Prenatal diagnosis has been shown to improve preoperative morbidity in newborns with congenital heart defects (CHDs), but there are conflicting data as to the association with mortality. We performed a population-based, retrospective, cohort study of infants with prenatally versus postnatally diagnosed CHDs from 1994 to 2005 as ascertained by the Metropolitan Atlanta Congenital Defects Program. Among infants with isolated CHDs, we estimated 1-year Kaplan-Meier survival probabilities for prenatal versus postnatal diagnosis and estimated Cox proportional hazard ratios adjusted for critical CHD status, gestational age, and maternal race/ethnicity. Of 539,519 live births, 4,348 infants had CHDs (411 prenatally diagnosed). Compared with those with noncritical defects, those with critical defects were more likely to be prenatally diagnosed (58% vs 20%, respectively, p <0.001). Of the 3,146 infants with isolated CHDs, 1-year survival rate was 77% for those prenatally diagnosed (n = 207) versus 96% for those postnatally diagnosed (n = 2,939, p <0.001). Comparing 1-year survival rate among those with noncritical CHDs alone (n = 2,455) showed no difference between prenatal and postnatal diagnoses (96% vs 98%, respectively, p = 0.26), whereas among those with critical CHDs (n = 691), prenatally diagnosed infants had significantly lower survival rate (71% vs 86%, respectively, p <0.001). Among infants with critical CHDs, the adjusted hazard ratio for 1-year mortality rate for those prenatally versus postnatally (reference) diagnosed was 2.51 (95% confidence interval 1.72 to 3.66). In conclusion, prenatal diagnosis is associated with lower 1-year survival rate for infants with isolated critical CHDs but shows no change for those with isolated noncritical CHDs. More severe disease among the critical CHD subtypes diagnosed prenatally might explain these findings.

BACKGROUND: Administrative databases are often used for congenital cardiac disease research and evaluation, with little validation of the accuracy of the diagnostic codes. METHODS: Metropolitan Atlanta Congenital Defects Program surveillance records were reviewed and classified using a version of the International Pediatric and Congenital Cardiac Code. Using this clinical nomenclature as the referent, we report the sensitivity and false positive fraction (1 - positive predictive value) of the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for tetralogy of Fallot, transposition of the great arteries, and hypoplastic left heart syndrome. RESULTS: We identified 4918 infants and foetuses with congenital cardiac disease from the surveillance records. Using only the International Classification of Diseases diagnosis codes, there were 280 records with tetralogy, 317 records with transposition, and 192 records with hypoplastic left heart syndrome. Based on the International Pediatric and Congenital Cardiac Code, 330 records were classified as tetralogy, 163 records as transposition, and 179 records as hypoplastic left heart syndrome. The sensitivity of International Classification of Diseases diagnosis codes was 83% for tetralogy, 100% for transposition, and 95% for hypoplastic left heart syndrome. The false positive fraction was 2% for tetralogy, 49% for transposition, and 11% for hypoplastic left heart syndrome. CONCLUSIONS: Analyses based on International Classification of Diseases diagnosis codes may have substantial misclassification of congenital heart disease. Isolating the major defect is difficult, and certain codes do not differentiate between variants that are clinically and developmentally different.

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

BACKGROUND In a recent study, high maternal periconceptional intake of vitamin E was found to be associated with risk of congenital heart defects (CHDs). To explore this association further, we investigated the association between total daily vitamin E intake and selected birth defects. METHODS: We analyzed data from 4525 controls and 8665 cases from the 1997 to 2005 National Birth Defects Prevention Study. We categorized estimated periconceptional energy-adjusted total daily vitamin E intake from diet and supplements into quartiles (referent, lowest quartile). Associations between quartiles of energy-adjusted vitamin E intake and selected birth defects were adjusted for demographic, lifestyle, and nutritional factors. RESULTS: We observed a statistically significant association with the third quartile of vitamin E intake (odds ratio [OR], 1.17; 95% confidence interval [CI], 1.01-1.35) and all CHDs combined. Among CHD sub-types, we observed associations with left ventricular outflow tract obstruction defects, and its sub-type, coarctation of the aorta and the third quartile of vitamin E intake. Among defects other than CHDs, we observed associations between anorectal atresia and the third quartile of vitamin E intake (OR, 1.66; 95% CI, 1.01-2.72) and hypospadias and the fourth quartile of vitamin E intake (OR, 1.42; 95% CI, 1.09-1.87). CONCLUSION: Selected quartiles of energy-adjusted estimated total daily vitamin E intake were associated with selected birth defects. However, because these few associations did not exhibit exposure-response patterns consistent with increasing risk associated with increasing intake of vitamin E, further studies are warranted to corroborate our findings.

The original version of this Article contained an error in the spelling of a member of the CAAPA Consortium, Hrafnhildur Bjarnadóttir which was incorrectly given as Hilda Bjarnadóttir. This has now been corrected in both the PDF and HTML versions of the Article..

OBJECTIVE: To evaluate the trends in survival for infants with critical congenital heart defects (CCHDs) and to examine the potential impact of timing of diagnosis and other prognostic factors on survival. METHODS: We performed a retrospective population-based cohort study in infants born with structural congenital heart defects (CHDs) between 1979 and 2005 and ascertained by the Metropolitan Atlanta Congenital Defects Program. We estimated Kaplan-Meier survival probabilities for 12 CCHD phenotypes by birth era and timing of diagnosis among infants without noncardiac defects or chromosomal disorders and used stratified Cox proportional hazards models to assess potential prognostic factors. RESULTS: Of 1 056 541 births, there were 6965 infants with CHDs (1830 with CCHDs). One-year survival was 75.2% for those with CCHDs (n = 1336) vs 97.1% for those with noncritical CHDs (n = 3530; P < .001). One-year survival for infants with CCHDs improved from 67.4% for the 1979-1993 birth era to 82.5% for the 1994-2005 era (P < .001). One-year survival was 71.7% for infants with CCHDs diagnosed at ≤1 day of age (n = 890) vs 82.5% for those with CCHDs diagnosed at >1 day of age (n = 405; P < .001). There was a significantly higher risk of 1-year mortality for infants with an earlier birth era, earlier diagnosis, and low birth weight and whose mothers were <30 years old. CONCLUSIONS: One-year survival for infants with CCHDs has been improving over time, yet mortality remains high. Later diagnosis is associated with improved 1-year survival. These benchmark data and identified prognostic factors may aid future evaluations of the impact of pulse oximetry screening on survival from CCHDs. Copyright © 2013 by the American Academy of Pediatrics.

Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12–q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations.

Purpose: Advanced maternal age and altered recombination are known risk factors for Down syndrome cases due to maternal nondisjunction of chromosome 21, whereas the impact of other environmental and genetic factors is unclear. The aim of this study was to investigate an association between low maternal socioeconomic status and chromosome 21 nondisjunction. Methods: Data from 714 case and 977 control families were used to assess chromosome 21 meiosis I and meiosis II nondisjunction errors in the presence of three low socioeconomic status factors: (i) both parents had not completed high school, (ii) both maternal grandparents had not completed high school, and (iii) an annual household income of <$25,000. We applied logistic regression models and adjusted for covariates, including maternal age and race/ethnicity. Results: As compared with mothers of controls (n = 977), mothers with meiosis II chromosome 21 nondisjunction (n = 182) were more likely to have a history of one low socioeconomic status factor (odds ratio = 1.81; 95% confidence interval = 1.07-3.05) and ≥2 low socioeconomic status factors (odds ratio = 2.17; 95% confidence interval = 1.02-4.63). This association was driven primarily by having a low household income (odds ratio = 1.79; 95% confidence interval = 1.14-2.73). The same statistically significant association was not detected among maternal meiosis I errors (odds ratio = 1.31; 95% confidence interval = 0.81-2.10), in spite of having a larger sample size (n = 532). Conclusion: We detected a significant association between low maternal socioeconomic status and meiosis II chromosome 21 nondisjunction. Further studies are warranted to explore which aspects of low maternal socioeconomic status, such as environmental exposures or poor nutrition, may account for these results. © American College of Medical Genetics and Genomics.

Relationships between ambient air pollution levels during pregnancy and adverse pregnancy outcomes have been investigated using one of three analytic approaches: ambient pollution levels have been contrasted over space, time, or both space and time. Although the three approaches share a common goal, to estimate the causal effects of pollution on pregnancy outcomes, they face different challenges with respect to confounding. In spatial analyses, risk factors that are spatially correlated with pollution levels are confounders; the primary challenges relate to the availability and validity of risk factor measurements. In temporal analyses, where smooth functions of time are commonly used to control for confounding, concerns relate to the adequacy of control and the possibility that abrupt changes in risk might be systematically related to pollution levels. Spatial-temporal approaches are subject to challenges faced in both spatial and temporal analyses. Thoughtful consideration of issues related to confounding is warranted because the causal effects of ambient air pollution on adverse pregnancy outcomes, if they exist, are likely to be small. We present a framework based on counterfactual effect definitions to examine issues related to confounding in spatial, temporal, and spatial-temporal analyses of air pollution and pregnancy outcomes, and we discuss their implications for inference.