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 <$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.

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.

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. © 2011 Wiley-Liss, Inc.

Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome.

Cardiac abnormalities are one of the most common congenital defects observed in individuals with Down syndrome. Considerable research has implicated both folate deficiency and genetic variation in folate pathway genes with birth defects, including both congenital heart defects (CHD) and Down syndrome (DS). Here, we test variation in folate pathway genes for a role in the major DS-associated CHD atrioventricular septal defect (AVSD). In a group of 121 case families (mother, father, and proband with DS and AVSD) and 122 control families (mother, father, and proband with DS and no CHD), tag SNPs were genotyped in and around five folate pathway genes: 5,10-methylenetetrahyrdofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine beta-synthase (CBS), and the reduced folate carrier (SLC19A1, RFC1). SLC19A1 was found to be associated with AVSD using a multilocus allele-sharing test. Individual SNP tests also showed nominally significant associations with odds ratios of between 1.34 and 3.78, depending on the SNP and genetic model. Interestingly, all marginally significant SNPs in SLC19A1 are in strong linkage disequilibrium (r(2)> or = 0.8) with the nonsynonymous coding SNP rs1051266 (c.80A>G), which has previously been associated with nonsyndromic cases of CHD. In addition to SLC19A1, the known functional polymorphism MTHFR c.1298A was over-transmitted to cases with AVSD (P=0.05) and under-transmitted to controls (P=0.02). We conclude, therefore, that disruption of the folate pathway contributes to the incidence of AVSD among individuals with DS.

Genetic and environmental factors in the etiology of esophageal atresia and/or tracheoesophageal fistula: an overview of the current concepts.

Esophageal atresia and/or tracheoesophageal fistula (EA/TEF) are severe congenital anomalies. Although recent years have brought significant improvement in clinical treatment, our understanding of the etiology of these defects is lagging. Many genes and genetic pathways have been implicated in the development of EA/TEF, but only a few genes have been shown to be involved in humans, in animals, or in both. Extrapolating data from animal models to humans is not always straightforward. Environmental factors may also carry a risk, but the mechanisms are yet to be elucidated. This review gives an overview of the current state of knowledge about both genetic and environmental risk factors in the etiology of EA/TEF.

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

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 >or=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 >or=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 >or=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.

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.

Environmental factors in the etiology of esophageal atresia and congenital diaphragmatic hernia: results of a case-control study.

BACKGROUND: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) and congenital diaphragmatic hernia (CDH) are severe congenital anomalies. Their etiologies are mostly unknown and are thought to be multifactorial. No specific environmental factors have consistently been described as risk factors. METHODS: In a study conducted during the years 2000 to 2004 in a pediatric surgical referral center in the Netherlands, parents of children with EA/TEF or with CDH of the Bochdalek type and parents of a group of children without major birth defects filled out a questionnaire about possible exposure to environmental risk factors during the period from 1 month before conception to the end of the first trimester of pregnancy. Children with chromosomal anomalies were excluded. RESULTS: Questionnaires were returned for 47 out of 64 cases (73%) with EA/TEF, for 63 out of 77 cases (82%) with CDH, and for 202 out of 243 controls (83%). In EA/TEF, maternal age was borderline significantly higher than in controls (32.2 vs. 30.6 years, p = .05). Contact with herbicides or insecticides was associated with EA/TEF in univariate analysis (OR 2.0; 95% CI: 1.0-4.1) and in multivariate analysis, although of borderline significance. In univariate analysis, CDH was significantly associated with maternal use of alcohol (OR 2.9; 95% CI: 1.6-5.2). CONCLUSIONS: We found a significant association between maternal alcohol use around the time of conception and CDH. A possible explanation might be the effect of alcohol on the retinoic acid pathway. An association was found between contact with herbicides or insecticides and EA/TEF.

Non-VACTERL-type anomalies are frequent in patients with esophageal atresia/tracheo-esophageal fistula and full or partial VACTERL association.

BACKGROUND: The VACTERL association is the nonrandom co-occurrence of Vertebral anomalies, Anal atresia, Cardiovascular malformations, Tracheo-esophageal fistula (TEF) and/or Esophageal atresia (EA), Renal anomalies, and/or Limb-anomalies. The full phenotype of patients with EA/TEF and other anomalies of the VACTERL spectrum of defects association is not well described in the literature. METHODS: Data on patients with EA/TEF seen in two pediatric surgical centers in the Netherlands between January 1988 and August 2006 were evaluated for defects of the VACTERL spectrum as well as non-VACTERL-type defects. The presence of two or more defects of the VACTERL spectrum in addition to EA/TEF was the criterion for inclusion in this study. A detailed description was made of all defects. RESULTS: Of 463 patients with EA and/or TEF, 107 (23.1%) fulfilled the inclusion criterion, of which seventeen cases had a recognized etiology and were excluded, leaving 90 cases (19.4%) for analysis. Other than the esophagus and the trachea, the vertebrae/ribs and the cardiovascular system were most commonly affected (68.9 and 65.6%, respectively). Interestingly, 70% of cases had additional non-VACTERL-type defects, with high occurrences for single umbilical artery (20%), genital defects (23.3%), and respiratory tract anomalies (13.3%). CONCLUSIONS: Many patients with EA/TEF and at least two other defects of the VACTERL spectrum also display non-VACTERL-type congenital anomalies.

Esophageal atresia and tracheoesophageal fistula in children of women exposed to diethylstilbestrol in utero.

OBJECTIVE: This study was undertaken to study the possible risk to mothers exposed in utero to diethylstilbestrol for offspring with esophageal atresia/tracheoesophageal fistula. STUDY DESIGN: Information on the mothers' in utero exposure to diethylstilbestrol was obtained from 3 sources: questionnaires completed by members of the parents' association of children with esophageal atresia/tracheoesophageal fistula; records of patients with esophageal atresia/tracheoesophageal fistula from a hospital database; and files from the Northern Netherlands EUROCAT birth defects registry. RESULTS: Three of 124 (2.4%) mothers from the parents' association and 6 of 192 (3.1%) mothers from the hospital cases reported in utero exposure to diethylstilbestrol. For 8848 children registered by EUROCAT, 33 (0.37%) mothers reported in utero exposure to diethylstilbestrol. Of 117 infants with esophageal atresia/tracheoesophageal fistula, 4 (3.4%) had a mother with in utero exposure to diethylstilbestrol; this association was statistically significant (P = .001). CONCLUSION: We report a possible transgenerational effect of diethylstilbestrol exposure in the cause of some cases of esophageal atresia/tracheoesophageal fistula.

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

Selected gene polymorphisms and their interaction with maternal smoking, as risk factors for gastroschisis.

BACKGROUND: Gastroschisis is a severe birth defect in which the infant is born with a portion of the intestines extruding through a small tear in the abdominal wall, usually to the right of the umbilical cord. Its etiology is unknown, but the prevailing hypothesis is that it results from a vascular accident at the time of involution of the right umbilical vein or of the development of the superior mesenteric artery. METHODS: In a case-control study of 57 cases of gastroschisis and 506 controls, we tested DNA for polymorphisms of 32 genes representing enzymes involved in angiogenesis, blood vessel integrity, inflammation, wound repair, and dermal or epidermal strength. RESULTS: In logistic regression, controlling for maternal ethnicity, and using the homozygote wild-type as referent, the following gene polymorphisms were associated with an increased risk for a gastroschisis for heterozygotes: ICAM1 gly241arg (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1 -3.4); NOS3 glu298asp (OR, 1.9; 95% CI, 1.1-3.4); NPPA 2238T > C (OR, 1.9; 95% CI, 1.0-3.4); and ADD1 gly460trp (OR, 1.5; 95% CI, 0.8-2.8). Additionally, for the NPPA and ADD1 single-nucleotide polymorphisms (SNPs), the homozygote variants had a significantly higher risk than the heterozygotes (OR, 7.5; 95% CI, 1.7-33.5 and OR, 4.9; 95% CI, 1.9-12.9, respectively). Three SNPs showed a strong interaction with maternal smoking. The risk for smokers with 1 or 2 variant alleles compared to nonsmokers with the wild-type allele were: NOS3 (OR, 5.2; 95% CI, 2.4-11.4); ICAM1 (OR, 5.2; 95% CI, 2.1-12.7); and NPPA (OR, 6.4; 95% CI, 2.8-14.6). CONCLUSIONS: These results support the hypothesis of a vascular compromise as part of a multifactorial etiology of gastroschisis involving both genes and environmental factors.

Interaction between maternal smoking and malnutrition in infant risk of gastroschisis.

BACKGROUND: Gastroschisis is a severe birth defect characterized by a tear in the infant's abdominal wall. Young mothers have the highest risk of having an infant with gastroschisis. In an animal model, the defect resulted from exposure of pregnant mice to carbon monoxide (CO) in combination with a low protein and low zinc diet. METHODS: We evaluated this model in a study of 55 infants with gastroschisis and 94 age-matched controls that included maternal interview with a food frequency questionnaire. Smoking cigarettes (> or = 1 pack/day) or marijuana (more than once) 3 months prior to pregnancy indicated CO exposure. Low protein or zinc intake and a low body mass index (BMI) indicated maternal malnutrition. RESULTS: When assessed separately, high CO, low protein, low zinc, and low BMI were each significantly associated with an increased risk of gastroschisis. Although we observed significant CO-BMI and CO-zinc interactions after adjusting for income, only a combination of high CO exposure and low BMI yielded a synergistic adverse effect. Compared to the low risk of having an infant with gastroschisis for mothers who did not have low BMI and did not smoke, the risk of having an infant with gastroschisis was 16.3 times (95% CI, 2.49-113.4) higher for mothers who did not have low BMI but smoked, and 19.7 times (95% CI, 4.33-89.6) higher for mothers who did not smoke but had low BMI. However, the risk was 26.5 times (95% CI, 7.85-89.4) higher for mothers who had low BMI and smoked. CONCLUSIONS: Our results suggest that young mothers are at increased risk of having an infant with gastroschisis if they smoke and are also malnourished.

Maternal meiosis II nondisjunction in trisomy 21 is associated with maternal low socioeconomic status.

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.

Fetal trisomy 21 and maternal preeclampsia.

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.

Association of congenital diaphragmatic hernia with limb-reduction defects.

BACKGROUND: The pathogenesis of congenital diaphragmatic hernia (CDH), a severe birth defect, is not well understood; however, both developmental genes and environmental factors have been suggested to be involved. CDH is frequently associated with malformations of other structures, such as limbs, whose embryogenesis is better understood. An examination of the co-occurrence of developmental defects may provide clues as to the origin and timing of the insult to the diaphragm and limbs. Our focus was on CDH-associated limb-reduction defects (LRDs). METHODS: For this descriptive study, we reviewed the medical records of infants with a posterolateral (Bochdalek) CDH and an associated LRD among 146 patients from the Sophia Children's Hospital, and among 810 infants and 36 stillbirths from the California Birth Defects Monitoring Program (CBDMP). RESULTS: In the hospital group, 14 patients (10%) had an associated limb defect, of which about one-third were LRDs (of these, most were of a nonsevere type, such as hypoplasia of fingers). In the registry group, a limb defect was found in 162 cases (18.5%), 18 of which were mostly severe LRD (usually of the upper extremities). Additional congenital anomalies were observed in all CDH-LRD cases in both groups. CONCLUSIONS: In the registry group, 77.8% of LRDs were either bilateral or ipsilateral, and were mostly preaxial, suggesting an early embryological insult affecting both precursor anlages. These results, from large numbers of cases, support the notion of a developmental association between CDH and LRD, as has been observed in several knockout mice. Future analyses of candidate genes from patients with CDH and LRD may elucidate this developmental association in humans.

Hypospadias in California: trends and descriptive epidemiology.

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.

Socioeconomic effects on the risk of having a recognized pregnancy with Down syndrome.

BACKGROUND: Appoximately 95% of Down syndrome (DS) cases are caused by an error in germ cell division (meiosis), resulting in an extra chromosome 21. The meiotic error, predominantly of maternal origin, occurs either during the mother's fetal life (meiosis I) or at ovulation (meiosis II). Because maternal-age-specific DS prevalence rates vary between and within populations, it has been hypothesized that environmental factors can affect the risk for a DS pregnancy. METHODS: In a population-based case-control study of 997 clinically recognized DS cases (including fetal losses) and 1007 controls without a birth defect, we examined the mother's socioeconomic status (SES) from the time of her fetal life to the time of conception. SES variables were considered as proxies for environmental factors. We used multiple logistic regression for the analyses. RESULTS: We found associations with low levels of each SES variable examined: mother's education less than high school (OR, 1.29; 95% CI, 1.01-1.65), father's low occupation (OR, 1.23; 95% CI, 0.95-1.60), father's low education (OR, 1.28; 95% CI, 0.99-1.64), mother's father's low occupation (OR, 1.35; 95% CI, 1.06-1.71), and family income <$20,000 (OR, 1.31; 95% CI, 1.02-1.68) [corrected]. The risk for DS increased as the number of low socioeconomic factors present throughout the mother's life increased. With four factors present, the risk (adjusted for confounders) almost doubled (OR, 1.98; 95% CI, 1.30-3.01). Those associations persisted among young (< 30) and old (> or = 30) maternal age groups. CONCLUSIONS: A mother's low SES during any period before conception increases her risk for a recognized pregnancy with DS. Because of the high birth prevalence of DS, the public health impact of maternal SES may be considerable.