Weizhi Zhao

Association Between Congenital Heart Defects and Small for Gestational Age

OBJECTIVES. Infants with congenital heart defects may experience inhibited growth during fetal life. In a large case-control study, we addressed the hypothesis that infants with congenital heart defects are more likely to be small for gestational age than infants without congenital heart defects after controlling for selected maternal and infant characteristics. METHODS. Using data from population-based birth defect registries, the National Birth Defects Prevention Study enrolled infants with nonsyndromic congenital heart defects (case subjects) and infants without congenital heart defects or any other birth defect (control subjects). Small for gestational age was defined as birth weight below the 10th percentile for gestational age and gender. Association between congenital heart defects and small for gestational age was examined by conditional logistic regression adjusting for maternal covariates related to fetal growth. RESULTS. Live-born singleton infants with congenital heart defects (case subjects, n = 3395) and live-born singleton infants with no birth defect (control subjects, n = 3924) were included in this study. Case subjects had lower birth weights compared with control subjects. Small for gestational age was observed among 15.2% of case subjects and among only 7.8% of control subjects. Congenital heart defect infants were significantly more likely to be small for gestational age than control infants. CONCLUSIONS. Infants with congenital heart defects are approximately twice as likely to be small for gestational age as control subjects. Small for gestational age status may affect clinical management decisions, therapeutic response, and prognosis of neonates with congenital heart defects. Although the etiology of growth retardation among infants with congenital heart defects is uncertain, further exploration may uncover a common pathogenesis or causal relationship between congenital heart defects and small for gestational age.

Maternal folate-related gene environment interactions and congenital heart defects.

OBJECTIVE: To investigate whether women with congenital heart defect (CHD)–affected pregnancies were more likely to have functional single-nucleotide polymorphisms in genes encoding enzymes in folate-dependent pathways. METHODS: A population-based case–control study of 572 women with CHD-affected pregnancies and 363 women in the control group was conducted. DNA samples were genotyped for single-nucleotide polymorphisms in three genes encoding for folate pathway enzymes. Maternal lifestyle factor information was obtained using standardized interviews. RESULTS: Women in the case group were 1.5 times more likely to be obese (body mass index of 30 or higher) compared with those in the control group. Obese women carrying the MTHFR TT genotype were 4.6 times more likely to have an affected pregnancy compared with normal-weight women carrying a CC genotype. Obese women carrying one or two copies of the A allele in the BHMT polymorphism were 1.8 times more likely to have a CHD-affected pregnancy than were normal-weight women carrying a BHMT GG genotype. Among women who smoked, those carrying a TCII CG or GG genotype were 1.8 times more likely to have an affected fetus than were women who smoked and carried a CC genotype. Among women who drank alcohol, those carrying a TCII CG or GG genotype were 1.7 times more likely to have an affected fetus than were women who drank and carried a CC genotype. CONCLUSION: Results indicate that functional polymorphisms in folate-related genes increase the risk of having a fetus with CHD when maternal lifestyle factors that alter folate metabolism are present. LEVEL OF EVIDENCE: II

Congenital heart defects and maternal biomarkers of oxidative stress

BACKGROUND Women who have had pregnancies that were affected by nonsyndromic congenital heart defects have alterations in the homocysteine-methionine pathway that may indicate increased exposure to oxidative stress or reduced antioxidant defense or both. OBJECTIVE Our goal was to establish a maternal metabolic risk profile for nonsyndromic congenital heart defects that would enhance current preventive strategies. DESIGN Using a case-control design, we measured biomarkers of the transsulfuration pathway in a population-based sample of women whose pregnancies were affected by congenital heart defects (331 cases) and in a control group of women (125 controls). Plasma concentrations of reduced and oxidized glutathione, vitamin B-6, homocysteine, cysteine, cysteinylglycine (CysGly), and glutamylcysteine (GluCys) were compared between cases and controls after adjustment for lifestyle and sociodemographic variables. RESULTS After covariate adjustment, cases had significantly lower mean plasma concentrations of reduced glutathione (P < 0.0001), GluCys (P < 0.0001), and vitamin B-6 (P = 0.0023) and significantly higher mean concentrations of homocysteine (P < 0.0001) and oxidized glutathione (P < 0.0001) than did controls. CONCLUSIONS Biomarkers of oxidative stress involved in the transsulfuration pathway were significantly higher in women with pregnancies affected by congenital heart defects than in women without such a history. Further analysis of relevant biomarkers of oxidative stress and genetic and environmental factors is required to define the basis for the observed alterations. Identifying the nature and extent of alterations in biomarkers of oxidative stress may suggest primary intervention strategies and provide clues to a greater understanding of the pathogenesis of congenital heart defects.

Racial Differences in Women’s Prodromal and Acute Symptoms of Myocardial Infarction

BACKGROUND Minority women, especially black and Hispanic women, have higher rates of coronary heart disease and resulting disability and death than do white women. A lack of knowledge of minority womens symptoms of coronary heart disease may contribute to these disparities. OBJECTIVE To compare black, Hispanic, and white womens prodromal and acute symptoms of myocardial infarction. METHODS In total, 545 black, 539 white, and 186 Hispanic women without cognitive impairment at 15 sites were retrospectively surveyed by telephone after myocardial infarction. With general linear models and controls for cardiovascular risk factors, symptom severity and frequency were compared among racial groups. Logistic regression models were used to examine individual prodromal or acute symptoms by race, with adjustments for cardiovascular risk factors. RESULTS Among the women, 96% reported prodromal symptoms. Unusual fatigue (73%) and sleep disturbance (50%) were the most frequent. Eighteen symptoms differed significantly by race (P<.01); blacks reported higher frequencies of 10 symptoms than did Hispanics or whites. Thirty-six percent reported prodromal chest discomfort; Hispanics reported more pain/discomfort symptoms than did black or white women. Minority women reported more acute symptoms (P < .01). The most frequent symptom, regardless of race, was shortness of breath (63%); 22 symptoms differed by race (P <.01). In total, 28% of Hispanic, 38% of black, and 42% of white women reported no chest pain/discomfort. CONCLUSIONS Prodromal and acute symptoms of myocardial infarction differed significantly according to race. Racial descriptions of womens prodromal and acute symptoms should assist providers in interpreting womens symptoms.

Cluster analysis of women's prodromal and acute myocardial infarction symptoms by race and other characteristics.

Background and Objective:Although research has identified womens prodromal and acute myocardial infarction (MI) symptoms, diagnosing coronary heart disease in women remains challenging. Knowing how individual symptoms cluster by race and other characteristics would provide key diagnostic information. We performed a secondary analysis to: (a) generate naturally occurring symptom clusters based on prodromal and acute MI symptom scores separately, (b) examine the association between womens characteristics and symptom clusters, and (c) describe the percentage of women who reported experiencing the same symptoms in both prodromal and acute MI phases. Subject and Methods:The database contained retrospective self-reported data obtained by telephone survey from 1270 women (43% black, 42% white, 15% Hispanic) with a confirmed MI recruited from 15 geographically diverse sites. Data included frequency and severity of 33 prodromal symptoms, intensity of 37 acute MI symptoms, and comorbidities/risk factors. We used both bivariate and multivariate analyses to examine associations between cluster assignment and characteristics/risk factors. Because of the possibility of complex interactions, we explored nonlinear interactions with recursive partitioning. Results:Cluster analysis yielded 3 naturally occurring clusters for each of the prodromal and acute symptom sets. Each cluster contained women who reported increasing frequency and severity of symptoms. Six characteristics (age, race, body mass index, personal history of heart disease, diabetes, smoking status) were strongly associated with the clusters. Body mass index was the most important factor in classifying prodromal symptoms, whereas age was for acute symptoms. Conclusions:Black women younger than 50 years were more likely to report frequent and intense prodromal symptoms, whereas older white women reported the least. Younger, obese, diabetic black women reported the most acute symptoms, whereas older nonobese, nondiabetic white women reported the fewest. Symptom clusters and characteristics of women in these clusters provide valuable diagnostic information. Further research with a control group is needed.

Maternal DNA hypomethylation and congenital heart defects

BACKGROUND Congenital heart defects (CHDs) are among the most prevalent and serious of birth defects. Multiple maternal factors are thought to contribute to CHD development, including folate intake. Maternal DNA methylation, which is dependent on folate metabolism, may impact the risk of CHDs. Our study was designed to determine whether maternal long interspersed nucleotide elements-1 (LINE-1) DNA hypomethylation is associated with increased occurrence of non-syndromic CHDs and whether maternal folate-dependent metabolites are correlated with DNA methylation status. METHODS Using a case-control study design, we measured global DNA methylation status among mothers whose pregnancies were affected by non-syndromic CHDs (n = 180) and mothers of unaffected pregnancies (n = 187). Methylation of LINE-1 was used as a surrogate marker of global DNA methylation status. The association between DNA methylation and CHD risk was determined while adjusting for selected lifestyle factors. RESULTS LINE-1 DNA methylation was significantly lower in cases compared to controls (p = 0.049). After covariate adjustments, a significant difference between cases and controls remained (p = 0.010). Among women with LINE-1 methylation in the lowest decile of DNA methylation, the estimated risk of having a CHD-affected pregnancy was almost twice that of women in all other deciles (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.03-3.58). CONCLUSIONS Our findings indicate that maternal LINE-1 DNA hypomethylation is associated with an increased risk of CHDs. Future studies investigating the association between maternal DNA methylation patterns and CHDs should be pursued.

Association between Selected Folate Pathway Polymorphisms and Nonsyndromic Limb Reduction Defects: A Case-Parental Analysis

Inadequate folate status resulting from either genetic variation or nutritional deficiencies has been associated with an increased risk of congenital malformations including orofacial clefting, limb, cardiac and neural tube defects. Few epidemiological studies have examined the association between limb reduction defects (LRDs) and folate-related genetic polymorphisms other than MTHFR 677C→T. We conducted a case-parental analysis of 148 families who participated in the National Birth Defects Prevention Study to examine the association between nonsyndromic transverse and longitudinal LRDs with five single nucleotide polymorphisms (SNPs) in genes encoding enzymes in folate and methionine pathways. Log-linear Poisson regression, adapted for analysis of case-parental data assuming an additive genetic model, was used to estimate genetic relative risks and 95% confidence intervals for the association between LRDs and each SNP. Among women who did not take multivitamin supplements, the MTHFR 677T variant acts via the offsprings genome to increase the risk of LRDs. No association between LRDs and any fetal SNP was found among women who used multivitamin supplements. These results suggest the possibility that initiating folic acid supplementation prior to pregnancy may reduce the risk of having a LRD-affected pregnancy, especially in women whose offspring inherit one or two copies of the MTHFR 677T variant.

Association between selected folate pathway polymorphisms and nonsyndromic limb reduction defects

Inadequate folate status resulting from either genetic variation or nutritional deficiencies has been associated with an increased risk of congenital malformations including orofacial clefting, limb, cardiac and neural tube defects. Few epidemiological studies have examined the association between limb reduction defects (LRDs) and folate-related genetic polymorphisms other than MTHFR 677C→T. We conducted a case-parental analysis of 148 families who participated in the National Birth Defects Prevention Study to examine the association between nonsyndromic transverse and longitudinal LRDs with five single nucleotide polymorphisms (SNPs) in genes encoding enzymes in folate and methionine pathways. Log-linear Poisson regression, adapted for analysis of case-parental data assuming an additive genetic model, was used to estimate genetic relative risks and 95% confidence intervals for the association between LRDs and each SNP. Among women who did not take multivitamin supplements, the MTHFR 677T variant acts via the offsprings genome to increase the risk of LRDs. No association between LRDs and any fetal SNP was found among women who used multivitamin supplements. These results suggest the possibility that initiating folic acid supplementation prior to pregnancy may reduce the risk of having a LRD-affected pregnancy, especially in women whose offspring inherit one or two copies of the MTHFR 677T variant.

Association between selected folate pathway polymorphisms and nonsyndromic limb reduction defects: a case-parental analysis: Folate polymorphisms & limb reduction defects

Inadequate folate status resulting from either genetic variation or nutritional deficiencies has been associated with an increased risk of congenital malformations including orofacial clefting, limb, cardiac and neural tube defects. Few epidemiological studies have examined the association between limb reduction defects (LRDs) and folate-related genetic polymorphisms other than MTHFR 677C→T. We conducted a case-parental analysis of 148 families who participated in the National Birth Defects Prevention Study to examine the association between nonsyndromic transverse and longitudinal LRDs with five single nucleotide polymorphisms (SNPs) in genes encoding enzymes in folate and methionine pathways. Log-linear Poisson regression, adapted for analysis of case-parental data assuming an additive genetic model, was used to estimate genetic relative risks and 95% confidence intervals for the association between LRDs and each SNP. Among women who did not take multivitamin supplements, the MTHFR 677T variant acts via the offsprings genome to increase the risk of LRDs. No association between LRDs and any fetal SNP was found among women who used multivitamin supplements. These results suggest the possibility that initiating folic acid supplementation prior to pregnancy may reduce the risk of having a LRD-affected pregnancy, especially in women whose offspring inherit one or two copies of the MTHFR 677T variant.