Congenital Heart Disease In Offspring Research Articles

Interdependence of placenta and fetal cardiac development.

The placenta and fetal heart undergo development concurrently during early pregnancy, and, while human studies have reported associations between placental abnormalities and congenital heart disease (CHD), the nature of this relationship remains incompletely understood. Evidence from animal studies suggests a plausible cause and effect connection between placental abnormalities and fetal CHD. Biomechanical models demonstrate the influence of mechanical forces on cardiac development, whereas genetic models highlight the role of confined placental mutations that can cause some forms of CHD. Similar definitive studies in humans are lacking; however, placental pathologies such as maternal and fetal vascular malperfusion and chronic deciduitis are frequently observed in pregnancies complicated by CHD. Moreover, maternal conditions such as diabetes and pre-eclampsia, which affect placental function, are associated with increased risk of CHD in offspring. Bridging the gap between animal models and human studies is crucial to understanding how placental abnormalities may contribute to human fetal CHD. The next steps will require new methodologies and multidisciplinary approaches combining innovative imaging modalities, comprehensive genomic testing, and histopathology. These studies may eventually lead to preventative strategies for some forms of CHD by targeting placental influences on fetal heart development.

Paternal peri-conceptional physical activity and the risk of congenital heart disease in offspring: A case-control study.

Genetic and environmental factors have been shown to contribute to the development of congenital heart disease (CHD). To date, the focus of scientific articles has primarily centered on genetics and maternal environmental factors, with comparatively less attention given to paternal risk factors. This study aims to investigate the potential association between paternal pre-conceptional physical activity levels (PA), along with paternal peri-conceptional smoking and alcohol consumption, and the risk of CHD in offspring. An observational case-control study was conducted in Lebanon, with 279 participants, aiming to investigate potential risk factors for CHD. We included children with confirmed CHD, born between 2012 and 2022. Controls born in the same timeframe were selected randomly from the general population using online questionnaire forms. Mean age of children included was 6 years old (0-10). The pre-conceptional PA was assessed using the Global Physical Activity Questionnaire validated in Arabic. In addition, paternal smoking, alcohol consumption, and maternal risk factors were collected. The study included 128 CHD cases (45.9%) and their parents, as well as 151 healthy infants (54.1%) and their parents. There were no statistically significant variations in the alcohol consumption noted between the fathers in the case and control groups (p=0.18). The paternal involvement in recreational-related PA during the peri-conception period was associated with a reduced risk of the CHD development in offspring by 46.9% (OR=0.531, 95% CI: 0.301-0.936, p=0.029). Additionally, increasing paternal total sitting time by 1 h above the average, which was approximately 260 min (4h), increased the risk of CHD in offspring by 0.4% (p=0.001). Moreover, paternal smoking exhibited an apparent association with a 56% increased risk of offspring developing CHD, notwithstanding that the confidence intervals included the null (OR=1.56, 95% CI: 0.86-2.8, p=0.136). This observational study is the first to report a potential association between paternal PA, and CHD in offspring. This study aligns with previous reports, advocating for the paternal engagement in PA and the adoption of healthy lifestyle habits, especially during the critical stages of conception. Such practices are strongly recommended to enhance fertility and promote optimal health for offspring. However, due to the subjectivity in reporting PA and lack of molecular proof, additional prospective and molecular studies are required to validate these findings.

Association of maternal weight gain in early pregnancy with congenital heart disease in offspring: a China birth cohort study

ObjectivesLittle study has reported the association of maternal weight gain in early pregnancy with fetal congenital heart disease (CHD). We aimed to explore the potential relationship based on a China...

Prenatal exposure to poly/perfluoroalkyl substances and risk for congenital heart disease in offspring

Congenital heart disease (CHD) is the most prevalent congenital malformation worldwide, and the association between per- and polyfluoroalkyl substances (PFASs) exposure and CHD in population has only received limited study. Therefore, we conducted a multicenter case-control study to explore the associations between prenatal exposure to individual PFASs, and also a PFAS mixture, and CHD risk, including 185 CHDs and 247 controls in China from 2016 to 2021. Thirteen PFASs in maternal plasma were quantified using liquid chromatography-tandem mass spectrometry. Logistic regression and two multipollutant models (Bayesian kernel machine regression [BKMR] and quantile g-computation [qgcomp]) were used to assess the potential associations between any individual PFAS, and also a PFAS mixture, and CHD risk. After adjusting for potential confounders, logistic regression indicated significant associations between elevated levels of perfluorononanoic acid (odds ratio [OR]= 1.30, 95% confidence intervals [CI]: 1.07–1.58), perfluorodecanoic acid (OR=2.07, 95%CI: 1.32–3.26), and perfluoroundecanoic acid (OR=2.86, 95%CI:1.45–5.65) and CHD risk. The BKMR model and qgcomp approach identified that a significant positive association between the PFAS mixture and risk for CHD. These findings provide essential evidence that there is indeed a health crisis associated with PFASs and that it is linked to CHD.

Maternal exposure to folate antagonists and susceptibility to congenital heart disease in offspring: A systematic review and meta-analysis.

The objective of this meta-analysis was to determine whether maternal exposure to folate antagonists is associated with increased rates of congenital heart disease in offspring. A comprehensive search for articles in the MEDLINE (PubMed) and EMBASE databases published up to 21 August 2023 was performed. The search strategy was not limited by study design but only for articles in the English language. Analysis of 6 cohort studies and 5 cross-sectional studies, published between 1976 and 2020, showed significant increase in rate of congenital heart disease (odds ratio 1.55, 95% confidence interval, 1.28-1.87) when exposed to folate antagonists compared with the control. Further subgroup analysis showed the increased rate for exposure to both dihydrofolate reductase inhibitors and antiepileptic drugs separately. No differences were observed when analyses were stratified by timing of study. Administration of folate antagonists within the 12-week period preceding conception and throughout the second and third months of gestation exhibited a statistically significant elevation in the susceptibility to congenital heart diseases. Notably, the protective effect of folic acid supplementation was reported in cases of congenital heart disease linked to dihydrofolate reductase inhibitors but not that associated with antiepileptic drugs.

Association between lipid profile in early pregnancy and the risk of congenital heart disease in offspring: a prospective cohort study

This study aimed to investigate the association of lipid profile in early pregnancy and the risk of congenital heart disease (CHD) in offspring. This study was a prospective cohort design based on the Fujian Birth Cohort Study in China. We recruited pregnant women at ≤ 14 weeks of gestation between 2019 and 2022, and all participants in this study filled out the questionnaire about periconceptional exposure. Simultaneously, we collected participants’ fasting blood samples to measure their lipid profile by automatic biochemical analyzer. The outcome was defined as offspring with CHD. A multivariable logistic regression model was used to calculate adjusted odds ratio (AOR) risk estimates, which indicate the associations between maternal lipid profiles and CHD in offspring. Restricted cubic splines were used to estimate their nonlinear relationship. A total of 21,425 pregnant women with an average gestational age of 11.3 (± 1.40) weeks were included in the analysis. The higher triglyceride (AOR 1.201, 95% CI [1.036, 1.394]), low-density lipoprotein (AOR 1.216, 95% CI [1.048, 1.410]), apolipoprotein B (Apo B) (AOR 2.107, 95% CI [1.179, 3.763]) levels were correlated with increased odds of CHD in offspring, while high-density lipoprotein (OR 0.672, 95% CI [0.490, 0.920]) related with decreased odds of CHD in offspring. The restricted cubic spline suggested a nonlinear relationship between total cholesterol (TC) levels and the risk of CHD in offspring (P = 0.0048), but no significant nonlinear relationships were found in other lipid profile. Apolipoprotein A was not related to the risk of CHD in offspring as either a continuous variable or a hierarchical variable. Elevated lipid profile in early pregnancy levels are associated with an increased risk of CHD in offspring. Additionally, there is a non-linear relationship between TC levels and the risk of CHD in offspring.

Maternal Gestational Diabetes Mellitus and Congenital Heart Disease in Offspring: A Meta-Analysis.

Maternal diabetes has been related to an increased risk of congenital heart disease (CHD) in offspring. However, inconsistent results were retrieved for studies evaluating the association between gestational diabetes mellitus (GDM) and CHD in offspring. We therefore performed a systematic review and meta-analysis for comprehensive investigation. Observational studies were identified by searching PubMed, Embase, and Web of Science according to the aim of the meta-analysis. A randomized-effects model was used to pool the data by incorporating the influence of potential heterogeneity. Twenty-three observational studies, involving 46953078 mother-child pairs, were available for the meta-analysis. Among them, 2131800 mothers were diagnosed as GDM and 214379 newborns had CHD. Overall, maternal GDM was associated with a higher incidence of CHD in offspring [odds ratio (OR): 1.32, 95% confidence interval (CI): 1.21 to 1.45, p<0.001; I2=62%]. Sensitivity analysis limited to studies with adjustment of maternal age and other potential confounding factors showed similar results (OR: 1.40, 95% CI: 1.30 to 1.51, p<0.001; I2=47%). Subgroup analysis suggested that the association between maternal GDM and CHD in offspring was not significantly affected by methods for diagnosis of GDM, methods for confirmation of CHD, or study quality scores (p for subgroup difference all>0.05). Subsequent analysis according to types of CHD showed that maternal GDM was associated with higher risks of atrial septal defect, ventricular septal defect, and Tetralogy of Fallot. Maternal GDM may be associated with a higher risk of CHD in offspring.

Exposure to volatile organic compounds induces cardiovascular toxicity that may involve DNA methylation

Volatile organic compounds (VOCs) are common air pollutants and water contaminants. We previously found maternal exposure to VOCs was associated with offspring congenital heart disease (CHD). However, little information is available about the effects of VOCs on cardiovascular development at embryonic stage and the underlying mechanism remains unclear. In this study, we aimed to investigate the effects of a mixture of six VOCs on cardiovascular development in zebrafish embryos. Embryos were exposed to different concentrations of VOCs mixture (32 mg/L, 64 mg/L and 128 mg/L) for 96 h, cardiovascular abnormalities including elongated heart shape, increased distance between sinus venosus and bulbus arteriosus, slowed circulation and altered heart rate were observed in a dose- and time-dependent manner. Meanwhile, VOCs exposure increased global DNA methylation levels in embryos. Analysis identified hundreds of differentially methylated sites and the enrichment of differentially methylated sites on cardiovascular development. Two differentially methylated-associated genes involved in MAPK pathway, hgfa and ntrk1, were identified to be the potential genes mediating the effects of VOCs. By enzyme-linked immunosorbent assay, altered human serum hgf and ntrk1 levels were detected in abnormal pregnancies exposed to higher VOCs levels with fetal CHD. For the first time, our study revealed exposure to VOCs induced severe cardiovascular abnormalities in zebrafish embryos. The toxicity might result from alterations in DNA methylation and corresponding expression levels of genes involved in MAPK pathway. Our study provides important information for the risk of VOCs exposure on embryonic cardiovascular development.

Associations of elevated glucose levels at each time point during OGTT with fetal congenital heart diseases: a cohort study of 72,236 births

BackgroundIt remains unclear how the condition of glucose metabolism during pregnancy affects fetal outcomes. This study aimed to investigate the associations of gestational diabetes mellitus (GDM) and elevated glucose levels at each time point during oral glucose tolerance test (OGTT) with congenital heart disease (CHD) risk in offspring.MethodsWe conducted a retrospective cohort study of mothers with singleton pregnancies of 20 weeks or more registered at Maternal and Child Health Centers in Fujian Province, China. The OGTT results and offspring CHD occurrence were collected. We used logistic regression to analyse the association between elevated blood glucose at each time point during OGTT and CHD.ResultsA total of 71,703 normal and 533 CHD fetuses were included. Compared to the corresponding normal group, women with GDM, elevated blood glucose at different time points in OGTT (0 h ≥ 5.1 mmol/L, 1 h ≥ 10 mmol/L, and 2 h ≥ 8.5 mmol/L) showed an increased risk of CHD in offspring (adjusted OR = 1.41, 1.36, 1.37, and 1.41, all P < 0.05, respectively). Compared to group 1 (normal OGTT 0 h, 1 h and 2 h), the risk of CHD was higher in group 3 (normal OGTT 0 h and abnormal OGTT 1 h or 2 h) and group 4 (abnormal OGTT 0 h, 1 h and 2 h), OR = 1.53 and 2.21, all P < 0.05, respectively. Moreover, we divided participants by advanced maternal age, multipara, assisted reproduction, fetal sex, and others, similar associations were observed in the subgroup analyses.ConclusionElevated blood glucose at different time points during OGTT was associated with CHD in offspring. Fetuses of pregnant women with GDM should be screened for a high risk of CHD.

Proteome profiling of early gestational plasma reveals novel biomarkers of congenital heart disease.

Prenatal diagnosis of congenital heart disease (CHD) relies primarily on fetal echocardiography conducted at mid-gestational age-the sensitivity of which varies among centers and practitioners. Anobjective method for early diagnosis is needed. Here, we conducted a case-control study recruiting 103 pregnant women with healthy offspring and 104 cases with CHD offspring, including VSD (42/104), ASD (20/104), and other CHD phenotypes. Plasma was collected during the first trimester and proteomic analysis was performed. Principal component analysis revealed considerable differences between the controls and the CHDs. Among the significantly altered proteins, 25 upregulated proteins in CHDs were enriched in amino acid metabolism, extracellular matrix receptor, and actin skeleton regulation, whereas 49 downregulated proteins were enriched in carbohydrate metabolism, cardiac muscle contraction, and cardiomyopathy. The machine learning model reached an area under the curve of 0.964 and was highly accurate in recognizing CHDs. This study provides a highly valuable proteomics resource to better recognize the cause of CHD and has developed a reliable objective method for the early recognition of CHD, facilitating early intervention and better prognosis.

Is maternal pre-pregnancy Body Mass Index associated with type of Congenital Heart Disease in offspring?

HIGHLIGHTS The most common CHD was atrial septal defect for acyanotic CHD and Tetralogy of Fallot for cyanotic CHD. There was no association between maternal pre-pregnancy BMI and type of CHD in offspring.   ABSTRACT Objectives: This study aimed to determine the association between maternal pre-pregnancy BMI and type of congenital heart disease (CHD) in offspring. Materials and Methods: This retrospective cross-sectional study involved all mothers of children with CHD who visited Pediatric Outpatient Unit at Dr. Soetomo General Academic Hospital, Surabaya, Indonesia, from January to December 2019. The maternal data were obtained from the KIA's (Maternal and Child Health) book or through anamnesis by telephone, while the offspring’s data were collected from medical records. The data were analyzed using the Chi-Square test. Significance was determined at a 5% level (p &lt;0.05). Results: We studied 117 mothers of children with CHD. The most frequent maternal pre-pregnancy body mass index (BMI) was normal (BMI 17-23 kg/m2) accounting for 56.4% of the study population. The most common CHD was atrial septal defect (33.3%) among acyanotic patients and Tetralogy of Fallot (8.5%) among cyanotic patients. The Chi-Square test showed p=0.958 for the association between maternal pre-pregnancy BMI and type of CHD in offspring. Conclusion: There was no association between maternal pre-pregnancy BMI and type of CHD in offspring.  

Association of maternal methionine synthase reductase gene polymorphisms with the risk of congenital heart disease in offspring: a hospital-based case-control study

Background Evidence suggests that periconceptional folic acid supplementation may prevent congenital heart disease (CHD). Methionine synthase reductase (MTRR) is one of the key regulatory enzymes in the folate metabolic pathway. This study aimed to comprehensively evaluate the association of single nucleotide polymorphisms (SNPs) in the maternal MTRR gene with CHD risk in offspring. Methods A hospital-based case-control study involving 740 mothers of CHD cases and 683 health controls was conducted. Results The study showed that maternal MTRR gene polymorphisms at rs1532268 (C/T vs. C/C: aOR = 1.524; T/T vs. C/C: aOR = 3.178), rs1802059 (G/A vs. G/G: aOR = 1.410; A/A vs. G/G: aOR = 3.953), rs2287779 (G/A vs. G/G: aOR = 0.540), rs16879334 (C/G vs. C/C: aOR = 0.454), and rs2303080 (T/A vs. T/T: aOR = 0.546) were associated with the risk of CHD. And seven haplotypes were observed to be associated with the risk of CHD, T-G-A haplotype (OR = 1.298), C-A-C-C (OR = 4.824) and A-G haplotype (OR = 1.751) were associated with increased risk of CHD in offspring; A-A-A (OR = 0.773), T-A-A (OR = 0.557), G-A-C-C (OR = 0.598) and G-C (OR = 0.740) were associated with decreased risk of CHD in offspring. Conclusions Maternal MTRR gene polymorphisms were associated with CHD in offspring, and its haplotypes have affected the occurrence of CHD. Furthermore, given the complexity and heterogeneity of CHD, the mechanisms by which these factors influence offspring cardiac development remain unknown, and studies in larger samples in an ethnically diverse population are needed.

Maternal exposure to housing renovation during the periconceptional period and the risk of offspring with isolated congenital heart disease: a case-control study

BackgroundCongenital heart disease (CHD) is the most prevalent birth defect in recent decades. The aim of this research was to examine the association between maternal housing renovation exposure during the periconceptional period and isolated congenital heart disease (CHD) in their offspring.MethodsA multi-hospitals case-control study was conducted from six tertiary A hospitals in Xi’an, Shaanxi, Northwest China based on questionnaires and interviews to address this question. The cases included fetuses or newborns diagnosed with CHD. Controls consisted of healthy newborns without birth defects. In total, 587 cases and 1180 controls were enrolled in this study. The association between maternal periconceptional housing renovation exposure and isolated CHD for offspring was assessed by estimating odds ratios (OR) with multivariate logistic regression models.ResultsAfter adjusting for potential confounding variables, it was found that maternal exposure to home improvement projects was associated with a higher probability of isolated CHD in offspring (adjusted OR: 1.77, 95% CI: 1.34, 2.33). Additionally, the risk of the ventricular septal defect (VSD) and patent ductus arteriosus (PDA) for CHD types was significantly associated with maternal exposure to housing renovations (VSD: adjusted OR = 1.56, 95% CI: 1.01, 2.41; PDA: adjusted OR = 2.50, 95% CI: 1.41, 4.45).ConclusionsOur study suggests that maternal exposure to housing renovation during the periconceptional period was associated with an increased risk of isolated CHD in offspring. Consequently, it would be beneficial to avoid living in a renovated home from 12 months before pregnancy through the first trimester to lower isolated CHD in infants.

Association between preeclampsia and offspring congenital heart disease

Prior literature has described an association between preeclampsia and congenital heart disease (CHD), while also suggesting that there may be a stronger relationship in individuals with early preeclampsia. We sought to explore that relationship within the same pregnancy in a large population-based study.

History of preeclampsia in pregnancy increases risk of offspring congenital heart disease

To explore the association between preeclampsia in a prior pregnancy and the development of congenital heart disease (CHD) in a subsequent pregnancy. Prior research has suggested a link between the two, though the relationship remains poorly understood.

History of offspring congenital heart disease in pregnancy increases risk of preeclampsia in subsequent pregnancy

History of offspring congenital heart disease in pregnancy increases risk of preeclampsia in subsequent pregnancy

Early delivery among preeclamptic patients associated with increased risk of congenital heart disease subtypes

Current data demonstrates an increased risk of congenital heart disease (CHD) in patients with preeclampsia. Given the possibility of different biological mechanisms behind early preeclampsia as compared to preeclampsia diagnosed and delivered beyond 34 weeks’ gestation, we sought to characterize the relationship of offspring CHD (including sub-categories of disease) with timing of delivery in a large cohort of pregnant patients with preeclampsia.

[Relationship between Chinese dietary guidelines compliance index for pregnant women and congenital heart disease in offspring].

Objective: To study the relationship between the Chinese dietary guidelines compliance index for pregnant women (CDGCI_PW) and congenital heart disease (CHD) in offspring. Methods: In a hospital-based case-control study conducted in Xi'an, Shaanxi province, semi-quantitative food frequency questionnaires were used to investigate the diets of pregnant women throughout pregnancy. The modified CDGCI_PW score was used to evaluate dietary quality during pregnancy, logistic regression was applied to analyze the relationship between CDGCI_PW score and offspring CHD, and the ROC curve was adopted to construct the prediction model of CDGCI_PW for offspring CHD. Results: A total of 1 422 subjects were enrolled, including 474 in the case group and 948 in the control group. The CDGCI_PW score in the case group M (Q1, Q3) was 46.0 (26.0, 65.0) lower than that in the control group, which was 60.0 (40.0, 77.0). The difference between the two groups was significant (P<0.001). Compared with those in the Q1 of CDGCI_PW, the offspring in the Q2, Q3, and Q4 of CDGCI_PW had a lower risk of total CHD (OR=0.60, 95%CI: 0.43-0.83; OR=0.64, 95%CI: 0.45-0.89; OR=0.29, 95%CI: 0.19-0.44), with the trend test P<0.001. The risk of total CHD was reduced by 17% (OR=0.83, 95%CI: 0.79-0.88) when 10 points increased the CDGCI_PW score. The area under curve predicted by constructing the ROC curve was 0.793 (95%CI: 0.768-0.818), and at the maximum of the Youden index, the sensitivity was 0.740, and the specificity was 0.725. Conclusion: This study suggests that improving dietary quality during pregnancy may reduce the risk of CHD in offspring.

The Association of Folic Acid, Iron Nutrition during Pregnancy and Congenital Heart Disease in Northwestern China: A Matched Case-Control Study.

Background: The purpose of this study was to investigate the relationship between folic acid and iron nutrition during pregnancy and congenital heart disease (CHD) in the offspring. Methods: Conditional logistic regression models and nonlinear mixed-effects models were used to analyze the effects of folic acid and iron nutrition during pregnancy on CHD in offspring. Results: After adjusting for confounders, folic acid or iron supplementation during pregnancy reduced the risk for fetal CHD (OR = 0.60 (0.45, 0.82) or 0.36 (0.27, 0.48)). Similarly, dietary iron intake during pregnancy (≥29 mg/d) was associated with a reduced risk of fetal CHD (OR = 0.64 (0.46, 0.88)). Additionally, compared with women who only supplemented folic acid (OR = 0.59 (0.41, 0.84)) or iron (OR = 0.32 (0.16, 0.60)), women who supplemented both folic acid and iron had lower risk for newborns with CHD (OR = 0.22 (0.15, 0.34)). Similarly, compared with women who only supplemented folic acid (OR = 0.59 (0.41, 0.84)) or higher dietary iron intake (≥29 mg/d) (OR = 0.60 (0.33, 1.09)), women who supplemented both folic acid and higher dietary iron intake (≥29 mg/d) had lower risk for the newborn with CHD (OR = 0.41 (0.28, 0.62)). The combined effects were significant in the multiplication model (OR = 0.35 (0.26, 0.48) or 0.66 (0.50, 0.85)) but not in the additive model. Conclusions: Our study found that folic acid and iron nutrition during pregnancy were associated with a reduced risk of CHD in the offspring and confirmed a statistically significant multiplicative interaction between folic acid and iron nutrition on the reduced risk of CHD in offspring.

The UA Doppler Index, Plasma HCY, and Cys C in Pregnancies Complicated by Congenital Heart Disease of the Fetus.

Background: Congenital heart disease/defect (CHD) is one of the most common congenital disabilities. Early diagnosis of CHD can improve the prognosis of newborns with CHD. The aim of this study was to evaluate the relationship between the factors and the onset of fetal congenital heart disease by measuring fetal umbilical artery (UA) Doppler index, maternal HCY, and Cys C levels during pregnancy. Methods: This retrospective study analyzed 202 fetuses with CHD, including 77 cases (39.1%) of simple CHD and 120 cases (60.9%) of complex CHD. Singleton pregnant women who were examined at the same time and whose malformation screening did not suggest any structural abnormalities in the fetus were assigned to the control group (n = 400). The UA Doppler index, plasma HCY, and Cys C levels were compared among the pregnant women across the three groups, and logistic regression analysis was performed on statistically significant markers. The ROC of UA S/D, PI, RI, HCY, and Cys C were plotted, and the area under the ROC (AUC) was calculated. Results: The UA S/D, PI, and RI in the complex CHD group were significantly higher than those in the control group (p < 0.05). The levels of HCY and Cys C in the CHD group were significantly higher than those in the control group (p < 0.05). HCY and S/D revealed a positive correlation (r = 0.157), and the difference was statistically significant (p < 0.001). Cys C and S/D were positively correlated (r = 0.131), and the difference was statistically significant (p < 0.05). The levels of UA Doppler indices, maternal plasma HCY, and Cys C were elevated in fetuses with CHD. The AUC of the combined test of the UA index, HCY, and Cys C was higher than that of each individual test. Conclusions: Elevated levels of the UA doppler indices, HCY, and Cys C during pregnancy are positively associated with the development of congenital heart disease in offspring. The combination of HCY and Cys C was the most efficient test for the diagnosis of CHD. We are the first to report that plasma Cys C levels of women pregnant with fetuses with CHD were higher than those of women pregnant with normal fetuses.