–35 months, 36–59 months, and ≥60 months. A multivariate logistic regression model was used to examine the association between IPI and CHD. Subgroup analysis was also performed to assess whether the associations differed across top three CHD subtypes. Results For 119,510 women enrolled in this study, the mean ages at two consecutive deliveries were 26.2 ± 3.8 and 28.8 ± 4.0 years, which yielded a median IPI of 51.2 (interquartile range, 32.1–77.2) months. Among them, 828 delivered infants with CHD during their second pregnancy. There was a J-shaped curve relationship between IPI and CHD with the lowest birth prevalence (5.33‰) at 24–35-month interval. Compared to women with an IPI of 24–35 months, those with an IPI ≥60 had an increased risk of delivering infants with CHD (adjusted odds ratio (OR), 1.41; 95% confidence interval (CI), 1.19–1.64). However, for those with an IPI <24 months (adjusted OR, 1.24; 95% CI, 0.97–1.51), IPI was statistically insignificant associated with the risk of delivering infants with CHD (p = .12). There were different patterns of associations for different CHD subtypes. Conclusions Longer maternal IPI (≥60 months) was associated with an increased risk of delivering infants with CHD in the Chinese population.

Abstract 11616: Seizures in Infants with Congenital Heart Disease

Background: Infants with congenital heart disease (CHD) may have an increased risk to develop seizures during hospitalization. Objectives: to examine the association of CHD with non-epileptic, non-traumatic seizures in hospitalized infants up to one year of age. Methods: We conducted a retrospective analysis of the U.S. National Inpatient Sample dataset (2015-2018). We used the international classification of disease-10 th version to identify infants with different types of CHD. We included infants up to one year of age. We excluded infants &lt;35 week gestational age, infants with central nervous system or with major congenital anomalies, common trisomy or genetic disorders. We used chi square testing to examine the association of subtypes of CHD with seizures excluding post traumatic and epileptic seizures. We calculated mortality in infants with CHD who developed seizures versus those who did not have seizures. Results: There was 12,023,781 infants in the weighted sample who met our inclusion criteria. Of them, 48.7% were females, 46.7% were Caucasians, 195,685 (1.63%) were identified with a CHD and 20,565 (0.17%) suffered at least one episode of seizure during hospitalization. Seizures occurred in 4225 (2.2%) of infants with any type of CHD compared to 16,340 (0.14%) in infants with no CHD, odds ratios for seizures is 15.6 (CI: 15.2-16.5, p &lt;0.001). The association of seizures with subtypes of CHD is shown in table-1. Among infants with CHD, 2205 infants expired during hospitalization. Mortality was higher in infants with CHD who suffered seizures (8.5%) vs. those who did not have seizures (1.0%), OR 9.6 (8.5-10.8, p &lt;0.001). Conclusion: Infants with CHD have a higher chance to experience seizure episodes during their hospitalization and those who have seizures have higher chances of mortality during hospitalization. Further analysis is required to understand the pathological correlation between seizures and CHD and its impact on long term developmental outcomes.

PROTEA, A Southern African Multicenter Congenital Heart Disease Registry and Biorepository: Rationale, Design, and Initial Results.

Objectives: The PartneRships in cOngeniTal hEart disease (PROTEA) project aims to establish a densely phenotyped and genotyped Congenital Heart Disease (CHD) cohort for southern Africa. This will facilitate research into the epidemiology and genetic determinants of CHD in the region. This paper introduces the PROTEA project, characterizes its initial cohort, from the Western Cape Province of South Africa, and compares the proportion or “cohort-prevalences” of CHD-subtypes with international findings.Methods: PROTEA is a prospective multicenter CHD registry and biorepository. The initial cohort was recruited from seven hospitals in the Western Cape Province of South Africa from 1 April 2017 to 31 March 2019. All patients with structural CHD were eligible for inclusion. Descriptive data for the preliminary cohort are presented. In addition, cohort-prevalences (i.e., the proportion of patients within the cohort with a specific CHD-subtype) of 26 CHD-subtypes in PROTEA's pediatric cohort were compared with the cohort-prevalences of CHD-subtypes in two global birth-prevalence studies.Results: The study enrolled 1,473 participants over 2 years, median age was 1.9 (IQR 0.4–7.1) years. Predominant subtypes included ventricular septal defect (VSD) (339, 20%), atrial septal defect (ASD) (174, 11%), patent ductus arteriosus (185, 11%), atrioventricular septal defect (AVSD) (124, 7%), and tetralogy of Fallot (121, 7%). VSDs were 1.8 (95% CI, 1.6–2.0) times and ASDs 1.4 (95% CI, 1.2–1.6) times more common in global prevalence estimates than in PROTEA's pediatric cohort. AVSDs were 2.1 (95% CI, 1.7–2.5) times more common in PROTEA and pulmonary stenosis and double outlet right ventricle were also significantly more common compared to global estimates. Median maternal age at delivery was 28 (IQR 23–34) years. Eighty-two percent (347/425) of mothers used no pre-conception supplementation and 42% (105/250) used no first trimester supplements.Conclusions: The cohort-prevalence of certain mild CHD subtypes is lower than for international estimates and the cohort-prevalence of certain severe subtypes is higher. PROTEA is not a prevalence study, and these inconsistencies are unlikely the result of true differences in prevalence. However, these findings may indicate under-diagnosis of mild to moderate CHD and differences in CHD management and outcomes. This reemphasizes the need for robust CHD epidemiological research in the region.

Cognitive and Executive Function in Congenital Heart Disease: A Meta-analysis.

Cognitive function and executive function (EF) impairments contribute to the long-term burden of congenital heart disease (CHD). However, the degree and profile of impairments are insufficiently described. To systematically review and meta-analyze the evidence on cognitive function and EF outcomes in school-aged children operated for CHD and identify the risk factors for an unfavorable outcome. Cochrane, Embase, Medline, and PsycINFO. Original peer-reviewed studies reporting cognitive or EF outcome in 5- to 17-year old children with CHD after cardiopulmonary bypass surgery. Results of IQ and EF assessments were extracted, and estimates were transformed to means and SE. Standardized mean differences were calculated for comparison with healthy controls. Among 74 studies (3645 children with CHD) reporting total IQ, the summary estimate was 96.03 (95% confidence interval: 94.91 to 97.14). Hypoplastic left heart syndrome and univentricular CHD cohorts performed significantly worse than atrial and ventricular septum defect cohorts (P = .0003; P = .027). An older age at assessment was associated with lower IQ scores in cohorts with transposition of the great arteries (P = .014). Among 13 studies (774 children with CHD) reporting EF compared with controls, the standardized mean difference was -0.56 (95% confidence interval: -0.65 to -0.46) with no predilection for a specific EF domain or age effect. Heterogeneity between studies was large. Intellectual impairments in CHD are frequent, with severity and trajectory depending on the CHD subtype. EF performance is poorer in children with CHD without a specific EF profile. The heterogeneity in studied populations and applied assessments is large. A uniform testing guideline is urgently needed.

Maternal trichloroethylene exposure and metabolic gene polymorphisms may interact during fetal cardiovascular malformation

This study aimed to analyze the potential association between trichloroethylene (TCE) exposure and congenital heart disease (CHD) and to explore the effect of metabolic enzyme gene polymorphisms on heart development. A multicenter case-control study was conducted. The trichloroethylene concentrations were measured by UPLC-MSMS in urine. Fourteen SNPs in the GSTA1, GSTP1, MPO, NAT1, NAT2, CYP1A1, CYP1A2, CYP2E1 and EPHX1 genes were genotyped using an improved multiplex ligation detection reaction (iMLDR) technique. A total of 283 cases and 331 controls with maternal urine and/or venous blood were included in the present study. The median NAcDCVC was 7.65 ng/mL in the case group and 7.43 ng/mL in the control group. There was no significant difference in the NAcDCVC concentration between the CHD subtypes and controls (P > 0.05). The GA/AA of GSTA1 rs3957357 could increase the risk of CHDs under the dominant model (aOR = 2.26, 95 % CI: 1.31, 3.90), but other SNPs were not associated with CHDs (P > 0.05). GA or AA genotypes of GSTA1 rs3957357 with lower levels of TCE exposure were 3.53 times at risk relative to mothers carrying the wild type genotype. In conclusion, maternal exposure to trichloroethylene alone is not associated with the occurrence of fetal CHD and CHD subtypes. Maternal GSTA1 rs3957357 may increase the risk of CHD in offspring. TCE exposure and metabolic gene polymorphisms probably interact with each other to induce fetal cardiovascular malformation, but larger sample size studies are needed to confirm this hypothesis.

Associations and interaction effects of maternal smoking and genetic polymorphisms of cytochrome P450 genes with risk of congenital heart disease in offspring: A case-control study.

To assess associations and interactions of maternal smoking and cytochrome P450 (CYP450) genetic variants with the developments of congenital heart disease (CHD) and specific subtypes.A case–control study of 654 cases and 666 controls was conducted from November 2017 to March 2020. The exposures of interest were maternal active and passive smoking before/in the early pregnancy and CYP450 genetic polymorphisms. Data were analyzed using the Chi-square test and logistic regression analysis.After adjusting for the potential confounding factors, our study showed maternal active (ORadj = 2.34, 95%CI: 1.19–4.60) or passive (ORadj = 1.76, 95%CI: 1.34–2.31) smoking before pregnancy, passive smoking in the early pregnancy (ORadj = 3.05, 95%CI: 2.26–4.12), as well as polymorphisms of CYP450 at rs1065852 (G/A vs G/G: ORadj = 1.46, 95%CI: 1.07–1.99; A/A vs G/G: ORadj = 1.63, 95%CI: 1.15–2.33) and rs16947 (A/A vs G/G: ORadj = 3.61, 95%CI: 2.09–6.23), were significantly associated with risk of total CHD in offspring. Similar results were also found for some subtypes of CHD. Additionally, significant interactions between maternal smoking and CYP450 genes on the risk of CHD were observed.Maternal smoking and CYP450 genetic variants were associated with increased risk of CHD and specific subtypes in offspring. And the effects of CYP450 genes on CHD may be modified by maternal smoking.

"Second line medications" for supraventricular arrhythmias in children: In-hospital efficacy and adverse events during treatment initiation of sotalol and flecainide.

Sotalol and flecainide are used as second line agents in children for the treatment of supraventricular arrhythmias (SA) refractory to anti-beta adrenergic antiarrhythmics or digoxin. Efficacy and adverse events in this cohort have not been well described. Here, we report our institutional experience of second line treatment initiation for SA in children. Utilizing an institutional database, 247 patients initiated on sotalol and 81 patients initiated on flecainide were identified. Congenital heart disease (CHD) was present in 40% of patients. Arrhythmia-free discharge on single or dual agent therapy (in combination with other antiarrhythmics) was 87% for sotalol and 91% for flecainide. Neither age, sex, dosing, presence of CHD nor arrhythmia subtype were associated with alterations in in-hospital efficacy. Compared to baseline, QTc intervals in sotalol patients (436 [416-452 ms] vs. 415 [400-431 ms], p < .01) and QRS intervals in flecainide patients (75 [68-88 ms] vs. 62 [56-71 ms], p < .01) were prolonged. Dose reduction or discontinuation due to QRS prolongation occurred in 9% of patients on flecainide. QTc prolongation resulting in dose reduction/discontinuation of sotalol was encountered in 9 patients (4%) and death with documented torsade de pointes in 2 patients (1%), with 9 of 11 patients having underlying CHD. In children requiring second line agents for treatment of SA, both sotalol and flecainide appear to be highly efficacious. Although predominantly safe in otherwise healthy patients, electrocardiogram changes can occur and children with underlying cardiac disease may have an increased risk of adverse events and rhythm-related side effects during initiation.

Causes of Death in Infants and Children with Congenital Heart Disease

With improved surgical outcomes, infants and children with congenital heart disease (CHD) may die from other causes of death (COD) other than CHD. We sought to describe the COD in youth with CHD in North Carolina (NC). Patients from birth to 20years of age with a healthcare encounter between 2008 and 2013 in NC were identified by ICD-9 code. Patients who could be linked to a NC death certificate between 2008 and 2016 were included. Patients were divided by CHD subtypes (severe, shunt, valve, other). COD was compared between groups. Records of 35,542 patients < 20years old were evaluated. There were 15,277 infants with an annual mortality rate of 3.5 deaths per 100 live births. The most frequent COD in infants (age < 1year) were CHD (31.7%), lung disease (16.1%), and infection (11.4%). In 20,265 children (age 1 to < 20years), there was annual mortality rate of 9.7 deaths per 1000 at risk. The most frequent COD in children were CHD (34.2%), neurologic disease (10.2%), and infection (9.5%). In the severe subtype, CHD was the most common COD. In infants with shunt-type CHD disease, lung disease (19.5%) was the most common COD. The mortality rate in infants was three times higher when compared to children. CHD is the most common underlying COD, but in those with shunt-type lesions, extra-cardiac COD is more common. A multidisciplinary approach in CHD patients, where development of best practice models regarding comorbid conditions such as lung disease and neurologic disease could improve outcomes in this patient population.

A Non-coding HES1 Variant Predisposes Children to Congenital Heart Disease in Chinese Population.

Background: As a key component in the NOTCH signaling pathway, HES1 plays an important role in vertebrate heart development. Variants in the HES1 coding sequence are known to be associated with congenital heart disease (CHD). However, little is known about HES1 non-coding sequence variants and their association with the risk of developing CHD.Method and Results: We initially analyzed the non-coding sequence of the HES1 gene in 12 unrelated CHD families by direct sequencing and identified a previously unreported promoter region variant (NM_005524.4: c.−1279−1278 insAC, rs148941464) in the HES1 gene in four CHD families. The homozygous variant in patients was inherited from carrier parents with normal phenotypes, indicating a likely recessive genetic model. Given that the HES1 gene is predicted to be likely to exhibit haploinsufficiency (%HI: 11.44), we hypothesized that the HES1 homozygous variant is a genetic risk factor underlying CHD. We then carried out sequencing of this HES1 variant in 629 sporadic non-syndromic CHD cases and 696 healthy controls and performed association analysis. Interestingly, we observed a significant association of the homozygous HES1 promoter variant with CHD (18.92% of cases vs. 9.91% of controls; OR: 2.291, 95% CI: 1.637-3.207, p = 9.72 × 10−7). No significant association with CHD was observed for the HES1 promoter heterozygous variant (p > 0.05). However, association analysis tests of the HES1 homozygous variant with each subtype of CHD revealed that this homozygous variant was strongly associated with transposition of the great arteries (TGA) (OR: 3.726, 95% CI: 1.745-7.956, p = 0.0003). Moreover, the prevalence of HES1 homozygous variants in CHD patients with TGA (27.66%) was significantly higher than that in patients with other CHD subtypes or controls. Similar results were observed in a replication group of TGA (n = 64). Functional studies demonstrated that the homozygous variant in the HES1 promoter can disrupt its ability to bind RXRA, an inhibitory transcription factor, which results in abnormally high expression of the HES1 gene, indicating that this variant harbors gain-of-function effects.Conclusions: Our findings reveal that the non-coding homozygous variant in the HES1 promoter has a gain-of-function effect and is associated with an increased risk of CHD development, especially the severe TGA subtype.

Unraveling the genomic basis of congenital heart disease.

The genetic, epigenetic, and environmental etiologic basis of congenital heart disease (CHD) for most heart anomalies remains unexplained. In this issue of the JCI, Lahm et al. performed the largest genome-wide association study (GWAS) to date of European individuals with CHD and clinical subtypes. The comprehensive meta-analysis included over 4000 patients and 8000 controls and uncovered common genetic variants that associated with cardiac anomalies. Lahm and colleagues performed single-cell analysis of induced pluripotent stem cells and heart cells, revealing a role for MACROD2, GOSR2, WNT3, and MSX1 in the developing heart. This study advances our understanding of the genetic basis of common forms of CHD.

Congenital heart defects in patients with isolated microtia: evaluation using colour Doppler echocardiographic image.

The objective of this study was to delineate the characteristics and incidence of congenital heart disease (CHD) in patients with isolated microtia and to determine whether the prevalence of CHD among patients with isolated microtia increases with the severity of microtia. A total of 804 consecutive patients had a pre-operative colour Doppler echocardiographic examination. A retrospective study was performed with the clinical and imaging data from November, 2017 to January, 2019. The χ2 test was performed to analyse the interaction between isolated microtia and CHD. With the colour Doppler echocardiographic examination's data from 804 consecutive isolated microtia patients, we found CHD, including atrial septal defect, ventricular septal defect, tetralogy of Fallot, patent ductus arteriosus, and others, occurred in 52 of 804 patients (6.5%). Atrial septal defect prevalence in patients with isolated microtia was significantly higher than ventricular septal defect (24/804 versus 11/804, p < 0.05) and patent ductus arteriosus (24/804 versus 2/804, p < 0.001). Ventricular septal defect prevalence in patients with isolated microtia was significantly higher than patent ductus arteriosus (11/804 versus 2/804, p < 0.05). All four types of microtia (concha-type microtia, small concha-type microtia, lobule-type microtia, and anotia) had similar incidences of CHD with no difference in the incidences among these types (p > 0.05 respectively). Furthermore, there was no significant difference in the incidence of the atrial septal defect among the four subtypes (p > 0.05 respectively). Similarly, ventricular septal defect and patent ductus arteriosus also showed no differences (p > 0.05 respectively). The overall incidences of CHD and three most common CHD subtypes (atrial septal defect, ventricular septal defect, and patent ductus arteriosus) in patients with isolated microtia are higher than general population. The prevalence of CHD among patients with isolated microtia does not increase with the severity of microtia. According to our experience in this study, we suggest colour Doppler echocardiographic imaging should be performed for isolated microtia patients soon after birth if possible. Furthermore, for the plastic surgeon and anaesthesiologist, it is important to take pre-operative colour Doppler echocardiographic images which can help evaluate heart function to ensure the safety of the peri-operative period. Future studies when investigating CHDs associated with isolated microtia could focus on genetic and molecular mechanisms.

Congenital heart diseases and parental occupational exposure in a Hungarian case-control study in 1997 to 2002.

The etiology of congenital heart diseases is not fully understood yet, however, endocrine disrupting chemicals may have a causative role in their development. The purpose of our study was to examine the association between congenital heart diseases and periconceptional parental occupational exposure to endocrine disrupting chemicals. In our Hungarian population-based case-control study, we examined 2263 live born cases with any congenital heart disease and 6789 matched controls selected between years 1997 to 2002. Occupational exposure was assessed with a job-exposure matrix developed for endocrine disrupting chemicals. Conditional multiple logistic regression analyses were performed to test associations between parental occupational exposure to endocrine disrupting chemicals and congenital heart diseases of the offspring as a whole and by congenital heart disease subtypes. The prevalence of exposure to endocrine disrupting chemicals was 4.5% for both case and control mothers and 19.1% and 19.4% for case and control fathers, respectively. We found a positive association between paternal pesticide (adjusted odds ratio = 1.66, 95% confidence interval: 1.03-2.69) and alkylphenolic compound exposure (adjusted odds ratio = 1.95, 95% confidence interval: 1.30-2.93) and the development of patent ductus arteriosus in the offspring. Alkylphenolic compound exposure occurred among painters, famers, and those working in the food service industry, while pesticide exposure occurred predominantly among farm workers. We identified that certain occupations may increase the occurrence of certain congenital heart disease phenotypes in the offspring. By paying closer attention to those working in these areas, antenatal detection rates of congenital heart diseases may be improved.

Abnormalities of placental development and function are associated with the different fetal growth patterns of hypoplastic left heart syndrome and transposition of the great arteries

BackgroundBirthweight is a critical predictor of congenital heart disease (CHD) surgical outcomes. Hypoplastic left heart syndrome (HLHS) is cyanotic CHD with known fetal growth restriction and placental abnormalities. Transposition of the great arteries (TGA) is cyanotic CHD with normal fetal growth. Comparison of the placenta in these diagnoses may provide insights on the fetal growth abnormality of CHD. MethodsClinical data and placental histology from placentas associated with Transposition of the Great Arteries (TGA) were analyzed for gross pathology, morphology, maturity and vascularity and compared to both control and previously analyzed HLHS placentas [1]. RNA was isolated from HLHS, TGA and control placentas and sequenced by Illumina HiSeq.Transcriptome analysis was performed using AltAnalyze. Immunohistochemistry was utilized to assess placental nutrient transporter expression in all three groups. ResultsPlacental weight was reduced in TGA cases, and demonstrated reduced villous vasculature, immature terminal villi in the parenchyma compared to controls and reflected our previous data from HLHS placentas. However, birth weight was not reduced in TGA cases compared to controls in contrast to the HLHS cohort and birthweight:placental weight ratio was significantly increased in TGA cases but not HLHS compared to control. Transcriptomic and histologic analysis demonstrates reduced cell activity and nutrient transport capability in HLHS but not TGA placentas which appear to increase/maintain these mechanisms. ConclusionsDespite common vascular disturbances in placentas from HLHAs and TGA, these do not account for the disparities in birthweights frequently seen between these CHD subtypes, in contrast our transcriptomic and histologic analyses reveal differentially regulated mechanisms between the subtypes that may explain these disparities.

Epidemiology, prenatal diagnosis, and neonatal outcomes of congenital heart defects in eastern China: a hospital-based multicenter study

BackgroundCongenital heart defect is the leading malformation in China. There may have been changes in congenital heart defect incidence because of birth policy shift in China over past years. This study aimed to investigate the epidemiology, prenatal diagnosis, and outcomes of congenital heart disease to improve medical and policy decisions.MethodsData on cases of congenital heart disease identified during 2014–2018 were taken from the Zhejiang provincial birth defects surveillance system. Chi-square test, odds ratio (OR) and 95% confidence interval (CI) were used to explore epidemiology, prenatal diagnosis, and birth outcomes of congenital heart disease.ResultsThe average incidence of congenital heart disease was 16.0 per 1000 births, which increased by 62.2% during 2014–2018(χ2trend = 181.41, P < 0.001). However, the average critical congenital heart incidence was 1.6 per 1000 births, which remained stable over time. Women aged ≤20 years (OR2.1, 95% CI 1.9–2.3) or ≥ 35 years (OR 1.2, 95% CI 1.2–1.3) were at higher risk of having babies with congenital heart disease than women aged 21–34 years. Women who gave birth in urban areas (OR 1.2, 95% CI 1.2–1.3), had a son (OR 1.3, 95% CI 1.3–1.4), or had multiple births (OR 4.0, 95% CI 3.7–4.4) were also at higher risk than those giving birth in rural areas, to girls, or single births, respectively. The three major subtypes of congenital heart disease were atrial septal defect (67.9%), patent ductus arteriosus (34.7%), and ventricular septal defect (6.4%). The prenatal detection rate of critical congenital heart disease was 90.0%, which was far higher than total congenital heart disease, at 22.2% (χ2 = 1687.67, P < 0.001). There were 1457 (17.1%) stillbirths, 106 (1.2%) early neonatal deaths, and 6983 (81.7%) live births associated with congenital heart disease.ConclusionsThe high incidence of congenital heart disease in Zhejiang might be attributable to the large proportion of mild congenital heart disease. The incidence of critical congenital heart disease, the prenatal detection rate, and perinatal deaths from congenital heart disease are comparable to those in other studies.

Physical Functioning, Mental Health, and Quality of Life in Different Congenital Heart Defects: Comparative Analysis in 3538 Patients From 15 Countries

BackgroundWe compared physical functioning, mental health, and quality of life (QoL) of patients with different subtypes of congenital heart disease (CHD) in a large international sample and investigated the role of functional class in explaining the variance in outcomes across heart defects. MethodsIn the cross-sectional Assessment of Patterns of Patient-Reported Outcome in Adults with Congenital Heart Disease-International Study (APPROACH-IS), we enrolled 4028 adult patients with CHD from 15 countries. Diagnostic groups with at least 50 patients were included in these analyses, yielding a sample of 3538 patients (median age: 32 years; 52% women). Physical functioning, mental health, and QoL were measured with the SF-12 health status survey, Hospital Anxiety and Depression Scale (HADS), linear analog scale (LAS) and Satisfaction with Life Scale, respectively. Functional class was assessed using the patient-reported New York Heart Association (NYHA) class. Multivariable general linear mixed models were applied to assess the relationship between the type of CHD and patient-reported outcomes, adjusted for patient characteristics, and with country as random effect. ResultsPatients with coarctation of the aorta and those with isolated aortic valve disease reported the best physical functioning, mental health, and QoL. Patients with cyanotic heart disease or Eisenmenger syndrome had worst outcomes. The differences were statistically significant, above and beyond other patient characteristics. However, the explained variances were small (0.6% to 4.1%) and decreased further when functional status was added to the models (0.4% to 0.9%). ConclusionsSome types of CHD predict worse patient-reported outcomes. However, it appears that it is the functional status associated with the heart defect rather than the heart defect itself that shapes the outcomes.

Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies.

BackgroundGlobally, access to healthcare and diagnostic technologies are known to substantially impact the reported birth prevalence of congenital heart disease (CHD). Previous studies have shown marked heterogeneity between different regions, with a suggestion that CHD prevalence is rising globally, but the degree to which this reflects differences due to environmental or genetic risk factors, as opposed to improved detection, is uncertain. We performed an updated systematic review to address these issues.MethodsStudies reporting the birth prevalence of CHD between the years 1970–2017 were identified from searches of PubMed, EMBASE, Web of Science and Google Scholar. Data on the prevalence of total CHD and 27 anatomical subtypes of CHD were collected. Data were combined using random-effect models. Subgroup and meta-regression analyses were conducted, focused on geographical regions and levels of national income.ResultsTwo hundred and sixty studies met the inclusion criteria, encompassing 130 758 851 live births. The birth prevalence of CHD from 1970–2017 progressively increased to a maximum in the period 2010–17 of 9.410/1000 [95% CI (confidence interval) 8.602–10.253]. This represented a significant increase over the fifteen prior years (P = 0.031). The change in prevalence of mild CHD lesions (ventricular septal defect, atrial septal defect and patent ductus arteriosus) together explained 93.4% of the increased overall prevalence, consistent with a major role of improved postnatal detection of less severe lesions. In contrast the prevalence of lesions grouped together as left ventricular outflow tract obstruction (which includes hypoplastic left heart syndrome) decreased from 0.689/1000 (95% CI 0.607–0.776) in 1995–99, to 0.475/1000 (95% CI 0.392–0.565; P = 0.004) in 2010–17, which would be consistent with improved prenatal detection and consequent termination of pregnancy when these very severe lesions are discovered. There was marked heterogeneity among geographical regions, with Africa reporting the lowest prevalence [2.315/1000 (95% CI 0.429–5.696)] and Asia the highest [9.342/1000 (95% CI 8.072–10.704)].ConclusionsThe reported prevalence of CHD globally continues to increase, with evidence of severe unmet diagnostic need in Africa. The recent prevalence of CHD in Asia for the first time appears higher than in Europe and America, where disease ascertainment is likely to be near-complete, suggesting higher genetic or environmental susceptibility to CHD among Asian people.