Bio

Academic Appointments


Administrative Appointments


  • Associate Chair Clinical Research, Dept of Pediatrics (2012 - Present)

Professional Education


  • DrPH, UC Berkeley, Epidemiology (1986)

Research & Scholarship

Current Research and Scholarly Interests


Primary research interests include 1) epidemiology of birth defects, 2) gene-environment approaches to perinatal outcomes, and 3) nutrition and reproductive outcomes.

Teaching

2013-14 Courses


Postdoctoral Advisees


Publications

Journal Articles


  • Maternal-fetal metabolic gene-gene interactions and risk of neural tube defects MOLECULAR GENETICS AND METABOLISM Lupo, P. J., Mitchell, L. E., Canfield, M. A., Shaw, G. M., Olshan, A. F., Finnell, R. H., Zhu, H. 2014; 111 (1): 46-51

    Abstract

    Single-gene analyses indicate that maternal genes associated with metabolic conditions (e.g., obesity) may influence the risk of neural tube defects (NTDs). However, to our knowledge, there have been no assessments of maternal-fetal metabolic gene-gene interactions and NTDs. We investigated 23 single nucleotide polymorphisms among 7 maternal metabolic genes (ADRB3, ENPP1, FTO, LEP, PPARG, PPARGC1A, and TCF7L2) and 2 fetal metabolic genes (SLC2A2 and UCP2). Samples were obtained from 737 NTD case-parent triads included in the National Birth Defects Prevention Study for birth years 1999-2007. We used a 2-step approach to evaluate maternal-fetal gene-gene interactions. First, a case-only approach was applied to screen all potential maternal and fetal interactions (n = 76), as this design provides greater power in the assessment of gene-gene interactions compared to other approaches. Specifically, ordinal logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for each maternal-fetal gene-gene interaction, assuming a log-additive model of inheritance. Due to the number of comparisons, we calculated a corrected p-value (q-value) using the false discovery rate. Second, we confirmed all statistically significant interactions (q < 0.05) using a log-linear approach among case-parent triads. In step 1, there were 5 maternal-fetal gene-gene interactions with q < 0.05. The "top hit" was an interaction between maternal ENPP1 rs1044498 and fetal SLC2A2 rs6785233 (interaction OR = 3.65, 95% CI: 2.32-5.74, p = 2.0910(-8), q=0.001), which was confirmed in step 2 (p = 0.00004). Our findings suggest that maternal metabolic genes associated with hyperglycemia and insulin resistance and fetal metabolic genes involved in glucose homeostasis may interact to increase the risk of NTDs.

    View details for DOI 10.1016/j.ymgme.2013.11.004

    View details for Web of Science ID 000330158100007

    View details for PubMedID 24332798

  • Hypospadias and variants in genes related to sex hormone biosynthesis and metabolism ANDROLOGY Carmichael, S. L., Witte, J. S., Ma, C., Lammer, E. J., Shaw, G. M. 2014; 2 (1): 130-137

    Abstract

    We examined whether variants in genes related to sex hormone biosynthesis and metabolism were associated with hypospadias in humans. We examined 332 relatively common tag single-nucleotide polymorphisms (tagSNPs) in 20 genes. Analyses included 633 cases (84 mild, 322 moderate, 212 severe and 15 undetermined severity) and 855 population-based non-malformed male controls born in California from 1990 to 2003. We used logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for each SNP. Several of the 332 studied SNPs had p<0.01: one in CYP3A4, four in HSD17B3, one in HSD3B1, two in STARD3, 10 in SRD5A2 and seven in STS. In addition, haplotype analyses gave several associations with p<0.01. For HSD17B3, 14-SNP and 5-SNP blocks had ORs of 1.5 (95% CI 1.1, 2.0, p<0.001) and 2.8 (95% CI 1.6, 4.8, p<0.001) respectively. For SRD5A2, 9-SNP, 3-SNP and 8-SNP blocks had ORs of 1.7 (95% CI 1.3, 2.2, p<0.001), 1.4 (95% CI 1.1, 1.8, p=0.008) and 1.5 (95% CI 1.2, 1.9, p=0.002) respectively. Our study indicates that several genes that contribute to sex hormone biosynthesis and metabolism are associated with hypospadias risk.

    View details for DOI 10.1111/j.2047-2927.2013.00165.x

    View details for Web of Science ID 000328729900019

    View details for PubMedID 24281767

  • Could genetic polymorphisms related to oxidative stress modulate effects of heavy metals for risk of human preterm birth? Reproductive toxicology Shachar, B. Z., Carmichael, S. L., Stevenson, D. K., Shaw, G. M. 2013; 42: 24-26

    Abstract

    Human preterm birth (PTB) is a complex medical outcome influenced by a combination of genetic and environmental factors. Research on the causative factors of PTB has mostly focused on demographic, socio-behavioral and environmental risk factors. Recent studies turn the spotlight on the effects of heavy metals exposure on adverse pregnancy outcomes. Here we present and evaluate the hypothesis that heavy metals may cause PTB through oxidative stress, and that this effect may be modified by polymorphisms in genes related to oxidative stress. Indeed, accumulating data suggest that the risk of PTB is correlated with polymorphisms in genes involved in detoxification, oxidative stress and lipid metabolism. These and other polymorphisms have independently been associated with susceptibility to the adverse effects of heavy metals.

    View details for DOI 10.1016/j.reprotox.2013.06.072

    View details for PubMedID 23811355

  • Traffic-related air pollution and selected birth defects in the San Joaquin Valley of California. Birth defects research. Part A, Clinical and molecular teratology Padula, A. M., Tager, I. B., Carmichael, S. L., Hammond, S. K., Yang, W., Lurmann, F. W., Shaw, G. M. 2013; 97 (11): 730-735

    Abstract

    Birth defects are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some structural anomalies, although evidence is limited and several anomalies have not been investigated previously.We used data from the California Center of the National Birth Defects Prevention Study and the Children's Health and Air Pollution Study to estimate the odds of 26 congenital birth defect phenotypes with respect to quartiles of seven ambient air pollutant and traffic exposures in California during the first 2 months of pregnancy, 1997 to 2006 (874 cases and 849 controls). We calculated odds ratios (adjusted for maternal race/ethnicity, education, and vitamin use; aOR) for 11 phenotypes that had at least 40 cases.Few odds ratios had confidence intervals that did not include 1.0. Odds of esophageal atresia were increased for the highest versus lowest of traffic density (aOR?=?2.8, 95% confidence interval [CI], 1.1-7.4) and PM10 exposure (aOR 4.9; 95% CI, 1.4-17.2). PM10 was associated with a decreased risk of hydrocephaly (aOR= 0.3; 95% CI, 0.1-0.9) and CO with decreased risk of anotia/microtia (aOR?=?0.4; 95% CI, 0.2-0.8) and transverse limb deficiency (aOR?=?0.4; 95% CI, 0.2-0.9), again reflecting highest versus lowest quartile comparisons.Most analyses showed no substantive association between air pollution and the selected birth defects with few exceptions of mixed results. Birth Defects Research (Part A) 97:730-735, 2013. 2013 Wiley Periodicals, Inc.

    View details for DOI 10.1002/bdra.23175

    View details for PubMedID 24108522

  • Hypospadias and Genes Related to Genital Tubercle and Early Urethral Development JOURNAL OF UROLOGY Carmichael, S. L., Ma, C., Choudhry, S., Lammer, E. J., Witte, J. S., Shaw, G. M. 2013; 190 (5): 1884-1892

    Abstract

    PURPOSE: We determined whether variants in genes associated with genital tubercle (the anlage for the penis) and early urethral development were associated with hypospadias in humans. MATERIALS AND METHODS: We examined 293 relatively common tagSNPs in BMP4, BMP7, FGF8, FGF10, FGFR2, HOXA13, HOXD13, HOXA4, HOXB6, SRY, WT1, WTAP, SHH, GLI1, GLI2, and GLI3. The analysis included 624 cases (81 mild, 319 moderate, 209 severe, 15 undetermined severity) and 844 population-based non-malformed male controls born in California from 1990-2003. RESULTS: There were 28 SNPs for which any of the comparisons (i.e., overall or for a specific severity) had a p-value <0.01. The homozygous variant genotypes for four SNPs in BMP7were associated with at least 2-fold increased risk of hypospadias, regardless of severity. Five SNPs for FGF10were associated with 3- to 4-fold increased risks, regardless of severity; for four of them, results were restricted to whites. For GLI1, GLI2and GLI3, there were 12 associated SNPs but results were inconsistent by severity and race-ethnicity. For SHH, one SNP was associated with 2.4-fold increased risk of moderate hypospadias. For WT1, six SNPs were associated with approximately 2-fold increased risks, primarily for severe hypospadias. CONCLUSIONS: This study provides evidence that SNPs in several genes that contribute to genital tubercle and early urethral development are associated with hypospadias risk.

    View details for DOI 10.1016/j.juro.2013.05.061

    View details for Web of Science ID 000325471400089

    View details for PubMedID 23727413

  • Periconceptional nutrient intakes and risks of orofacial clefts in California. Pediatric research Wallenstein, M. B., Shaw, G. M., Yang, W., Carmichael, S. L. 2013; 74 (4): 457-465

    Abstract

    Background:Evidence indicates that maternal nutrient intake may play a role in the development of birth defects. We investigated the association of maternal periconceptional intake of vitamin supplements and dietary nutrients with risk of developing cleft palate (CP) and cleft lip with or without cleft palate (CLP).Methods:Data were from a population-based, case-control study of fetuses and liveborn infants delivered in California,1999-2003. Analyses included 170 cases with CP, 425 with CLP, and 534 nonmalformed controls. Dietary intake was estimated from a food frequency questionnaire.Results:Vitamin supplement intake was associated with a modestly decreased risk of clefts, but the confidence intervals include one. Among women who did not use vitamin supplements, dietary intake of several micronutrients was associated with risk of clefts. We found at least a two-fold elevated risk of CP with low intake of riboflavin, magnesium, calcium, vitamin B12, and zinc; all CIs excluded 1.0. For CLP, we found at least a two-fold elevated risk with low intake of niacin, riboflavin, vitamin B12, and calcium, and a decreased risk with high intake of folate and cryptoxanthin; all CIs excluded 1.0.Conclusion:Results suggest that periconceptional nutrient intake may be associated with risk of CP and CLP.Pediatric Research (2013); doi:10.1038/pr.2013.115.

    View details for DOI 10.1038/pr.2013.115

    View details for PubMedID 23823175

  • A Genome-Wide Association Study (GWAS) for Bronchopulmonary Dysplasia. Pediatrics Wang, H., St Julien, K. R., Stevenson, D. K., Hoffmann, T. J., Witte, J. S., Lazzeroni, L. C., Krasnow, M. A., Quaintance, C. C., Oehlert, J. W., Jelliffe-Pawlowski, L. L., Gould, J. B., Shaw, G. M., O'Brodovich, H. M. 2013; 132 (2): 290-297

    Abstract

    Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD.The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 25(0)-29(6/7) weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks' postmenstrual age. At 36 weeks' postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip.Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 10(-8)) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative.We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.

    View details for DOI 10.1542/peds.2013-0533

    View details for PubMedID 23897914

  • Maternal Dietary Nutrient Intake and Risk of Preterm Delivery AMERICAN JOURNAL OF PERINATOLOGY Carmichael, S. L., Yang, W., Shaw, G. M. 2013; 30 (7): 579-588

    Abstract

    Objective?To examine maternal dietary intake and preterm delivery.Study Design?Data included 5738 deliveries from the National Birth Defects Prevention Study. Odds ratios (ORs) reflected risks of delivery at <32, 32-34, or 35-36 versus ?37 weeks for maternal intake in the lowest or highest quartile of nutrient intake compared with the middle two.Results?Among deliveries?

    View details for DOI 10.1055/s-0032-1329686

    View details for Web of Science ID 000322021900009

    View details for PubMedID 23208764

  • Hypospadias and Maternal Intake of Phytoestrogens AMERICAN JOURNAL OF EPIDEMIOLOGY Carmichael, S. L., Cogswell, M. E., Ma, C., Gonzalez-Feliciano, A., Olney, R. S., Correa, A., Shaw, G. M. 2013; 178 (3): 434-440

    Abstract

    Experimental data indicate that gestational exposures to estrogenic compounds impact risk of hypospadias. We examined whether risk of hypospadias (i.e., a congenital malformation in which the opening of the penile urethra occurs on the ventral side of the penis) was associated with maternal intake of phytoestrogens, given their potential impact on estrogen metabolism. The analysis included data on mothers of 1,250 hypospadias cases and 3,118 controls who delivered their infants from 1997 to 2005 and participated in the National Birth Defects Prevention Study, a multistate, population-based, case-control study. After adjustment for several covariates, high intakes of daidzein, genistein, glycetin, secoisolariciresinol, total isoflavones, total lignans, and total phytoestrogens were associated with reduced risks; odds ratios comparing intakes ?90th percentile with intakes between the 11th and 89th percentiles ranged from 0.6 to 0.8. For example, the odds ratio for total phytoestrogen intake was 0.7 (95% confidence interval: 0.5, 1.0). This study represents the first large-scale analysis of phytoestrogen intake and hypospadias. The observed associations merit investigation in additional populations before firm conclusions can be reached.

    View details for DOI 10.1093/aje/kws591

    View details for Web of Science ID 000322734500012

    View details for PubMedID 23752918

  • A Pilot Study Using Residual Newborn Dried Blood Spots to Assess the Potential Role of Cytomegalovirus and Toxoplasma gondii in the Etiology of Congenital Hydrocephalus BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Simeone, R. M., Rasmussen, S. A., Mei, J. V., Dollard, S. C., Frias, J. L., Shaw, G. M., Canfield, M. A., Meyer, R. E., Jones, J. L., Lorey, F., Honein, M. A. 2013; 97 (7): 431-436

    Abstract

    Congenital hydrocephalus is a condition characterized by accumulation of cerebrospinal fluid in the ventricles of the brain. Prenatal infections are risk factors for some birth defects. This pilot study investigated whether residual dried blood spots (DBS) could be used to assess infections as risk factors for birth defects by examining the associations between prenatal infection with Toxoplasma gondii (T. gondii) or cytomegalovirus (CMV) with congenital hydrocephalus.Case-infants with hydrocephalus (N=410) were identified among live-born infants using birth defects surveillance systems in California, North Carolina, and Texas. Control-infants without birth defects were randomly selected from the same geographic areas and time periods as case-infants (N=448). We tested residual DBS from case- and control-infants for T. gondii immunoglobulin M and CMV DNA. When possible, we calculated crude odds ratios (cORs) and confidence intervals (CIs).Evidence for prenatal T. gondii infection was more common among case-infants (1.2%) than control-infants (0%; p=0.11), and evidence for prenatal CMV infection was higher among case-infants (1.5%) than control-infants (0.7%; cOR: 2.3; 95% CI: 0.48, 13.99).Prenatal infections with T. gondii and CMV occurred more often among infants with congenital hydrocephalus than control-infants, although differences were not statistically significant. This pilot study highlighted some challenges in using DBS to examine associations between certain infections and birth defects, particularly related to reduced sensitivity and specimen storage conditions. Further study with increased numbers of specimens and higher quality specimens should be considered to understand better the contribution of these infections to the occurrence of congenital hydrocephalus.

    View details for DOI 10.1002/bdra.23138

    View details for Web of Science ID 000326397800001

    View details for PubMedID 23716471

  • Ambient air pollution and traffic exposures and congenital heart defects in the san joaquin valley of california. Paediatric and perinatal epidemiology Padula, A. M., Tager, I. B., Carmichael, S. L., Hammond, S. K., Yang, W., Lurmann, F., Shaw, G. M. 2013; 27 (4): 329-339

    Abstract

    Congenital anomalies are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited.We used data from the California Center of the National Birth Defects Prevention Study and the Children's Health and Air Pollution Study to estimate the odds of 27 congenital heart defects with respect to quartiles of seven ambient air pollutant and traffic exposures in California during the first 2 months of pregnancy, 1997-2006 (n?=?822 cases and n?=?849 controls).Particulate matter

    View details for DOI 10.1111/ppe.12055

    View details for PubMedID 23772934

  • Association of early-preterm birth with abnormal levels of routinely collected first- and second-trimester biomarkers AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Jelliffe-Pawlowski, L. L., Shaw, G. M., Currier, R. J., Stevenson, D. K., Baer, R. J., O'Brodovich, H. M., Gould, J. B. 2013; 208 (6)

    Abstract

    The purpose of this study was to examine the relationship between typically measured prenatal screening biomarkers and early-preterm birth in euploid pregnancies.The study included 345 early-preterm cases (<30 weeks of gestation) and 1725 control subjects who were drawn from a population-based sample of California pregnancies who had both first- and second-trimester screening results. Logistic regression analyses were used to compare patterns of biomarkers in cases and control subjects and to develop predictive models. Replicability of the biomarker early-preterm relationships that was revealed by the models was evaluated by examination of the frequency and associated adjusted relative risks (RRs) for early-preterm birth and for preterm birth in general (<37 weeks of gestation) in pregnancies with identified abnormal markers compared with pregnancies without these markers in a subsequent independent California cohort of screened pregnancies (n = 76,588).The final model for early-preterm birth included first-trimester pregnancy-associated plasma protein A in the ?5th percentile, second-trimester alpha-fetoprotein in the ?95th percentile, and second-trimester inhibin in the ?95th percentile (odds ratios, 2.3-3.6). In general, pregnancies in the subsequent cohort with a biomarker pattern that were found to be associated with early-preterm delivery in the first sample were at an increased risk for early-preterm birth and preterm birth in general (<37 weeks of gestation; adjusted RR, 1.6-27.4). Pregnancies with ?2 biomarker abnormalities were at particularly increased risk (adjusted RR, 3.6-27.4).When considered across cohorts and in combination, abnormalities in routinely collected biomarkers reveal predictable risks for early-preterm birth.

    View details for DOI 10.1016/j.ajog.2013.02.012

    View details for Web of Science ID 000320596600029

    View details for PubMedID 23395922

  • The Association of Ambient Air Pollution and Traffic Exposures With Selected Congenital Anomalies in the San Joaquin Valley of California AMERICAN JOURNAL OF EPIDEMIOLOGY Padula, A. M., Tager, I. B., Carmichael, S. L., Hammond, S. K., Lurmann, F., Shaw, G. M. 2013; 177 (10): 1074-1085

    Abstract

    Congenital anomalies are a leading cause of infant mortality and are important contributors to subsequent morbidity. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited. We aimed to investigate whether ambient air pollutant and traffic exposures in early gestation contribute to the risk of selected congenital anomalies in the San Joaquin Valley of California, 1997-2006. Seven exposures and 5 outcomes were included for a total of 35 investigated associations. We observed increased odds of neural tube defects when comparing the highest with the lowest quartile of exposure for several pollutants after adjusting for maternal race/ethnicity, education, and multivitamin use. The adjusted odds ratio for neural tube defects among those with the highest carbon monoxide exposure was 1.9 (95% confidence interval: 1.1, 3.2) compared with those with the lowest exposure, and there was a monotonic exposure-response across quartiles. The highest quartile of nitrogen oxide exposure was associated with neural tube defects (adjusted odds ratio = 1.8, 95% confidence interval: 1.1, 2.8). The adjusted odds ratio for the highest quartile of nitrogen dioxide exposure was 1.7 (95% confidence interval: 1.1, 2.7). Ozone was associated with decreased odds of neural tube defects. Our results extend the limited body of evidence regarding air pollution exposure and adverse birth outcomes.

    View details for DOI 10.1093/aje/kws367

    View details for Web of Science ID 000318801200006

    View details for PubMedID 23538941

  • Maternal occupational exposure to polycyclic aromatic hydrocarbons and risk of oral cleft-affected pregnancies. Cleft palate-craniofacial journal Langlois, P. H., Hoyt, A. T., Lupo, P. J., Lawson, C. C., Waters, M. A., Desrosiers, T. A., Shaw, G. M., Romitti, P. A., Lammer, E. J. 2013; 50 (3): 337-346

    Abstract

    Objective :? To evaluate whether there is an association between maternal occupational exposure to polycyclic aromatic hydrocarbons and oral clefts in offspring. This is the first human study of polycyclic aromatic hydrocarbons and clefts of which the authors are aware. Design :? Case-control study. Setting, Participants :? Data for 1997 to 2002 from the National Birth Defects Prevention Study, a large population-based case-control study in the United States, were analyzed. Maternal telephone interviews yielded information on jobs held in the month before through 3 months after conception. Two industrial hygienists independently assessed occupational exposure to polycyclic aromatic hydrocarbons; all jobs rated as exposed or with rating difficulty were reviewed with a third industrial hygienist to reach consensus on all exposure parameters. Logistic regression estimated crude and adjusted odds ratios with 95% confidence intervals for cleft lip with or without cleft palate and cleft palate alone. Results :? There were 2989 controls (3.5% exposed), 805 cases of cleft lip with or without cleft palate (5.8% exposed), and 439 cases of cleft palate alone (4.6% exposed). The odds of maternal occupational exposure to polycyclic aromatic hydrocarbons (any versus none) during pregnancy was increased for cleft lip with or without cleft palate cases as compared with controls (odds ratio, 1.69; 95% confidence interval, 1.18 to 2.40); the odds ratio was 1.47 (95% confidence interval 1.02 to 2.12) when adjusted for maternal education. There was a statistically significant adjusted exposure-response relationship for cleft lip with or without cleft palate (Ptrend = .02). Odd ratios for cleft palate alone were not statistically significant. Conclusions :? Maternal occupational exposure to polycyclic aromatic hydrocarbons was associated with increased risk of cleft lip with or without cleft palate in offspring.

    View details for DOI 10.1597/12-104

    View details for PubMedID 23136939

  • Considering the vascular hypothesis for the pathogenesis of small intestinal atresia: A case control study of genetic factors AMERICAN JOURNAL OF MEDICAL GENETICS PART A Gupta, T., Yang, W., Iovannisci, D. M., Carmichael, S. L., Stevenson, D. K., Shaw, G. M., Lammer, E. J. 2013; 161A (4): 702-710

    Abstract

    Small intestinal atresia (SIA) is a rare congenital occlusion of the small intestine. SIA development, particularly in the jejunum and ileum, has been associated with in utero disruption of vascular supply. However, the number of studies of the vascular hypothesis is limited. This study considers the vascular hypothesis by exploring risks associated with 32 SNPs of genes involved in vascular processes of homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation. A total of 206 SIA cases were ascertained by the California Birth Defects Monitoring Program, and 573 infants with no major congenital anomalies by their first birthday were selected as controls. Genomic DNA was genotyped for 32 SNPs involving the following genes: MTHFR, F2, F5, F7, SERPINE1, FGB, ITGA2, ITGB3, SELE, ICAM1, MMP3, TNF, LTA, NOS3, AGTR1, AGT, NPPA, ADD1, SCNN1A, GNB3, and ADRB2. Risks were estimated as odds ratios, adjusted for maternal age and race, with 95% confidence intervals. Cases were considered collectively and by subgroups based on atresia location (duodenal/jejunum/ileum). Three SNPs had reduced risk: SERPINE1 11053 T/G, MMP3 (-1171) A6/A5, and ADRB2 gln27glu. Two had increased risk: ITGA2 873 G/A and NPPA 2238 T/C. No intestinal subphenotypes showed a unique pattern of SNP associations. The association of two SNPs with increased risk lends some, albeit limited, support to vascular impairment as a possible mechanism leading to SIA. These results also identify genes meriting further exploration in SIA studies. Hence, this study makes an important contribution by exploring the long-held but not well-investigated vascular hypothesis.

    View details for DOI 10.1002/ajmg.a.35775

    View details for Web of Science ID 000316631300012

    View details for PubMedID 23444056

  • Transdisciplinary translational science and the case of preterm birth JOURNAL OF PERINATOLOGY Stevenson, D. K., Shaw, G. M., Wise, P. H., Norton, M. E., Druzin, M. L., Valantine, H. A., McFarland, D. A. 2013; 33 (4): 251-258

    Abstract

    Medical researchers have called for new forms of translational science that can solve complex medical problems. Mainstream science has made complementary calls for heterogeneous teams of collaborators who conduct transdisciplinary research so as to solve complex social problems. Is transdisciplinary translational science what the medical community needs? What challenges must the medical community overcome to successfully implement this new form of translational science? This article makes several contributions. First, it clarifies the concept of transdisciplinary research and distinguishes it from other forms of collaboration. Second, it presents an example of a complex medical problem and a concrete effort to solve it through transdisciplinary collaboration: for example, the problem of preterm birth and the March of Dimes effort to form a transdisciplinary research center that synthesizes knowledge on it. The presentation of this example grounds discussion on new medical research models and reveals potential means by which they can be judged and evaluated. Third, this article identifies the challenges to forming transdisciplines and the practices that overcome them. Departments, universities and disciplines tend to form intellectual silos and adopt reductionist approaches. Forming a more integrated (or 'constructionist'), problem-based science reflective of transdisciplinary research requires the adoption of novel practices to overcome these obstacles.

    View details for DOI 10.1038/jp.2012.133

    View details for Web of Science ID 000316833300001

    View details for PubMedID 23079774

  • Progress in understanding the genetics of bronchopulmonary dysplasia SEMINARS IN PERINATOLOGY Shaw, G. M., O'Brodovich, H. M. 2013; 37 (2): 85-93

    Abstract

    Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in infants. Its treatment imposes considerable healthcare burden and costs in the perinatal and early childhood period and patients are usually left with lifelong deficits in lung function. Evidence exists for different pathophysiologic pathways that can promote the structural changes that characterize BPD, including the impairment in alveolarization; however, there is increasing interest regarding heritable factors that may predispose very low birth weight infants to BPD. Our review focuses on recent publications that have investigated genetic factors that may potentially contribute to such reported heritability. These publications point us toward some possible genomic candidates for further study, but certainly do not identify any particular gene or gene pathway that would be inferred to be contributing substantially to the underlying etiology of BPD.

    View details for DOI 10.1053/j.semperi.2013.01.004

    View details for Web of Science ID 000317870800005

    View details for PubMedID 23582962

  • Thymidylate synthase polymorphisms and risks of human orofacial clefts BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Yang, W., Perloff, S., Shaw, N. M., Carmichael, S. L., Zhu, H., Lammer, E. J. 2013; 97 (2): 95-100

    Abstract

    Underlying mechanisms are unknown by which folic acid use in early pregnancy may reduce risks of orofacial clefts. Thymidylate synthase (TYMS) is a folate-dependent enzyme that catalyzes reductive methylation of deoxyuridylate to thymidylate, thereby playing a central role in DNA synthesis and repair. We investigated two TYMS functional variants (a 28-bp tandem repeat in the promoter enhancer region of the 5'-UTR; and TYMS 1494del6 (rs16430): a 6-bp deletion in the 3'-UTR) for their risk of cleft palate (CP) and of cleft lip with/without CP (CLP). We investigated effect measure modification between these variants and maternal folate intake for cleft risk.This case-control study included deliveries from July 1999 to June 2003 from select areas of California. Case groups included CLP or CP alone. Nonmalformed, liveborn controls were randomly selected. Maternal interviews provided information on vitamin use and dietary folate intake. DNA was derived from newborn bloodspots.Data were available for 304 CLP cases, 123 CP cases, and 581 controls. 1496del6 variants did not appear to influence risk of CP or CLP. Homozygosity for the 28-bp VNTR variant influenced CP risk (odds ratios, OR = 1.8, 95% confidence interval, 1.1-3.1), particularly among Hispanic infants, OR 2.1 (1.0-4.6). Effect measure modification was observed between the 28-bp VNTR and combined folate intake for CP with an OR of 10.0 (1.6-60.9).Although these findings are consistent with biological mechanisms, they were based on relatively small sample sizes and may represent false-positive discoveries. Replication is warranted in other populations.

    View details for DOI 10.1002/bdra.23114

    View details for Web of Science ID 000314982400004

    View details for PubMedID 23404871

  • Diacylglycerol Kinase K Variants Impact Hypospadias in a California Study Population JOURNAL OF UROLOGY Carmichael, S. L., Mohammed, N., Ma, C., Iovannisci, D., Choudhry, S., Baskin, L. S., Witte, J. S., Shaw, G. M., Lammer, E. J. 2013; 189 (1): 305-311

    Abstract

    A recent genome wide association study demonstrated the novel finding that variants in DGKK are associated with hypospadias. Our objectives were to determine whether this finding could be replicated in a more racially/ethnically diverse study population of California births and to provide a more comprehensive investigation of variants.We examined the association of 27 DGKK single nucleotide polymorphisms with hypospadias relative to population based nonmalformed controls born in selected California counties from 1990 to 2003. Analyses included a maximum of 928 controls and 665 cases (mild in 91, moderate in 336, severe in 221 and undetermined in 17). Results for mild and moderate cases were similar, so they were grouped together.For mild and moderate cases OR for 15 of the 27 single nucleotide polymorphisms had p values less than 0.05, with 2 less than 1 and the others ranging from 1.3 to 1.8. Among severe cases ORs tended to be closer to 1, and none of the p values were less than 0.05. Due to high linkage disequilibrium across the single nucleotide polymorphisms, haplotype analyses were conducted and 2 blocks were generated. These analyses identified a set of 8 variants associated with a threefold to fourfold increased risk relative to the most common haplotype, regardless of severity of the phenotype (OR 4.1, p <10(-4) for mild to moderate cases and 3.3, p = 0.001 for severe cases).This study confirms that DGKK variants are associated with hypospadias. Additional studies are needed to allow a more thorough investigation of DGKK variability and to delineate the mechanism by which DGKK contributes to urethral development.

    View details for DOI 10.1016/j.juro.2012.09.002

    View details for Web of Science ID 000312604800107

    View details for PubMedID 23177175

  • High Quality Genome-Wide Genotyping from Archived Dried Blood Spots without DNA Amplification. PLoS One St Julien KR, Jelliffe-Pawlowski LL, Shaw GM, Stevenson DK, O'Brodovich HM, Krasnow MA, Stanford BPD Study Group (Gould JB, Oehlert JW, Quaintance C, Wang H, Lazzeroni L, Hoffman T, Witte J, Lorey F) 2013; 8 (5): e4710

    View details for PubMedID 23737996

  • Diabetes and Obesity-Related Genes and the Risk of Neural Tube Defects in the National Birth Defects Prevention Study AMERICAN JOURNAL OF EPIDEMIOLOGY Lupo, P. J., Canfield, M. A., Chapa, C., Lu, W., Agopian, A. J., Mitchell, L. E., Shaw, G. M., Waller, D. K., Olshan, A. F., Finnell, R. H., Zhu, H. 2012; 176 (12): 1101-1109

    Abstract

    Few studies have evaluated genetic susceptibility related to diabetes and obesity as a risk factor for neural tube defects (NTDs). The authors investigated 23 single nucleotide polymorphisms among 9 genes (ADRB3, ENPP1, FTO, LEP, PPARG, PPARGC1A, SLC2A2, TCF7L2, and UCP2) associated with type 2 diabetes or obesity. Samples were obtained from 737 NTD case-parent triads included in the National Birth Defects Prevention Study during 1999-2007. Log-linear models were used to evaluate maternal and offspring genetic effects. After application of the false discovery rate, there were 5 significant maternal genetic effects. The less common alleles at the 4 FTO single nucleotide polymorphisms showed a reduction of NTD risk (for rs1421085, relative risk (RR) = 0.73 (95% confidence interval (CI): 0.62, 0.87); for rs8050136, RR = 0.79 (95% CI: 0.67, 0.93); for rs9939609, RR = 0.79 (95% CI: 0.67, 0.94); and for rs17187449, RR = 0.80 (95% CI: 0.68, 0.95)). Additionally, maternal LEP rs2071045 (RR = 1.31, 95% CI: 1.08, 1.60) and offspring UCP2 rs660339 (RR = 1.32, 95% CI: 1.06, 1.64) were associated with NTD risk. Furthermore, the maternal genotype for TCF7L2 rs3814573 suggested an increased NTD risk among obese women. These findings indicate that maternal genetic variants associated with glucose homeostasis may modify the risk of having an NTD-affected pregnancy.

    View details for DOI 10.1093/aje/kws190

    View details for Web of Science ID 000312634900006

    View details for PubMedID 23132673

  • Dietary Glycemic Index and the Risk of Birth Defects AMERICAN JOURNAL OF EPIDEMIOLOGY Parker, S. E., Werler, M. M., Shaw, G. M., Anderka, M., Yazdy, M. M. 2012; 176 (12): 1110-1120

    Abstract

    Prepregnancy diabetes and obesity have been identified as independent risk factors for several birth defects, providing support for a mechanism that involves hyperglycemia and hyperinsulinemia in the development of malformations. Data from the National Birth Defects Prevention Study from 1997 to 2007 were used to investigate the association between the maternal dietary glycemic index (DGI) and the risk of birth defects among nondiabetic women. DGI was categorized by using spline regression models and quartile distributions. Adjusted odds ratios and 95% confidence intervals were calculated. The joint effect of DGI and obesity was also examined. Among the 53 birth defects analyzed, high DGI, categorized by spline regression, was significantly associated with encephalocele (adjusted odds ratio (aOR) = 2.68), diaphragmatic hernia (aOR = 2.58), small intestinal atresia/stenosis (aOR = 2.97) including duodenal atresia/stenosis (aOR = 2.48), and atrial septal defect (aOR = 1.37). Using quartiles to categorize DGI, the authors identified associations with cleft lip with cleft palate (aOR = 1.23) and anorectal atresia/stenosis (aOR = 1.40). The joint effect of high DGI and obesity provided evidence of a synergistic effect on the risk of selected birth defects. High DGI is associated with an increased risk of a number of birth defects under study. Obesity coupled with high DGI appears to increase the risk further for some birth defects.

    View details for DOI 10.1093/aje/kws201

    View details for Web of Science ID 000312634900007

    View details for PubMedID 23171874

  • Improved Survival Among Children with Spina Bifida in the United States JOURNAL OF PEDIATRICS Shin, M., Kucik, J. E., Siffel, C., Lu, C., Shaw, G. M., Canfield, M. A., Correa, A. 2012; 161 (6): 1132-U205

    Abstract

    To evaluate trends in survival among children with spina bifida by race/ethnicity and possible prognostic factors in 10 regions of the United States.A retrospective cohort study was conducted of 5165 infants with spina bifida born during 1979-2003, identified by 10 birth defects registries in the United States. Survival probabilities and adjusted hazard ratios were estimated for race/ethnicity and other characteristics using the Cox proportional hazard model.During the study period, the 1-year survival probability among infants with spina bifida showed improvements for whites (from 88% to 96%), blacks (from 79% to 88%), and Hispanics (from 88% to 93%). The impact of race/ethnicity on survival varied by birth weight, which was the strongest predictor of survival through age 8. There was little racial/ethnic variation in survival among children born of very low birth weight. Among children born of low birth weight, the increased risk of mortality to Hispanics was approximately 4-6 times that of whites. The black-white disparity was greatest among children born of normal birth weight. Congenital heart defects did not affect the risk of mortality among very low birth weight children but increased the risk of mortality 4-fold among children born of normal birth weight.The survival of infants born with spina bifida has improved; however, improvements in survival varied by race/ethnicity, and blacks and Hispanics continued to have poorer survival than whites in the most recent birth cohort from 1998-2002. Further studies are warranted to elucidate possible reasons for the observed differences in survival.

    View details for DOI 10.1016/j.jpeds.2012.05.040

    View details for Web of Science ID 000311348400032

    View details for PubMedID 22727874

  • Expected Body Weight in Adolescents: Comparison Between Weight-for-Stature and BMI Methods PEDIATRICS Golden, N. H., Yang, W., Jacobson, M. S., Robinson, T. N., Shaw, G. M. 2012; 130 (6): E1607-E1613

    Abstract

    To test the hypothesis that the weight-for-stature (WFS) and BMI methods are not equivalent in determining expected body weight (EBW) in adolescents with eating disorders and to determine the sensitivity, specificity, and positive predictive value of each method to detect those <75% EBW. We hypothesized that differences in EBW would be greatest at the extremes of height.EBW was determined for 12 047 individual adolescents aged 12 to 19 years by the WFS and BMI methods by utilizing the same National Center for Health Statistics data sets. Absolute difference between the 2 methods for each individual was calculated and plotted against height by using a generalized additive model. The number of individuals whose weights were <75% EBW was determined by each method.For girls, EBW was 3.52 3.13% higher when using the WFS method compared with the BMI method. For boys, EBW(WFS) was 3.45 2.72% higher than EBW(BMI). Among adolescent girls, 65% had EBW(WFS) higher than EBW(BMI). By using the EBW(WFS) method as the gold standard, specificity of the EBW(BMI) method to detect those <75% EBW was 0.999, but sensitivity was only 0.329. Absolute differences in EBW were most pronounced at the extremes of height.The WFS and BMI methods are not equivalent in determining EBW in adolescents and are not interchangeable. EBW(WFS) was ~3.5% higher than EBW(BMI). In adolescents with eating disorders, use of the BMI method will underestimate the degree of malnutrition compared with the WFS method. Which method better predicts meaningful clinical outcomes remains to be determined.

    View details for DOI 10.1542/peds.2012-0897

    View details for Web of Science ID 000314802000024

    View details for PubMedID 23147977

  • Association of microtia with maternal nutrition BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Ma, C., Shaw, G. M., Scheuerle, A. E., Canfield, M. A., Carmichael, S. L. 2012; 94 (12): 1026-1032

    Abstract

    Few studies have investigated the potential association of maternal dietary intake and risk of microtia among offspring.The study included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Nonsyndromic cases of microtia were compared to nonmalformed, population-based, live-born control infants by estimating adjusted odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models that included maternal race or ethnicity, education, folic acid-containing supplement intake, fertility treatment, study site, and total energy intake.Comparing intake in the lowest 10th percentile versus the 10th to 90th percentiles, lower maternal intakes of carbohydrate (OR, 1.59; 95% CI, 1.07-2.38) and dietary folate (OR, 1.57; 95% CI, 1.09-2.25) were associated with elevated risk of microtia. In addition, results suggested that higher diet quality (as measured by the Diet Quality Index, and comparing the highest with the lowest quartile) was protective, but the CI did not exclude one (OR, 0.73; 95% CI, 0.50-1.07). Results were similar among obese and nonobese women.These data contribute to the limited body of evidence regarding the potential contribution of maternal nutrition to the etiology of microtia.

    View details for DOI 10.1002/bdra.23053

    View details for Web of Science ID 000312527100010

    View details for PubMedID 22821770

  • Association between weight gain during pregnancy and neural tube defects and gastroschisis in offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Yang, W., Carmichael, S. L., Tinker, S. C., Shaw, G. M. 2012; 94 (12): 1019-1025

    Abstract

    Limited information is available about the association of maternal weight gain during pregnancy and birth defects. The objective of this study was to investigate the association of maternal weight gain with neural tube defects (NTDs) and gastroschisis among offspring.We used data from the National Birth Defects Prevention Study, an ongoing multicenter, population-based, case-control study. Mothers of cases and controls were interviewed by telephone. Analyses included 255 anencephaly, 577 spina bifida, 648 gastroschisis cases, and 5587 controls with deliveries from 1999 to 2005. After subtracting birth weight, the associations of total and average weekly weight gain (kg) with each phenotype were estimated, stratified by gestational age (<37 vs. ?37 weeks) and adjusted for relevant covariates.Among deliveries <37 weeks gestation, mothers of infants with anencephaly and spina bifida had lower weight gains compared to control mothers; no association between weight gains and gastroschisis was observed. Among deliveries ?37 weeks, mothers of infants with anencephaly had lower weight gains during pregnancy; a similar association was not observed for spina bifida; mothers of infants with gastroschisis were twice as likely to have weight gains in the highest quartile. Stratification by maternal age (gastroschisis) or body mass index (BMI) or race/ethnicity (all phenotypes) did not alter odds ratio estimates.Altered weight gain during pregnancy may be a consequence of carrying an NTD/gastroschisis affected fetus or a marker for underlying factors common to the etiology of these birth defects. It is possible that whatever mechanisms influence weight gain may also influence the development of NTDs and gastroschisis, but in opposite directions.

    View details for DOI 10.1002/bdra.23057

    View details for Web of Science ID 000312527100009

    View details for PubMedID 22847944

  • Neural tube defects and maternal intake of micronutrients related to one-carbon metabolism or antioxidant activity BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Chandler, A. L., Hobbs, C. A., Mosley, B. S., Berry, R. J., Canfield, M. A., Qi, Y. P., Siega-Riz, A. M., Shaw, G. M. 2012; 94 (11): 864-874

    Abstract

    Maternal nutritional status has been evaluated to clarify its role in development of neural tube defects (NTDs). Maternal folate intake during pregnancy has been closely evaluated for its association with NTDs. The study objective was to examine associations between NTDs and other dietary periconceptional micronutrient intake, particularly nutrients involved in one-carbon metabolism or antioxidant activity.Using data from the National Birth Defects Prevention Study, 1997-2005, logistic regression models were used to estimate the relative risk of NTDs based on maternal micronutrient intake.Results were stratified according to folic acid supplement use, race/ethnicity, and maternal body mass index. Analyses included 954 cases (300 with anencephaly, 654 with spina bifida) and 6268 controls. Higher intakes of folate, thiamin, betaine, iron, and vitamin A were associated with decreased risk of anencephaly among some ethnic and clinical groups. In some groups, higher intakes of thiamin, riboflavin, vitamin B(6) , vitamin C, vitamin E, niacin, and retinol were associated with decreased risk of spina bifida.In addition to folic acid, other micronutrients, including thiamin, betaine, riboflavin, vitamin B(6) , vitamin C, vitamin E, niacin, iron, retinol, and vitamin A, may decrease the risk of NTD occurrence. Birth Defects Research (Part A) 2012. 2012 Wiley Periodicals, Inc.

    View details for DOI 10.1002/bdra.23068

    View details for Web of Science ID 000311234400002

    View details for PubMedID 22933447

  • A GCH1 haplotype and risk of neural tube defects in the National Birth Defects Prevention Study MOLECULAR GENETICS AND METABOLISM Lupo, P. J., Chapa, C., Nousome, D., Duhon, C., Canfield, M. A., Shaw, G. M., Finnell, R. H., Zhu, H. 2012; 107 (3): 592-595

    Abstract

    Tetrahydrobiopterin (BH(4)) is an essential cofactor and an important cellular antioxidant. BH(4) deficiency has been associated with diseases whose etiologies stem from excessive oxidative stress. GTP cyclohydrolase I (GCH1) catalyzes the first and rate-limiting step of de novo BH(4) synthesis. A 3-SNP haplotype in GCH1 (rs8007267, rs3783641, and rs10483639) is known to modulate GCH1 gene expression levels and has been suggested as a major determinant of plasma BH(4) bioavailability. As plasma BH(4) bioavailability has been suggested as a mechanism of neural tube defect (NTD) teratogenesis, we evaluated the association between this GCH1 haplotype and the risk of NTDs. Samples were obtained from 760 NTD case-parent triads included in the National Birth Defects Prevention Study (NBDPS). The three SNPs were genotyped using TaqMan SNP assays. An extension of the log-linear model was used to assess the association between NTDs and both offspring and maternal haplotypes. Offspring carrying two copies of haplotype C-T-C had a significantly increased NTD risk (risk ratio [RR]=3.40, 95% confidence interval [CI]: 1.02-11.50), after adjusting for the effect of the maternal haplotype. Additionally, mothers carrying two copies of haplotype C-T-C had a significantly increased risk of having an NTD-affected offspring (RR=3.46, 95% CI: 1.05-11.00), after adjusting for the effect of the offspring haplotype. These results suggest offspring and maternal variation in the GCH1 gene and altered BH(4) biosynthesis may contribute to NTD risk.

    View details for DOI 10.1016/j.ymgme.2012.09.020

    View details for Web of Science ID 000310720200050

    View details for PubMedID 23059057

  • Maternal occupational exposure to polycyclic aromatic hydrocarbons and congenital heart defects among offspring in the national birth defects prevention study BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Lupo, P. J., Symanski, E., Langlois, P. H., Lawson, C. C., Malik, S., Gilboa, S. M., Lee, L. J., Agopian, A. J., Desrosiers, T. A., Waters, M. A., Romitti, P. A., Correa, A., Shaw, G. M., Mitchell, L. E. 2012; 94 (11): 875-881

    Abstract

    There is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) results in congenital heart defects (CHDs); however, to our knowledge, this relationship has not been examined in humans. Therefore, we conducted a case-control study assessing the association between estimated maternal occupational exposure to PAHs and CHDs in offspring.Data on CHD cases and control infants were obtained from the National Birth Defects Prevention Study for the period of 1997 to 2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to evaluate the association between maternal occupational PAH exposure and specific CHD phenotypic subtypes among offspring.The prevalence of occupational PAH exposure was 4.0% in CHD case mothers (76/1907) and 3.6% in control mothers (104/2853). After adjusting for maternal age, race or ethnicity, education, smoking, folic acid supplementation, and study center, exposure was not associated with conotruncal defects (adjusted odds ratio [AOR], 0.98; 95% confidence interval [CI], 0.58-1.67), septal defects (AOR, 1.28; 95% CI, 0.86-1.90), or with any isolated CHD subtype.Our findings do not support an association between potential maternal occupational exposure to PAHs and various CHDs in a large, population-based study. For CHD phenotypic subtypes in which modest nonsignificant associations were observed, future investigations could be improved by studying populations with a higher prevalence of PAH exposure and by incorporating information on maternal and fetal genotypes related to PAH metabolism. Birth Defects Research (Part A), 2012.

    View details for DOI 10.1002/bdra.23071

    View details for Web of Science ID 000311234400003

    View details for PubMedID 22945317

  • Analysis of Selected Maternal Exposures and Non-Syndromic Atrioventricular Septal Defects in the National Birth Defects Prevention Study, 1997-2005 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Patel, S. S., Burns, T. L., Botto, L. D., Riehle-Colarusso, T. J., Lin, A. E., Shaw, G. M., The, P. A. 2012; 158A (10): 2447-2455

    Abstract

    Although the descriptive epidemiology of atrioventricular septal defects (AVSDs), a group of serious congenital heart defects (CHDs), has been recently reported, non-genetic risk factors have not been consistently identified. Using data (1997-2005) from the National Birth Defects Prevention Study, an ongoing multisite population-based case-control study, the association between selected non-genetic factors and non-syndromic AVSDs was examined. Data on periconceptional exposures to such factors were collected by telephone interview from 187 mothers of AVSD case infants and 6,703 mothers of unaffected infants. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated from logistic regression models. Mothers who reported cigarette smoking during the periconceptional period were more likely to have infants with AVSDs compared with non-smokers, independent of maternal age, periconceptional alcohol consumption, infant gestational age, family history of CHDs, and study site (aOR 1.5, 95% CI 1.1-2.4). The association was strongest in mothers who smoked more than 25 cigarettes/day. In addition, mothers with periconceptional passive smoke exposure were more likely to have infants with AVSDs than unexposed mothers, independent of maternal age, active periconceptional smoking, infant gestational age, and family history of CHDs (aOR 1.4, 95% CI 1.0-2.0). No associations were observed between AVSDs and maternal history of a urinary tract infection or pelvic inflammatory disease, maternal use of a wide variety of medications, maternal occupational exposure, parental drug use, or maternal alcohol consumption. If the results of this preliminary study can be replicated, minimizing maternal active and passive smoke exposure may decrease the incidence of AVSDs.

    View details for DOI 10.1002/ajmg.a.35555

    View details for Web of Science ID 000310070700012

  • Transcriptional analyses of two mouse models of spina bifida BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Cabrera, R. M., Finnell, R. H., Zhu, H., Shaw, G. M., Wlodarczyk, B. J. 2012; 94 (10): 782-789

    Abstract

    Spina bifida is one of the most common of all human structural birth defects. Despite considerable effort over several decades, the causes and mechanisms underlying this malformation remain poorly characterized.To better understand the pathogenesis of this abnormality, we conducted a microarray study using Mouse Whole Genome Bioarrays which have ~36,000 gene targets, to compare gene expression profiles between two mouse models; CXL-Splotch and FKBP8(Gt(neo)) which express a similar spina bifida phenotype. We anticipated that there would be a collection of overlapping genes or shared genetic pathways at the molecular level indicative of a common mechanism underlying the pathogenesis of spina bifida during embryonic development.A total of 54 genes were determined to be differentially expressed (25 downregulated, 29 upregulated) in the FKBP8Gt((neo)) mouse embryos; whereas 73 genes were differentially expressed (56 downregulated, 17 upregulated) in the CXL-Splotch mouse relative to their wild-type controls. Remarkably, the only two genes that showed decreased expression in both mutants were v-ski sarcoma viral oncogene homolog (Ski), and Zic1, a transcription factor member of the zinc finger family. Confirmation analysis using quantitative real-time (qRT)-PCR indicated that only Zic1 was significantly decreased in both mutants. Gene ontology analysis revealed striking enrichment of genes associated with mesoderm and central nervous system development in the CXL-Splotch mutant embryos, whereas in the FKBP8(Gt(neo)) mutants, the genes involved in dorsal/ventral pattern formation, cell fate specification, and positive regulation of cell differentiation were most likely to be enriched. These results indicate that there are multiple pathways and gene networks perturbed in mouse embryos with shared phenotypes.

    View details for DOI 10.1002/bdra.23081

    View details for Web of Science ID 000310068400006

    View details for PubMedID 23024056

  • Maternal and Infant Gene-Folate Interactions and the Risk of Neural Tube Defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Etheredge, A. J., Finnell, R. H., Carmichael, S. L., Lammer, E. J., Zhu, H., Mitchell, L. E., Shaw, G. M. 2012; 158A (10): 2439-2446

    Abstract

    Neural tube defects (NTDs) are common, serious malformations with a complex etiology that suggests involvement of both genetic and environmental factors. The authors evaluated maternal or offspring folate-related gene variants and interactions between the gene variants and maternal intake of folates on the risk of NTDs in their offspring. A case-control study was conducted on mothers and/or their fetuses and infants who were born in California from 1999 to 2003 with an NTD (cases n = 222, including 24 mother-infant pairs) or without a major malformation (controls n = 454, including 186 mother-infant pairs). Maternal intake of folates was assessed by food frequency questionnaire and genotyping was performed on samples from mothers and infants. For mothers in the lowest folate-intake group, risk of NTDs in offspring was significantly decreased for maternal MTHFR SNPs rs1476413, rs1801131, and rs1801133 (odds ratio [OR] = 0.55, 80% confidence interval [CI]: 0.20, 1.48; OR = 0.58, 80% CI: 0.24, 1.43; OR = 0.69, 80% CI: 0.41, 1.17, respectively), and TYMS SNPs rs502396 and rs699517 (OR = 0.91, 80% CI: 0.53, 1.56; OR = 0.70, 80% CI: 0.38, 1.29). A gene-only effect was observed for maternal SHMT1 SNP rs669340 (OR?=?0.69, 95% CI: 0.49, 0.96). When there was low maternal folate intake, risk of NTDs was significantly increased for infant MTHFD1 SNPs rs2236224, rs2236225, and rs11627387 (OR = 1.58, 80% CI: 0.99, 2.51; OR = 1.53, 80% CI: 0.95, 2.47; OR = 4.25, 80% CI: 2.33, 7.75, respectively) and SHMT1 SNP rs12939757 (OR = 2.01, 80% CI: 1.20, 3.37), but decreased for TYMS SNP rs2847153 (OR = 0.73, 80% CI: 0.37, 1.45). Although power to detect interaction effects was low for this birth defects association study, the gene-folate interactions observed in this study represent preliminary findings that will be useful for informing future studies on the complex etiology of NTDs.

    View details for DOI 10.1002/ajmg.a.35552

    View details for Web of Science ID 000310070700011

    View details for PubMedID 22903727

  • Maternal occupational exposure to polycyclic aromatic hydrocarbons and risk of neural tube defect-affected pregnancies BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Langlois, P. H., Hoyt, A. T., Lupo, P. J., Lawson, C. C., Waters, M. A., Desrosiers, T. A., Shaw, G. M., Romitti, P. A., Lammer, E. J. 2012; 94 (9): 693-700

    Abstract

    This study evaluated whether there is an association between maternal occupational exposure to polycyclic aromatic hydrocarbons (PAHs) and neural tube defects (NTDs) in offspring. This is the first such study of which the authors are aware.Data were analyzed from 1997 to 2002 deliveries in the National Birth Defects Prevention Study, a large population-based case-control study in the United States. Maternal interviews yielded information on jobs held in the month before through 3 months after conception. Three industrial hygienists blinded to case or control status assessed occupational exposure to PAHs. Crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using unconditional logistic regression.Of the 520 mothers of children with NTDs, 5.0% were classified as exposed to occupational PAHs, as were 3.5% of the 2989 mothers of controls. The crude OR for PAH exposure was 1.43 (95% CI, 0.92-2.22) for any NTD and 1.71 (95% CI, 1.03-2.83) for spina bifida. Adjusted ORs were smaller in magnitude and not significant. Among women who were normal weight or underweight, the crude OR for spina bifida was 3.13 (95% CI, 1.63-6.03) and adjusted OR was 2.59 (95% CI, 1.32-5.07). Based on estimated cumulative exposure, a statistically significant dose-response trend was observed for spina bifida; however, it was attenuated and no longer significant after adjustment.Maternal occupational exposure to PAHs may be associated with increased risk of spina bifida in offspring among women who are normal weight or underweight. Other comparisons between PAHs and NTDs were consistent with no association.

    View details for DOI 10.1002/bdra.23045

    View details for Web of Science ID 000308473800003

    View details for PubMedID 22807044

  • Thymidylate Synthase Polymorphisms and Risk of Conotruncal Heart Defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Zhu, H., Yang, W., Shaw, N., Perloff, S., Carmichael, S. L., Finnell, R. H., Shaw, G. M., Lammer, E. J. 2012; 158A (9): 2194-2203

    Abstract

    In this study, we investigated whether the two TYMS functional variants (28?bp VNTR and 1494del6) (275 cases and 653 controls) and six selected SNPs (265 case infants, 535 control infants; 169 case mothers and 276 control mothers) were associated with risks of conotruncal heart defects. Further, we evaluated interaction effects between these gene variants and maternal folate intake for risk of CTD. Cases with diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. DNA samples were collected using buccal brushes or drawn from the repository of newborn screening blood specimens when available. Genetic variants were treated as categorical variables (homozygous referent, heterozygote, homozygous variant). Odds ratios and 95% confidence intervals (CI) were computed to estimate risks among all subjects, Hispanic and non-Hispanic whites, respectively, using logistic regression. Gene-folate interactions were assessed for these variants by adding an interaction term to the logistic model. A dichotomized composite variable, "combined folate intake," was created by combining maternal peri-conceptional use of folic acid-containing vitamin supplements with daily dietary intake of folate. In general, the results do not show strong gene-only effects on risk of CTD. We did, however, observe a 3.6-fold increase in CTD risk (95% CI: 1.1-11.9) among infants who were homozygotes for the 6?bp deletion in the 3'-untranslated region (UTR) (1694del6) and whose mothers had low folate intake during the peri-conceptional period.

    View details for DOI 10.1002/ajmg.a.35310

    View details for Web of Science ID 000310068700015

    View details for PubMedID 22887475

  • Environmental and genetic contributors to hypospadias: A review of the epidemiologic evidence BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Shaw, G. M., Lammer, E. J. 2012; 94 (7): 499-510

    Abstract

    This review evaluates current knowledge related to trends in the prevalence of hypospadias, the association of hypospadias with endocrine-disrupting exposures, and the potential contribution of genetic susceptibility to its etiology. The review focuses on epidemiologic evidence. Increasing prevalence of hypospadias has been observed, but such increases tend to be localized to specific regions or time periods. Thus, generalized statements that hypospadias is increasing are unsupported. Owing to the limitations of study designs and inconsistent results, firm conclusions cannot be made regarding the association of endocrine-disrupting exposures with hypospadias. Studies with more rigorous study designs (e.g., larger and more detailed phenotypes) and exposure assessment that encompasses more breadth and depth (e.g., specific endocrine-related chemicals) will be critical to make better inferences about these important environmental exposures. Many candidate genes for hypospadias have been identified, but few of them have been examined to an extent that enables solid conclusions. Further study is needed that includes larger sample sizes, comparison groups that are more representative of the populations from which the cases were derived, phenotype-specific analyses, and more extensive exploration of variants. In conclusion, examining the associations of environmental and genetic factors with hypospadias remain important areas of inquiry, although our actual understanding of their contribution to hypospadias risk in humans is currently limited.

    View details for DOI 10.1002/bdra.23021

    View details for Web of Science ID 000306186100001

    View details for PubMedID 22678668

  • Nutritional Factors and Hypospadias Risks PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Carmichael, S. L., Ma, C., Feldkamp, M. L., Munger, R. G., Olney, R. S., Botto, L. D., Shaw, G. M., Correa, A. 2012; 26 (4): 353-360

    Abstract

    We examined whether hypospadias was associated with several aspects of the diet, including intake of animal products, intake of several nutrients and food groups related to a vegetarian diet and oestrogen metabolism, and diet quality.The study included deliveries from 1997 to 2005 that were part of the National Birth Defects Prevention Study. Diet was assessed by food frequency questionnaire during maternal telephone interviews, and two diet quality indices were developed based on existing indices. Analyses included 1250 cases with second- or third-degree hypospadias (urethra opened at the penile shaft, scrotum or perineum) and 3118 male, liveborn, non-malformed controls. All odds ratios (OR) and 95% confidence intervals [CI] were estimated from logistic regression models that included several potential confounders, including energy intake.Intake of animal products was not associated with hypospadias; for example, the adjusted OR for any vs. no intake of meat was 1.0 [95% CI 0.6, 1.6]. Frequency of intake of meat or other animal products was also not associated with hypospadias, nor was intake of iron or several nutrients that are potentially related to oestrogen metabolism. Diet quality was also not associated with hypospadias; the OR for diet quality in the highest vs. lowest quartile for the two diet quality indices were 1.0 [95% CI 0.6, 1.6] and 0.9 [95% CI 0.7, 1.1].This large study does not support an association of a vegetarian diet or worse diet quality with hypospadias.

    View details for DOI 10.1111/j.1365-3016.2012.01272.x

    View details for Web of Science ID 000305121500013

    View details for PubMedID 22686387

  • Cancer in Children with Nonchromosomal Birth Defects JOURNAL OF PEDIATRICS Fisher, P. G., Reynolds, P., Von Behren, J., Carmichael, S. L., Rasmussen, S. A., Shaw, G. M. 2012; 160 (6): 978-983

    Abstract

    To examine whether the incidence of childhood cancer is elevated in children with birth defects but no chromosomal anomalies.We examined cancer risk in a population-based cohort of children with and without major birth defects born between 1988 and 2004, by linking data from the California Birth Defects Monitoring Program, the California Cancer Registry, and birth certificates. Cox proportional hazards models generated hazard ratios (HRs) and 95% CIs based on person-years at risk. We compared the risk of childhood cancer in infants born with and without specific types of birth defects, excluding infants with chromosomal anomalies.Of the 4869 children in the birth cohort with cancer, 222 had a major birth defect. Although the expected elevation in cancer risk was observed in children with chromosomal birth defects (HR, 12.44; 95% CI, 10.10-15.32), especially for the leukemias (HR, 28.99; 95% CI, 23.07-36.42), children with nonchromosomal birth defects also had an increased risk of cancer (HR, 1.58; 95% CI, 1.33-1.87), but instead for brain tumors, lymphomas, neuroblastoma, and germ cell tumors.Children with nonchromosomal birth defects are at increased risk for solid tumors, but not leukemias. Dysregulation of early human development likely plays an important role in the etiology of childhood cancer.

    View details for DOI 10.1016/j.jpeds.2011.12.006

    View details for Web of Science ID 000304377300019

    View details for PubMedID 22244463

  • Maternal Occupational Exposure to Polycyclic Aromatic Hydrocarbons: Effects on Gastroschisis among Offspring in the National Birth Defects Prevention Study ENVIRONMENTAL HEALTH PERSPECTIVES Lupo, P. J., Langlois, P. H., Reefhuis, J., Lawson, C. C., Symanski, E., Desrosiers, T. A., Khodr, Z. G., Agopian, A. J., Waters, M. A., Duwe, K. N., Finnell, R. H., Mitchell, L. E., Moore, C. A., Romitti, P. A., Shaw, G. M. 2012; 120 (6): 910-915

    Abstract

    Exposure to polycyclic aromatic hydrocarbons (PAHs) occurs in many occupational settings. There is evidence in animal models that maternal exposure to PAHs during pregnancy is associated with gastroschisis in offspring; however, to our knowledge, no human studies examining this association have been conducted.Our goal was to conduct a case-control study assessing the association between estimated maternal occupational exposure to PAHs and gastroschisis in offspring.Data from gastroschisis cases and control infants were obtained from the population-based National Birth Defects Prevention Study for the period 1997-2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to determine the association between estimated occupational PAH exposure and gastroschisis among children whose mothers were employed for at least 1 month during the month before conception through the third month of pregnancy.The prevalence of estimated occupational PAH exposure was 9.0% in case mothers (27 of 299) and 3.6% in control mothers (107 of 2,993). Logistic regression analyses indicated a significant association between occupational PAHs and gastroschisis among mothers ? 20 years of age [odds ratio (OR) = 2.53; 95% confidence interval (CI): 1.27, 5.04] after adjusting for maternal body mass index, education, gestational diabetes, and smoking. This association was not seen in mothers < 20 years (OR = 1.14; 95% CI: 0.55, 2.33), which is notable because although young maternal age is the strongest known risk factor for gastroschisis, most cases are born to mothers ? 20 years.Our findings indicate an association between occupational exposure to PAHs among mothers who are ? 20 years and gastroschisis. These results contribute to a body of evidence that PAHs may be teratogenic.

    View details for DOI 10.1289/ehp.1104305

    View details for Web of Science ID 000304765700034

    View details for PubMedID 22330681

  • Gene variants in the folate-mediated one-carbon metabolism (FOCM) pathway as risk factors for conotruncal heart defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Zhu, H., Yang, W., Lu, W., Etheredge, A. J., Lammer, E. J., Finnell, R. H., Carmichael, S. L., Shaw, G. M. 2012; 158A (5): 1124-1134

    Abstract

    We evaluated 35 variants among four folate-mediated one-carbon metabolism pathway genes, MTHFD1, SHMT1, MTHFR, and DHFR as risk factors for conotruncal heart defects. Cases with a diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. Odds ratios (OR) and the 95% confidence intervals (CI) were computed for each genotype (homozygous variant or heterozygote, vs. homozygous wildtype) and for increase of each less common allele (log-additive model). Interactions between each variant and three folate intake variables (maternal multivitamin use, maternal dietary folate intake, and combined maternal folate intake) were also evaluated under the log-additive model. In general, we did not identify notable associations. The A allele of MTHFD1 rs11627387 was associated with a 1.7-fold increase in conotruncal defects risk in both Hispanic mothers (OR = 1.7, 95% CI = 1.1-2.5) and Hispanic infants (OR = 1.7, 95% CI = 1.2-2.3). The T allele of MTHFR rs1801133 was associated with a 2.8-fold increase of risk among Hispanic women whose dietary folate intake was ? 25th centile. The C allele of MTHFR rs1801131 was associated with a two-fold increase of risk (OR = 2.0, 95% CI = 1.0-3.9) only among those whose dietary folate intake was >25th centile. Our study suggested that MTHFD1 rs11627387 may be associated with risk of conotruncal defects through both maternal and offspring genotype effect among the Hispanics. Maternal functional variants in MTHFR gene may interact with dietary folate intake and modify the conotruncal defects risk in the offspring.

    View details for DOI 10.1002/ajmg.a.35313

    View details for Web of Science ID 000303000200022

    View details for PubMedID 22495907

  • Risk of bronchopulmonary dysplasia by second-trimester maternal serum levels of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol PEDIATRIC RESEARCH Jelliffe-Pawlowski, L. L., Shaw, G. M., Stevenson, D. K., Oehlert, J. W., Quaintance, C., Santos, A. J., Baer, R. J., Currier, R. J., O'Brodovich, H. M., Gould, J. B. 2012; 71 (4): 399-406

    Abstract

    Although maternal serum ?-fetoprotein (AFP), human chorionic gonandotropin (hCG), and estriol play important roles in immunomodulation and immunoregulation during pregnancy, their relationship with the development of bronchopulmonary dysplasia (BPD) in young infants is unknown despite BPD being associated with pre- and postnatal inflammatory factors.We found that these serum biomarkers were associated with an increased risk of BPD. Risks were especially high when AFP and/or hCG levels were above the 95th percentile and/or when unconjugated estriol (uE3) levels were below the 5th percentile (relative risks (RRs) 3.1-6.7). Risks increased substantially when two or more biomarker risks were present (RRs 9.9-75.9).Data suggested that pregnancies that had a biomarker risk and yielded an offspring with BPD were more likely to have other factors present that suggested early intrauterine fetal adaptation to stress, including maternal hypertension and asymmetric growth restriction.The objective of this population-based study was to examine whether second-trimester levels of AFP, hCG, and uE3 were associated with an increased risk of BPD.

    View details for DOI 10.1038/pr.2011.73

    View details for Web of Science ID 000301884500013

    View details for PubMedID 22391642

  • Reduced Risks of Neural Tube Defects and Orofacial Clefts With Higher Diet Quality ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Carmichael, S. L., Yang, W., Feldkamp, M. L., Munger, R. G., Siega-Riz, A. M., Botto, L. D., Shaw, G. 2012; 166 (2): 121-126

    Abstract

    To examine whether better maternal diet quality was associated with reduced risk for selected birth defects.A multicenter, population-based case-control study, the National Birth Defects Prevention Study.Ten participating centers in the United States.Eligible subjects' estimated due dates were from October 1997 through December 2005. Telephone interviews were conducted with 72% of case and 67% of control mothers. Analyses included 936 cases with neural tube defects (NTDs), 2475 with orofacial clefts, and 6147 nonmalformed controls.Food-frequency data were used to calculate the Mediterranean Diet Score (MDS) and Diet Quality Index (DQI), modeled after existing indices.Adjusted odds ratios (ORs).After covariate adjustment, increasing diet quality based on either index was associated with reduced risks for the birth defects studied. The strongest association was between anencephaly and DQI; the OR for highest vs lowest quartile was 0.49 (95% CI, 0.31-0.75). The ORs for cleft lip with or without cleft palate and cleft palate and DQI were also notable (0.66 [95% CI, 0.54-0.81] and 0.74 [95%CI, 0.56-0.96], respectively).Healthier maternal dietary patterns, as measured by diet quality scores, were associated with reduced risks of NTDs and clefts. These results suggest that dietary approaches could lead to further reduction in risks of major birth defects and complement existing efforts to fortify foods and encourage periconceptional multivitamin use.

    View details for DOI 10.1001/archpediatrics.2011.185

    View details for Web of Science ID 000301211000002

    View details for PubMedID 21969361

  • Paternal Age and Congenital Malformations in Offspring in California, 1989-2002 MATERNAL AND CHILD HEALTH JOURNAL Grewal, J., Carmichael, S. L., Yang, W., Shaw, G. M. 2012; 16 (2): 385-392

    Abstract

    This study examined the association between paternal age and a wide range of structural birth defects. Data were drawn from The California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with defects born between 1989 and 2002. The analysis included 46,114 cases with defects, plus a random sample of 36,838 non-malformed births. After adjustment for maternal age, risks of anomalies of the nervous system for 38 and 42 year-old fathers, as compared to 29 year-old fathers, were 1.05-fold [1.00, 1.11] and 1.10-fold [1.02, 1.18] higher, respectively. Similar results were observed for anomalies of the limbs, where 38 and 42 year-old fathers had a 1.06-fold [1.02, 1.11] and 1.11-fold [1.05, 1.18] higher risk, respectively. Risks of anomalies of the integument were 1.05-fold [1.00, 1.09] and 1.10-fold [1.03, 1.16] higher for 38 and 42 year olds, respectively. Young paternal age, i.e., less than 29 years, was associated with an increased risk of amniotic bands (OR: 0.87 [0.78, 0.97]), pyloric stenosis (OR: 0.93 [0.90, 0.96]) and anomalies of the great veins (OR: 0.93 [0.87, 1.00]). In sum, both advanced and young paternal age was associated with select birth defects in California between 1989 and 2002.

    View details for DOI 10.1007/s10995-011-0759-z

    View details for Web of Science ID 000299370400013

    View details for PubMedID 21344170

  • Spina Bifida Subtypes and Sub-Phenotypes by Maternal Race/Ethnicity in the National Birth Defects Prevention Study AMERICAN JOURNAL OF MEDICAL GENETICS PART A Agopian, A. J., Canfield, M. A., Olney, R. S., Lupo, P. J., Ramadhani, T., Mitchell, L. E., Shaw, G. M., Moore, C. A. 2012; 158A (1): 109-115

    Abstract

    Spina bifida refers to a collection of neural tube defects, including myelomeningocele, meningocele, and myelocele (SB(M) ), as well as lipomyelomeningocele and lipomeningocele (SB(L) ). Maternal race/ethnicity has been associated with an increased risk for spina bifida among offspring. To better understand this relationship, we evaluated different spina bifida subtypes (SB(M) vs. SB(L) ) and sub-phenotypes (anatomic level or presence of additional malformations) by maternal race/ethnicity using data from the National Birth Defects Prevention Study. This study is a large, multisite, population-based study of nonsyndromic birth defects. Prevalence estimates were obtained using data from spina bifida cases (live births, fetal deaths, and elective terminations) and total live births in the study regions. From October 1997 through December 2005, 1,046 infants/fetuses with spina bifida were delivered, yielding a prevalence of 3.06 per 10,000 live births. Differences in the prevalences of SB(M) vs. SB(L) , isolated versus non-isolated SB(M) , and lesion level in isolated SB(M) among case offspring were observed by maternal race/ethnicity. Compared to non-Hispanic (NH) White mothers, offspring of Hispanic mothers had higher prevalences of each subtype and most sub-phenotypes, while offspring of NH Black mothers generally had lower prevalences. Furthermore, differences in race/ethnicity among those with isolated SB(M) were more pronounced by sex. For instance, among male offspring, the prevalence of isolated SB(M) was significantly higher for those with Hispanic mothers compared to NH White mothers [prevalence ratio (PR): 1.55, 95% confidence interval: 1.23-1.95]. These findings provide evidence that certain spina bifida subtypes and sub-phenotypes may be etiologically distinct.

    View details for DOI 10.1002/ajmg.a.34383

    View details for Web of Science ID 000299381800016

    View details for PubMedID 22140002

  • A Genetic Signature of Spina Bifida Risk from Pathway-Informed Comprehensive Gene-Variant Analysis PLOS ONE Marini, N. J., Hoffmann, T. J., Lammer, E. J., Hardin, J., Lazaruk, K., Stein, J. B., Gilbert, D. A., Wright, C., Lipzen, A., Pennacchio, L. A., Carmichael, S. L., Witte, J. S., Shaw, G. M., Rine, J. 2011; 6 (11)

    Abstract

    Despite compelling epidemiological evidence that folic acid supplements reduce the frequency of neural tube defects (NTDs) in newborns, common variant association studies with folate metabolism genes have failed to explain the majority of NTD risk. The contribution of rare alleles as well as genetic interactions within the folate pathway have not been extensively studied in the context of NTDs. Thus, we sequenced the exons in 31 folate-related genes in a 480-member NTD case-control population to identify the full spectrum of allelic variation and determine whether rare alleles or obvious genetic interactions within this pathway affect NTD risk. We constructed a pathway model, predetermined independent of the data, which grouped genes into coherent sets reflecting the distinct metabolic compartments in the folate/one-carbon pathway (purine synthesis, pyrimidine synthesis, and homocysteine recycling to methionine). By integrating multiple variants based on these groupings, we uncovered two provocative, complex genetic risk signatures. Interestingly, these signatures differed by race/ethnicity: a Hispanic risk profile pointed to alterations in purine biosynthesis, whereas that in non-Hispanic whites implicated homocysteine metabolism. In contrast, parallel analyses that focused on individual alleles, or individual genes, as the units by which to assign risk revealed no compelling associations. These results suggest that the ability to layer pathway relationships onto clinical variant data can be uniquely informative for identifying genetic risk as well as for generating mechanistic hypotheses. Furthermore, the identification of ethnic-specific risk signatures for spina bifida resonated with epidemiological data suggesting that the underlying pathogenesis may differ between Hispanic and non-Hispanic groups.

    View details for DOI 10.1371/journal.pone.0028408

    View details for Web of Science ID 000298168100069

    View details for PubMedID 22140583

  • Periconceptional Intake of Folic Acid and Food Folate and Risks of Preterm Delivery AMERICAN JOURNAL OF PERINATOLOGY Shaw, G. M., Carmichael, S. L., Yang, W., Siega-Riz, A. M. 2011; 28 (10): 747-751

    Abstract

    We investigated multiple sources of folate and folic acid to determine whether their periconceptional intakes were associated with preterm delivery. Studied were controls from the National Birth Defects Prevention Study delivered September 1998 to December 2005. Telephone interviews were conducted with 5952 (68% of eligible) mothers. Women were queried about intake of vitamin supplements in the 12 weeks before conception through delivery. A version of the Nurse's Health Study food frequency questionnaire was used to assess food sources. Eight percent of infants ( N?=?487) were preterm (<37 weeks). Compared with women who began intake of supplements with folic acid before pregnancy, those who began any time during pregnancy had an ~20% lowered risk of preterm delivery. Lower dietary intakes showed a modest increased risk of preterm delivery: odds ratios were 1.44 (1.01 to 2.04) for lowest quartile intake of folate and 1.27 (0.95 to 1.69) for lowest quartile intake of folic acid compared with the highest. Findings suggest some evidence that folates influenced risks; however, an interpretation of results was also consistent with no association between intake of folates and preterm delivery.

    View details for DOI 10.1055/s-0031-1280855

    View details for Web of Science ID 000298200500002

    View details for PubMedID 21681695

  • Estimated dietary phytoestrogen intake and major food sources among women during the year before pregnancy NUTRITION JOURNAL Carmichael, S. L., Gonzalez-Feliciano, A. G., Ma, C., Shaw, G. M., Cogswell, M. E. 2011; 10

    Abstract

    Phytoestrogens may be associated with a variety of different health outcomes, including outcomes related to reproductive health. Recently published data on phytoestrogen content of a wide range of foods provide an opportunity to improve estimation of dietary phytoestrogen intake.Using the recently published data, we estimated intake among a representative sample of 6,584 women of reproductive age from a multi-site, population-based case-control study, the National Birth Defects Prevention Study (NBDPS). The NBDPS uses a shortened version of the Willett food frequency questionnaire to estimate dietary intake during the year before pregnancy. We estimated intake among NBDPS control mothers.Lignans contributed 65% of total phytoestrogen intake; isoflavones, 29%; and coumestrol, 5%. Top contributors to total phytoestrogen intake were vegetables (31%) and fruit (29%); for isoflavones, dairy (33%) and fruit (21%); for lignans, vegetables (40%) and fruit (29%); and for coumestans, fruit (55%) and dairy (18%). Hispanic women had higher phytoestrogen intake than non-Hispanic white or black women. Associations with maternal age and folic acid-containing supplements were more modest but indicated that older mothers and mothers taking supplements had higher intake.The advantage of the approach used for the current analysis lies in its utilization of phytoestrogen values derived from a single laboratory that used state-of-the-art measurement techniques. The database we developed can be applied directly to other studies using food frequency questionnaires, especially the Willett questionnaire. The database, combined with consistent dietary intake assessment, provides an opportunity to improve our ability to understand potential associations of phytoestrogen intake with health outcomes.

    View details for DOI 10.1186/1475-2891-10-105

    View details for Web of Science ID 000295960300001

    View details for PubMedID 21978267

  • Discovery of Genetic Susceptibility Factors for Human Birth Defects: An Opportunity for a National Agenda AMERICAN JOURNAL OF MEDICAL GENETICS PART A Olshan, A. F., Hobbs, C. A., Shaw, G. M. 2011; 155A (8): 1794-1797

    Abstract

    A recent workshop highlighted the current challenges and new opportunities for studying the role of genetic factors in the etiology of human birth defects. The workshop provided a series of recommendations pertaining to the use of animal models, key elements of population-based designs, the need for national collaborative projects, biorepositories, and consortia, investigation of new types of structural genetic variants, examination of gene-exposure interactions, and a strategy for gene variant discovery. A key reason to hold the recent workshop and contribute this concise communication to the literature is to draw attention to and initiate action toward advancing discoveries about the genetic etiologies of birth defects.

    View details for DOI 10.1002/ajmg.a.34103

    View details for Web of Science ID 000294088100005

    View details for PubMedID 21739590

  • Defective Sumoylation Pathway Directs Congenital Heart Disease BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Wang, J., Chen, L., Wen, S., Zhu, H., Yu, W., Moskowitz, I. P., Shaw, G. M., Finnell, R. H., Schwartz, R. J. 2011; 91 (6): 468-476

    Abstract

    Congenital heart defects (CHDs) are the most common of all birth defects, yet molecular mechanism(s) underlying highly prevalent atrial septal defects (ASDs) and ventricular septal defects (VSDs) have remained elusive. We demonstrate the indispensability of "balanced" posttranslational small ubiquitin-like modifier (SUMO) conjugation-deconjugation pathway for normal cardiac development. Both hetero- and homozygous SUMO-1 knockout mice exhibited ASDs and VSDs with high mortality rates, which were rescued by cardiac reexpression of the SUMO-1 transgene. Because SUMO-1 was also involved in cleft lip/palate in human patients, the previous findings provided a powerful rationale to question whether SUMO-1 was mutated in infants born with cleft palates and ASDs. Sequence analysis of DNA from newborn screening blood spots revealed a single 16 bp substitution in the SUMO-1 regulatory promoter of a patient displaying both oral-facial clefts and ASDs. Diminished sumoylation activity whether by genetics, environmental toxins, and/or pharmaceuticals may significantly contribute to susceptibility to the induction of congenital heart disease worldwide. Birth Defects Research (Part A) 2011. 2011 Wiley-Liss, Inc.

    View details for DOI 10.1002/bdra.20816

    View details for Web of Science ID 000291545100007

    View details for PubMedID 21563299

  • Maternal nutrition and gastroschisis: findings from the National Birth Defects Prevention Study AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Feldkamp, M. L., Carmichael, S. L., Shaw, G. M., Panichello, J. D., Moore, C. A., Botto, L. D. 2011; 204 (5)

    Abstract

    Gastroschisis is increasing in many countries, especially among young women. Because young women may have inadequate nutrition, we assessed the relationship between individual nutrients and the risk for gastroschisis.We analyzed data from the National Birth Defects Prevention Study, a population-based case-control study. Cases were ascertained from 10 birth defect surveillance systems. Controls were randomly selected from birth certificates or hospital records. Nutrient intake was estimated for the year prior to conception from maternal interviews based on a 58-item food frequency questionnaire and cereal consumption reported. A total of 694 cases and 6157 controls were available for analysis.Reported intake of individual nutrients did not substantially affect the risk for gastroschisis. Stratification by maternal age, preconception body mass index, folic acid-containing supplements, or energy intake (kilocalories) did not alter risk estimates.This study does not support an increased risk for gastroschisis with decreasing tertiles of individual nutrients.

    View details for DOI 10.1016/j.ajog.2010.12.053

    View details for Web of Science ID 000290206200025

    View details for PubMedID 21396620

  • Effect of specimen storage conditions on newborn dried blood spots used to assess Toxoplasma gondii immunoglobulin M (IgM) CLINICA CHIMICA ACTA Mei, J. V., Li, L., Rasmussen, S. A., Collier, S., Frias, J. L., Honein, M. A., Shaw, G. M., Lorey, F., Meyer, R., Chaing, S., Canfield, M. A., Jones, J., Hannon, W. H. 2011; 412 (5-6): 455-459

    Abstract

    Newborn screening programs store-under varying conditions-residual dried blood spots (DBS). Residual DBS were used to investigate the contribution of congenital infection with Toxoplasma gondii to the etiology of hydrocephalus and as a key step, we assessed the effect of storage conditions on the stability of newborn screening biomarkers.Infants with hydrocephalus (410 cases) were identified using population-based birth defects surveillance systems in California, North Carolina, and Texas. Infants without birth defects (448 controls) were randomly selected from the same geographic areas and time periods. California stores DBS with controlled temperature, while North Carolina and Texas store DBS under ambient conditions. After removal of personal identifiers, DBS were tested for Toxo-specific immunoglobulin-M (Toxo-IgM). Because of poor elution of DBS stored in ambient conditions, additional biomarkers were tested on a specimen subset.Among 858 DBS tested, Toxo-IgM was found in 3 cases and no controls from California (N=515) and in no specimens from North Carolina or Texas (N=343). Among the 98 specimens tested for selected biomarkers, statistically significant differences were found for California vs. combined North Carolina and Texas DBS (thyroid stimulating hormone, phenylalanine, methionine, leucine and citrulline p<0.0001; tyrosine and valine p<0.001).Storage conditions for residual DBS had an effect on the ability to extract, recover, and accurately measure Toxo-IgM and other biomarkers from the filter paper matrix.

    View details for DOI 10.1016/j.cca.2010.11.028

    View details for Web of Science ID 000286713800009

    View details for PubMedID 21114968

  • Craniosynostosis and Nutrient Intake during Pregnancy BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Rasmussen, S. A., Lammer, E. J., Ma, C., Shaw, G. M. 2010; 88 (12): 1032-1039

    Abstract

    To examine the association of craniosynostosis with maternal intake of folic acid-containing supplements and dietary nutrients.The study included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Nonsyndromic infants with craniosynostosis (n = 815) were compared to nonmalformed, population-based liveborn control infants (n = 6789), by estimating adjusted odds ratios (AORs) and 95% confidence intervals (CIs) from logistic regression models that included mother's age, parity, race-ethnicity, education, body mass index, smoking, alcohol, fertility treatments, plurality, and study center. We compared quartiles of intake and specified nutrients as continuous.Intake of folic acid-containing supplements was not associated with craniosynostosis (AORs were close to 1). Analyses of dietary nutrients were restricted to mothers who took supplements during the first trimester (i.e., most women). Based on continuous specifications of nutrients, sagittal synostosis risk was significantly lower among women with higher intake of riboflavin and vitamins B?, E, and C; metopic synostosis risk was significantly higher among women with higher intakes of choline and vitamin B??; and coronal synostosis risk was significantly lower among women with higher intake of methionine and vitamin C. As examples, AORs for sagittal synostosis among women with intakes of vitamin B? and riboflavin in the highest versus lowest quartiles were 0.4 (95% CI, 0.2-0.6) and 0.5 (95% CI, 0.3-0.7), respectively.This analysis suggests that dietary intake of certain nutrients may be associated with craniosynostosis, and results may vary by suture type.

    View details for DOI 10.1002/bdra.20717

    View details for Web of Science ID 000285396200006

    View details for PubMedID 20842649

  • Association of Microtia With Maternal Obesity and Periconceptional Folic Acid Use AMERICAN JOURNAL OF MEDICAL GENETICS PART A Ma, C., Carmichael, S. L., Scheuerle, A. E., Canfield, M. A., Shaw, G. M. 2010; 152A (11): 2756-2761

    Abstract

    The study objective was to examine the association of microtia with maternal intake of folic-acid-containing supplements and obesity. The study data included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Non-syndromic cases of microtia were compared to non-malformed, population-based liveborn control infants, by estimating adjusted odds ratios (AORs) and 95% confidence intervals (CIs) from logistic regression models that included maternal race/ethnicity, education, and study site. Maternal obesity was only weakly associated with microtia. Maternal periconceptional intake of folic-acid-containing vitamin supplements reduced the risk for microtia, but only among non-obese women (OR: 0.63; 95% CI: 0.44-0.91). The reduced risk was stronger when analyses were restricted to isolated cases (OR: 0.51; 95% CI: 0.34-0.77), and it was independent of the level of maternal dietary folate intake. Adjusting for maternal race/ethnicity did not reveal alternative interpretations of this association. This analysis suggests that maternal periconceptional intake of folic-acid-containing supplements may provide protection from microtia for non-obese women.

    View details for DOI 10.1002/ajmg.a.33694

    View details for Web of Science ID 000284005700013

    View details for PubMedID 20949601

  • Candidate Gene Sequencing of LHX2, HESX1, and SOX2 in a Large Schizencephaly Cohort AMERICAN JOURNAL OF MEDICAL GENETICS PART A Mellado, C., Poduri, A., Gleason, D., Elhosary, P. C., Barry, B. J., Partlow, J. N., Chang, B. S., Shaw, G. M., Barkovich, A. J., Walsh, C. A. 2010; 152A (11): 2736-2742

    Abstract

    Schizencephaly is a malformation of cortical development characterized by gray matter-lined clefts in the cerebral cortex and a range of neurological presentations. In some cases, there are features of septo-optic dysplasia concurrently with schizencephaly. The etiologies of both schizencephaly and septo-optic dysplasia are thought to be heterogeneous, but there is evidence that at least some cases have genetic origin. We hypothesized that these disorders may be caused by mutations in three candidate genes: LHX2, a gene with an important cortical patterning role, and HESX1 and SOX2, genes that have been associated with septo-optic dysplasia. We sequenced a large cohort of patients with schizencephaly, some with features of septo-optic dysplasia, for mutations in these genes. No pathogenic mutations were observed, suggesting that other genes or non-genetic factors influencing genes critical to brain development must be responsible for schizencephaly.

    View details for DOI 10.1002/ajmg.a.33684

    View details for Web of Science ID 000284005700010

    View details for PubMedID 20949537

  • Folic acid in early pregnancy: a public health success story FASEB JOURNAL Obican, S. G., Finnell, R. H., Mills, J. L., Shaw, G. M., Scialli, A. R. 2010; 24 (11): 4167-4174

    Abstract

    Folate is a water-soluble B vitamin that must be obtained in the diet or through supplementation. For >50 yr, it has been known that folate plays an integral role in embryonic development. In mice, inactivation of genes in the folate pathway results in malformations of the neural tube, heart, and craniofacial structures. It has been shown that diets and blood levels of women who had a fetus with a neural tube defect are low for several micronutrients, particularly folate. Periconceptional use of folic acid containing supplements decreased recurrent neural tube defects in the offspring of women with a previously affected child and the occurrence of a neural tube defect and possibly other birth defects in the offspring of women with no prior history. Based on these findings, the U.S. Public Health Service recommended that all women at risk take folic acid supplements, but many did not. Mandatory food fortification programs were introduced in numerous countries, including the United States, to improve folate nutritional status and have resulted in a major decrease in neural tube defect prevalence. The success story of folate represents the cooperation of embryologists, experimentalists, epidemiologists, public health scientists, and policymakers.

    View details for DOI 10.1096/fj.10-165084

    View details for Web of Science ID 000283861100004

    View details for PubMedID 20631328

  • Genes encoding critical transcriptional activators for murine neural tube development and human spina bifida: a case-control study BMC MEDICAL GENETICS Lu, W., Guzman, A. R., Yang, W., Chapa, C. J., Shaw, G. M., Greene, R. M., Pisano, M. M., Lammer, E. J., Finnell, R. H., Zhu, H. 2010; 11

    Abstract

    Spina bifida is a malformation of the neural tube and is the most common of neural tube defects (NTDs). The etiology of spina bifida is largely unknown, although it is thought to be multi-factorial, involving multiple interacting genes and environmental factors. Mutations in transcriptional co-activator genes-Cited2, p300, Cbp, Tfap2?, Carm1 and Cart1 result in NTDs in murine models, thus prompt us to investigate whether homologues of these genes are associated with NTDs in humans.Data and biological samples from 297 spina bifida cases and 300 controls were derived from a population-based case-control study conducted in California. 37 SNPs within CITED2, EP300, CREBBP, TFAP2A, CARM1 and ALX1 were genotyped using an ABI SNPlex assay. Odds ratios and 95% confidence intervals were calculated for alleles, genotypes and haplotypes to evaluate the risk for spina bifida.Several SNPs showed increased or decreased risk, including CITED2 rs1131431 (OR = 5.32, 1.04~27.30), EP300 rs4820428 (OR = 1.30, 1.01~1.67), EP300 rs4820429 (OR = 0.50, 0.26~0.50, in whites, OR = 0.7, 0.49~0.99 in all subjects), EP300 rs17002284 (OR = 0.43, 0.22~0.84), TFAP2A rs3798691 (OR = 1.78, 1.13~2.87 in Hispanics), CREBBP rs129986 (OR = 0.27, 0.11~0.69), CARM1 rs17616105 (OR = 0.41, 0.22~0.72 in whites). In addition, one haplotype block in EP300 and one in TFAP2A appeared to be associated with increased risk.Modest associations were observed in CITED2, EP300, CREBBP, TFAP2A and CARM1 but not ALX1. However, these modest associations were not statistically significant after correction for multiple comparisons. Searching for potential functional variants and rare causal mutations is warranted in these genes.

    View details for DOI 10.1186/1471-2350-11-141

    View details for Web of Science ID 000283360200001

    View details for PubMedID 20932315

  • Prepregnancy Obesity: A Complex Risk Factor for Selected Birth Defects BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Rasmussen, S. A., Shaw, G. M. 2010; 88 (10): 804-810

    Abstract

    Obesity is associated with increased risk of many adverse health conditions. During pregnancy, obesity presents particularly important challenges for both mother and baby. Over the last 20 years, studies have emerged indicating an association between prepregnancy weight and risks of birth defects. However, few studies have examined the mechanisms through which this association occurs. Understanding the underlying mechanisms may provide clues to public health strategies for the prevention of birth defects associated with maternal obesity. This article briefly reviews existing literature on the association between maternal obesity and birth defects, discusses potential underlying mechanisms, and suggests research needed to improve our understanding of this important association.

    View details for DOI 10.1002/bdra.20679

    View details for Web of Science ID 000283638500006

    View details for PubMedID 20973050

  • Hypospadias and halogenated organic pollutant levels in maternal mid-pregnancy serum samples CHEMOSPHERE Carmichael, S. L., Herring, A. H., Sjoedin, A., Jones, R., Needham, L., Ma, C., Ding, K., Shaw, G. M. 2010; 80 (6): 641-646

    Abstract

    Environmental contaminants that disrupt endocrine function may contribute to hypospadias etiology.To compare levels of selected halogenated organic pollutants in women delivering infants with and without hypospadias.This study examined levels of nine polybrominated flame retardants (PBDEs), 30 polychlorinated biphenyls (PCBs) and nine persistent pesticides in mid-pregnancy serum samples from 20 women who delivered infants with hypospadias and 28 women who delivered unaffected infants, in California. Analytes were measured using isotope dilution high-resolution mass spectrometry. Values below individual limits of detection (LOD) for each analyte were imputed based on a truncated multivariate normal distribution. Levels of 17 analytes for which at least 50% of cases and controls had values above the LOD were compared using t-tests and by generating odds ratios from logistic regression analyses.Means were greater for cases than controls for 11 of the 17 reported analytes (4 of 5 PBDEs, 7 of 9 PCBs, and 0 of 3 other persistent pesticides), but none of the differences were statistically significant. Eleven of the 17 odds ratios exceeded one (the same analytes that had greater means), but none of the confidence intervals excluded one. After adjustment for sample processing time and foreign-born Hispanic race-ethnicity, only four of the odds ratios exceeded one.Levels of the PBDEs and PCBs were not statistically significantly different, but the sample size was small. The current study adds to a relatively limited knowledge base regarding the potential association of specific contaminants with hypospadias or other birth defects.

    View details for DOI 10.1016/j.chemosphere.2010.04.055

    View details for Web of Science ID 000280749500005

    View details for PubMedID 20494400

  • Does global hypomethylation contribute to susceptibility to neural tube defects? AMERICAN JOURNAL OF CLINICAL NUTRITION Finnell, R. H., Blom, H. J., Shaw, G. M. 2010; 91 (5): 1153-1154

    View details for DOI 10.3945/ajcn.2010.29534

    View details for Web of Science ID 000276845100002

    View details for PubMedID 20375188

  • Patterns of tobacco exposure before and during pregnancy ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA Anderka, M., Romitti, P. A., Sun, L., Druschel, C., Carmichael, S., Shaw, G. 2010; 89 (4): 505-514

    Abstract

    To describe maternal exposure to tobacco in the three months before conception and throughout pregnancy, examine risk factors associated with tobacco exposure in pregnancy and smoking cessation, assess use of pharmacotherapy for smoking cessation and evaluate birth outcomes by smoking status.A cohort of women from a multi-site United States study were asked retrospectively about their exposure to tobacco.The study population was comprised of 4,667 mothers of non-malformed control infants who participated in the National Birth Defects Prevention Study from 1997 to 2003.Using computer-assisted telephone interview responses from this population-based sample, we assessed patterns of maternal smoking and exposure to environmental tobacco smoke (ETS) as well as use of pharmacotherapy for quitting smoking during pregnancy.Overall, 961 (20.6%) mothers reported any smoking and 1,401 (30.0%) reported any exposure to ETS at home or work during the three months before conception through pregnancy. Of the 961 smokers, 512 (53.3%) reportedly quit smoking before or during pregnancy, including 379 (74% of quitters) in the first trimester, and 420 (43.7%) continued to smoke throughout the pregnancy. Only 2.1% of smokers reportedly used pharmacotherapy to quit smoking anytime from three months before conception through pregnancy. Low birthweight and preterm delivery rates were lowest among offspring of non-smokers and highest in offspring of those who continued to smoke throughout pregnancy.About one-half of mothers who reported preconceptional smoking quit before or during pregnancy. Use of pharmacotherapy to quit smoking during pregnancy was not common.

    View details for DOI 10.3109/00016341003692261

    View details for Web of Science ID 000277094700011

    View details for PubMedID 20367429

  • A Maternally Inherited Chromosome 18q22.1 Deletion in a Male With Late-Presenting Diaphragmatic Hernia and Microphthalmia-Evaluation of DSEL as a Candidate Gene for the Diaphragmatic Defect AMERICAN JOURNAL OF MEDICAL GENETICS PART A Zayed, H., Chao, R., Moshrefi, A., LopezJimenez, N., Delaney, A., Chen, J., Shaw, G. M., Slavotinek, A. M. 2010; 152A (4): 916-923

    Abstract

    Using an Affymetrix GeneChip(R) Human Mapping 100K Set to study a patient with a late-presenting, right-sided diaphragmatic hernia and microphthalmia, we found a maternally inherited deletion that was 2.7 Mb in size at chromosome 18q22.1. Mapping of this deletion using fluorescence in situ hybridization revealed three deleted genes-CDH19, DSEL, and TXNDC10, and one gene that contained the deletion breakpoint, CCDC102B. We selected DSEL for further study in 125 patients with diaphragmatic hernias, as it is involved in the synthesis of decorin, a protein that is required for normal collagen formation and that is upregulated during myogenesis. We found p.Met14Ile in an unrelated patient with a late-presenting, anterior diaphragmatic hernia. In the murine diaphragm, Dsel was only weakly expressed at the time of diaphragm closure and its expression in C2C12 myoblast cells did not change significantly during myoblast differentiation, thus reducing the likelihood that the gene is involved in myogenesis of the diaphragm. Although it is possible that the 18q22.1 deletion and haploinsufficiency for DSEL contributed to the diaphragmatic defect in the patient, a definite role for DSEL and decorin in the formation of the collagen-containing, central tendon of the diaphragm has not yet been established.

    View details for DOI 10.1002/ajmg.a.33341

    View details for Web of Science ID 000276754000017

    View details for PubMedID 20358601

  • Examination of FGFRL1 as a candidate gene for diaphragmatic defects at chromosome 4p16.3 shows that Fgfrl1 null mice have reduced expression of Tpm3, sarcomere genes and Lrtm1 in the diaphragm HUMAN GENETICS LopezJimenez, N., Gerber, S., Popovici, V., Mirza, S., Copren, K., Ta, L., Shaw, G. M., Trueb, B., Slavotinek, A. M. 2010; 127 (3): 325-336

    Abstract

    Fgfrl1 (also known as Fgfr5; OMIM 605830) homozygous null mice have thin, amuscular diaphragms and die at birth because of diaphragm hypoplasia. FGFRL1 is located at 4p16.3, and this chromosome region can be deleted in patients with congenital diaphragmatic hernia (CDH). We examined FGFRL1 as a candidate gene for the diaphragmatic defects associated with 4p16.3 deletions and re-sequenced this gene in 54 patients with CDH. We confirmed six known coding single nucleotide polymorphisms (SNPs): c.209G > A (p.Pro20Pro), c.977G > A (p.Pro276Pro), c.1040T > C (p.Asp297Asp), c.1234C > A (p.Pro362Gln), c.1420G > T (p.Arg424Leu), and c.1540C > T (p.Pro464Leu), but we did not identify any gene mutations. We genotyped additional CDH patients for four of these six SNPs, including the three non-synonymous SNPs, to make a total of 200 chromosomes, and found that the allele frequency for the four SNPs, did not differ significantly between patients and normal controls (p > or = 0.05). We then used Affymetrix Genechip Mouse Gene 1.0 ST arrays and found eight genes with significantly reduced expression levels in the diaphragms of Fgfrl1 homozygous null mice when compared with wildtype mice-Tpm3, Fgfrl1 (p = 0.004), Myl2, Lrtm1, Myh4, Myl3, Myh7 and Hephl1. Lrtm1 is closely related to Slit3, a protein associated with herniation of the central tendon of the diaphragm in mice. The Slit proteins are known to regulate axon branching and cell migration, and inhibition of Slit3 reduces cell motility and decreases the expression of Rac and Cdc42, two genes that are essential for myoblast fusion. Further studies to determine if Lrtm1 has a similar function to Slit3 and if reduced Fgfrl1 expression can cause diaphragm hypoplasia through a mechanism involving decreased myoblast motility and/or myoblast fusion, seem indicated.

    View details for DOI 10.1007/s00439-009-0777-8

    View details for Web of Science ID 000274456500006

    View details for PubMedID 20024584

  • Periconceptional Nutrient Intakes and Risks of Conotruncal Heart Defects BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Carmichael, S. L., Yang, W., Lammer, E. J. 2010; 88 (3): 144-151

    Abstract

    Few inquiries into periconceptional nutrition, other than folate, and risk of heart defects exist. We investigated the observed association between conotruncal heart defects and periconceptional vitamin use, as well as potential associations with other dietary nutrients.Data derived from a population-based, case-control study of fetuses and liveborn infants among California births between July 1999 and June 2004; 76% of eligible case mothers and 77% of eligible control mothers were interviewed. Cases included 140 with d-transposition of great arteries (dTGA), and 163 with tetralogy of Fallot (TOF). Total number of controls was 698. Use of vitamins was elicited by questionnaire for the periconceptional period. Dietary nutrient intake was elicited by a well-known food frequency questionnaire.The odds ratio for dTGA associated with supplemental vitamin use was 1.0 (95% confidence interval [CI], 0.7-1.5) and for TOF was 0.9 (95% CI, 0.6-1.3). We observed increased risks associated with lower dietary intakes of linoleic acid, total carbohydrate, and fructose for dTGA, whereas decreased risks were observed for lower intakes of total protein and methionine for TOF. Lower dietary intake of several micronutrients-namely folate, niacin, riboflavin, and vitamins B(12), A, and E, even after simultaneous adjustment for other studied nutrients-was associated with increased risk of dTGA but not TOF. These associations were observed among women who did not use vitamin supplements periconceptionally. Analytic consideration of several potential confounders did not reveal alternative interpretations of the results.Evidence continues to accumulate to show that nutrients, particularly folate, influence risks of structural birth defects. Our results extend observations that other nutrients may also be important in heart development.

    View details for DOI 10.1002/bdra.20648

    View details for Web of Science ID 000276125800002

    View details for PubMedID 20063270

  • Planar Cell Polarity Pathway Genes and Risk for Spina Bifida AMERICAN JOURNAL OF MEDICAL GENETICS PART A Wen, S., Zhu, H., Lu, W., Mitchell, L. E., Shaw, G. M., Lammer, E. J., Finnell, R. H. 2010; 152A (2): 299-304

    Abstract

    Spina bifida, a neural tube closure defect (NTD) involving the posterior portion of what will ultimately give rise to the spinal cord, is one of the most common and serious birth defects. The etiology of spina bifida is thought to be multi-factorial and involve multiple interacting genes and environmental factors. The causes of this congenital malformation remain largely unknown. However, several candidate genes for spina bifida have been identified in lower vertebrates, including the planar cell polarity (PCP) genes. We used data from a case-control study conducted in California to evaluate the association between variation within several key PCP genes and the risk of spina bifida. The PCP genes included in this study were the human homologs of the Xenopus genes Flamingo, Strabismus, Prickle, Dishevelled, and Scrib, two of the homologs of Xenopus Wnt genes, WNT5A and WNT11, and two of the homologs of Xenopus Frizzled, FZD3 and FZD6. None of the 172 SNPs that were evaluated were significantly associated with spina bifida in any racial/ethnic group after correction for multiple testing. However, several SNPs in the PRICKLE2 gene had unadjusted P-value <0.01. In conclusion, our results, though largely negative, suggest that the PRICKLE2 gene may potentially modify the risk of spina bifida and deserves further investigation.

    View details for DOI 10.1002/ajmg.a.33230

    View details for Web of Science ID 000274508300005

    View details for PubMedID 20101694

  • Fetal Constraint as a Potential Risk Factor for Craniosynostosis AMERICAN JOURNAL OF MEDICAL GENETICS PART A Sanchez-Lara, P. A., Carmichael, S. L., Graham, J. M., Lammer, E. J., Shaw, G. M., Ma, C., Rasmussen, S. A. 2010; 152A (2): 394-400

    Abstract

    Non-syndromic craniosynostosis is multifactorial, and fetal head constraint has been hypothesized as one factor thought to play a role. Data from the National Birth Defects Prevention Study (NBDPS), a large multi-site case-control study of birth defects, were used to evaluate associations between four selected factors related to fetal constraint and craniosynostosis: plurality (twins or higher), macrosomia (birth weight >4,000 g), post-term gestational age (> or =42 weeks), and nulliparity (no previous live births). Case infants (n = 675) had craniosynostosis documented either by radiographic evidence or by surgical intervention. Infants with a recognized or strongly suspected single-gene conditions or chromosomal abnormalities were excluded. Control infants (n = 5,958) had no major birth defects and were randomly selected from the same population as case infants. Logistic regression was used to estimate odds ratios for the association between these four factors and craniosynostosis, while adjusting for several covariates. We found that plurality and nulliparity were associated with a twofold increased risk for metopic craniosynostosis, and macrosomia had almost twice the risk of developing coronal craniosynostosis. Contrary to our hypothesis, prematurity and low birth weight were also associated with craniosynostosis. In conclusion, these four constraint-related factors were not found to be associated with craniosynostosis when all suture types were combined, though some types of craniosynostosis were associated with individual constraint-related factors.

    View details for DOI 10.1002/ajmg.a.33246

    View details for Web of Science ID 000274508300019

    View details for PubMedID 20101684

  • Association of Congenital Cardiovascular Malformations with 33 Single Nucleotide Polymorphisms of Selected Cardiovascular Disease-Related Genes BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Kuehl, K., Loffredo, C., Lammer, E. J., Iovannisci, D. M., Shaw, G. M. 2010; 88 (2): 101-110

    Abstract

    Clark (1996) proposed that abnormal blood flow is related to some congenital cardiovascular malformations (CCVMs), particularly CCVM with obstruction to blood flow. Our hypothesis is that CCVMs may relate to genes that affect blood coagulation or flow. We studied whether polymorphisms of such genes are related to CCVMs; previous association of these SNPs to conotruncal CCVMs is described.We assessed risk of pulmonary stenosis (PS, N = 120), atrial septal defect (ASD, N = 108), aortic stenosis (AS, N = 36), and coarctation of the aorta (CoAo, N = 64), associated with 33 candidate genes, selected for their relationship to blood flow affected by homocysteine metabolism, coagulation, cell-cell interaction, inflammation, or blood pressure regulation.Effects were specific to cardiac phenotype and race. CoAo was associated with MTHFR (-667) C>T (odds ratio [OR] for TT 3.5, 95% confidence limits [CI] 1.4-8.6). AS was associated with a polymorphism of SERPINE1, G5>G4, OR = 5.6 for the homozygote with 95% CI 1.4-22.9. Unique polymorphisms were associated with increased risk of ASD and PS: NPPA 664G>A with ASD (OR of 2.4, 95%CI 1.3-4.4) and NOS3 (-690) C>T with PS (OR 6.1; 95% CI 1.6-22.6 in the African American population only). For ASD, the NPPA (-664) G>A SNP there was increased risk from the variant genotype only in maternal smokers (OR 2.6; 95% CI 1.0-7.2).Genes affecting vascular function and coagulation appear to be promising candidates for the etiology of cardiac malformations and warrant further study.

    View details for DOI 10.1002/bdra.20630

    View details for Web of Science ID 000275389800005

    View details for PubMedID 19764075

  • Second-Trimester Serum Cytokines in Women Who Develop Spontaneous Preterm Labor at Less than 28 Weeks' Gestation versus Term Labor AMERICAN JOURNAL OF PERINATOLOGY Yang, Q., El Sayed, Y., Shaw, G. M., Fu, J., Schilling, J., Madan, A. 2010; 27 (1): 31-36

    Abstract

    We sought to determine if there is a relationship between serum concentrations of cytokines and the development of preterm labor. A panel of 28 cytokines was measured using the multiplex assay in serum samples collected between 15 and 18 weeks' gestation from women who developed spontaneous preterm labor and delivered between 24 and 28 weeks' gestation (N = 25) and from women who delivered at term (>or=37 weeks; N = 25). Sixteen of the 28 cytokines measured were detected. Except for vascular endothelial growth factor, which showed a trend toward a significant increase in patients who developed preterm labor, there was no difference in cytokine levels between groups in preterm labor and in term labor. Serum cytokine changes in women who develop spontaneous preterm labor possibly occur in the period between 18 weeks' gestation and the onset of labor.

    View details for DOI 10.1055/s-0029-1234037

    View details for Web of Science ID 000273825200006

    View details for PubMedID 19644787

  • Nested Case-Control Study of One-Carbon Metabolites in Mid-Pregnancy and Risks of Cleft Lip With and Without Cleft Palate PEDIATRIC RESEARCH Shaw, G. M., Vollset, S. E., Carmichael, S. L., Yang, W., Finnell, R. H., Blom, H., Ueland, P. M. 2009; 66 (5): 501-506

    Abstract

    Evidence exists for an association between use of vitamin supplements with folic acid in early pregnancy and reduced risk for offspring with cleft lip with/without cleft palate (CLP). A few observations have been made about nutrients related to one-carbon metabolism other than folate. Our prospective study attempted to extend information on nutrition and CLP by measuring nutrient analytes in mid-pregnancy sera. This study included data from a repository of women's mid-pregnancy serum specimens collected in California from 2003-04. Each woman's specimen was linked with delivery information to determine whether her fetus had CLP or another structural malformation, or was nonmalformed. We identified 89 CLP cases. We randomly selected 409 specimens as controls. Specimens were tested for homocysteine, methylmalonic acid, folate, vitamin B12, pyridoxal phosphate, pyridoxal, pyridoxic acid, riboflavin, choline, betaine, methionine, methionine sulfoxide, cysteine, cystathionine, arginine, and asymmetric and symmetric dimethylarginine. We observed three analytes with odds ratios unlikely to be explained by random variation, i.e., elevated CLP risks were observed for low levels and for high levels of pyridoxal phosphate (vitamin B6), higher levels of choline, and low levels of symmetric dimethylarginine. These data did not show meaningful differences between cases and controls for any other analytes.

    View details for Web of Science ID 000271039100003

    View details for PubMedID 19668105

  • Control Selection and Participation in an Ongoing, Population-based, Case-Control Study of Birth Defects AMERICAN JOURNAL OF EPIDEMIOLOGY Cogswell, M. E., Bitsko, R. H., Anderka, M., Caton, A. R., Feldkamp, M. L., Sherlock, S. M., Meyer, R. E., Ramadhani, T., Robbins, J. M., Shaw, G. M., Mathews, T. J., Royle, M., Reefhuis, J. 2009; 170 (8): 975-985

    Abstract

    To evaluate the representativeness of controls in an ongoing, population-based, case-control study of birth defects in 10 centers across the United States, researchers compared 1997-2003 birth certificate data linked to selected controls (n = 6,681) and control participants (n = 4,395) with those from their base populations (n = 2,468,697). Researchers analyzed differences in population characteristics (e.g., percentage of births at > or =2,500 g) for each group. Compared with their base populations, control participants did not differ in distributions of maternal or paternal age, previous livebirths, maternal smoking, or diabetes, but they did differ in other maternal (i.e., race/ethnicity, education, entry into prenatal care) and infant (i.e., birth weight, gestational age, and plurality) characteristics. Differences in distributions of maternal, but not infant, characteristics were associated with participation by selected controls. Absolute differences in infant characteristics for the base population versus control participants were < or =1.3 percentage points. Differences in infant characteristics were greater at centers that selected controls from hospitals compared with centers that selected controls from electronic birth certificates. These findings suggest that control participants in the National Birth Defects Prevention Study generally are representative of their base populations. Hospital-based control selection may slightly underascertain infants affected by certain adverse birth outcomes.

    View details for DOI 10.1093/aje/kwp226

    View details for Web of Science ID 000270445300007

    View details for PubMedID 19736223

  • Socioeconomic Measures, Orofacial Clefts, and Conotruncal Heart Defects in California BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Ma, C., Shaw, G. M. 2009; 85 (10): 850-857

    Abstract

    To examine the association of multiple measures of socioeconomic status (SES) with risks of orofacial clefts and conotruncal heart defects.Data were from a recent population-based case-control study conducted in California that included 608 patients with orofacial clefts, 277 patients with conotruncal heart defects, and 617 nonmalformed controls.The odds ratio for the worst versus best score on a household-level SES index was strongest for cleft lip with or without palate, at 1.7 (95% confidence interval, 0.9-3.4); the odds ratios for this comparison were closer to 1 and less precise for the other defect groups. An index based on neighborhood-level SES was also not associated with increased risk of the studied defects.This detailed analysis of SES and selected birth defects did not suggest worse SES was associated with increased risk of the studied defects, with the possible exception of cleft lip with or without cleft palate.

    View details for DOI 10.1002/bdra.20614

    View details for Web of Science ID 000271348700006

    View details for PubMedID 19645048

  • Choline and Risk of Neural Tube Defects in a Folate-fortified Population EPIDEMIOLOGY Shaw, G. M., Finnell, R. H., Blom, H. J., Carmichael, S. L., Vollset, S. E., Yang, W., Ueland, P. M. 2009; 20 (5): 714-719

    Abstract

    Folic acid is known to reduce risk of neural tube defects (NTDs). Even so, NTDs continue to occur despite individual supplementation or population fortification with folic acid. We investigated other nutrients related to one-carbon metabolism that may affect NTD risk.This prospective study included data from more than 180,000 pregnant women in California from 2003 through 2005. Midpregnancy serum specimens were linked with delivery information regarding the presence of a NTD, another structural malformation, or no malformation in the fetus. We identified 80 NTD-affected pregnancies (cases) and we randomly selected 409 pregnancy controls. Serum specimens were tested for methylmalonic acid, homocysteine, cysteine, methionine, total choline, betaine, cystathionine, vitamin B6, folate, vitamin B12, riboflavin, and creatinine.We observed elevated NTD risks associated with lower levels of total choline, and reduced risks with higher levels of choline. Specifically, we observed an odds ratio of 2.4 (95% confidence interval = 1.3-4.7) associated with the lowest decile and an odds ratio of 0.14 (0.02-1.0) associated with the highest decile, both relative to the 25th-74th percentiles of the control distribution. These data did not show meaningful differences between cases and controls for any other analytes.This is the first study to investigate total choline in NTD-affected pregnancies. Our findings for choline, for which low levels were a risk factor and higher levels were a protective factor for NTDs, may offer a useful clue toward understanding the complex etiologies of NTDs in an era of folic acid fortification of the food supply.

    View details for DOI 10.1097/EDE.0b013e3181ac9fe7

    View details for Web of Science ID 000269103500017

    View details for PubMedID 19593156

  • Whole genome microarray analysis, from neonatal blood cards BMC GENETICS Hardin, J., Finnell, R. H., Wong, D., Hogan, M. E., Horovitz, J., Shu, J., Shaw, G. M. 2009; 10

    Abstract

    Neonatal blood, obtained from a heel stick and stored dry on paper cards, has been the standard for birth defects screening for 50 years. Such dried blood samples are used, primarily, for analysis of small-molecule analytes. More recently, the DNA complement of such dried blood cards has been used for targeted genetic testing, such as for single nucleotide polymorphism in cystic fibrosis. Expansion of such testing to include polygenic traits, and perhaps whole genome scanning, has been discussed as a formal possibility. However, until now the amount of DNA that might be obtained from such dried blood cards has been limiting, due to inefficient DNA recovery technology.A new technology is employed for efficient DNA release from a standard neonatal blood card. Using standard Guthrie cards, stored an average of ten years post-collection, about 1/40th of the air-dried neonatal blood specimen (two 3 mm punches) was processed to obtain DNA that was sufficient in mass and quality for direct use in microarray-based whole genome scanning. Using that same DNA release technology, it is also shown that approximately 1/250th of the original purified DNA (about 1 ng) could be subjected to whole genome amplification, thus yielding an additional microgram of amplified DNA product. That amplified DNA product was then used in microarray analysis and yielded statistical concordance of 99% or greater to the primary, unamplified DNA sample.Together, these data suggest that DNA obtained from less than 10% of a standard neonatal blood specimen, stored dry for several years on a Guthrie card, can support a program of genome-wide neonatal genetic testing.

    View details for DOI 10.1186/1471-2156-10-38

    View details for Web of Science ID 000269503400001

    View details for PubMedID 19624846

  • Maternal Corticosteroid Use and Hypospadias JOURNAL OF PEDIATRICS Carmichael, S. L., Ma, C., Werler, M. M., Olney, R. S., Shaw, G. M. 2009; 155 (1): 39-44

    Abstract

    To explore whether women who reported corticosteroid use during pregnancy were more likely to deliver an infant with hypospadias than women who did not.The analysis encompassed data on deliveries with an estimated due date between 1997 and 2004 from the National Birth Defects Prevention Study, a large population-based, case-control study conducted in the United States. Included were 1165 cases of moderate to severe hypospadias and 3000 nonmalformed male controls.The mothers of 39 cases (3.3%) and 62 controls (2.1%) reported using a corticosteroid medication during the period extending from 4 weeks before conception to 14 weeks after conception. The odds ratio (OR) for any corticosteroid exposure versus no corticosteroid exposure was 1.6 (95% confidence interval [CI] = 1.1 to 2.5); after adjustment for maternal race/ethnicity, education, age, and study site, it was 1.3 (95% CI = 0.8 to 2.0). Analyses by route of administration and specific component suggest that elevated ORs occurred only for nasal spray/inhaled corticosteroids (OR = 1.5; 95% CI = 0.9 to 2.6).Maternal use of corticosteroid medications was weakly associated with risk of hypospadias, but the association was negligible after adjustment for potential confounders.

    View details for DOI 10.1016/j.jpeds.2009.01.039

    View details for Web of Science ID 000267672600013

    View details for PubMedID 19394038

  • 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects BMC MEDICAL GENETICS Shaw, G. M., Lu, W., Zhu, H., Yang, W., Briggs, F. B., Carmichael, S. L., Barcellos, L. F., Lammer, E. J., Finnell, R. H. 2009; 10

    Abstract

    Folic acid taken in early pregnancy reduces risks for delivering offspring with several congenital anomalies. The mechanism by which folic acid reduces risk is unknown. Investigations into genetic variation that influences transport and metabolism of folate will help fill this data gap. We focused on 118 SNPs involved in folate transport and metabolism.Using data from a California population-based registry, we investigated whether risks of spina bifida or conotruncal heart defects were influenced by 118 single nucleotide polymorphisms (SNPs) associated with the complex folate pathway. This case-control study included 259 infants with spina bifida and a random sample of 359 nonmalformed control infants born during 1983-86 or 1994-95. It also included 214 infants with conotruncal heart defects born during 1983-86. Infant genotyping was performed blinded to case or control status using a designed SNPlex assay. We examined single SNP effects for each of the 118 SNPs, as well as haplotypes, for each of the two outcomes.Few odds ratios (ORs) revealed sizable departures from 1.0. With respect to spina bifida, we observed ORs with 95% confidence intervals that did not include 1.0 for the following SNPs (heterozygous or homozygous) relative to the reference genotype: BHMT (rs3733890) OR = 1.8 (1.1-3.1), CBS (rs2851391) OR = 2.0 (1.2-3.1); CBS (rs234713) OR = 2.9 (1.3-6.7); MTHFD1 (rs2236224) OR = 1.7 (1.1-2.7); MTHFD1 (hcv11462908) OR = 0.2 (0-0.9); MTHFD2 (rs702465) OR = 0.6 (0.4-0.9); MTHFD2 (rs7571842) OR = 0.6 (0.4-0.9); MTHFR (rs1801133) OR = 2.0 (1.2-3.1); MTRR (rs162036) OR = 3.0 (1.5-5.9); MTRR (rs10380) OR = 3.4 (1.6-7.1); MTRR (rs1801394) OR = 0.7 (0.5-0.9); MTRR (rs9332) OR = 2.7 (1.3-5.3); TYMS (rs2847149) OR = 2.2 (1.4-3.5); TYMS (rs1001761) OR = 2.4 (1.5-3.8); and TYMS (rs502396) OR = 2.1 (1.3-3.3). However, multiple SNPs observed for a given gene showed evidence of linkage disequilibrium indicating that the observed SNPs were not individually contributing to risk. We did not observe any ORs with confidence intervals that did not include 1.0 for any of the studied SNPs with conotruncal heart defects. Haplotype reconstruction showed statistical evidence of nonrandom associations with TYMS, MTHFR, BHMT and MTR for spina bifida.Our observations do not implicate a particular folate transport or metabolism gene to be strongly associated with risks for spina bifida or conotruncal defects.

    View details for DOI 10.1186/1471-2350-10-49

    View details for Web of Science ID 000267862600001

    View details for PubMedID 19493349

  • Increased Prevalence of Cardiovascular Defects Among 56,709 California Twin Pairs AMERICAN JOURNAL OF MEDICAL GENETICS PART A Hardin, J., Carmichael, S. L., Selvin, S., Lammer, E. J., Shaw, G. M. 2009; 149A (5): 877-886

    Abstract

    This study compared the prevalence of cardiovascular defects in twin and singleton births and explored the influences of zygosity (monozygotic and dizygotic) and maternal age (<35 and >or=35 years of age) on concordance. Data on twin and singleton infants with (n = 628 twin pairs and n = 14,078 singletons) and without (n = 53,974 twin pairs and n = 4,858,255 singletons) cardiovascular defects were obtained from the California Birth Defects Monitoring Program and the California vital statistics birth and fetal death records during the period 1983-2003. Prevalence ratios (PR) (prevalence of twin/singleton) and approximate 95% confidence intervals were calculated for 16 congenital cardiovascular categories. Poisson regression techniques using log-linear models were employed to assess whether the probability of concordance of defects within each cardiovascular category varied by zygosity or maternal age. An increased prevalence was observed in twins compared to singletons in all 16 cardiovascular categories. Seven of the cardiovascular categories had at least double the prevalence in twins compared to singletons. Like-sex twins, as a proxy of monozygosity, had an increased prevalence of cardiovascular defects compared to unlike sex twins. Probabilities of concordance for flow lesions were higher among monozygotic than dizygotic twins. Our study provides evidence that twinning is associated with more cardiovascular defects than singletons. Increased concordance for flow lesions in monozygotic twins was observed, an observation that is in agreement with findings from familial recurrence studies of cardiovascular defects.

    View details for DOI 10.1002/ajmg.a.32745

    View details for Web of Science ID 000265805900010

    View details for PubMedID 19353581

  • Sequence variants in the HLX gene at chromosome 1q41-1q42 in patients with diaphragmatic hernia CLINICAL GENETICS Slavotinek, A. M., Moshrefi, A., Lopez Jiminez, N., Chao, R., Mendell, A., Shaw, G. M., Pennacchio, L. A., Bates, M. D. 2009; 75 (5): 429-439

    Abstract

    Congenital diaphragmatic hernia (CDH) is a common birth defect for which few causative genes have been identified. Several candidate regions containing genes necessary for normal diaphragm development have been identified, including a 4-5 Mb deleted region at chromosome 1q41-1q42 from which the causative gene(s) has/have not been cloned. We selected the HLX gene from this interval as a candidate gene for CDH, as the Hlx homozygous null mouse has been reported to have diaphragmatic defects and the gene was described as being expressed in the murine diaphragm. We re-sequenced HLX in 119 CDH patients and identified four novel single nucleotide substitutions that predict amino acid changes: p.S12F, p.S18L, p.D173Y and p.A235V. These sequence alterations were all present in patients with isolated CDH, although patients with both isolated CHD and CDH with additional anomalies were studied. The single-nucleotide substitutions were absent in more than 186 control chromosomes. In-situ hybridization studies confirmed expression of Hlx in the developing murine diaphragm at the site of the junction of the diaphragm and the liver. Although functional studies to determine if these novel sequence variants altered the inductive activity of Hlx on the alpha-smooth muscle actin and SM22alpha promoters showed no significant differences between the variants and wild-type Hlx, sequence variants in HLX may still be relevant in the pathogenesis of CDH in combination with additional genetic and environmental factors.

    View details for DOI 10.1111/j.1399-0004.2009.01182.x

    View details for Web of Science ID 000265708200005

    View details for PubMedID 19459883

  • Neural Tube Defects and Maternal Folate Intake Among Pregnancies Conceived After Folic Acid Fortification in the United States AMERICAN JOURNAL OF EPIDEMIOLOGY Mosley, B. S., Cleves, M. A., Siega-Riz, A. M., Shaw, G. M., Canfield, M. A., Waller, D. K., Werler, M. M., Hobbs, C. A. 2009; 169 (1): 9-17

    Abstract

    Rates of neural tube defects have decreased since folic acid fortification of the food supply in the United States. The authors' objective was to evaluate the associations between neural tube defects and maternal folic acid intake among pregnancies conceived after fortification. This is a multicenter, case-control study that uses data from the National Birth Defects Prevention Study, 1998-2003. Logistic regression was used to compute crude and adjusted odds ratios between cases and controls assessing maternal periconceptional use of folic acid and intake of dietary folic acid. Among 180 anencephalic cases, 385 spina bifida cases, and 3, 963 controls, 21.1%, 25.2%, and 26.1%, respectively, reported periconceptional use of folic acid supplements. Periconceptional supplement use did not reduce the risk of having a pregnancy affected by a neural tube defect. Maternal intake of dietary folate was not significantly associated with neural tube defects. In this study conducted among pregnancies conceived after mandatory folic acid fortification, the authors found little evidence of an association between neural tube defects and maternal folic acid intake. A possible explanation is that folic acid fortification reduced the occurrence of folic acid-sensitive neural tube defects. Further investigation is warranted to possibly identify women who remain at increased risk of preventable neural tube defects.

    View details for DOI 10.1093/aje/kwn331

    View details for Web of Science ID 000262152200002

    View details for PubMedID 18953063

  • Mid-Pregnancy Cotinine and Risks of Orofacial Clefts and Neural Tube Defects JOURNAL OF PEDIATRICS Shaw, G. M., Carmichael, S. L., Vollset, S. E., Yang, W., Finnell, R. H., Blom, H., Midttun, O., Ueland, P. M. 2009; 154 (1): 17-19

    Abstract

    Past studies of cigarette smoking as a contributor to orofacial clefts and neural tube defects (NTDs) used self-reports of smoke exposures. We have correlated measurements of cotinine (a nicotine metabolite) in mid-pregnancy sera with clefts and NTDs.From a repository of >180 000 mid-pregnancy serum specimens collected in California from 2003 to 2005 and linked to delivery outcome information, we identified 89 orofacial cleft-associated pregnancies, 80 NTD-affected pregnancies, and randomly selected 409 pregnancy specimens that corresponded to infants without malformations as control subjects. Cotinine was measured by liquid chromatography-mass spectrometry. No smoke exposure was defined as cotinine values <2 ng/mL, and any exposure was defined as >or=2 ng/mL.We observed odds ratios of 2.1 (95% CI, 1.0-4.4) for clefts and 0.4 (95% CI, 0.1-1.7) for NTDs associated with exposure. After adjusting for race/ethnicity, age, and serum folate levels, odds ratios were 2.4 (95% CI, 1.1-5.3) and 0.6 (95% CI, 0.1-2.5). We explored 2 cotinine levels, 2 to 10 ng/mL and >10 ng/mL for clefts (data were too sparse for NTDs). Odds ratios for these levels were 3.3 (95% CI, 0.9-11.9) and 1.7 (95% CI, 0.7-4.2), respectively.Smoking exposures, as measured with cotinine levels during mid-pregnancy, were associated with increased risks of clefts and possibly reduced risks of NTDs.

    View details for DOI 10.1016/j.jpeds.2008.08.006

    View details for Web of Science ID 000262272500006

    View details for PubMedID 18990410

  • Bayesian Methods for Correcting Misclassification An Example from Birth Defects Epidemiology EPIDEMIOLOGY MacLehose, R. F., Olshan, A. F., Herring, A. H., Honein, M. A., Shaw, G. M., Romitti, P. A. 2009; 20 (1): 27-35

    Abstract

    Cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) are common congenital malformations. Numerous epidemiologic studies have shown an increased risk for orofacial clefts among children whose mothers smoked during early pregnancy; however, there is concern that the results of these studies may have been biased because of exposure misclassification. The purpose of this study is to use previous research on the reliability of self-reported cigarette smoking to produce corrected point estimates (and associated credible intervals) of the effect of maternal smoking on children's risk of clefts.We accounted for misclassification using 4 Bayesian models that made different assumptions about the sensitivity and specificity of self-reported maternal smoking data. We used results from previous studies to specify the prior distributions for sensitivity and specificity of reporting and used Markov chain Monte Carlo algorithms to calculate the posterior distribution of the effect of maternal smoking on children's risk for CL/P and CPO.After correcting for potential sources of misclassification in data from the National Birth Defects Prevention Study, we found an increased risk of CL/P among children born to mothers who smoked during early pregnancy (posterior odds ratio [OR] = 1.6, 95% credible interval = 1.1-2.2). The posterior effect of smoking on CPO provided less evidence of effect (posterior OR = 1.1, 95% credible interval = 0.7-1.7).Our results lend some credibility to the hypothesis that periconceptional maternal smoking increases the risk of a child being born with CL/P. The results concerning CPO provide no overall evidence of effect, although the estimates were relatively imprecise. We suggest that future research should emphasize validity studies, especially those of differential reporting, rather than replicating existing analyses of the relationship between maternal smoking and clefts. We discuss how our approach is also applicable to evaluating misclassification in a wide range of exposure-outcome scenarios.

    View details for DOI 10.1097/EDE.0b013e31818ab3b0

    View details for Web of Science ID 000261930800007

    View details for PubMedID 19234399

  • Periconceptional glycaemic load and intake of sugars and their association with neural tube defects in offspring PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Shaw, G. M., Carmichael, S. L., Laurent, C., Siega-Riz, A. M. 2008; 22 (6): 514-519

    Abstract

    In a California population, we previously observed increased neural tube defect (NTD) risks associated with maternal intakes of periconceptional diets predicting higher glycaemic responses and higher sucrose. Our objective here was to replicate these results in a larger study of multiple regions within the United States. This population-based case-control study included deliveries from 1997 to 2003 from the National Birth Defects Prevention Study. NTD cases were infants or fetuses born with spina bifida or anencephaly. Infants without malformations were eligible as controls. Interview participation was 71% among case mothers and 68% among control mothers. There were 720 NTD case and 4699 control mothers with completed interviews included in analyses. Diet was assessed using a 58-item food frequency questionnaire focusing on the year before conception, whereas cereals, beverages and supplement use was assessed periconceptionally. We found no increased risks of NTD-affected pregnancies with increased intakes (adjusted for kcal/day) of sucrose, glucose, fructose or with maternal diets with a higher glycaemic load. The reasons for current findings to be inconsistent with previous findings are unknown.

    View details for DOI 10.1111/j.1365-3016.2008.00964.x

    View details for Web of Science ID 000259818200003

    View details for PubMedID 19000288

  • Autoantibodies to folate receptor during pregnancy and neural tube defect risk JOURNAL OF REPRODUCTIVE IMMUNOLOGY Cabrera, R. M., Shaw, G. M., Ballard, J. L., Carmichael, S. L., Yang, W., Lammer, E. J., Finnell, R. H. 2008; 79 (1): 85-92

    Abstract

    Periconceptional folic acid can reduce the occurrence of neural tube defects (NTDs) by up to 70%, and autoantibodies for folate receptors (FRs) have been observed in serum from women with a pregnancy complicated by an NTD. This population-based cohort study has examined serum from pregnant mothers for autoantibodies to FRs, antibodies to bovine folate binding protein (FBP), and inhibition of folic acid binding to FR and FBP in association with NTD risk. The mid-gestational maternal serum specimens used for this study were collected during the 15-18th week of pregnancy. Samples were obtained from the California Birth Defects Monitoring Program; 29 mothers had a pregnancy complicated by spina bifida and 76 mothers had unaffected children. The presence of IgG and IgM antibodies to human FR, bovine FBP, and inhibition of folic acid binding to FR and FBP was determined. Higher activity of IgM to FBP in cases verses controls was observed (P=0.04). Higher activity of IgM and IgG autoantibodies to FR was observed (P<0.001 and P=0.04, respectively). Risk estimates at two standard deviations above average control antibody concentrations were OR=2.07 (CI=1.02, 4.06) for anti-FBP IgM, OR=2.15 (CI=1.02, 4.69) for anti-FR IgG and OR=3.19 (CI=1.47, 6.92) for anti-FR IgM. These data support the hypothesis that high titers of antibodies and blocking of folic acid binding to FRs by maternal serum should be regarded as risk factors for NTDs.

    View details for DOI 10.1016/j.jri.2008.08.002

    View details for Web of Science ID 000260989000012

    View details for PubMedID 18804286

  • Gastroschisis: A gene-environment model involving the VEGF-NOS3 pathway AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS Lammer, E. J., Iovannisci, D. M., Tom, L., Schultz, K., Shaw, G. M. 2008; 148C (3): 213-218

    Abstract

    Gastroschisis is a severe major malformation in which an infant is delivered with a portion of intestines and possible other abdominal organs extruding through a defect in the abdominal wall, usually to the right of the umbilical cord. Etiologies of gastroschisis are largely unknown, and even its pathogenesis is poorly understood. Several recent epidemiological studies have identified interactions between maternal smoking during pregnancy, genetic variants of endothelial nitric oxide synthase, and risk for gastroschisis. We present a brief review of the endothelial nitric oxide synthase pathway and its relationship to vasculogenesis, suggesting that disruption of this pathway by environmental exposures or by genetic variation may represent one pathogenetic model for gastroschisis.

    View details for DOI 10.1002/ajmg.c.30182

    View details for Web of Science ID 000258293400007

    View details for PubMedID 18655103

  • Gene-nutrient interactions: Importance of folic acid and vitamin B-12 during early embryogenesis FOOD AND NUTRITION BULLETIN Finnell, R. H., Shaw, G. M., Lammer, E. J., Rosenquist, T. H. 2008; 29 (2): S86-S98

    Abstract

    The role that nutritional factors play in mammalian development has received renewed attention over the past two decades as the scientific literature has exploded with reports that folic acid supplementation in the periconceptional period can protect embryos from a number of highly significant malformations. As is often the case, the relationship between B vitamin supplementation and improved pregnancy outcomes is more complicated than initially perceived, as the interaction between nutritional factors and selected genes must be considered. In this review, we attempt to summarize the complex clinical and experimental literature on nutritional factors, their biological transport mechanisms, and interactions with genetic polymorphisms that impact early embryogenesis. While not exhaustive, our goal was to provide an overview of important gene-nutrient interactions, focusing on folic acid and vitamin B12, to serve as a framework for understanding the multiple roles they play in early embryogenesis.

    View details for Web of Science ID 000257425800011

    View details for PubMedID 18709884

  • Maternal corticosteroid use and orofacial clefts AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Carmichael, S. L., Shaw, G. M., Ma, C., Werler, M. M., Rasmussen, S. A., Lammer, E. J. 2007; 197 (6)

    Abstract

    The purpose of this study was to examine whether maternal corticosteroid use during pregnancy is associated with delivering an infant with an orofacial cleft.This study included data on deliveries from the National Birth Defects Prevention Study, which is a population-based case-control study. Exposures were assessed by telephone interviews for mothers of 1141 cases with cleft lip +/- cleft palate (CLP), 628 with cleft palate (CP), and 4143 controls.Mothers of 33 infants with CLP (2.9%), mothers of 6 infants with CP (1.0%), and 72 control subjects (1.7%) reported corticosteroid use from 4 weeks before through 12 weeks after conception. The crude odds ratio for "any" vs "no" use was 1.7 (95% CI, 1.1-2.6) for CLP and 0.5 (0.2-1.3) for CP. When analyzed by route of administration and medication components, odds ratios for CLP tended to be elevated, and odds ratios for CP tended to be close to 1.Our results suggest a moderately increased risk of CLP among women who use corticosteroids during early pregnancy.

    View details for DOI 10.1016/j.ajog.2007.05.046

    View details for Web of Science ID 000251675700008

    View details for PubMedID 18060943

  • Nutrient intakes in women and risks of anophthalmia and microphthalmia in their offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Carmichael, S. L., Laurent, C., Louik, C., Finnell, R. H., Lammer, E. J. 2007; 79 (10): 708-713

    Abstract

    There is a paucity of information about risk factors for the human eye anomalies anophthalmia and microphthalmia. In this population-based case-control study we investigated whether periconceptional intakes of supplemental folic acid, dietary folate, vitamin A, and several other nutrients were associated with these eye defects.This study included data on deliveries that had estimated due dates from 1997-2002 and were part of the National Birth Defects Prevention Study (the National Birth Defects Prevention Study is a population-based case-control study of a wide spectrum of birth defects, incorporating data from 10 birth defects surveillance systems in the United States [Arkansas, California, Georgia/Centers for Disease Control and Prevention, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah]). Cases were those infants or fetuses born with either anophthalmia or microphthalmia. Liveborn infants without major malformations were eligible as controls. Maternal interviews were conducted, primarily by telephone, in English or Spanish. Participation in the interview was 71% among case mothers and 68% among control mothers. Interviews were completed with 89 case mothers and 4,143 control mothers. A shortened version of the food frequency questionnaire from the Nurse's Health Study was used to assess frequency of intake of 58 food items during the year before pregnancy.Our results did not indicate reduced risks for these eye malformations associated with maternal intake of vitamin supplements containing folic acid. The data did not show an association between malformation risk and higher or lower intakes of vitamin A. We also did not observe strong evidence that an abundance or a lack of dietary intake of any other nutrient was associated with increased risk of the studied eye malformations.Our observations contribute to a limited body of findings on these rare eye defects.

    View details for DOI 10.1002/bdra.20398

    View details for Web of Science ID 000250222400007

    View details for PubMedID 17847120

  • Association between 49 infant gene polymorphisms and preterm delivery AMERICAN JOURNAL OF MEDICAL GENETICS PART A Chen, B. H., Carmichael, S. L., Shaw, G. M., Iovannisci, D. M., Lammer, E. J. 2007; 143A (17): 1990-1996

    Abstract

    The occurrence of preterm delivery has been increasing in the U.S. Previous studies have identified risk factors for preterm delivery that may have genetic influences. We conducted a case-control study comparing the frequencies of 49 genetic polymorphisms among 62 preterm infants and 553 term infants. The polymorphisms that we examined were involved in xenobiotic-metabolism, blood pressure, coagulation, the inflammatory response, cell-cell interaction, or folate-homocysteine metabolism. Univariate analyses on the individual polymorphisms revealed a statistically significant effect for the variant genotypes compared to the wildtype genotypes in SERPINE1 11053G > T (OR = 0.4, 95% CI = 0.2-0.8). This finding suggests the coagulation/thrombophilic pathway may influence the development of preterm delivery.

    View details for DOI 10.1002/ajmg.a31868

    View details for Web of Science ID 000249173900007

    View details for PubMedID 17676631

  • Candidate genes for congenital diaphragmatic hernia from animal models: sequencing of FOG2 and PDGFR alpha reveals rare variants in diaphragmatic hernia patients EUROPEAN JOURNAL OF HUMAN GENETICS Bleyl, S. B., Moshrefi, A., Shaw, G. M., Saijoh, Y., Schoenwolf, G. C., Pennacchio, L. A., Slavotinek, A. M. 2007; 15 (9): 950-958

    Abstract

    Congenital diaphragmatic hernia (CDH) is a common, life threatening birth defect. Although there is strong evidence implicating genetic factors in its pathogenesis, few causative genes have been identified, and in isolated CDH, only one de novo, nonsense mutation has been reported in FOG2 in a female with posterior diaphragmatic eventration. We report here that the homozygous null mouse for the Pdgfralpha gene has posterolateral diaphragmatic defects and thus is a model for human CDH. We hypothesized that mutations in this gene could cause human CDH. We sequenced PDGFRalpha and FOG2 in 96 patients with CDH, of which 53 had isolated CDH (55.2%), 36 had CDH and additional anomalies (37.5%), and 7 had CDH and known chromosome aberrations (7.3%). For FOG2, we identified novel sequence alterations predicting p.M703L and p.T843A in two patients with isolated CDH that were absent in 526 and 564 control chromosomes respectively. These altered amino acids were highly conserved. However, due to the lack of available parental DNA samples we were not able to determine if the sequence alterations were de novo. For PDGFRalpha, we found a single variant predicting p.L967V in a patient with CDH and multiple anomalies that was absent in 768 control chromosomes. This patient also had one cell with trisomy 15 on skin fibroblast culture, a finding of uncertain significance. Although our study identified sequence variants in FOG2 and PDGFRalpha, we have not definitively established the variants as mutations and we found no evidence that CDH commonly results from mutations in these genes.

    View details for DOI 10.1038/sj.ejhg.5201872

    View details for Web of Science ID 000249144200008

    View details for PubMedID 17568391

  • Prepregnancy obesity as a risk factor for structural birth defects ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Waller, D. K., Shaw, G. M., Rasmussen, S. A., Hobbs, C. A., Canfield, M. A., Siega-Riz, A., Gallaway, M. S., Correa, A. 2007; 161 (8): 745-750

    Abstract

    To describe the relation between maternal obesity, overweight and underweight status, and 16 categories of structural birth defects.An ongoing multisite, case-control study. Clinical geneticists reviewed all of the cases, excluding those that had or were strongly suspected to have a single-gene disorder or chromosomal abnormality. Mothers with preexisting diabetes were also excluded. Body mass index was based on maternal report of height and weight prior to pregnancy.Eight participating states in the United States.Mothers enrolled in the National Birth Defects Prevention Study who had index pregnancies between October 1, 1997, and December 31, 2002.Maternal obesity.Crude and adjusted odds ratios.Mothers of offspring with spina bifida, heart defects, anorectal atresia, hypospadias, limb reduction defects, diaphragmatic hernia, and omphalocele were significantly more likely to be obese than mothers of controls, with odds ratios ranging between 1.33 and 2.10. Mothers of offspring with gastroschisis were significantly less likely to be obese than mothers of controls.To our knowledge, this is the first population-based study of its scale to examine prepregnancy obesity and a range of structural birth defects. These results suggest a weak to moderate positive association of maternal obesity with 7 of 16 categories of birth defects and a strong inverse association with gastroschisis. The mechanisms underlying these associations are not yet understood but may be related to undiagnosed diabetes.

    View details for Web of Science ID 000248583000003

    View details for PubMedID 17679655

  • Maternal smoking during early pregnancy, GSTP1 and EPHX1 variants, and risk of isolated orofacial clefts CLEFT PALATE-CRANIOFACIAL JOURNAL Ramirez, D., Lammer, E. J., Iovannisci, D. M., Laurent, C., Finnell, R. H., Shaw, G. M. 2007; 44 (4): 366-373

    Abstract

    To examine the interactions between four fetal xenobiotic metabolizing gene polymorphisms, maternal cigarette smoking, and risk for oral cleft defects.California population-based case-control study of 431 infants born with isolated orofacial clefts and 299 nonmalformed controls.Infants were genotyped for functional polymorphisms of the detoxification enzymes microsomal epoxide hydrolase-1 (EPHX1 T-->C [Tyr113His], and A-->G [His139Arg]), and glutathione-S transferase Pi-1 (GSTP1 A-->G [Ile105Val] and C-->T [Ala114Val]), and risks for cleft outcomes were measured for gene only and gene-maternal smoking effects.Although smoking was associated with an increased risk for isolated cleft lip+/-palate, we found no independent associations of genotypes of EPHX1-codon 113 or GSTP1-codon 105 polymorphisms for either isolated cleft lip+/-palate or isolated cleft palate. The heterozygote genotype for the EPHX1-codon 139 polymorphism was associated with an increased risk of isolated cleft palate (odds ratio=1.6 [95% confidence interval, 1.0 to 2.6]). Infant EPHX1 and GTSP1 polymorphic variants did not appreciably alter the risks for clefts associated with maternal smoking, nor were any EPHX1 combined genotype-specific risks found. Infant genotypes of the GSTP1-codon 105 polymorphism, combined with glutathione-S-transferase-mu-1 null genotypes, did not appreciably alter the risk of orofacial clefts.Our results suggest that genetic variation of the detoxification enzymes EPHX1 and GSTP1 did not increase the risks of orofacial clefting, nor do they influence the risks associated with maternal smoking.

    View details for DOI 10.1597/06-011.1

    View details for Web of Science ID 000248295300003

    View details for PubMedID 17608547

  • Maternal reproductive and demographic characteristics as risk factors for hypospadias PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Laurent, C., Olney, R. S., Lammer, E. J. 2007; 21 (3): 210-218

    Abstract

    This study examined the association of hypospadias risk with several maternal reproductive and demographic characteristics: age, parity, body mass index (BMI), nausea and vomiting of pregnancy (NVP), multiple pregnancy, fertility treatments and procedures, education and race-ethnicity. The study included data on deliveries with estimated due dates from October 1997 to December 2000 that were part of the National Birth Defects Prevention Study, a multi-state case-control study of many birth defects. The analysis included 502 cases with second or third degree hypospadias (i.e. the urethra opened at the penile shaft, scrotum or perineum) and 1286 male, liveborn, non-malformed controls. Risks were estimated from a multivariable logistic regression model that included all exposures of interest. Results indicated particularly elevated risks among births to women who were primiparae, aged >or=35 years and had a BMI of >26, compared with women who were multiparae, aged <30 years and had a BMI of

    View details for Web of Science ID 000245676100003

    View details for PubMedID 17439529

  • Screening for novel PAX3 polymorphisms and risks of spina bifida BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Lu, W., Zhu, H., Wen, S., Laurent, C., Shaw, G. M., Lammer, E. J., Finnell, R. H. 2007; 79 (1): 45-49

    Abstract

    PAX3 plays an important role in mammalian embryonic development. Known mutations in PAX3 are etiologically associated with Waardenburg syndrome and syndromic neural tube defects (NTDs). Mutations in the murine homologue, pax3, are responsible for the phenotype of splotch mice, in which nullizygotes are 100% penetrant for NTDs.The study sample included 74 infants with spina bifida (cases) and 87 nonmalformed infant controls. The conserved paired-box domain as well as the upstream genomic region of PAX3 were subjected to resequencing and those identified SNPs were evaluated as haplotypes. The associations of haplotypes for selected gene regions and the risks of spina bifida were further studied.Nineteen SNPs were observed; 15 observed in controls had been submitted to the National Center for Biotechnology Information (NCBI) database with allele frequencies. The PAX3 gene variant T-1186C (rs16863657) and its related haplotype, TCTCCGCCC of nine SNPs, were found to be associated with an increased risk of spina bifida, with an OR of 3.5 (95% CI: 1.2-10.0) among Hispanic Whites.Our analyses indicated that PAX3 SNPs were not strong risk factors for human spina bifida. However, additional follow-up of the PAX3 gene variant T-1186C (rs16863657) and its related haplotype, TCTCCGCCC, may be important in other populations.

    View details for DOI 10.1002/bdra.20322

    View details for Web of Science ID 000243314500007

    View details for PubMedID 17149730

  • Infant C677T MTHFR polymorphism and severe mental retardation BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Jelliffe-Pawlowski, L., Nelson, V., Zhu, H., Harris, J. A., Finnell, R. H. 2007; 79 (1): 24-26

    Abstract

    We investigated whether infants with homozygous genotype TT of the MTHFR gene were at increased risk of severe mental retardation.One hundred children with severe mental retardation (cases) were investigated from a large geographic-based study of infants born in California in 1992-1993. Cases were compared to 743 randomly selected nonmalformed control infants born in California during 1987-1991. DNA was extracted from newborn screening filter papers. Cases and controls were genotyped TT if homozygous for the MTHFR C677T allele, CT if heterozygous for the C677T allele, and CC if homozygous for the C677 (wild type) allele.Overall, case and control infants had similar percentages of TT and CT genotypes. Percentages between cases and controls differed somewhat across race/ethnic groups. Elevated ORs of 1.9 (95% CI: 0.7-5.0) and 2.6 (95% CI: 1.1-5.8) were observed for the TT and CT genotypes, respectively, among Hispanic children. Observed results were not substantially altered for analyses that removed 41 case children who also had structural birth defects.Folate-related mechanisms are important to investigate for etiologies of birth defects, and such lines of inquiry may be revealing for mental retardation given the relationships between mental retardation and birth defects and potential relationships between folate, DNA methylation, and mental retardation.

    View details for DOI 10.1002/bdra.20321

    View details for Web of Science ID 000243314500004

    View details for PubMedID 17149733

  • Risks of human limb deficiency anomalies associated with 29 SNPs of genes involved in homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation AMERICAN JOURNAL OF MEDICAL GENETICS PART A Carmichael, S. L., Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Cheng, S., Lammer, E. J. 2006; 140A (22): 2433-2440
  • Risks of human limb deficiency anomalies associated with 29 SNPs of genes involved in homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation. American journal of medical genetics. Part A Carmichael, S. L., Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Cheng, S., Lammer, E. J. 2006; 140 (22): 2433-2440

    Abstract

    This study explored risks of limb deficiency anomalies associated with 29 single nucleotide polymorphisms (SNPs) of genes involved in homocysteine metabolism, coagulation, cell-cell interaction, inflammatory response, and blood pressure regulation. The authors genotyped 96 cases and 437 non-malformed controls from a California population-based case-control study (1987-1988 birth cohort). Increased risk of limb anomaly was observed for three SNPs: heterozygosity for F5 Arg506Gln, with an odds ratio (OR) of 2.5 (95% confidence interval (CI), 1.0, 6.5); heterozygosity for TNF (-376)G > A, OR 2.1 (0.7, 6.2); and homozygosity for NPPA 2238T > C, OR 4.0 (1.1, 15.4). We hypothesized that effects of variant genotypes in the presence of maternal smoking, and/or in the absence of supplement intake, may exceed effects of any of these factors alone. In particular, findings for polymorphisms in SERPINE1, ITGA2, SELE, TNF, LTA, NPPA, GNB3, and ADRB2 supported the hypotheses, both for smoking and for supplement intake. These results suggest involvement of genetic variation of biologically relevant candidate genes, and gene-environment interaction, for some limb anomalies whose pathogenesis may be related to altered vascular tone or integrity.

    View details for PubMedID 17036337

  • Risk of limb deficiency defects associated with NAT1, NAT2, GSTT1, GSTM1, and NOS3 genetic variants, maternal smoking, and vitamin supplement intake AMERICAN JOURNAL OF MEDICAL GENETICS PART A Carmichael, S. L., Shaw, G. M., Yang, W., Iovannisci, D. M., Lammer, E. 2006; 140A (18): 1915-1922
  • Risk of limb deficiency defects associated with NAT1, NAT2, GSTT1, GSTM1, and NOS3 genetic variants, maternal smoking, and vitamin supplement intake. American journal of medical genetics. Part A Carmichael, S. L., Shaw, G. M., Yang, W., Iovannisci, D. M., Lammer, E. 2006; 140 (18): 1915-1922

    Abstract

    Increasing epidemiologic evidence suggests that genetic susceptibilities contribute to birth defects risks, especially in combination with other environmental exposures. This analysis examines the association of risk of limb deficiency defects with infant genotypes for N-acetyltranferases (NAT1, NAT2), glutathione-S-tranferases (GSTT1, GSTM1), and endothelial nitric oxide synthase (NOS3). The combined effects of infant genotype with maternal smoking and supplement intake were also examined. The authors genotyped 92 cases and 201 non-malformed controls from a California population-based case-control study (1987-1988 birth cohort). Several of the infant genotypes were associated with an at least 1.5-fold increased risk for limb deficiency defects: homozygosity for the NAT1 1088 and 1095 polymorphisms, heterozygosity and homozygosity for the NOS3 A(-922)G polymorphism, and heterozygosity (but not homozygosity) for the NOS3 G894T polymorphism. The authors hypothesized that the effects of selected variant genotypes in the presence of maternal smoking, or in the absence of supplement intake, may exceed effects of any of these factors alone. A few observations suggested that risks were greatest among infants with variant genotypes, whose mothers also smoked or did not take supplements, but most did not, and risk estimates were imprecise. Further studies exploring genetic susceptibility and combined gene-environment effects with respect to limb development will be important to continued improvement of our understanding of the etiology of limb anomalies.

    View details for PubMedID 16906563

  • Neural tube defects and folate: case far from closed NATURE REVIEWS NEUROSCIENCE Blom, H. J., Shaw, G. M., den Heijer, M., Finnell, R. H. 2006; 7 (9): 724-731

    Abstract

    Neural tube closure takes place during early embryogenesis and requires interactions between genetic and environmental factors. Failure of neural tube closure is a common congenital malformation that results in morbidity and mortality. A major clinical achievement has been the use of periconceptional folic acid supplements, which prevents approximately 50-75% of cases of neural tube defects. However, the mechanism underlying the beneficial effects of folic acid is far from clear. Biochemical, genetic and epidemiological observations have led to the development of the methylation hypothesis, which suggests that folic acid prevents neural tube defects by stimulating cellular methylation reactions. Exploring the methylation hypothesis could direct us towards additional strategies to prevent neural tube defects.

    View details for DOI 10.1038/nrn1986

    View details for Web of Science ID 000240512500014

    View details for PubMedID 16924261

  • Recovery of genomic DNA from residual frozen archival blood clots suitable for amplification and use in genotyping assays GENETIC TESTING Iovannisci, D. M., Ha, T. T., Shaw, G. M. 2006; 10 (1): 44-49

    Abstract

    A greatly neglected source of DNA potentially useful for genetic or forensic studies is the clot remaining from blood samples collected for serum chemistry measurements. We have investigated the utility of residual clots remaining from venipunctures collected for California's Expanded Maternal Serum Alpha-Fetoprotein Screening Program. We report a protocol based on the salting out method for the extraction of DNA from samples which have been archived and frozen for up to 2.5 years. As much as 57 microg of high-quality DNA can be obtained from a 2-ml clot as determined by PicoGreen (Molecular Probes, Inc., Eugene, OR) fluorescence measurements. Quality of the purified DNA was evaluated by its ability to serve as template in polymerase chain reaction (PCR) amplifications, using primers that flank the polymorphic regions of six genes of pharmacogenetic interest distributed throughout the human genome. Sizes of the gene regions successfully amplified range from 215 bp to 2064 bp, using as little as 10 ng of template DNA. Because many genotyping protocols routinely recommend the design of amplicons in the 100-200 bp range, and 10-50 ng of template, we conclude that the clot remaining after serum has been removed from blood collected for serum chemistry measurements can serve as a reliable source of DNA for genotyping studies.

    View details for Web of Science ID 000236347300008

    View details for PubMedID 16545003

  • Correlates of intake of folic acid-containing supplements among pregnant women AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Carmichael, S. L., Shaw, G. M., Yang, W., Laurent, C., Herring, A., Royle, M. H., Canfield, M. 2006; 194 (1): 203-210

    Abstract

    This study describes the timing and correlates of folic acid supplement intake among pregnant women.Data from 2518 women with estimated delivery dates from 1997 to 2000, collected for the National Birth Defects Prevention Study, a population-based case-control study, were analyzed. Multinomial logistic regression was used to identify correlates of supplement intake.Fifty-three percent of women began taking folic acid supplement during the periconceptional period, 35% during early pregnancy, and 8% during late pregnancy (ie, 3 months before through 1 month after conception, 2-3 months after conception, or more than 3 months after conception, respectively). Women who did not take folic acid supplement periconceptionally tended to be nonwhite, speak Spanish, have low education, be younger than 25 years old, be nulliparous, smoke, have no previous miscarriage and no fertility treatments, begin prenatal care and become aware of their pregnancy after the first trimester, have nonplanned pregnancies, and eat less breakfast cereal.This study identifies correlates of folic acid supplement intake, which may contribute to the design of interventions to improve intake during early pregnancy.

    View details for DOI 10.1016/j.ajog.2005.06.018

    View details for Web of Science ID 000234386200031

    View details for PubMedID 16389033

  • Endothelial nitric oxide synthase (NOS3) genetic variants, maternal smoking, vitamin use, and risk of human orofacial clefts AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Carmichael, S. L., Cheng, S., Lammer, E. J. 2005; 162 (12): 1207-1214

    Abstract

    Orofacial clefts have been associated with maternal cigarette smoking and lack of folic acid supplementation (which results in higher plasma homocysteine concentrations). Because endothelial nitric oxide synthase (NOS3) activity influences homocysteine concentration and because smoking compromises NOS3 activity, genetic variation in NOS3 might interact with smoking and folic acid use in clefting risk. The authors genotyped 244 infants with isolated cleft lip with or without cleft palate (CL/P), 99 with isolated cleft palate, and 588 controls from a California population-based case-control study (1987-1989 birth cohort) for two NOS3 polymorphisms: A(-922)G and G894T. Analyses of gene-only effects for each polymorphism revealed a 60% increased risk of CL/P among NOS3 A(-922)G homozygotes (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.6). There was some evidence for higher risk of CL/P with maternal periconceptional smoking in infants with an NOS3 -922G allele (for homozygotes, OR = 2.5, 95% CI: 1.2, 5.6) but not in those with an 894T allele. For CL/P risk, odds ratios were over 4 among mothers who smoked, who did not use vitamins, and whose infants had at least one variant allele for each NOS3 polymorphism (for A(-922)G, OR = 4.6, 95% CI: 2.1, 10.2; for 894T, OR = 4.4, 95% CI: 1.8, 10.7). No similar patterns were observed for risk of cleft palate.

    View details for DOI 10.1093/aje/kwi336

    View details for Web of Science ID 000233850400009

    View details for PubMedID 16269583

  • Hypospadias and maternal exposures to cigarette smoke PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Laurent, C., Lammer, E. J., Olney, R. S. 2005; 19 (6): 406-412

    Abstract

    The few previous studies of hypospadias and smoking have suggested either no association or a reduced risk. This study, which uses data from the National Birth Defects Prevention Study, a multi-state, population-based case-control study, includes data on males born with severe hypospadias (i.e. the urethra opens at the penile shaft, scrotum or perineum) from 1997 to 2000. Non-malformed, liveborn male controls were selected randomly from birth certificates or from birth hospitals. Maternal interviews were completed by telephone with 453 case mothers and 1267 control mothers. Maternal smoking was not associated with hypospadias risk. For example, during the third month of pregnancy, smoking < 0.5 pack/day had an odds ratio (OR) of 1.1 [95% CI 0.6, 1.9]; 0.5 pack/day, 0.6 [0.4, 1.1]; and > or = 1 pack/day, 0.8 [0.4, 1.6]. Exposure to any secondhand smoke at home during the third month of pregnancy showed an OR of 0.6 [95% CI 0.4, 1.0], and exposure at work or school, an OR of 0.7 [0.5, 1.1]. Similar risks were observed for other months during the periconceptional period, and adjustment for several potential confounders did not substantially alter results. This analysis does not confirm a recent report suggesting that maternal smoking is associated with a reduced risk of having offspring with hypospadias.

    View details for Web of Science ID 000233020700002

    View details for PubMedID 16269066

  • Maternal progestin intake and risk of hypospadias ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Carmichael, S. L., Shaw, G. M., Laurent, C., Croughan, M. S., Olney, R. S., Lammer, E. J. 2005; 159 (10): 957-962

    Abstract

    Previous studies have suggested that maternal intake of progestins during early pregnancy may be associated with an increased risk of hypospadias. Progesterone and its derivatives are commonly prescribed during early pregnancy, for example, in cases of luteal phase dysfunction and in conjunction with ovulation stimulation drugs.To examine whether risk of hypospadias was associated with periconceptional progestin intake.The National Birth Defects Prevention Study, a population-based, multistate, case-control study including deliveries that had estimated due dates from October, 1997 to December, 2000.Participation in the study was 71% among case mothers and 68% among control mothers. This analysis included 502 subjects diagnosed with second- or third-degree hypospadias (ie, the urethra opened at the penile shaft, scrotum, or perineum) and 1286 male, live-born, nonmalformed control subjects.Forty-two case mothers (8.4%) and 31 control mothers (2.4%) reported any pregnancy-related progestin intake from 4 weeks before through 14 weeks after conception, resulting in an odds ratio of 3.7 (95% confidence interval [CI], 2.3-6.0). Analyses stratified by several potential covariates also suggested elevated risks. For example, among the 10 cases and 13 controls who did not report any fertility-related procedures or treatments other than progestins, the odds ratio was 2.2 (95% CI, 1.0-5.0). Progestin intake for the purpose of contraception was not associated with increased risk.This study found that pregnancy-related intake of progestins was associated with increased hypospadias risk.

    View details for Web of Science ID 000232322000008

    View details for PubMedID 16203941

  • Risks of human conotruncal heart defects associated with 32 single nucleotide polymorphisms of selected cardiovascular disease-related genes AMERICAN JOURNAL OF MEDICAL GENETICS PART A Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Carmichael, S. L., Cheng, S., Lammer, E. J. 2005; 138A (1): 21-26
  • Risks of human conotruncal heart defects associated with 32 single nucleotide polymorphisms of selected cardiovascular disease-related genes. American journal of medical genetics. Part A Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Carmichael, S. L., Cheng, S., Lammer, E. J. 2005; 138 (1): 21-26

    Abstract

    Investigating possible genetic polymorphisms and gene-environment interactions in the etiology of human conotruncal defects is a prudent research approach. In this study we explore gene-only and gene-environment effects of 32 single nucleotide polymorphisms (SNPs) on conotruncal defect risks. The genes bearing these SNPs participate in one of five pathogenetic processes, homocysteine metabolism, coagulation, cell-cell interaction, inflammatory response, and blood pressure regulation. We used DNA samples and data from a California population-based case-control interview study (1987-1988 birth cohort). We employed a multilocus allele-specific hybridization assay. Allelic variants were determined by genotyping 155 infants with conotruncal defects (cases) and 437 infants without malformations (controls). Among the 32 SNPs, four were associated with odds ratios of 2 or more, and two with odds ratios of 0.5 or less. The four SNPs were F2 G20210A (prothrombin) with an odds ratio of 2.5 (95% confidence interval; 0.9-7.0), F7 promoter (-323) 10-bp del/ins with an odds ratio of 2.3 (0.8-6.8), ITGB3 leu33pro (platelet glycoprotein IIIa) with an odds ratio of 2.2 (0.9-5.7), and NPPA T2238C (atrial natriuretic precursor peptide) with an odds ratio of 2.9 (0.8-10.1). Two SNPs were associated with decreased risks: TNF (tumor necrosis factor, G (-376A)) and ADD1 gly460trp (alpha adducin) with odds ratios of 0.5 (0.1-2.3) and 0.5 (0.2-1.9), respectively. Analyses that investigated a potential gene-nutrient interaction between maternal periconceptional vitamin use and MTHFR genotypes did not indicate that the CT or TT genotype contributed to conotruncal defect risk in infants even in the absence of maternal use of multivitamin supplements with folic acid. Analyses that investigated a potential interaction on risk between NOS3 genes and maternal cigarette smoking, revealed some evidence for higher risk of conotruncal defects in infants whose mothers smoked cigarettes periconceptionally and who had one of the variant alleles for NOS3 A(-922G) or NOS3 glu298asp compared to those infants whose mothers did not smoke and whose genotypes were wild-type. Our results provide some support for involvement of genetic variation of biologically relevant candidate genes for some birth defects whose pathogenesis may be related to altered vascular tone or integrity. In particular, NPPA appears to be a good candidate gene for conotruncal defects and warrants further investigation.

    View details for PubMedID 16100725

  • Maternal smoking, genetic variation of glutathione S-transferases, and risk for orofacial clefts EPIDEMIOLOGY Lammer, E. J., Shaw, G. M., Iovannisci, D. M., Finnell, R. H. 2005; 16 (5): 698-701

    Abstract

    Maternal smoking is a known risk factor for orofacial clefts. We investigated whether risk is greater among offspring who lack the genetic capacity to produce glutathione S-transferase enzymes relevant to detoxification of chemicals in cigarette smoke.Using a population-based case-control design, we genotyped 423 California infants with an isolated cleft and 294 nonmalformed controls for null variants of the glutathione S-transferases GSTT1 and GSTM1.If a mother smoked during pregnancy and her fetus was homozygous null for GSTT1, the risk of isolated cleft lip with or without cleft palate was tripled (odds ratio = 2.9; 95% confidence interval = 1.2-7.2). For fetuses who were homozygous null for GSTM1 and whose mothers smoked >/=20 cigarettes per day, we found nearly a 7-fold increased risk (6.8; 0.82-57). Combined absence of GSTM1 and GSTT1 enzymes among the offspring of smoking mothers was associated with a nearly 6-fold increased risk for cleft lip (6.3; 1.3-42). A similar increased risk for cleft palate was associated with absence of GSTM1, but not for absence of GSTT1.Maternal smoking during pregnancy increases risks for clefts among fetuses lacking enzymes involved in the detoxification of tobacco-derived chemicals.

    View details for DOI 10.1097/01.ede.0000172136.26733.4b

    View details for Web of Science ID 000231783200017

    View details for PubMedID 16135950

  • Genes encoding catalytic subunits of protein kinase A and risk of spina bifida BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Zhu, H. P., Lu, W., Laurent, C., Shaw, G. M., Lammer, E. J., Finnell, R. H. 2005; 73 (9): 591-596

    Abstract

    PRKACA and PRKACB are genes encoding the cAMP-dependent protein kinase A (PKA) catalytic subunits alpha and beta, respectively. PKA is known to be involved in embryonic development, as it down-regulates the Hedgehog (Hh) signaling pathway, which is critical to normal pattern formation and morphogenesis. The PKA-deficient mouse model, which has only a single catalytic subunit, provided intriguing evidence demonstrating a relationship between decreased PKA activity and risk for posterior neural tube defects (NTDs) in the thoracic to sacral regions of gene-knockout mice. Unlike most other mutant mouse models of NTDs, the PKA-deficient mice develop spina bifida with 100% penetrance. We hypothesized that sequence variations in human genes encoding the catalytic subunits may alter the PKA activity and similarly increase the risk of spina bifida.We sequenced the coding regions and the exon/intron boundaries of PRKACA and PRKACB. We also examined 3 common single-nucleotide polymorphisms (SNPs) of these 2 genes by allele discrimination.Five sequence variants in coding region and 2 intronic sequence variants proximal to exons were detected. None of the 3 SNPs examined in the association study appeared to be associated with substantially increased risk for spina bifida.Our results did not reveal a strong association between these PKA SNPs and spina bifida risk. Nonetheless, it is important to examine the possible gene-gene interactions between PRKACA and PRKACB when evaluating the risk for NTDs, as well as genes encoding regulatory subunits of PKA. In addition, interactions with other genes such as Sonic Hedgehog (SHH) should also be considered for future investigations.

    View details for DOI 10.1002/bdra.20175

    View details for Web of Science ID 000232323300002

    View details for PubMedID 16080189

  • Epidemiologic characteristics of anophthalmia and bilateral microphthalmia among 2.5 million births in California, 1989-1997 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Shaw, G. M., Carmichael, S. L., Yang, W., Harris, J. A., Finnell, R. H., Lammer, E. J. 2005; 137A (1): 36-40
  • Epidemiologic characteristics of anophthalmia and bilateral microphthalmia among 2.5 million births in California, 1989-1997. American journal of medical genetics. Part A Shaw, G. M., Carmichael, S. L., Yang, W., Harris, J. A., Finnell, R. H., Lammer, E. J. 2005; 137 (1): 36-40

    Abstract

    There is a paucity of epidemiologic information about the eye malformations anophthalmia and microphthalmia. Using data from a large population-based registry, we explored prevalences and maternal/infant characteristics associated with anophthalmia and bilateral microphthalmia. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 2.5 million births (liveborn and stillborn) occurred during the ascertainment period, 1989-1997. Information on maternal and infant/fetal characteristics was obtained from California birth certificate and fetal death files. The prevalence per 10,000 livebirths and stillbirths for anophthalmia was 0.18 and for bilateral microphthalmia was 0.22. These estimates reflect prevalences among births without chromosomal anomalies. Relative risks of anophthalmia were modestly higher among women aged 40 or more (relative risk = 2.0, 95% confidence interval 0.5-8.6). Risks were substantially lower for those mothers with >12 years of education, even after adjusting for other study factors, relative risk = 0.6 (0.2-1.7). The risk of anophthalmia was approximately twofold among multiple births compared to singletons. Similar to results for anophthalmia, decreased risks for bilateral microphthalmia were observed for maternal education of 12 years or more and increased risks observed for multiple births. These data show descriptive epidemiologic features of anophthalmia and bilateral microphthalmia.

    View details for PubMedID 16007635

  • Risks for severe mental retardation occurring in isolation and with other developmental disabilities AMERICAN JOURNAL OF MEDICAL GENETICS PART A Jelliffe-Pawlowski, L. L., Shaw, G. M., Nelson, V., Harris, J. A. 2005; 136A (2): 152-157
  • Risks for severe mental retardation occurring in isolation and with other developmental disabilities. American journal of medical genetics. Part A Jelliffe-Pawlowski, L. L., Shaw, G. M., Nelson, V., Harris, J. A. 2005; 136 (2): 152-157

    Abstract

    Individual and maternal characteristics as potential risk factors for having severe mental retardation (SMR) occurring with and without cerebral palsy (CP), epilepsy, or a pervasive developmental disorder (PDD) were explored among a cohort of 119,404 children without Down syndrome born in the California Central Valley in 1992 and 1993. Unadjusted and adjusted relative risks (RRs) and their 95% confidence intervals (CIs) based on the Poisson distribution were used to estimate the risks associated with each individual and maternal factor studied for each SMR diagnostic category. The most notable increased risks for SMR occurring in isolation or with CP or epilepsy was for children born low-birth-weight or preterm who were at a substantially increased risk (RRs 2.6-9.9). In contrast, the risk of SMR occurring with a PDD was the greatest among males compared to females (RR = 3.4, 95% CI 1.5, 7.9), Blacks compared to Whites (RR = 5.1, 95% CI 1.7, 15.5), and Asians compared to Whites (RR = 3.9, 95% CI 1.3, 12.0). Etiologic heterogeneity when SMR occurs with a PDD was suggested.

    View details for PubMedID 15940698

  • Polymorphisms in DNA repair genes as risk factors for spina bifida and orofacial clefts. American journal of medical genetics. Part A Olshan, A. F., Shaw, G. M., Millikan, R. C., Laurent, C., Finnell, R. H. 2005; 135 (3): 268-273

    Abstract

    Repairing DNA damage is critical during embryogenesis because development involves sensitive periods of cell proliferation, and abnormal cell growth or death can result in malformations. Knockout mouse experiments have demonstrated that disruption of DNA repair genes results in embryolethality and structural defects. Studies using mid-organogenesis rat embryos showed that DNA repair genes were variably expressed. It is hypothesized that polymorphisms that alter the functionality of DNA repair enzymes may modify the risk of malformations. We conducted a case-control analysis to investigate the relationship between DNA repair gene polymorphisms and the risk of spina bifida and oral clefts. Newborn screening blood spot DNA was obtained for 250 cases (125 spina bifida, 125 oral clefts) identified by the California Birth Defects Monitoring Program, and 350 non-malformation controls identified from birth records. Six single nucleotide polymorphisms of five DNA repair genes representing three distinct repair pathways were interrogated including: XRCC1 (Arg399Gln), APE1 (Asp148Glu), XRCC3 (Thr241Met), hOGG1(Ser326Cys), XPD (Asp312Asn, Lys751Gln). Elevated or decreased odds ratios (OR, adjusted for race/ethnicity) for spina bifida were found for genotypes containing at least one copy of the variant allele for XPD [751Gln, OR = 1.62; 95% confidence interval (CI) = 1.05-2.50] and APE 148 (OR = 0.58; CI = 0.37-0.90). A decreased risk of oral clefts was found for XRCC3 (OR = 0.62; CI = 0.39-0.99) and hOGG1 (326 Cys/Cys, OR = 0.22; CI = 0.06-0.78). This study suggested that polymorphisms of DNA repair genes, representing different major repair pathways, may affect risk of two major birth defects. Future, larger studies, examining additional repair genes, birth defects, and interaction with exposures are recommended.

    View details for PubMedID 15887293

  • Polymorphisms in DNA repair genes as risk factors for spina bifida and Orofacial clefts AMERICAN JOURNAL OF MEDICAL GENETICS PART A Olshan, A. F., Shaw, G. M., Millikan, R. C., Laurent, C., Finnell, R. H. 2005; 135A (3): 268-273
  • Maternal obesity, gestational diabetes, and central nervous system birth defects EPIDEMIOLOGY Anderson, J. L., Waller, D. K., Canfield, M. A., Shaw, G. M., Watkins, M. L., Werler, M. M. 2005; 16 (1): 87-92

    Abstract

    Maternal obesity and diabetes are both associated with increased risk of congenital central nervous system (CNS) malformations in the offspring and may share a common underlying mechanism. Our objective was to evaluate whether gestational diabetes influenced the association of prepregnancy maternal obesity and risks for CNS birth defects.This Texas population-based case-control study evaluated births occurring January 1997 through June 2001. Data came from structured telephone interviews. Cases (n=477) were mothers of offspring with anencephaly (n=120), spina bifida (n=184), holoprosencephaly (n=49), or isolated hydrocephaly (n=124). Controls (n=497) were mothers of live infants without abnormalities randomly selected from the same hospitals as cases. Response rates were approximately 60% for both cases and controls. We evaluated maternal obesity (body mass index > or =30.0 kg/m) and risks for CNS birth defects, as well as whether gestational diabetes influenced the risks.After adjusting for maternal ethnicity, age, education, smoking, alcohol use, and periconceptional vitamin use, obese women had substantially increased risks of delivering offspring with anencephaly (odds ratio=2.3; 95% confidence interval=1.2-4.3), spina bifida (2.8; 1.7-4.5), or isolated hydrocephaly (2.7; 1.5-5.0), but not holoprosencephaly (1.4; 0.5-3.8). Odds ratios were higher for the joint effects of maternal obesity and gestational diabetes, with evidence for interaction on a multiplicative scale.Maternal obesity and gestational diabetes may increase the risk of CNS birth defects through shared causal mechanisms.

    View details for DOI 10.1097/01.ede.0000147122.97061.bb

    View details for Web of Science ID 000226079600013

    View details for PubMedID 15613950

  • Periconceptional multivitamin intake during early pregnancy, genetic variation of acetyl-N-transferase 1 (NAT1), and risk for Orofacial clefts BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Lammer, E. J., Shaw, G. M., Iovannisci, D. M., Finnell, R. H. 2004; 70 (11): 846-852

    Abstract

    Periconceptional supplementation of multivitamins that include folic acid have been shown to prevent several birth defects, including neural tube defects and orofacial clefts. We investigated whether polymorphic variants of fetal acetyl-N-transferase 1 (NAT1), an enzyme involved in the catabolism of folates, differentially interacted with maternal multivitamin use during early pregnancy to alter the risk of delivering an infant with an orofacial cleft malformation.Using a large population-based case-control study, we genotyped 421 California infants born with an isolated cleft and 299 controls for two NAT1 polymorphisms.Compared to the homozygous wild-type genotypes, odds ratios for isolated cleft lip with/without cleft palate were slightly increased among infants who were homozygous for the variant alleles of NAT1 1088 and 1095. For isolated cleft palate, no similar associations with these two NAT1 variants were observed. For NAT1 1088 genotypes, we did not observe any differential risks for clefts related to maternal multivitamin intake. For NAT1 1095 genotypes, however, we found a two-fold higher risk for isolated cleft lip with/without cleft palate among infants who were homozygous for the variant allele and whose mothers did not take multivitamins during early pregnancy.We found evidence suggestive of an interaction between the NAT1 1095 polymorphism and lack of maternal multivitamin use that increased risks of isolated cleft lip with/without cleft palate.

    View details for DOI 10.1002/bdra.20081

    View details for Web of Science ID 000225522500005

    View details for PubMedID 15523664

  • Gene-nutrient interactions: importance of folates and retinoids during early embryogenesis TOXICOLOGY AND APPLIED PHARMACOLOGY Finnell, R. H., Shaw, G. M., Lammer, E. J., Brandl, K. L., Carmichael, S. L., Rosenquist, T. H. 2004; 198 (2): 75-85

    Abstract

    The role that nutritional factors play in mammalian development has received renewed attention over the past two decades, as the scientific literature exploded with reports of retinoid compounds disrupting craniofacial development, and with other reports that folic acid supplementation in the periconceptional period can protect embryos from highly significant malformations. As was often the case, the situation became far more complicated, as the interaction between nutritional factors with selected genes was recognized. In this review, we attempt to summarize a complex clinical and experimental literature of nutritional factors, their biological transport mechanisms, and the impact that they have during early embryogenesis. Although not exhaustive, our goal was to provide an overview of important gene-nutrient interactions and a framework for their investigation.

    View details for DOI 10.1016/j.taap.2003.09.031

    View details for Web of Science ID 000222713900001

    View details for PubMedID 15236946

  • Limb deficiency defects, MSX1, and exposure to tobacco smoke AMERICAN JOURNAL OF MEDICAL GENETICS PART A Carmichael, S. L., Shaw, G. M., Yang, W., Lammer, E. J., Zhu, H. P., Finnell, R. H. 2004; 125A (3): 285-289

    Abstract

    There is increasing evidence from epidemiologic studies that genetic susceptibilities may modify the teratogenic effects of smoking. A previous study suggested that maternal smoking in the presence of a dinucleotide repeat polymorphism for MSX1 produced an almost fivefold increased risk for limb anomalies, providing evidence for a gene-environment interaction. The current study examined this potential interaction, using case-control data with several methodologic improvements, including a larger sample size and more detailed information on cigarette smoke exposures. Cases (n = 92) were ascertained from pregnancies ending in 1987-1989, and controls (n = 180) were randomly selected from eligible liveborn infants. In telephone interviews, women reported smoking behaviors during the month before pregnancy through the end of the first trimester. Odds ratios (OR) for maternal and paternal smoking ranged from 1.0 to 1.4, risk estimates were imprecise; for example, the OR for maternal smoking >or=20 cigarettes per day, versus none, was 1.3 (95% confidence interval (CI) 0.5-3.4). Relative to the homozygous wildtype, the OR was 1.5 (95% CI 0.7-3.5) for the homozygous variant genotype and 0.8 (95% CI 0.5-1.4) for the heterozygous variant genotype. There was no evidence that maternal smoking or both parents smoking, in combination with a susceptible MSX1 genotype, conferred an additional increase in risk of limb defects. This study did not find a gene-environment interaction between maternal smoking, infant MSX1 CA repeat polymorphism, and risk of limb deficiency defects. This finding contrasts with results of a previous study, which provided initial evidence for such an interaction. Several important methodological differences may have contributed to the differences in findings between the two studies.

    View details for DOI 10.1002/ajmg.a.20517

    View details for Web of Science ID 000189316800011

    View details for PubMedID 14994238

  • Maternal smoking and the risk of orofacial clefts - Susceptibility with NAT1 and NAT2 polymorphisms EPIDEMIOLOGY Lammer, E. J., Shaw, G. M., Iovannisci, D. M., Van Waes, J., Finnell, R. H. 2004; 15 (2): 150-156

    Abstract

    Orofacial clefts are etiologically heterogeneous malformations. One probable cause is maternal smoking during pregnancy. The effect of maternal smoking may be modified by genes involved in biotransformation of toxic compounds derived from tobacco. We investigated whether polymorphic variants of fetal acetyl-N-transferases 1 (NAT1) and 2 (NAT2) interact with maternal cigarette smoking during early pregnancy to increase the risk of delivering an infant with an orofacial cleft.In a California population-based case-control study, we genotyped 421 infants born with an isolated cleft and 299 nonmal-formed controls for 2 NAT1 and 3 NAT2 single nucleotide polymorphismsAlthough smoking was independently associated with increased risks for both isolated cleft lip +/- cleft palate and isolated cleft palate, no independent associations were found for NAT1 1088 or 1095 genotypes or for NAT2 acetylator status. However, the infant NAT1 1088 and 1095 polymorphisms were strongly associated with the risk of clefts among smoking mothers; infants with NAT1 1088 genotype AA versus TT (odds ratio [OR] = 3.9; 95% confidence interval = 1.1-17.2) and with NAT1 1095 genotype AA versus CC (OR = 4.2; 1.2-18.0). Infant NAT2 acetylator status did not appreciably affect susceptibility of the fetus to the teratogenic effects of maternal smoking.Our results suggest that maternal smoking during pregnancy may increase risk for orofacial clefts particularly among smokers whose fetuses have polymorphic variants of NAT1, an enzyme involved in phase II detoxification of tobacco smoke constituents.

    View details for DOI 10.1097/01.ede.0000112214.33432.cc

    View details for Web of Science ID 000189286900006

    View details for PubMedID 15127906

  • Associations between polymorphisms within the thymidylate synthase gene and spina bifida BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Volcik, K. A., Shaw, G. M., Zhu, H. P., Lammer, E. J., Laurent, C., Finnell, R. H. 2003; 67 (11): 924-928

    Abstract

    Polymorphisms within the thymidylate synthase (TS) gene that influence enzyme activity may affect plasma folate levels and, indirectly, plasma homocysteine concentrations. We investigated whether TS polymorphisms contribute to spina bifida (SB) risk, given that a reduction in the risk of SB has been linked to folate metabolism.Genomic DNA was extracted from newborn-screening blood spots obtained from case infants with SB, and randomly selected, nonmalformed control infants. Genotype frequencies of two polymorphisms in the TS gene-a 28-bp tandem repeat in the promoter enhancer region (TSER) and a 6-bp deletion in the 3'UTR-were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. Additionally, all seven exons of the TS gene were sequenced to identify variations within the coding region of the gene.We found that the TSER 2/2 homozygous genotype was associated with a slightly increased risk for SB infants (odds ratio [OR] = 1.4 [0.8-2.4], p = 0.1). When the cohort was divided into separate ethnic groups, this risk increased by 4-fold with the TSER 2/2 homozygous genotype (OR = 4.0 [1.8-8.8], p = 0.001), and by 3-fold with the 3'UTR +/+ homozygous genotype (OR = 3.6 [1.3-10.1], p = 0.02) in non-Hispanic white cases. The combined TSER,3'UTR (2/2,+/+) genotype showed a more than 4-fold increased risk for SB within this specific ethnic group (OR = 4.7 [1.1-19.8], p = 0.04).This study is the first to evaluate how TS polymorphisms contribute to the risk of SB. The current findings indicate that polymorphisms in the untranslated regions of the TS gene are associated with 4-fold or more increased risks of SB in non-Hispanic whites, but not in Hispanic whites, African-Americans, or Asian-Americans.

    View details for DOI 10.1002/bdra.10029

    View details for Web of Science ID 000186851600007

    View details for PubMedID 14745930

  • Genetic variation of infant reduced folate carrier (A80G) and risk of orofacial and conotruncal heart defects AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Zhu, H. P., Lammer, E. J., Yang, W., Finnell, R. H. 2003; 158 (8): 747-752

    Abstract

    How folate reduces the risks of congenital anomalies is unknown. The authors focused on a gene involved in folate transport-reduced folate carrier-1 gene (RFC1). Using data from a California case-control study (1987-1989 births), the authors investigated whether the risks of orofacial clefts or conotruncal heart defects were influenced by a polymorphism of infant RFC1 or by an interaction between the RFC1 gene and maternal periconceptional use of vitamins containing folic acid. A total of 305 liveborn infants with cleft lip with or without cleft palate, 123 with cleft palate, 163 with conotruncal heart defects, and 364 nonmalformed controls were genotyped. Odds ratios of 1.6 (95% confidence interval: 0.9, 2.8) for the G80/G80 genotype and of 2.3 (95% confidence interval: 1.3, 3.9) for the G80/A80 genotype were observed relative to the A80/A80 genotype for conotruncal defects. Among mothers who did not use vitamins, the risk of conotruncal defects was 2.1 (95% confidence interval: 0.7, 5.9) for infants with genotype G80/G80 compared with those with the A80/A80 genotype. Among mothers who did use vitamins, the risk was 1.3 (95% confidence interval: 0.7, 2.7). Substantially elevated risks for either cleft group were not observed irrespective of genotype and use/nonuse of vitamins. Thus, this study found modest evidence for a gene-nutrient interaction between infant RFC1 genotype and periconceptional intake of vitamins on the risk of conotruncal defects.

    View details for DOI 10.1098/aje/kwg189

    View details for Web of Science ID 000185897700005

    View details for PubMedID 14561664

  • Maternal periconceptional alcohol consumption and risk for conotruncal heart defects BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Shaw, G. M., Yang, W., Lammer, E. J. 2003; 67 (10): 875-878

    Abstract

    In this study we investigated whether the risk of delivering infants with conotruncal heart defects was increased among mothers who consumed alcohol during the periconceptional period (i.e., 1 month before conception to 3 months after conception).Data were obtained from a population-based case-control study of California births from 1987-1988. Information concerning alcohol consumption was obtained via telephone interviews with mothers of 207 (87% of eligibles) case infants and 481 (76%) nonmalformed control infants.Bivariate results indicated that relative to nonconsumers, women who consumed alcohol less than once a week had a 1.3-fold increased risk of delivering infants with a conotruncal heart defect (95% confidence interval (CI) 1.0, 1.9), and women who consumed alcohol once a week or more had a 1.9-fold increased risk (95% CI 1.0, 3.4). The risks associated with consuming five or more drinks per drinking occasion were 1.6 (95% CI 0.8, 3.2) for less than once a week, and 2.4 for once a week or more (95% CI 0.6, 9.7). The results for the phenotypic subgroups were similar to those for all cases. Adjustment for potential covariates resulted in somewhat weaker, but still elevated, risks.This study found that the risk of conotruncal heart defects in offspring was moderately elevated among women who consumed alcoholic beverages during the periconceptional period, and that risk was higher with increased frequency of drinking or increased number of drinks consumed per occasion. Most of the risk estimates were imprecise, and chance could not be ruled out as an explanation for the observed findings.

    View details for DOI 10.1002/bdra.10087

    View details for Web of Science ID 000186148500007

    View details for PubMedID 14745941

  • Risk of mental retardation among children born with birth defects ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Jelliffe-Pawlowski, L. L., Shaw, G. M., Nelson, V., Harris, J. A. 2003; 157 (6): 545-550

    Abstract

    A paucity of epidemiologic research exists concerning the co-occurrence of birth defects and mental retardation (MR). Study of this co-occurrence may yield important clues about the causes of both.To examine the co-occurrence of birth defects and MR, taking into consideration the type of birth defect, level of MR, co-occurrence of MR with other developmental disabilities, and individual and maternal factors.A retrospective cohort study of infants born in the California Central Valley with and without a structural birth defect by 1 year of age, and with or without MR by 7 to 9 years of age. Setting andOne-year survivors (N = 119 556) born in nonmilitary hospitals in 8 California counties between January 1, 1992, and December 31, 1993, for whom information about birth defects was recorded within the first year of life.Diagnosis of MR by age 7 years considered as being mild or severe and as occurring without other developmental disabilities (isolated MR) or as occurring with other developmental disabilities, including cerebral palsy, epilepsy, or a pervasive developmental disorder.Children with birth defects were nearly 27 times more likely to have MR by 7 years of age compared with children without a diagnosed birth defect regardless of type of defect (prevalence ratio, 26.8; 95% confidence interval, 22.7-31.7). Among those with birth defects, children with Down syndrome (prevalence ratio, 211.7; 95% confidence interval, 171.3-261.5) and children with sex chromosomal defects (prevalence ratio, 57.4; 95% confidence interval, 23.7-138.6) were at the highest risk for MR. Children with nonchromosomal defects, including central nervous system defects and all types of organ and system defects, were at substantially increased risk for all levels of MR. Risks of MR among children with Down syndrome and nonchromosomal defects were not substantially altered when adjusted for individual and maternal factors.Children with chromosomal and other structural birth defects are at a substantially increased risk for having MR by 7 years of age compared with children born without a birth defect. Children with birth defects are at an especially increased risk for having severe MR and MR occurring independently of other developmental disabilities.

    View details for Web of Science ID 000183408900007

    View details for PubMedID 12796234

  • Fertility treatments and craniosynostosis: California, Georgia, and Iowa, 1993-1997 PEDIATRICS Reefhuis, J., Honein, M. A., Shaw, G. M., Romitti, P. A. 2003; 111 (5): 1163-1166

    Abstract

    Craniosynostosis, a malformation caused by premature closure of 1 or more cranial sutures, is a rare birth defect usually of unknown cause; however, it is often associated with advanced maternal age. Because fertility treatments are also associated with increased maternal age, this study investigated the possible association between fertility treatments and craniosynostosis.Data from the Birth Defect Risk Factor Surveillance study were used, which included infants who were delivered from 1993 through 1997 in California, Georgia, and Iowa. Cases were defined as infants who had nonfamilial, nonsyndromic craniosynostosis and were ascertained through existing birth defect surveillance systems. Controls, infants without birth defects, were selected from the same regions and time period.Mothers of 99 case infants and 777 control infants from the 3 study locations participated in this study by completing a telephone interview. Unadjusted analyses showed associations with craniosynostosis for mothers who had used clomiphene citrate (odds ratio[OR]: 3.8; 95% confidence interval [CI]: 1.1-12.3), artificial insemination (OR: 4.2; 95% CI: 0.8-9.4), or assisted reproductive techniques (OR: 4.2; 95% CI: 0.5-27.3).This is the first study that has found associations between fertility treatments and craniosynostosis. However, the numbers are small; therefore, the results should be viewed with caution.

    View details for Web of Science ID 000182579700008

    View details for PubMedID 12728131

  • Maternal occupational chemical exposures and biotransformation genotypes as risk factors for selected congenital anomalies AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Nelson, V., Iovannisci, D. M., Finnell, R. H., Lammer, E. J. 2003; 157 (6): 475-484

    Abstract

    In a case-control study using an assessment of occupational tasks by an industrial hygienist, the authors investigated whether women's occupational exposures increased risks of delivering infants with cleft palate (CP), cleft lip with or without cleft palate (CLP), conotruncal defects, or limb deficiencies. For CP and CLP, exposures were further considered in the presence/absence of infant genetic variants for glutathione-S-transferase M1, glutathione-S-transferase T1, and N-acetyltransferases 1 and 2. The study included 1987-1989 California stillbirths and livebirths. Telephone interviews were conducted with mothers of 662 CLP and CP cases, 207 conotruncal defect cases, 165 limb deficiency cases, and 734 nonmalformed controls. Occupational tasks were assigned to a priori-defined exposure categories: 74 chemical groups and nine "end-use" chemical groups. Odds ratios of 1.5 or greater were observed for a small number of exposure-defect comparisons. Risks associated with end-use groups revealed odds ratios of 1.5 or greater for exposures to dyes and pigments (conotruncal and CP), propellants (CP), and insecticides (conotruncal and CP). Numerous odds ratios of 2.5 or greater were observed for combined effects of exposures and homozygous mutant genotypes, particularly for CP. Although potential associations were observed, most results suggested that maternal occupational chemical exposures did not contribute substantially to the occurrence of these anomalies in this California population.

    View details for Web of Science ID 000181611600001

    View details for PubMedID 12631536

  • Evaluation of infant methylenetetrahydrofolate reductase genotype, maternal vitamin use, and risk of high versus low level spina bifida defects BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Volcik, K. A., Shaw, G. M., Lammer, E. J., Zhu, H. P., Finnell, R. H. 2003; 67 (3): 154-157

    Abstract

    Several studies have suggested that homozygosity for the C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) variant is a potential risk factor for neural tube defects (NTDs), as individuals homozygous for the C677T allele have slightly elevated homocysteine concentrations under conditions of low folic acid intake. It has been hypothesized that maternal folic acid supplementation prevents NTDs by partially correcting reduced MTHFR activity associated with the variant form of the enzyme.Genomic DNA was extracted from newborn screening blood spots obtained from 145 infants with spina bifida (SB) and 260 nonmalformed control infants. The MTHFR C677T genotype was determined by restriction enzyme digestion of PCR amplification products with Hinf1. We investigated whether infant MTHFR genotype influenced the risk for the anatomic level of the SB lesion (high vs. low); we also explored whether maternal vitamin use influenced this risk.Compared to controls, the frequency of SB infants with the homozygous 677 TT genotype was greatest in those infants with high level SB defects (26%; odds ratio [OR] = 2.9; 95% confidence interval [CI] = 0.9-10.1) than for those with low level SB defects (22%; OR = 1.8; 95% CI = 0.9-3.2). Furthermore, homozygous 677TT infants whose mothers did not use vitamins containing folic acid had a modestly increased risk of SB (OR = 1.8; 95% CI = 0.8-3.9), with this risk increasing more than three-fold (OR = 5.5; 95% CI = 0.8-28.1) for those infants with high level SB defects whose mothers did not use vitamins.Based upon our observations, it is suggested that the association between the infant MTHFR homozygous variant genotype and spina bifida risk may be conditional upon both lesion level and maternal vitamin use.

    View details for DOI 10.1002/bdra.10008

    View details for Web of Science ID 000185286600002

    View details for PubMedID 12797455

  • Maternal periconceptional vitamins: Interactions with selected factors and congenital anomalies? EPIDEMIOLOGY Shaw, G. M., Nelson, V., Carmichael, S. L., Lammer, E. J., Finnell, R. H., Rosenquist, T. H. 2002; 13 (6): 625-630

    Abstract

    The mechanisms by which folic acid may contribute to reductions in risk of several congenital anomalies are unknown. The data gap includes a lack of information on possible effect modification between maternal folic acid use and other maternal exposures. We hypothesized that effects of congenital anomalies associated with maternal fever, cigarette smoking or alcohol use would be modified by intake of vitamins.We explored case-control data that showed risk reductions among infants and fetuses whose mothers consumed vitamins. Data were from California deliveries of infants and fetuses in the period 1987-1989. Maternal telephone interviews were completed for 207 (87%) conotruncal cases, 489 (85%) orofacial cleft cases, 265 (84%) neural tube defect cases, 165 (82%) limb anomaly cases, and 734 controls (nonmalformed infants).Considering women who reported vitamin use and no periconceptional fever as referents, for each anomaly group we observed elevated effects for the combinations of maternal vitamin use/fever, no use/no fever and no use/fever. Effects were most elevated for the combination of no vitamin use and fever. Adjusted for maternal body mass index, education and race/ethnicity, odds ratios were 2.4 (95% confidence inter-val = 1.0-5.9) for conotruncal defects, 2.9 (1.4-5.8) for cleft lip with or without cleft palate, 1.3 (0.4-3.9) for cleft palate, 3.1 (1.4-6.8) for neural tube defects, and 2.6 (1.0-6.4) for limb-deficiency defects. These interactions were further investigated relative to maternal use of fever-reducing medications. Effects tended to be highest among those women who did not use vitamins, had fevers, and did not use fever-reducing medications. Compared with women who used vitamins and did not smoke periconceptionally, anomaly risks tended to be highest among women who did not use vitamins and smoked. No specific pattern emerged involving alcohol intake.These data further suggest that the underlying mechanisms of folic acid associated with congenital anomalies may be complex.

    View details for DOI 10.1097/01.EDE.0000032431.83648.8D

    View details for Web of Science ID 000178637200005

    View details for PubMedID 12410002

  • Apolipoprotein E and apolipoprotein B genotypes and risk for spina bifida TERATOLOGY Volcik, K. A., Zhu, H. P., Shaw, G. M., Lammer, E. J., Finnell, R. H. 2002; 66 (5): 257-259

    Abstract

    Altered cholesterol metabolism and defects in cholesterol biosynthesis may influence abnormal central nervous system (CNS) development. During early stages of embryonic development, high levels of cholesterol are needed by rapidly proliferating cells that utilize cholesterol as a key cell membrane component. Alterations in cholesterol levels are influenced by variations in the apolipoprotein E (apoE) and apolipoprotein B (apoB) genes. The purpose of our study was to explore the possible association between infant genetic variations in the apoE and apoB genes and spina bifida (SB) risk.Genomic DNA was extracted from newborn screening blood spots obtained from 26 infants with SB and 73 non-malformed control infants. ApoE and apoB genotypes were determined by restriction enzyme digestion of PCR amplification products.Genotype frequencies for the apoE and apoB polymorphisms were not statistically different between case and control infants. For each apoB polymorphism, however, the frequency of the wild-type allele was higher in SB infants as compared to controls. Additionally, the apoE genotype E2/E3 was observed more frequently in the controls than in SB infants [15% in controls compared to 4% in cases; OR = 0.2 (0-1.6)].Results from this study suggest that genetic variations in the apoE and apoB genes, known to regulate cholesterol metabolism, do not substantially contribute to the risk of SB in infants.

    View details for DOI 10.1002/tera.10097

    View details for Web of Science ID 000178997500011

    View details for PubMedID 12397634

  • Paternal occupational group and risk of offspring with neural tube defects PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Shaw, G. M., Nelson, V., Olshan, A. F. 2002; 16 (4): 328-333

    Abstract

    Selected paternal occupations as well as specific occupational exposures to chemicals such as organic solvents have been suggested as possible risk factors for neural tube defects (NTD). We investigated data from a population-based, case-control study of fetuses and liveborn infants with NTDs among 1989-91 California births and fetal deaths. Interviews were conducted with mothers of 538 NTD cases and 539 non- malformed controls. Mothers were asked to report the occupations that the fathers had in the period 3 months before and 3 months after conception. Each job title and industry reported was coded in accordance with the 1990 US Census. Considering those fathers who worked in managerial and professional occupations as the reference group, elevated odds ratios (OR) for NTDs were observed for the categories: technical, sales and administrative, OR = 1.5 [95% confidence interval 1.0, 2.4]; service, OR = 2.0 [1.2, 3.1]; farming, forestry and fishing, OR = 2.1 [1.3, 3.3]; operators, fabricators and labourers, OR = 1.8 [1.2, 2.7]; and military, OR = 1.9 [0.7, 5.0]. Stratification by NTD phenotype revealed that these elevated ORs were primarily observed for spina bifida phenotypes. Analyses adjusted for maternal body mass index, maternal periconceptional use of multivitamins containing folic acid, paternal race/ethnicity, maternal race/ethnicity and maternal education revealed attenuated risk estimates for most of the occupational groups. Analyses of 182 more specific occupational groups defined by aggregating fathers on similar job titles, when compared with fathers who worked in managerial and professional occupations, revealed that four job title groups were associated with fairly precise effect estimates of >or=1.5. These groups were: cooks; janitors and cleaners; farm workers; and groundsmen/gardeners. Using occupational titles as defined in previous investigations, we did not observe an elevated OR associated with paternal occupational solvent exposures, OR = 0.8 [0.5, 1.3]. These analyses generated potential clues regarding paternal occupational exposures as NTD risk factors. Risk variation observed by spina bifida phenotype is interesting and will need to be investigated further.

    View details for Web of Science ID 000179413600007

    View details for PubMedID 12445149

  • Integration of DNA sample collection into a multi-site birth defects case-control study TERATOLOGY Rasmussen, S. A., Lammer, E. J., Shaw, G. M., Finnell, R. H., McGehee, R. E., Gallagher, M., Romitti, P. A., Murray, J. C. 2002; 66 (4): 177-184

    Abstract

    Advances in quantitative analysis and molecular genotyping have provided unprecedented opportunities to add biological sampling and genetic information to epidemiologic studies. The purpose of this article is to describe the incorporation of DNA sample collection into the National Birth Defects Prevention Study (NBDPS), an ongoing case-control study in an eight-state consortium with a primary goal to identify risk factors for birth defects.Babies with birth defects are identified through birth defects surveillance systems in the eight participating centers. Cases are infants with one or more of over 30 major birth defects. Controls are infants without defects from the same geographic area. Epidemiologic information is collected through an hour-long interview with mothers of both cases and controls. We added the collection of buccal cytobrush DNA samples for case-infants, control-infants, and their parents to this study.We describe here the methods by which the samples have been collected and processed, establishment of a centralized resource for DNA banking, and quality control, database management, access, informed consent, and confidentiality issues.Biological sampling and genetic analyses are important components to epidemiologic studies of birth defects aimed at identifying risk factors. The DNA specimens collected in this study can be used for detection of mutations, study of polymorphic variants that confer differential susceptibility to teratogens, and examination of interactions among genetic risk factors. Information on the methods used and issues faced by the NBDPS may be of value to others considering the addition of DNA sampling to epidemiologic studies.

    View details for DOI 10.1002/tera.10086

    View details for Web of Science ID 000178375100006

    View details for PubMedID 12353214

  • Does prenatal screening for 5,10-methylenetetrahydrofolate reductase (MTHFR) mutations in high-risk neural tube defect pregnancies make sense? GENETIC TESTING Finnell, R. H., Shaw, G. M., Lammer, E. J., Volcik, K. A. 2002; 6 (1): 47-52

    Abstract

    Despite the fact that neural tube defects (NTDs) are the most common congenital malformations of the central nervous system, investigators have yet to identify responsible gene(s). Research efforts have been productive in the identification of environmental factors, such as periconceptional folic acid supplementation, that modulate risk for the development of NTDs. Studies of the folic acid biosynthetic pathway led to the discovery of an association between elevated levels of homocysteine and NTD risk. Researchers subsequently identified single nucleotide polymorphisms in the gene coding for the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). Association studies suggested it was a potential risk factor for NTDs, because the thermolabile form of the enzyme led to elevated homocysteine concentrations when folic acid intake is low. Numerous studies analyzing MTHFR variants have resulted in positive associations with increased NTD risk only in certain populations, suggesting that these variants are not large contributors to the etiology of NTDs. With our limited understanding of the genes involved in regulating NTD susceptibility, the paucity of data on how folic acid protects the developing embryo, as well as the observed decrease in birth prevalence of NTDs following folic acid supplementation and food fortification, it makes little sense for prospective parents to be tested for MTHFR variants, or for variants of other known folate pathway genes.

    View details for Web of Science ID 000176105200008

    View details for PubMedID 12180076

  • Spina bifida phenotypes in infants or fetuses of obese mothers TERATOLOGY Shaw, G. M., Todoroff, K., Finnell, R. H., Lammer, E. J. 2000; 61 (5): 376-381

    Abstract

    A twofold or greater risk of neural tube defect (NTD)-affected pregnancy has been associated with prepregnant obesity, where obesity was defined as body mass index (BMI) of >29 kg/m(2). Risks have been more elevated for spina bifida than for anencephaly.We investigated whether finer phenotypic classifications of spina bifida, in combination with other factors, were associated with a BMI of >29 kg/m(2). Data were derived from a case-control study of fetuses and infants with NTDs among 1989-1991 California births. Interviews were conducted with mothers of 277 spina bifida cases and 517 nonmalformed controls.Women with a BMI of >29 kg/m(2) compared with those 29 kg/m(2) compared with males whose mothers were

    View details for Web of Science ID 000086815900009

    View details for PubMedID 10777833

  • Microsatellites proximal to leptin and leptin receptor as risk factors for spina bifida TERATOLOGY Shaw, G. M., Barber, R., Todoroff, K., Lammer, E. J., Finnell, R. H. 2000; 61 (3): 231-235

    Abstract

    Several recent studies have observed an association between neural tube defect risk and prepregnant obesity. This association was generally stronger for spina bifida and was observed irrespective of additional maternal factors, including periconceptional intake of vitamin supplements. Other studies have identified mutations within the genes that code for leptin (LEP) and its receptor (LEPR), which have been linked to obesity in mice and humans. We investigated the potential association between nucleotide variation at the LEP and LEPR loci, and increased risk of spina bifida. We searched specifically for allelic association at a pair of highly polymorphic microsatellites closely linked to either the LEP or LEPR gene. Data were derived from a population-based case-control study that had previously identified an association between a woman's prepregnant obesity and her risk of delivering an infant with spina bifida. A total of 56 spina bifida case infants and 126 nonmalformed control infants were genotyped for 10 microsatellite alleles closely linked to the LEP gene, and 49 cases and 125 controls were genotyped for 10 microsatellite alleles closely linked to the LEPR gene. In general, alleles were not observed to be exclusively associated with substantially greater spina bifida risk in the body mass index (BMI) category (obese) of >29 kg/m(2) compared with the BMI category (nonobese) of 29 kg/m; (2) having either allele and BMI 29 kg/m(2). The odds ratios (95% confidence interval) for these comparisons were: for allele 257, 4.5 (1.1-19.4), 1.9 (0.5-6.3), and 2.9 (1.3-6.4), respectively, and for allele 271, 6.7 (1.6-30.4), 2.7 (0.7-10.9), and 2.7 (1.2-5.9), respectively. Owing to the exploratory nature of this investigation, the significance of these latter results is unclear.

    View details for Web of Science ID 000085525700011

    View details for PubMedID 10661913

  • Maternal periconceptional alcohol consumption and risk for orofacial clefts JOURNAL OF PEDIATRICS Shaw, G. M., Lammer, E. J. 1999; 134 (3): 298-303

    Abstract

    To investigate whether periconceptional maternal alcohol consumption increased the risk of delivering infants with orofacial cleft phenotypes.Data were derived from a large population-based case control study of fetuses and infants among a cohort of California births from 1987 to 1989 (n = 548,844). Information concerning alcohol consumption was obtained by telephone interviews with mothers of 731 infants (84.7% of eligible) with orofacial clefts and of 734 (78.2%) infants in a nonmalformed control group.Thirty-nine percent of mothers in the case group and 42% of mothers in the control group reported that they consumed alcohol during the period 1 month before through 3 months after conception. Relative to nonconsumers, women who reported alcohol consumption (/=5 drinks per drinking occasion compared with those who did not, we observed increased risks for isolated (no other major congenital anomaly) cleft lip with or without cleft palate, odds ratio = 3.4 (95% confidence interval, 1.1 to 9.7); multiple cleft lip with or without cleft palate, odds ratio = 4.6 (1. 2 to 18.8); and "known syndrome" clefts, odds ratio = 6.9 (1.9 to 28. 6). Adjustment for maternal cigarette smoking, race, education, or vitamin use did not substantially change observed risks.We observed a lack of increased risks of clefts for relatively low quantities of maternal alcohol consumption and increased risks of clefts for higher quantities of maternal alcohol consumption.

    View details for Web of Science ID 000078985800011

    View details for PubMedID 10064665

  • Infant C677T mutation in MTHFR, maternal periconceptional vitamin use, and cleft lip AMERICAN JOURNAL OF MEDICAL GENETICS Shaw, G. M., Rozen, R., Finnell, R. H., Todoroff, K., Lammer, E. J. 1998; 80 (3): 196-198

    Abstract

    Studies have reported an association between homozygosity for a variant form of the methylenetetrahydrofolate reductase (MTHFR) gene and risk for neural tube defects. Because of MTHFR's involvement with folate metabolism and evidence that maternal use of a multivitamin with folic acid in early pregnancy reduces risk for cleft lip with or without cleft palate (CLP), we hypothesized that infants homozygous for the C677T genotype would be at increased risk for CLP because of lower MTHFR enzymatic activity. Data were derived from a large population-based, case-control study of fetuses and liveborn infants among a cohort of 1987 to 1989 California births. The analyses involved 310 infants with isolated CLP whose mothers completed a telephone interview and whose DNA was available from newborn screening blood specimens and involved 383 control infants without a congenital anomaly whose mothers completed a telephone interview and whose DNA was available. Cases and controls were genotyped TT if homozygous for the C677T allele, CT if heterozygous for the C677T allele, and CC if homozygous for the C677 (wild-type) allele. Odds ratios for CLP were 0.89 (0.55 to 1.4) and 0.78 (0.56 to 1.1) for infants with TT versus CC and infants with CT versus CC genotypes, respectively. Compared with the CC genotype, the odds ratios for CLP among infants with the TT genotype were 0.74 (0.39 to 1.4) for those infants whose mothers were users and 1.4 (0.54 to 3.6) for those infants whose mothers were not users of multivitamins containing folic acid periconceptionally. The two estimates were not statistically heterogeneous (P = 0.30). Our results did not indicate increased risks for CLP among infants homozygous for the C677T genotype, nor do they indicate an interaction between infant C677T genotype and maternal multivitamin use on the occurrence of CLP.

    View details for Web of Science ID 000077117700002

    View details for PubMedID 9843036

  • Maternal vitamin use, genetic variation of infant methylenetetrahydrofolate reductase, and risk for spina bifida AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Rozen, R., Finnell, R. H., Wasserman, C. R., Lammer, E. J. 1998; 148 (1): 30-37

    Abstract

    Maternal periconceptional use of vitamin supplements containing folic acid substantially reduces the risk of neural tube defects (NTDs) in the offspring. The mechanism underlying this reduction in risk is unknown. Several recent studies have reported an association between homozygosity for a variant form (the C677T genotype) of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and risk for NTDs in individuals. It has been hypothesized that maternal folic acid supplementation prevents NTDs by partially correcting reduced MTHFR activity associated with the variant form of the enzyme. Using data from two California case-control interview studies (1987-1991 birth cohorts), the authors investigated whether an interaction for spina bifida risk existed between infant MTHFR C677T genotype and maternal use of supplements containing folic acid. The authors genotyped the allelic variants of MTHFR in 214 liveborn case infants with spina bifida and 503 control infants for whom information on maternal periconceptional vitamin use was available. The percentage of all case infants with the C677T MTHFR mutation, for both homozygous (TT) and heterozygous (TC) genotypes, was slightly higher than that of controls. The C677T genotype was substantially more frequent among both case and control Hispanic infants than among non-Hispanic infants. Among all infants whose mothers did not periconceptionally use vitamins containing folic acid, the risk of spina bifida, as measured by the odds ratio, was 1.6 (95% confidence interval (CI) 0.8-3.1) for all infants with the TT genotype and 2.0 (95% CI 0.5-7.4) for non-Hispanic white infants with the TT genotype, as compared with infants with the CC genotype. This result indicates a modestly increased risk associated with the C677T genotype. A lower risk estimate (odds ratio=1.2, 95% CI 0.4-4.0) was observed among infants whose mothers periconceptionally used vitamin supplements containing folic acid. This population-based California study found a modestly increased risk of spina bifida among infants who were homozygous for the C677T genotype, but only minimal evidence of an interaction between the C677T genotype and maternal folic acid intake in the occurrence of spina bifida. If this mutant MTHFR genotype plays a role in the association between maternal vitamin use and NTD risk, it may be a small role, or it may be conditional on maternal genotype.

    View details for Web of Science ID 000074710300006

    View details for PubMedID 9663401

  • Incorporating molecular genetic variation and environmental exposures into epidemiologic studies of congenital anomalies REPRODUCTIVE TOXICOLOGY Shaw, G. M., Lammer, E. J. 1997; 11 (2-3): 275-280

    Abstract

    Epidemiologic studies of congenital anomalies rarely incorporate measurements of both environmental and genetic factors. Given the suspected etiologic heterogeneity that exists among congenital anomalies, focusing on only environmental or on only genetic factors may substantially decrease the likelihood for identifying either type of factor as a contributor to the risk of congenital anomalies. Incorporating information on genotypic variation into an epidemiologic study of environmental exposures may potentially lead to improvements in case classification with accompanying potential improvements in risk estimation. Such genotypic information may also lead to a clearer understanding of the underlying pathogenesis and etiology of congenital anomalies. Using recent research findings on congenital anomalies, we illustrated the issues of case classification and how a clearer impression of the underlying pathogenesis can be achieved with the addition of genotypic information to epidemiologic studies of congenital anomalies.

    View details for Web of Science ID A1997WQ84000016

    View details for PubMedID 9100302

Conference Proceedings


  • Prevalence of Spina Bifida Among Children and Adolescents in 10 Regions in the United States Shin, M., Besser, L. M., Siffel, C., Kucik, J. E., Shaw, G. M., Lu, C., Correa, A. AMER ACAD PEDIATRICS. 2010: 274-279

    Abstract

    The goal was to estimate the number of children and adolescents, 0 to 19 years of age, living with spina bifida (SB) in the United States.A retrospective study was conducted by using population-based, birth defect surveillance data from 10 US regions, with vital status ascertainment. Birth defect surveillance data were obtained from Arkansas, Georgia (5 central counties of metropolitan Atlanta), California (11 counties), Colorado, Iowa, New York (New York City excluded), North Carolina, Oklahoma, Texas, and Utah. We estimated the numbers of children 0 to 19 years of age who were living with SB in the 10 US regions in 2002, according to age group, race/ethnicity, and gender, and examined a long-term trend in the prevalence of SB among children 0 to 11 years of age in 1991-2002.The overall prevalence of SB among children and adolescents 0 to 19 years of age in the study regions was 3.1 cases per 10,000 in 2002. The prevalence of SB among children was lower among male and non-Hispanic black children.The prevalence estimates of SB among children and adolescents varied according to region, race/ethnicity, and gender, which suggests possible variations in prevalence at birth and/or inequities in survival rates. Additional studies are warranted to elucidate the reasons for these variations and to derive prevalence estimates of SB among adults.

    View details for DOI 10.1542/peds.2009-2084

    View details for Web of Science ID 000280565700013

    View details for PubMedID 20624803

  • Periconceptional Nutrient Intakes and Risks of Neural Tube Defects in California Carmichael, S. L., Yang, W., Shaw, G. M. WILEY-LISS. 2010: 670-678

    Abstract

    This study investigated the association of neural tube defects (NTDs) with maternal periconceptional intake of folic acid-containing supplements and dietary nutrients, including folate, among deliveries that occurred after folic acid fortification in selected California counties.The population-based case-control study included fetuses and live born infants with spina bifida (189) or anencephaly (141) and 625 nonmalformed, live born controls delivered from 1999 to 2003. Mothers reported supplement use during telephone interviews, which included a 107-item food frequency questionnaire. For dietary nutrients, intakes <25th, 25th to <75th (reference), and > or =75th percentile were compared, based on control distributions.After adjustment for potential confounders, any versus no supplement intake resulted in ORs of 0.8 (95% CI, 0.5-1.3) for anencephaly and 0.8 (95% CI, 0.6-1.2) for spina bifida. After stratification by maternal intake of vitamin supplements, most factors in the glycemic pathway were not associated with either NTD, with the exception of low levels of fructose and glucose that were significantly associated with anencephaly. Some nutrients that contribute to one-carbon metabolism showed lowered risks (folate, riboflavin, vitamins B(6) and B(12)); others did not (choline, methionine, zinc). Antioxidant nutrients tended to be associated with lowered risks (vitamins C, E, A, beta-carotene, lutein).Mothers' intake of vitamin supplements was modestly if at all associated with a lowered risk of NTDs. Dietary intake of several nutrients contributing to one-carbon metabolism and oxidative stress were associated with reduced NTD risk.

    View details for DOI 10.1002/bdra.20675

    View details for Web of Science ID 000281529700009

    View details for PubMedID 20740594

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