Risk Of Congenital Heart Disease Research Articles

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.

Association of maternal anxiety with congenital heart disease in offspring based on case-control study

Objective: To explore the association of maternal anxiety with congenital heart disease (CHD) in offspring. Methods: A case-control study design was used in this study. The data were collected in Shaanxi province from January 2014 to December 2016. Neonatal information is provided through specialized hospitals or institutions. Logistic regression model with adjustment for confounding factors was established to analyze the association between maternal perinatal anxiety and CHD in offspring. Meanwhile, subgroup analysis was carried out to explore its stability. Results: Our study included 2 429 subjects, consisting of 773 cases and 1 656 controls. Women with anxiety during pregnancy accounted for 10.3% in the case group, while 7.8% in the control group. After adjusting for confounding factors, the level of maternal anxiety during pregnancy was positively correlated with CHD in the offspring (OR=1.04, 95%CI: 1.01-1.07). The risk of CHD in the offspring of mothers with anxiety during pregnancy was 1.43 times higher than that in those whose mothers had no anxiety (OR=1.43, 95%CI: 1.00-2.05). Conclusion: Maternal anxiety during pregnancy is probably a risk factor for congenital heart disease in offspring.

Impact of maternal hyperglycemia on cardiac development: Insights from animal models.

Congenital heart disease (CHD) is the leading cause of birth defect-related death in infants and is a global pediatric health concern. While the genetic causes of CHD have become increasingly recognized with advances in genome sequencing technologies, the etiology for the majority of cases of CHD is unknown. The maternal environment during embryogenesis has a profound impact on cardiac development, and numerous environmental factors are associated with an elevated risk of CHD. Maternal diabetes mellitus (matDM) is associated with up to a fivefold increased risk of having an infant with CHD. The rising prevalence of diabetes mellitus has led to a growing interest in the use of experimental diabetic models to elucidate mechanisms underlying this associated risk for CHD. The purpose of this review is to provide a comprehensive summary of rodent models that are being used to investigate alterations in cardiac developmental pathways when exposed to a maternal diabetic setting and to summarize the key findings from these models. The majority of studies in the field have utilized the chemically induced model of matDM, but recent advances have also been made using diet based and genetic models. Each model provides an opportunity to investigate unique aspects of matDM and is invaluable for a comprehensive understanding of the molecular and cellular mechanisms underlying matDM-associated CHD.

Abstract P331: Upregulated TBX1 by genetic variants are associated with human congenital heart disease

Congenital heart disease (CHD) is the most common human birth defect worldwide. The cause of CHD is so far not well understood. Uncovering genetic factors leading to CHD is still a pressing task to be solved. TBX1 is one of the transcription factors early expressed in embryonic cardiac progenitors. In animal models, imbalanced TBX1 activity leads to cardiac defects. Given the dosage effect of TBX1, it is possible that genetic variant altering TBX1 function or expression level would affect heart development and contribute to CHD. In order to study the association of genetic variants of TBX1 and CHD susceptibility, we performed genetic screening in 409 CHD patients and 213 healthy controls. Bioinformatic and in vitro functional studies were performed to evaluate the impact of genetic variants. One single nucleotide polymorphism (SNP), rs41260844, in TBX1 promoter region was identified to be associated with CHD. The minor allele of rs41260844 is associated with higher CHD risk and shows increased TBX1 promoter activity (Fig A). Further study showed the minor allele attenuates TBX1 promoter binding affinity with nuclear protein(s) (Fig B). In addition, a novel case-specific missense rare mutation, p.P164L, in T-box domain was identified and predicted as a deleterious mutation. Functional analysis showed a trend of increased TBX1 function with the rare mutation. In summary, we concluded that a higher TBX1 expression level or activity is associated with CHD susceptibility, which could affect TBX1 downstream targets and thus disrupt the balance of the complex regulation network during cardiogenesis.

High maternal blood lipid levels during early pregnancy are associated with increased risk of congenital heart disease in offspring.

IntroductionThis study aimed to investigate whether maternal blood lipid levels during early pregnancy are associated with the occurrence of congenital heart disease (CHD) in their offspring.Material and methodsIn this single‐center case–control study, mothers of offspring with CHD (n = 230) and without CHD (n = 381) were included. Maternal lipid levels were determined on fasting blood samples taken in the first trimester. Relevant demographic and clinical data were extracted from the medical records. Maternal lipid profile was compared between the two groups, and regression analysis was performed to evaluate the association between lipid profile and CHD risk in offspring.ResultsCompared with the control group, levels of triglyceride, apolipoprotein‐A1, and apolipoprotein‐B in early pregnancy were significantly higher in the CHD group. Multivariate analyses showed that triglyceride (odds ratio [OR] 2.46, 95% CI 1.62–3.73, p < 0.01), total/high‐density lipoprotein cholesterol (OR 2.10, 95% CI 1.07–4.13, p = 0.03), and apolipoprotein‐A1 (OR 2.73, 95% CI 1.16–6.40, p = 0.02) were positively associated with CHD risk in offspring.ConclusionsElevated maternal lipid profile was associated with increased risk of CHD in offspring.

Association of NFKB1, NKX2-5, GATA4 and RANKL Gene Polymorphisms with Sporadic Congenital Heart Disease in Greek Patients.

Congenital heart disease (CHD) is a group of structural defects of the heart and the great vessels, and one of the leading causes of death among infants and young adults. Several gene variants are involved in diverse mechanisms of cardiac and vessel development and could thus be considered candidate mutated genes for a congenital heart defect or a specific variant could predispose a person to CHD. In the present study, variants in four such genes are investigated for the first time in a group of young Greek CHD patients: the NFKB1 gene polymorphism (–94ins/ delATTG), rs28362491, NKX2-5 gene polymorphism rs2277923, GATA4 gene polymorphism rs11785481 and RANKL gene polymorphism rs4531631. A total of 43 CHD patients and 100 healthy adults were included in the study. The polymerase chain reaction-restriction fragment length polymorphism (PRC-RFLP) method was used to genotype the aforementioned polymorphisms of NFKB1, NKX2-5, GATA4 and RANKL. The association analysis identified that there was a protective association between CHD and the A allele of rs2277923 polymorphism (p = 0.004). The D allele of the rs28362491 polymorphism is also a likely risk factor for causing CHD (p = 0.006). The differences of the rs4531631 and rs11785481 variant contribution had no statistical significance between the groups (p >0.05). In conclusion, our results revealed that the rs28362491 and rs2277923 gene polymorphisms, but not the rs4531631 and rs11785481 polymorphisms, may contribute to CHD risk in a cohort of Greek CHD patients.

First-Trimester Maternal Folic Acid Supplementation Modifies the Effects of Risk Factors Exposures on Congenital Heart Disease in Offspring.

This study aimed to examine effect modification of maternal risk factor exposures and congenital heart disease (CHD) by maternal folic acid supplementation (FAS)/non-FAS. We included 8379 CHD cases and 6918 CHD-free controls from 40 clinical centers in Guangdong Province, Southern China, 2004–2016. Controls were randomly chosen from malformation-free fetuses and infants and frequency matched to the echocardiogram-confirmed cases by enrollment hospital and year of birth. We used multiple regression models to evaluate interactions between FAS/non-FAS and risk factors on CHDs and major CHD categories, adjusted for confounding variables. We detected statistically significant additive and multiplicative interactions between maternal FAS/non-FAS and first-trimester fever, viral infection, and threatened abortion on CHDs. An additive interaction on CHDs was also identified between non-FAS and living in a newly renovated home. We observed a statistically significant dose-response relationship between non-FAS and a greater number of maternal risk factors on CHDs. Non-FAS and maternal risk factors interacted additively on multiple critical CHDs, conotruncal defects, and right ventricular outflow tract obstruction. Maternal risk factor exposures may have differential associations with CHD risk in offspring, according to FAS. These findings may inform the design of targeted interventions to prevent CHDs in highly susceptible population groups.

Comparison of Blood Lead Concentrations in Mothers of Children with Congenital Heart Disease and Mothers of Healthy Children.

Congenital heart disease (CHD) is the most prevalent congenital defect that causes several problems for patients and their families and medical specialists. It is important to investigate CHD risk factors due to their significantly destructive load on society. This study aims to determine the association between maternal lead exposure and conceiving a child with CHD. This case-control study was performed on a total of 246 mothers in the pediatric clinic of Vali-e-Asr Hospital in Birjand, Iran. One hundred forty-six mothers with CHD children were defined as the case group, and 100 age-matched mothers with healthy children were considered the control group. All the mothers were between 20 and 40years old, and their children were under the age of 6months. Demographic data was collected from mothers using a well-designed questionnaire. In addition, all mothers were referred to the laboratory for measuring blood lead concentrations. The mean blood lead concentration (BLC) of mothers in the group of children with heart problems was 4.11 ± 10.02 with a median of 2.50μg/dL and in the control group was 2.66 ± 2.06 with a median of 2.30μg/dL. The Mann-Whitney test results showed that mothers' lead concentration in the group of children with heart problems was significantly higher than the control group (z = 2.13, p = 0.03). The chi-square test results showed that lead concentrations in the two groups were significantly different from each other (χ2 = 9.11, p = 0.01). The results of our study showed that mothers of children with CHD had higher blood concentrations than mothers of healthy children.

Risk Factors Associated with Congenital Heart Disease in Patients Presenting to Aljalila Cardiology Clinic between January 2020- May 2020: A Case Control Study

Objective: To investigate the association of maternal diabetes, maternal smoking and syndromes with congenital heart disease (CHD) in patients attending Aljalila cardiology clinic between January 2020 and May of 2020. Methods: A case control study to assess the association of maternal diabetes, maternal smoking and syndromes with CHD. All patients that presented to the clinic between January 2020 and May of 2020 were included. An interviewer administered questionnaire was used to record the presence of maternal diabetes, maternal smoking, and the type of syndrome and type of CHD. Patients with CHD were included in the case group and patients who did not have CHD were in the control group. Age, gender, and nationality were also collected from the hospital records. Fisher exact test and logistic regression was used to analyze the results. Results: A total of 177 cases and 211 controls were recruited. All the risk factors increase the risk of CHD, with maternal diabetes (OR 6.3, 95% CI 2.7-14.6) having the strongest association, then syndromes (OR 5.1, 95% CI 2.3-11.3) and lastly maternal smoking (OR 4.0, 95% CI 1.0-16.3). The most common type of CHD is ventricular septal defect.

Molecular Genetics and Complex Inheritance of Congenital Heart Disease.

Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number variations and aneuploidy account for ~23% of cases overall, and high-throughput genomic technologies have revealed additional types of genetic variation in CHD. The first CHD risk genotypes identified through high-throughput sequencing were de novo mutations, many of which occur in chromatin modifying genes. Murine models of cardiogenesis further support the damaging nature of chromatin modifying CHD mutations. Transmitted mutations have also been identified through sequencing of population scale CHD cohorts, and many transmitted mutations are enriched in cilia genes and Notch or VEGF pathway genes. While we have come a long way in identifying the causes of CHD, more work is required to end the diagnostic odyssey for all CHD families. Complex genetic explanations of CHD are emerging but will require increasingly sophisticated analysis strategies applied to very large CHD cohorts before they can come to fruition in providing molecular diagnoses to genetically unsolved patients. In this review, we discuss the genetic architecture of CHD and biological pathways involved in its pathogenesis.

The Mathematical Limitations of Fetal Echocardiography as a Screening Tool in the Setting of a Normal Second-Trimester Ultrasound

BackgroundThe effectiveness of screening strategies targeting pregnancies at higher risk of congenital heart disease (CHD) is reduced by the low prevalence of severe CHD, the increase in CHD detection rates by second-trimester ultrasound (U/S), and the high proportion of severe CHD in low-risk pregnancies. We aimed to determine situations in which additional screening by fetal echocardiography (FE) would result in a significant increase in sensitivity and a sizable decrease in the false-negative rate of detection of severe CHD. MethodsWe simulated the change in the numbers of detected severe CHD cases when FE is offered to women with a normal second-trimester U/S who have a higher risk of bearing a child with CHD, compared to U/S alone. The primary outcome was the increase in sensitivity. Secondary outcomes were the number needed to screen and the reduction in the rate of missed cases. ResultsFor an U/S sensitivity of 60%, the addition of FE in pregnancies at high risk of CHD (risk ratio 3.5; range: 2 to 5) increased sensitivity by 2.4 percentage points (1.1 to 7.9). The number needed to screen to detect one additional case of severe CHD was 436 (156 to 952). The rate of additional severe CHD cases detected by FE was 4 per 100,000 pregnancies (2 to 32). ConclusionsThe addition of FE to U/S for severe CHD prenatal screening in pregnancies at high risk of CHD yielded marginal benefits in terms of increased sensitivity and decreased rates of false negatives, at the expense of significant resource utilization.

Association analysis of maternal MTHFR gene polymorphisms and the occurrence of congenital heart disease in offspring

BackgroundAlthough many studies showed that the risk of congenital heart disease (CHD) was closely related to genetic factors, the exact pathogenesis is still unknown. Our study aimed to comprehensively assess the association of single nucleotide polymorphisms (SNPs) of maternal MTHFR gene with risk of CHD and its three subtypes in offspring.MethodsA case–control study involving 569 mothers of CHD cases and 652 health controls was conducted. Thirteen SNPs were detected and analyzed.ResultsOur study showed that genetic polymorphisms of maternal MTHFR gene at rs4846052 and rs1801131 were significantly associated with risk of CHD in the homozygote comparisons (TT vs. CC at rs4846052: OR = 7.62 [95%CI 2.95–19.65]; GG vs. TT at rs1801131: OR = 5.18 [95%CI 2.77–9.71]). And six haplotypes of G–C (involving rs4846048 and rs2274976), A–C (involving rs1801133 and rs4846052), G–T (involving rs1801133 and rs4846052), G–T–G (involving rs2066470, rs3737964 and rs535107), A–C–G (involving rs2066470, rs3737964 and rs535107) and G–C–G (involving rs2066470, rs3737964 and rs535107) were identified to be significantly associated with risk of CHD. Additionally, we observed that a two-locus model involving rs2066470 and rs1801131 as well as a three-locus model involving rs227497, rs1801133 and rs1801131 were significantly associated with risk of CHD in the gene–gene interaction analyses. For three subtypes including atrial septal defect, ventricular septal defect and patent ductus arteriosus, similar results were observed.ConclusionsOur study indicated genetic polymorphisms of maternal MTHFR gene were significantly associated with risk of fetal CHD in the Chinese population. Additionally, there were significantly interactions among different SNPs on risk of CHD. However, how these SNPs affect the development of fetal heart remains unknown, and more studies in different ethnic populations and with a larger sample are required to confirm these findings.

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.

CCN1 gene polymorphisms associated with congenital heart disease susceptibility in Northwest Chinese population from different high-altitude areas.

High-altitude hypoxic environment exposure is considered one of the risk factors for congenital heart disease (CHD), but the genetic factors involved are still unclear. CCN1, one of the synergistic molecules in the hypoxic response, is also an indispensable molecule in cardiac development. Considering that CCN1 may play an important role in the occurrence of CHD in high-altitude areas, we investigated the association between CCN1 polymorphisms and CHD susceptibility in Northwest Chinese population from different high-altitude areas. We conducted a case-control study with a total of 395 CHD cases and 486 controls to evaluate the associations of CCN1 polymorphisms with CHD risk. Our results showed that the protective alleles rs3753793-C (OR = 0.59, 95% CI = 0.42-0.81, P = 0.001), rs2297141-A (OR = 0.66, 95% CI = 0.49-0.90, P = 0.001), and C-A haplotype of rs3753793-rs2297141 (OR = 0.58, 95% CI = 0.42-0.82, P = 0.002) were significantly associated with a decreased atrial septal defect (ASD) risk. Further subgroup analysis in different geography populations revealed robust association of SNP rs2297141 with ASD risk in a Han population residing in high altitude of 2500-4287 m. We also found that the frequency of protective alleles was higher in high-altitude population, and the alleles were responsible for the difference of oxygen physiology-related erythrocyte parameters in different high-altitude populations. rs3753793-C and rs2297141-A are likely related to high altitude and hypoxia adaptation, which may also be the reason for the association between CCN1 polymorphism and ASD risk.

Incidence and risk factors of congenital heart disease in Qingdao: a prospective cohort study

BackgroundMany studies have been conducted to assess the incidence of congenital heart disease (CHD). However, results were greatly inconsistent among these studies with a broad range of findings.MethodsA prospective census-based cohort study was conducted in Qingdao, China, from August 1, 2018 to April 30, 2019. All of the local registered pregnant women were continuously investigated and followed from 15 to 20 weeks of gestation to delivery, tracking the CHD cases in both the fetal and neonatal stages. A logistic regression model was applied to assess the association between CHD and possible risk factors.ResultsThe positive rate of prenatal CHD screening was 14.36 per 1000 fetuses and the incidence of CHD was 9.38 per 1000 live births. Results from logistic regression indicated that, living in the countryside (odds ratio, (OR): 0.771; 95% confidence interval, (CI): 0.628–0.946) and having a childbearing history (OR: 0.802; 95%CI: 0.676–0.951) were negatively associated with CHD. However, twin pregnancy (OR: 1.957, 95% CI: 1.245–3.076), illness in the first trimester (OR: 1.306; 95% CI: 1.048–1.628), a family history of CHD (OR: 7.156; 95% CI: 3.293–15.552), and having a child with a birth defect (OR: 2.086; 95% CI: 1.167–3.731) were positively associated with CHD.ConclusionCHD is a serious health problem in Qingdao. The CHD incidence found in this study was similar to existing research. The positive rate of prenatal CHD screening was higher than the incidence of neonatal CHD. Moreover, CHD risk factors were identified in our study, and our findings may have great implications for formation CHD intervention strategies.

Association of maternal folate use and reduced folate carrier gene polymorphisms with the risk of congenital heart disease in offspring.

Although it is generally recognized that genetic and environmental factors are associated with the risk of congenital heart disease (CHD), the mechanism remains largely uncertain. This study aimed to investigate the association of maternal folate use, the time when folate use was started, and polymorphisms of the reduced folate carrier (RFC1) gene with the risk of CHD in offspring of Chinese descent, which can help provide new insight into the etiology of folate-related birth defects. A case-control study of 683 mothers of CHD patients and 740 mothers of healthy children was performed. The present study showed that mothers who did not use folate were at a significantly increased risk of CHD (OR=2.04; 95% CI: 1.42-2.93). When compared with those who started using folate prior to conception, mothers who started using folate from the first trimester of pregnancy (OR=1.90; 95% CI: 1.43-2.54) or from the second trimester of pregnancy (OR=8.92; 95% CI: 4.20-18.97) had a significantly higher risk of CHD. Maternal RFC1 gene polymorphisms at rs2236484 (AG vs AA: OR=1.79 [95% CI: 1.33-2.39]; GG vs AA: OR=1.64 [95% CI: 1.15-2.35]) and rs2330183 (CT vs CC: OR=1.54 [95% CI: 1.14-2.09]) were also significantly associated with CHD risk. Additionally, the risk of CHD was significantly decreased among mothers who had variant genotypes but used folate when compared with those who had variant genotypes and did not use folate.Conclusion: In those of Chinese descent, maternal folate use and the time when use started are significantly associated with the risk of CHD in offspring. Furthermore, maternal folate supplementation may help to offset some of the risks of CHD in offspring due to maternal RFC1 genetic variants. What is Known: • Folate use could help prevent CHD, but the relationship between the time when folate use is started and CHD has not received sufficient attention. • Studies have assessed the associations of folate metabolism-related genes with CHD, but genes involved in cellular transportation of folate, such as the RFC1 gene, have not garnered enough attention. What is New: • In those of Chinese descents, the time when folate use is started is significantly associated with the risk of CHD in offspring. • Maternal RFC1 polymorphisms were significantly associated with the risk of CHD. • Folate supplementation may help to offset some risks of CHD due to RFC1 genetic variants.

Association and interaction effect of UCP2 gene polymorphisms and dietary factors with congenital heart diseases in Chinese Han population

Congenital heart diseases (CHDs) are the most common birth defects and the leading cause of non-infectious deaths in infants, with an unknown etiology. We aimed to assess the association of genetic variations in UCP2 gene, dietary factors, and their interactions with the risk of CHDs in offspring. The hospital-based case–control study included 464 mothers of children with CHDs and 504 mothers of healthy children. The exposures of interest were maternal dietary factors in early pregnancy and UCP2 genetic variants. Logistic regression analyses were used to assess the association and interaction of UCP2 gene and dietary factors with CHDs. Our results found that the polymorphisms of UCP2 gene at rs659366 and rs660339, together with maternal dietary factors including excessive intake of pickled vegetables and smoked foods were associated with increased risks of CHDs in offspring. Regular intake of fresh meat, fish and shrimp, and milk products were associated with lower risks of CHDs in offspring. Besides, positive interaction between the dominant model of rs659366 and excessive intake of pickled vegetables was found in the additive interaction model (RERI = 1.19, P = 0.044). These findings provide the theoretical basis for gene screening and a new clue for the prevention of CHDs in offspring.

The Predisposing Risk Factors for Non-syndromic Congenital Heart Disease: A Case-Control Study

Objectives: Despite the importance of congenital heart disease (CHD) in the population, the risk factors predisposing infants to be born with non-syndromic CHD are not well understood yet. Materials and Methods: In a case-control study, we recruited consecutive 109 infants with non-syndromic CHD who were referred to our pediatric cardiac care clinic and then compared them with 117 infants without CHD (2015-2016). Paternal, maternal, and neonatal demographic information, maternal past medical history, and antenatal history were recorded for each child. To investigate the potential risk factors for developing CHD, infants with and without CHD were compared in terms of study variables. In a second analysis, preterm infants were excluded and term infants were compared regarding the study variables. Results: The findings revealed that higher maternal and paternal education were both associated with a lower risk of CHD (odds ratio [OR]: 0.47, 95% confidence interval [CI]: 0.24-0.93, P=0.031, and OR: 0.45, 95% CI: 0.23-0.89, P=0.023, respectively). The family history of CHD in the first- or second-degree relatives of infants was significantly associated with CHD (OR: 3.56, 95% CI: 1.35-9.40, P=0.007). Several parameters were more prevalent in the CHD group, including having lower birth weight, having preterm birth, being the fourth birth order or higher, and not receiving maternity care under the supervision of a gynecologist. However, higher birth order and lower birth weight were not associated with CHD in exclusively term infants. Finally, a higher maternal educational level was related to lower CHD in term infants even after adjusting for a family history of CHD and preconception diabetes mellitus (OR: 5.45, 95% CI: 1.71-17.37, P=0.004). Conclusions: Our study findings demonstrate the need for a more enhanced primary care program, especially in patients with poor financial status and a family history of CHD.

Maternal fever during preconception and conception is associated with congenital heart diseases in offspring: An updated meta-analysis of observational studies.

Backgrounds:Many studies have evaluated the effect of maternal fever on the development risk of congenital heart diseases (CHDs) in offspring, but the findings were inconsistent. Furthermore, a complete overview of the existing data was also missing. Therefore, we intend to provide updated epidemiologic evidence to estimate the association between maternal fever and the risk of overall CHDs and specific CHD phenotypes in offspring.Methods:Pubmed, Embase, and Web of Science were searched through March 2020 to identify eligible studies that assessed the association between maternal fever and CHDs risk in offspring. The summary risk estimates were calculated using random-effects models. Potential heterogeneity source was explored by subgroup analyses and potential publication bias was assessed by Begg funnel plots and Begg rank correlation test.Results:Sixteen studies involving 31,922 CHDs cases among 183,563 participants were included in this meta-analysis. Overall, mothers who had a fever experience during preconception and conception periods had a significantly higher risk of overall CHDs in offspring (odds ratio [OR] = 1.45, 95% confidence interval [CI]: 1.21–1.73) when compared with those who did not have a fever experience. For specific CHD phenotypes in offspring, a statistically significant association was found between maternal fever and risk of conotruncal defects (CTD) (OR = 1.38, 95%CI: 1.01–1.89), atrial septal defects (ASD) (OR = 1.48, 95% CI: 1.01–2.17), transposition of the great vessels (TGA) (OR = 1.81, 95% CI: 1.14–2.88), and right ventricular outflow tract obstruction (RVOTO) (OR = 1.66, 95% CI: 1.04–2.65). Relevant heterogeneity moderators have been identified by subgroup analyses, and sensitivity analyses yielded consistent results.Conclusions:Although the role of potential bias and evidence of heterogeneity should be carefully evaluated, our review indicates that maternal fever is significantly associated with the risk of CHDs in offspring, which highlights that preventing maternal fever during the preconception and conception periods play an important role in decreasing the risk of CHDs in offspring. However, given the limited number of current case-control studies, larger-sample prospective studies are required to further confirm our results. Besides, due to the underlying mechanisms between maternal fever and the risk of specific CHD phenotypes in offspring are still unreported, more research is needed to explore the possible mechanisms.

Association of maternal gut microbiota and plasma metabolism with congenital heart disease in offspring: a multi-omic analysis

Congenital heart disease (CHD) is the most common congenital disorder diagnosed in newborns. Although lots of related studies have been published, yet the pathogenesis has not been fully elucidated. A growing body of evidence indicates perturbations of the gut microbiota may contribute in a significant way to the development of obesity and diabetes. Given that maternal obesity and diabetes are well-known risk factors for CHD, maternal gut microbiota may be considered as one of the environmental factors involved in the pathogenesis of CHD. The object of this study is to explore the association between maternal gut microbiota and risk of congenital heart disease (CHD) in offspring, as well as the possible mechanisms linking gut microbiota and disease risk. A case–control study was conducted in mothers of infants with CHD (n = 101) and mothers of infants without CHD (n = 95). By applying 16S rRNA gene sequencing and metabolic approaches to 196 stool and plasma samples, we determined microbiome and metabolome profiles in mothers of infants with CHD and controls, and their association with risk of CHD in offspring. The gut microbiome of mothers of infants with CHD was characterized with lower alpha-diversity and distinct overall microbial composition compared with mothers of infants without CHD. A distinct different metabolic profile was found between mothers of infants with CHD and controls. After controlling for the possible confounders, thirty-four bacterial genera and fifty-three plasma metabolites showed distinct abundances between the two groups. The results of the Spearman correlation analyses revealed a great number of significant correlations between the abundant bacterial genera and differentially expressed metabolites. In particular, the genus Bifidobacterium and Streptococcus showed comparable moderate positive correlations with a range of metabolites that involved in lipid metabolism pathway. Our findings suggest that perturbations of maternal gut microbiota and plasma metabolites may be associated with risk of CHD in offspring, and co-variation between microbiota and metabolites may play a part in the linkage between gut microbiota and risk of CHD in offspring.