Charlotte A. Hobbs

The National Birth Defects Prevention Study.

The National Birth Defects Prevention Study was designed to identify infants with major birth defects and evaluate genetic and environmental factors associated with the occurrence of birth defects. The ongoing case-control study covers an annual birth population of 482,000 and includes cases identified from birth defect surveillance registries in eight states. Infants used as controls are randomly selected from birth certificates or birth hospital records. Mothers of case and control infants are interviewed and parents are asked to collect buccal cells from themselves and their infants for DNA testing. Information gathered from the interviews and the DNA specimens will be used to study independent genetic and environmental factors and gene-environment interactions for a broad range of birth defects. As of December 2000, 7470 cases and 3821 controls had been ascertained in the eight states. Interviews had been completed with 70% of the eligible case and control mothers, buccal cell collection had begun in all of the study sites, and researchers were developing analysis plans for the compiled data. This study is the largest and broadest collaborative effort ever conducted among the nations leading birth defect researchers. The unprecedented statistical power that will result from this study will enable scientists to study the epidemiology of some rare birth defects for the first time. The compiled interview data and banked DNA of approximately 35 categories of birth defects will facilitate future research as new hypotheses and improved technologies emerge.

Diabetes mellitus and birth defects.

OBJECTIVE The purpose of this study was to examine associations between diabetes mellitus and 39 birth defects. STUDY DESIGN This was a multicenter case-control study of mothers of infants who were born with (n = 13,030) and without (n = 4895) birth defects in the National Birth Defects Prevention Study (1997-2003). RESULTS Pregestational diabetes mellitus (PGDM) was associated significantly with noncardiac defects (isolated, 7/23 defects; multiples, 13/23 defects) and cardiac defects (isolated, 11/16 defects; multiples, 8/16 defects). Adjusted odds ratios for PGDM and all isolated and multiple defects were 3.17 (95% CI, 2.20-4.99) and 8.62 (95% CI, 5.27-14.10), respectively. Gestational diabetes mellitus (GDM) was associated with fewer noncardiac defects (isolated, 3/23 defects; multiples, 3/23 defects) and cardiac defects (isolated, 3/16 defects; multiples, 2/16 defects). Odds ratios between GDM and all isolated and multiple defects were 1.42 (95% CI, 1.17-1.73) and 1.50 (95% CI, 1.13-2.00), respectively. These associations were limited generally to offspring of women with prepregnancy body mass index > or =25 kg/m(2). CONCLUSION PGDM was associated with a wide range of birth defects; GDM was associated with a limited group of birth defects.

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.

Assisted reproductive technology and major structural birth defects in the United States.

BACKGROUND With >1% of US births occurring following use of assisted reproductive technology (ART), it is critical to examine whether ART is associated with birth defects. METHODS We analyzed data from the National Birth Defects Prevention Study, a population-based, multicenter, case-control study of birth defects. We included mothers of fetuses or live-born infants with a major birth defect (case infants) and mothers who had live-born infants who did not have a major birth defect (control infants), delivered during the period October 1997-December 2003. We compared mothers who reported ART use (IVF or ICSI) with those who had unassisted conceptions. Multiple logistic regression was used to adjust for the following confounders: maternal race/ethnicity, maternal age, smoking and parity; we stratified by plurality. RESULTS ART was reported by 1.1% of all control mothers, and by 4.5% of control mothers 35 years or older. Among singleton births, ART was associated with septal heart defects (adjusted odds ratio [aOR] = 2.1, 95% confidence intervals [CI] 1.1-4.0), cleft lip with or without cleft palate (aOR = 2.4, 95% CI 1.2-5.1), esophageal atresia (aOR = 4.5, 95% CI 1.9-10.5) and anorectal atresia (aOR = 3.7, 95% CI 1.5-9.1). Among multiple births, ART was not significantly associated with any of the birth defects studied. CONCLUSIONS These findings suggest that some birth defects occur more often among infants conceived with ART. Although the mechanism is not clear, couples considering ART should be informed of all potential risks and benefits.

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.

Maternal Smoking and Congenital Heart Defects

OBJECTIVES. In a population-based case-control study, we investigated the association between congenital heart defects and maternal smoking. METHODS. The National Birth Defects Prevention Study enrolled 3067 infants with nonsyndromic congenital heart defects and their parents and 3947 infants without birth defects and their parents. Affected infants had ≥1 of the following defects: conotruncal, septal, anomalous pulmonary venous return, atrioventricular septal defects, and left-sided or right-sided obstructive heart defects. Mothers of case and control infants were asked if they smoked during the periconceptional period, defined as 1 month before pregnancy through the first trimester. Maternal home and workplace exposure to tobacco smoke during the same period was also determined. Logistic regression was used to compute odds ratios and 95% confidence intervals while controlling for potential confounders. RESULTS. Case infants were more likely to be premature and have lower birth weight than control infants. Women who smoked anytime during the month before pregnancy to the end of the first trimester were more likely to have infants with septal heart defects than women who did not smoke during this time period. This association was stronger for mothers who reported heavier smoking during this period. This relation was independent of potential confounding factors, including prenatal vitamin use, alcohol intake, maternal age, and race or ethnicity. Women who smoked ≥25 cigarettes per day were more likely than nonsmoking mothers to have infants with right-sided obstructive defects. There was no increased risk of congenital heart defects with maternal exposure to environmental tobacco smoke. CONCLUSIONS. Maternal smoking during pregnancy was associated with septal and right-sided obstructive defects. Additional investigation into the timing of tobacco exposure and genetic susceptibilities that could modify this risk will provide a more precise evidence base on which to build clinical and public health primary prevention strategies.

Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study.

OBJECTIVE To estimate the association between antibacterial medications and selected birth defects. DESIGN, SETTING, AND PARTICIPANTS Population-based, multisite, case-control study of women who had pregnancies affected by 1 of more than 30 eligible major birth defects identified via birth defect surveillance programs in 10 states (n = 13 155) and control women randomly selected from the same geographical regions (n = 4941). MAIN EXPOSURE Reported maternal use of antibacterials (1 month before pregnancy through the end of the first trimester). MAIN OUTCOME MEASURE Odds ratios (ORs) measuring the association between antibacterial use and selected birth defects adjusted for potential confounders. RESULTS The reported use of antibacterials increased during pregnancy, peaking during the third month. Sulfonamides were associated with anencephaly (adjusted OR [AOR] = 3.4; 95% confidence interval [CI], 1.3-8.8), hypoplastic left heart syndrome (AOR = 3.2; 95% CI, 1.3-7.6), coarctation of the aorta (AOR = 2.7; 95% CI, 1.3-5.6), choanal atresia (AOR = 8.0; 95% CI, 2.7-23.5), transverse limb deficiency (AOR = 2.5; 95% CI, 1.0-5.9), and diaphragmatic hernia (AOR = 2.4; 95% CI, 1.1-5.4). Nitrofurantoins were associated with anophthalmia or microphthalmos (AOR = 3.7; 95% CI, 1.1-12.2), hypoplastic left heart syndrome (AOR = 4.2; 95% CI, 1.9-9.1), atrial septal defects (AOR = 1.9; 95% CI, 1.1-3.4), and cleft lip with cleft palate (AOR = 2.1; 95% CI, 1.2-3.9). Other antibacterial agents that showed associations included erythromycins (2 defects), penicillins (1 defect), cephalosporins (1 defect), and quinolones (1 defect). CONCLUSIONS Reassuringly, penicillins, erythromycins, and cephalosporins, although used commonly by pregnant women, were not associated with many birth defects. Sulfonamides and nitrofurantoins were associated with several birth defects, indicating a need for additional scrutiny.

The population-based prevalence of achondroplasia and thanatophoric dysplasia in selected regions of the US†

There have been no large population‐based studies of the prevalence of achondroplasia and thanatophroic dysplasia in the United States. This study compared data from seven population‐based birth defects monitoring programs in the United States. We also present data on the association between older paternal age and these birth defects, which has been described in earlier studies. The prevalence of achondroplasia ranged from 0.36 to 0.60 per 10,000 livebirths (1/27,780–1/16,670 livebirths). The prevalence of thanatophoric dysplasia ranged from 0.21 to 0.30 per 10,000 livebirths (1/33,330–1/47,620 livebirths). In Texas, fathers that were 25–29, 30–34, 35–39, and ≥40 years of age had significantly increased rates of de novo achondroplasia among their offspring compared with younger fathers. The adjusted prevalence odds ratios were 2.8 (95% CI; 1.2, 6.7), 2.8 (95% CI; 1.0, 7.6), 4.9 (95% CI; 1.7, 14.3), and 5.0 (95% CI; 1.5, 16.1), respectively. Using the same age categories, the crude prevalence odds ratios for de novo cases of thanatophoric dysplasia in Texas were 5.8 (95% CI; 1.7, 9.8), 3.9 (95% CI; 1.1, 6.7), 6.1 (95% CI; 1.6, 10.6), and 10.2 (95% CI; 2.6, 17.8), respectively. These data suggest that thanatophoric dysplasia is one‐third to one‐half as frequent as achondroplasia. The differences in the prevalence of these conditions across monitoring programs were consistent with random fluctuation. Birth defects monitoring programs may be a good source of ascertainment for population‐based studies of achondroplasia and thanatophoric dysplasia, provided that diagnoses are confirmed by review of medical records.

Lack of periconceptional vitamins or supplements that contain folic acid and diabetes mellitus–associated birth defects

OBJECTIVE The purpose of this study was to examine the risk of birth defects in relation to diabetes mellitus and the lack of use of periconceptional vitamins or supplements that contain folic acid. STUDY DESIGN The National Birth Defects Prevention Study (1997-2004) is a multicenter, population-based case-control study of birth defects (14,721 cases and 5437 control infants). Cases were categorized into 18 types of heart defects and 26 noncardiac birth defects. We estimated odds ratios for independent and joint effects of preexisting diabetes mellitus and a lack of periconceptional use of vitamins or supplements that contain folic acid. RESULTS The pattern of odds ratios suggested an increased risk of defects that are associated with diabetes mellitus in the absence vs the presence of the periconceptional use of vitamins or supplements that contain folic acid. CONCLUSION The lack of periconceptional use of vitamins or supplements that contain folic acid may be associated with an excess risk for birth defects due to diabetes mellitus.

Congenital heart defects and genetic variants in the methylenetetrahydroflate reductase gene

Background: Most non-syndromic congenital heart defects (CHD) are caused by a complex interaction between maternal lifestyle factors, environmental exposures, and maternal and fetal genetic variants. Maternal periconceptional intake of folic acid containing vitamin supplements is reported to decrease the risk of CHD. The 677C→T and 1298A→C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene decrease enzyme activity. Objective: To examine the relation between CHD and maternal and fetal MTHFR polymorphisms Methods: 375 nuclear families were studied. The transmission/disequilibrium test was used to test for transmission distortion in complete triads. A log-linear approach was used to test for associations between CHD and maternal and offspring polymorphisms, and to estimate independently the contributions of maternal and fetal variants to relative risks. Haplotype frequencies were estimated and a haplotype transmission disequilibrium test carried out. Results: The 1298C allele was transmitted less often than expected (p = 0.0013). There was no distortion in the transmission of the 677T allele, neither was there evidence of a parent of origin effect in the transmission of either of the single nucleotide polymorphisms. The 677C–1298C haplotype was also transmitted less often than expected (p = 0.0020). The relative risk associated with inheriting one copy of the 1298C allele was 0.64 (95% confidence interval, 0.48 to 0.87) and the that associated with inheriting two copies of the 1298C allele, 0.38 (0.21 to 0.70). Conclusions: The apparent protective effect of the MTHFR 1298C allele against CHD could have several explanations and further study is needed.