Risk Of Congenital Heart Defects In Offspring Research Articles

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.

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.

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.

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.

Folic Acid and the Risk of Congenital Heart Defects

Source: Wang D, Jin L, Zhang J, et al. Maternal periconceptional folic acid supplementation and risk for fetal congenital heart defects [published online ahead of print September 8, 2021]. J Pediatr. doi: 10.1016/j.jpeds.2021.09.004.Investigators from Peking University and Tongzhou Maternal and Child Health Hospital, both in Beijing, China, conducted a retrospective study to assess the effectiveness of periconceptional folic acid (FA) supplementation in preventing congenital heart defects (CHD). For the study, they reviewed data contained in the Prenatal Health Care System (PHCS) and Birth Defects Surveillance System (BDSS) databases on singleton deliveries (including live births, stillbirths, and terminated pregnancies) between 2013 and 2018 in the Tongzhou District, Beijing, China. PHCS is a registry that includes data on women during pregnancy and after delivery, including maternal age and educational level, delivery date, and periconceptional FA supplementation. Information about FA supplementation was based on maternal self-report and included type of FA supplementation and when it started (prior to or after conception). In China, women are provided FA in a daily dose of 0.4 mg by the central government. However, some women take micronutrient supplements containing FA (MMFA). The BDSS includes information on birth defects, beginning at 13 weeks of gestation, including CHD.Primary study outcomes were any CHD, ventricular septal defect (VSD), and critical CHD (defined using standardized criteria). Poisson regression was used to compare the risks of these outcomes in women with FA/MMFA supplementation and in those without supplementation. Risk of CHD also was compared in women taking FA vs MMFA, and with FA/MMFA supplementation beginning prior to or after conception. Regression models also included maternal age, education, and year of delivery.Data were analyzed on 63,969 women and their offspring. Women using FA/MMFA supplementation were significantly older and more educated than those who didn’t. There were 308 cases of CHD in the offspring of study women, including 152 live births and 156 stillbirths or terminated pregnancies; the most common CHD was VSD (125 cases). The use of periconceptional FA/MMFA was associated with a reduced risk of any CHD (adjusted risk ratio [ARR], 0.60; 95% CI, 0.44, 0.83), VSD (ARR, 0.47; 95% CI, 0.30, 0.74) and critical CHD (ARR, 0.41; 95% CI, 0.26, 0.67). There were no statistical differences between FA and MMFA supplementation for risk of any CHD (ARR, 0.84; 95% CI, 0.66, 1.09), VSD (ARR, 0.94; 95% CI, 0.63, 1.41) or critical CHD (ARR, 0.64; 95% CI, 0.44, 1.00). Initiation of FA/MMFA supplementation before conception, compared to post-conception, was associated with a reduced risk of any CHD (ARR, 0.68; 95% CI, 0.48, 0.95) and critical CHD (ARR, 0.26; 95% CI, 0.10, 0.71).The authors conclude that maternal periconceptional FA supplementation was associated with a decreased risk of CHD in off-spring, particularly when initiated prior to conception.Dr Doolittle has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.FA, one of the B vitamins, is a micronutrient found in fresh fruit, vegetables, nuts, and eggs.1 FA deficiency has been associated with megaloblastic anemia and neural tube defects in infants, as well as heart disease and cancer in adults.1 Humans are unable to synthesize FA, and thus must rely on ingestion in the form of food or conversion of precursors in the gut microflora.1 FA is an important co-factor in DNA and RNA synthesis, and the formation of the heart neural crest cells are highly sensitive to FA.2 Since 1992, FA and other micronutrient deficiencies have been associated with CHD.3 However, the results of supplementation trials to prevent CHD have been equivocal.4 The results of the current investigation provide convincing evidence to support FA/MMFA supplementation to prevent CHD.The study design was robust, with a governmental registry of more than 63,000 women who were followed prospectively over 5 years. Of note, the investigators evaluated self-report of FA/MMFA supplementation. Although self-report may be imperfect, the study represents a real-world evaluation. Women who took FA/MMFA supplementation were older and better educated. As maternal age is a risk for CHD, and education usually confers better health outcomes, the investigators controlled for these variables.The results of the current study raises several provocative questions that merit future investigation. Pre-conception supplementation was associated with reduced CHD compared to peri-conception supplementation. This suggests that some independent maternal factors may influence CHD formation prior to conception. Also, despite the reduction of CHD due to supplementation, the continued prevalence of CHD suggests other factors such as genetic defects, exogenous toxin, or infection are at play.Maternal periconceptual supplementation with FA may be associated with a reduced risk of CHD, especially when initiated before conception. (See AAP Grand Rounds. 2020;44[6]:68.)5Perhaps the greater protective efficacy of preconceptual FA supplementation is related to the time it takes to achieve effective folate levels during the critical period of heart development.2

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.

Gene-based analyses of the maternal genome implicate maternal effect genes as risk factors for conotruncal heart defects.

Congenital heart defects (CHDs) affect approximately 1% of newborns. Epidemiological studies have identified several genetically-mediated maternal phenotypes (e.g., pregestational diabetes, chronic hypertension) that are associated with the risk of CHDs in offspring. However, the role of the maternal genome in determining CHD risk has not been defined. We present findings from gene-level, genome-wide studies that link CHDs to maternal effect genes as well as to maternal genes related to hypertension and proteostasis. Maternal effect genes, which provide the mRNAs and proteins in the oocyte that guide early embryonic development before zygotic gene activation, have not previously been implicated in CHD risk. Our findings support a role for and suggest new pathways by which the maternal genome may contribute to the development of CHDs in offspring.

Maternal dietary diversity during pregnancy and congenital heart defects: a case-control study.

Maternal diet is critical to fetal development. This study aimed to explore the association between maternal dietary diversity during pregnancy and congenital heart defects (CHD) in Chinese population. A hospital-based case-control study was conducted including 474 cases and 948 controls in Northwest China. We recruited eligible women waiting for delivery in the hospital and gathered their diets during the whole pregnancy by a validated food frequency questionnaire. According to the FAO Minimum Dietary Diversity for Women (MDD-W) guideline, the participants were categorized into "inadequate dietary diversity score (DDS)" (DDS < 5) and "adequate DDS" (DDS ≥ 5) groups. The association between dietary diversity and CHD was estimated using the mixed logistic regression models. Case mothers had a lower DDS during pregnancy than the controls (P < 0.001). The proportions of women consuming all the ten defined food groups were lower in the inadequate DDS group than in the adequate DDS group among both cases and controls (all P < 0.001). The prevalence of inadequate micronutrient intake was higher in the inadequate DDS group than in the adequate DDS group among both cases and controls (all P < 0.05). Women in the adequate DDS group had reduced risks of having fetuses with total CHD (OR = 0.62, 95% CI = 0.45-0.84) and ventricular septal defects (OR = 0.58, 95% CI = 0.38-0.88). Adequate DDS during pregnancy might be associated with a lower risk of CHD in offspring. Efforts to promote dietary diversity during pregnancy need to be strengthened to reduce the prevalence of CHD in Chinese population.

Maternal dietary fat intake and the risk of congenital heart defects in offspring.

BackgroundFatty acids are crucial in embryologic development, including cardiogenesis. The impact of maternal periconceptional dietary fat intake on the risk of congenital heart defects (CHDs) has not been clearly elucidated. We hypothesized that maternal dietary fat intake during pregnancy is associated with risk of CHDs in offspring.MethodsWe analyzed CHD cases and non-malformed controls from the National Birth Defects Prevention Study, a case-control, multicenter population-based study of birth defects. We used multivariable logistic regression to analyze the association between maternal periconceptional dietary fat intake and occurrence of CHDs.ResultsWe examined 11,393 infants with CHDs (cases) and 11,029 infants without birth defects (controls). Multivariable analysis of maternal dietary fat intake adjusted for maternal energy intake demonstrated modest change in risk for 2 of the 25 CHDs analyzed; otherwise there was no association. Maternal dietary fat intake unadjusted for total energy was associated with increased risk for several CHDs.ConclusionAfter adjusting for total energy intake, maternal periconceptional dietary fat intake has a modest association with risk of a few specific CHDs. If maternal dietary fat intake does impact CHD risk, the effect is minimal.

Risk of congenital heart defects in offspring exposed to maternal diabetes mellitus: an updated systematic review and meta-analysis.

A systematic review and meta-analysis was performed to assess the risk of congenital heart defects (CHDs) and its specific phenotypes associated with maternaldiabetes mellitus (DM) including pregestational diabetes mellitus (PGDM) and gestational diabetes mellitus (GDM). PubMed, Embase, Medline, Google Scholar, Cochrane Libraries, China National Knowledge Infrastructure, Wanfang Database, Chinese Scientific Journals Fulltext Database and China Biology Medicine disc were searched from the inception dates to 15 December 2018, to identify case-control or cohort studies assessing the association between maternal DM and risk of CHDs. The exposure of interest was maternal DM; the outcomes of interest were CHDs and its specific phenotypes. Either a fixed- or a random-effects model was used to calculate the overall combined risk estimates. Subgroup analyses were performed to explore potential heterogeneity moderators. Total 52 studies, which involved 259,917 patients with CHDs among 16,929,835 participants, were included for analysis. Overall, mothers with DM compared with those without DM had a significantly higher risk of CHDs in offspring [odds ratios (OR) = 2.71, 95% confidence intervals (CI) 2.28-3.23]. When data were restricted to different types of DM, a significantly increased risk of CHDs was observed among mothers with PGDM (OR = 3.18, 95% CI 2.77-3.65) and GDM (OR = 1.98, 95% CI 1.66-2.36). Our study suggested the risk of CHDs was significantly higher among mothers with PGDM than those with GDM. Additionally, this study suggested maternal DM was significantly associated with most phenotypes of CHDs; of these, double outlet of the right ventricle (OR = 10.89; 95% CI 8.77-13.53), atrioventricular septal defect (OR = 5.74; 95% CI 3.20-10.27) and truncus arteriosus (OR = 5.06; 95% CI 2.65-9.65) were identified as the first three of the most common phenotypes of CHDs associated with maternal DM. The maternal DM including PGDM and GDM are significantly associated with risk of CHDs and its most phenotypes. The PGDM seems to be more likely to cause CHDs in offspring than GDM. Further studies are needed to clarify the underlying mechanisms.

Parental smoking and the risk of congenital heart defects in offspring: An updated meta-analysis of observational studies.

Although previous reviews confirmed maternal active smoking was significantly associated with risk of fetal congenital heart defects (CHDs), association between maternal passive smoking and paternal smoking and risk of CHDs is inconclusive nowadays; furthermore, a complete overview is lacking. A meta-analysis of observational studies was conducted to assess the risk of CHDs associated with maternal active and passive smoking and paternal smoking. Seven electronic databases were searched for qualified research up to June 2018. We summarized study characteristics and the summary risk estimates were calculated using either the random-effect model or fixed-effect model. Sensitivity and subgroup analysis were carried out to identify the potential heterogeneity moderators. One hundred and twenty-five studies involving 137,574 CHDs cases in 8,770,837 study participants were included. Overall, maternal active (risk ratio (RR) = 1.25; 95% confidence interval (CI): 1.16-1.34; p < 0.01) and passive (RR = 2.24, 95% CI: 1.81-2.77; p < 0.01) smoking as well as paternal active smoking (RR = 1.74, 95% CI: 1.48-2.06; p < 0.01) were significantly associated with CHDs risk. For specific CHD subtypes, our study showed that maternal active smoking was significantly associated with risk of atrial septal defect (RR = 1.27, 95% CI: 1.02-1.59; p = 0.03) and right ventricular outflow tract obstruction (RR = 1.43, 95% CI: 1.04-1.97; p = 0.03). Relevant heterogeneity moderators have been identified by subgroup analysis. Sensitivity analysis yielded consistent results. Maternal active smoking, maternal passive smoking as well as paternal smoking all increased the risk of CHDs in offspring. Preventing parental smoking during peri-pregnancy is a priority for CHDs prevention.

Maternal vitamin D level and vitamin D receptor gene polymorphism as a risk factor for congenital heart diseases in offspring; An Egyptian case-control study

Vitamin D & vitamin D receptor (VDR) signaling play a very crucial role in early embryonic heart development. We construct this case-control study to investigate the association between maternal serum vitamin D level & VDR gene Fok1 polymorphism and risk of congenital heart defects (CHD) in offspring. Fifty mothers who had term neonates with CHD were considered as cases. Fifty age-comparable healthy mothers who had neonates without CHD were contemplated as controls. Maternal serum 25 hydroxyvitamin D [25(OH) D] level was tested using ELISA. Maternal VDR gene Fok1 polymorphism was analyzed using PCR-based RFLP-assay. There was a significant decrease in maternal vitamin D level (P = 0.002) and a significant increase in vitamin D deficient status (P = 0.007) among cases when compared to controls. VDR gene Fok1 genotypes distribution frequency were in accordance with Hardy Weinberg equilibrium (HW) among controls. A significant increase in VDR gene Fok1 F/f & f/f genotypes and f allele were observed in cases compared to controls with estimated odds ratio (95% confidence interval) &P-value of 3 (1–8) &P = 0.006, 11 (1–97) &P = 0.01 and 3 (2–6) &P = 0.001 respectively. There was a significant decrease in maternal vitamin D level in neonates with cyanotic CHD (P = 0.000) compared to those with a cyanotic CHD while there was no significant difference in VDR Fok1 genotype (P = 0.18) & allele (P = 0.05) distribution between two groups. We concluded that maternal vitamin D deficiency and VDR gene Fok1 F/f, f/f genotype and f allele were associated with increased risk of CHD in offspring.

Review of epidemiological studies on individual and environmental risk factors in the aetiology of congenital heart defects

among all congenital malformations, congenital heart defects (CHDs) are the main cause of neonatal mortality and infant mortality and morbidity, thus representing a major public health burden. Several epidemiological studies suggested the role of environmental factors in the genesis of CHDs. to collect the recently literature (2011-2015) on the increasing risk of CHDs in the offspring of exposure to industries, mines, landfills, and incinerators and individual risk factors (cigarette smoking, alcohol use, occupational exposure, socioeconomic status, and air pollution). a search was carried out in PubMed following SENTIERI project criteria to evaluate evidence by selecting English and Italian articles regarding human studies. 2,066 abstracts were collected and examined individually. Systematic reviews of epidemiological and individual studies reporting association estimates between the outcome (CHDs) and at least one of the risk factors were selected. studies on industries and landfills exposures provided limited evidence of increased risk of CHDs associated with the proximity of maternal residence to the sites. Inadequate evidence was found for positive association between exposure to mines or incinerators and risk of CHDs. Regarding maternal cigarette smoking, literature provided sufficient evidence of an increased risk of CHDs in offspring. A limited evidence of an increased risk of CHDs among pregnant women working in agriculture or exposed to solvents and polycyclic aromatic hydrocarbons emerged. Sufficient epidemiological evidence emerged for the association between CHDs and maternal exposure to high concentrations of NO2 and SO2. meta-analysis results should be interpreted with caution as they are based on a few studies, some of which are subject to high heterogeneity. For future research, epidemiological studies including spontaneous abortions and voluntary termination of pregnancy, an accurate individual exposure characterisation and an adequate control of the main confounding variables are needed.

Paternal age and offspring congenital heart defects: a national cohort study.

Paternal age has been associated with offspring congenital heart defects (CHDs), which might be caused by increased mutations in the germ cell line because of cumulated cell replications. Empirical evidences, however, remain inconclusive. Furthermore, it is unknown whether all subtypes of CHDs are affected by paternal age. We aimed to explore the relationship between paternal age and the risk of offspring CHDs and its five common subtypes using national register data in Denmark. A total of 1 893 899 singletons born in Denmark from 1977 to 2008 were included in this national-based cohort study. Cox’s proportion hazards model with robust sandwich estimate option was used to estimate the hazards ratio (95% confidence interval) for the associations between paternal age and all CHDs, as well as subtypes of CHDs (patent ductus arteriosus (PDA), ventricular septal defect (VSD), atrial septal defect (ASD), tetralogy of fallot (TOF) and coarctation of the aorta (CoA)). We did not observe an overall association between paternal age and offspring CHDs. However, compared to the paternal age of 25–29 years, paternal age of older than 45 years was associated with a 69% increased risk of PDA (HR45+ = 1.69, 95%CI:1.17–2.43). We observed similar results when subanalyses were restricted to children born to mothers of 27–30 years old. After taking into consideration of maternal age, our data suggested that advanced paternal age was associated with an increased prevalence of one subtype of offspring congenital heart defects (CHDs), namely patent ductus arteriosus (PDA).

The Good SHP2 Association

In this issue of the Journal, Goodship and colleagues report results from an association study for common genetic variants underlying tetralogy of Fallot (TOF).1 By studying a limited number of single-nucleotide polymorphisms (SNPs) tagging haplotypes at 22 candidate genes, they associated a single SNP at a chromosome 12 locus harboring PTPN11 , which encodes the protein tyrosine phosphatase SHP2, and other genes with TOF. This SNP was calculated to have a per-allele risk of 1.34 and a population-attributable risk of roughly 5%. If this study, undertaken with British white subjects, can be replicated in additional populations, it will represent a significant advance in our understanding of the genetics of congenital heart defects (CHD). Article see p 287 The genetic architecture of CHD has been the source of considerable debate and uncertainty. It has been known for some time that chromosomal defects and single-gene mutations can cause CHD, often in the context of a multisystem disease. For TOF, examples include trisomy 21 and TBX5 point mutations underlying Down and Holt-Oram syndromes, respectively.2 The discovery of 22q11 microdeletions, usually arising de novo, added significantly to our understanding of the genetic underpinnings of conotruncal forms of CHD, as these account for substantial percentages of some cardiac lesions (eg, 34% of truncus arteriosus and 16% of TOF).3 Nonetheless, these known genetic causes of CHD are estimated to account for less than 20% of cases overall. Epidemiological studies of CHD have strongly pointed to genetic factors as the predominant cause, although environmental exposures are also relevant. Parental consanguinity significantly increases the risk of CHD in offspring, probably as the result of the shared genetic background of unaffected parents.4 In countries where consanguineous marriages are customary, the rates of consanguinity are 2- to 3-fold higher among couples with offspring with CHD than …

Abstract P140: Maternal Smoking During Pregnancy and Risk of Congenital Heart Defects: A Systematic Review and A Meta-Analysis

Objective: Congenital heart defects (CHDs) are the most common group of structural malformations occurring in approximately 1 out of every 100 births. In addition to being the most prevalent birth defect, CHDs are the leading cause of death due to congenital malformations. Despite their prevalence and clinical importance, little is known about the etiology of CHDs, and there are currently no strategies for reducing their prevalence. Maternal smoking during pregnancy has been suggested as a potential risk factor for congenital heart defects, but the evidence is inconclusive. We systematically reviewed epidemiological studies and conducted a meta-analysis of the association between maternal cigarette smoking during pregnancy and the risk of CHDs among the infants. Methods: From a search of published literature through July 2011, we extracted 35 original human epidemiological studies that examined the association between maternal smoking during pregnancy (including a month before conception) and the risk of CHDs in offspring. Odds ratios (ORs) and 95% confidence intervals (CIs) were extracted from each study or calculated from available data, comparing smoking to no smoking during pregnancy. Summary risk estimates were also calculated for a number of CHDs subtypes (e.g., conotruncal defects, ventricular septal defects) using both fixed- and random-effects models. Random effects estimates were reported if there was evidence of heterogeneity among the studies. Effects of paternal and environmental smoking were not considered in our analysis. Results: We observed statistically significant positive association between maternal smoking anytime during pregnancy and the risk of CHDs (OR = 1.10; 95% CI: 1.01–1.19; number of cases (n) = 19,552). Additionally, we found a positive and significant association between maternal smoking and the risk of conotruncal defects in offspring (OR = 1.14; 95% CI: 1.03–1.26; n = 1953). Although not statistically significant, stronger elevated risks were observed for ventricular septal defects (OR = 1.11; 95% CI: 0.87–1.41; n = 4605) and atrial septal defects (OR = 1.34; 95% CI: 0.97–1.86; n = 565). Conclusion: Our systematic review and meta-analysis suggest maternal smoking is modestly associated with an increased risk of CHDs and some CHDs subtypes. This work adds to the existing body of evidence that implicated maternal smoking during pregnancy as a possible risk factor for CHDs. Future studies should consider evaluating paternal and environmental smoking exposure to better understand the relationship between smoking and CHDs.