Deml B, Reis LM, Muheisen S
… +2 more, Bick D, Semina EV
Birth Defects Res A Clin Mol Teratol
· 2015 Jul · PMID 26118977
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BACKGROUND: Congenital microphthalmia and coloboma are severe developmental defects that are frequently associated with additional systemic anomalies and display a high level of genetic heterogeneity. METHODS: To identif...BACKGROUND: Congenital microphthalmia and coloboma are severe developmental defects that are frequently associated with additional systemic anomalies and display a high level of genetic heterogeneity. METHODS: To identify the pathogenic variant in a patient with microphthalmia, coloboma, retinal dystrophy, microcephaly, and other features, whole exome sequencing analysis of the patient and parental samples was undertaken. To further explore the identified variant/gene, expression and functional studies in zebrafish were performed. RESULTS: Whole exome sequencing revealed a de novo variant, c.473_474delGA, p.(Arg158Lysfs*4), in EFTUD2 which encodes a component of the spliceosome complex. Dominant mutations in EFTUD2 cause Mandibulofacial Dysostosis, Guion-Almeida type, which does not involve microphthalmia, coloboma, or retinal dystrophy; analysis of genes known to cause these ocular phenotypes identified several variants of unknown significance but no causal alleles in the affected patient. Zebrafish eftud2 demonstrated high sequence conservation with the human gene and broad embryonic expression. TALEN-mediated disruption was employed to generate a c.378_385 del, p.(Ser127Aspfs*23) truncation mutation in eftud2. Homozygous mutants displayed a reduced head size, small eye, curved body, and early embryonic lethality. Apoptosis assays demonstrated a striking increase in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells in the developing brain, eye, spinal cord, and other tissues starting at 30 hours postfertilization. CONCLUSION: This study reports a novel mutation in EFTUD2 in a Mandibulofacial Dysostosis, Guion-Almeida type patient with unusual ocular features and the generation of a first animal model of eftud2 deficiency. The severe embryonic phenotype observed in eftud2 mutants indicates an important conserved role during development of diverse tissues in vertebrates.
Zhu Y, Romitti PA, Caspers Conway KM
… +7 more, Shen DH, Sun L, Browne ML, Botto LD, Lin AE, Druschel CM, National Birth Defects Prevention Study
Birth Defects Res A Clin Mol Teratol
· 2015 Jul · PMID 26118863
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BACKGROUND: Congenital heart defects (CHDs) are the leading cause of infant death from birth defects. Animal studies suggest in utero alcohol exposure is a teratogen for cardiogenesis; however, results from epidemiologic...BACKGROUND: Congenital heart defects (CHDs) are the leading cause of infant death from birth defects. Animal studies suggest in utero alcohol exposure is a teratogen for cardiogenesis; however, results from epidemiologic studies are mixed. METHODS: Data from the National Birth Defects Prevention Study were used to estimate associations between CHDs and case (n = 7076) and control (n = 7972) mother reports of periconceptional (1 month before pregnancy through the first trimester) alcohol consumption with expected delivery dates during 1997 to 2007. CHDs were examined by category (conotruncal, septal, left ventricular outflow tract obstruction, and right ventricular outflow tract obstruction, heterotaxy with CHD) and subtype (e.g., tetralogy of Fallot [TOF]). Alcohol measures examined were any consumption, maximum average drinks per month, binge drinking, and alcohol type. Adjusted odds ratios and 95% confidence intervals were estimated using unconditional logistic regression analysis. RESULTS: Increased risks, albeit marginally statistically significant, were observed for TOF and each maternal alcohol measure examined and for right ventricular outflow tract obstruction and heterotaxy with CHD and consumption of distilled spirits. Significantly reduced risks were observed for several CHD categories (septal defects, left ventricular outflow tract obstruction, and right ventricular outflow tract obstruction) and some corresponding subtypes with different alcohol measures. Significant risks were not observed for the other CHDs examined. CONCLUSION: Analysis of this large, well-defined study sample did not show statistically significant increased risks between measures of maternal alcohol consumption and most CHDs examined. These findings may reflect, in part, limitations with retrospective exposure assessment or unmeasured confounders. Additional studies with continued improvement in measurement of alcohol consumption are recommended.
Birth Defects Res A Clin Mol Teratol
· 2015 Aug · PMID 26109026
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BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a large U.S. multi-site case-control study first established in 1996 to identify potentially preventable environmental causes and genetic risk factors fo...BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a large U.S. multi-site case-control study first established in 1996 to identify potentially preventable environmental causes and genetic risk factors for more than 30 selected categories of major birth defects. METHODS: Numerous reports with both positive and negative findings have been produced by the NBDPS, and many have influenced clinical practice. Many NBDPS reports have included novel findings, and in some cases these findings could only be considered hypothesis-generating. Other reports have met criteria for causality such as replication of findings in other studies, biological plausibility, and coherence. RESULTS: However, translation of even strongly supported associations, in some cases, has required clinicians to learn to communicate information to patients about small and uncertain absolute risks in the context of the potential effects of under- or poorly treated maternal conditions. CONCLUSION: The NBDPS has continued to play an important role as a rich U.S. data source that can advance the understanding of maternal conditions and their treatments in relation to birth defects.
Mody SK, Wu J, Ornelas M
… +5 more, Kernahan C, Salas E, Kao K, Felix R, Chambers C
Birth Defects Res A Clin Mol Teratol
· 2015 Jul · PMID 26100297
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BACKGROUND: Women taking teratogens may not receive teratogen and contraceptive counseling. The objective of this study is to explore the feasibility of an electronic medical record (EMR) alert and referral system to imp...BACKGROUND: Women taking teratogens may not receive teratogen and contraceptive counseling. The objective of this study is to explore the feasibility of an electronic medical record (EMR) alert and referral system to improve teratogen and contraceptive counseling. METHODS: We conducted a descriptive study in an academic outpatient setting to evaluate the feasibility of an EMR alert and referral system. Reproductive age women taking category D or X medications seen in family medicine clinics were referred by means of an EMR alert for teratogen and contraceptive counseling. A subset of these women consented to follow-up surveys assessing contraceptive usage before counseling, intended contraceptive method after counseling and satisfaction with the counseling. Participants were contacted at 1 and 3 months to assess contraceptive usage. RESULTS: A total of 354 women were prescribed category D or X medications by clinicians who received the EMR alert, 170 women were referred, 59 women received counseling, and 33 participants enrolled in the study. One participant did not use any contraception. Among the 32 participants using contraception, 12 (37.5%) used oral contraceptives, 11 (34.4%) used condoms, 3 (9.4%) used withdrawal, 3 (9.4%) used intrauterine devices, 2 (6.3%) used contraceptive rings, and 1 (3.1%) used the diaphragm. After counseling, one-third of participants were considering more effective contraception. Almost all participants strongly agreed or agreed that the counseling was helpful. CONCLUSION: Creating an EMR alert and referral system for women prescribed category X or D medications is feasible. Counseling on teratogen exposure and contraception may improve the acceptability of more effective contraception.
Birth Defects Res A Clin Mol Teratol
· 2015 Aug · PMID 26097048
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BACKGROUND: Various experts in clinical teratology have proposed what they consider to be well-established teratogens. With the recent growth in the number of resources and investigations, there has been a notable prolif...BACKGROUND: Various experts in clinical teratology have proposed what they consider to be well-established teratogens. With the recent growth in the number of resources and investigations, there has been a notable proliferation of proposed risk factors as potential causes of human congenital structural defects. The purpose of this Commentary is to provide a concise summary of the current state of knowledge regarding known causes and environmental risk factors of structural defects. METHODS: We performed a comprehensive search of PubMed for papers in English and in humans only, 2010 to 2014, that included birth defects, risk factors, and teratogens as key terms. RESULTS: Our search led to over 9000 papers dealing with these categories. From this, we were able to construct a timetable documenting the recognition of human teratogens and list several proposed environmental risk factors. Three relevant current trends were noticed: An increase of prescription and nonprescription medication use by women during pregnancy; the rise in obesity and its association with structural defects; and a growing body of work regarding outcomes associated with assisted reproductive technology. CONCLUSION: There are numerous risk factors, some modifiable, that have been proposed in recent years. These factors (associations) are only at the preliminary level in the causal chain and require replication. There is a need for more work on protective factors. The phenotypic characterization of cases with congenital defects has improved remarkably in recent years. However, there remains considerable concern with the precise characterization of exposures and the documentation of timing during embryologic development.
Nair DB, Tucker D, Hughes R
… +2 more, Greenacre J, Morgan M
Birth Defects Res A Clin Mol Teratol
· 2015 Jul · PMID 26097020
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BACKGROUND: Trisomy 13 is one of the three autosomal trisomies compatible with viability. It is associated with structural anomalies, learning disability and poor survival. Advanced maternal age is the most frequently su...BACKGROUND: Trisomy 13 is one of the three autosomal trisomies compatible with viability. It is associated with structural anomalies, learning disability and poor survival. Advanced maternal age is the most frequently suggested risk factor. This is a population based register study to investigate the temporal trends of trisomy 13. METHODS: Chromosomal trisomies were reviewed by the Welsh Congenital Anomaly Register using data from 1998-2012. All pregnancy outcomes were included. Prevalence rates and trends for all cases and for cases with mothers aged below 35 years and those aged 35 years and older were plotted for trisomy 13, 18 and 21. Possible risk factors contributing to the trend in older mothers were compared in the early and late period of the study. RESULTS: There were 124 cases of trisomy 13 over the 15 year period with 55 mothers aged 35 years and older. Overall prevalence was 2.5 per 10,000 total births. A significant declining trend in the prevalence of trisomy 13 in mothers aged 35 and older (χ(2) trend = 4.98, p=0.026) was noted. Rates for younger mothers were lower and remained stable. Prevalence of trisomy 18 and 21 in older mothers remained stable. CONCLUSION: The unexpected declining trend in trisomy 13 in older mothers could not be explained by the risk factors examined in this study. There have been no other reports of trends in the prevalence of trisomy 13 in older mothers in recent years. There is further need for surveillance of trends in future and in other populations.
Simeone RM, Oster ME, Hobbs CA
… +3 more, Robbins JM, Collins RT, Honein MA
Birth Defects Res A Clin Mol Teratol
· 2015 Sep · PMID 26069215
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BACKGROUND: Congenital heart defects (CHDs) are common birth defects and are associated with high hospital costs. The objectives of this study were to assess hospitalization costs, across the lifespan, of patients with C...BACKGROUND: Congenital heart defects (CHDs) are common birth defects and are associated with high hospital costs. The objectives of this study were to assess hospitalization costs, across the lifespan, of patients with CHDs in Arkansas. METHODS: Data from the 2006 to 2011 Healthcare Cost and Utilization Project Arkansas State Inpatient Databases were used. We included hospitalizations of patients whose admission occurred between January 1, 2006, and December 31, 2011, and included a principal or secondary CHD ICD-9-CM diagnosis code (745.0-747.49, except 747.0 and 745.5 for preterm infants). Hospitalizations were excluded if they involved out-of-state residents, normal newborn births, or if missing data included age at admission, state of residence, or hospital charges. Children were defined as those < 18 years-old at time of admission. RESULTS: Between 2006 and 2011, there were 2,242,484 inpatient hospitalizations in Arkansas. There were 9071 (0.4%) hospitalizations with a CHD, including 5,158 hospitalizations of children (2.2% of hospitalizations among children) and 3,913 hospitalizations of adults (0.2% of hospitalizations of adults). Hospital costs for these CHD hospitalizations totaled $355,543,696. The average annual cost of CHD hospitalizations in Arkansas was $59,257,283 during this time period. Infants accounted for 72% of all CHD-related hospital costs; total costs of CHD hospitalizations for children were almost five times those of hospitalization costs for adults with CHD. CONCLUSION: Hospitalizations with CHDs account for a disproportionate share of hospital costs in Arkansas. Hospitalizations of children with CHD accounted for a higher proportion of total hospitalizations than did hospitalizations of adults with CHD.
Mostowska A, Hozyasz KK, Wójcicki P
… +7 more, Żukowski K, Dąbrowska A, Lasota A, Zadurska M, Radomska A, Dunin-Wilczyńska I, Jagodziński PP
Birth Defects Res A Clin Mol Teratol
· 2015 Oct · PMID 26043427
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BACKGROUND: The locus on chromosome 15q13.3 containing GREM1 is correlated with the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P). The aim of the present study was to find the GREM1 functional vari...BACKGROUND: The locus on chromosome 15q13.3 containing GREM1 is correlated with the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P). The aim of the present study was to find the GREM1 functional variants implicated in the aetiology of this common developmental anomaly in the Polish population. METHODS: Eight polymorphisms were genotyped in 334 NSCL/P patients and 955 controls. In addition, the GREM1 protein-coding region was sequenced in 96 NSCL/P patients. RESULTS: Significant association with a risk of oral clefts was found for 5 tested polymorphisms. The lowest p(trend) values were identified for rs16969681, rs16969816, and rs1258763 (p(trend) 4.09E-05, 3.35E-05, and 0.0002, respectively). The putative functional variant rs16969681, located in a region that has enhancer activity, was associated with a 2.6-fold lower risk for NSCL/P (odds ratio [OR] = 0.38; 95% confidence interval [CI], 0.24-0.61, p = 2.37E-05). The previously reported association of rs1258763 with NSCL/P was replicated (OR = 0.57; 95% CI, 0.44-0.73; p = 1.10E-05). For all tested GREM1 variants, no significant sex-by-genotype interaction effects were observed. The sequencing analysis did not detect any rare variants implicated in the development of oral clefts. CONCLUSION: Our results might suggest that variants influencing GREM1 expression levels, rather than variants affecting the function of the encoded protein, are significant factors in NSCL/P etiology.
Birth Defects Res A Clin Mol Teratol
· 2015 Sep · PMID 26043318
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BACKGROUND: Thalidomide is a known teratogen and it is estimated that more than ten thousand babies were affected by thalidomide embryopathy (TE), which is characterized mainly by limb defects, but can involve many organ...BACKGROUND: Thalidomide is a known teratogen and it is estimated that more than ten thousand babies were affected by thalidomide embryopathy (TE), which is characterized mainly by limb defects, but can involve many organs and systems. Most people with TE were only evaluated at birth and it is not well established if thalidomide exposure during embryonic development leads to later effects. We analyzed the clinical history of adults with TE to better understand this gap in the clinical findings of TE. METHODS: Brazilian individuals with TE were invited to answer a clinical questionnaire which considered family history, social information, medical history, and current clinical and psychological health status. A clinical examination was also performed, including on the infant subjects to evaluate congenital anomalies. The characterization of the features was analyzed using descriptive statistics and Chi-square or Fisher's exact test. RESULTS: The congenital anomalies caused by thalidomide were reviewed in 28 Brazilian individuals, and the questionnaire was applied to the 23 adult subjects with TE (aged 19 to 55). Progressive deafness and dental loss were reported. From the comparison of TE individuals with the general Brazilian population, the early onset of cardiovascular diseases (p = 0.009) and a higher frequency of psychological disorders (p = 0.011) were observed. CONCLUSION: Although there is no sufficient evidence that thalidomide exposure caused or worsened the described events, this approach helps to better understand the TE phenotype, improves the clinical diagnosis, and can lead to adequate health support for these individuals.
O'Brien JL, Langlois PH, Lawson CC
… +8 more, Scheuerle A, Rocheleau CM, Waters MA, Symanski E, Romitti PA, Agopian AJ, Lupo PJ, National Birth Defects Prevention Study
Birth Defects Res A Clin Mol Teratol
· 2016 Jan · PMID 26033890
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BACKGROUND: Evidence in animal models and humans suggests that exposure to polycyclic aromatic hydrocarbons (PAHs) may lead to birth defects. To our knowledge, this relationship has not been evaluated for craniosynostosi...BACKGROUND: Evidence in animal models and humans suggests that exposure to polycyclic aromatic hydrocarbons (PAHs) may lead to birth defects. To our knowledge, this relationship has not been evaluated for craniosynostosis, a birth defect characterized by the premature closure of sutures in the skull. We conducted a case-control study to examine associations between maternal occupational exposure to PAHs and craniosynostosis. METHODS: We used data from craniosynostosis cases and control infants in the National Birth Defects Prevention Study (NBDPS) with estimated delivery dates from 1997 to 2002. Industrial hygienists reviewed occupational data from the computer-assisted telephone interview and assigned a yes/no rating of probable occupational PAH exposure for each job from 1 month before conception through delivery. We used logistic regression to assess the association between occupational exposure to PAHs and craniosynostosis. RESULTS: The prevalence of exposure was 5.3% in case mothers (16/300) and 3.7% in control mothers (107/2,886). We observed a positive association between exposure to PAHs during the 1 month before conception through the third month of pregnancy and craniosynostosis (odds ratio [OR] = 1.75; 95% confidence interval [CI], 1.01-3.05) after adjusting for maternal age and maternal education. The number of cases for each craniosynostosis subtype limited subtype analyses to sagittal craniosynostosis; the odds ratio remained similar (OR = 1.76, 95% CI, 0.82-3.75), but was not significant. CONCLUSION: Our findings support a moderate association between maternal occupational exposure to PAHs and craniosynostosis. Additional work is needed to better characterize susceptibility and the role PAHs may play on specific craniosynostosis subtypes.
Nicchia E, Benedicenti F, De Rocco D
… +11 more, Greco C, Bottega R, Inzana F, Faleschini M, Bonin S, Cappelli E, Mogni M, Stanzial F, Svahn J, Dufour C, Savoia A
Birth Defects Res A Clin Mol Teratol
· 2015 Dec · PMID 26033879
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BACKGROUND: Fanconi anemia (FA) is a rare genetic disease characterized by congenital malformations, aplastic anemia and increased risk of developing malignancies. FA is genetically heterogeneous as it is caused by at le...BACKGROUND: Fanconi anemia (FA) is a rare genetic disease characterized by congenital malformations, aplastic anemia and increased risk of developing malignancies. FA is genetically heterogeneous as it is caused by at least 17 different genes. Among these, FANCA, FANCC, and FANCG account for approximately 85% of the patients whereas the remaining genes are mutated in only a small percentage of cases. For this reason, the molecular diagnostic process is complex and not always extended to all the FA genes, preventing the characterization of individuals belonging to rare groups. METHODS: The FA genes were analyzed using a next generation sequencing approach in two unrelated families. RESULTS: The analysis identified the same, c.484_485del, homozygous mutation of FANCF in both families. A careful examination of three electively aborted fetuses in one family and one affected girl in the other indicated an association of the FANCF loss-of-function mutation with a severe phenotype characterized by multiple malformations. CONCLUSION: The systematic use of next generation sequencing will allow the recognition of individuals from rare complementation groups, a better definition of their clinical phenotypes, and consequently, an appropriate genetic counseling.
Birth Defects Res A Clin Mol Teratol
· 2015 Aug · PMID 26033863
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Birth defects are a major cause of morbidity and mortality worldwide. There has been much progress in understanding the genetic basis of familial and syndromic forms of birth defects. However, the etiology of nonsydromic...Birth defects are a major cause of morbidity and mortality worldwide. There has been much progress in understanding the genetic basis of familial and syndromic forms of birth defects. However, the etiology of nonsydromic birth defects is not well-understood. Although there is still much work to be done, we have many of the tools needed to accomplish the task. Advances in next-generation sequencing have introduced a sea of possibilities, from disease-gene discovery to clinical screening and diagnosis. These advances have been fruitful in identifying a host of candidate disease genes, spanning the spectrum of birth defects. With the advent of CRISPR-Cas9 gene editing, researchers now have a precise tool for characterizing this genetic variation in model systems. Work in model organisms has also illustrated the importance of epigenetics in human development and birth defects etiology. Here we review past and current knowledge in birth defects genetics. We describe genotyping and sequencing methods for the detection and analysis of rare and common variants. We remark on the utility of model organisms and explore epigenetics in the context of structural malformation. We conclude by highlighting approaches that may provide insight into the complex genetics of birth defects.
Reefhuis J, Gilboa SM, Anderka M
… +13 more, Browne ML, Feldkamp ML, Hobbs CA, Jenkins MM, Langlois PH, Newsome KB, Olshan AF, Romitti PA, Shapira SK, Shaw GM, Tinker SC, Honein MA, National Birth Defects Prevention Study
Birth Defects Res A Clin Mol Teratol
· 2015 Aug · PMID 26033852
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BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a large population-based multicenter case-control study of major birth defects in the United States. METHODS: Data collection took place from 1998 throug...BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a large population-based multicenter case-control study of major birth defects in the United States. METHODS: Data collection took place from 1998 through 2013 on pregnancies ending between October 1997 and December 2011. Cases could be live born, stillborn, or induced terminations, and were identified from birth defects surveillance programs in Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah. Controls were live born infants without major birth defects identified from the same geographical regions and time periods as cases by means of either vital records or birth hospitals. Computer-assisted telephone interviews were completed with women between 6 weeks and 24 months after the estimated date of delivery. After completion of interviews, families received buccal cell collection kits for the mother, father, and infant (if living). RESULTS: There were 47,832 eligible cases and 18,272 eligible controls. Among these, 32,187 (67%) and 11,814 (65%), respectively, provided interview information about their pregnancies. Buccal cell collection kits with a cytobrush for at least one family member were returned by 19,065 case and 6,211 control families (65% and 59% of those who were sent a kit). More than 500 projects have been proposed by the collaborators and over 200 manuscripts published using data from the NBDPS through December 2014. CONCLUSION: The NBDPS has made substantial contributions to the field of birth defects epidemiology through its rigorous design, including case classification, detailed questionnaire and specimen collection, large study population, and collaborative activities across Centers.
Birth Defects Res A Clin Mol Teratol
· 2015 Sep · PMID 26033843
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BACKGROUND: In most patients affected by isolated oesophageal atresia (IOA) the etiology is largely unknown. Thus, the aim of this study was to analyze potential risk factors in mothers. METHODS: The study samples includ...BACKGROUND: In most patients affected by isolated oesophageal atresia (IOA) the etiology is largely unknown. Thus, the aim of this study was to analyze potential risk factors in mothers. METHODS: The study samples included 221 cases with IOA, 356 matched and 38,151 population controls without any defect in the population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980 to 1996. Only those exposures were evaluated that were medically recorded in prenatal maternity logbooks during the critical period of IOA. RESULTS: The findings of this case-control study suggested that the mothers of cases with IOA had a higher proportion of first delivery and lower socioeconomic status. Acute respiratory diseases (odds ratio [OR] 95% confidence interval [CI], 3.8, 1.8-8.1) and essential hypertension treated with nifedipine (OR 95% CI, 3.8, 1.7-8.7) in the mothers of cases associated with a higher risk for IOA in their children. CONCLUSION: First delivery, lower socioeconomic status, acute respiratory diseases and essential hypertension treated with nifedipine in the mothers may associate with a higher risk for IOA in their children.
Carter EH, Carmichael SL, Birnie K
… +3 more, Yang W, Lammer EJ, Shaw GM
Birth Defects Res A Clin Mol Teratol
· 2015 Oct · PMID 26033835
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BACKGROUND: Maternal nutritional status has been recognized as a contributor to conotruncal heart defects, but there is limited understanding of the specific nutrition-related factors involved. In this California case-co...BACKGROUND: Maternal nutritional status has been recognized as a contributor to conotruncal heart defects, but there is limited understanding of the specific nutrition-related factors involved. In this California case-control study of 296 conotruncal cases and 695 nonmalformed controls we explored whether weight loss during early pregnancy was associated with an increased risk of d-transposition of the great arteries (dTGA) and tetralogy of Fallot (TOF) conotruncal defects. METHODS: During telephone interviews women were asked whether they were dieting to lose weight or using weight loss remedies during 2 months before or 2 months after conception, and how much weight they gained or lost in the first 2 months of pregnancy or during the year before pregnancy. RESULTS: Odds ratios for dieting to lose weight and use of weight loss remedies for dTGA and TOF were not substantially elevated and all had confidence intervals that included 1.0. Mothers who had a loss of >5 lbs in the first 2 months of pregnancy as well as mothers who lost and gained >5 lbs in the first 2 months of pregnancy also did not show a significant increased risk of delivering case infants when compared with women with no weight change in the year before pregnancy. CONCLUSION: Given current recommendations about limited weight gain for obese pregnant women, these data indicate that dieting may not substantially increase a fetus' risk of having a conotruncal defect.
Tang X, Hobbs CA, Cleves MA
… +4 more, Erickson SW, MacLeod SL, Malik S, National Birth Defects Prevention Study
Birth Defects Res A Clin Mol Teratol
· 2015 Oct · PMID 26033827
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BACKGROUND: Congenital heart defects (CHDs) are among the most prevalent and serious birth defects, occurring in 8 to 10 of every 1000 live births in the United States. Epidemiologic studies have reported an association...BACKGROUND: Congenital heart defects (CHDs) are among the most prevalent and serious birth defects, occurring in 8 to 10 of every 1000 live births in the United States. Epidemiologic studies have reported an association between CHDs and maternal smoking, but it remains unknown how genes impact the susceptibility of offspring to CHDs in the presence of maternal tobacco use. METHODS: Using data from 403 case- and 219 control-parental triads enrolled in the National Birth Defects Prevention Study between 1998 and 2008, we investigated the association between CHDs and maternal and infant genetic variants involved in the tobacco metabolism and DNA repair pathways among mothers who smoked prenatally. RESULTS: The maternal genotypes of single nucleotide polymorphisms in the excision repair cross-complementation group 1 (ERCC1), poly (ADP-ribose) polymerase 2 (PARP2), and ERCC5 genes were identified to be significantly associated with the occurrence of CHDs in the presence of maternal tobacco use. Our analysis also revealed a moderate association between the infant genotypes of polymorphisms in the O-sialoglycoprotein endopeptidase (OSGEP) gene and increased risk of CHDs among mothers who smoked. CONCLUSION: Our study provides evidence that maternal and infant polymorphisms within the ERCC1, PARP2, ERCC5, and OSGEP genes are associated with CHD risk in the presence of maternal tobacco use. These results may provide insight into the susceptibility of having a pregnancy affected by CHDs among women who smoke.
Birth Defects Res A Clin Mol Teratol
· 2015 Sep · PMID 26033770
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BACKGROUND: In utero exposure to thalidomide causes a wide range of birth defects, including phocomelia, hearing loss and visceral disorders, known as thalidomide embryopathy (TE). Fifty years after the first report of T...BACKGROUND: In utero exposure to thalidomide causes a wide range of birth defects, including phocomelia, hearing loss and visceral disorders, known as thalidomide embryopathy (TE). Fifty years after the first report of TE, we conducted the first cross-sectional multicenter study to investigate the development of lifestyle-related diseases and identify risk factors for visceral disorders in subjects with TE. METHODS: Seventy-six cases with TE (31 men, 45 women) underwent medical examinations between 2011 and 2014 to determine the types of TE-related anomalies (limbs, auditory organs, or visceral organs) and lifestyle-related diseases present. Logistic multiple regression analyses, adjusted for gender and age, were conducted between TE and lifestyle-related diseases and to evaluate association between block vertebra and gallbladder aplasia. RESULTS: Fatty liver (FL), nonalcoholic FL disease and dyslipidemia were detected in 52.6%, 35.0%, and 23.7% of subjects, respectively, with higher incidences among men. Dyslipidemia was detected in 40.0% of subjects with FL and was significantly associated with FL (odds ratio = 8.86; p = 0.008). Block vertebrae were detected in 44.4% of subjects with gallbladder aplasia, and this association was significant (odds ratio = 9.96; p = 0.006). CONCLUSION: Subjects with TE have also a risk for lifestyle-related disease as well as the general Japanese population. In addition, cervical spine radiography and magnetic resonance imaging are recommended to assess block vertebrae in subjects with TE with gallbladder aplasia who develop shoulder pain.
Rocheleau CM, Bertke SJ, Lawson CC
… +10 more, Romitti PA, Sanderson WT, Malik S, Lupo PJ, Desrosiers TA, Bell E, Druschel C, Correa A, Reefhuis J, National Birth Defects Prevention Study
Birth Defects Res A Clin Mol Teratol
· 2015 Oct · PMID 26033688
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BACKGROUND: Congenital heart defects (CHDs) are common birth defects, affecting approximately 1% of live births. Pesticide exposure has been suggested as an etiologic factor for CHDs, but previous results were inconsiste...BACKGROUND: Congenital heart defects (CHDs) are common birth defects, affecting approximately 1% of live births. Pesticide exposure has been suggested as an etiologic factor for CHDs, but previous results were inconsistent. METHODS: We examined maternal occupational exposure to fungicides, insecticides, and herbicides for 3328 infants with CHDs and 2988 unaffected control infants of employed mothers using data for 1997 through 2002 births from the National Birth Defects Prevention Study, a population-based multisite case-control study. Potential pesticide exposure from 1 month before conception through the first trimester of pregnancy was assigned by an expert-guided task-exposure matrix and job history details self-reported by mothers. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. RESULTS: Maternal occupational exposure to pesticides was not associated with CHDs overall. In examining specific CHD subtypes compared with controls, some novel associations were observed with higher estimated pesticide exposure: insecticides only and secundum atrial septal defect (OR = 1.8; 95% CI, 1.3-2.7, 40 exposed cases); both insecticides and herbicides and hypoplastic left heart syndrome (OR = 5.1; 95% CI, 1.7-15.3, 4 exposed cases), as well as pulmonary valve stenosis (OR = 3.6; 95% CI, 1.3-10.1, 5 exposed cases); and insecticides, herbicides, and fungicides and tetralogy of Fallot (TOF) (OR = 2.2; 95% CI, 1.2-4.0, 13 exposed cases). CONCLUSION: Broad pesticide exposure categories were not associated with CHDs overall, but examining specific CHD subtypes revealed some increased odds ratios. These results highlight the importance of examining specific CHDs separately. Because of multiple comparisons, additional work is needed to verify these associations.