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. The National Down Syndrome Project (NDSP) seeks to investigate the etiology and phenotypic consequences of trisomy 21 Down syndrome (DS). 1 Aside from the universal findings of mental retardation and hypotonia, congenital heart defects (CHDs) are arguably the most important clinical sequelae of an extra chromosome 21. In 1998 the Atlanta Down syndrome Project (ADSP), a forerunner of the NDSP, reported that 41% of newborns with DS were born with one or more major heart defects, including atrioventricular septal defect (AVSD), secundum atrial septal defect (ASDII), ventricular septal defect (VSD), and tetralogy of Fallot (TOF). 2 Findings from the ADSP and other recent population-based studies of DS and CHDs 2-5 are summarized in Table 1.With the birth prevalence of major DS-associated CHDs well established by multiple studies using modern diagnostic methods, attention can now be directed toward understanding the etiology of these defects. Not only do infants with DS have a higher rate of CHDs than do infants without DS, but one defect, the AVSD, is particularly characteristic. To understand the etiology of CHDs in DS and of AVSD specifically, both genetic and environmental determinants must be explored. For example, several recent reports have suggested that the distribution of CHDs in DS varies by ethnicity (race/ethnicity), 6 -13 but most population-based studies have not had broad ethnic representation (Table 1). Drawing on our experience with the ADSP, we designed the multicenter NDSP to explore possible CHD risk factors singly and in combination. The NDSP is one of the largest population-based studies of CHDs in DS and the first to assemble clinical, demographic, a...

To evaluate the representativeness of controls in an ongoing, population-based, case-control study of birth defects in 10 centers across the United States, researchers compared 1997-2003 birth certificate data linked to selected controls (n = 6,681) and control participants (n = 4,395) with those from their base populations (n = 2,468,697). Researchers analyzed differences in population characteristics (e.g., percentage of births at > or =2,500 g) for each group. Compared with their base populations, control participants did not differ in distributions of maternal or paternal age, previous livebirths, maternal smoking, or diabetes, but they did differ in other maternal (i.e., race/ethnicity, education, entry into prenatal care) and infant (i.e., birth weight, gestational age, and plurality) characteristics. Differences in distributions of maternal, but not infant, characteristics were associated with participation by selected controls. Absolute differences in infant characteristics for the base population versus control participants were < or =1.3 percentage points. Differences in infant characteristics were greater at centers that selected controls from hospitals compared with centers that selected controls from electronic birth certificates. These findings suggest that control participants in the National Birth Defects Prevention Study generally are representative of their base populations. Hospital-based control selection may slightly underascertain infants affected by certain adverse birth outcomes.

We examined the association between maternal age and chromosome 21 nondisjunction by origin of the meiotic error. We analyzed data from two population-based, case-control studies: Atlanta Down Syndrome Project (1989Project ( -1999 and National Down Syndrome Project (2001)(2002)(2003)(2004). Cases were live born infants with trisomy 21 and controls were infants without trisomy 21 delivered in the same geographical regions. We enrolled 1,215 of 1,881 eligible case families and 1,375 of 2,293 controls. We report four primary findings. First, the significant association between advanced maternal age and chromosome 21 nondisjunction was restricted to meiotic errors in the egg; the NIH Public AccessAuthor Manuscript Hum Genet. Author manuscript; available in PMC 2010 March 8. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript association was not observed in sperm or in post-zygotic mitotic errors. Second, advanced maternal age was significantly associated with both meiosis I (MI) and meiosis II (MII). For example, compared to mothers of controls, mothers of infants with trisomy 21 due to MI nondisjunction were 8.5 times more likely to be ≥40 years old than 20-24 years old at the birth of the index case (95% CI = 5.6-12.9). Where nondisjunction occurred in MII, mothers were 15.1 times more likely to be ≥40 years (95% CI = 8.4-27.3). Third, the ratio of MI to MII errors differed by maternal age. The ratio was lower among women <19 years of age and those ≥40 years (2.1, 2.3, respectively) and higher in the middle age group (3.6). Lastly, we found no effect of grand-maternal age on the risk for maternal nondisjunction. This study emphasizes the complex association between advanced maternal age and nondisjunction of chromosome 21 during oogenesis.

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

Less acculturated Hispanic parents seemed to be at highest risk of NTDs. For anencephaly, U.S.-born and English-speaking Hispanic parents were also at increased risk. Finally, from an etiologic standpoint, spina bifida and anencephaly appeared to be etiologically heterogeneous from these analyses.