Congenital Heart Defects Subtypes Research Articles

Maternal obesity, interpregnancy weight changes and congenital heart defects in the offspring: a nationwide cohort study.

To evaluate the association between maternal BMI and congenital heart defects (CHDs) in the offspring when including live births, stillbirths, aborted and terminated pregnancies and to investigate if maternal interpregnancy weight changes between the first and second pregnancy influences the risk of foetal CHDs. A nationwide cohort study of all singleton pregnancies in Denmark from 2008 to 2018. Data were retrieved from the Danish Foetal Medicine Database, which included both pre- and postnatal diagnoses of CHDs. Children or foetuses with chromosomal aberrations were excluded. Odds ratios were calculated with logistic regression models for CHDs overall, severe CHDs and five of the most prevalent subtypes of CHDs. Of the 547 105 pregnancies included in the cohort, 5 442 had CHDs (1.0%). Risk of CHDs became gradually higher with higher maternal BMI; for BMI 25-29.9 kg/m2, adjusted odds ratio (aOR) 1.17 (95% CI 1.10-1.26), for BMI 30-34.9 kg/m2, aOR 1.21 (95% CI 1.09-1.33), for BMI 35-39.9 kg/m2, aOR 1.29 (95% CI 1.11-1.50) and for BMI ≥ 40 kg/m2, aOR 1.85 (95% CI 1.54-2.21). Data was adjusted for maternal age, smoking status and year of estimated due date. The same pattern was seen for the subgroup of severe CHDs. Among the atrioventricular septal defects (n = 231), an association with maternal BMI ≥ 30 kg/m2 was seen, OR 1.67 (95% CI 1.13-2.44). 109 654 women were identified with their first and second pregnancies in the cohort. Interpregnancy BMI change was associated with the risk of CHDs in the second pregnancy (BMI 2 to < 4 kg/m2: aOR 1.29, 95% CI 1.09-1.53; BMI ≥ 4 kg/m2: aOR 1.36, 95% CI 1.08-1.68). The risk of foetal CHDs became gradually higher with higher maternal BMI and interpregnancy weight increases above 2 BMI units were also associated with a higher risk of CHDs.

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.

Are congenital heart defects connected to more severe attention-deficit/hyperactivity disorder?: A systematic review and meta-analysis.

Congenital heart defects (CHDs) are the most common cause of birth defect-related infant morbidity and mortality, affecting 1% of 40,000 births per year in the United States. On the other side, the etiology of attention-deficit/hyperactivity disorder (ADHD) is multifactorial. Multiple studies have found that cardiac surgery patients have higher morbidity of having this disorder. Many studies have investigated the prevalence of ADHD in different subtypes of CHD, but few have focused on the severity of ADHD symptoms. Thus, we conducted this systematic review and meta-analysis to investigate the severity of ADHD symptoms in CHD patients. We searched PubMed, Embase, Scopus, and Web of Science were searched from inception to March 6, 2023 without any restrictions. We included observational studies published in English language that evaluated burden of symptom of ADHD in CHD patients. Moreover, the standardized mean difference (SMD) for continuous outcomes with 95% confidence interval (CI) was pooled. P-values <.05 are considered as significant, and we performed all statistical analyses using RevMan software Version 5.4.1. Eight studies were included in our review with a total number of 120,158 patients. CHD was associated with a statistically significant increase in both ADHD index T score and ADHD Hyperactivity-Impulsivity Subscale (informant) with (SMD = 0.65, 95% CI [0.40, 0.90], P < .00001, I2 = 81%) and (SMD = 0.16, 95% CI [0.04, 0.28], P = .008, I2 = 0%). Regarding ADHD Inattention Subscale (informant), the pooled data showed that a significant increase of this score in the CHD group (SMD = 0.25, 95% CI [0.13, 0.37], P < .001, I2 = 0%), and ADHD Combined Score (informant) showed a significant increase of this score in the CHD group (SMD = 0.23, 95% CI [0.11, 0.35], P = .0002, I2 = 0%). Our study revealed a strong association between CHD and not only ADHD, but also the severity of ADHD, making early diagnosis of ADHD in children with CHD a mandatory step in the clinical evaluation practice to improve these children on both clinical and psychological aspects.

Noncardiac anomalies in children with congenital heart disease.

Noncardiac anomalies (NCAs) in patients with congenital heart defects (CHDs) are crucial for perioperative management and etiology studies. This study aimed to investigate NCAs in Chinese children with CHDs. Medical records for CHD-diagnosed children hospitalized from 1 January 2015 to 31 December 2019 were collected and subjected to retrospective analyses to excavate potential association rules between CHDs and noncardiac malformations. A total of 3,788 CHD patients were included in this study. The main phenotypes of CHD were Ventricular Septal Defect (VSD, 33.69%), Atrial Septal Defect (ASD, 12.72%), and Tetralogy of Fallot (TOF, 5.54%). A total of 887 (23.42%) cases showed noncardiac anomalies, which were mainly associated with the central nervous system (34.61%), nose/ear/mandibular/face (19.39%), genitourinary system (15.78%), and musculoskeletal system (15.56%). Compared to other CHD subtypes, septal defects had a lower percentage of associated NCAs (P = 3.7 × 10-9) while AVSD had a higher percentage (P = 0.0018). NCAs are prevalent among CHD-diagnosed children in China, and the spectrums of NCAs in different CHD subcategories were different.

Gender differences in congenital heart defects: a narrative review.

Congenital heart defects (CHD) represent the most frequent human birth defects, occurring in almost 1% of all live newborns. Understanding the effects of gender in the prevalence of CHD has a key role in defining personalized prevention, disease identification, prognosis definition and individualized therapeutic strategies. Recently, the attempt to achieve a holistic approach to patients with CHD cannot be separated from accounting for existing gender differences. The main aim of this narrative review is to provide an overview of gender differences in the epidemiology of CHD. A standardized research through three electronic databases (PubMed/Scopus/Embase) was performed using a combination of keywords and Medical Subject Headings (MeSH) terms to include congenital heart diseases, gender difference(s), prevalence. Observational, prospective, population based and retrospective studies reporting gender differences in the prevalence of CHD were included. Conference abstracts were excluded as well as studies not written in English language and non-human studies. Further relevant papers were selected by hand-searching of the references list of selected articles. Search results returned 1,904 papers. Screening articles by title and abstracts resulted in 17 articles for full text review. Of these, 10 were included for analysis and additional 11 articles were included after hand searching review of reference lists. A total of 21 articles were included. Our narrative review confirms that there is a significant gender variation in specific CHD subgroups. In particular, we summarized the evidence that there is a significantly greater risk for males to be born with severe CHD and for females with milder CHD subtypes. The etiology of the different distribution of CHD among genders is still under investigation and a deeper understanding of how gender influences the risk for CHD is warranted. In the future, a gender-based management of CHD should become an established medical approach.

Prenatal exposure to ambient air pollutants and congenital heart defects: An umbrella review

BackgroundPrenatal exposure to ambient air pollutants has been linked to congenital heart defects (CHD), but findings of existing systematic reviews have been mixed. ObjectiveTo assess the epidemiological evidence on associations between prenatal exposure to ambient air pollutants and CHD subtypes, based on a systematic overview of reviews (“umbrella review”). MethodsWe conducted a systematic search for reviews assessing associations between prenatal exposure to criteria air pollutants and CHD. The risk of bias was evaluated using the Risk of Bias in Systematic Reviews (ROBIS) tool. The certainty of the systematic review findings was graded using the Navigation Guide methodology. ResultsWe identified eleven systematic reviews, including eight with meta-analyses, assessing in total 35 primary studies of prenatal exposure to criteria air pollutants and various CHD subtypes. The certainty of the findings of four meta-analyses indicating an increased risk for coarctation of the aorta associated with nitrogen dioxide exposure was rated as moderate. The certainty of findings indicating positive, inverse, or null associations for other pollutant-subtype combinations was rated as very low to low, based on low precision and high statistical heterogeneity of summary odds ratios (SOR), substantial inconsistencies between review findings, and methodological limitations of the systematic reviews. DiscussionThe inconsistent findings and high statistical heterogeneity of many SOR of the included systematic reviews may partly be traced to differences in methodological approaches, and the risk of bias across included reviews (e.g., inclusion criteria, systematic search strategies, synthesis methods) and primary studies (e.g., exposure assessment, diagnostic criteria). Adherence to appropriate systematic review guidelines for environmental health research, as well as rigorous evaluation of risk of bias in primary studies, are essential for future risk assessments and policy-making. Still, our findings suggest that prenatal exposure to ambient air pollutants may increase risks for at least some CHD subtypes.

Maternal age and the prevalence of congenital heart defects in Europe, 1995-2015: A register-based study.

Evidence on the direction and strength of association between maternal age and the prevalence of congenital heart defects (CHD) in different age group categories is conflicting. Some studies have illustrated different trends with an increase in prevalence in younger and older age groups while other studies have reported a linear relationship. Given the increase in maternal age over recent years, it is important to study the CHD prevalence by maternal age. To examine the association between maternal age and the prevalence of CHD in Europe between 1995 and 2015 using population-based data from 24 registries belonging to the European Surveillance of Congenital Anomalies (EUROCAT) network. Associations over time of all nonsyndromic CHD according to maternal age category and for three CHD severity groupings (severity group I: very severe; severity group II: severe; severity group III: less severe) were examined using Bayesian multilevel Poisson regression modeling. Further subgroup analyses were undertaken within four maternal age-bands: ≤24, 25-29, 30-34 and 35-44 years. Descriptive summaries are also presented. There were 51,608 nonsyndromic CHD cases in Europe over the 20-year study period. Total prevalence for all CHD combined was increased for younger mothers (≤24 years) and for mothers 35-44 years of age when compared with mothers aged 25-29 years (reference group) (IRR: 1.05, 95% CI: 1.02, 1.07). The total prevalence was increased for severity group I (very severe) only for younger mothers compared to those aged 25-29 years (IRR: 1.14, 95% CI: 1.04, 1.23). We found an increased prevalence of the following CHD subtypes: double outlet right ventricle (IRR:1.33, 95% CI: 1.09, 1.60), hypoplastic left heart syndrome (IRR: 1.18, 95% CI: 1.05, 1.32), hypoplastic right heart syndrome (IRR: 1.41, 95% CI: 1.05, 1.84), atrioventricular septal defect (IRR: 1.15, 95% CI: 1.01, 1.32), coarctation of aorta (IRR: 1.15, 95% CI: 1.03, 1.28) and atrial septal defect (IRR: 1.08, 95% CI: 1.02, 1.13). For older mothers (35-44 years) compared to the reference category, we observed an increased risk in the prevalence for severity group II (IRR: 1.09, 95% CI: 1.03, 1.14), severity group III (IRR: 1.05, 95% CI: 1.01, 1.08) and an increased prevalence of the CHD subtypes: Pulmonary valve stenosis (IRR: 1.22, 95% CI: 1.09, 1.34), ASD (IRR: 1.07, 95% CI: 1.02, 1.13), CoA (IRR: 1.18, 95% CI: 1.06, 1.32) and Tetralogy of Fallot (IRR: 1.14, 95% CI: 1.01, 1.28). Finally, for all age categories compared to the reference category, different associations of ASD and an increased prevalence of CoA was also observed. Based on data for cases of CHD from 24 European population-based registries, evidence of a positive association between maternal age and the total prevalence of CHD for younger (≤24 years old) and older (35-44 years old) mothers was observed. The results suggest that young maternal age (≤24 years old) is a factor associated with severe CHD phenotypes while a positive association between advanced maternal age (35-44 years old) and mild CHD phenotypes was observed.

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.

The association of congenital heart defects with prenatal exposure to air pollutants: An umbrella review

Background and aim: For idiopathic congenital heart defects (CHD), air pollution during fetal development is a potential risk factor. However, findings of previous epidemiological studies and consequently of systematic reviews, have been mixed. We aimed to synthesize and evaluate the extant evidence on associations between gestational exposure to air pollutants and CHD subtypes, using a systematic review of reviews approach (&amp;#x22;umbrella review”). Methods: We systematically searched PubMed, Embase, and Epistemonikos for published and unpublished systematic reviews. The search was supplemented by the use of internet search engines and hand-searching of reference lists. The Risk of Bias in Systematic Reviews (&amp;#x22;ROBIS”) tool was used to evaluate included systematic reviews. Results: We identified ten systematic reviews, including eight meta-analyses. Moderately strong evidence for an increased risk of coarctation of the aorta following prenatal exposure to NO2 was provided by five reviews, which reported statistically homogeneous pooled odds ratios of 1.10 to 1.20 (95% confidence interval range: 0.99 to 1.41). Also, there was limited evidence for positive associations between SO2 and coarctation of the aorta, PM10 and atrial septal defects, NO2 and pulmonary artery and valve anomalies, and for both, PM2.5 and NO2 and Tetralogy of Fallot. Findings for other pollutant-CHD associations were inconsistent. Based on the ROBIS tool, a high or unclear risk of bias rating was assigned to eight out of ten reviews. Conclusion: Beyond the increased risk of coarctation of the aorta following exposure to NO2, a clear pollutant-outcome pattern was not identified. These incoherent findings may partly be explained by differences in methods used across the reviews (e.g., inclusion criteria) as well as between individual studies (e.g., exposure and outcome assessment methods). Further establishment of and adherence to systematic review methods for environmental exposures and children’s health may improve the validity and consistency of future systematic review findings.

Early mortality in infants born with neonatal-operated congenital heart defects and low or very-low birthweight: Systematic review and meta-analysis

Congenital heart defects (CHD) are the most frequent congenital anomalies. Mortality outcomes of children with isolated (i.e. not associated with chromosomal anomalies, malformations from other systems or syndromes) neonatal operated CHD (NOCHD) born low or very-low birthweight (LBW and VLBW; birthweight < 1500 and < 2500 g, respectively) remain ambiguous. To summarize early mortality outcomes of infants born with NOCHD and LBW or VLBW. We searched Medline and Embase (from inception until May 2022) and included studies that evaluated early mortality in infants born with NOCHD and LBW or VLBW. Risk of bias was assessed using the Critical Appraisal Skills Programme cohort checklist. Meta-analysis involved use of random-effects models. We explored variability in mortality across birthweight subgroups, NOCHD subtypes, and study designs. Registration: PROSPERO, CRD42020170289. From 2,035 reports, we included 23 studies in qualitative synthesis, and the meta-analysis included 11 studies (1,658 CHD cases). Risk of bias was deemed low in 4/11 studies. Overall, mortality before discharge or within one month after surgery was 32% (95%CI 23–40%, I2 95%). Early mortality varied between VLBW and LBW infants (45% vs. 13%; P = 0.009) and across CHD subtypes (hypoplastic left heart syndrome 50%, total anomalous pulmonary venous return 47%, transposition of the great arteries 17%, coarctation of the aorta 14%; P = 0.03). Mortality was higher in population-based studies (45% vs. 7%; P = 0.003). One-third of infants born with NOCHD and LBW or VLBW will die within 30 days after surgery. Mortality varies substantially across infant and study characteristics.

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.

Predisposition to atrioventricular septal defects may be caused by SOX7 variants that impair interaction with GATA4.

Atrioventricular septal defects (AVSD) are a complicated subtype of congenital heart defects for which the genetic basis is poorly understood. Many studies have demonstrated that the transcription factor SOX7 plays a pivotal role in cardiovascular development. However, whether SOX7 single nucleotide variants are involved in AVSD pathogenesis is unclear. To explore the potential pathogenic role of SOX7 variants, we recruited a total of 100 sporadic non-syndromic AVSD Chinese Han patients and screened SOX7 variants in the patient cohort by targeted sequencing. Functional assays were performed to evaluate pathogenicity of nonsynonymous variants of SOX7. We identified three rare SOX7 variants, c.40C > G, c.542G > A, and c.743C > T, in the patient cohort, all of which were found to be highly conserved in mammals. Compared to the wild type, these SOX7 variants had increased mRNA expression and decreased protein expression. In developing hearts, SOX7 and GATA4 were highly expressed in the region of atrioventricular cushions. Moreover, SOX7 overexpression promoted the expression of GATA4 in human umbilical vein endothelial cells. A chromatin immunoprecipitation assay revealed that SOX7 could directly bind to the GATA4 promoter and luciferase assays demonstrated that SOX7 activated the GATA4 promoter. The SOX7 variants had impaired transcriptional activity relative to wild-type SOX7. Furthermore, the SOX7 variants altered the ability of GATA4 to regulate its target genes. In conclusion, our findings showed that deleterious SOX7 variants potentially contribute to human AVSD by impairing its interaction with GATA4. This study provides novel insights into the etiology of AVSD and contributes new strategies to the prenatal diagnosis of AVSD.

Associations between ambient heat exposure early in pregnancy and risk of congenital heart defects: a large population-based study.

Some epidemiological studies have confirmed the association between environmental factors and congenital heart defects (CHD). While the possibility that maternal ambient heat exposures are related to CHD has received little attention. Our study aims to investigate the association between maternal ambient extreme heat exposure early in pregnancy and the risk of CHD in offspring in China. We conducted a retrospective cohort study of 1,918,105 fetuses between 2 and 8 weeks after gestation from May to October in Guangdong, China, 2015-2019. The main heat exposure was defined as extreme heat events (EHE) by using the 90th (EHE90) or 95th (EHE95) percentile of the daily maximum temperature. For each EHE definition, we further defined four indicators: having EHE or not, frequency, duration, and cumulative days. We used the log-binomial regression models to calculate the prevalence ratios (PR) of CHD with 95% confidence intervals (CI) for the associations between CHD and EHE, adjusted for potentially confounding covariates. There are 1,918,105 infants included in the study, of which 9588 had CHD, with a prevalence rate of 499.9 per 100,000 (95% CI: 489.9, 509.8). We found that all EHE indicators were positively associated with the increased risks of overall CHD, some CHD classes (congenital malformations of cardiac septa, congenital malformations of great arteries, and congenital malformations of great arteries), and some CHD subtypes (atrial septal defect and patent ductus arteriosus). In addition, the PR yielded higher estimates when exposing to EHE95. For instance, the risk of suffering congenital malformations of great arteries was 1.548 (95% CI: 1.401, 1.712) for EHE90 exposure and 1.723 (95% CI: 1.565, 1.898) for EHE95 exposure, respectively. Our study demonstrated that EHE during 2-8 weeks postconception was associated with overall CHD in offspring, particularly atrial septal defects and patent ductus arteriosus. The associations strengthened with the extent and cumulative days of maternal exposure to EHE.

Prevalence of growth restriction at birth for newborns with congenital heart defects: A population-based prospective cohort study

Congenital heart defects (CHD) and growth restriction at birth are two major causes of childhood and adult morbidity and mortality. The aim of this study was to assess the overall risk of growth restriction at birth, as measured by its imperfect proxy small (< 10th percentile) for gestational age (SGA), for newborns with CHD. Using data from a population-based cohort of children born with CHD, we assessed the risk of growth restriction at birth using SGA and severe SGA (3rd percentile). To compare the odds of SGA and severe SGA across five specific major CHD, we used ordinal logistic regression using isolated, minor (non-operated) ventricular septal defect (VSD) as the control group. The overall proportion of SGA for “isolated” CHD (i.e., those not associated with other anomalies) was 13 % (95 % CI, 12 %–15 %), which is 30 % higher than what would be expected in the general population (i.e., 10 %). The risk of severe SGA was 5 % (95 % CI, 4 %–6 %) as compared with the expected 3 % in the general population. There were substantial differences in the risk of overall SGA and more so severe SGA across the different CHD. The highest risk of SGA occurred for Tetralogy of Fallot (adjusted OR 2.7, 95 % CI, 1.3–5.8) and operated VSD (adjusted OR 2.1, 95 % CI, 1.1–3.8) as compared with the control group of minor (non-operated) VSD. The overall risks of both SGA and severe SGA were higher in isolated CHD than what would be expected in the general population with substantial differences across the subtypes of CHD. These Results may provide a clue for understanding the underlying mechanisms of the relation between alternations in fetal circulation associated with different types of CHD and their effects on fetal growth.

Association between maternal exposure to gaseous pollutants and atrial septal defect in China: A nationwide population-based study

BackgroundThe association between maternal exposure to gaseous air pollutants and congenital heart defects (CHD) remains unclear. The concentration-response relationship and the time windows of susceptibility to gaseous pollutants may vary by pollutant species and CHD subtypes. ObjectiveWe aimed to examine the relationship between maternal exposures to four species of gaseous pollutants (NO2, O3, SO2, and CO) and atrial septal defect (ASD), which is a common subtype of CHD, and to determine the critical time windows of susceptibility for each gaseous pollutant. MethodsAmong 1,253,633 infants born between October 1, 2013 and December 31, 2016 in China, 1937 newborns were diagnosed with isolated ASD, a prevalence of 1.55‰. Maternal exposures to the gaseous pollutants were estimated by matching the geocoded maternal addresses with the gridded ambient concentrations. The adjusted odds ratios (aOR) between exposures and ASD were quantified by using mixed-effects logistic regression models. ResultsWe found significantly positive associations between ASD and maternal exposures to NO2, O3, SO2, and CO during entire pregnancy, first-, second-, and third-trimester. However, no statistically significant association was found between maternal exposure to PM2.5, PM2.5-10 and ASD risk (P > 0.05). In the fully adjusted model with respect to average exposure over entire pregnancy, the adjusted odds ratios (aOR) for each 10 μg/m3 increment of NO2, O3, SO2 were 1.33 (95% CI: 1.22–1.45), 1.13 (95% CI: 1.10–1.16), 1.28 (95% CI: 1.20–1.35), respectively; the aOR for each 100 μg/m3 increment of CO was 1.10 (95% CI: 1.06–1.15). The observed concentration-response relationships varied by exposure periods and pollutants, with the strongest association for NO2 during the 1st-8th embryology weeks, for O3 during the third trimester, for SO2 during the second trimester, and for CO without obvious variation. ConclusionsThe findings suggest an increased risk of ASD in association with maternal exposures to four common gaseous pollutants. From the perspective of birth defects prevention and ASD risk mitigation, it is critical to reduce maternal exposure to gaseous pollutants especially during the most susceptible time windows.

Prevalence of Growth Restriction at Birth for Newborns With Congenital Heart Defects: A Population-Based Prospective Cohort Study EPICARD.

Background and Objectives: Congenital heart defects (CHD) and growth restriction at birth are two major causes of childhood and adult morbidity and mortality. The aim of this study was to assess the overall risk of growth restriction at birth, as measured by its imperfect proxy small (< 10th percentile) for gestational age (SGA), for newborns with CHD.Methods: Using data from a population-based cohort of children born with CHD, we assessed the risk of growth restriction at birth using SGA and severe SGA (3rd percentile). To compare the odds of SGA and severe SGA across five specific major CHD, we used ordinal logistic regression using isolated, minor (non-operated) ventricular septal defect (VSD) as the control group.Results: The overall proportion of SGA for “isolated” CHD (i.e., those not associated with other anomalies) was 13% (95% CI, 12–15%), which is 30% higher than what would be expected in the general population (i.e., 10%). The risk of severe SGA was 5% (95% CI, 4–6%) as compared with the expected 3% in the general population. There were substantial differences in the risk of overall SGA and more so severe SGA across the different CHD. The highest risk of SGA occurred for Tetralogy of Fallot (adjusted OR 2.7, 95% CI, 1.3–5.8) and operated VSD (adjusted OR 2.1, 95% CI, 1.1–3.8) as compared with the control group of minor (non-operated) VSD.Conclusion: The overall risks of both SGA and severe SGA were higher in isolated CHD than what would be expected in the general population with substantial differences across the subtypes of CHD. These results may provide a clue for understanding the underlying mechanisms of the relation between alterations in fetal circulation associated with different types of CHD and their effects on fetal growth.

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

BackgroundAccumulating 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. MethodsA 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. ResultsMaternal 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. ConclusionThese 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.

Maternal exposure to ambient air pollution and congenital heart defects in China

BackgroundEvidence of maternal exposure to ambient air pollution on congenital heart defects (CHD) has been mixed and are still relatively limited in developing countries. We aimed to investigate the association between maternal exposure to air pollution and CHD in China. MethodThis longitudinal, population-based, case-control study consecutively recruited fetuses with CHD and healthy volunteers from 21 cities, Southern China, between January 2006 and December 2016. Residential address at delivery was linked to random forests models to estimate maternal exposure to particulate matter with an aerodynamic diameter of ≤ 1 µm (PM1), ≤2.5 µm, and ≤10 µm as well as nitrogen dioxides, in three trimesters. The CHD cases were evaluated by obstetrician, pediatrician, or cardiologist, and confirmed by cardia ultrasound. The CHD subtypes were coded using the International Classification Diseases. Adjusted logistic regression models were used to assess the associations between air pollutants and CHD and its subtypes. ResultsA total of 7055 isolated CHD and 6423 controls were included in the current analysis. Maternal air pollution exposures were consistently higher among cases than those among controls. Logistic regression analyses showed that maternal exposure to all air pollutants during the first trimester was associated with an increased odds of CHD (e.g., an interquartile range [13.3 µg/m3] increase in PM1 was associated with 1.09-fold ([95% confidence interval, 1.01–1.18]) greater odds of CHD). No significant associations were observed for maternal air pollution exposures during the second trimester and the third trimester. The pattern of the associations between air pollutants and different CHD subtypes was mixed. ConclusionsMaternal exposure to greater levels of air pollutants during the pregnancy, especially the first trimester, is associated with higher odds of CHD in offspring. Further longitudinal well-designed studies are warranted to confirm our findings.

Birth defects and unconventional natural gas developments in Texas, 1999–2011

Unconventional natural gas developments (UNGD) may release air and water pollutants into the environment, potentially increasing the risk of birth defects. We conducted a case-control study evaluating 52,955 cases with birth defects and 642,399 controls born between 1999 and 2011 to investigate the relationship between UNGD exposure and the risk of gastroschisis, congenital heart defects (CHD), neural tube defects (NTDs), and orofacial clefts in Texas. We calculated UNGD densities (number of UNGDs per area) within 1, 3, and 7.5 km of maternal address at birth and categorized exposure by density tertiles. For CHD subtypes with large case numbers, we also performed time-stratified analyses to examine temporal trends. We calculated adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the association with UNGD exposure, accounting for maternal characteristics and neighborhood factors. We also included a bivariable smooth of geocoded maternal location in an additive model to account for unmeasured spatially varying risk factors. Positive associations were observed between the highest tertile of UNGD density within 1 km of maternal address and risk of anencephaly (aOR: 2.44, 95% CI: 1.55, 3.86), spina bifida (aOR: 2.09, 95% CI: 1.47, 2.99), gastroschisis among older mothers (aOR: 3.19, 95% CI: 1.77, 5.73), aortic valve stenosis (aOR: 1.90, 95% CI: 1.33, 2.71), hypoplastic left heart syndrome (aOR: 2.00, 95% CI: 1.39, 2.86), and pulmonary valve atresia or stenosis (aOR: 1.36, 95% CI: 1.10, 1.66). For CHD subtypes, results did not differ substantially by distance from maternal address or when residual confounding was considered, except for atrial septal defects. We did not observe associations with orofacial clefts. Our results suggest that UNGDs were associated with some CHDs and possibly NTDs. In addition, we identified temporal trends and observed presence of spatial residual confounding for some CHDs.

Association between metal cobalt exposure and the risk of congenital heart defect occurrence in offspring: a multi-hospital case-control study

BackgroundMany studies have investigated heavy metal exposure could increase the occurrence of congenital heart defects (CHDs). However, there are limited data regarding the relationship between cobalt exposure and CHD occurrence in offspring. The aim of this study was to analyze the association between cobalt exposure in mothers and the risk of CHDs in offspring.Materials and methodsIn order to explore the association between cobalt exposure and occurrence of congenital heart defect (CHD), a case-control study with 490 controls and 399 cases with CHDs in China were developed. The concentrations of cobalt in hair of pregnant woman and fetal placental tissue were measured and processed by a logistic regression analysis to explore the relationship between cobalt exposure and risk of CHDs.ResultsThe median concentration of hair cobalt in the control and case group was 0.023 ng/mg and 0.033 ng/mg (aOR, 1.837; 95% CI, 1.468–2.299; P < 0.001), respectively. And the median (5–95% range) fetal placental cobalt concentrations were 19.350 ng/g and 42.500 ng/g (aOR, 2.924; 95% CI, 2.211–3.868; P < 0.001) in the control and case groups, respectively. Significant differences in the middle level of cobalt in hair were found in the different CHD subtypes, including septal defects, conotruncal defects, right ventricular outflow tract obstruction, and left ventricular outflow tract obstruction (P < 0.001). Dramatically, different cobalt concentrations in fetal placental tissue were found in all subtypes of cases with CHDs (P < 0.01).ConclusionsThe finding suggested that the occurrence of CHDs may be associated with cobalt exposure.