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.

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.

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.

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.

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.

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.

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.

Epidemiologic research in hypertension: a critical appraisal.

Epidemiologic studies of blood pressure have been conducted for over twenty-five years, but the results of this research can only be described as modest. The basic epidemiologic and demographic description of blood pressure distributions in human populations remains problematic and psychosocial studies have not yielded clear and solid hypotheses pointing the way to future research. There is no doubt that blood pressures vary among and between population groups, and there seems little doubt that variations in life-style are associated with these differences. It is puzzling that we have failed to discern systematic and patterned relationships among these variables. It is suggested that a more useful approach to research in this field would be to distinguish factors that affect general susceptibility to becoming ill from those that initiate or maintain particular disease states.

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.

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.

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.

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.

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.

Genetic interrelationship between insulin-dependent diabetes mellitus, the autoimmune thyroid diseases, and rheumatoid arthritis.

To investigate the possible coinheritance of autoimmune diseases that are associated with the same HLA antigen, we studied 70 families in which at least two siblings had either type I diabetes mellitus (IDDM), autoimmune thyroid disease (ATD), rheumatoid arthritis (RA), or a combination of these diseases. HLA-A, B, and C typing was performed on all affected sibs in one generation or more. First, we estimated by sib-pair analysis the disease allele frequency (pD) and the mode of inheritance for each disease. According to the method of ascertainment entered into the analysis, the pD for ATD ranged from .120 to .180, for an additive (dominant) mode of inheritance. For RA, the pD ranged from .254 to .341, also for additive inheritance, although recessive inheritance could not be excluded. For IDDM, the pD ranged from .336 to .337 for recessive inheritance; additive inheritance was rejected. Second, we examined the distribution of shared parental haplotypes in pairs of siblings that were discordant for their autoimmune diseases. The results suggested that the same haplotype may predispose to both IDDM and ATD, or IDDM and RA, but not to both RA and ATD. Analysis of pedigrees supported this hypothesis. In 16 families typed for HLA-DR also, the haplotype predisposing to both IDDM and ATD was assigned from pedigree information to DR3 (44%), DR4 (39%), or DR5, DR6, or DR7 (5.5% each). In some families, these haplotypes segregated over several generations with ATD only (either clinical or subclinical), suggesting that in such families, ATD was a marker for a susceptibility to IDDM. In several families, an IDDM haplotype segregated with RA but not with ATD. This suggests that ATD- and RA-associated susceptibilities to IDDM may be biologically different and thus independently increase the risk of IDDM.

Thyroid antibodies as a risk factor for Down syndrome and other trisomies.

To test whether the presence of thyroid antibodies in a parent is a risk factor for meiotic nondisjunction, we measured the levels of thyroid antibodies in serum samples drawn during early pregnancy from 101 gravidas who delivered a child with a trisomy, from 11 gravidas who had had a trisomic child in a previous pregnancy, and from 44 of their husbands. For each case mother, three controls were randomly selected from the same population and matched for age, race, sex of the child, and hospital of birth. Cases and controls came from two longitudinal populations, the Child Health and Development Studies (CHDS) and the national Collaborative Perinatal Project (CPP), together comprising more than 70,000 live births. All cases with both a definite diagnosis of trisomy-Down syndrome (DS) or other-and available serum were included. Overall, there was no association between the presence of thyroid antibodies in a mother and a trisomy in her offspring (odds ratio [OR] = .98, confidence interval [CI] = .54-1.85). The lack of association was seen in all three subgroups (DS only, other trisomies, and DS in a previous pregnancy), in all ethnic groups, and in the age groups of white mothers either less than 30 years of age (OR = .80, CI = .40-1.6) or greater than or equal to 30 years of age (OR = 1.26, CI = .82-1.9). In the CHDS population, case fathers, as compared with control fathers, did not have a higher prevalence of thyroid antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Prenatal and perinatal factors in the etiology of cerebral palsy.

Among 19,044 children born to mothers with monitored pregnancies and followed medically for at least 5 years, 41 (0.2%) had cerebral palsy that was not the result of a progressive disease or of a neural tube defect. All children without cerebral palsy were entered as controls subjects in the analysis. Significant prenatal or gestational predictors of cerebral palsy were a severe or nonsevere birth defect other than cerebral palsy or its sequelae, low birth weight, low placental weight, abnormal fetal position, and premature separation of the placenta. Maternal antecedents of cerebral palsy were unusually long or unusually short intervals between pregnancies and unusually long menstrual cycles. Perinatal risk factors were delayed crying as a measure of birth asphyxia and abnormal delivery. Children who had seizures within 48 hours of birth were at high risk for the development of cerebral palsy. Seventy-eight percent of children with cerebral palsy did not have birth asphyxia, and the 22% who did had other prenatal risk factors that may have compromised their recovery.

The relationship between hormonal pregnancy tests and congenital anomalies: a prospective study.

In a prospective study of some 20,000 pregnancies in the Child Health and Development Studies in the San Francisco East Bay area, 226 gravidas were tested for pregnancy with estrogen/progestogen preparations. The two control groups were women who were tested for pregnancy by either a serum or urine test. There were no statistically differences (p greater than 0.05) in the rates of severe congenital anomalies between the hormone test group and the two control groups. The relative risks and the 95% confidence intervals were 1.01 (0.47-2.19) for the hormone/serum test comparison and 1.60 (0.60-4.18) for the hormone/urine test comparison.

PIP: Several retrospective and prospective studies have positively associated EPP (estrogen/progestogen preparations) with birth defects in the offsprings of exposed gravidas. Some 20,000 pregnancies of women in the Child Health and Development Studies (CHDS) in the San Francisco bay area between 1959 and 1966 were observed longitudinally. Congenital defects of children in the study (ascertained at birth and followed up in subsequent years) include structural aberrations and errors of metabolism. The CHDS study population includes 227 gravidas who were tested for pregnancy with EPP. 2 control groups consisted of those who were tested for pregnancy by either a serum or urine test. No statistically significant differences in the rates of severe congenital defects were observed between the hormonal test group and the 2 control groups (p 0.05). Relative risks and 95% confidence intervals were 1.01 (0.45-2.19) for the hormone/serum test comparison and 1.60 (0.60 to 4.18) for the hormone/urine test comparison. An insignificant increased risk for nonsevere genitourinary anomalies as observed in the male infants in the hormone group. Although this study did not confirm the hypothesized association between EPP and congenital anomalies in the CHDS population, the numbers in this series are not large enough to reject the hypothesis either. Further use of hormonal pregnancy tests appears unjustified in the light of the availability of non-risk pregnancy tests.

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.