Maternal intake of vitamin E and birth defects,national birth defects prevention study, 1997 to 2005

BACKGROUND In a recent study, high maternal periconceptional intake of vitamin E was found to be associated with risk of congenital heart defects (CHDs). To explore this association further, we investigated the association between total daily vitamin E intake and selected birth defects. METHODS: We analyzed data from 4525 controls and 8665 cases from the 1997 to 2005 National Birth Defects Prevention Study. We categorized estimated periconceptional energy‐adjusted total daily vitamin E intake from diet and supplements into quartiles (referent, lowest quartile). Associations between quartiles of energy‐adjusted vitamin E intake and selected birth defects were adjusted for demographic, lifestyle, and nutritional factors. RESULTS: We observed a statistically significant association with the third quartile of vitamin E intake (odds ratio [OR], 1.17; 95% confidence interval [CI], 1.01–1.35) and all CHDs combined. Among CHD sub‐types, we observed associations with left ventricular outflow tract obstruction defects, and its sub‐type, coarctation of the aorta and the third quartile of vitamin E intake. Among defects other than CHDs, we observed associations between anorectal atresia and the third quartile of vitamin E intake (OR, 1.66; 95% CI, 1.01–2.72) and hypospadias and the fourth quartile of vitamin E intake (OR, 1.42; 95% CI, 1.09–1.87). CONCLUSION: Selected quartiles of energy‐adjusted estimated total daily vitamin E intake were associated with selected birth defects. However, because these few associations did not exhibit exposure‐response patterns consistent with increasing risk associated with increasing intake of vitamin E, further studies are warranted to corroborate our findings. Birth Defects Research (Part A), 100:647–657, 2014. © 2014 Wiley Periodicals, Inc.     

Periconceptional maternal alcohol consumption and neural tube defects

BACKGROUND: Neural tube defects (NTD)s, which occur when the neural tube fails to close during early gestation, are some of the most common birth defects worldwide. Alcohol is a known teratogen and has been shown to induce NTDs in animal studies, although most human studies have failed to corroborate these results. Using data from the National Birth Defects Prevention Study, associations between maternal reports of periconceptional (1 month prior through 2 months postconception) alcohol consumption and NTDs were examined. METHODS: NTD cases and unaffected live born control infants, delivered from 1997 through 2005, were included. Interview reports of alcohol consumption (quantity, frequency, variability, and type) were obtained from 1223 case mothers and 6807 control mothers. Adjusted odds ratios (aOR)s and 95% confidence intervals were estimated using multivariable logistic regression analysis. RESULTS: For all NTDs combined, most aORs for any alcohol consumption, one or more binge episodes, and different type(s) of alcohol consumed were near unity or modestly reduced (≥0.7<aOR≤1.1) and were not statistically significant. Findings were similar for individual NTD subtypes. CONCLUSIONS: These findings suggest no elevated association between maternal periconceptional alcohol consumption and NTDs. Underreporting of alcohol consumption, due to negative social stigma associated with alcohol consumption during pregnancy, and limited reports for mothers with early pregnancy loss of a fetus with an NTD may have affected the estimated odds ratios. Future studies should aim to increase sample sizes for less prevalent subtypes, reduce exposure misclassification, and improve ascertainment offetal deaths and elective terminations. Birth Defects Research (Part A), 2013. © 2013 Wiley Periodicals, Inc.     

Gene-environment interactions in rare diseases that include common birth defects

Rare syndromes often feature specific types of birth defects that frequently are major diagnostic clues to the presence of a given disorder. Despite this specificity, not everyone with the same syndrome is equally or comparably affected, and not everyone with a specific birth defect manifests the same syndrome or is affected with all the features of a particular syndrome. A symposium sponsored by the National Institutes of Health Office of Rare Diseases, and the National Toxicology Program Center for the Evaluation of Risks to Human Reproduction attempted to explore how much of this variability is due to genetic factors and how much is due to environmental factors. The specific types of birth defects examined included cardiovascular defects, holoprosencephaly, clefts of the lip and/or palate, neural tube defects, and diaphragmatic hernias.     

男性不育与基因缺陷

目前全世界约有15%的育龄夫妇不育, 其中男性因素占50%。男性不育(Male infertility)病因复杂, 许多内外因素可导致男性不育, 其中生育相关基因缺陷是重要原因之一, 患者临床多表现为无精子症及少弱畸精子症。文章主要论述了已知基因缺陷与男性不育的关系。     

Maternal occupational exposure to polycyclic aromatic hydrocarbons and congenital heart defects among offspring in the national birth defects prevention study

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

Maternal obesity and morbid obesity: The risk for birth defects in the offspring

BACKGROUND : The objective of this study was to assess, in a large data set from Swedish Medical Health Registries, whether maternal obesity and maternal morbid obesity were associated with an increased risk for various structural birth defects. METHODS : The study population consisted of 1,049,582 infants born in Sweden from January 1, 1995, through December 31, 2007, with known maternal weight and height data. Women were grouped in six categories of body mass index (BMI) according to World Health Organization classification. Infants with congenital birth defects were identified from three sources: the Swedish Medical Birth Registry, the Register of Birth Defects, and the National Patient Register. Maternal age, parity, smoking, and year of birth were thought to be potential confounders and were included as covariates in the adjusted odds ratio analyses. RESULTS : Ten percent of the study population was obese. Morbid obesity (BMI ≥ 40) occurred in 0.7%. The prevalence of congenital malformations was 4.7%, and the prevalence of relatively severe malformations was 3.2%. Maternal prepregnancy morbid obesity was associated with neural tube defects OR 4.08 (95% CI 1.87–7.75), cardiac defects OR 1.49 (95% CI 1.24–1.80), and orofacial clefts OR 1.90 (95% CI 1.27–2.86). Maternal obesity (BMI ≥ 30) significantly increased the risk of hydrocephaly, anal atresia, hypospadias, cystic kidney, pes equinovarus, omphalocele, and diaphragmatic hernia. CONCLUSION : The risk for a morbidly obese pregnant woman to have an infant with a congenital birth defect is small, but for society the association is important in the light of the ongoing obesity epidemic. Birth Defects Research (Part A), 2010. © 2009 Wiley‐Liss, Inc.     

Localized articular cartilage defects

Current operative and non-operative treatments for articular cartilage (AC) defect repair still fail to meet clinical expectations. These treatment options and challenges will be reviewed from a clinical perspective. Various polymeric and naturally occurring materials serving as scaffolds have shown promising neocartilage formation, but few studies are able to draw good clinical correlations. While tissue and organ engineering have generated public demand and expectations that engineered tissues will soon be available, there are still several critical hurdles that need to be overcome. There is a general preference for (1) avoiding the harvesting of normal tissues, (2) a single minimally invasive operative procedure for material insertion, and (3) a durable material that reproduces normal hyaline cartilage and will provide a good lifetime warranty. To avoid harvesting normal tissues, alternative cell sourcing is considered. On the materials front, there is a demand for molecular diversity and synthetic flexibility. For minimally invasive surgery, injectable materials have been actively researched. While initial studies are promising, there still remain a few challenges to overcome before injectable scaffolds will become clinically relevant. Key considerations are reviewed in this article. Advances in nanotechnology have enabled us to employ bottom-up approaches to scaffold design, fabrication, and characterization to better mimic the biological dimensions of matter. One approach involves self-assembly of small DNA-like molecules into larger superaggregates with nanoscale dimensions. One such self-assembling organic system is the rosette nanotubes. The design and properties are highlighted as they are related to solving orthopedic problems.     

DNA methylation and epigenetic defects in carcinogenesis

It is frequently assumed that DNA-damaging agents are carcinogenic because they induce mutations. However, another strong possibility is that the damage leads to heritable changes in the methylation of cytosine in DNA. Considerable evidence exists that gene expression in mammalian cells is in part controlled by methylation of specific DNA sequences. Carcinogens may act by altering the normal epigenetic controls of gene activity in specialised cells, and thereby produce aberrant heritable phenotypes. It is known that agents which inhibit DNA methylation can be carcinogenic and that tumour cells are altered in DNA methylation.     

Distal trisomy 10q and limb defects

Analysis of the literature showed that hypoplasia (or aplasia) of tibiae was found at least in six persons with trisomy 10q25.2-qter. Therefore, these defects should be considered as a characteristic manifestation of the distal trisomy 10q. In most of these patients, tibial abnormalities were associated with other defects of the lower extremities (hypoplastic femora, ectrodactyly, preaxial polydactyly). Upper limbs were affected in one patient (as well as in her sib without tibial defects). Most likely, segment 10q25.2-qter contains a gene which (when triplicated) leads to maldevelopment of the limbs, and tibial malformations are only one manifestation of this field defect.     

Gene therapy for cartilage defects

Focal defects of articular cartilage are an unsolved problem in clinical orthopaedics. These lesions do not heal spontaneously and no treatment leads to complete and durable cartilage regeneration. Although the concept of gene therapy for cartilage damage appears elegant and straightforward, current research indicates that an adaptation of gene transfer techniques to the problem of a circumscribed cartilage defect is required in order to successfully implement this approach. In particular, the localised delivery into the defect of therapeutic gene constructs is desirable. Current strategies aim at inducing chondrogenic pathways in the repair tissue that fills such defects. These include the stimulation of chondrocyte proliferation, maturation, and matrix synthesis via direct or cell transplantation-mediated approaches. Among the most studied candidates, polypeptide growth factors have shown promise to enhance the structural quality of the repair tissue. A better understanding of the basic scientific aspects of cartilage defect repair, together with the identification of additional molecular targets and the development of improved gene-delivery techniques, may allow a clinical translation of gene therapy for cartilage defects. The first experimental steps provide reason for cautious optimism.     

Failure of homocysteine to induce neural tube defects in a mouse model

BACKGROUND: Folate deficiencies have been associated with many adverse congenital abnormalities. It is not clear, however, whether these defects are due to a folate deficiency or to an increase in homocysteine. Homocysteine has been shown to be teratogenic in the chicken-embryo model and it has been suggested that homocysteine-induced defects are mediated by inhibiting the N-methyl-D-aspartate (NMDA) receptor on neural crest cells. The majority of the teratology studies have been carried out using the chicken embryo model. In an effort to develop a murine model of homocysteine-induced neural tube defects, several inbred mouse strains were treated with homocysteine or the NMDA inhibitor MK801 and the fetuses examined for any induced-NTD. METHODS: Several in-bred mouse strains were administered homocysteine once on gestational day (GD) E8.5 or once daily on GD 6.5-10.5. Additionally, because homocysteine was been reported to mediate its effects through the NMDA receptor, the effect of MK801, an antagonist of this receptor, was also investigated. RESULTS: Regardless of the mouse treatment time, homocysteine failed to induce neural tube defects in our in-bred mouse strains. Homocysteine also failed to increase the number of neural tube defects in the splotch strain, regardless of the genotype. CONCLUSIONS: Irrespective of the mouse strain or treatment, homocysteine failed to induce neural tube defects in our mouse models, which is in contrast to what has been reported in the chicken embryo models.     

Multiple calvarial defects in lmx1b mutant mice

The vertebrate cranial vault, or calvaria, forms during embryonic development from cranial mesenchyme of multiple embryonic origins. Inductive interactions are thought to specify the number and location of the calvarial bones, including interactions between the neuroepithelium and cranial mesenchyme. An important feature of calvarial development is the local inhibition of osteogenic potential which occurs between specific bones and results in the formation of the cranial sutures. These sutures allow for postnatal growth of the skull to accommodate postnatal increase in brain size. The molecular genetic mechanisms responsible for the patterning of individual calvarial bones and for the specification of the number and location of sutures are poorly understood at the molecular genetic level. Here we report on the function and expression pattern of the LIM-homeodomain gene, lmx1b, during calvarial development. Lmx1b is expressed in the neuroepithelium underlying portions of the developing skull and in cranial mesenchym which contributes to portions of the cranial vault. Lmx1b is essential for proper patterning and morphogenesis of the calvaria since the supraoccipital and interparietal bones of lmx1b mutant mice are either missing or severely reduced. Moreover, lmx1b mutant mice have severely abnormal sutures between the frontal, parietal, and interparietal bones. Our results indicate that lmx1b is required for multiple events in calvarial development and suggest possible genetic interaction with other genes known to regulate skull development and suture formation. Dev. Genet. 22:314–320, 1998. © 1998 Wiley-Liss, Inc.