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.

Mutations in PITX2 may contribute to cases of omphalocele and VATER-like syndromes.

Omphalocele is a congenital anomaly with substantial morbidity. Rieger syndrome, an autosomal dominant disorder, is characterized by craniofacial abnormalities and abdominal wall defects. PITX2 mutations are etiologic in >40% of cases of Rieger syndrome. We demonstrate that the birth prevalence of omphalocele is significantly higher in Rieger syndrome than in the general population, with omphaloceles found in 0.03% in the Iowa newborn population and 4.3% of patients with Rieger syndrome. Our objective was to screen coding and conserved non-coding regions of PITX2 for mutations in 209 patients with omphalocele. We identified remarkable evolutionarily conserved regions by comparing the 3'UTR of Pitx2 in 13 vertebrate and 3 invertebrate species. No mutations changing the amino acid sequence were found within the omphalocele population. In one case of omphalocele with VATER-like additional anomalies, a three nucleotide deletion was found in the 3'UTR. This deletion was not seen in 1,186 controls. Also in the 3'UTR, we identified a single nucleotide polymorphism at a highly conserved residue. Our findings suggest additional studies of PITX2 conserved regions will be valuable. We also screened the omphalocele cases for mutations in exon 5 of the gene FLNA. Mutations in FLNA have been shown to cause a broad range of congenital malformations, including otopalatodigital syndrome type 2 in which a missense mutation occurring in exon 5 of FLNA results in omphalocele as part of the phenotype. We did not find any mutations in exon 5 of FLNA in 179 omphalocele cases studied.

Effect of maternal smoking and coffee consumption on the risk of having a recognized Down syndrome pregnancy.

To evaluate the possible effects of maternal smoking and caffeine or coffee consumption on the occurrence of a recognized pregnancy with Down syndrome, the authors analyzed data from a case-control study of 997 liveborn infants or fetuses with Down syndrome ascertained in California from 1991 to 1993 and 1,007 liveborn controls without a birth defect. Interviews with mothers covered demographic information, pregnancy, and medical history, with detailed questions on the use of tobacco, alcohol, and caffeinated beverages. All analyses were age-adjusted. High alcohol consumption (> or =4 drinks/week) in the first month of pregnancy was associated with reduced risk for a recognized Down syndrome conceptus (odds ratio (OR) = 0.54; 95% confidence interval (CI): 0.34, 0.85). Maternal smoking during the periconceptional period was not associated with risk of recognized Down syndrome (OR = 1.04; 95% CI: 0.79, 1.37), but maternal consumption of four or more cups of coffee per day was inversely associated (OR = 0.63; 95% CI: 0.41, 0.96). In multivariate analysis, a significant interaction between coffee drinking and smoking was observed. The inverse association remained only for nonsmoking mothers who drank four or more cups of coffee per day (OR = 0.48; 95% CI: 0.28, 0.82). These results suggest that among nonsmoking mothers, high coffee consumption is more likely to reduce the viability of a Down syndrome conceptus than that of a normal conceptus.

Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome.

Down syndrome is a complex genetic and metabolic disorder attributed to the presence of three copies of chromosome 21. The extra chromosome derives from the mother in 93% of cases and is due to abnormal chromosome segregation during meiosis (nondisjunction). Except for advanced age at conception, maternal risk factors for meiotic nondisjunction are not well established. A recent preliminary study suggested that abnormal folate metabolism and the 677C-->T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene may be maternal risk factors for Down syndrome. The present study was undertaken with a larger sample size to determine whether the MTHFR 677C-->T polymorphism was associated with increased risk of having a child with Down syndrome. Methionine synthase reductase (MTRR) is another enzyme essential for normal folate metabolism. A common polymorphism in this gene was recently associated with increased risk of neural tube defects and might also contribute to increased risk for Down syndrome. The frequencies of the MTHFR 677C-->T and MTRR 66A-->G mutations were evaluated in DNA samples from 157 mothers of children with Down syndrome and 144 control mothers. Odds ratios were calculated for each genotype separately and for potential gene-gene interactions. The results are consistent with the preliminary observation that the MTHFR 677C-->T polymorphism is more prevalent among mothers of children with Down syndrome than among control mothers, with an odds ratio of 1.91 (95% confidence interval [CI] 1.19-3.05). In addition, the homozygous MTRR 66A-->G polymorphism was independently associated with a 2. 57-fold increase in estimated risk (95% CI 1.33-4.99). The combined presence of both polymorphisms was associated with a greater risk of Down syndrome than was the presence of either alone, with an odds ratio of 4.08 (95% CI 1.94-8.56). The two polymorphisms appear to act without a multiplicative interaction.

A low pregnancy body mass index is a risk factor for an offspring with gastroschisis.

A mother's prepregnancy obesity has been suggested as a risk factor for having offspring with an abdominal 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 (QI<18.1 kg/m2) and a lower risk (OR = 0.2; 0.05-0.9) for overweight mothers (QI>28.3 kg/m2) 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.

Malrotation in conjunction with esophageal atresia/tracheo-esophageal fistula.

Esophageal atresia or tracheo-esophageal fistula (EA/TEF) often occurs in association with a well-defined group of other anomalies. We report the prevalence of malrotation and other intestinal anomalies in a large data series comprising 632 nontrisomic infants with EA/TEF ascertained by the California Birth Defects Monitoring Program from January 1, 1983 to December 31, 1994. Consistent with findings reported previously in smaller case series, our findings showed a notable prevalence of imperforate anus (9.0%) and duodenal atresia (5.2%), among other gastrointestinal defects. They also showed a previously unrecognized high prevalence of intestinal malrotation (4.4%). Compared with other infants studied, the infants with EA/TEF and malrotation of the intestine had a higher proportion of other associated anomalies (in particular intestinal, central nervous system, vertebral and rib, renal and genital anomalies). These findings indicate that intestinal malrotation is more common in infants with EA/TEF than is generally perceived, and that intestinal malrotation in an infant with EA/TEF is associated with a higher burden of additional congenital anomalies, suggesting that this group of infants may have more pervasive developmental deficits and poorer prognosis than has previously been recognized.

Maternal risk factors and major associated defects in infants with Down syndrome.

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.

Elucidating the mechanisms of paternal non-disjunction of chromosome 21 in humans.

Paternal non-disjunction of chromosome 21 accounts for 5-10% of Down syndrome cases, therefore, relative to the maternally derived cases, little is known about paternally derived trisomy 21. We present the first analysis of recombination and non-disjunction for a large paternally derived population of free trisomy 21 conceptuses ( n = 67). Unlike maternal cases where the ratio of meiosis I (MI) to meiosis II (MII) errors is 3:1, a near 1:1 ratio exists among paternal cases, with a slight excess of MII errors. We found no paternal age effect for the overall population nor when classifying cases according to stage of non-disjunction error. Among 22 MI cases, only five had an observable recombinant event. This differs significantly from the 11 expected events ( P < 0.02, Fisher's exact), suggesting reduced recombination along the non-disjoined chromosomes 21 involved in paternal MI non-disjunction. No difference in recombination was detected among 27 paternal MII cases as compared with controls. However, cases exhibited a slight increase in the frequency of proximal and medial exchange when compared with controls (0.37 versus 0.28, respectively). Lastly, this study confirmed previous reports of excess male probands among paternally derived trisomy 21 cases. However, we report evidence suggesting an MII stage-specific sex ratio disturbance where 2.5 male probands were found for each female proband. Classification of MII cases based on the position of the exchange event suggested that the proband sex ratio disturbance was restricted to non-telomeric exchange cases. Based on these findings, we propose new models to explain the association between paternally derived trisomy 21 and excessive male probands.

Anomalies in Down syndrome individuals in a large population-based registry.

In a population of close to 2.5 million infants born from 1983 to 1993 registered in the California Birth Defects Monitoring Program, we compared the prevalence of structural birth defects among 2,894 infants with Down syndrome (DS) with that of infants without DS. Among 61 defects uniformly ascertained in affected and unaffected infants, 45 were significantly more common in DS, with atrioventricular canal (risk ratio = 1,009), duodenal atresia (risk ratio = 265), and annular pancreas (risk ratio = 430) being the most common. Most defects of blastogenesis and most midline defects were either nonsignificantly associated or not observed in infants with DS. Theories on the pathogenesis of defects in trisomies must account for the lack of and for the presence of specific defects.

Association between mothers' nutrient intake and their offspring's risk of gastroschisis.

The young age of mothers of infants with gastroschisis, a congenital defect of the abdominal wall, suggested that deficient nutrition, with maternal-fetal competition for nutrients, could be a risk factor for gastroschisis. This population-based hypothesis-generating study consisted of 55 cases of gastroschisis and 182 matched controls. We assessed maternal nutrient intake during the trimester before conception with a self-reported food-frequency questionnaire and screened 38 nutrients to identify those most likely to be associated with gastroschisis. We used statistical classification trees to empirically generate cutpoints that determined the low and high levels of nutrient intakes corresponding to the risk of gastroschisis; cutpoints for most nutrients were similar to the corresponding recommended daily dietary allowances (RDAs). In univariate analysis, low intake of several nutrients emerged as the leading risk factors: carotenoids, e.g., alpha-carotene (odds ratio (OR) = 4.6; 95% confidence interval (CI) = 2.2-9.5), beta-carotene (OR = 3.1; 95% CI = 1.6-6.0); amino-acid compounds, e.g., total glutathione (OR = 3.5; 95% CI = 1.7-7.2); vitamin C (OR = 2.2; 95% CI = 1.5-7.8); vitamin E (OR = 2.3; 95% CI = 1.2-4.4); and minerals, fiber, and the fruit-and-vegetable group (OR = 3.1; 95% CI = 1.5-6.2). High intake of nitrosamines (OR = 2.4; 95% CI = 1.3-4.5) was also a good candidate. Many nutrient values were correlated and, in multivariate analysis, those most associated with gastroschisis were low alpha-carotene (OR = 4.3; 95% CI = 1.9-9.8), low total glutathione (OR = 3.3; 95% CI = 1.4-7.6), and high nitrosamines (OR = 2.6; 95% CI = 1.3-5.4). Adjusting for variables associated with gastroschisis in previous analyses of this population did not substantially alter those risks. These results suggest that maternal dietary inadequacy may be a risk factor for gastroschisis, and the three nutrients that emerged from the nutrient screening appear to be the best candidates to examine in further epidemiological analyses or biological studies.

The epidemiology of infantile hypertrophic pyloric stenosis.

Infants with infantile hypertrophic pyloric stenosis (IHPS) born from 1983 to 1988 and recorded in the California Birth Defects Monitoring Program (CBDMP) database were compared with their birth cohort by demographic characteristics and selected associated birth defects. We identified 1963 cases of IHPS for a cumulative incidence of 1.9 per 1000 livebirths. The cumulative incidence per 1000 livebirths was 2.4 in White, 1.8 in Hispanic, 0.7 in Black, and 0.6 in Asian infants. Between weeks 3-12 after birth, 1871 (95%) IHPS cases were diagnosed. Premature infants were diagnosed with IHPS later than term or post-term infants. The incidence of IHPS declined for those born to maternal age groups of > or = 25 years and, independently, for successive birth ranks. The probandwise concordance rate for IHPS in monozygous twins was less than unity (0.25-0.44), although higher than the concordance for dizygous twins (0.05-0.10). The incidence of Smith-Lemli-Opitz syndrome (SLO) diagnosed in infants with IHPS (3 of 1963) was 157-fold higher than the incidence of SLO diagnosed in the CBDMP population. IHPS occurs in all of the largest racial and ethnic groups in California, most frequently in White and Hispanic infants. Pyloric stenosis presents only within a brief phase of development, which may be delayed in premature infants. A predominant discordance of disease state in monozygous twins implies an aetiological role for undetermined environmental factors. The association between SLO, caused by deficient cholesterol synthesis, and IHPS deserves additional study. Infants with suspected SLO require close observation for the onset of IHPS.

Epidemiologic study of Down syndrome in a racially diverse California population, 1989-1991.

The prevalence of Down syndrome was studied among all live births occurring between 1989 and 1991 in the California counties monitored by the California Birth Defects Monitoring Program. Objectives of this study were: 1) to calculate adjusted prevalence rates and quinquennial maternal age-specific risk rates of Down syndrome after adjusting for elective abortion of prenatally diagnosed fetuses; 2) to estimate the impact of prenatal diagnosis and subsequent elective abortion of affected fetuses on the observed prevalence of Down syndrome; and 3) to examine sex ratios among liveborn infants and fetuses with Down syndrome. The racial/ethnic diversity and large size of the population allowed the data to be stratified into five racial categories-Hispanics, whites, Asians, blacks, and others. For the period 1989-1991, the observed prevalence of Down syndrome was 1.13 per 1,000 live births, and the adjusted total prevalence, which took into account the termination of affected pregnancies following prenatal diagnosis, was 1.53 per 1,000 live births. In a comparison of quinquennial maternal age-specific risk rates of Down syndrome by race, Hispanics and whites were the only groups with rates that differed significantly from each other, with Hispanics exhibiting higher rates at maternal ages under 40 years. The overall reduction in live births with Down syndrome in 1989-1991 that could be attributed to prenatal diagnosis and elective abortion of affected fetuses was 25.8%, with a 49.1% reduction being observed at maternal ages > or = 35 years. In 1990-1991, Hispanics had the lowest overall reduction (10.0%), while whites had the highest reduction (46.3%). The male: female ratios among liveborns with Down syndrome were significantly higher than those among all live births, and race had a significant association with sex ratios in both cases and controls. These findings indicate that prenatal diagnosis and elective termination of affected pregnancies has had a substantial impact in reducing the number of liveborns with Down syndrome in the monitored California counties. The effect was greatest for whites and least for Hispanics, with results indicating considerable variation in the use of prenatal diagnostic services among racial/ethnic groups. Estimates of adjusted total prevalence and reduction in live births with Down syndrome in this study should be considered minimal because of some underascertainment of prenatally diagnosed cases.

Is there an association of Down syndrome and omphalocele?

The possible association of Down syndrome (DS) with omphalocele is controversial. We reviewed the 2,979 live births and stillbirths with DS born from 1983 to 1993 in the catchment area of the California Birth Defects Monitoring Program (CBDMP). We observed one infant with both defects, a number that did not differ significantly from what was expected (P < 0.40). We also reviewed the pathological reports of one of us (L.H.H.) from a series of 36 DS fetuses and neonatal deaths; none had an omphalocele. We then reviewed the literature for epidemiological studies of DS and for epidemiological, surgical, prenatal, and familial studies of omphalocele. Possible biases inherent in each type of study were evaluated. The majority of epidemiological studies showed no association of DS with omphalocele. In surgical series, the occasional infant with both defects was more likely to undergo surgery than infants with omphalocele and trisomies 13 and 18 or other severe birth defects. Inclusion of both omphalocele and umbilical hernia in the same ICD-9 code may explain some of the correlations with DS noticed in a few epidemiological studies. In conclusion, our data suggest that trisomy 21 does not predispose the fetus to an increased risk for an omphalocele.

Maternal medications and environmental exposures as risk factors for gastroschisis.

In a case-control study of gastroschisis, we evaluated the risks associated with mother's first-trimester use of medications and with hobby or occupational exposures for 110 cases and 220 controls without a birth defect. Mothers of cases and controls were age-matched. For hobby or occupational exposures, we found significantly elevated risks for high levels of solvents (odds ratio (OR) = 3.8; 95% confidence interval (CI) = 1.6-9.2) and for colorants (OR = 2.3; 95% CI = 1.3-4.0). For medications, we found significantly elevated risks for two strong cyclooxygenase inhibitors, aspirin (OR = 4.7; 95% CI = 1.2-18.1) and ibuprofen (OR = 4.0; 95% CI = 1.0-16.0), but not for acetaminophen, a weak cyclooxygenase inhibitor. Periconceptional exposure to X rays was also associated with gastroschisis (OR = 2.5; 95% CI = 1.2-5.5), but exposure to antibiotics, antinauseants, sulfonamides, or oral contraceptives was not. We also found elevated risks for two decongestants, pseudoephedrine (OR = 2.1; 95% CI = 0.8-5.5) and phenylpropanolamine (OR = 10.0; 95% CI = 1.2-85.6). For the group of all decongestants, including also oxymetazoline and ephedrine, the risk was significantly elevated (OR = 2.4; 95% CI = 1.0-5.4). Controlling in multivariate analyses for several demographic and pregnancy variables associated with gastroschisis in a previous analysis [Torfs et al. (1994) Teratology 50: 44-53] did not substantially change the level or direction of the associations. Most of these associations are for vasoactive substances, which supports a vascular hypothesis for the pathogenesis of gastroschisis.

Sex ratios in fetuses and liveborn infants with autosomal aneuploidy.

Ten data sources were used substantially to increase the available data for estimating fetal and livebirth sex ratios for Patau (trisomy 13), Edwards (trisomy 18), and Down (trisomy 21) syndromes and controls. The fetal sex ratio estimate was 0.88 (N = 584) for trisomy 13, 0.90 (N = 1702) for trisomy 18, and 1.16 (N = 3154) for trisomy 21. All were significantly different from prenatal controls (1.07). The estimated ratios in prenatal controls were 1.28 (N = 1409) for CVSs and 1.06 (N = 49427) for amniocenteses, indicating a clear differential selection against males, mostly during the first half of fetal development. By contrast, there were no sex ratio differences for any of the trisomies when comparing gestational ages < 16 and > 16 weeks. The livebirth sex ratio estimate was 0.90 (N = 293) for trisomy 13, 0.63 (N = 497) for trisomy 18, and 1.15 (N = 6424) for trisomy 21, the latter two being statistically different than controls (1.05) (N = 3660707). These ratios for trisomies 13 and 18 were also statistically different than the ratio for trisomy 21. Only in trisomy 18 did the sex ratios in fetuses and livebirths differ, indicating a prenatal selection against males > 16 weeks. No effects of maternal age or race were found on these estimates for any of the fetal or livebirth trisomies. Sex ratios for translocations and mosaics were also estimated for these aneuploids. Compared to previous estimates, these results are less extreme, most likely because of larger sample sizes and less sample bias. They support the hypothesis that these trisomy sex ratios are skewed at conception, or become so during embryonic development through differential intrauterine selection. The estimate for Down syndrome livebirths is also consistent with the hypothesis that its higher sex ratio is associated with paternal nondisjunction.

Population-based study of tracheoesophageal fistula and esophageal atresia.

From a multiracial population of 1,035,384 births monitored by the California Birth Defects Monitoring Program (CBDMP) from 1983 to 1988, we ascertained 34 cases of esophageal atresia (EA), 204 cases of tracheoesophageal fistula (TEF) with an EA (TEF/EA), and 54 cases of TEF without EA. The total prevalence rate was 2.82 per 10,000 live births and stillbirths and showed no secular trend nor marked seasonal variation. Rates of multiple birth were high for each defect (TEF 3.7%, TEF/EA 4.9%, EA 8.8%; population 1.1%). Non-Hispanic whites were overrepresented for TEF and TEF/EA, but not for EA. Excluding trisomies, mean maternal age was above the population mean (26.8 years) for TEF (27.9 years) and TEF/EA (28.0 years), but not for EA (26.2 years). The proportion of trisomies was significantly higher for EA (23.5%) than for TEF (9.3%; P < 0.02) or for TEF/EA (7.4%; P < 0.003). We subdivided each defect into five mutually exclusive types: isolated, multiple, syndromic, chromosomal, and trisomic. Male-to-female (M/F) ratios varied considerably between types, both within and between defects. The highest M/F ratios within each defect were for the multiple type (TEF 2.29, TEF/EA 1.44, EA 1.33; population 1.05), and the lowest for trisomies (TEF 0.25; TEF/EA 0.25, and EA 0.60). All types except trisomies were significantly associated with a single umbilical artery. We found an association of EA and TEF/EA with dextrocardia (3.1% of cases), and confirmed the association of primary hydrocephalus with TEF and TEF/EA (2.7% of cases). The proportion of cases with additional midline defects or VATER or VACTERL type anomalies was similar for all three defects, suggesting a common developmental pathogenesis. Epidemiologic differences between defects, and between types within defects, may reflect differences in timing of the pathological process or differences in susceptibilities (e.g., by sex or aneuploidy) and emphasize the need to evaluate each defect and its types separately in epidemiologic studies.

A population-based study of gastroschisis: demographic, pregnancy, and lifestyle risk factors.

Gastroschisis, an abdominal wall defect, most often occurs in infants of young mothers. To identify risk factors for gastroschisis, we conducted a case-control study in the population surveyed by the California Birth Defects Monitoring Program (CBDMP). From structured questionnaire data, we compared sociodemographic, reproductive, and lifestyle factors for 110 mothers of infants with gastroschisis with those for 220 age-matched mothers of normal infants. Univariate matched-pair analysis showed significant associations of gastroschisis with mother's education, yearly family income, marital status, a history of mother's mother smoking, mother's father's absence from home during the mother's youth, more than one elective abortion, a short interval between menarche and first pregnancy, siblings from different fathers, and use of either a recreational drug (either cocaine, amphetamine, marijuana, or LSD), alcohol, or tobacco during the trimester preceding pregnancy. For cocaine, amphetamine, and marijuana, use of more than one drug showed a stronger association than single drug use. The association was stronger if both parents used drugs. Although many variables were correlated, odds ratios (OR) were significant (95% confidence intervals) in multivariate conditional logistic analysis for: yearly family income < $10,000 [OR = 4.34 (1.54, 12.22)] or $10,000-$49,999 [OR = 3.93 (1.43, 10.80)]; mother's mother's smoking status not known [OR = 3.99 (1.66, 9.56)]; mother's father's absence from home during her youth [OR = 3.11 (1.14, 8.46)]; and drug use by mother [OR = 2.21 (1.21, 4.03)], father [OR = 1.66 (1.02, 2.69)], or both [OR = 3.05 (1.48, 6.28)]. The best predictive model explained 32% of the deviance. Young, socially disadvantaged women with a history of substance use were at highest risk for a child with a gastroschisis.

Possible association between the hernia of Morgagni and trisomy 21.

Of the 5 liveborn infants with the hernia of Morgagni recorded in the California Birth Defects Monitoring Program, 3 had trisomy 21. This significant association (P < 10(-6)) between the hernia of Morgagni and trisomy 21 may reflect defective dorsoventral migration of rhabdomyoblasts from the paraxial myotomes, caused by increased cellular adhesiveness in trisomy 21.

Familial cases of gastroschisis in a population-based registry.

Only a few familial cases of gastroschisis have been reported. Consequently, the risk of a recurrence has been thought to be very small. In a population-based study of gastroschisis that included an extended pedigree of all probands, 6 (4.7%) out of 127 families had more than one affected relative. The relationships of the affected were: sib, half-sib (2), first cousin, second cousin once removed, and great uncle. Sib recurrence was 3.5%. Our results suggest that pregnancies occurring in a family with a history of gastroschisis may be at higher risk of recurrence than previously thought.

A population-based study of congenital diaphragmatic hernia.

From 1983 through 1987, in a California population of 718,208 births, 237 infants were born with a congenital diaphragmatic hernia (CDH), a birth prevalence of 3.30 per 10,000 total births (live births and stillbirths). We proposed that the various types of this defect, characterized by their different pathogeneses, would be reflected in differences in their descriptive epidemiologies. We evaluated various demographic, maternal, and infant characteristics for three major types of defects, the Morgagni hernia, the pars sternalis hernia, and the posterolateral hernia, categorizing the latter type into isolated defect (N = 129), multiple congenital anomalies including nonchromosomal syndromes (N = 86), trisomies (N = 10), and chromosomal anomalies other than trisomies (N = 2). For the posterolateral hernia, we present the distribution of associated anomalies (43%) and specifically of midline defects (19%). Although the number of cases for the Morgagni hernia (N = 5) and the pars sternalis hernia (N = 5) were small, comparisons with the posterolateral hernia suggested lower sex ratios, of borderline significance for the pars sternalis hernia (P < 0.09), and higher mean maternal ages for both groups. Within the posterolateral type, we found a significantly higher male to female ratio (M/F = 1.58) only for the isolated subgroup compared to the population (P < 0.03), and a borderline significant rural/urban difference in prevalences (2.12 vs. 1.45 per 10,000) (P < 0.06). Additionally, the distribution of monthly prevalence rates adjusted for gestational age suggested opposite seasonal trends between the isolated and the other posterolateral hernias; within this latter subgroup the difference between the highest monthly rate (1.68) and the lowest (0.96) was of borderline significance (P < 0.09). Our results suggest the need to consider the respective types and subgroups of CDH separately in epidemiologic studies.