Maternal Outcomes Among Pregnant Women With Congenital Heart Disease-Associated Pulmonary Hypertension.

BACKGROUND: Studies focused on pregnant women with congenital heart disease (CHD)-associated pulmonary hypertension (PH) are scarce and limited by small sample sizes and single-center design. This study sought to describe the pregnancy outcomes in women with CHD with and without PH. METHODS: Outcomes for pregnant women with CHD were evaluated retrospectively from 1993 to 2016 and prospectively from 2017 to 2019 from 7 tertiary hospitals. PH was diagnosed on the basis of echocardiogram or catheterization. The incidence of maternal death, cardiac complications, and obstetric and offspring complications was compared for women with CHD and no PH, mild, and moderate-to-severe PH. RESULTS: A total of 2220 pregnant women with CHD had completed pregnancies. PH associated with CHD was identified in 729 women, including 398 with mild PH (right ventricle to right atrium gradient 30-50 mm Hg) and 331 with moderate-to-severe PH (right ventricle to right atrium gradient >50 mm Hg). Maternal mortality occurred in 1 (0.1%), 0, and 19 (5.7%) women with CHD and no, mild, or moderate-to-severe PH, respectively. Of the 729 patients with PH, 619 (85%) had CHD-associated pulmonary arterial hypertension, and 110 (15%) had other forms of PH. Overall, patients with mild PH had better maternal outcomes than those with moderate-to-severe PH, including the incidence of maternal mortality or heart failure (7.8% versus 39.6%; P<0.001), other cardiac complications (9.0% versus 32.3%; P<0.001), and obstetric complications (5.3% versus 15.7%; P<0.001). Brain natriuretic peptide >100 ng/L (odds ratio, 1.9 [95% CI, 1.0-3.4], P=0.04) and New York Heart Association class III to IV (odds ratio, 2.9 [95% CI, 1.6-5.3], P<0.001) were independently associated with adverse maternal cardiac events in pregnancy with PH, whereas follow-up with a multidisciplinary team (odds ratio, 0.4 [95% CI, 0.2-0.6], P<0.001) and strict antenatal supervision (odds ratio, 0.5 [95% CI, 0.3-0.7], P=0.001) were protective. CONCLUSIONS: Women with CHD-associated mild PH appear to have better outcomes compared with women with CHD-associated moderate-to-severe PH, and with event rates similar for most outcomes with women with CHD and no PH. Multimodality risk assessment, including PH severity, brain natriuretic peptide level, and New York Heart Association class, may be useful in risk stratification in pregnancy with PH. Follow-up with a multidisciplinary team and strict antenatal supervision during pregnancy may also help to mitigate the risk of adverse maternal cardiac events.

Fetal Pulmonary Valvuloplasty in Fetuses with Right Ventricular Outflow Tract Obstructive Disease: Experience and Outcome of the First Five Cases in China.

The current study was to report our initial experiences of fetal pulmonary valvuloplasty (FPV) for fetuses with pulmonary atresia with intact ventricular septum (PA/IVS) and critical pulmonary stenosis (CPS), including case selection, technical feasibility, and the effects of FPV on utero and postnatal outcome. Two fetuses with PA/IVS and three fetuses with CPS were enrolled between September 2016 and April 2018. All fetuses were with concomitant severe right ventricular dysplasia and growth arrest. Parameters of right cardiac development and hemodynamics, including tricuspid/mitral annulus ratio (TV/MV), right ventricle/left ventricle long-axis ratio (RV/LV), tricuspid valve inflow duration/cardiac cycle ratio (TVI/CC), degree of tricuspid regurgitation (TR), and blood flow direction of arterial duct and ductus venosus, were evaluated using echocardiogram. FPV was performed trans-abdominally under ultrasound guidance. Echocardiogram was performed post-FPV and every 2-4 weeks thereafter until delivery. The median gestational age at the time of FPV was 28 weeks. From technical perspective, pulmonary balloon valvuloplasty was successfully performed and the opening of pulmonary valve was improved in all fetuses in 2-4 weeks. However, progressive restenosis was observed in four fetuses with gestation advancing, and re-atresia occurred in two PA/IVS fetuses at 36th and 37th weeks' gestation, respectively. The growth trajectories of TV/MV, RV/LV, and TVI/CC were improved in the 1st week after FPV and then slowed down along with pulmonary valve restenosis. All fetuses were born alive and underwent postnatal interventions, including pulmonary balloon valvuloplasty in three fetuses and surgical procedures in two fetuses. During follow-up, three fetuses turned to be biventricular, one became one and a half ventricular at 1-year old, and one died of neonatal infection. Although pulmonary valve restenosis might occur as gestation advancing, FPV seems to be a safe and feasible procedure to improve the growth trajectories of right heart for fetuses with PA/IVS and CPS.

Prevalence and associated risk factors of insomnia among pregnant women in China.

BACKGROUND: Insomnia is common during pregnancy but the prevalence and risk factors of insomnia in Chinese women during pregnancy is not well studied. This study aimed to examine the prevalence of insomnia and its risk factors in Chinese women during pregnancy. METHODS: In this cross sectional study, 436 Chinese pregnant women with Insomnia Severity Index (ISI) ≥ 8 were clinically assessed using the insomnia criteria based on the combination of DSM-IV (Diagnostic and Statistical Manual-4th Edition) and ICD-10 (International Classification of Dieases, 10th Edition). Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), Dysfunctional Beliefs and Attitudes about Sleep Scale (DBAS), Pregnancy Pressure Scale (PPS), Perceived physical discomfort level and number, Epworth Sleepiness Scale (ESS), and a general socio-demographic questionnaire were administered. RESULTS: The results showed that about 20% of the pregnant women met the strict diagnosis criteria of insomnia. Independent-samples t-test revealed that several risk factors were correlated with the group with insomnia (N = 84) compared to the group without insomnia (N = 352). Binary Logistic regression analysis found that more significant bed partner influence (OR = 1.92, 95% CI: 1.03-3.60), depressive symptoms (OR = 1.07, 95% CI: 1.00-1.14), daytime sleepiness (OR = 1.07, 95% CI: 1.01-1.14), subjective somatic discomfort (OR = 2.27, 95% CI: 1.11-4.65), kinds of somatic discomfort (OR = 1.14, 95% CI: 1.03-1.27) and later gestation (OR = 1.05, 95% CI: 1.01-1.09) were significantly associated with insomnia. CONCLUSION: In this cohort of Chinese pregnant women, about a fifth of women suffered from clinically significant insomnia. Measures to prevent the adverse effects of insomnia should be provided to pregnant women with depressive symptoms, Sleep disturbance of the bed partner, excessive daytime sleepiness and somatic discomfort, especially late in gestation.

Long noncoding RNA SNHG6 contributes to ventricular septal defect formation via negative regulation of miR-101 and activation of Wnt/ß-catenin pathway.

This study aimed to investigate the role and regulatory mechanism of small nucleolar RNA host gene 6 (SNHG6), a long noncoding RNA, in the formation of ventricular septal defect (VSD). The expression of SNHG6 in fetal cardiac tissues with VSD, mouse heart embryo development and the differentiation of P19 cells into cardiomyocytes were determined. Moreover, the effect of aberrant expression of SNHG6 on P19 cell proliferation, cell cycle, apoptosis and differentiation was further analyzed to explore the role of SNHG6 in affecting myocardial development. Furthermore, the regulatory mechanism between SNHG6 and miR-101 as well as between SNHG6 and activation of Wnt/ß-catenin pathway was investigated. SNHG6 was upregulated in fetal cardiac tissues with VSD, and decreased in the embryonic development of mice and differentiation of P19 cells into cardiomyocytes. Overexpression of SNHG6 inhibited P19 cell proliferation and induced apoptosis, as well as promoted cell differentiation into cardiomyocytes. Furthermore, SNHG6 could negative regulate the expression of miR-101, and the effects of SNHG6 on the modulation of P19 cell function were through negative regulation of miR-101. In addition, overexpression of SNHG6 activated Wnt/ß-catenin pathway, which was reversed after overexpression of SNHG6 and miR-101 synchronously. Our study reveals that SNHG6 may contribute to VSD formation via negative regulation of miR-101 and activation of Wnt/ß-catenin pathway. SNHG6 may constitute a potential therapeutic target in this disease.

Perinatal and early postnatal outcomes for fetuses with prenatally diagnosed d-transposition of the great arteries: a prospective cohort study assessing the effect of standardised prenatal consultation.

BACKGROUND: The aim of this study was to explore perinatal and early postnatal outcomes in fetuses with prenatally diagnosed d-transposition of the great arteries and impacts of standardised prenatal consultation. METHODS: All fetuses with prenatally diagnosed d-transposition of the great arteries prospectively enrolled at South China cardiac centre from 2011 to 2015. Standardised prenatal consultation was introduced in 2013 and comprehensive measures were implemented, such as establishing fetal CHD Outpatient Consultation Service, performing standard prenatal consultation according to specifications, and establishing a multidisciplinary team with senior specialists performing in-person consultations. Continuous follow-up investigation was conducted. Perinatal and postnatal outcomes were compared before and after consultation including live birth, elective termination of pregnancy, spontaneous fetal death, stillbirths, referral for surgery, and survival. RESULTS: In all, 146 fetuses were enrolled with 41 (28%) lost to follow-up. Among 105 remaining fetuses, 29 (28%) were live births and 76 (72%) were terminated. After consultation, live birth rate was higher (50 versus 33%) and termination rate was lower (50 versus 76%), although there was no statistical significance. Excluding three live births without postnatal d-transposition of the great arteries, 65% (17/26) underwent arterial switch operation within 30 days. A total of three in-hospital deaths occurred and during the 10-month follow-up period, one death was observed. In one case, the switch procedure was performed at 13 months and the infant survived. Out of eight infants without arterial switch operation, two died. CONCLUSIONS: Live birth rate increased after consultation; however, termination remained high. Combining termination, patients without arterial switch operation, and operative mortality, outcomes of d-transposition of the great arteries infants can be improved. Standard consultation, multidisciplinary collaboration, and improved perinatal care are important to improve outcomes.

Case Report: Totally endoscopic minimally invasive mitral valve surgery during pregnancy: a case series.

A totally endoscopic minimally invasive approach is widely used for cardiac valve surgery in normal adults. However, minimally invasive cardiac surgery during pregnancy is rarely reported. In addition to traditional median thoracotomy, totally endoscopic minimally invasive approaches can now be used for pregnant patients. We describe our experience with totally endoscopic cardiac valve surgery (TECVS) during pregnancy, which is safe for both mothers and fetuses.

Transcatheter mitral valve-in-valve for pregnancy with anti-phospholipid syndrome: a case report.

BACKGROUND: Perioperative management and cardiac surgery in pregnant women with anti-phospholipid syndrome combined with heart valve disease have been rarely reported. CASE PRESENTATION: We describe a case of transcatheter mitral valve-in-valve replacement in a pregnant woman with bioprosthetic valve failure and anti-phospholipid syndrome at 18 weeks' gestation. The patient underwent a cesarean section delivery at 34 weeks of gestation, resulting in the birth of a healthy baby. CONCLUSIONS: Transapical mitral valve-in-valve surgery resulted in safe maternal and infant outcomes in a pregnant woman with anti-phospholipid syndrome combined with mitral bioprosthetic valve failure. The success of this procedure underscored the importance of multidisciplinary teamwork.

Management of left atrial myxoma in pregnant women: a case series.

BACKGROUND: Left atrial myxoma during pregnancy is rare. We present three cases in order to aid in the management. CASE PRESENTATION: Three cases of left atrial myxoma during pregnancy were presented in this article. Three patients all received multidisciplinary team work and acquired good outcomes. The case 1 had no symptoms and delivered before traditional cardiac surgery. The case 2 and case 3 undergone totally endoscopic minimally invasive cardiac surgery during pregnancy. The case 3 maintained pregnancy to term and gave birth to a healthy baby via vaginal delivery. No relapse of the tumor was observed. CONCLUSIONS: The management of left atrial myxoma during pregnancy ought to be individualized and combined with the gestational age. If the diagnosis was made in the first two trimesters of pregnancy, totally endoscopic minimally invasive cardiac surgery during pregnancy would be an optimal choice. The patients can benefit from the multidisciplinary team work.

Maternal serum neonicotinoids during early-mid pregnancy and congenital heart diseases in offspring: An exploratory study.

Experimental evidence has indicated a correlation between in-utero exposure to neonicotinoid pesticides (NEOs) and adverse birth outcomes in mammals. However, the distribution of NEO exposure during human pregnancy, as well as its association with congenital heart diseases (CHDs), the most common birth defects, are unclear. Our purpose was to explore the distribution of and contributing factors to NEO exposure in pregnant women during early-mid pregnancy and to assess the associations between NEOs and CHDs. This nested case-control study was conducted within an ongoing prospective birth cohort study and enrolled 141 CHD singletons and their 282 individually matched controls. Six "parent" NEOs and three NEO metabolites were measured in maternal serum collected at an average gestational age of 16 weeks, using liquid chromatography-tandem mass spectrometry. Logistic regression was used to quantify the NEOs-CHDs associations and explore potential contributing factors to serum NEO levels in controls. N-desmethyl acetamiprid (N-dm-ACE) and imidacloprid (IMI) were the most frequently detected NEOs, found in 100% and 20% of maternal sera, respectively. We did not find a statistically significant association between total NEOs and overall CHDs. However, there was a trend towards a higher risk of septal defects with greater serum NEOs (ORs ranged from 1.80 to 2.36), especially nitro-containing NEOs represented by IMI. Pregnant women with lower education had elevated serum total NEOs compared to women with higher education (OR = 48.39, 95% CI: 23.48-99.72). Pregnant women were primarily exposed to N-dm-ACE and IMI during early-mid pregnancy. Gestational exposure to NEOs may be associated with an increased risk of septal defects, but the evidence is limited at present. Education is a potential contributing factor to NEO exposure in pregnant women. Larger and more precise studies with longitudinal biospecimen collection, are recommended to validate our exploratory findings.

Maternal Serum Folate During Pregnancy and Congenital Heart Disease in Offspring.

Importance: The association of folate supplementation with congenital heart disease (CHD) prevention is controversial. Objective: To examine the association of maternal serum folate levels at early to midpregnancy with CHD risk in offspring. Design, Setting, and Participants: This case-control study recruited participants from one of China's largest cardiac referral centers between 2015 and 2018. CHD cases and non-CHD controls were matched according to maternal age at a ratio of 1:4. Data were analyzed from May to August 2023. Exposures: Maternal serum levels of folate, vitamin B12, and homocysteine were measured around the gestational age of 16 weeks. Main Outcomes and Measures: The primary outcome was CHD, which was confirmed using echocardiography. The association between CHD risk in offspring with maternal folate levels was measured using adjusted odds ratios (aORs) with 95% CIs in conditional logistic regression analyses. Interactions between folate, vitamin B12, and homocysteine and CHD were estimated on a multiplicative scale. Results: A total of 129 CHD cases with ventricular septal defect as the most common phenotype and 516 matched controls were included. The mean (SD) maternal age at pregnancy was 31.6 (5.3) years. There was a U-shaped association between maternal serum folate levels at early to midpregnancy and CHD risk in offspring. Compared with the offspring in the second and third quartiles of maternal folate, those in the lowest (aOR, 3.09; 95% CI, 1.88-5.08) and highest quartiles (OR, 1.81; 95% CI, 1.07-3.06) had increased odds of CHD. The ORs were higher when applying the World Health Organization criteria to determine the normal range for serum folate levels. Interaction analyses suggested that the adverse associations between low and high maternal folate and CHD risk might be further magnified by vitamin B12 deficiency or elevated homocysteine. Conclusions and relevance: In this case-control study of CHD, low maternal serum folate levels in early to midpregnancy were associated with an increased CHD risk in offspring, and excessively high folate levels were also associated with an elevated CHD risk. Further investigation is needed to make causal inferences for the observed associations and elucidate the underlying mechanisms.

Development of gut microbiota and bifidobacterial communities of neonates in the first 6 weeks and their inheritance from mother.

Microbiota especially Bifidobacterium play an important role in adjusting and maintaining homeostatic balance within the infant intestine. The aim of this study was to elucidate the relationship between maternal and infant gut microbiota and identify the Bifidobacterium species that may transfer from mother to infant over the first 42 days of the infant's life. Nineteen mother-infant-pair fecal samples were collected and the diversity and composition of the total bacterial and Bifidobacterium communities were analyzed via 16S rDNA and bifidobacterial groEL gene high throughput sequencing. The results revealed that the relative abundance of Bifidobacterium was significantly higher in the infant gut while Parabacteroides, Blautia, Coprococcus, Lachnospira and Faecalibacterium were at lower relative abundance in 7-day and 42-day infant fecal samples compared to the maternal samples. The maternal gut has more B. pseudocatenulatum. In the infant group, B. breve and B. dentium relative abundance increased while B. animalis subsp. lactis decreased from days 7 to 42. Additionally, B. longum subsp. longum isolated from FGZ16 and FGZ35 may have transferred from mother to infant and colonized the infant gut. The results of the current study provide insight toward the infant gut microbiota composition and structure during the first 42 days and may help guide Bifidobacterium supplementation strategies in mothers and infants.

Gestational exposure to perfluoroalkyl substances and congenital heart defects: A nested case-control pilot study.

BACKGROUND: Accumulating evidence suggests that environmental pollutants may contribute to the occurrence of congenital heart defects (CHDs). However, no previous studies have evaluated the impact of perfluoroalkyl substances (PFAS), persistent environmental pollutants, on CHDs. This exploratory study aimed to generate testable hypotheses of the association between gestational PFAS and the risk of CHDs. METHODS: A nested case-control study was conducted in a cohort of 11,578 newborns. Exposure odds ratios were compared between 158 CHD cases and 158 non-malformed controls delivered at the same hospital, individually matched by maternal age (±5 years) and parity. Concentrations of 27 PFAS, including linear and branched isomers, were determined in maternal peripheral blood and cord blood plasma collected before and during delivery using a ultra-performance liquid chromatography coupled to mass spectrometry. Conditional logistic regression was utilized to evaluate associations between individual PFAS and the risk of CHDs, adjusted for confounding variables. RESULTS: Maternal gestational exposure to the highly branched perfluorooctanesulfonate (PFOS) isomer potassium 6-trifluoromethyperfluoroheptanesulfonate [6 m-PFOS, adjusted odds ratio (aOR) (95% CI) = 2.47(1.05,5.83)] and perfluorodecanoic acid [PFDA, aOR (95% CI) = 2.33(1.00,5.45)] were associated with increased odds of septal defects with statistical significance, while linear PFOS [aOR (95% CI) = 3.65(1.09,12.16)] and perfluoro-n-dodecanoic acid [PFDoA, aOR (95% CI) = 6.82(1.75, 26.61)] were associated with conotruncal defects. Effect estimates also suggested associations for higher maternal 6 m-PFOS and PFDA concentrations with ventricular septal defect. However, we did not observe these associations in cord blood. CONCLUSION: These exploratory findings suggested that gestational exposure to most PFAS, especially linear PFOS, 6 m-PFOS, PFDA, and PFDoA, was associated with greater risks for septal and conotruncal defects. However, a larger, adequately powered study is needed to confirm our findings, and to more comprehensively investigate the potential teratogenic effects of other more recently introduced PFAS, and on associations with individual CHD subtypes.

Using Innovative Machine Learning Methods to Screen and Identify Predictors of Congenital Heart Diseases.

Objective: Congenital heart diseases (CHDs) are associated with an extremely heavy global disease burden as the most common category of birth defects. Genetic and environmental factors have been identified as risk factors of CHDs previously. However, high volume clinical indicators have never been considered when predicting CHDs. This study aimed to predict the occurrence of CHDs by considering thousands of variables from self-reported questionnaires and routinely collected clinical laboratory data using machine learning algorithms. Methods: We conducted a birth cohort study at one of the largest cardiac centers in China from 2011 to 2017. All fetuses were screened for CHDs using ultrasound and cases were confirmed by at least two pediatric cardiologists using echocardiogram. A total of 1,127 potential predictors were included to predict CHDs. We used the Explainable Boosting Machine (EBM) for prediction and evaluated the model performance using area under the Receive Operating Characteristics (ROC) curves (AUC). The top predictors were selected according to their contributions and predictive values. Thresholds were calculated for the most significant predictors. Results: Overall, 5,390 mother-child pairs were recruited. Our prediction model achieved an AUC of 76% (69-83%) from out-of-sample predictions. Among the top 35 predictors of CHDs we identified, 34 were from clinical laboratory tests and only one was from the questionnaire (abortion history). Total accuracy, sensitivity, and specificity were 0.65, 0.74, and 0.65, respectively. Maternal serum uric acid (UA), glucose, and coagulation levels were the most consistent and significant predictors of CHDs. According to the thresholds of the predictors identified in our study, which did not reach the current clinical diagnosis criteria, elevated UA (>4.38 mg/dl), shortened activated partial thromboplastin time (<33.33 s), and elevated glucose levels were the most important predictors and were associated with ranges of 1.17-1.54 relative risks of CHDs. We have developed an online predictive tool for CHDs based on our findings that may help screening and prevention of CHDs. Conclusions: Maternal UA, glucose, and coagulation levels were the most consistent and significant predictors of CHDs. Thresholds below the current clinical definition of "abnormal" for these predictors could be used to help develop CHD screening and prevention strategies.

Correction to: Nicotine Suppresses the Invasiveness of Human Trophoblasts by Downregulation of CXCL12 Expression through the Alpha-7 Subunit of the Nicotinic Acetylcholine Receptor.

Due to an error in production, the article should have indicated that Jing Chen and Min Qiu are co-first authors, as displayed here.

Cardiac operation under cardiopulmonary bypass during pregnancy.

BACKGROUND: Certain pregnant women suffer from cardiac pathology,and a few of them need cardiac operations under cardiopulmonary bypass during pregnancy. Feto-neonatal and maternal outcomes have not been sufficiently described. METHODS: We conducted a retrospective review of 22 cases of women undergoing cardiac operations under cardiopulmonary bypass during pregnancy in our hospital from Jan.2014 to Mar.2019. RESULTS: All 22 patients were alive after treatment. The types of cardiac disorders included congenital heart defects, rheumatic heart disease,infective endocarditis,aortic dissection, obstruction and/or thrombosis of a prosthetic valve. Only one case was a twin pregnancy,and the other 21 cases were singletons. Four fetuses died in the utero after surgery. Three patients chose termination of the pregnancy after the cardiac operations: one fetus was detected abnormity of the brain and the other two patients abandoned pregnancy. Fourteen fetuses were alive and born without any abnormity. Two fetuses suffered from neonatal intracranial hemorrhage and died after birth. CONCLUSIONS: Cardiac operation under cardiopulmonary bypass during pregnancy is a challenge for physicians in multidisciplinary teams. Strictly evaluating the indication is vital. On the other hand, some patients can benefit from this management.

Nicotine Suppresses the Invasiveness of Human Trophoblasts by Downregulation of CXCL12 Expression through the Alpha-7 Subunit of the Nicotinic Acetylcholine Receptor.

Smoke exposure during pregnancy has detrimental effects upon numerous fetal and neonatal outcomes. Nicotine (the main component of tobacco) has been suggested to affect placental development. During placental development, efficient invasion by trophoblasts is required for establishment of the fetus-maternal circulation. In this study we explored the regulation of trophoblast invasion by nicotine. An immortalized first trimester extravillous trophoblast cell line (HTR-8/SVneo cells) was used for all the experiments, which were treated by nicotine, methyllycaconitine, and C-X-C motif chemokine ligand 12 (CXCL12). Total RNA and protein were used to study the expressions of nicotinic acetylcholine receptors (nAChRs), and transwell assay was used to study invasiveness. Changes of RNA expression due to nicotine treatment were detected by RNA sequence. Level of CXCL12 mRNA was verified by quantitative PCR. We showed that HTR-8/SVneo expressed subunits α2-4, α7, α9, ß1, and ß2 of nAChRs. Nicotine downregulated CXCL12 expression and inhibited trophoblast invasion. Methyllycaconitine, as an antagonist of the α7 homopolymer, blocked the inhibitory effect of nicotine. CXCL12 could rescue the nicotine-induced inhibitory effect on invasion of HTR-8/SVneo cells. These results suggest that the α7 subunit of the nAChR has important roles in modulating trophoblast invasion through CXCL12.

Weighted gene co­expression network analysis identifies key genes from extracellular vesicles as potential prognostic biomarkers for congenital pulmonary stenosis.

Pulmonary stenosis (PS) is a congenital heart disease characterized by a dynamic or fixed anatomic obstruction of blood flow from the right ventricle to the pulmonary arterial vasculature. In the present study, extracellular vesicle long RNAs (EVLRs) from pregnant females who had healthy infants or PS infants were analyzed by RNA sequencing, and their diagnostic potential for PS during pregnancy was evaluated. A method for the selection of genes that could be considered as informative for the prediction PS based on extracellular vesicles (EVs) from pregnant females using long­read RNA sequencing was developed. Blood samples were collected from females carrying fetuses with PS and females carrying unaffected fetuses (n=6 in each group). Physical characterization of EVs was performed using nanoparticle tracking analysis, transmission electron microscopy and western blotting. EVLRs from plasma were profiled by RNA sequencing and mRNA co­expression modules were constructed by weighted gene co­expression network analysis (WGCNA). Gene Ontology (GO) enrichment analysis was used to predict the function of the genes in each module. Hub genes were filtered out based on WGCNA and visualized using Cytoscape. EVLRs consisted of mRNAs, microRNAs and long non­coding RNA. Overall, 26 modules were identified containing 16,394 genes. All modules were independent of each other. One particular module, referred to as the blue module, was markedly different between the two groups. A total of 735 hub genes in the blue module were identified, of which 33 were visualized, demonstrating the connection between these hub genes. GO enrichment analysis demonstrated that the analyzed hub genes were enriched in 'glucose transport', 'ATP­dependent chromatin remodeling', 'histone deacetylation', 'histone H3­K4 methylation', 'DNA methylation', 'apoptotic signaling pathway' and 'glucocorticoid receptor signaling pathway'. The hub genes identified in this module may provide a genetic framework for prenatal PS diagnosis. Furthermore, functional analysis of these associated genes may provide a theoretical basis for further research on PS pathogenesis.

Evaluation of interactive effects between paternal alcohol consumption and paternal socioeconomic status and environmental exposures on congenital heart defects.

BACKGROUND: While the maternal risk factors on congenital heart defects (CHDs) have often been assessed, paternal contribution to CHDs, especially the joint effects of paternal risk factors on CHDs remain unknown. This study examined the major impacts of paternal alcohol consumption and its interaction (on multiplicative and additive scales) with paternal socioeconomic status (SES) and environmental exposures on CHDs in China. METHODS: A population-based case-control study involving 4,726 singleton CHDs cases and 4,726 controls (without any malformation and matched on hospital, gender, and gestational age) was conducted in Guangdong, China, 2004-2014. Information on parental demographics, behavioral patterns, disease/medication, and environmental exposures (3 months before pregnancy) was collected through face-to-face interviews. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) while controlling for all parental factors. RESULTS: Paternal alcohol consumption was associated with an increased OR of CHDs (adjusted OR = 2.87, 95% CI: 2.25-3.65). Additionally, paternal smoking, industry occupation, organic solvent contact, virus infection and antibiotic use, living in rural areas, low household income, and migrant status were significantly associated with CHDs (ORs ranged: 1.42-4.44). Significant additive or multiplicative interactions were observed between paternal alcohol consumption and paternal smoking, industrial occupation, and low income on any CHDs (interaction contrast ratio [ICR] = 4.72, 95% CI: 0.96-8.47] and septal defects (ICRs ranged from 2.04 to 2.79, p < .05). CONCLUSIONS: Paternal alcohol consumption and multiple paternal factors were significantly associated with CHDs in China. Paternal smoking and low SES factors modified paternal alcohol consumption-CHDs relationships. Further studies are needed to confirm these findings.

Maternal residential greenness and congenital heart defects in infants: A large case-control study in Southern China.

BACKGROUND: Proximity to greenness has shown protective effects on coronary heart diseases by limiting exposure to environmental hazards, encouraging physical activity, and reducing mental stress. However, no studies have previously evaluated the impacts of greenness on congenital heart defects (CHDs). We examined the association between maternal residential greenness and the risks of CHDs. METHODS: We conducted a case-control study (8042 children with major CHDs and 6887 controls without malformations) in 21 cities in Southern China, 2004 - 2016. CHDs cases were diagnosed and verified by obstetrician, pediatrician, or pediatric cardiologists, within one year. We estimated maternal residential greenness using satellite-derived normalized difference vegetation index (NDVI) in zones of 500 meters (m) and 1000 m surrounding participants' residences. Logistic regression models were used to assess NDVI-CHD relationships adjusting for confounders. RESULTS: Interquartile range NDVI increases within 500 m or 1000 m were associated with odds ratios (OR) of 0.95 (95% confidence interval (CI): 0.92, 0.98) and 0.94 (95%CI: 0.91, 0.97) for total CHDs respectively. Air pollutants mediated 52.1% of the association. We also identified a protective threshold at 0.21 NDVI on CHD. Similar protective effects from greenness were found in most CHDs subtypes. The protective associations were stronger for fall, urban or permanent residents, higher household income maternal age ≤35 years of age, and high maternal education (ORs: ranged from 0.85 to 0.96). CONCLUSION: Our findings suggest a beneficial effect of maternal residential greenness on CHDs. Further studies are needed to confirm our findings, which will help to refine preventive health and urban design strategies.

Associations between toxic and essential trace elements in maternal blood and fetal congenital heart defects.

Prenatal exposure to toxic trace elements, including heavy metals, is an important public health concern. Few studies have assessed if individual and multiple trace elements simultaneously affect cardiac development. The current study evaluated the association between maternal blood lead (Pb), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), and selenium (Se) levels and congenital heart defects (CHDs) in offspring. This hospital-based case-control study included 112 case and 107 control infants. Maternal peripheral blood draw was made during gestational weeks 17-40 and used to determine trace element levels by inductively coupled plasma mass spectrometry. Multivariable logistic regression was used to assess associations and interactions between individual and multiple trace elements and fetal CHDs, adjusted for maternal age, parity, education, newborn gender, migrant, folic acid or multivitamin intake, cigarette smoking, maternal prepregnancy body mass index, and time of sample collection. Control participants had medians of 2.61µg/dL Pb, 1.76µg/L Cd, 3.57µg/L Cr, 896.56µg/L Cu, 4.17µg/L Hg, and 186.47µg/L Se in blood. In a model including all measured trace elements and adjusted for confounders, high levels of maternal Pb (OR=12.09, 95% CI: 2.81, 51.97) and Se (OR=0.25, 95% CI: 0.08, 0.77) were harmful and protective predictors of CHDs, respectively, with positive and negative interactions suggested for Cd with Pb and Se with Pb, respectively. Similar associations were detected for subgroups of CHDs, including conotruncal defects, septal defects, and right ventricle outflow tract obstruction. Our results suggest that even under the current standard for protecting human health (10µg/dL), Pb exposure poses an important health threat. These data can be used for developing interventions and identifying high-risk pregnancies.