Background: Advances have been made in identifying genetic etiologies and maternal risk factors of congenital heart defects (CHDs), while few literatures are available regarding paternal risk factors for CHDs. Thus, we aim to conduct a meta‐analysis and systematic review about the non‐genetic paternal risk factors for CHDs.Methods: We searched the PubMed, MEDLINE, and Cochrane Library online databases and identified 31 studies published between 1990 and 2018 according to the inclusion criteria. Paternal risk factors were divided into subgroups, and summarized odd ratios (OR) were calculated.Results: Paternal age between 24 and 29 years decreased the risk of CHDs in the offspring (OR = 0.90 [0.82, 0.98]), while paternal age ≥ 35 years old increased the risk of CHDs (35‐39 years old: OR = 1.14 [1.09, 1.19], and ≥ 40 years: OR = 1.27 [1.14, 1.42]). Paternal cigarette smoking increased the risk of CHDs in a dose‐dependent way. Paternal wine drinking (OR = 1.47 [1.05, 2.07]) and exposure to chemical agents or drugs (OR = 2.15 [1.53, 3.02]) also increased the risk of CHDs. Some specific paternal occupations were also associated with increased risk for CHDs or CHD subtypes including factory workers, janitors, painters, and plywood mill workers.Conclusions: This meta‐analysis and systematic review suggested that advanced paternal age, cigarette smoking, wine drinking, exposure to chemical agents or drugs and some specific occupations were associated with an increased risk of CHDs. More measures should be taken to reduce occupational and environment exposures. At the same time, fertility at certain age and establishment of healthy life habits are strongly recommended.

Background: Previous research suggested an association between maternal exposure to ambient air pollutants and the risk of congenital heart disease (CHD). However, the effect of individual prenatal exposure to indoor air pollutants on CHD occurrence was not reported. Methods: We performed a hospital-based case–control study to investigate the association between personal air pollution exposure during pregnancy and the risk of CHD in offspring. A total of 44 cases and 75 controls were included from two hospitals in East China. We investigated maternal and residential environmental characteristics using a questionnaire and obtained personal indoor air samples to assess particulate matter (PM) and volatile organic compounds (VOCs) from 22–30 gestational weeks. Formaldehyde, benzene, toluene, xylene, total volatile organic compounds (TVOCs), PM_2.5, and PM₁₀ were assessed. Logistic regression was performed to assess associations and interactions between individual indoor air pollutants and CHD after adjusting for confounders. The potential residential environmental factors affecting the risks of indoor air pollutants on CHD were also assessed. Results: Median TVOC (0.400 vs. 0.005 mg/m³, P < 0.001) exposure levels in cases were significantly higher than controls. A logistic regression model adjusted for confounders revealed that exposure to high levels of indoor TVOCs (AOR 7.09, 95% CI 2.10–23.88) during pregnancy was associated with risks for CHD and the occurrence of some major CHD subtype in offspring. These risk effects were enhanced in pregnant women living in a newly renovated house but were mitigated by household use of smoke ventilators when cooking. We observed a positive interaction of maternal exposure to TVOCs and PM_2.5 and the risk for CHD. Conclusions: Maternal exposure to indoor VOCs and PMs may increase the risk of giving birth to foetuses with CHD.

Background: Humans are widely exposed to perfluoroalkyl substances (PFAS), which have been found to be associated with various adverse birth outcomes. As blood pressure (BP) is an important parameter reflecting cardiovascular health in early life, it is necessary to investigate the association of PFAS exposure during early lifetime and BP in childhood. Therefore, we investigated the potential association between PFAS levels in umbilical cord blood and BP of the offspring at 4 years of age in a prospective cohort study. Methods: PFAS in umbilical cord blood samples after birth were measured with high-performance liquid chromatography/tandem mass spectrometry in the Shanghai Birth Cohort. BP was measured at 4 years of age in the offspring. Multiple linear regression model was used to investigate the association between individual PFAS level and BP of the offspring. Bayesian kernel machine regression (BKMR) was used to analyze the relationship between the PFAS mixture and BP of the offspring, while weighted quantile sum (WQS) regression was utilized for sensitivity analysis. Results: A total of 129 mother-child pairs were included in our analysis. In multiple linear regressions, we observed that long-chain PFAS, mainly including perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA) and perfluoroundecanoic acid (PFUA), was negatively associated with systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MAP). BKMR showed that an increase in umbilical cord blood PFAS mixture levels was significantly associated with a decrease in SBP, DBP and MAP [Estimated differences (SD): -0.433 (0.161); -0.437 (0.176); -0.382 (0.179), respectively]. The most important component in the association with SBP, DBP, and MAP was PFUA. PFDoA was found to be positively associated with SBP, DBP and MAP in both models. Sensitivity analysis with WQS regression showed consistent results. Conclusion: Our findings suggested that umbilical blood PFAS exposure was negatively associated with BP in offspring at 4 years of age, including SBP, DBP, and MAP.

Background: Conotruncal defects (CTDs) are a type of heterogeneous congenital heart diseases (CHDs), but little is known about their etiology. Increasing evidence has demonstrated that fibroblast growth factor (FGF) 8 and FGF10 may be involved in the pathogenesis of CTDs. Methods: The variants of FGF8 and FGF10 in unrelated Chinese Han patients with CHDs (n = 585), and healthy controls (n = 319) were investigated. The expression and function of these patient-identified variants were detected to confirm the potential pathogenicity of the non-synonymous variants. The expression of FGF8 and FGF10 during the differentiation of human embryonic stem cells (hESCs) to cardiomyocytes and in Carnegie stage 13 human embryo was also identified. Results: Two probable deleterious variants (p.C10Y, p.R184H) of FGF8 and one deletion mutant (p.23_24del) of FGF10 were identified in three patients with CTD. Immunofluorescence suggested that variants did not affect the intracellular localization, whereas ELISA showed that the p.C10Y and p.23_24del variants reduced the amount of secreted FGF8 and FGF10, respectively. Quantitative RT-PCR and western blotting showed that the expression of FGF8 and FGF10 variants was increased compared with wild-type; however, their functions were reduced. And we found that FGF8 and FGF10 were expressed in the outflow tract (OFT) during human embryonic development, and were dynamically expressed during the differentiation of hESCs into cardiomyocytes. Conclusion: Our results provided evidence that damaging variants of FGF8 and FGF10 were likely contribute to the etiology of CTD. This discovery expanded the spectrum of FGF mutations and underscored the pathogenic correlation between FGF mutations and CTD.

Background: Current evidence relating birthweight and gestational age to cardiovascular risk is conflicting. Whether these factors have independent or interactive impacts on cardiovascular parameters during early childhood remains unclear. The goal of this study was to explore whether there were any independent and interactive effects of gestational age and birthweight on blood pressure, left ventricle (LV) structure, and function in 4 years old. Methods: This study included 1194 children in the Shanghai Birth Cohort from 2013 to 2016. Information about the mothers and children was recorded at time of birth using a questionnaire. Follow-up measurements, including anthropometric, blood pressure, and echocardiography, were taken between 2018 and 2021, when the children were 4 years old. Multiple linear or logistic regressions and restricted cubic spline were used to explore the association of birthweight and gestational age with cardiovascular measurements. Results: Gestational age had a significant negative correlation with both systolic blood pressure [β = − 0.41, 95% CI: (− 0.76, − 0.07)] and mean arterial pressure [β = − 0.36, 95%CI: (− 0.66, − 0.07)]. The risk of prehypertension decreased with increased gestational age [OR = 0.54, 95% CI: (0.32, 0.93)]. The relationship between birthweight with blood pressure was U-shape (P for non-linear < 0.001). The wall thickness, volume, mass, and cardiac output of LV increased with birthweight, though the ejection fraction [β = − 1.02, 95% CI: (− 1.76, − 0.27)] and shorten fraction [β = 0.72, 95% CI: (− 1.31, − 0.14)] decreased with birthweight. The risk of LV hypertrophy was not associated with birthweight [OR = 1.59, 95% CI: (0.68, 3.73)]. Conclusions: In this study, we found different associations of birthweight and gestational age with cardiovascular measurements in the offspring at 4 years old. Gestational age influenced blood pressure independent of birthweight. Heart size and function at 4 years old was influenced mostly by birthweight and not by gestational age.

Previous research investigating the correlation between prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and subsequent blood pressure (BP) in offspring has yielded limited and contradictory findings. This study was conducted to investigate the potential relationship between maternal PFAS levels during pregnancy and subsequent BP in early childhood. A total of 129 expectant mothers from the Shanghai Birth Cohort were included in the study. Using high-performance liquid chromatography/tandem mass spectrometry, we measured ten PFAS compounds in maternal plasma throughout the pregnancy. When the children reached the age of 4, we examined their systolic BP (SBP) and diastolic BP (DBP), along with mean arterial pressure (MAP) and pulse pressure (PP). Data interpretation employed multiple linear and logistic regression models, complemented by Bayesian kernel machine regression (BKMR).We found that the majority of PFAS concentrations remained stable during pregnancy. The linear and BKMR models indicated a positive relationship between the PFAS mixture in maternal plasma and offspring's DBP and MAP, with perfluorohexanesulphonic acid (PFHxS) having the most significant influence (PFHxS and DBP [first trimester:β=3.03, 95%CI: (1.01,5.05); second trimester: β=2.35, 95%CI: (0.94,3.75); third trimester: β=2.57, 95%CI:(0.80,4.34)]; MAP [first trimester:β=2.55, 95%CI: (0.64,4.45); second trimester: β=2.28, 95%CI: (0.95,3.61); third trimester: β=2.35, 95%CI:(0.68,4.01)]). Logistic regression highlighted an increased risk of prehypertension and hypertension in offspring with higher maternal PFHxS concentrations during all three trimesters [first trimester: OR=2.53, 95%CI:(1.11,5.79), second trimester: OR=2.05, 95%CI:(1.11,3.78), third trimester: OR=3.08, 95%CI:(1.40,6.79)]. A positive correlation was identified between the half-lives of PFAS and the odds ratio (OR) of prehypertension and hypertension in childhood (β=0.139, P=0.010). In conclusion, this research found maternal plasma PFAS concentrations to be positively associated with BP in offspring, with PFHxS showing the most significant influence. This correlation remained consistent throughout pregnancy, and this effect was proportional to the half-lives of PFAS.