Bio

Academic Appointments


Honors & Awards


  • F. Clarke Fraser New Investigator Award, Teratology Society (2005)
  • Public Health Citation, Public Health Service, DHHS (1997)
  • Warren Winkelstein Epidemiology Award, U.C., Berkeley (1996)
  • Regents Fellowship and Kaiser Fellowship, U.C., Berkeley (1994-95)
  • A.J. Bryan Scholarship, Kaiser Fellowship, U.C., Berkeley (1993-94)
  • Lechner Fellowship, Texas A&M University (1984-88)

Professional Education


  • PhD, U.C., Berkeley, Epidemiology (1996)
  • M.S., U.C., Davis, Int'l Agricultural Development (1992)
  • B.S., Texas A&M University, Nutrition (1988)

Research & Scholarship

Current Research and Scholarly Interests


Our research focuses on epidemiologic studies related to maternal and child health. Current projects address congenital anomalies of craniofacial, urogenital, musculoskeletal and central nervous system structures and exposures related to nutrition, stress, environmental contaminants, and genes. Physiologic pathways encompassed by these studies include one-carbon metabolism, oxidative stress, HPA axis activation, and sex steroid metabolism. In particular, we are interested in discovering how exposures from these pathways, including genetic susceptibility, may interact to impact risks of these outcomes.

Publications

Journal Articles


  • One-carbon metabolite levels in mid-pregnancy and risks of conotruncal heart defects. Birth defects research. Part A, Clinical and molecular teratology Shaw, G. M., Yang, W., Carmichael, S. L., Vollset, S. E., Hobbs, C. A., Lammer, E. J., Ueland, P. M. 2014; 100 (2): 107-115

    Abstract

    Evidence exists for an association between use of vitamin supplements with folic acid in early pregnancy and reduced risk for offspring with conotruncal heart defects. 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 conotruncal heart defects by measuring analytes in mid-pregnancy sera.This study included data from a repository of women's mid-pregnancy serum specimens based on screened pregnancies in California from 2002-2007. Each woman's specimen was linked with delivery information to determine whether her fetus had a conotruncal heart defect or another structural malformation, or was nonmalformed. We identified 140 conotruncal cases and randomly selected 280 specimens as nonmalformed controls. Specimens were tested for a variety of analytes, including homocysteine, methylmalonic acid, folate, vitamin B12 , pyridoxal phosphate, pyridoxal, pyridoxic acid, riboflavin, total choline, betaine, methionine, cysteine, cystathionine, arginine, asymmetric and symmetric dimethylarginine.We did not observe statistical evidence for substantial differences between cases and controls for any of the measured analytes. Analyses specifically targeting B-vitamins also did not reveal differences between cases and controls. Birth Defects Research (Part A) 100:107-115, 2014. © 2014 Wiley Periodicals, Inc.

    View details for DOI 10.1002/bdra.23224

    View details for PubMedID 24532477

  • 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

  • Hypospadias and residential proximity to pesticide applications. Pediatrics Carmichael, S. L., Yang, W., Roberts, E. M., Kegley, S. E., Wolff, C., Guo, L., Lammer, E. J., English, P., Shaw, G. M. 2013; 132 (5): e1216-26

    Abstract

    Experimental evidence suggests pesticides may be associated with hypospadias.Examine the association of hypospadias with residential proximity to commercial agricultural pesticide applications.The study population included male infants born from 1991 to 2004 to mothers residing in 8 California counties. Cases (n = 690) were ascertained by the California Birth Defects Monitoring Program; controls were selected randomly from the birth population (n = 2195). We determined early pregnancy exposure to pesticide applications within a 500-m radius of mother's residential address, using detailed data on applications and land use. Associations with exposures to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for maternal race or ethnicity and age and infant birth year.Forty-one percent of cases and controls were classified as exposed to 57 chemical groups and 292 chemicals. Despite >500 statistical comparisons, there were few elevated odds ratios with confidence intervals that excluded 1 for chemical groups or specific chemicals. Those that did were for monochlorophenoxy acid or ester herbicides; the insecticides aldicarb, dimethoate, phorate, and petroleum oils; and adjuvant polyoxyethylene sorbitol among all cases; 2,6-dinitroaniline herbicides, the herbicide oxyfluorfen, and the fungicide copper sulfate among mild cases; and chloroacetanilide herbicides, polyalkyloxy compounds used as adjuvants, the insecticides aldicarb and acephate, and the adjuvant nonyl-phenoxy-poly(ethylene oxy)ethanol among moderate and severe cases. Odds ratios ranged from 1.9 to 2.9.Most pesticides were not associated with elevated hypospadias risk. For the few that were associated, results should be interpreted with caution until replicated in other study populations.

    View details for DOI 10.1542/peds.2013-1429

    View details for PubMedID 24167181

  • 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

  • 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

  • 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 < 32 weeks, many ORs were ≥1.5 or ≤0.7, but few confidence intervals excluded one. ORs were ≥1.5 for lowest quartiles of protein, thiamin, riboflavin, choline, vitamin A, α-carotene, β-carotene, vitamin E, iron, copper, and zinc and for highest quartiles of carbohydrate, glycemic index, and Mediterranean Diet Score. ORs were ≤0.7 for lowest quartiles of glycemic index and betaine and for highest quartiles of protein, alanine, methionine, vitamin B6, betaine, and calcium. Few ORs met these criteria for later preterm deliveries.Conclusions Results suggested an association of nutrient intake with earlier preterm deliveries.

    View details for DOI 10.1055/s-0032-1329686

    View details for Web of Science ID 000322021900009

    View details for PubMedID 23208764

  • Maternal medication and herbal use and risk for hypospadias: data from the National Birth Defects Prevention Study, 1997-2007 PHARMACOEPIDEMIOLOGY AND DRUG SAFETY Lind, J. N., Tinker, S. C., Broussard, C. S., Reefhuis, J., Carmichael, S. L., Honein, M. A., Olney, R. S., Parker, S. E., Werler, M. M. 2013; 22 (7): 783-793

    Abstract

    To investigate associations between maternal use of common medications and herbals during early pregnancy and risk for hypospadias in male infants.We used data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study. We analyzed data from 1537 infants with second-degree or third-degree isolated hypospadias and 4314 live-born male control infants without major birth defects, with estimated dates of delivery from 1997 to 2007. Exposure was reported use of prescription or over-the-counter medications or herbal products, from 1 month before to 4 months after conception. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, adjusting for maternal age, race/ethnicity, education, pre-pregnancy body mass index, previous live births, maternal subfertility, study site, and year.We assessed 64 medication and 24 herbal components. Maternal uses of most components were not associated with an increased risk of hypospadias. A new associations was observed for venlafaxine (aOR 2.4; 95%CI 1.0, 6.0) [Correction made here after initial online publication.]. The previously reported association for clomiphene citrate was confirmed (aOR 1.9; 95%CI 1.2, 3.0). Numbers were relatively small for exposure to other specific patterns of fertility agents, but elevated aORs were observed for the most common of them.Overall, findings were reassuring that hypospadias is not associated with most medication components examined in this analysis. New associations will need to be confirmed in other studies. Increased risks for hypospadias associated with various fertility agents raise the possibility of confounding by underlying subfertility.

    View details for DOI 10.1002/pds.3448

    View details for Web of Science ID 000325867800013

    View details for PubMedID 23620412

  • 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

  • Maternal Dietary Patterns are Associated With Risk of Neural Tube and Congenital Heart Defects AMERICAN JOURNAL OF EPIDEMIOLOGY Sotres-Alvarez, D., Siega-Riz, A. M., Herring, A. H., Carmichael, S. L., Feldkamp, M. L., Hobbs, C. A., Olshan, A. F. 2013; 177 (11): 1279-1288

    Abstract

    Studying empirically derived dietary patterns is useful in understanding dietary practice. We classified women by their dietary patterns using latent class analysis of 66 foods and studied the association of these patterns with neural tube defects (NTDs) and congenital heart defects (CHDs) in the U.S. National Birth Defects Prevention Study (1997-2005). Logistic regression models used data from 1,047 with an NTD, 6,641 with a CHD, and 6,123 controls that were adjusted for maternal characteristics and tested the effect modification of multivitamin supplement use. Four latent dietary patterns were identified: prudent, Western, low-calorie Western, and Mexican. Among participants who did not use supplements, those in the Mexican, Western, and low-calorie Western classes were significantly more likely (odds ratios of 1.6, 1.5, and 1.4, respectively) to have offspring born with NTDs than were those in the prudent class after adjustment of for dietary folic acid intake. In contrast, among supplement users, there was no difference in the incidence of NTDs between classes. Associations between dietary class and CHD subgroups were not modified by supplement use except for tetralogy of Fallot; among supplement users, those in the Western class were twice as likely (95% confidence interval: 1.4, 2.8) as the prudent class to have offspring with tetralogy of Fallot. Women who adhered to a Western diet were 1.2 (95% confidence interval: 1.03, 1.35) times more likely to have an infant with septal heart defect than were women who adhered to a prudent diet. A prudent dietary pattern, even with folate fortification, may decrease the risk of NTDs and some heart defects.

    View details for DOI 10.1093/aje/kws349

    View details for Web of Science ID 000319752400014

    View details for PubMedID 23639938

  • 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

  • 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

  • Fever Literacy and Fever Phobia CLINICAL PEDIATRICS Wallenstein, M. B., Schroeder, A. R., Hole, M. K., Ryan, C., Fijalkowski, N., Alvarez, E., Carmichael, S. L. 2013; 52 (3): 254-259

    Abstract

    To identify the percentage of parents who define the threshold for fever between 38.0°C and 38.3°C, which has not been reported previously, and to describe parental attitudes toward fever and antipyretic use.Thirteen-question survey study of caregivers.Overall, 81% of participants defined the threshold for fever as <38.0°C, 0% correctly defined fever between 38.0°C and 38.3°C, and 19% defined fever as >38.3°C. Twenty percent of children brought to clinic for a chief complaint of fever were never truly febrile. Ninety-three percent of participants believed that high fever can cause brain damage. For a comfortable-appearing child with fever, 89% of caregivers reported that they would give antipyretics and 86% would schedule a clinic visit.Our finding that 0% of parents correctly defined fever is both surprising and unsettling, and it should inform future discussions of fever between parents and clinicians.

    View details for DOI 10.1177/0009922812472252

    View details for Web of Science ID 000317849900007

    View details for PubMedID 23349363

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • Is Maternal Parity an Independent Risk Factor for Birth Defects? BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Duong, H. T., Hoyt, A. T., Carmichael, S. L., Gilboa, S. M., Canfield, M. A., Case, A., McNeese, M. L., Waller, D. K. 2012; 94 (4): 230-236

    Abstract

    Although associations between maternal parity and birth defects have been observed previously, few studies have focused on the possibility that parity is an independent risk factor for birth defects. We investigated the relation between levels of parity and a range of birth defects, adjusting each defect group for the same covariates.We included infants who had an estimated delivery date between 1997 and 2007 and participated in the National Birth Defects Prevention Study, a multisite case-control study. Cases included infants or fetuses belonging to 38 phenotypes of birth defects (n = 17,908), and controls included infants who were unaffected by a major birth defect (n = 7173). Odds ratios (ORs) were adjusted for 12 covariates using logistic regression.Compared with primiparous mothers, nulliparous mothers were more likely to have infants with amniotic band sequence, hydrocephaly, esophageal atresia, hypospadias, limb reduction deficiencies, diaphragmatic hernia, omphalocele, gastroschisis, tetralogy of Fallot, and septal cardiac defects, with significant ORs (1.2 to 2.3). Compared with primiparous mothers, multiparous mothers had a significantly increased risk of omphalocele, with an OR of 1.5, but had significantly decreased risk of hypospadias and limb reduction deficiencies, with ORs of 0.77 and 0.77.Nulliparity was associated with an increased risk of specific phenotypes of birth defects. Most of the phenotypes associated with nulliparity in this study were consistent with those identified by previous studies. Research into biologic or environmental factors that are associated with nulliparity may be helpful in explaining some or all of these associations.

    View details for DOI 10.1002/bdra.22889

    View details for Web of Science ID 000302606600005

    View details for PubMedID 22371332

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • Clinical anatomy and the physical examination part I: Thorax, abdomen, perineum, and pelvis - Educational Affairs Committee, American Association of Clinical Anatomists CLINICAL ANATOMY Leonard, R. J., Hoos, P. C., Lozanoff, S., MARKS, S. C., Mathers, L. H., Page, D. W., Pawlina, W., Petterborg, L. J., Abrahams, P., Akesson, E. J., Aker, F. D., Bedell, A. W., Carmichael, S., Cheng, J. C., Haukoos, J. S., Heller, R. F., Huddleston, H. T., Liang, A., Mau, C. K., Nguyen, C., Patwardhan, R., Schlunt, K., Seifert, M. F., Serrao, R., The, T. L., Weiglein, A. H., Williams, V. F., Blevins, C. E., Cahill, D. R. 2001; 14 (5): 332-348

Conference Proceedings


  • 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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