Marjorie H. Royle

Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project

Purpose: The population-based National Down Syndrome Project combined epidemiological and molecular methods to study congenital heart defects in Down syndrome.Methods: Between 2000 and 2004, six sites collected DNA, clinical, and epidemiological information on parents and infants. We used logistic regression to examine factors associated with the most common Down syndrome-associated heart defects.Results: Of 1469 eligible infants, major cardiac defects were present in 44%; atrioventricular septal defect (39%), secundum atrial septal defect (42%), ventricular septal defect (43%), and tetralogy of Fallot (6%). Atrioventricular septal defects showed the most significant sex and ethnic differences with twice as many affected females (odds ratio, 1.93; 95% confidence interval, 1.40–2.67) and, compared with whites, twice as many blacks (odds ratio, 2.06; 95% confidence interval, 1.32–3.21) and half as many Hispanics (odds ratio, 0.48; 95% confidence interval, 0.30–0.77). No associations were found with origin of the nondisjunction error or with the presence of gastrointestinal defects.Conclusions: Sex and ethnic differences exist for atrioventricular septal defects in Down syndrome. Identification of genetic and environmental risk factors associated with these differences is essential to our understanding of the etiology of congenital heart defects.

Congenital gastrointestinal defects in Down syndrome: a report from the Atlanta and National Down Syndrome Projects

We report Down syndrome (DS)‐associated congenital gastrointestinal (GI) defects identified during a 15 year, population‐based study of the etiology and phenotypic consequences of trisomy 21. Between 1989 and 2004, six sites collected DNA, clinical and epidemiological information on live‐born infants with standard trisomy 21 and their parents. We used chi‐squared test and logistic regression to explore relationships between congenital GI defects and infant sex, race, maternal age, origin of the extra chromosome 21, and presence of a congenital heart defect. Congenital GI defects were present in 6.7% of 1892 eligible infants in this large, ethnically diverse, population‐based study of DS. Defects included esophageal atresia/tracheoesophageal fistula (0.4%), pyloric stenosis (0.3%), duodenal stenosis/atresia (3.9%), Hirschsprung disease (0.8%), and anal stenosis/atresia (1.0%). We found no statistically significant associations between these defects and the factors examined. Although not significant, esophageal atresia was observed more often in infants of younger mothers and Hispanics, Hirschsprung disease was more frequent in males and in infants of younger mothers and blacks, and anal stenosis/atresia was found more often among females and Asians.

The National Down Syndrome Project: Design and Implementation

Objective. The National Down Syndrome Project (NDSP), based at Emory University in Atlanta, Georgia, represents a multi-site, population-based, case-control study with two major aims: (1) to identify molecular and epidemiological factors contributing to chromosome nondisjunction and the consequent packaging of an extra chromosome into an egg or sperm, and (2) to identify risk factors for Down syndrome-associated birth defects. Methods. The six national sites represent approximately 11% of U.S. births. Cases were newborns with Down syndrome (trisomy 21), and controls were infants without major birth defects randomly selected from the same birth populations. Biological samples were collected from case infants and their parents, and genetic markers were typed to determine the parental origin of chromosome 21 nondisjunction. Each site interviewed parents of case and control infants addressing pregnancy, medical and family history, occupation, and exposures. Sites collected medical information on case infants. Results. The NDSP enrolled 907 infants as cases and 977 infants as controls (participation rates: 60.7% for cases; 56.9% for controls). Participation rates varied widely by site as did important demographic factors such as maternal age, race, and education. Nondisjunction during oogenesis accounted for 93.2% of the cases. Errors in spermatogenesis were found in 4.1%, and 2.7% were post-zygotic errors. Conclusions. This exceptional compilation of questionnaire, clinical, and molecular data makes the NDSP a unique resource for ongoing studies of the etiology and phenotypic consequences of trisomy 21. The combined approach increases study power by defining subgroups of cases by the origin of nondisjunction. This report describes the design and successful implementation of the NDSP.

Lack of maternal folic acid supplementation is associated with heart defects in Down syndrome: a report from the National Down Syndrome Project

BACKGROUND Maternal folic acid supplementation has been associated with a reduced risk for neural tube defects and may be associated with a reduced risk for congenital heart defects and other birth defects. Individuals with Down syndrome are at high risk for congenital heart defects and have been shown to have abnormal folate metabolism. METHODS As part of the population-based case-control National Down Syndrome Project, 1011 mothers of infants with Down syndrome reported their use of supplements containing folic acid. These data were used to determine whether a lack of periconceptional maternal folic acid supplementation is associated with congenital heart defects in Down syndrome. We used logistic regression to test the relationship between maternal folic acid supplementation and the frequency of specific heart defects correcting for maternal race or ethnicity, proband sex, maternal use of alcohol and cigarettes, and maternal age at conception. RESULTS Lack of maternal folic acid supplementation was more frequent among infants with Down syndrome and atrioventricular septal defects (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.08-2.63; p = 0.011) or atrial septal defects (OR, 1.69; 95% CI, 1.11-2.58; p = 0.007) than among infants with Down syndrome and no heart defect. Preliminary evidence suggests that the patterns of association differ by race or ethnicity and sex of the proband. There was no statistically significant association with ventricular septal defects (OR, 1.26; 95% CI, 0.85-1.87; p = 0.124). CONCLUSIONS Our results suggest that lack of maternal folic acid supplementation is associated with septal defects in infants with Down syndrome. Birth Defects Research (Part A), 2011.

Preconception folic acid supplementation and risk for chromosome 21 nondisjunction: A report from the National Down Syndrome Project

Both a lack of maternal folic acid supplementation and the presence of genetic variants that reduce enzyme activity in folate pathway genes have been linked to meiotic nondisjunction of chromosome 21; however, the findings in this area of research have been inconsistent. To better understand these inconsistencies, we asked whether maternal use of a folic acid‐containing supplement before conception reduces risk for chromosome 21 nondisjunction. Using questionnaire data from the National Down Syndrome Project, a population‐based case–control study, we compared the use of folic acid‐containing supplements among mothers of infants with full trisomy 21 due to maternal nondisjunction (n = 702) and mothers of infants born with no major birth defects (n = 983). Using logistic regression, adjusting for maternal age, race/ethnicity, and infant age at maternal interview, we found no evidence of an association between lack of folic acid supplementation and maternal nondisjunction among all case mothers (OR = 1.16; 95% CI: 0.90–1.48). In analyses stratified by meiotic stage and maternal age (<35 or ≥35 years), we found an association among older mothers experiencing meiosis II nondisjunction errors (OR = 2.00; 95% CI: 1.08–3.71). These data suggest that lack of folic acid supplementation may be associated specifically with MII errors in the aging oocyte. If confirmed, these results could account for inconsistencies among previous studies, as each study sample may vary by maternal age structure and proportion of meiotic errors.

The association of low socioeconomic status and the risk of having a child with Down syndrome: a report from the National Down Syndrome Project

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 <

Do foreign‐ and U.S.‐born mothers across racial/ethnic groups have a similar risk profile for selected sociodemographic and periconceptional factors?

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.Genet Med 15 9, 698–705.Genetics in Medicine (2013); 15 9, 698–705. doi:10.1038/gim.2013.34

Birth defects, causal attributions, and ethnicity in the national birth defects prevention study

BACKGROUND We examined differences in selected pregnancy-related risk factors, including maternal sociodemographic characteristics, health-related conditions, and periconceptional behavioral factors, among foreign-born versus U.S.-born control mothers across race/ethnic groups. METHODS We used data from the National Birth Defects Prevention Study, and calculated odds ratios (ORs) and 95% confidence intervals (CIs) of the risk factors, for foreign-born Hispanic, non-Hispanic white, non-Hispanic black, and Asian/Pacific Islander (API) mothers, compared to their U.S.-born counterparts. RESULTS Across all race/ethnic groups, foreign-born mothers were older and had lower odds of obesity compared to their U.S.-born counterparts. With the exception of foreign-born black mothers, foreign-born mothers from other race/ethnic groups had significantly lower odds of binge drinking during the periconceptional period. Compared to U.S.-born, foreign-born Hispanic mothers had twice the odds of gestational diabetes (OR = 2.23; 95% CI = 1.36-3.66). Certain health behaviors were less prevalent in foreign-born black mothers (e.g., folic acid use; OR = 0.54; 95% CI = 0.31-0.96) and foreign-born API mothers (e.g., cigarette smoking; OR = 0.10; 95% CI = 0.02-0.48). CONCLUSIONS Significant differences in pregnancy related risk factors during the periconceptional period and throughout pregnancy were observed between maternal nativity groups and across race/ethnicity. Prevention efforts for both prepregnancy and after conception should be designed and delivered according to maternal nativity for each racial/ethnic group.

Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects

In order to translate research findings into effective prevention strategies, it is important to understand peoples beliefs about the causes of poor health outcomes. However, with the exception of knowledge and beliefs about folic acid supplementation, little is known regarding womens causal attributions women regarding birth defects. We employed Attribution Theory constructs to analyze open-text interview responses from 2,672 control mothers in the National Birth Defects Prevention Study who gave birth in 1997–2005. Common themes included use of alcohol, tobacco, illicit drugs, and medications during pregnancy. Stress and emotional upset were also suggested as possible causes of birth defects. Genetic- and heredity-related responses were more likely to be mentioned by Asian/Pacific Islander women compared to non-Hispanic Whites. Hispanic women were less likely to suggest several specific possible teratogens, such as paint, pesticides, or other chemicals, but were more likely to suggest events occurring during childbirth. Differences also emerged among ethnic groups for theoretical constructs, although most responses were categorized as controllable, changeable over time, and with an internal locus of causality.