Fetal Congenital Heart Defects Research Articles

Folic Acid and Selected Risk Factors for Fetal Heart Defects-Preliminary Study Results.

The available data on the relationship between diet/folic acid and congenital heart disease (CHD) are not consistent. This study aimed to investigate the relationship between the intake and supplementation of folic acid and other selected factors in mothers and the risk of congenital heart defects in fetuses. A case-control study was conducted. The study group included pregnant women with fetuses from singleton pregnancies with prenatally diagnosed heart defects in the fetus (n = 79) and pregnant women whose course of pregnancy was normal with no heart defects or other developmental anomalies diagnosed in the fetus (n = 121). The patients were diagnosed at a reference center in Poland. The women completed a lifestyle questionnaire and FFQ and precisely described their use of dietary supplements. A univariate logistic regression model was used to evaluate the association between folic acid and selected risk factors and CHD. The association was significant and included such risk factors such as nutritional status, medications taken, smoking, and alcohol consumption. Additionally, the time of starting folic acid supplementation turned out to be statistically significant. The reference period of supplementation was the period before pregnancy. Lack of supplementation increases the risk of heart defects in children by more than four times compared to supplementation before pregnancy (OR = 4.19; p = 0.0117), whereas supplementation beyond the eighth week of gestation increases the risk almost threefold (OR = 2.90; p = 0.0474). The presence of congenital defects in the family is also an important factor. A history of congenital heart defects or other defects, lack of periconceptional folic acid supplementation, and lack of dietary supplementation before pregnancy were associated with congenital heart defects in the fetus. Place of residence, parents' education, lifestyle habits such as smoking and alcohol consumption, nutritional status before pregnancy, and mother's diseases did not show a significant relationship with congenital heart defects in the children. There is an urgent need to develop preventive strategies and conduct extensive public education.

Maternal exposure to ambient ozone and fetal congenital heart defects: a national multicenter study in China.

Ambient O3 has demonstrated an aggravated increasing trend in the context of global warming. The available evidence of maternal exposure to ambient O3 on fetal congenital heart defects (CHD) is still limited, especially in high polluted areas. To examine associations of maternal exposure to ambient O3 during early pregnancy with fetal CHDs. We conducted a national multicenter study in 1313 hospitals from 26 provinces in China and collected a total of 27,817 participants athigh risk of CHD from 2013 to 2021. Exposure to ambient O3 during the embryonic period, preconception, the first trimester and periconception was assessed by extracting daily concentrations from a validated grid dataset at each subject's residential district. CHDs were diagnosed based on fetal echocardiography. Each 10 µg/m3 increase of exposure to ambient O3 during the embryonic period was approximately linearly associated with a 12.7% (odds ratio [OR]: 1.127, 95% confidence interval [CI]: 1.098, 1.155) increase in odds of pooled CHD (p < 0.001). The associations remain robust after adjusting for ambient PM2.5 and NO2 exposure. The odds of different types of CHD in association with ambient O3 exposure varied greatly. We observed significant association of ambient O3 exposure with ventricular septal defect (VSD), tetralogy of Fallot (TOF); pulmonary stenosis (PS), pulmonary atresia (PA), transposition of great arteries (TGA) and persistent left superior vena cava (PLSVC), with TOF demonstrating the strongest estimates (OR: 1.194, 95% CI:1.107, 1.288). The estimates for preconception, the first trimester and periconception demonstrate consistent findings with the main analyses, indicating stronger associations of ambient O3 exposure during the periconception period. Our study provides evidence that higher ambient O3 during early pregnancy was significantly associated with increased odds of fetal CHD. Our findings suggest that pregnant women, clinical practitioners, and policy makers need to pay more attention to the exposure to higher ambient O3 during early pregnancy to reduce the risk of developing CHD and to improve outcomes across the life span.

Maternal Oxidative Balance Score during Pregnancy and Congenital Heart Defects.

The relationship between maternal oxidative balance score (OBS) in pregnancy, representing overall oxidative balance status by integrating dietary and lifestyle factors, and congenital heart defects (CHD) remains unclear; therefore, this study attempted to explore their associations among the Chinese population. We conducted a case-control study including 474 cases and 948 controls in Northwest China. Pregnant women were interviewed to report diets and lifestyles in pregnancy by structured questionnaires. Logistic regression models were used to estimate the adjusted ORs (95%CIs). Maternal OBS ranged from 6 to 34 among cases, and 5 to 37 among controls. Comparing the highest with the lowest tertile group, the adjusted OR for CHD was 0.31 (0.19-0.50). The CHD risk was reduced by 7% (OR = 0.93, 95%CI = 0.90-0.95) in association with per 1 higher score of OBS during pregnancy. The inverse relationship between maternal OBS and CHD risk appeared to be more pronounced among participants in urban areas (OR = 0.89, 95%CI = 0.86-0.93). Maternal OBS during pregnancy showed good predictive values for fetal CHD, with the areas under the receiver operating characteristic curve 0.78 (0.76-0.81). These findings highlighted the importance of reducing oxidative stress through antioxidant-rich diets and healthy lifestyles among pregnant women to prevent fetal CHD.

Contribution of genetic variants to congenital heart defects in both singleton and twin fetuses: a Chinese cohort study

BackgroundThe contribution of genetic variants to congenital heart defects (CHDs) has been investigated in many postnatal cohorts but described in few prenatal fetus cohorts. Overall, specific genetic variants especially copy number variants (CNVs) leading to CHDs are somewhat diverse among different prenatal cohort studies. In this study, a total of 1118 fetuses with confirmed CHDs were recruited from three units over a 5-year period, composing 961 of singleton pregnancies and 157 of twin pregnancies. We performed chromosomal microarray analysis on all cases to detect numerical chromosomal abnormalities (NCAs) and pathogenic/likely pathogenic CNVs (P/LP CNVs) and employed whole-exome sequencing for some cases without NCAs and P/LP CNVs to detect P/LP sequence variants (P/LP SVs).ResultsOverall, NCAs and P/LP CNVs were identified in 17.6% (197/1118) of cases, with NCA accounting for 9.1% (102/1118) and P/LP CNV for 8.5% (95/1118). Nonisolated CHDs showed a significantly higher frequency of NCA than isolated CHD (27.3% vs. 4.4%, p < 0.001), but there was no significant difference in the frequency of P/LP CNVs between isolated and nonisolated CHD (11.7% vs. 7.7%). A total of 109 P/LP CNVs were identified in 95 fetuses, consisting of 97 (89.0%) de novo, 6 (5.5%) parental inherited and 6 (5.5%) with unavailable parental information. The 16p11.2 proximal BP4-BP5 deletion was detected in 0.9% (10/1118) of all cases, second only to the most common 22q11.21 proximal A-D deletion (2.1%, 23/1118). Most of the 16p11.2 deletions (8/10) detected were de novo, and were enriched in CHD cases compared with a control cohort from a previous study. Additionally, SV was identified in 12.9% (8/62) of cases without NCA and P/LP CNV, most of which were de novo with autosomal dominant inheritance.ConclusionsOur cohort study provides a deep profile of the contribution of genetic variants to CHDs in both singleton and twin fetuses; NCA and P/LP CNV contribute to 9.1% and 8.5% of CHD in fetuses, respectively. We confirmed the 16p11.2 deletion as a CHD-associated hotspot CNV, second only to the 22q11.21 deletion in frequency. Most 16p11.2 deletions detected were de novo. Additionally, P/LP SV was identified in 12.9% (8/62) of fetuses without NCA or P/LP CNV.

Association between abnormal uterine artery pulsatility index and the risk of fetal congenital heart defects: a hospital-based cohort study

To explore the associations between high uterine artery pulsatility index (UtA-PI) values and congenital heart disease (CHD) risk and whether they differed between singleton and multiple pregnancies. This hospital-based cohort study involving 52,047 pregnant women who underwent prenatal examinations from 2012 to 2016. Infants born to the included pregnant women were followed until 42 days after birth to identify those with CHDs. Generalized estimating equations were used to estimate the associations of high right UtA-PI (> 95th percentile) values with maternal preeclampsia and fetal CHDs. Logistic regression analyses were conducted using path analysis models to quantify the effect of high right UtA-PI values on fetal CHD risk. A total of 42,552 women and 43,470 infants (147 with CHDs) were included. Preeclampsia risk was associated with a high right UtA-PI in singleton-pregnant women (adjusted PR, 3.01; 95% CI 2.57–3.52). CHD risk was marginally associated with a high right UtA-PI in singleton-pregnant women (adjusted PR, 2.26, 95% CI 1.03–4.95). Considering only two factors, 96.0% of the fetal CHD risk was mediated by preeclampsia in singleton-pregnant women, while 93.8% of the risk was related to a high right UtA-PI in multiple-pregnant women. A high right UtA-PI was marginally associated with an increased fetal CHD risk in singleton-pregnant women and might play an important role in multiple-pregnant women. Further studies are warranted to confirm these findings given the high loss to follow-up rate.

Associations of maternal exposure to multiple plasma trace elements with the prevalence of fetal congenital heart defects: A nested case-control study

BackgroundScanty knowledge prevails regarding the combined impact of multiple plasma trace elements and main contributors on the prevalence of congenital heart defects (CHDs) in offspring. Thus, we performed a nested case-control analysis in a neonates cohort to investigate this important public health issue. MethodsWe selected 164 pairs of cases and non-malformed controls from live births registered in the parent cohort (n = 11,578) at the same hospital. Plasma levels of 14 trace elements were determined by inductively coupled plasma-mass spectrometry. The odds ratios (ORs) of exposure were compared between cases and controls. Bayesian Kernel Machine Regression (BKMR) and Quantile g-Computation (QgC) models were employed to assess the cumulative effect of exposure to trace elements. ResultsWe found positive associations and linear dose-response relationships between plasma Pb and Sn and CHD. BKMR models indicated that the overall effect of the trace element mixture was associated with CHDs below the 45th percentile or above the 50th percentile, and the combined effect was primarily attributed to Sn and Pb. The QgC model indicated significantly increased odds of CHD with simultaneous exposure to all studied trace elements (OR: 2.19, 95%CI: 1.44–3.33). ConclusionsThis study is the first to report an association between elevated levels of mixed trace elements in maternal plasma with an increased prevalence of fetal CHDs, particularly in the case of Pb and Sn. Findings from this study provide further evidence of the important of heavy metal pollution to human health, and can help stakeholders prioritize policies and develop interventions to target the leading contributors to human exposure.

Associations of maternal exposure to multiple plasma metals with the risk of fetal congenital heart defects: a prospective nested case-control study

Abstract Background Congenital heart defects (CHDs) are the most common congenital anomalies with complex etiologies. There is knowledge gap with respect to the association between single and combined exposures to multiple heavy metals during pregnancy and the risk of CHDs in the fetus. Thus, we aimed to examine the association between maternal plasma heavy metal concentrations in mid-pregnancy and the risk of CHDs in the fetus. Methods A prospective nested case-control study was conducted in a cohort of 11,578 newborns. Exposure odds ratios (ORs) were compared between 164 CHD cases and 164 non-malformed controls delivered at the same hospital, individually matched by maternal age (±5 years) and parity. Concentrations of 21 metals were determined in maternal peripheral blood plasma via an ultra-performance liquid chromatography inductively coupled to mass spectrometry (ICP-MS). Single- and multiple-metal logistic regressions, the adaptive least absolute shrinkage and selection operator (LASSO) penalized regression analysis and restricted cubic spline (RCS) analysis were applied to explore the associations and dose-response relationships of plasma metals with CHD. We also applied Bayesian Kernel Machine Regression (BKMR) model to evaluate the cumulative effect of the exposure metals. Results Median (interquartile range, IQR) Vanadium (V) [0.3 (0.3-0.4) vs. 0.3 (0.3-0.4) μg/L, P = 0.027] and cadmium (Cd) [0.1 (0.0-0.1) vs. 0.1 (0.0-0.1) μg/L, P = 0.036] levels were different between the CHDs and control groups. Compared with the first quartile, the Directed acyclic graph(DAG) model-adjusted ORs (95% CI) were 3.12 (1.72-5.64) for kalium (K), 2.21 (1.23-3.94) for manganese (Mn), 0.55 (0.33-0.94) for cerium (Ce), 1.96 (1.06-3.64) for lead (Pb) in the second quartile, and ORs (95%CIs) were 1.88 (1.08-3.26) for V, 0.53 (0.30-0.93) for Cr, 1.92 (1.10-3.35) for copper (Cu), 2.09 (1.18-3.70) for Cd, 2.14 (1.24-3.70) for stannum (Sn) and 3.05 (1.69-5.49) for Pb in the third quartile. In the multi-metal model, compared to the lowest quartile, the ORs for Sn and Pb in the second quartile were 1.32 (95% CI: 0.69-2.55) and 1.94 (95% CI: 0.98-3.84), respectively, and the ORs for both metals in the third quartiles were 2.15 (95% CI: 1.16-3.98) and 3.32 (OR=0.66, 95% CI: 1.68-6.55), suggesting that Sn and Pb had relatively stable positive results with a linear dose progression. BKMR models with 2 cluster for 9 metals showed that the overall effect of metal mixture was not statistically significant at or below 35th percentile and at or above the 70th percentile, compared to their median levels. Pb was the major contributor to the combined effect. Conclusions Elevated level of plasma plumbum was associated with increased risk of CHDs. Further investigations in larger perspective cohorts are needed to confirm our findings.fig 1fig 2

OC11.04: Diagnostic value of chromosomal microarray analysis for fetal congenital heart defects with different cardiac phenotypes and extracardiac abnormalities

OC11.04: Diagnostic value of chromosomal microarray analysis for fetal congenital heart defects with different cardiac phenotypes and extracardiac abnormalities

Assessment of the course of the gestational process using survey method and depending on the laboratory confirmed prenatal alcohol use (cross-section study)

Background. Studying the problem of alcohol consumption by pregnant women using modern laboratory research methods has valuable theoretical and practical significance. The aim of the study. To determine the characteristics of the pregnancy course in women consuming alcohol in the prenatal period confirmed by survey and laboratory tests, depending on the phosphatidylethanol levels. Materials and methods. We examined 863 women under observation at the Irkutsk Regional Perinatal Center for the period from 2014 to 2021. To confirm the fact of alcohol consumption in the prenatal period, 545 women were surveyed, 318 women were examined using laboratory analysis. The diagnostic biomarker for alcohol was PEth:16:0/18:1. To assign pregnant women to the control group, a PEth concentration of ≤ 8 ng/ml was taken. If the PEth concentration was &gt; 8 ng/ml, pregnant women were classified as heavy drinkers. Clinical and laboratory indicators of the course of pregnancy and childbirth were carried out in comparative groups. Results. It has been established that every second woman of reproductive age took alcohol before pregnancy. 24.2 % of women did not stop consuming alcohol in the prenatal period. At the same time, the risk of congenital malformations was high, since 20.4 % of women consumed alcohol in the first trimester of pregnancy. Based on the results of the survey, it was revealed that in women who consumed alcohol in the prenatal period, the following pathological conditions are statistically significantly more common: anemia, congenital heart defects in fetuses, prematurity of gestational age, labor anomalies, uterus subinvolution. Based on the results of laboratory confirmation of alcohol consumption, it was established that parity of birth, intrauterine growth retardation, and premature birth were statistically significantly more often in pregnant women who drink. Conclusion. Thus, in order to obtain the most meaningful and high-quality results, it is necessary to conduct larger studies. In addition, maternal blood biomarkers should be used to confirm levels of alcohol consumption throughout all trimesters of pregnancy.

Interaction between ozone and paternal smoking on fetal congenital heart defects among pregnant women at high risk: a multicenter maternal-fetal medicine study.

Evidence remains limited on the association between maternal ozone (O3) exposure and congenital heart defects (CHDs) in offspring, and few studies have investigated the interaction and modification of paternal smoking on this association. Using a sample including pregnant women at high risk of fetal CHD (with metabolic disease, first-trimester viral infection, family history of CHD, etc.) from a maternal-fetal medicine study covering 1313 referral hospitals in China during 2013-2021, we examined the associations between maternal O3 exposure during 3-8 weeks of gestational age and fetal CHD in offspring and investigated the interaction and modification of paternal smoking on this association. CHD was diagnosed by fetal echocardiograms, maximum daily 8-hour average O3 exposure data at a 10 km × 10 km spatial resolution came from the Tracking Air Pollution in China dataset, and paternal smoking was collected using questionnaires. Logistic regression models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Among 27,834 pregnant women at high risk of fetal CHD, 17.4% of fetuses were diagnosed with CHD. Each 10 μg/m3 increase in maternal O3 exposure was associated with a 17% increased risk of CHD in offspring (OR= 1.17, 95% CI =1.14-1.20). Compared with paternal nonsmoking and maternal low O3 exposure, the ORs (95% CI) of CHD for smoking and low O3 exposure, nonsmoking and high O3 exposure, and smoking and high O3 exposure were 1.25 (1.08-1.45), 1.81 (1.56-2.08), and 2.23 (1.84-2.71), respectively. Paternal smoking cessation seemingly mitigated the increased risk of CHD. Maternal O3 exposure and paternal smoking were interactively associated with an increased risk of fetal CHD in offspring, which calls for effective measures to decrease maternal exposure to O3 pollution and secondhand smoke for CHD prevention.

Cell-Free DNA in Maternal Blood and Artificial Intelligence: Accurate Prenatal Detection of Fetal Congenital Heart Defects

(Abstracted from Am J Obstet Gynecol 2023;228(1):76.e1–76.e10) Congenital heart defects (CHDs) are one of the leading causes of child morbidity and mortality. Previous research has shown that prenatal detection of CHD can significantly reduce the risk of death for severe cases, yet the current techniques available for prenatal diagnosis detect approximately only half of cases.

A short session of maternal hyperoxygenation ameliorates the cerebral oxygenation difference between fetuses with and without congenital heart defects

ObjectivesTo assess if a 10 min session of maternal hyperoxygenation increases cerebral tissue oxygenation as measured by magnetic resonance imaging (MRI) T2* in fetuses with and without congenital heart defects (CHDs). Study designAt mean gestational ages of 32 (early) and 37 (late), we measured fetal cerebral T2* before and during the last minutes of a 10 min maternal hyperoxygenation (oxygen 10 l/min, Hudson non-rebreathing mask) in 22 fetuses without CHDs and 11 fetuses with CHDs using a 1.5 Tesla Philips scanner with a breath-hold, multi-echo, gradient-echo sequence. ResultsDuring maternal hyperoxygenation equilibrium, the mean fetal cerebral T2* values in CHD fetuses seemingly normalized and were comparable to those in fetuses without CHD breathing ambient air. Hyperoxygenation T2* was 160 ms (CI 149–170) early and 123 ms (CI 112–134) late in fetuses with CHD and ambient air T2* was 158 ms (CI 152 to 164) early and 126 ms (CI 120–131) late in fetuses without CHD, (p=0.97). Lower ambient air cerebral T2* z-score at the late-stage scan was correlated with lower head circumference z-scores at birth. ConclusionOur findings suggest that fetal cerebral oxygenation in CHD fetuses can reach normal values during a short session of maternal hyperoxygenation. This supports the hypothesis that tissue hypoxia can influence brain development in fetuses with CHD. However, since side effects of fetal hyperoxygenation have been described, it remains to be determined if chronic maternal hyperoxygenation has a positive impact on the fetal brain in CHDs.

Dietary Inflammatory Index during Pregnancy and Congenital Heart Defects.

The relationship between diet-related inflammation during pregnancy and congenital heart defects (CHD) is unclear. This study attempted to investigate the association between the dietary inflammation index (DII) during pregnancy, reflecting the overall inflammatory potential of the maternal diet, and CHD in Northwest China. A case-control study with 474 cases and 948 controls was performed in Xi'an City, China. Eligible women awaiting delivery were recruited, and their dietary and other information during pregnancy was collected. Logistic regression models were applied to estimate the risk of CHD in association with DII. The maternal DII ranged from -1.36 to 5.73 in cases, and 0.43 to 5.63 in controls. Pregnant women with per 1 higher DII score were at 31% higher risk of fetal CHD (OR = 1.31, 95%CI = 1.14-1.51), and the adjusted OR (95%CI) comparing the pro-inflammatory diet group with the anti-inflammatory diet group was 2.04 (1.42-2.92). The inverse association of maternal DII score with CHD risk was consistent across various subgroups of maternal characteristics. Maternal DII in pregnancy had good predictive value for CHD in offspring, with the areas under the receiver operating characteristic curve higher than 0.7. These findings suggested that avoiding a pro-inflammatory diet in pregnancy should be emphasized in the prevention of CHD.

Diagnostic Value of Chromosomal Microarray Analysis for Fetal Congenital Heart Defects with Different Cardiac Phenotypes and Extracardiac Abnormalities.

(1) Background: The objective of this study was to investigate the diagnostic value of chromosomal microarray analysis (CMA) for congenital heart defects (CHDs) with different cardiac phenotypes and extracardiac abnormalities (ECAs) and to explore the pathogenic genetic factors of CHDs. (2) Methods: We collected fetuses diagnosed with CHDs by echocardiography at our hospital from January 2012 to December 2021. We analyzed the CMA results of 427 fetuses with CHDs. We then categorized the CHD into different groups according to two dimensions: different cardiac phenotypes and whether it was combined with ECAs. The correlation between the numerical chromosomal abnormalities (NCAs) and copy number variations (CNVs) with CHDs was analyzed. Statistical analyses, including Chi-square tests and t-tests, were performed on the data using IBM SPSS and GraphPad Prism. (3) Results: In general, CHDs with ECAs increased the detection rate for CA, especially the conotruncal defects. CHD combined with the thoracic and abdominal walls and skeletal, thymic and multiple ECAs, were more likely to exhibit CA. Among the CHD phenotypes, VSD and AVSD were associated with NCA, while DORV may be associated with NCA. The cardiac phenotypes associated with pCNVs were IAA (type A and B), RAA, TAPVC, CoA and TOF. In addition, IAA, B, RAA, PS, CoA and TOF were also associated with 22q11.2DS. The length distribution of the CNV was not significantly different between each CHD phenotype. We detected twelve CNV syndromes, of which six syndromes may be related to CHDs. The pregnancy outcome in this study suggests that termination of pregnancy with fetal VSD and vascular abnormality is more dependent on genetic diagnosis, whereas the outcome in other phenotypes of CHDs may be associated with other additional factors. (4) Conclusions: CMA examination for CHDs is still necessary. We should identify the existence of fetal ECAs and specific cardiac phenotypes, which are helpful for genetic counseling and prenatal diagnosis.

Detection of Novel Pathogenic Variants in Two Families with Recurrent Fetal Congenital Heart Defects.

Congenital heart disease (CHD) is the most common birth defect with strong genetic heterogeneity. To date, about 400 genes have been linked to CHD, including cell signaling molecules, transcription factors, and structural proteins that are important for heart development. Genetic analysis of CHD cases is crucial for clinical management and etiological analysis. Whole-exome sequencing (WES) was performed to identify the genetic variants in two independent CHD cases with DNA samples from fetuses and their parents, followed by the exclusion of aneuploidy and large copy number variations (CNVs). The WES results were verified by Sanger sequencing. In family A, a compound heterozygous variation in PLD1 gene consisting of c.1132dupA (p.I378fs) and c.1171C>T (p.R391C) was identified in the fetus. The two variants were inherited from the father (c.1132dupA) and the mother (c.1171C>T), respectively. In family B, a hemizygous variant ZIC3: c.861delG (p.G289Afs*119) was identified in the fetus, which was inherited from the heterozygous mother. We further confirmed that these variants PLD1: c.1132dupA and ZIC3: c.861delG were novel. The findings in our study identified novel variants to the mutation spectrum of CHD and provided reliable evidence for the recurrent risk and reproductive care options to the affected families. Our study also demonstrates that WES has considerable prospects of clinical application in prenatal diagnosis.

Maternal Exposure to PM2.5 and the Risk of Congenital Heart Defects in 1.4 Million Births: A Nationwide Surveillance-Based Study.

Evidence remains limited about the association of maternal exposure to ambient fine particulate matter (airborne particles with an aerodynamic diameter ≤2.5 µm [PM2.5]) with fetal congenital heart defects (CHDs) in highly polluted regions, and few studies have focused on preconception exposure. Using a nationwide surveillance-based case-control design in China, we examined the association between maternal exposure to PM2.5 during periconception (defined as 3 months before conception until 3 months into pregnancy) and risk of CHD in offspring. The study included 1 434 998 births involving 7335 CHDs from 2014 through 2017 on the basis of the National Population-Based Birth Defects Surveillance System, covering 30 provinces, municipalities, or municipal districts in China. We assigned maternal PM2.5 exposure during the periconception period to each participant using satellite-based PM2.5 concentrations at 1-km spatial resolution. Multilevel logistic regression models were used to calculate the multivariable-adjusted odds ratio and 95% CI for CHDs in offspring associated with maternal PM2.5 exposure, and the exposure-response association was investigated using restricted cubic spline analysis. Subgroup or sensitivity analyses were conducted to identify factors that may modify the association. The average maternal exposure to PM2.5 levels across all participants was 56.51 μg/m3 (range, 10.95 to 182.13 μg/m3). For each 10 μg/m³ increase in maternal PM2.5 exposure, the risk of CHDs in offspring was increased by 2% (odds ratio, 1.02 [95% CI, 1.00 to 1.05]), and septal defect was the most influenced subtype (odds ratio, 1.04 [95% CI, 1.01 to 1.08]). The effect of PM2.5 on CHD risk was more pronounced during the preconception period. Mothers <35 years of age, those living in northern China, and those living in low-income areas were more susceptible to PM2.5 exposure than their counterparts (all P<0.05). PM2.5 exposure showed a linear association with total CHDs or specific CHD types. High maternal PM2.5 exposure, especially during the preconception period, increases risk of certain types of CHD in offspring. These findings are useful for CHD prevention and highlight the public health benefits of improving air quality in China and other highly polluted regions.

Prenatal exome sequencing versus targeted gene panel for evaluation of fetal congenital heart defects

In children and adults, exome sequencing has a higher diagnostic yield than targeted gene panels for both familial and sporadic congenital heart disease. However, these approaches have not been compared in the prenatal setting. Given differences in cost and insurance coverage, we sought to evaluate the yield of exome sequencing versus targeted gene panels for prenatal diagnosis when a congenital heart defect is present. Retrospective cohort of 44 pregnancies with prenatal ultrasound findings of congenital functional or structural heart defects, either isolated or in combination with other fetal anomalies, for which exome sequencing identified a likely pathogenic (LP) or pathogenic (P) variant thought to be causative of the fetal phenotype. All included cases had normal karyotype and/or microarray. Commercial laboratories offering targeted gene panels for prenatal diagnosis of cardiac disorders were identified using an internet search with the terms: “congenital,” and “cardiac defect,” or “cardiomyopathy,” or “heart defect,” or “heart disease.” We then reviewed each panel to determine if the variants would have been detected if the panels were used. The primary outcome was the proportion of P or LP variants identified through exome sequencing that also would have been identified by targeted gene panels. Nine commercial laboratories were identified that offer prenatal diagnosis for congenital heart disease. Three of the nine laboratories offered two applicable panels with different numbers of genes. There was an average of 140 genes per panel, ranging from 6-398. Targeted panels would have detected 7-52% of the 44 variants detected by exome sequencing. Fourteen P or LP variants (14/44, 32%) identified by exome sequencing would not have been detected by any of the targeted gene panels. Only one genetic variant (CHD7) would have been correctly identified by all laboratories. Following a normal karyotype and/or microarray, exome sequencing confers a diagnostic advantage over targeted gene panels for evaluating congenital heart defects identified on prenatal imaging.

Shared developmental pathways of the placenta and fetal heart

Congenital heart defects (CHD) remain the most common class of birth defect worldwide, affecting 1 in every 110 live births. A host of clinical and morphological indicators of placental dysfunction are observed in pregnancies complicated by fetal CHD and, with the recent emergence of single-cell sequencing capabilities, the molecular and physiological associations between the embryonic heart and developing placenta are increasingly evident. In CHD pregnancies, a hostile intrauterine environment may negatively influence and alter fetal development. Placental maldevelopment and dysfunction creates this hostile in-utero environment and may manifest in the development of various subtypes of CHD, with downstream perfusion and flow-related alterations leading to yet further disruption in placental structure and function. The adverse in-utero environment of CHD-complicated pregnancies is well studied, however the specific etiological role that the placenta plays in CHD development remains unclear. Many mouse and rat models have been used to characterize the relationship between CHD and placental dysfunction, but these paradigms present substantial limitations in the assessment of both the heart and placenta. Improvements in non-invasive placental assessment can mitigate these limitations and drive human-specific investigation in relation to fetal and placental development. Here, we review the clinical, structural, and molecular relationships between CHD and placental dysfunction, the CHD subtype-dependence of these changes, and the future of Placenta-Heart axis modeling and investigation.

Functional assessment of atrial wall excursion and foramen ovale flap tracings in 3rd trimester as predictor of short-term hemodynamic stability in congenital heart defects fetuses.

Right atrium and left atrium of the fetal heartplay a fundamental role in fetal heart circulatory physiology. Excursion of fetal atria walls and tracings of foramen ovale (FO) flap movement were analyzed by M-mode echocardiography by new FO index to determine fetal and neonatal outcome in the first week and month of life in various congenital heart defects. The study group was divided into 3 subgroups: group A: neonates stable after birth (all on I.V. prostaglandin infusion) for at least 7days, group B: neonates unstable after birth (despite I.V. prostaglandin infusion) requiring catheterization procedure or early cardiac surgery<6th day of life and group C: fetuses with in utero demise. The average values of FO index: group A- 32, group B- 20, group C- 12.Schaffe test showed statistical difference of FO index between group A and B (p=0.029) and group A and C (p=0.001), but no difference between group B and C (p=0.24) The FO index of stability was determined by ROC curve analysis. Cut-off point distinguishing between postnatal stability and postnatal instability+in utero demise constituted FO index=25 (specificity 82%; sensitivity 90%). Prenatal features of atrial M-mode echocardiography shortly before birth might be helpful to predict the short term prognosis of fetal hemodynamic stability or instability shortly after birth regardless of the type of congenital heart defects (CHD).

A Prospective Cohort to Evaluate Second-trimester Fetal Echocardiography Accuracy and to Evaluate Perinatal Outcomes in Iran

Background: Congenital heart defects (CHDs) are the most costly congenital disorders and despite significant advances in the diagnostic modalities, still its perinatal and neonatal consequences require extensive studies. In the current study, we investigated diagnostic value of fetal heart echocardiography for CHDs diagnosis while postnatal echocardiography was considered as Gold standard. Additionally, maternal and perinatal outcomes were evaluated.&#x0D; Methods: In this prospective Cohort study, 400 high risk pregnant women with regards to carrying a fetus with CHDs underwent fetal echocardiography during pre and postnatal period and maternal, fetal and neonatal outcomes were followed. Moreover, diagnostic value of fetal echocardiography for predicting CHDs was calculated.&#x0D; Results: Among 400 fetal echocardiographies done, CHDs was found in 63 fetuses and consequently postnatal echocardiography confirmed the diagnosis in 52 (82.53%) of them. The most common CHDs were atrial and ventricular septal defects (ASD and/or VSD). Although there were no association between presence of CHDs with consanguineous marriage, maternal age, maternal body mass index, smoking, pregnancy complications, fetal weight, gestational age, neonatal gender, and associated anomalies, the first and fifth Apgar Scores were significantly lower in neonates with CHDs on postnatal echocardiography.&#x0D; Conclusion: Second trimester fetal echocardiography, especially among high risk mothers has high diagnostic value for fetal CHDs diagnosis. This Imaging technique can lessen postnatal complications by facilitating early diagnosis and subsequent planned delivery in a proper well-equipped center.