Showing papers in "Birth Defects Research Part A-clinical and Molecular Teratology in 2010"

Updated national birth prevalence estimates for selected birth defects in the United States, 2004–2006†

Abstract: BACKGROUND: The National Birth Defects Prevention Network collects state-specific birth defects surveillance data for annual publication of prevalence estimates and collaborative research projects. In 2006, data for 21 birth defects from 1999 through 2001 were presented as national birth prevalence estimates. The purpose of this report was to update these estimates using data from 2004 through 2006. METHODS: Population-based data from 11 active case-finding programs, 6 passive case-finding programs with case confirmation, and 7 passive programs without case confirmation were used in this analysis. Pooled birth prevalence estimates for 21 birth defects, stratified by case ascertainment approach, were calculated. National prevalence estimates, adjusted for maternal race/ethnicity and maternal age (trisomy 13, trisomy 18, and Down syndrome only) were determined using data from 14 programs. The impact of pregnancy outcomes on prevalence estimates was also assessed for five specific defects. RESULTS: National birth defects prevalence estimates ranged from 0.72 per 10,000 live births for common truncus to 14.47 per 10,000 live births for Down syndrome. Stratification by type of surveillance system showed that active programs had a higher prevalence of anencephaly, anophthalmia/microphthalmia, cleft lip with or without cleft palate, reduction defect of upper limbs, and trisomy 18. The birth prevalence of anencephaly, trisomy 13, and trisomy 18 also varied substantially with inclusion of elective terminations. CONCLUSION: Accurate and timely national estimates of the prevalence of birth defects are needed for monitoring trends, assessing prevention efforts, determining service planning, and understanding the burden of disease due to birth defects in the United States. Birth Defects Research (Part A) 88:1008–1016, 2010. 2010 Wiley-Liss, Inc.

An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure

Abstract: The number of mouse mutants and strains with neural tube defects (NTDs) now exceeds 240, including 205 representing specific genes, 30 for unidentified genes, and 9 multifactorial strains These mutants identify genes needed for embryonic neural tube closure Reports of 50 new NTD mutants since our 2007 review (Harris and Juriloff, 2007) were considered in relation to the previously reviewed mutants to obtain new insights into mechanisms of NTD etiology In addition to null mutations, some are hypomorphs or conditional mutants Some mutations do not cause NTDs on their own, but do so in digenic, trigenic, and oligogenic combinations, an etiology that likely parallels the nature of genetic etiology of human NTDs Mutants that have only exencephaly are fourfold more frequent than those that have spina bifida aperta with or without exencephaly Many diverse cellular functions and biochemical pathways are involved; the NTD mutants draw new attention to chromatin modification (epigenetics), the protease-activated receptor cascade, and the ciliopathies Few mutants directly involve folate metabolism Prevention of NTDs by maternal folate supplementation has been tested in 13 mutants and reduces NTD frequency in six diverse mutants Inositol reduces spina bifida aperta frequency in the curly tail mutant, and three new mutants involve inositol metabolism The many NTD mutants are the foundation for a future complete genetic understanding of the processes of neural fold elevation and fusion along mechanistically distinct cranial-caudal segments of the neural tube, and they point to several candidate processes for study in human NTD etiology

Epigenomic disruption: The effects of early developmental exposures

Abstract: Through DNA methylation, histone modifications, and small regulatory RNAs the epigenome systematically controls gene expression during development, both in utero and throughout life. The epigenome is also a very reactive system; its labile nature allows it to sense and respond to environmental perturbations to ensure survival during fetal growth. This pliability can lead to aberrant epigenetic modifications that persist into later life and induce numerous disease states. Endocrine-disrupting compounds (EDCs) are ubiquitous chemicals that interfere with growth and development. Several EDCs also interfere with epigenetic programming. The investigation of the epigenotoxic effects of bisphenol A (BPA), an EDC used in the production of plastics and resins, has further raised concern over the impact of EDCs on the epigenome. Using the Agouti viable yellow (A(vy)) mouse model, dietary BPA exposure was shown to hypomethylate both the A(vy) and the Cabp(IAP) metastable epialleles. This hypomethylating effect was counteracted with dietary supplementation of methyl donors or genistein. These results are consistent with reports of BPA and other EDCs causing epigenetic effects. Epigenotoxicity could lead to numerous developmental, metabolic, and behavioral disorders in exposed populations. The heritable nature of epigenetic changes also increases the risk for transgenerational inheritance of phenotypes. Thus, epigenotoxicity must be considered when assessing these compounds for safety.

Cryptorchidism and hypospadias as a sign of testicular dysgenesis syndrome (TDS): Environmental connection

Abstract: Cryptorchidism and hypospadias are common genital birth defects that affect 2–9% and 0.2–1% of male newborns, respectively. The incidence of both defects shows large geographic variation, and in several countries increasing trends have been reported. The conditions share many risk factors, and they are also interlinked to the risk of testis cancer and poor semen quality. Testicular Dysgenesis Syndrome (TDS) may underlie many cases of all these male reproductive health problems. Genetic defects in androgen production or action can cause both cryptorchidism and hypospadias, but these are not common. A monogenic reason for cryptorchidism or hypospadias has been identified only in a small proportion of all cases. Environmental effects appear to play a major role in TDS. Exposure to several persistent chemicals has been found to be associated with the risk of cryptorchidism, and exposure to anti-androgenic phthalates has been shown to be associated with hormonal changes predisposing to male reproductive problems. Despite progress in identification of endocrine-disrupting substances, we are still far from knowing all the risk factors for these birth defects, and advice for prevention must be based on precautionary principles. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Prenatal choline supplementation mitigates behavioral alterations associated with prenatal alcohol exposure in rats

Abstract: BACKGROUND Prenatal alcohol exposure can alter physical and behavioral development, leading to a range of fetal alcohol spectrum disorders (FASD). Despite warning labels, pregnant women continue to drink alcohol, creating a need to identify effective interventions to reduce the severity of alcohol’s teratogenic effects. Choline is an essential nutrient that influences brain and behavioral development. Recent studies indicate that choline supplementation can reduce the teratogenic effects of developmental alcohol exposure. The present study examined whether choline supplementation during prenatal ethanol treatment could mitigate the adverse effects of ethanol on behavioral development.

The relationship between sonic Hedgehog signaling, cilia, and neural tube defects.

Abstract: The Hedgehog signaling pathway is essential for many aspects of normal embryonic development, including formation and patterning of the neural tube. Absence of the sonic hedgehog (shh) ligand is associated with the midline defect holoprosencephaly, whereas increased Shh signaling is associated with exencephaly and spina bifida. To complicate this apparently simple relationship, mutation of proteins required for function of cilia often leads to impaired Shh signaling and to disruption of neural tube closure. In this article, we review the literature on Shh pathway mutants and discuss the relationship between Shh signaling, cilia, and neural tube defects.

First trimester paroxetine use and the prevalence of congenital, specifically cardiac, defects: A meta‐analysis of epidemiological studies

Abstract: BACKGROUND: Several studies have evaluated maternal first trimester paroxetine use and the prevalence of congenital defects, particularly cardiac defects. To synthesize current epidemiologic information, a meta-analysis was conducted. METHODS: A systematic literature search was conducted for original research published from January 1, 1992, through September 30, 2008. Results were extracted using predefined criteria, and authors were contacted for additional information when necessary. Compiled results were evaluated for funnel plot asymmetry, heterogeneity, and study characteristic associations. Where appropriate, fixed-effect summary estimates were calculated and sensitivity analyses performed. RESULTS: Twenty reports (11 including results for aggregated congenital and combined cardiac defects, six for aggregated congenital defects only, and three for combined cardiac defects only) met prespecified inclusion criteria. There was little evidence of funnel plot asymmetry or overall heterogeneity. Summary estimates were produced for combined cardiac defects (prevalence odds ratio [POR], 1.46; 95% confidence interval [CI], 1.17–1.82) and aggregated congenital defects (POR, 1.24; 95% CI, 1.08–1.43) and first trimester paroxetine use. Some study characteristics may be associated with differential POR estimates for paroxetine and either combined cardiac or aggregated congenital defects. CONCLUSIONS: This meta-analysis found little evidence of publication bias or overall statistical heterogeneity and only weak evidence of associations with some study characteristics. Although subject to limitations, the summary estimate indicates an increased prevalence of combined cardiac defects with first trimester paroxetine use. The summary estimate also indicates an increased prevalence of aggregated congenital defects with paroxetine; however, this association may be explained, in part, by the increased prevalence of combined cardiac defects. Birth Defects Research (Part A), 2010. © 2009 Wiley-Liss, Inc.

International trends of Down syndrome 1993-2004: Births in relation to maternal age and terminations of pregnancies.

Abstract: BACKGROUND: The aim of this study was to examine trends of Down syndrome (DS) in relation to maternal age and termination of pregnancies (ToP) in 20 registries of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) METHODS: Trends of births with DS (live-born and stillborn), ToP with DS, and maternal age (percentage of mothers older than 35 years) were examined by year over a 12-year period (1993-2004) The total mean number of births covered was 1550,000 annually RESULTS: The mean percentage of mothers older than 35 years of age increased from 109% in 1993 to 188% in 2004 However, a variation among the different registers from 4-8% to 20-25% of mothers >35 years of age was found The total mean prevalence of DS (still births, live births, and ToP) increased from 131 to 182/10,000 births between 1993 and 2004 The total mean prevalence of DS births remained stable at 83/10,000 births, balanced by a great increase of ToP In the registers from France, Italy, and the Czech Republic, a decrease of DS births and a great increase of ToP was observed The number of DS births remained high or even increased in Canada Alberta, and Norway during the study period CONCLUSIONS: Although an increase in older mothers was observed in most registers, the prevalence of DS births remained stable in most registers as a result of increasing use of prenatal diagnostic procedures and ToP with DS

The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis

Abstract: Retinoic acid (RA) is a pleiotropic derivative of vitamin A, or retinol, which is responsible for all of the bioactivity associated with this vitamin. The teratogenic influences of vitamin A deficiency and excess RA in rodents were first observed more than 50 years ago. Efforts over the last 15-20 years have refined these observations by defining the molecular mechanisms that control RA availability and signaling during murine embryonic development. This review will discuss our current understanding of the role of RA in teratogenesis, with specific emphasis on the essential function of the RA catabolic CYP26 enzymes in preventing teratogenic consequences caused by uncontrolled distribution of RA. Particular focus will be paid to the RA-sensitive tissues of the caudal and cranial regions, the limb, and the testis, and how genetic mutation of factors controlling RA distribution have revealed important roles for RA during embryogenesis.

Understanding diabetic teratogenesis: where are we now and where are we going?

Abstract: Maternal pregestational diabetes (type 1 or type 2) poses an increased risk for a broad spectrum of birth defects To our knowledge, this problem first came to the attention of the Teratology Society at the 14th Annual Meeting in Vancouver, BC in 1974, with a presentation by Lewis Holmes, "Etiologic heterogeneity of neural tube defects" Although advances in the control of diabetes in the decades since the discovery of insulin in the 1920's have reduced the risk for birth defects during diabetic pregnancy, the increasing incidence of diabetes among women of childbearing years indicates that this cause of birth defects is a growing public health concern Major advances in understanding how a disease of maternal fuel metabolism can interfere with embryogenesis of multiple organ systems have been made in recent years In this review, we trace the history of the study of diabetic teratogenesis and discuss a model in which tissue-specific developmental control genes are regulated at specific times in embryonic development by glucose metabolism The major function of such genes is to suppress apoptosis, perhaps to preserve proliferative capability, and inhibit premature senescence

Prevalence of multiple congenital contractures including arthrogryposis multiplex congenita in Alberta, Canada, and a strategy for classification and coding

Abstract: BACKGROUND The population prevalence of multiple congenital contractures, many of which have either arthrogryposis multiplex congenita or amyoplasia congenita, ranges from 1/3300 to 1/56,000. Three other studies report a range of 1/4500 to 1/12,500. Classification and coding of these disorders in the International Classification of Diseases, tenth edition, (ICD-10) is less than satisfactory, even when augmented by the Royal College of Pediatrics and Child Health (RCPCH). expansion. METHODS The database of the Alberta Congenital Anomalies Surveillance System (ACASS) was used to review all cases (1980–2007) of the previously named disorders with special emphasis on the 1997–2007 cohort. The latter period was chosen because more complete ascertainment was likely due to the addition of terminations of pregnancy data beginning in 1997. This cohort was further analyzed into the three practical groups: I, limb only; II, limb plus non–central nervous system anomalies; and III, limb plus lethality, central nervous system anomalies, or both, with further syndrome identification in groups II and III. The ICD-10–RCPCH classification and codes were reviewed. RESULTS The prevalence for multiple congenital contractures in Alberta is 1/8700 for 1980-1996 and 1/4300 for 1997-2007. Rates for the three groups were calculated. Specific diagnostic categories were found in groups II and III of 43% and 65%, respectively. Mortality is high, especially in the first month of life (45% total losses). New classification and coding systems are proposed. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

The visceral yolk sac endoderm provides for absorption of nutrients to the embryo during neurulation

Abstract: Neural tube defects (NTDs) represent some of the most common congenital malformations in humans. The causes of NTDs are complex with both genetic and environmental contributing factors. Periconception nutrition is an important environmental factor influencing the penetrance of NTDs. NTDs arise from failure to close the neural tube completely during development, an event that occurs before establishment of the chorioallantoic placenta. During neurulation, nutrients are absorbed by histotrophic mechanisms and absorbed by endocytosis in the endoderm-derived cell layer of the visceral yolk sac (VYS). Here we review the histotrophic mechanisms by which nutrients are delivered to the human embryo during this critical time period. Because more detailed studies on the molecular mechanisms regulating uptake of nutrients have been performed using rodent models, most importantly mouse and rat models, we will also review nutrient uptake in these model organisms to set the stage for presentation of experimental data that have provided valuable information about how nutrients are delivered to the neurulating embryo.

Neural Tube Defect Genes and Maternal Diabetes during Pregnancy

Abstract: BACKGROUND: Maternal diabetes during pregnancy is a well-known teratogen that increases the risk for birth defects, such as neural tube defects (NTDs). We have previously shown that maternal diabetes profoundly affects gene expression in the developing embryo, in particular a suite of known NTD genes. In rodent experimental systems, NTDs present as phenotypes of incomplete penetrance in diabetic pregnancies. This property is difficult to reconcile with observations of consistently altered gene expression in exposed embryos. We here show that maternal diabetes increases the overall variability of gene expression levels in embryos. RESULTS: Altered gene expression and increased variability of gene expression together may constitute the molecular correlates for incomplete phenotype penetrance. DISCUSSION: Based on this model, we suggest that maternal diabetes reduces the precision of gene regulation in exposed individuals. Loss of precision in embryonic gene regulation may include changes to the epigenome via deregulated expression of chromatin-modifying factors. Unraveling the mechanisms underlying such epigenetic modifications in diabetic pregnancies will help to understand how teratogenic insults compromise embryonic development and possibly provide avenues for therapeutic intervention. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Studies with Wnt genes and nonsyndromic cleft lip and palate.

Abstract: BACKGROUND: Clefts of the lip and/or palate (cleft lip/palate) are notable for their complex etiology. The WNT pathway regulates multiple developmental processes including craniofacial development and may play a role in cleft lip/palate and other defects of craniofacial development such as tooth agenesis. Variations in WNT genes have been recently associated with cleft lip/palate in humans. In addition, two WNT genes, Wnt3 and Wnt9B, are located in the clf1 cleft locus in mice. METHODS: We investigated 13 SNPs located in Wnt3A, Wnt5A, Wnt8A, Wnt11, Wnt3, and Wnt9B genes for association with cleft lip/palate subphenotypes in 463 cleft cases and 303 unrelated controls. Genotyping of selected polymorphisms was carried out using Taqman assays. PLINK 1.06 software was used to test for differences in allele frequencies of each polymorphism between affected and unaffected individuals. Haplotype analysis was also performed. RESULTS: Individuals carrying variant alleles in WNT3 presented an increased risk for cleft lip/palate (p 5 0.0003; OR, 1.61; 95% CI, 1.29‐2.02) in the population studied. CONCLUSION: Our results continue to support a role for WNT genes in the pathogenesis of cleft lip/palate. Although much remains to be learned about the function of individual WNT genes during craniofacial development, additional studies should focus on the identification of potentially functional variants in these genes as contributors to human clefting. Birth Defects Research (Part A) 88:995‐1000, 2010. ! 2010 Wiley-Liss, Inc.

Maternal exposures to endocrine disrupting chemicals and hypospadias in offspring.

Abstract: BACKGROUND Prenatal exposures to endocrine-disrupting chemicals (EDCs) are suspected risk factors in the etiology of hypospadias. The aim of this case-control study was to test the hypothesis of an association between maternal environmental exposures to EDCs and hypospadias in the offspring. METHODS Detailed questionnaire data on occupational and dietary exposures to EDCs in the perinatal period were collected from 80 mothers with hypospadiac infants and from 80 mothers with healthy controls within 24 months of childbirth. Maternal exposure to selected EDCs was also ascertained by measuring the concentration of dichlorodiphenyldichloroethylene, hexachlorobenzene, and several polychlorinated biphenyl congeners in the serum of primiparous mothers of 37 cases and 21 controls. RESULTS The risk to bear an hypospadiac infant was associated with perinatal maternal occupational exposures to EDCs evaluated by a job-exposure matrix: jobs with exposure to one class of EDCs (odds ratios [OR]crude, 2.83; 95% confidence intervals [CI], 1.32–6.07; ORadjusted, 2.44; 95% CI, 1.06–5.61) and jobs with exposure to more than one group of EDCs (ORcrude, 4.27; 95% CI, 1.43–12.78; ORadjusted, 4.11; 95%CI, 1.34–12.59). Increase in risk was also found among mothers consuming a diet rich in fish or shellfish (ORcrude, 3.41; 95% CI, 1.42–8.23; ORadjusted, 2.73; 95%CI, 1.09–6.82). Serum hexachlorobenzene concentration above the median of all subjects was significantly associated with the risk of hypospadias (ORadjusted, 5.50; 95% CI, 1.24–24.31). CONCLUSIONS This study, although based on a limited number of cases, for the first time provides evidence of an association between maternal exposure to EDCs, in particular elevated plasma hexachlorobenzene concentration, and the development of hypospadias in the offspring. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Cleft lip and palate results from Hedgehog signaling antagonism in the mouse: phenotypic characterization and clinical implications

Abstract: Background The Hedgehog (Hh) pathway provides inductive signals critical for developmental patterning of the brain and face. In humans as well as in animal model systems, interference with this pathway yields birth defects; among the most well-studied of which fall within the holoprosencephaly (HPE) spectrum.

Preconception care for women with diabetes and prevention of major congenital malformations.

Abstract: This article provides an overview of the rationale for diabetes preconception care interventions for women with diabetes and the efficacy in reducing the excess occurrence of major congenital malformations. The problems with broad use of individualized preconception care are considered. In addition, suggestions are made for the implementation of more comprehensive interventions in the community and usual diabetes care settings, to address the multiple ongoing challenges in the prevention of structural anomalies associated with preexisting diabetes. Based on the published evidence, successful preconception care can be considered to include: achievement of individualized target standardized glycosylated hemoglobin levels, adequate nutrition, and minimizing hypoglycemia before and after discontinuing effective contraception and during the transition to early prenatal care. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Oral cleft defects and maternal exposure to ambient air pollutants in New Jersey

Abstract: BACKGROUND Evidence links exposure to ambient air pollution during pregnancy, particularly gaseous pollutants and particulate matter, to an increased risk of adverse reproductive outcomes though the results for birth defects have been inconsistent. METHODS We compared estimated exposure to ambient air pollutants during early pregnancy among mothers of children with oral cleft defects (cases) to that among mothers of controls, adjusting for available risk factors from birth certificates. We obtained ambient air pollutant data from air monitoring sites in New Jersey for carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), sulfur dioxide (SO2), particulate matter <10 μm in aerodynamic diameter (PM10) and particulate matter <2.5 μm in aerodynamic diameter (PM2.5). We used values from the nearest monitor (within 40 km of the residence at birth) for controls, cleft lip with or without cleft palate (CLP) and cleft palate only (CPO). RESULTS Based on logistic regression analyses for each contaminant and all contaminants together, there were no consistent elevated associations between selected air pollutants and cleft malformations. Quartile of CO concentration showed a consistent protective association with CPO (p < 0.01). For other contaminants, confidence intervals (95%) of the odds ratios for some quartiles excluded one. CLP showed limited evidence of an association with increasing SO2 exposure while CPO showed weak associations with increasing O3 exposure. CONCLUSION There was little consistent evidence associating cleft malformations with maternal exposure to ambient air pollutants. Evaluating particular pollutants or disease subgroups would require more detailed measurement of exposure and classification of cleft defects. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Magnetic resonance microscopy‐based analyses of the brains of normal and ethanol‐exposed fetal mice

Abstract: Background The application of magnetic resonance microscopy (MRM) to the study of normal and abnormal prenatal mouse development has facilitated discovery of dysmorphology following prenatal ethanol insult. The current analyses extend this work, providing a regional brain volume-based description of normal brain growth and illustrating the consequences of gestational day (GD) 10 ethanol exposure in the fetal mouse.

Association between genetic variants of reported candidate genes or regions and risk of cleft lip with or without cleft palate in the polish population.

Abstract: BACKGROUND Cleft lip with or without cleft palate (CL/P) is one of the most common craniofacial malformations, with a complex and multifactorial etiology. Because of the genetic heterogeneity of facial clefts, the aim of this study was to investigate the contribution of previously reported candidate genes and chromosomal loci to the risk of CL/P in the Polish population. METHODS We performed an analysis of 18 polymorphisms of FOXE1, IRF6, MSX1, PAX9, TBX10, FGF10, FGFR1, TGFα, TGFβ3, SUMO1, and the chromosomal region 8q24 in a group of 175 patients with CL/P and a properly matched control group. RESULTS Highly significant results were observed for the IRF6 rs642961 variant and the 8q24 region's rs987525 (odds ratio [OR]AG+AAvsGG, 1.635; 95% confidence interval [CI], 1.153–2.319; p = 0.005; and ORAC+AAvsCC, 1.962; 95% CI, 1.382–2.785; p = 1.4 × 10−4, respectively). For rs987525, the results were also significant after correction for multiple comparisons. Borderline association with an increased risk of CL/P was also identified for the SUMO1 locus (rs2350350; ORCGvsGG, 1.580; 95% CI, 1.056–2.363; p = 0.025). CONCLUSIONS Our findings confirmed that genetic variants of IRF6 and the polymorphism located in the 8q24 gene desert are strongly involved in the etiology of facial clefts in the Polish population sample. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

The Ribavirin Pregnancy Registry: Findings after 5 years of enrollment, 2003–2009

Abstract: INTRODUCTION: Ribavirin, with interferons or pegylated interferons, is used to treat chronic hepatitis C. Ribavirin is contraindicated in pregnancy (FDA Pregnancy Category X) and in men whose partners may become pregnant. In 2003, the Ribavirin Pregnancy Registry was established to monitor pregnancy exposures to ribavirin and to evaluate the potential human teratogenicity of prenatal exposure. METHODS: This voluntary registry enrolls pregnant women who have been exposed to ribavirin during pregnancy or during the six months prior to conception either directly, by taking ribavirin, or indirectly through sexual contact with a man taking ribavirin. Women are followed until delivery; live born infants are followed for one year. The Registry aims to enroll 131 live births following direct (maternal) exposure to ribavirin and 131 live births following indirect (male) exposures. RESULTS: After more than five years of operation, the Registry has enrolled 49 live births with direct exposure and 69 live births following indirect exposure. Six outcomes with birth defects have been reported. All were among live born infants: torticollis (2), hypospadias (1), polydactyly and a neonatal tooth (1), glucose-6-phosphate dehydrogenase deficiency (1), ventricular septal defect and cyst of 4th ventricle of the brain (1). Three received direct exposures ([6.1% (95% CI: 1.2, 16.9)], three were exposed indirectly [4.3% (95% CI: 0.9, 12.2)]. CONCLUSIONS: Although current enrollment is far short of the required sample size, preliminary findings have not detected a signal indicating human teratogenicity for ribavirin. However, findings must be interpreted with caution concerning direct or indirect prenatal ribavirin exposures. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Maternal and paternal risk factors for anorectal malformations: a Dutch case-control study.

Abstract: BACKGROUND: Anorectal malformations (ARM) are major congenital malformations that usually require a multitude of surgical procedures at a very early age and have a large impact on the lives of patients and their parents. The causes of ARM are still largely unknown, but they are assumed to have a multifactorial etiology. A few studies focused on environmental risk factors, but evidence is still scarce. METHODS: In this Dutch case-control study (1996-2008), we investigated the role of maternal and paternal risk factors in the etiology of ARM. Parents of 85 ARM cases and 650 controls filled in a questionnaire. Controls were children treated with ear ventilation tubes. RESULTS: A higher occurrence of fever during the first trimester of pregnancy was found for case mothers compared to control mothers (odds ratio [OR], 5.1; 95% Confidence Interval [CI], 0.9, 28.1). Maternal occupational exposure to industrial cleaning agents and solvents increased the risk of ARM three times (OR, 2.9; 95% CI, 0.9, 9.3). Overweight (Body Mass Index [BMI] > or = 25 kg/m(2)) before pregnancy also seemed to be associated with ARM (OR, 1.8; 95% CI, 1.1, 2.8), as well as maternal multivitamin use during pregnancy (OR, 1.6; 95% CI, 1.0, 2.7), paternal smoking (OR, 1.8; 95% CI, 1.1, 2.9), and paternal occupational exposure to exhaust fumes (OR, 1.9; 95% CI, 1.0, 3.6). Reported ARM in at least one first- or second-degree family member greatly increased the risk of having a child with an ARM (OR, 40.3; 95% CI, 4.8, 342.8). CONCLUSIONS: This study revealed potential risk factors for ARM, including fever during pregnancy, maternal overweight, use of multivitamins, paternal smoking, and occupational exposures, but a familial component seems important as well.

Effect of maternal asthma on the risk of specific congenital malformations: A population-based cohort study.

Abstract: BACKGROUND There is a lack of consensus in the literature about the effect of maternal asthma on the development of congenital malformations. OBJECTIVE To further examine the association between maternal asthma and the risk of congenital malformations. METHODS A cohort of 41,637 pregnancies from women with and without asthma who delivered between 1990 and 2002 was reconstructed by linking three Quebec (Canada) administrative databases. All cases of malformations were identified using either the medical services or the hospital databases. The main exposure was maternal asthma, defined by the presence of at least one asthma diagnosis and at least one prescription for an asthma medication at any time in the two years before or during pregnancy. Generalized Estimation Equation models were performed to estimate the adjusted odds ratio (OR) of congenital malformations as a function of maternal asthma. RESULTS The crude prevalences of any congenital malformation were 9.5% and 7.5% for women with and without asthma, respectively. Maternal asthma was significantly associated with an increased risk of any malformation (OR=1.30; 95% CI: 1.20-1.40) and three specific groups (at the 0.0028 level): nervous system (excluding spina bifida: OR=1.83; 1.37-2.83); respiratory system (OR=1.75; 1.21-2.53); and digestive system (OR=1.48; 1.19-1.85). CONCLUSIONS Maternal asthma increases the risk of specific groups of congenital malformations. The disease itself, through fetal oxygen impairment, is likely to play a role in this increased risk, but more research is needed to disentangle the relative effect of asthma and medications used to treat this disease. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Malformations in infants of diabetic mothers. Teratology 25:385-94. 1982.

Abstract: Maternal insulin-dependent diabetes has long been associated with congenital malformations. As other causes of mortality and morbidity have been eliminated or reduced, malformations have become increasingly prominent. Although there is not universal agreement, the great majority of investigators find a two- to threefold increase in malformations in infants of insulin-dependent diabetic mothers. This increase is not seen in infants of gestational diabetics. It probably is not present in women whose diabetes can be controlled by diet or oral hypoglycemic agents. The risk does not appear to be primarily genetic since diabetic fathers do not have an increased number of malformed offspring. Most studies show a generalized increase in malformations involving multiple organ systems. Multiple malformations seem to be more common in diabetic than non-diabetic infants. Caudal regression has the strongest association with diabetes, occurring roughly 200 times more frequently in infants of diabetic mothers than in other infants. The teratogenic mechanism in diabetes is not known. Hyperglycemia may be important but human studies focusing on the period of organogenesis are lacking. Hypoglycemia has also been suggested based mainly on animal experiments. Insulin appears unlikely. Numerous other factors including vascular disease, hypoxia, ketone and amino acid abnormalities, glycosylation of proteins, or hormone imbalances could be teratogenic. None has been studied in sufficient detail to make a judgment. A large-scale prospective study is required to determine early fetal loss rates, correlate metabolic status during organogenesis with outcome, and assess the effect of diabetic control on malformation rates.

Global DNA hypomethylation is associated with NTD‐affected pregnancy: A case‐control study

Abstract: BACKGROUND: Neural tube defects are severe, common birth defects that result from failure of neural tube closure. They are considered to be a multifactorial disorder, and our knowledge of causal mechanisms remains limited. We hypothesized that abnormal DNA methylation occurs in NTD-affected fetuses. The correlations of global DNA methylation levels with complexity of NTDs and known risk factors of NTDs, MTHFR genotype and fever, were analyzed. METHODS: A hospital-based case-control study was performed. Epidemiologic data, pathologic diagnosis, and methylenetetrahydrofolate reductase (MTHFR) genotype analysis were completed. Array comparative genomic hybridization was used to exclude cytogenetic abnormalities. Global DNA methylation statuses were determined for both brain and skin tissue. RESULTS: Sixty-five NTD-affected fetuses and 65 normal controls matched for gestational and maternal ages were collected. In brain tissue, global DNA methylation levels were significantly decreased in cases compared with controls (4.12 vs. 4.99%; p < 0.001). DNA hypomethylation (<4.35%) resulted in a significant 5.736-fold increased risk for NTDs (95% confidence interval, 1.731–19.009; p = 0.004). Nonisolated NTDs had lower levels of global DNA methylation than did isolated NTDs (3.77 vs. 4.70%; p = 0.022). After stratifying subjects by MTHFR genotype, we observed a skewed distribution of global DNA methylation levels. For genotype C/C, global DNA methylation status was the same in the two groups (4.51 vs. 4.72%; p = 0.687). For T/T, cases had significantly lower global methylation levels than did controls (5.23 vs. 3.79%; p < 0.001). CONCLUSIONS: Global DNA hypomethylation in fetal brain tissue was associated with NTD-affected pregnancy. DNA methylation levels were correlated with NTD complexity. The MTHFR genotype contributed to global DNA hypomethylation. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Prepregnancy obesity: A complex risk factor for selected birth defects

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.

Genetic risk factors for nonsyndromic cleft lip with or without cleft palate in a Mesoamerican population: Evidence for IRF6 and variants at 8q24 and 10q25

Abstract: INTRODUCTION: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all birth defects. NSCL/P has a multifactorial etiology that includes both genetic and environmental factors. The IRF6 gene and three further susceptibility loci at 8q24, 10q25, and 17q22, which were identified by a recent genome-wide association scan (GWAS), are confirmed genetic risk factors for NSCL/P in patients of European descent. METHODS: A case-control association study was performed to investigate whether these four risk loci contribute to NSCL/P in a Mesoamerican population using four single nucleotide polymorphisms to represent IRF6 and the three novel susceptibility loci. A total of 149 NSCL/P patients and 303 controls of Mayan origin were included. RESULTS: Single marker analysis revealed a significant association between NSCL/P and risk variants in IRF6 and the 8q24 and 10q25 loci. In contrast to previous findings, the association at the 8q24 locus was driven solely by homozygote carriers of the risk allele. This suggests that this locus might act in a recessive manner in the Mayan population. No evidence for association was found at the 17q22 locus. This may have been attributable to the limited power of the sample. CONCLUSION: These results suggest that IRF6 and the 10q25 and 8q24 loci confer a risk for the development of NSCL/P in persons of Mayan origin. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Periconceptional nutrient intakes and risks of neural tube defects in California

Abstract: Background 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. Methods 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 or =75th percentile were compared, based on control distributions. Results 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). Conclusions 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.

Maternal fever during early pregnancy and the risk of oral clefts.

Abstract: An increased risk of birth defects after hyperthermic exposures has been confirmed in animal studies, but population studies have yielded inconsistent results. Oral clefts are a common birth defect and have been associated with these exposures in some of these studies. In this study, data from the National Birth Defects Prevention Study was used to evaluate the association of maternal report of febrile illness in early pregnancy and the risk of oral clefts. All oral cleft cases born between 1997 and 2004 were compared with nonmalformed controls born in the same geographical region during the same time period. Mothers reporting febrile illness during pregnancy were stratified by fever grade and antipyretic use. Logistic regression models were used to generate crude and adjusted odds ratios for exposure to fever and association with each oral cleft phenotype. The dataset included 5821 controls, 1567 cases of cleft lip with or without cleft palate (CL+/-P) and 835 cases of cleft palate only. A modestly increased risk was observed for isolated CL+/-P (odds ratio, 1.28; 95% confidence interval, 1.01-1.63). Stratification by fever grade (body temperature or =101.5 degrees F) did not yield significant differences in risk. Risk estimates were higher among women who reported a fever, but did not take antipyretics to control their fever, particularly for nonisolated compared with isolated oral clefts. This finding suggests that adequate control of fever may diminish the deleterious effects of fever in cases of oral cleft.

Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate

Abstract: BACKGROUND: Orofacial clefts are among the most common birth defects with a strong genetic component Nonsyndromic cleft palate (NSCP) is a complex malformation determined by the interaction between multiple genes and environmental risk factors METHODS: We conducted a case-control association study to investigate the role of 40 candidate genes in predisposition to orofacial clefting Five hundred ninety-one haplotype tagging single nucleotide polymorphism (tagSNPs) were genotyped in a clefting sample from the Baltic region, composed of 104 patients with nonsyndromic cleft palate and 606 controls from an Estonian, Latvian, and Lithuanian population RESULTS: In case-control comparisons, the minor alleles of IRF6 rs17389541 (p 5 545 3 10 24 ) and COL2A1 rs1793949 (p 5 726 3 10 24 ) were associated with increased risk of NSCP Multiple haplotypes in COL2A1 and COL11A2 and haplotypes in WNT3, FGFR1, and CLPTM1were associated with NSCP The strongest associations were found for IRF6 haplotype rs17389541/rs9430018 GT (p 5 223 3 10 24 ) and COL2A1 haplotype rs12822608/rs6823 GC (p 5 368 3 10 24 ) The strongest epistatic interactions were observed between MSX1 and BMP2, FGF1 and PVRL2, and COL2A1 and FGF2 genes CONCLUSIONS: This study provides for the first time evidence of the implication of IRF6, COL2A1, and WNT3 in the occurrence of NSCP It is likely that variation in cartilage collagen II and XI genes, IRF6, and the Wnt and FGF signaling pathway genes contributes susceptibility to nonsyndromic cleft palate in Northeastern European populations Birth Defects Research (Part A) 88:748– 756, 2010 2010 Wiley-Liss, Inc