Congenital Heart Defects In Offspring Research Articles

Maternal cardiovascular health in early pregnancy and the risk of congenital heart defects in offspring

BackgroundCongenital heart disease (CHD) is the predominant birth defect. This study aimed to explore the association between maternal cardiovascular health (CVH) and the CHD risk in offspring.MethodsWe used the prospective data from the Fujian Birth Cohort Study, collected from March 2019 to December 2022 on pregnant women within 14 weeks of gestation. Overall maternal CVH was assessed by seven CVH metrics (including physical activity, smoking, sleep duration, body mass index, blood pressure, total cholesterol, and fasting plasma glucose), with each metric classified as ideal, intermediate or poor with specific points. Participants were further allocated into high, moderate and low CVH categories based on the cumulative CVH score. The association with offspring CHD was determined with log-binominal regression models.ResultsA total of 19810 participants aged 29.7 (SD: 3.9) years were included, with 7846 (39.6%) classified as having high CVH, 10949 (55.3%) as having moderate CVH, and 1015 (5.1%) as having low CVH. The average offspring CHD rate was 2.52%, with rates of 2.35%, 2.52% and 3.84% across the high, moderate and low CVH categories, respectively (P = 0.02). Adjusted relative risks (RRs) of having offspring CHD were 0.64 (95% CI: 0.45-0.90, P = 0.001) for high CVH and 0.67 (95% CI: 0.48-0.93, P = 0.02) for moderate CVH compared to low CVH. For individual metrics, only ideal total cholesterol was significantly associated with lower offspring CHD (RR: 0.73, 95% CI: 0.59-0.83, P = 0.002).ConclusionsPregnant women of high or moderate CVH categories in early pregnancy had reduced risks of CHD in offspring, compared to those of low CVH. It is important to monitor and improve CVH during pre-pregnancy counseling and early prenatal care.

Maternal Diabetes and Overweight and Congenital Heart Defects in Offspring

Maternal diabetes and overweight or obesity are known to be associated with increased risk of congenital heart defects (CHDs) in offspring, but there are no large studies analyzing outcomes associated with these factors in 1 model. To investigate the association of maternal diabetes and overweight or obesity with CHDs among offspring in 1 model. This nationwide, population-based register study was conducted in a birth cohort from Finland consisting of all children born between 2006 and 2016 (620 751 individuals) and their mothers. Data were analyzed from January 2022 until November 2023. Maternal prepregnancy body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), categorized as underweight (<18.5), normal (18.5-24.9), overweight (25.0-29.9), and obesity (≥30), was assessed. Maternal diabetes status, classified as no diabetes, type 1 diabetes (T1D), type 2 or other diabetes, and gestational diabetes, was assessed. Odds ratios (ORs) of isolated CHDs in children were found. In addition, 9 anatomical CHD subgroups were studied. Of 620 751 children (316 802 males [51.0%]; 573 259 mothers aged 20-40 years [92.3%]) born in Finland during the study period, 10 254 children (1.7%) had an isolated CHD. Maternal T1D was associated with increased odds of having a child with any CHD (OR, 3.77 [95% CI, 3.26-4.36]) and 6 of 9 CHD subgroups (OR range, 3.28 [95% CI, 1.55-6.95] for other septal defects to 7.39 [95% CI, 3.00-18.21] for transposition of great arteries) compared with no maternal diabetes. Maternal overweight was associated with left ventricular outflow tract obstruction (OR, 1.28 [95% CI, 1.10-1.49]) and ventricular septal defects (OR, 0.92 [95% CI, 0.86-0.98]), and obesity was associated with complex defects (OR, 2.70 [95% CI, 1.14-6.43]) and right outflow tract obstruction (OR, 1.31 [95% CI, 1.09-1.58]) compared with normal maternal BMI. This study found that maternal T1D was associated with increased risk for most types of CHD in offspring, while obesity and overweight were associated with increased risk for complex defects and outflow tract obstruction and decreased risk for ventricular septal defects. These different risk profiles of T1D and overweight and obesity may suggest distinct underlying teratogenic mechanisms.

Fever and antibiotic use in maternal urinary tract infections during pregnancy and risk of congenital heart defects: Findings from the National Birth Defects Prevention Study.

Previous studies report an association between prenatal maternal urinary tract infections (UTI) and specific congenital heart defects (CHDs); however, the role of fever and antibiotic use on this association is poorly understood. Using data from the National Birth Defects Prevention Study, we examined whether the relationship between maternal UTIs during the periconceptional period and occurrence of CHDs is modified by the presence of fever due to UTI and corresponding antibiotic use among 11,704 CHD case infants and 11,636 live-born control infants. Information on UTIs, fever associated with UTI and antibiotic use (sulfonamides, nitrofurantoin, cephalosporins, penicillin, macrolides, and quinolones) during pregnancy were obtained using a computer-assisted telephone interview. Using unconditional multivariable logistic regression, we calculated adjusted odds ratios (ORs) to determine the association between maternal UTIs and subtypes of CHDs. Analyses were stratified by the presence of fever and medication use associated with UTI. The prevalence of UTIs during the periconceptional period was 7.6% in control mothers, and 8.7% in case mothers. In the absence of fever, UTI was associated with secundum atrial septal defects (ASD) (OR 1.3; 95% confidence interval [CI] 1.1-1.5) and in the absence of antibiotics, UTI was associated with conotruncal defects as a group and for four specific CHDs. When fever and UTI occurred concomitantly, no significantly elevated odds ratios were noticed for any subtypes of CHD. Among women with UTIs who used antibiotics, an elevated but statistically non-significant estimate was observed for secundum ASD (OR 1.4; 95% CI 1.0-2.0). Findings in the present study suggest that fever due to UTI and corresponding maternal antibiotic use do not substantially modify the association between maternal UTIs and specific CHDs in offspring. Further studies with larger sample sizes are warranted to guide clinical management of UTIs during the periconceptional period.

Assisted Reproductive Technology and Cardiovascular Outcomes in Parents and Offspring

BackgroundThe impact of assisted reproductive technology (ART) on the cardiovascular system is unclear. MethodsWe conducted a retrospective longitudinal cohort study of 1,001,593 pregnancies conceived naturally or through ART from 2008 to 2019 in Québec to assess the association of ART with cardiovascular disease in families. The exposure measure was ART. The outcome included severe maternal cardiovascular morbidity, congenital heart defects in offspring, and long-term risk of cardiovascular hospitalisation in mothers, fathers, and offspring during 11 years of follow-up. We estimated the association between ART and cardiovascular outcomes with the use of adjusted log-binomial regression (risk ratio, 95% confidence interval [CI]) and Cox proportional hazards regression models (hazard ratio [HR]). ResultsCompared with natural conception, ART was associated with 2.04 times the risk of severe cardiovascular morbidity in mothers (95% CI 1.86-2.23) and 1.38 times the risk of congenital heart defects in offspring (95% CI 1.26-1.50). ART was not associated with the risk of maternal cardiovascular hospitalisation following pregnancy (HR 1.03, 95% CI 0.88-1.21). However, ART was associated with an increased risk of paternal cardiovascular hospitalisation (HR 1.24, 95% CI 1.11-1.38) and offspring cardiovascular hospitalisation (HR 1.27, 95% CI 1.01-1.61), mainly due to an increased risk of hypertension. ConclusionsART is associated with only a small increase in the risk of cardiovascular complications in families. Parents and offspring may be reassured that ART likely has no major impact on the cardiovascular system.

Expression pattern of HLA-G and HLA-DR molecules on lymphocytes of women and their children with septal congenital heart defects

The aim of our study was to evaluate the features of HLA-G and HLA-DR expression on lymphocytes of women and their children with congenital heart defects (CHD) under the influence of allogeneic and autologous blood sera.38 women and their children with sporadic septal congenital heart defects (main group) were examined. The comparison groups included 21 women and their children without congenital heart disease (comparison group 1), as well as 17 apparently healthy men (comparison group 2). A total of 115 individuals were examined. The cross-match studies were carried out using a CytoFlex flow cytometer (Beckman Coulter, USA). The effects of autologous and allogeneic blood sera on HLA-G and HLA-DR expression on lymphocytes were evaluated. Statistical processing of the obtained results was carried out using Statistica for WINDOWS software packages from StatSoftInc. Version 10.0 and MedCalc 17.5.3. by the rules of variation statistics.The expression of HLA-G and HLA-DR molecules on the lymphocytes did not significantly change under the influence of autologous serum from men and women of children with CHD. At the same time, in women with more than two births of apparently healthy children, autologous serum significantly suppressed expression of HLA-G and HLA-DR on their lymphocytes. In particular, a pronounced and significant suppression was noted with autologous serum for HLA-DR molecules on CD3-positive lymphocytes. One may suggest that inflammation in the mother-embryo system is limited by this mechanism. Other significant differences concerned the effect of autologous and allogeneic (maternal) sera on the expression of HLA-G and HLA-DR molecules on the children’s lymphocytes. We have shown that in the group of children with septal CHD, autologous and allogeneic sera did not suppress the expression of HLA-G and HLA-DR on lymphocytes. At the same time, in the group of apparently healthy children, autologous and allogeneic (maternal) sera suppressed the expression of HLA-G and HLA-DR on lymphocytes. Moreover, the suppressive effect upon expression of both HLA-G and HLA-DR was significantly higher in allogeneic (maternal) sera than in autologous serum (p &lt; 0.01). This effect seems to be determined by the presence of autoand alloimmune antibodies to HLA-G and HLA-DR molecules in blood serum of multiparous women.The suppressor activity of female sera against allogeneic (embryo / fetus / child) and autologous (intrinsic) HLA-G and HLA-DR antigenic molecules may determine a protective effect related to development of septal congenital heart defects in offspring.

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.

Association Between Maternal Factors in Early Pregnancy and Congenital Heart Defects in Offspring: The Japan Environment and Children's Study.

Background Many prenatal factors are reported to be associated with congenital heart defects (CHD) in offspring. However, these associations have not been adequately examined using large-scale birth cohorts. Methods and Results We evaluated a data set of the Japan Environmental and Children's Study. The primary outcome was a diagnosis of CHD by age 2 years. We defined the following variables as exposures: maternal baseline characteristics, fertilization treatment, maternal history of diseases, socioeconomic status, maternal alcohol intake, smoking, tea consumption, maternal dietary intake, and maternal medications and supplements up to 12 weeks of gestation. We used multivariable logistic regression analysis to assess the associations between various exposures and CHD in offspring. A total of 91 664 singletons were included, among which 1264 (1.38%) had CHD. In multivariable analysis, vitamin A supplements (adjusted odds ratio [aOR], 5.78 [95% CI, 2.30-14.51]), maternal use of valproic acid (aOR, 4.86 [95% CI, 1.51-15.64]), maternal use of antihypertensive agents (aOR, 3.80 [95% CI, 1.74-8.29]), maternal age ≥40 years (aOR, 1.59 [95% CI, 1.14-2.20]), and high maternal hemoglobin concentration in the second trimester (aOR, 1.10 per g/dL [95% CI, 1.03-1.17]) were associated with CHD in offspring. Conclusions Using a Japanese large-scale birth cohort study, we found 6 maternal factors to be associated with CHD in offspring.

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.

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.

The risk of congenital heart defects associated with corticosteroids use during the first trimester of pregnancy: a systematic review and meta-analysis.

Prior studies have suggested that maternal corticosteroids exposure during the first trimester may be associated with an increased risk of congenital heart defects (CHDs) in offspring. However, the findings are discrepant. Moreover, a complete overview of the existing data in the literature is lacking. Our objective was to identify whether such an association exists. Relevant studies were identified via searching PubMed, Web of Science, Embase, Chinese databases, and the Cochrane Library databases (search date July 15, 2021) and through checking the reference lists of retrieved articles. The overall pooled risk estimate was calculated using random-effect models. We used the GRADE approach to assess the overall strength of the evidence and the Newcastle-Ottawa Scale to assess study quality. Subgroup analyses were performed to evaluate the association within studies or samples with different characteristics. Sensitivity analyses were performed to assess the robustness of the results. Nine studies involving 1,901,599 participants were included in the final analysis. All studies were evaluated as high quality. In the meta-analysis, no statistically significant association was found between maternal corticosteroids exposure during the first trimester and increased risk of CHDs in offspring (OR = 1.06, 95% CI: 1.00-1.13, P = 0.06, low certainty of evidence). Additionally, we also did not find significant differences in subgroup analyses of corticosteroids exposure patterns, including oral corticosteroids exposure (OR = 1.23, 95% CI: 1.00-1.52), ointment corticosteroids exposure (OR = 1.03, 95% CI: 0.90-1.19), inhalation corticosteroids exposure (OR = 1.06, 95% CI: 0.96-1.17), topical corticosteroids or systemic corticosteroids exposure (OR = 0.95, 95% CI: 0.79-1.15), and nasal corticosteroids exposure (OR = 1.12, 95% CI: 0.80-1.57). Our study does not find an association between maternal corticosteroids exposure during the first trimester and offspring CHDs. However, the existing evidence is of low quality; thus, long-term prospective cohort studies are warranted to verify the safety of corticosteroids in this population, with adequate adjustments for confounding variables.

Association between Maternal Selenium Exposure and Congenital Heart Defects in Offspring: A Systematic Review and Meta-Analysis.

The association between congenital heart defects (CHDs) and selenium (Se) is still unclear. We aimed to systematically review and quantitative analyze the potential relationship between maternal Se exposure and CHDs in the offspring. PubMed, Embase, Web of Science and Scopus databases were searched from inception up to August 2021 for relevant studies. Methodological quality of the studies was assessed through Newcastle-Ottawa scale. The Standard mean difference (SMD) and corresponding 95% confidence interval (CI) were calculated to compare maternal Se levels between CHDs groups and control groups using a random-effects model. Four articles covering five studies were included in the systematic review, and three articles covering four studies were included in the meta-analysis. One study measured Se concentrations in maternal hair and found a positive correlation between high concentrations and increased risk of CHDs in offspring. However, one study on cord blood, and one on whole blood illustrated that Se exposure was associated with decreased risk of CHDs. There was no significant association found between serum Se levels and CHDs in two studies. Pooled results showed decreased Se levels in the circulation of mothers with CHDs offspring (SMD = -108.27, 95% CI: -192.72, -23.82), with statistically significant heterogeneity (I2 = 99.8%, P < 0.001) but not in hair, as compared with controls. Low maternal Se status may be associated with increased risk of CHDs in offspring. However, further larger-scale studies with strict and consistent design methods are still required to investigate this issue.

Association between maternal smoke exposure and congenital heart defects from a case–control study in China

There is a gap in knowledge how maternal exposure to environmental tobacco smoke (ETS) is associated with offspring congenital heart defects (CHDs). In this case–control study, we collected data on 749 fetuses with CHDs and 880 fetuses without any congenital anomalies to examine the association of maternal ETS with fetal CHDs and the potentially moderating effect by maternal hazardous and noxious substances (HNS), periconceptional folate intake and paternal smoking. Maternal exposure to ETS in first trimester was associated with increased risk of CHDs in a dose–response gradient, with the AORs (95% CI) were1.38 (1.00–1.92), 1.60 (1.07–2.41), and 4.94 (2.43–10.05) for ETS < 1 h/day, 1–2 h/day, and ≥ 2 h/day, respectively. With the doubly unexposed group as reference categories, AORs for maternal ETS exposure ≥ 2 h/day in the absence of folate intake, in the presence of HNS exposure or paternal smoking, were 7.21, 11.43, and 8.83, respectively. Significant additive interaction between ETS exposure and maternal folate intake on CHDs was detected. Maternal ETS exposure during first trimester may increase the risk of offspring CHDs in a dose–response shape, and such effect may be modified by maternal folate intake or other potential factors.

Relationship between maternal exposure to heavy metal titanium and offspring congenital heart defects in Lanzhou, China: A nested case-control study.

BackgroundPrevious studies have found that exposure to heavy metals increased the incidence of congenital heart defects (CHDs). However, there is a paucity of information about the connection between exposure to titanium and CHDs. This study sought to examine the relationship between prenatal titanium exposure and the risk of CHDs in offspring.MethodsWe looked back on a birth cohort study that was carried out in our hospital between 2010 and 2012. The associations between titanium exposure and the risk of CHDs were analyzed by using logistic regression analysis to investigate titanium concentrations in maternal whole blood and fetal umbilical cord blood.ResultsA total of 97 case groups and 194 control groups were included for a nested case-control study. The [P50 (P25, P75)] of titanium were 371.91 (188.85, 659.15) μg/L and 370.43 (264.86, 459.76) μg/L in serum titanium levels in pregnant women and in umbilical cord serum titanium content in the CHDs group, respectively. There was a moderate positive correlation between the concentration of titanium in pregnant women's blood and that in umbilical cord blood. A higher concentrations of maternal blood titanium level was associated with a greater risk of CHDs (OR 2.706, 95% CI 1.547–4.734), the multiple CHDs (OR 2.382, 95% CI 1.219–4.655), atrial septal defects (OR 2.367, 95% CI 1.215–4.609), and patent ductus arteriosus (OR 2.412, 95% CI 1.336–4.357). Dramatically higher concentrations of umbilical cord blood levels had an increased risk of CHDs and different heart defects.ConclusionTitanium can cross the placental barrier and the occurrence of CHDs may be related to titanium exposure.

Maternal Hypertensive Disorders of Pregnancy and Cardiac Structure and Function in the Newborn

BackgroundMaternal hypertensive disorders of pregnancy (HDPs) are strongly associated with offspring congenital heart defects. ObjectivesThis study assessed whether infants exposed to maternal HDPs were also more likely to have subtle cardiac structural and functional abnormalities than unexposed infants. MethodsWe used regression analyses to compare: 1) left ventricular parameters from conventional echocardiography performed in infants from the Copenhagen Baby Heart Study born to mothers with preeclampsia, gestational hypertension (GH), or no HDP; and 2) advanced echocardiographic parameters for 545 term infants born to mothers with preeclampsia and 545 matched infants not exposed to HDPs. ResultsCompared with infants unexposed to HDPs (n = 17,384), infants exposed to preeclampsia (n = 754) had a thicker interventricular septum in end-diastole (adjusted mean difference [± SD] 0.05 [±0.02] mm; P = 0.004), thicker left ventricular posterior wall (0.04 [±0.02] mm; P = 0.009), larger left ventricular internal diameter (0.12 [±0.06] mm; P = 0.04), and larger left ventricular volume (0.21 [±0.10] mL; P = 0.03). Systolic function changes included increased fractional shortening (0.36% [±0.14%]; P = 0.01) and stroke volume (0.18 [±0.07] mL; P = 0.006), whereas diastolic function changes included lower transmitral early peak inflow velocity (−1.76 [±0.49] mL; P = 0.0003), lower mitral annulus lateral wall a' (−0.21 [±0.09] cm/s; P = 0.02), and smaller lateral E/e’ (−1.06 [±0.38] cm/s; P = 0.005). Conversely, there was little evidence of any association between maternal GH (n = 469) and offspring left ventricular parameters. ConclusionsMaternal preeclampsia, but not GH, was associated with subtle newborn cardiac morphological and functional alterations, including thickening of the left ventricular myocardium and altered systolic and diastolic function.

Relationship between maternal heavy metal exposure and congenital heart defects: a systematic review and meta-analysis.

Congenital heart defects (CHDs) are one of the major causes of death in infants and young children, and heavy metal exposure during pregnancy is one of the possible risk factors. However, the effect of heavy metal exposure on CHDs is still controversial. We searched English (PubMed, Web of Science) and Chinese (CNKI and WanFang database) databases for relevant articles. The summarized effect sizes and 95% confidence intervals (CIs) were calculated by pooling estimates using the random-effects model. Egger's test was used to estimate publication bias. Heterogeneity among studies was indicated by p-values and I2. Finally, we conducted subgroup analyses to elucidate the causes of heterogeneity. Thirteen studies were included in this meta-analysis. A positive association between maternal exposure to heavy metals and CHDs was found. Pooling odds ratios (ORs) for arsenic, cadmium, mercury, and lead were 2.12, 1.30, 1.22, and 2.30, respectively for total CHDs. Regarding CHD subtypes, arsenic was associated with an increased risk of septal defects (OR: 1.82), barium with left ventricular outflow tract obstruction (LVOTO) (OR: 1.15) and septal defects (OR: 1.21), and lead with conotruncal defects (OR: 2.34) and LVOTO (OR: 1.93). A heterogeneous relationship was found between studies using different methods of measurement, which were mainly due to differences in actual exposure levels to heavy metals. This meta-analysis suggests significant associations between arsenic, cadmium, mercury, and lead exposure during pregnancy and an increased risk of specific CHDs in offspring. These findings underscore the importance of heavy metal exposure during pregnancy in the risk of CHDs in offspring.

Risk of Congenital Heart Defects in Offspring of Affected Mothers and Fathers.

Background:Smaller studies have reported a higher offspring risk of congenital heart defects (CHDs) for mothers with CHDs than for fathers with CHDs. In a large population-based study, we investigated whether offspring risk of CHD differed for mothers and fathers with CHDs.Methods:All people born in Denmark, 1977 to 2011, with at least 1 registered parent, were included in our cohort (n=2 341 061). Parent-child recurrence of CHDs was evaluated using risk ratios (RRs) comparing risks of CHDs in individuals with and without a parent with a CHD, estimated using log-linear binomial regression.Results:The RRs for any CHD in offspring were 5.39 (95% CI, 4.88–5.96) for mothers and 3.04 (95% CI, 2.59–3.57) for fathers affected with any CHD; the ratio of RRs for mothers versus fathers was 1.82 (P<0.0001). Recurrence RRs for the same cardiac phenotype in parent and offspring were significantly stronger for mothers than for fathers for conotruncal defects (ratio of RRs, 4.98), left ventricular outlet tract obstruction (ratio of RRs, 4.98), and ventricular septal defects (ratio of RRs, 2.51) but not for atrioventricular septal defects (ratio of RRs, 1.06). Birth rates among people with CHDs, relative to the general population, were 18% higher for women than for men, regardless of parental cardiac phenotype.Conclusions:Recurrence risks of CHDs were significantly greater in the offspring of affected women than in the offspring of affected men. The excess maternal recurrence risks could not be explained by the slightly higher birth rates in women with CHDs.

Maternal exposure to heavy metals and risk for severe congenital heart defects in offspring

BackgroundCongenital heart defects (CHDs) are the most common congenital malformations with a complex etiology, and environmental factors play an important role. Large epidemiology studies on prenatal exposure to selected heavy metals and their association with risk for CHDs are scarce and joint effects are not well understood. ObjectivesTo examine the association between prenatal exposure to selected heavy metals and risk for CHDs. MethodsInductively coupled plasma mass spectrometry (ICP-MS) was used to determine the maternal plasma concentrations of arsenic, cadmium, mercury, lead, and manganese were in 303 CHD cases and 303 healthy controls that were recruited in eight hospitals in China. Generalized linear mixed model (GLMM) and Bayesian kernel machine regression (BKMR) were fitted to evaluate the individual and joint effects of metal concentrations on CHDs. ResultsIn GLMM, two metals were each significantly associated with an increased risk for CHDs [adjusted odds ratio (95% confidence interval): mercury, 2.88 (1.22–6.77); lead, 2.74 (1.00–7.57)]. In BKMR, CHD risk increased with mixture levels of the five metals when their concentrations were at the 40th percentile or higher, compared to when all metals were below their 35th percentile, and mercury was the major metal that contributed to the mixture effect. The interaction between mercury and lead was observed in BKMR. ConclusionsUsing metal concentrations in maternal plasma obtained during the second or third trimester as exposure markers, we found that the risk of CHDs increased with the levels of the mixtures of As, Cd, Hg, Pb, and Mn, with Hg being the most important contributor to the mixture effect.

Hypertensive Disorders in Pregnancy Are Associated With Congenital Heart Defects in Offspring: A Systematic Review and Meta-Analysis.

BackgroundAlthough research indicates an association between hypertensive disorders of pregnancy (HDP) and congenital heart defects (CHDs) in offspring, consistency is still lacking. Therefore, we aimed to synthesize the updated published epidemiologic evidence to estimate the association of maternal HDP with the risk of total CHDs and its phenotypes in offspring.MethodsA systematic search of Web of Science Database, PubMed, and Embase were searched from inception through April 30, 2021 based on a preprepared protocol, and the reference lists were also manually searched. The combined risk estimates were calculated using either the fixed-effect models or random-effect models. Possible heterogeneity moderators were detected by subgroup, sensitivity analyses, and Galbraith plot.ResultsTwenty-four studies involving 477,839 CHDs cases among 40,394,699 participants were included in our meta-analysis. Mothers who had HDP exposure were significantly associated with an increased risk of total CHDs compared with non-exposure. When maternal HDP exposure was further subdivided into pre-eclampsia (OR = 1.79, 95% CI: 1.50–2.13), gestational hypertension (OR = 1.16, 95% CI: 1.02–1.31), and chronic hypertension (OR = 1.68, 95% CI: 1.49–1.89), a significantly increased risk of total CHDs were still presented. Furthermore, a statistically significant increased association was found between maternal HDP exposure and most CHD phenotypes. Besides, relevant heterogeneity moderators have been identified by subgroup and sensitivity analyses.ConclusionOur study suggested that maternal HDP exposure may be associated with an increase in the risk of CHDs in offspring. These findings highlight the need for greater surveillance of pregnant women with HDP exposure to allow early prevention that may be good for reducing the risk of CHDs in offspring.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [CRD42021268093].

Association of the levels of heavy metals and trace elements during pregnancy with congenital heart defects in offspring: a prospective cohort study.

To study the association of the levels of heavy metals and trace elements during pregnancy with congenital heart defects (CHD) in offspring, and to establish a model for predicting the probability of CHD based on the levels of heavy metals and trace elements during pregnancy. Based on the prospective birth cohort study in Gansu Provincial Maternal and Child Health Hospital in 2010-2012, a nested case-control study was conducted for the follow-up observation of 14 359 pregnant women. Among the pregnant women, 97 pregnant women whose offspring were diagnosed with CHD during follow-up were enrolled as the CHD group, and 194 pregnant women whose offspring had no CHD were selected as the control group. Inductively coupled plasma mass spectrometry was used to measure the levels of heavy metals and trace elements in maternal blood samples and fetal umbilical cord blood samples. A multivariate logistic regression analysis was used to evaluate the association between heavy metal and trace elements and CHD in offspring. A nomogram model for predicting the probability of CHD in offspring was established based on the levels of heavy metals and trace elements during pregnancy. Compared with the control group, the CHD group had significantly higher levels of aluminum (Al), natrium (Na), calcium (Ca), titanium (Ti), selenium (Se), strontium (Sr), stannum (Sn), stibium (Sb), barium (Ba), and thorium (Th) in maternal blood samples (P<0.05), as well as significantly higher levels of Al, zinc (Zn), magnesium (Mg), kalium (K), Ca, Ti, chromium (Cr), copper (Cu), arsenic (As), Se, Sr, argentum (Ag), cadmium (Cd), Sn, and plumbum (Pb) in umbilical cord blood (P<0.05). The multivariate logistic regression analysis showed that the increase in the Sb level in maternal blood was associated with the increase in the risk of CHD in offspring [adjusted odds ratio (aOR)=4.81, 95% confidence interval (CI): 1.65-14.07, P=0.004], while in umbilical cord blood, the high levels of Al (aOR=4.22, 95%CI: 1.35-13.16, P=0.013), Mg (aOR=8.00, 95%CI: 1.52-42.08, P=0.014), and Pb (aOR=3.82, 95%CI: 0.96-15.23, P=0.049) were significantly associated with the risk of CHD in offspring. The levels of Al, Th, and Sb in maternal blood and levels of Al, Mg, and Pb in umbilical cord blood were included in the predictive model for CHD in offspring based on the levels of heavy metals and trace elements during pregnancy, and the calibration curve of the nomogram predictive model was close to the ideal curve. Increases in the levels of Al, Th, Sb, Mg, and Pb during pregnancy may indicate the increase in the risk of CHD in offspring, and the nomogram predictive model based on these indices can be used to predict the probability of CHD in offspring.

Association between Maternal Drug Use and Cytochrome P450 Genetic Polymorphisms and the Risk of Congenital Heart Defects in Offspring

ObjectiveThis study aimed to assess the associations between maternal drug use, cytochrome P450 (CYP450) genetic polymorphisms, and their interactions with the risk of congenital heart defects (CHDs) in offspring. MethodsA case-control study involving 569 mothers of CHD cases and 652 controls was conducted from November 2017 to January 2020. ResultsAfter adjusting for potential confounding factors, the results show that mothers who used ovulatory drugs (adjusted odds ratio [aOR] = 2.12; 95% confidence interval [CI]: 1.08–4.16), antidepressants (aOR = 2.56; 95% CI: 1.36–4.82), antiabortifacients (aOR = 1.55; 95% CI: 1.00–2.40), or traditional Chinese drugs (aOR = 1.97; 95% CI: 1.26–3.09) during pregnancy were at a significantly higher risk of CHDs in offspring. Maternal CYP450 genetic polymorphisms at rs1065852 (A/T vs. A/A: OR = 1.53, 95% CI: 1.10–2.14; T/T vs. A/A: OR = 1.57, 95% CI: 1.07–2.31) and rs16947 (G/G vs. C/C: OR = 3.41, 95% CI: 1.82–6.39) were also significantly associated with the risk of CHDs in offspring. Additionally, significant interactions were observed between the CYP450 genetic variants and drug use on the development of CHDs. ConclusionsIn those of Chinese descent, ovulatory drugs, antidepressants, antiabortifacients, and traditional Chinese medicines may be associated with the risk of CHDs in offspring. Maternal CYP450 genes may regulate the effects of maternal drug exposure on fetal heart development.