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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 (1989–1999) and National Down Syndrome Project (2001–2004). 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 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.

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.

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. 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. 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). 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 Med15 9, 698–705.

Background: The occurrence of hypospadias has been reported to be increasing. The objectives of this study were to extend the literature on the descriptive epidemiology of hypospadias and to determine whether its birth prevalence increased in California in recent years. We used actively ascertained, population-based data for which detailed clinical descriptions permitted careful phenotypic classifications. Methods: We examined registry data on 5838 male live births and stillbirths that occurred in California from 1984 through 1997. To reduce pathogenic heterogeneity, cases were classified as mild, severe, or not otherwise specified based on the anatomic position of the urethral opening. We also classified cases as isolated or nonisolated based on the presence and type of accompanying malformations. We used multivariable Poisson regression analysis to examine time trends and risk factors. Results: There was no evidence for an increase in prevalence of any of the case groups between 1989 and 1997. The adjusted relative risk (RR) for change in prevalence per year of isolated severe cases was 0.99 (95% confidence interval = 0.96-1.03). Adjusted RRs indicated increased risks for specific types of hypospadias with maternal non-Hispanic white race-ethnicity, higher education, older age, and nulliparity. Delivery before 37 weeks and multiple births tended either not to be associated with risk or to be associated with reduced risk. Lower birthweight was associated with increased risk for all case groups. Conclusions: This study suggests that hypospadias prevalence has not been increasing in California in recent years. Differences by phenotype suggest that examining certain phenotypes separately could help to understand hypospadias etiology.

Purpose: We evaluated whether the association of socioeconomic risk factors for trisomy 21 differed by type of maternal meiotic error. Methods: We determined meiotic errors by DNA analysis for 150 trisomy 21 cases, and maternal lifetime exposures to low socioeconomic factors by questionnaire. Results: Mothers of meiosis II cases were significantly more likely to be exposed to four low socioeconomic factors than mothers of meiosis I cases (odds ratio = 9.50; 95% confidence interval = 1.8–49.8). Conclusion: Maternal lifetime exposure to poor socioeconomic environment is a risk factor for a trisomy 21, particularly if nondisjunction leads to a maternal meiosis II.

Background: Placental trophoblast shedding into maternal circulation has been hypothesized as a potential cause of preeclampsia. Because pregnancies with a trisomy 21 fetus also have high levels of fetal cells and cell-free fetal DNA in maternal circulation, we examined whether trisomy 21 pregnancies have a higher risk of preeclampsia than euploid pregnancies. Methods: We used 2 population-based databases. We identified 7763 pregnancies with a singleton trisomy 21-affected fetus and 15,293 matched euploid gestations from the U.S. Natality files for the period 1995-1999. The second database consisted of 665 pregnancies with fetal trisomy 21 and 987 euploid controls in a population-based Down syndrome study in California. In the latter study, women were interviewed by telephone regarding characteristics and pregnancy complications. Gestational hypertension and preeclampsia are the outcomes of this study. Results: The U.S. Natality files showed that in nulliparous women fetal trisomy 21 was associated with a reduced risk of pregnancy-induced hypertension (adjusted relative risk [aRR] = 0.67; 95% confidence interval [CI] = 0.53 to 0.85). Findings from the California study confirmed this association in nulliparous women, and further revealed that the decrease in overall risk of pregnancy-induced hypertension was mainly the result of a large reduction in the risk of preeclampsia (aRR = 0.19; CI = 0.04 to 0.88) rather than in gestational hypertension by itself (0.83; 0.37 to 1.84). Neither dataset showed these effects among multiparous pregnancies. Conclusion: Fetal trisomy 21 is associated with a reduced, rather than increased, risk of preeclampsia, specifically in nulliparous women.

More than 50% of infants with Down syndrome have associated defects that cause considerable morbidity and mortality. We evaluated the hypothesis that the trisomic genome interacts with environmental factors to increase the risk for specific associated defects. We evaluated risk factors present during early pregnancy in a multiracial population of 687 infants with Down syndrome. Mother's cigarette smoking was associated with the grouped cardiac defects [odds ratio (OR) = 2.0; 95% confidence interval (CI)=1.2-3.2]. When adjusted for other cardiac defects and maternal race, the following specific defects were associated with smoking: atrioventricular canal (OR = 2.3; 95% CI = 1.2-4.5), tetralogy of Fallot (OR = 4.6; 95% CI = 1.2-17.0), and atrial septal defects without ventricular septal defect (OR = 2.2; 95% CI = 1.1-4.3). Hirschsprung disease was associated with mother's daily consumption of more than three cups of coffee (OR = 6.02; 95% CI = 1.2-29.7) and with mother's fever (OR = 3.4; 95% CI = 0.7-16.4), but the number of cases was small. Use of alcohol was not associated with any defect. Mother's race, age, parity, income, or education did not confound the associations. Results suggest that environmental factors can modify the occurrence of associated anomalies in the embryo with Down syndrome.

A mother's prepregnancy obesity has been suggested as a risk factor for having offspring with an obdominal wall defect. We evaluated this hypothesis among 104 cases of gastroschisis-a severe birth defect of the abdominal wall most prevalent in infants of young women-and 220 controls with no defect. Using Quetelet's index (QI = weight in kg/height in m2) as a measure of body mass, we found a higher risk of gastroschisis (odds ratio (OR) = 3.2; 95% confidence interval (CI) = 1.4-7.3) for underweight mothers $({\\rm QI}\\ <18.1\\ {\\rm kg}/{\\rm m}^{2})$ and a lower risk (OR = 0.2; 0.05-0.9) for overweight mothers $({\\rm QI}\\ >28.3\\ {\\rm kg}/{\\rm m}^{2})$ as compared with mothers of normal weight. As QI was correlated to height, with the correlation varying according to mother's ethnicity and age, we adjusted for these factors in the analysis; the adjusted values approximated the unadjusted values. Evaluation of QI as a continuous variable showed that, for every unit increase in QI, the risk for gastroschisis decreased by about 11%. Sociodemographic, pregnancy, and nutrient factors did not confound the association. These results suggest that low prepregnancy body mass rather than obesity is a risk factor for gastroschisis.

To the Editor: Harrison et al. (May 31 issue) 1 describe the successful repair of a fetal diaphragmatic hernia, and they are to be congratulated for developing this skill from use in a variety of animals to clinical application. Having said this, we must now ask whether fetal surgery is indicated for congenital diaphragmatic hernia. The authors' premise that 75 percent of infants born with diaphragmatic hernia die is simply not true. In fact, they incorrectly cite our paper 2 and do not cite others 3 4 5 that demonstrate the contrary as justification for fetal repair of this condition. It is generally accepted that . . .