Risk Factors For Congenital Heart Disease Research Articles

Environmental Risk Factors for Congenital Heart Disease.

Congenital heart disease (CHD) has many forms and a wide range of causes. Clinically, it is important to understand the causes. This allows estimation of recurrence rate, guides treatment options, and may also be used to formulate public health advice to reduce the population prevalence of CHD. The recent advent of sophisticated genetic and genomic methods has led to the identification of more than 100 genes associated with CHD. However, despite these great strides, to date only one-third of CHD cases have been shown to have a simple genetic cause. This is because CHD can also be caused by oligogenic factors, environmental factors, and/or gene-environment interaction. Although solid evidence for environmental causes of CHD have been available for almost 80 years, it is only very recently that the molecular mechanisms for these risk factors have begun to be investigated. In this review, we describe the most important environmental CHD risk factors, and what is known about how they cause CHD.

Exploring associations of maternal sleep during periconceptional period with congenital heart disease in offspring.

BackgroundIn general, the existing evidence points to a role for maternal sleep in pregnancy complications and fetal growth, however, little has been focused on birth defects. We aimed to explore the association between periconceptional poor sleep and the risk of congenital heart disease (CHD), and to examine if daytime napping could to some extent change the association.MethodsA case–control study was conducted in Shanghai Children's Medical Center, in which, a total of 524 cases (262 simple CHD vs. 262 severe CHD), along with 262 controls.ResultsIn the multivariable logistic analysis, poor sleep could increase the risk of both simple CHD (OR = 2.486, 95% CI = 1.619–3.818) and severe CHD (OR = 1.950, 95% CI = 1.269–2.997), while routine daytime nap could decrease risk of simple CHD (OR = 0.634, 95% CI = 0.435–0.923). In the stratified analysis, the concurrence with routine daytime nap could weaken the risk of simple CHD caused by poor sleep (OR = 3.183, 95% CI: 1.830–5.537 decreased to OR = 2.236, 95% CI: 1.200–4.165). The examinations were repeated in ventricular septal defect and tetralogy of Fallot, and the established associations can be verified. Moreover, all these findings were also similarly observed in both propensity‐score‐adjusted and propensity‐score‐matched analyses.ConclusionsPoor maternal sleep around periconceptional period seems to be an independent risk factor for CHD. The concurrence with daytime nap could to some extent reduce the risk in simple CHD. The results individually and collectively put forward the importance of maternal sleep in embryonic heart development.

Maternal hyperglycemia and fetal cardiac development: Clinical impact and underlying mechanisms.

Congenital heart disease (CHD) is the most common type of birth defect and is both a significant pediatric and adult health problem, in light of a growing population of survivors. The etiology of CHD has been considered to be multifactorial with genetic and environmental factors playing important roles. The combination of advances in cardiac developmental biology, which have resulted in the elucidation of molecular pathways regulating normal cardiac morphogenesis, and genome sequencing technology have allowed the discovery of numerous genetic contributors of CHD ranging from chromosomal abnormalities to single gene variants. Conversely, mechanistic details of the contribution of environmental factors to CHD remain unknown. Maternal diabetes mellitus (matDM) is a well-established and increasingly prevalent environmental risk factor for CHD, but the underlying etiologic mechanisms by which pregestational matDM increases the vulnerability of embryos to cardiac malformations remains largely elusive. Here, we will briefly discuss the multifactorial etiology of CHD with a focus on the epidemiologic link between matDM and CHD. We will describe the animal models used to study the underlying mechanisms between matDM and CHD and review the numerous cellular and molecular pathways affected by maternal hyperglycemia in the developing heart. Last, we discuss how this increased understanding may open the door for the development of novel prevention strategies to reduce the incidence of CHD in this high-risk population.

Targeted Next-Generation Sequencing of 406 Genes Identified Genetic Defects Underlying Congenital Heart Disease in Down Syndrome Patients.

Down syndrome (DS) is the most common autosomal chromosome anomaly. DS is frequently associated with congenital heart disease (CHD). Patients with DS have 40-60% chance of having CHD. It means that CHD in DS is not only due to trisomy 21 and there are some other genetic factors underlying CHD in DS children. In this study, a total of 240 DNA samples from patients were analyzed including 100 patients with CHD only, 110 patients having CHD along with DS and 30 patients with isolated DS. A cardiovascular gene panel consisting of probes for 406 genes was used to screen DNA samples of all 240 patients for mutation identification. All variants were annotated and common variants were obtained. Briefly, 28 common variants (variants common in two or more than two individuals) were obtained in a group of samples containing DNA from DS patients having CHD as well, 63 variants were found to be unique to DS group of samples and 73 variants have been identified in patients with CHD only. In order to identify genomic variations determining the risk for CHD in DS, only those variants present in DS-CHD group and absent in isolated CHD and/or isolated DS group were considered for further analysis. Variants specific to DS-CHD group were further evaluated based on expression and function data and pathogenicity of the variant of interest. We have implicated mutations in GATA3, KCNH2, ENG, FLNA, and GUSB genes as an underlying risk factor for CHD in DS patients.

Consanguinity and congenital heart disease in offspring

Background Congenital heart disease (CHD) is a common congenital abnormality in children. Consanguineous marriage has been identified as a risk factor of CHD. There was an autosomal recessive pattern of inheritance seen in children with some forms of congenital heart disease.Objective To assess the possible association between consanguineous marriage and congenital heart disease incidence in the offspring.Methods A case-control study was conducted from March to May 2016 on pediatric patients at H. Adam Malik General Hospital, Medan. Subjects were allocated into two groups, 100 children with CHD in the case group, and the rest in the control group. Data were analyzed using Chi-square and logistic regression tests. In the present study, P value less than 0.05 was considered statistically significant.Results In the case group, 14 patients (14%) were born of consanguineous marriages. In the control group, only 5 patients (5%) were born of consanguineous marriages. There was a significant association between consanguineous marriage and CHD (OR 1.551; 95%CI 1.138 to 2.113). Based on the result of multivariate analysis, consanguineous marriage was a risk factor for CHD in offspring (Wald=4.525; P=0.033).Conclusion Consanguineous marriage is a risk factor for CHD in offspring.

Spatial pattern and variations in the prevalence of congenital heart disease in children aged 4–18 years in the Qinghai-Tibetan Plateau

PurposeThis study aimed to investigate the spatial distribution pattern of the prevalence of congenital heart disease (CHD) in children in Qinghai-Tibetan Plateau (QTP), a high-altitude region in China. MethodsEpidemiological data from a survey on the prevalence of CHD in Qinghai Province including 288,066 children (4–18 years) were used in this study. The prevalence and distribution pattern of CHD was determined by sex, CHD subtype, and nationality and altitude. Spatial pattern analysis using Getis-Ord Gi⁎ was used to identify the spatial distribution of CHD. Bayesian spatial binomial regression was performed to examine the relationship between the prevalence of CHD and environmental risk factors in the QTP. ResultsThe prevalence of CHD showed a significant spatial clustering pattern. The Tibetan autonomous prefecture of Yushu (average altitude > 4000 m) and the Mongolian autonomous county of Henan (average altitude > 3600 m) in Huangnan had the highest prevalence of CHD. Univariate analysis showed that with ascending altitude, the total prevalence of CHD, that in girls and boys with CHD, and that of the subtypes PDA and ASD increasing accordingly. Thus, environmental factors greatly contributed to the prevalence of CHD. ConclusionsThe prevalence of CHD shows significant spatial clustering pattern in the QTP. The CHD subtype prevalence clustering pattern has statistical regularity which would provide convenient clues of environmental risk factors. Our results may provide support to make strategies of CHD prevention, to reduce the incidence of CHD in high altitude regions of China.

Association Between the Polymorphism of Methylenetetrahydrofolate Reductase Gene C677T and Risks of Congenital Heart Disease: Meta-analysis of Case-control Study

This paper discussed the association between the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene C677T and congenital heart disease (CHD). Methods: We developed literature with inclusion and exclusion criteria, and searching strategy in the meta-analysis. Studies related to the association between MTHFR C677T polymorphism of parents or progeny and CHD were identified by a search through PubMed, CNKI, CBN, and Springer Link databases, and their qualities were evaluated. Heterogeneity of these results was tested through Review Manager version 5.3.3. Appropriate effect models based on the heterogeneity were selected to complete the meta-analysis. Results: A total of 27 eligible studies (2800 cases from 3720 controls in progeny, and 2238 cases from 17175 controls in maternity) were evaluated. Statistical association was found between MTHFR gene (677 points TT/CC gene variant in maternity) and CHD risk in progeny (Odds ratio (OR) = 1.41 (1.16, 1.70), 95% confidence interval (CI) = p 0.05, respectively. In addition, MTHFR gene (677 points TT/CC) in progeny was related to CHD risk, as well as CT/CC (OR = 1.57 (1.22, 2.02), and 1.20 (1.03, 1.39), respectively, 95% CI = p < 0.05). Results show that MTHFR C677T polymorphism is associated with CHD risk. Conclusions: Furthermore, mutations of homozygous and heterozygous (TT/CC and CT/CC, respectively) MTHFR C677T in progeny, and those of homozygous MTHFR C677T (TT/CC) in maternity are risk factors of CHD.

Folate, vitamin B12, homocysteine and polymorphisms in folate metabolizing genes in children with congenital heart disease and their mothers.

The objective of the study was to assess the role of variations in serum folate, vitamin B12, homocysteine and the presence of genetic polymorphisms as risk factors for congenital heart disease (CHD) in children. A total of 32 children with CHD, and their mothers and 32 normal children and their mothers formed the study and control groups, respectively. Serum folate, vitamin B12 and homocysteine as well as genetic polymorphisms MTHFR C677→︀T, MTHFR A1298→︀C, MTR A2756→︀G and MTRR A66→︀G were assessed. Low serum folate and genetic polymorphisms MTHFR C677→︀T and MTRR A66→︀G among children and their mothers and high homocysteine among mothers were noted as risk factors for CHD (P<0.05). Vitamin B12 levels were normal and showed no association. Presence of MTHFR C677→︀T and MTRR A66→︀G, both concurrently among children as well as mothers and simultaneously among mother-child pairs, showed several fold increase in the risk for CHD. On multivariate analysis, the risk factors noted for CHD were presence of MTHFR C677→︀T among children and their mothers and MTRR A66→︀G among mothers. Analyses for nutrient-gene interaction revealed significant associations between low serum folate and high serum homocysteine levels, and the presence of selected genetic polymorphisms. Low serum folate, high homocysteine and presence of selected genetic polymorphisms among children and their mothers were noted as risk factors for CHD. Nutrient-gene interaction being a modifiable risk factor, the study recommends the use of peri-conceptional folate supplementation with vitamin B12 sufficiency for primary prevention of CHD.

Risk factors for congenital heart disease in Chinese neonates: a Meta analysis

To investigate the major risk factors for congenital heart disease (CHD) in Chinese neonates and to provide a reference for the prevention of CHD. A literature search was performed to collect the case-control studies on the risk factors for CHD in Chinese neonates published in 2001-2016. The relevant data were extracted accordingly. The quality of included studies was assessed by Newcastle-Ottawa Scale. Sensitivity analysis was conducted using different models to analyze the same data. The publication bias was assessed by Egger's test. A total of 17 case-control studies involving 2 930 cases and 4 952 controls were included. The Meta analysis showed that the major risk factors for CHD in Chinese neonates were as follows: mother with advanced age (OR=2.649, 95%CI: 1.675-4.189), cold or fever (OR=4.558, 95%CI: 2.901-7.162), medication use in early pregnancy (OR=3.961, 95%CI: 2.816-5.573), passive smoking (OR=2.766, 95%CI: 1.982-3.859), abnormal childbearing history (OR=2.992, 95%CI: 1.529-5.856), noise exposure (OR=3.030, 95%CI: 1.476-6.217), radiation exposure (OR=2.363, 95%CI: 1.212-4.607), decoration (OR=4.979, 95%CI: 3.240-7.653), gestational diabetes (OR=5.090, 95%CI: 3.132-8.274), and pet raising (OR=2.048, 95%CI: 1.385-3.029). Mothers with advanced age, cold or fever, medication use in early pregnancy, passive smoking, abnormal childbearing history, noise exposure, radiation exposure, decoration, gestational diabetes, and pet raising may increase the risk of CHD in Chinese neonates.

A Genetic Variant in FIGN Gene Reduces the Risk of Congenital Heart Disease in Han Chinese Populations.

Congenital heart disease (CHD) is one of the most common birth anomalies worldwide. Folate deficiency is an independent risk factor for CHD. Genome-wide association studies (GWAS) revealed that human folate level could be significantly influenced by fidgetin (FIGN), methylenetetrahydrofolate reductase (MTHFR), prickle homolog 2 (PRICKLE2), synaptotagmin 9 (SYT9), gamma-aminobutyric acid B receptor 2 (GABBR2), and alkaline phosphatase (ALPL) genes. The association between the above-mentioned six variants and CHD was examined in the two independent case-control studies in a total of 868 CHD patients and 931 healthy controls. Our results showed that the G>C (rs2119289) variant in intron 4 of FIGN led to a significant reduction of CHD susceptibility in both the separate and combined case-control studies (allele distribution P<0.001, genotype distribution P<0.001). Specifically, by analyzing the combined samples, we observed that the risks of CHD in individuals carrying the heterozygous G/C and homozygous C/C genotypes were reduced by 45% (adjusted OR 0.55, 95% CI 0.47-0.67) and 66% (adjusted OR 0.34, 95% CI 0.23-0.50), respectively, in comparison with individuals carrying the wild-type G/G genotype. Our findings have demonstrated that the C allele of variant rs2119289 of FIGN gene is an important genetic marker for decreased CHD risk. Considering that the rs2119289 of FIGN gene is related to the appropriate folate level, FIGN might play an important role in CHD by upregulating plasma folate concentration during embryo heart development. This work provides a new insight for risk assessment of CHD.

Is Advance Maternal Age an Indication for Fetal Echocardiogram? [18P

INTRODUCTION: Pregnancies in women of advanced maternal age (AMA) are at increased risk for aneuploidy and therefore could be at increased risk for congenital heart disease (CHD). Our objective was to assess whether AMA without another risk factor for CHD is associated with abnormal fetal echocardiogram. METHODS: This is a retrospective cohort study of all patients who were referred for specialized sonogram and fetal echocardiogram January 1, 2015 through December 31, 2015 at a single academic institution. Data was collected on demographics, indications for specialized sonogram and fetal echocardiogram, aneuploidy screening, amniocentesis results and obstetric outcomes. Patients were grouped by age (&lt; 35 or &gt; 35 at delivery) and rate of abnormal fetal echocardiograms were compared by Fisher's exact test. RESULTS: 483 patients underwent specialized sonogram, 189 (39%) were AMA patients. Fetal echocardiogram was performed in 87 (46%) patients in the AMA group versus 134 (45.4%) patients in the non-AMA group. Abnormal fetal echocardiograms were found in 2 (2.2%) of the AMA group compared to 8 (6%) of the non-AMA group (p=0.32). Of the 65 AMA patients who did not have another indication for fetal echocardiogram, 2 (3%) had abnormal results (mild cardiomyopathy, VSD) whereas there were no abnormal echocardiograms in AMA patients with another indication (0/22). One of the two patients had an abnormal quad screen for increased risk for trisomy 21. CONCLUSION: In this cohort, AMA without another indication for fetal echocardiogram had a 3% rate of abnormal fetal echocardiogram. This suggests that a fetal echocardiogram should be considered in patients who are AMA.

CMyBP-C was decreased via KLHL3-mediated proteasomal degradation in congenital heart diseases

Cardiac myosin binding protein C (cMyBP-C) is a cardiac structural and regulatory protein; mutations of cMyBP-C are frequently associated with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Cardiac special transcription factors may regulate the expression of cMyBP-C. However, the role of cMyBP-C in congenital heart diseases (CHD) remains poorly understood. In the current study, western blotting and the MRM approach showed that cMyBP-C expression was significantly reduced in fetuses with CHD compared to those without. Furthermore, we found that cMyBP-C interacted with KLHL3 by immunoprecipitation and immunofluorescence, and the degradation of cMyBP-C was caused by KLHL3-mediated ubiquitination. In addition, homocysteine (Hcy, a risk factor of CHD) treatment caused a decrease in cMyBP-C and an increase in KLHL3 expression, and the proteasome inhibitor MG132 reversed the Hcy-induced reduction of cMyBP-C expression. Finally, we verified that reduced cMyBP-C by Hcy promoted apoptosis in cardiomyocytes. These results demonstrate that Hcy decreases the expression of cMyBP-C through a KLHL3-mediated ubiquitin–proteasome pathway, and thereby influences heart development.

Lower Circulating Folate Induced by a Fidgetin Intronic Variant Is Associated With Reduced Congenital Heart Disease Susceptibility.

Folate deficiency is an independent risk factor for congenital heart disease (CHD); however, the maternal plasma folate level is paradoxically not a good diagnostic marker. Genome-wide surveys have identified variants of nonfolate metabolic genes associated with the plasma folate level, suggesting that these genetic polymorphisms are potential risk factors for CHD. To examine the effects of folate concentration-related variations on CHD risk in the Han Chinese population, we performed 3 independent case-control studies including a total of 1489 patients with CHD and 1745 control subjects. The expression of the Fidgetin (FIGN) was detected in human cardiovascular and decidua tissue specimens with quantitative real-time polymerase chain reaction and Western blotting. The molecular mechanisms were investigated by luciferase reporter assays, surface plasmon resonance, and chromatin immunoprecipitation. FIGN-interacting proteins were confirmed by tandem affinity purification and coimmunoprecipitation. Proteasome activity and metabolite concentrations in the folate pathway were quantified with a commercial proteasome activity assay and immunoassays, respectively. The +94762G>C (rs2119289) variant in intron 4 of the FIGN gene was associated with significant reduction in CHD susceptibility (P=5.1×10-14 for the allele, P=8.5×10--13 for the genotype). Analysis of combined samples indicated that CHD risks in individuals carrying heterozygous (GC) or homozygous (CC) genotypes were reduced by 44% (odds ratio [OR]=0.56; 95% confidence interval [CI]=0.47-0.67) and 66% (OR=0.34; 95% CI=0.23-0.50), respectively, compared with those with the major GG genotype. Minor C allele carriers who had decreased plasma folate levels exhibited significantly increased FIGN expression because the transcription suppressor CREB1 did not bind the alternative promoter of FIGN isoform X3. Mechanistically, increased FIGN expression led to the accumulation of both reduced folate carrier 1 and dihydrofolate reductase via inhibition of their proteasomal degradation, which promoted folate absorption and metabolism. We report a previously undocumented finding that decreased circulating folate levels induced by increased folate transmembrane transport and utilization, as determined by the FIGN intronic variant, serves as a protective mechanism against CHD. Our results may explain why circulating folate levels do not have a good diagnostic value.

Ultrasound Examination of the Fetal Heart.

Congenital heart disease (CHD) occurs in 4-13 per 1000 births in the United States. While many risk factors for CHD have been identified, more than 90% of cases occur in low-risk patients. Guidelines for fetal cardiac screening during the second trimester anatomy ultrasound have been developed by the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) in order to improve antenatal detection rates and to standardize the fetal cardiac screening examination. Patients found to be at increased risk of CHD because of risk factors or an abnormal screening examination should be referred for second trimester fetal echocardiography. Recently, 3D and 4D ultrasound techniques are being utilized to enhance detection rates and to better characterize cardiac lesions, and several first trimester ultrasound screening markers have been proposed to identify patients at increased risk of CHD. However, detection rates have not improved significantly due to limitations such as cost, access, and training that are associated with new technologies and screening methods. The most cost effective way to improve detection rates of CHD may be to standardize screening protocols across practices according to established guidelines and to have a low threshold for referral for fetal echocardiography.

Association of genetic polymorphisms of de novo nucleotide biosynthesis with increased CHD susceptibility in the northern Chinese population

Congenital heart disease (CHD) is one of most prevalent birth defects in the world. However, the underlying molecular mechanism(s) have not been fully understood. Here we report that increased CHD susceptibility is associated with genetic polymorphisms for de novo nucleotide biosynthesis in northern Chinese population, which has been reported with lower plasma folate levels. Nine tagSNPs of four genes (GART, ATIC, MTHFD1 and SHMT1) in de novo nucleotide biosynthesis were sequenced in 802 sporadic CHD patients and 1093 controls from two Han Chinese populations, located in north China (Shandong) and South China (Shanghai), respectively. Six SNPs were found to be significantly associated with CHDs or septation defects only in the Shandong population dataset, but none displayed significant association with any CHDs in the Shanghai population dataset as well as in the combined dataset. We also showed that the minor A allele of rs7279549 in GART reduced transcriptional activity and displayed lower affinity for unknown transcription factor(s), demonstrating the allele is a functional risk factor for CHD in Shandong population. Our study indicates that dysregulation of de novo nucleotide biosynthesis pathway may conditionally contribute to CHD pathogenesis in northern Chinese.

MTRR rs326119 polymorphism is associated with plasma concentrations of homocysteine and cobalamin, but not with congenital heart disease or coronary atherosclerosis in Brazilian patients

BackgroundDifferences in the distribution of the MTRR rs326119 polymorphism (c.56+781 A>C) between patients with congenital heart disease (CHD) and controls have been described in Chinese individuals. The association is thought to be due to deregulation of homocysteine-cobalamin pathways. This has not been replicated in other populations. The primary objective of this study was to assess the influence of the MTRR rs326119 polymorphism on biochemical parameters of vitamin B12 metabolism, coronary lesions, and congenital heart disease in Brazilian subjects. MethodsWe selected 722 patients with CHD, 1432 patients who underwent coronary angiography, and 156 blood donors. Genotyping for the MTRR polymorphism was evaluated by high-resolution melting analysis, and biochemical tests of vitamin B12 metabolism were measured. ResultsSubjects carrying the AC or CC genotypes had higher homocysteine concentrations (9.7±0.4μmol/L and 10.1±0.6μmol/L) and lower cobalamin concentrations (260.5±13.3pmol/L and 275.6±19.9pmol/L) compared with the subjects carrying the AA genotype (8.7±0.5μmol/L and 304.8±14.7pmol/L), respectively. A multiple linear regression model also identified a significant association between the number of C variant alleles with the concentrations of homocysteine and cobalamin. Nonetheless, the allelic and genotypic distributions for MTRR rs326119 were not associated with CHD or coronary atherosclerosis in the studied samples. ConclusionOur findings indicate that the MTRR rs326119 variant might be a genetic marker associated with homocysteine and cobalamin concentrations, but not a strong risk factor for CHD or coronary atherosclerosis in the Brazilian population.

Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier.

Down syndrome (DS) is a significant risk factor for congenital heart disease (CHD), increasing the incidence 50 times over the general population. However, half of people with DS have a normal heart and thus trisomy 21 is not sufficient to cause CHD by itself. Ts65Dn mice are trisomic for orthologs of >100 Hsa21 genes, and their heart defect frequency is significantly higher than their euploid littermates. Introduction of a null allele of Creld1 into Ts65Dn increases the penetrance of heart defects significantly. However, this increase was not seen when the Creld1 null allele was introduced into Ts1Cje, a mouse that is trisomic for about two thirds of the Hsa21 orthologs that are triplicated in Ts65Dn. Among the 23 genes present in three copies in Ts65Dn but not Ts1Cje, we identified Jam2 as necessary for the increased penetrance of Creld1-mediated septal defects in Ts65Dn. Thus, overexpression of the trisomic gene, Jam2, is a necessary potentiator of the disomic genetic modifier, Creld1 No direct physical interaction between Jam2 and Creld1 was identified by several methods. Regions of Hsa21 containing genes that are risk factors of CHD have been identified, but Jam2 (and its environs) has not been linked to heart formation previously. The complexity of this interaction may be more representative of the clinical situation in people than consideration of simple single-gene models.

Maternal Midpregnancy Glucose Levels and Risk of Congenital Heart Disease in Offspring.

There is a well-described association between maternal diabetes mellitus and risk of congenital heart disease (CHD) in offspring. Although the clinical diagnoses of type 2 diabetes or gestational diabetes are strong risk factors for CHD, subclinical abnormalities of glucose and insulin metabolism are common within the general population and could also confer risk for CHD. We hypothesize that continuous measures of blood analytes related to maternal diabetes are related to odds of cardiac malformations. To explore the potential association of 2 different CHD phenotypes in offspring with maternal midpregnancy measures of glucose and insulin. Case-control study from a population-based cohort of 277 pregnant women in southern and central California carrying infants with tetralogy of Fallot (TOF) (n = 55), dextrotransposition of the great arteries (dTGA) (n = 42), or healthy infants without CHD (n = 180). Serum samples were collected from 2003 through 2007. The analysis was conducted from March through June 2015. Blood analytes related to maternal glucose metabolism were measured from random nonfasting second-trimester blood samples. We measured serum insulin levels by a validated radioimmunoassay, and we measured glucose levels. Multivariable logistic regression models estimated the association between these levels and case status. Serum glucose values were elevated in the maternal samples for offspring with TOF (median, 97.0 mg/dL [to convert to millimoles per liter, multiply by 0.0555]) relative to controls (median, 91.5 mg/dL) (P = .01, Wilcoxon rank sum test), a phenomenon not observed in the maternal samples for offspring with dTGA (median, 90.0 mg/dL) relative to controls (P = .18, Wilcoxon rank sum test). Serum insulin levels were significantly different between controls (median, 18.8 μIU/mL [to convert to picomoles per liter, multiply by 6.945]) and maternal samples for offspring with dTGA (median, 13.1 μIU/mL; P = .048, Wilcoxon rank sum test) but not with TOF (median, 14.3 μIU/mL; P = .35, Wilcoxon rank sum test). Relative to maternal blood glucose levels of infants without cardiac malformations, we observed that maternal blood glucose levels in models including insulin were strongly associated with odds of TOF (adjusted odds ratio = 7.54; 95% CI, 2.30-24.69) but not with dTGA (adjusted odds ratio = 1.16; 95% CI, 0.28-4.79). These results represent a direct correlation of glucose as a continuous variable to odds of specific cardiac malformations. The association between serum glucose and odds of TOF indicates the need for additional epidemiological and mechanistic investigations into the risk conferred by insulin signaling and glucose metabolism during early pregnancy.

Prenatally diagnosed single umbilical artery: The role and relationship of additional risk factors in the fetus for congenital heart disease.

Single umbilical artery (SUA) has been associated with an increased risk of congenital heart disease (CHD). Women carrying fetuses with an SUA are often referred for fetal echocardiography, but data to support the need for this testing remain controversial. A retrospective review of the records for all women carrying fetuses with an SUA who had undergone fetal echocardiography between 2009 and 2012 at our center was performed. Data on the maternal and fetal risk factors for CHD were collected, and the fetuses were categorized into three groups: low risk (LR; an SUA with no additional risk factors for CHD), moderate risk (MR; an SUA with one additional risk factor for CHD), and high risk (HR; an SUA with two or more additional risk factors for CHD). In total, 101 such patients were identified: 69 LR, 26 MR, and 6 HR. No fetuses in the LR group, three in the MR group, and two in the HR group had CHD (p = 0.0005). An SUA in an LR fetus did not increase the risk of CHD in our cohort, whereas an SUA in the presence of additional risk factors was associated with significantly increased risk for CHD. Our results suggest that referral for a fetal echocardiogram is indicated for women carrying fetuses with an SUA when additional risk factors for CHD are present. In an LR fetus with an SUA, however, echocardiography may not provide additional benefit unless CHD is suggested on screening obstetric sonography.

Association of TBX20 gene polymorphism with congenital heart disease in Han Chinese neonates.

As a transcription factor mainly expressed in cardiovascular system, T-box 20 (TBX20) plays an important role in embryonic cardiovascular system development and adult heart function. Previous studies have identified associations of two SNPs in the T-box DNA-binding domain of TBX20 with congenital heart disease (CHD) in two Caucasian families, but the associations of TBX20 mutations underlying the more common populations with CHD remain to be uncovered. In this study, 25 unrelated Chinese Han neonates with CHD and 25 healthy children as controls were investigated for TBX20 mutations. SNP genotyping was performed by PCR-DNA sequencing. The selected SNPs were well genotyped and SNP rs3999941 was found to be strongly associated with CHD (p=0.007). The minor allele of rs3999941 showed a high-risk factor for CHD (OR 4.24; 95% CI 1.41-12.71). Besides, we found a new SNP site located at the 657th nucleotide of the exon 5 of TBX20 gene which may also be associated with CHD, c.657A>C. The frequency was significantly different between two groups (p=0.011), the minor allele of SNP c.657A>C also showed a risk factor for CHD (OR 2.56; 95% CI 1.02-6.46). These findings suggested that the TC genotype of SNP rs3999941 and AC genotype of the new SNP c.657A>C in the TBX20 gene may be risk factors for CHD and thus screening of these SNPs may have some implications in the prevention and treatment of CHD in Han Chinese children.