Charlotte M. Druschel

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.

Delayed Diagnosis in Duchenne Muscular Dystrophy: Data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet)

OBJECTIVE To identify key factors for the delay in diagnosis of Duchenne muscular dystrophy (DMD) without known family history. STUDY DESIGN The cohort comes from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet), a multistate, multiple-source, population-based surveillance system that identifies and gathers information on all cases of Duchenne and Becker muscular dystrophy born since 1982. We analyzed medical records of 453 Duchenne and Becker muscular dystrophy boys to document the time course and steps taken to reach a definitive diagnosis. RESULTS Among 156 boys without known family history of DMD prior to birth, first signs or symptoms were noted at a mean age of 2.5 years. Concerns resulted in primary care provider evaluation of the child at a mean age of 3.6 years. Mean age at time of initial creatine kinase was 4.7 years. Mean age at definitive diagnosis of DMD was 4.9 years. CONCLUSIONS There is a delay of about 2.5 years between onset of DMD symptoms and the time of definitive diagnosis, unchanged over the previous 2 decades. This delay results in lost opportunities for timely genetic counseling and initiation of corticosteroid treatment. We recommend checking creatine kinase early in the evaluation of boys with unexplained developmental delay.

Maternal obesity and congenital heart defects: a population-based study

BACKGROUND Obesity affects almost one-third of pregnant women and causes many complications, including neural tube defects. It is not clear whether the risk of congenital heart defects, the most common malformations, is also increased. OBJECTIVE This study was conducted to determine whether obesity is associated with an increased risk of congenital heart defects. DESIGN A population-based, nested, case-control study was conducted in infants born with congenital heart defects and unaffected controls from the cohort of all births (n = 1,536,828) between 1993 and 2003 in New York State, excluding New York City. The type of congenital heart defect, maternal body mass index (BMI; in kg/m(2)), and other risk factors were obtained from the Congenital Malformations Registry and vital records. Mothers of 7392 congenital heart defect cases and 56,304 unaffected controls were studied. RESULTS All obese women (BMI > or = 30) were significantly more likely than normal-weight women (BMI: 19-24.9) to have children with a congenital heart defect [odds ratio (OR): 1.15; 95% CI: 1.07, 1.23; P < 0.0001]. Overweight women were not at increased risk (OR: 1.00; 95% CI: 0.94, 1.06). The risk in morbidly obese women (BMI > or = 40) was higher (OR: 1.33; 95% CI: 1.15, 1.54; P = 0.0001) than that in obese women with a BMI of 30-39.9 (OR: 1.11; 95% CI: 1.04, 1.20; P = 0.004). There was a highly significant trend of increasing OR for congenital heart defects with increasing maternal obesity (P < 0.0001). The offspring of obese women had significantly higher ORs for atrial septal defects, hypoplastic left heart syndrome, aortic stenosis, pulmonic stenosis, and tetralogy of Fallot. CONCLUSIONS Obese, but not overweight, women are at significantly increased risk of bearing children with a range of congenital heart defects, and the risk increases with increasing BMI. Weight reduction as a way to reduce risk should be investigated.

Maternal Low-Level Lead Exposure and Fetal Growth

Background Limited epidemiologic studies have examined the association between maternal low-level lead exposure [blood lead (PbB) < 10 μg/dL] and fetal growth. Objective We examined whether maternal low-level lead exposure is associated with decreased fetal growth. Methods We linked New York State Heavy Metals Registry records of women who had PbB measurements with birth certificates to identify 43,288 mother–infant pairs in upstate New York in a retrospective cohort study from 2003 through 2005. We used multiple linear regression with fractional polynomials and logistic regression to relate birth weight, preterm delivery, and small for gestational age to PbB levels, adjusting for potential confounders. We used a closed-test procedure to identify the best fractional polynomials for PbB among 44 combinations. Results We found a statistically significant association between PbB (square root transformed) and birth weight. Relative to 0 μg/dL, PbBs of 5 and 10 μg/dL were associated with an average of 61-g and 87-g decrease in birth weight, respectively. The adjusted odds ratio for PbBs between 3.1 and 9.9 μg/dL (highest quartile) was 1.04 [95% confidence interval (CI), 0.89–1.22] for preterm delivery and 1.07 (95% CI, 0.93–1.23) for small for gestational age, relative to PbBs ≤ 1 μg/dL (lowest quartile). No clear dose–response trends were evident when all of the quartiles were assessed. Conclusions Low-level PbB was associated with a small risk of decreased birth weight with a supralinear dose–response relationship, but was not related to preterm birth or small for gestational age. The results have important implications regarding maternal PbB.

Prevalence and correlates of gastroschisis in 15 states, 1995 to 2005.

OBJECTIVE: To identify trends in the prevalence and epidemiologic correlates of gastroschisis using a large population-based sample with cases identified by the National Birth Defects Prevention Network over the course of an 11-year period. METHODS: This study examined 4,713 cases of gastroschisis occurring in 15 states during 1995–2005, using public use natality data sets for denominators. Multivariable Poisson regression was used to identify statistically significant risk factors, and Joinpoint regression analyses were conducted to assess temporal trends in gastroschisis prevalence by maternal age and race and ethnicity. RESULTS: Results show an increasing temporal trend for gastroschisis (from 2.32 per 10,000 to 4.42 per 10,000 live births). Increasing prevalence of gastroschisis has occurred primarily among younger mothers (11.45 per 10,000 live births among mothers younger than age 20 years compared with 5.35 per 10,000 among women aged 20 to 24 years). In the multivariable analysis, using non-Hispanic whites as the referent group, non-Hispanic black women had the lowest risk of having a gastroschisis-affected pregnancy (prevalence ratio 0.42, 95% confidence interval [CI] 0.37–0.48), followed by Hispanics (prevalence ratio 0.86, 95% CI 0.81–0.92). Gastroschisis prevalence did not differ by newborn sex. CONCLUSIONS: Our findings demonstrate that the prevalence of gastroschisis has been increasing since 1995 among 15 states in the United States, and that higher rates of gastroschisis are associated with non-Hispanic white maternal race and ethnicity, and maternal age younger than 25 years (particularly younger than 20 years of age). LEVEL OF EVIDENCE: III

Residential mobility during pregnancy and the potential for ambient air pollution exposure misclassification.

Studies of environmental exposures and adverse birth outcomes often rely on maternal address at birth obtained from the birth certificate to classify exposure. Although the gestational age of interest is often early pregnancy, maternal addresses are not available for women who move during pregnancy when using maternal addresses abstracted from birth certificates. The aim of this study was to explore the extent of ambient air pollutant exposure misclassification due to maternal residential mobility during pregnancy among the subgroup of a New York birth cohort. The authors obtained the maternal addresses at birth from the New York Birth Certificate, and the maternal addresses by gestational age from the National Birth Defect Prevention Study for New York participants for the study period 1997-2002. Among the 1324 mothers, 172 (13.0%) moved once during pregnancy and 46 (3.5%) moved at least twice. When accounting for multiple addresses among some individuals, of the 218 mothers who moved, 38 (2.9%) moved in the 3rd to 8th weeks after conception (critical period, not exclusive from the 1st trimester), 80 (6.0%) moved in the 1st trimester, 112 (8.5%) in the 2nd trimester, and 51 (3.9%) in the 3rd trimester. Air monitoring data from the New York Department of Environmental Conservation were used as surrogates to compute the ambient ozone and PM(10) exposures for mothers with complete residential data. This study estimates exposure using maternal address at birth obtained from birth certificates, compared to exposure estimates when using maternal addresses by gestational age obtained from maternal interview, the gold standard. Average exposures during pregnancy were similar when using interview based versus birth certificate addresses (0.035 vs. 0.035 ppm for ozone, and 20.11 vs. 20.09 microg/m(3) for PM(10), respectively). Kappa statistics and percent agreement were calculated to measure the degree of agreement for dichotomous exposure measurements (=median) and weighted kappa for quartile exposure measurements by gestational age. All the statistics indicated a high agreement between the two measurements. For mothers who moved, the majority maintained their address in the same exposure region. Given the low mobility during pregnancy and the short distance moved, the exposure assignment did not change substantially when using the more accurate interview based addresses in this study. However, the level of observed agreement may decrease for studies that require smaller geographic zones for exposure assignments or with more mobile study populations.

Mode of delivery and neonatal survival of infants with isolated gastroschisis.

OBJECTIVE: We sought to compare neonatal survival of infants with gastroschisis by mode of delivery. METHODS: We conducted a retrospective cohort study on infants with gastroschisis who were delivered in New York State from 1983 through 1999. We compared neonatal mortality between infants born vaginally and those delivered by cesarean using adjusted hazard ratios derived from Cox proportional hazards regression models. RESULTS: A total of 354 infants were found to have isolated gastroschisis. Of these, 174 were delivered vaginally, whereas 180 were delivered by cesarean. Neonatal mortality was registered among 18 infants (5.1%); 12 (6.9%) in the vaginal and 6 (3.3%) in the cesarean group. After controlling for potential confounders, the risk for neonatal demise was similar in both the vaginal and cesarean subcohorts (adjusted hazard ratio 0.84, 95% confidence interval [CI] 0.29–2.43). Preterm birth was the morbidity pathway that explained the early demise of infants with gastroschisis, irrespective of mode of delivery (adjusted hazard ratio 3.4, 95% CI 1.10–10.4) whereas small for gestational age did not predict mortality (adjusted hazard ratio 1.04, 95% CI 0.13–8.14). CONCLUSION: In this study the mode of delivery was not found to be associated with neonatal survival of infants with gastroschisis. Preterm birth rather than small for gestational age was the predictor of neonatal death among gastroschisis infants. LEVEL OF EVIDENCE: III

A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9

Sagittal craniosynostosis is the most common form of craniosynostosis, affecting approximately one in 5,000 newborns. We conducted, to our knowledge, the first genome-wide association study for nonsyndromic sagittal craniosynostosis (sNSC) using 130 non-Hispanic case-parent trios of European ancestry (NHW). We found robust associations in a 120-kb region downstream of BMP2 flanked by rs1884302 (P = 1.13 × 10−14, odds ratio (OR) = 4.58) and rs6140226 (P = 3.40 × 10−11, OR = 0.24) and within a 167-kb region of BBS9 between rs10262453 (P = 1.61 × 10−10, OR = 0.19) and rs17724206 (P = 1.50 × 10−8, OR = 0.22). We replicated the associations to both loci (rs1884302, P = 4.39 × 10−31 and rs10262453, P = 3.50 × 10−14) in an independent NHW population of 172 unrelated probands with sNSC and 548 controls. Both BMP2 and BBS9 are genes with roles in skeletal development that warrant functional studies to further understand the etiology of sNSC.

Characteristics of pregnant illicit drug users and associations between cannabis use and perinatal outcome in a population-based study

BACKGROUND According to the 2004 National Survey on Drug Use and Health, 4.6% of American women reported use of an illicit drug during pregnancy. Previous studies on illicit drug use during pregnancy and perinatal outcomes showed inconsistent results. METHODS This population-based study included mothers who delivered live-born infants without birth defects between 1997 and 2004 and completed interviews for the National Birth Defects Prevention Study (response rate 69%; n=5871). Prevalence of self-reported illicit drug use (specifically cannabis, cocaine, and stimulants) during pregnancy and its associations with demographic and social factors were assessed. We used multivariable linear and logistic regression analyses to study the associations of cannabis use with birth weight and gestational age. RESULTS The prevalence of reported illicit drug use during pregnancy was 3.6% (standard error 0.24). Pregnant users of cannabis, cocaine, and stimulants were younger, had a lower level of education and lower household income, and were less likely to have used folic acid in the periconceptional period than nonusers. Illicit drug users were also more likely to have used alcohol and tobacco. After adjustment for confounding, cannabis use was not associated with mean birth weight or gestational age or with low birth weight or preterm delivery. CONCLUSION Women who report use of illicit drugs during pregnancy differ in demographic and socioeconomic background from nonusers. Reported cannabis use does not seem to be associated with low birth weight or preterm birth.

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.