Showing papers in "Teratology in 2000"

Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies

Abstract: Background Corticosteroids are first-line drugs for the treatment of a variety of conditions in women of childbearing age Information regarding human pregnancy outcome with corticosteroids is limited Methods We collected prospectively and followed up 184 women exposed to prednisone in pregnancy and 188 pregnant women who were counseled by Motherisk for nonteratogenic exposure The primary outcome was the rate of major birth defects A meta-analysis of all epidemiological studies was conducted The Mantel-Haenszel summary odds ratio was calculated for the pooled studies with 95% confidence intervals A cumulative summary odds ratio was also calculated by combining studies in chronological order Chi-squared for homogeneity was determined to establish the comparability of the studies Results In our prospective study, there was no statistical difference in the rate of major anomalies between the corticosteroid-exposed and control groups In the meta-analysis, the Mantel-Haenszel summary odds ratio for major malformations with all cohort studies was 145 [95% CI 080, 260] and 303 [95% CI 108, 854] when Heinonen et al ('77) was removed This suggests a marginally increased risk of major malformations after first-trimester exposure to corticosteroids In addition, summary odds ratio for case-control studies examining oral clefts was significant (335 [95% CI 197, 569]) Conclusions Although prednisone does not represent a major teratogenic risk in humans at therapeutic doses, it does increase by an order of 34-fold the risk of oral cleft, which is consistent with the existing animal studies Teratology 62:385–392, 2000 © 2000 Wiley-Liss, Inc

Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders.

Abstract: Background Family studies have demonstrated that the autism spectrum disorders (ASDs) have a major genetic etiologic component, but expression and penetrance of the phenotype are variable. Mice with null mutations of Hoxa1 or Hoxb1, two genes critical to hindbrain development, have phenotypic features frequently observed in autism, but no naturally occurring variants of either gene have been identified in mammals. Methods By sequencing regions of genomic DNA of patients with autism spectrum disorders, we detected a substitution variant at HOXA1 and an insertion variant at HOXB1, both in coding regions of the genes. Fifty-seven individuals ascertained for a diagnosis of an ASD, along with 166 of their relatives, were typed for these variants. Two non-ASD populations were typed, and the frequency of the newly identified alleles was determined in all groups. The genotypes of the ASD families were tested for conformation to Hardy-Weinberg proportions and Mendelian expectations for gene transmission. Results The frequency of the variants was 10–25% in persons of European or African origin. In the ASD families, there was a significant deviation from the HOXA1 genotype ratios expected from Hardy-Weinberg proportions (P = 0.005). Among affected offspring, a significant deviation from Mendelian expectation in gene transmission (P = 0.011) was observed. No statistically significant effects were detected when the same analyses were applied to the HOXB1 locus, but there was evidence of an interaction between HOXA1, HOXB1, and gender in susceptibility to ASDs. Conclusions The results support a role for HOXA1 in susceptibility to autism, and add to the existing body of evidence implicating early brain stem injury in the etiology of ASDs. Teratology 62:393–405, 2000. © 2000 Wiley-Liss, Inc.

Teratogen update: maternal myasthenia gravis as a cause of congenital arthrogryposis.

Abstract: Background: Arthrogryposis multiplex congenita (AMC) is defined as nonprogressive congenital contractures that generally result from lack of fetal movement in utero. AMC is a feature of many congenital disorders caused by genetic, environmental, or other factors. One rare cause of AMC is maternal myasthenia gravis (MG). This is an autoimmune disorder, caused by antibodies to the nicotinic acetylcholine receptor (AChR), and resulting in weakness of voluntary muscles. In 10 ‐15% of babies born to MG mothers, transient signs of MG are noted after placental transfer of anti-AChR antibodies. In a few cases, AMC predominates. Methods: We review the role of antibodies to AChR in MG and in AMC associated with maternal antibodies to AChR. Results: In anti-AChR antibody-associated AMC, fetal or neonatal death is common; other deformities or CNS abnormalities are common as well. The condition usually recurs in each pregnancy unless the mother is treated for MG, but some mothers are asymptomatic. The maternal antibodies cross the placenta and block the function of the fetal isoform of the AChR leading to fetal paralysis. Injection of maternal plasma into pregnant mice results in AMC in mouse fetuses. Some women with recurrent AMC in their babies have no detectable anti-AChR suggesting the presence of antibodies to other fetal muscle or neuronal proteins. Conclusions: Although rare, anti-AChR-associated AMC is potentially treatable and can be diagnosed by a routine antibody test. The mouse model can be used to investigate the role of these and other maternal antibodies in causing congenital conditions.

Hypothesis: thalidomide embryopathy-proposed mechanism of action.

Abstract: We propose that thalidomide affects the following pathway during limb development: Growth factors (FGF-2 and IGF-I) attach to receptors on limb bud mesenchymal cells and initiate some second messenger system (perhaps SP-1), which activates αv and β3 integrin subunit genes. The resulting αv β3 integrin proteins stimulate angiogenesis in the developing limb bud. Several steps in this pathway depend on the activation of genes with primarily GC promoters (GGGCGG). Thalidomide, or a hydrolysis or metabolic breakdown product, specifically binds to GC promoter sites and inhibits the transcription of those genes. Inhibition of the genes interferes with normal angiogenesis, which results in truncation of the limb. Teratology 61:189–195, 2000. © 2000 Wiley-Liss, Inc.

Risk factors for congenital hypothyroidism : An investigation of infant's birth weight, ethnicity, and gender in California, 1990-1998

Abstract: Background Approximately 85% of primary congenital hypothyroidism (CH) is sporadic and due to malformations of the thyroid gland. Past studies have reported an increased birth weight among infants with CH. We have attempted to replicate and expand these observations, examining the association between different birth weight categories and CH stratified by infant's sex. We have also examined the prevalence of CH by mother's age and infant's ethnicity, gender, and year of birth. Methods A cross-sectional study was conducted on 5,049,185 infants screened by the statewide California Newborn Screening Program between 1990 and 1998, an estimated 98.6% of all newborns in the state. Dried blood spots from a heel stick were assayed for thyroxine (T4), and presumptive positives had follow-up assays of thyroid-stimulating hormone (TSH) to determine definite positives. Results A total of 1,806 cases of CH were identified. The following findings are unlikely to be due to chance. Compared with infants with birth weights of 3,000–3,499 g, infants weighing <2,000 g and those weighing ≥4,500 g had a twofold or greater increase in the prevalence of CH. This was not explained as a result of confounding by the infant's ethnicity or gender. Compared with whites, elevated prevalence rates were found in most ethnic groups, which include the following: Hispanics, Chinese, Vietnamese, Asian Indians, Filipinos, Middle Easterners, and Hawaiians. As reported previously, black infants had about one-third the prevalence rate of whites. We also observed the frequently described female preponderance of CH. The female excess was maintained at all birth weights, however it varied by infant's ethnicity. Trends in the prevalence of CH were not associated with mother's age or with the time interval between 1990 and 1998. Conclusions We observed an increased risk of CH in both low-birth-weight (<2,000-g) and macrosomic (≥4,500-g) infants. This U-shaped association has not been described in past studies. We have also expanded the previously described ethnic differences in CH risk to include ethnic groups not previously studied. The unique pattern of CH occurrence suggests that further studies to define modifiable risk factors may be useful. Teratology 62:36–41, 2000. © 2000 Wiley-Liss, Inc.

Growth retardation and microcephaly induced in mice by placental infection with murine cytomegalovirus.

Abstract: Background The placenta is regarded as a site of congenital cytomegalovirus (CMV) infection. The placental infection of fetuses with murine CMV (MCMV) was investigated in a mouse model. Methods The placentas and fetuses were examined using the polymerase chain reaction (PCR) and Southern blotting for viral DNA and immunostaining for viral antigen. Since the transplacental infection rarely occurs, the placentas were directly injected with MCMV at day 12.5 of gestation; the embryos were then allowed to develop until day 18.5 of gestation. Results Formation of infected foci at day 18.5 of gestation was found in more than 60% of the injected placentas. Infection of about 50% of the embryos occurred from the infected placentas. The frequency of infection in the brain was 27%, which was the same as that in the liver and higher than that in the lungs. In the brains, infected cells were often observed in the ventricular zone of the cerebrum and sometimes in the cortical plate and the hippocampus. Developmental retardation with microcephaly was observed in about 25% of offspring exposed to infection in utero. Conclusions These results suggest that formation of infected foci in the placenta is important for embryonic congenital infection, and that the cerebral ventricular zone is one of the most susceptible sites for CMV infection in the embryonic stage. Teratology 62:79–85, 2000. © 2000 Wiley-Liss, Inc.

Malformations in offspring of diabetic rats: Morphometric analysis of neural crest‐derived organs and effects of maternal vitamin E treatment

Abstract: BACKGROUND: We have previously reported on a malformation-prone Sprague-Dawley rat substrain (U), which presents a high frequency of micrognathia in the offspring of diabetic mothers. This malforma ...

Hind limb malformations in free‐living northern leopard frogs (Rana pipiens) from Maine, Minnesota, and Vermont suggest multiple etiologies

Abstract: Background: Reports of malformed frogs have increased throughout the North American continent in recent years. Most of the observed malformations have involved the hind limbs. The goal of this study was to accurately characterize the hind limb malformations in wild frogs as an important step toward understanding the possible etiologies. Methods: During 1997 and 1998, 182 recently metamorphosed northern leopard frogs (Rana pipiens) were collected from Minnesota, Vermont, and Maine. Malformed hind limbs were present in 157 (86%) of these frogs, which underwent necropsy and radiographic evaluation at the National Wildlife Health Center. These malformations are described in detail and classified into four major categories: (1) no limb (amelia); (2) multiple limbs or limb elements (polymelia, polydactyly, polyphalangy); (3) reduced limb segments or elements (phocomelia, ectromelia, ectrodactyly, and brachydactyly; and (4) distally complete but malformed limb (bone rotations, bridging, skin webbing, and micromelia). Results: Amelia and reduced segments and/or elements were the most common finding. Frogs with bilateral hind limb malformations were not common, and in only eight of these 22 frogs were the malformations symmetrical. Malformations of a given type tended to occur in frogs collected from the same site, but the types of malformations varied widely among all three states, and between study sites within Minnesota.

Normal development of the male anterior urethra

Abstract: A histological study was performed on serially sectioned human and mouse embryos to study the influences of programmed cell death (PCD) during morphogenesis for clarifying the existing controversies on the morphology and basic processes involved in the embryonic development of the male anterior urethra. The following new insights into the development of the anterior urethra could be established. The formation of the urethra starts with the early adhesion of the arms of the genital tubercle. In this way an epithelial plate is formed, located in the ventral midline, that is in continuity with the cloacal membrane. Male sex differentiation takes place following rupture of this cloacal membrane through programmed cell death. Fusion of the urogenital swellings with primary luminization gives rise to the penile urethra, whereas the glandular part of the urethra is formed through secondary luminization of the epithelial cord that is formed during fusion of the arms of the genital tubercle, i.e., the glans. In both fusion processes, apoptosis plays a key role. The consequence of fusion of the urogenital swellings is that their mesodermal cores unite on the ventral aspect of the penile urethra, where they differentiate into the integumental structures. The prepuce starts to develop as a fold of ectoderm with a mesodermal core after complete fusion of the entire urethra. Finally, the scrotum was found to develop through merging of the labioscrotal swellings and not by fusion.

Effects of excess vitamin A on development of cranial neural crest-derived structures: a neonatal and embryologic study.

Abstract: Background: Vitamin A and its metabolites have been shown to be teratogenic in animals and humans producing defects of neural crest derived structures that include abnormalities of the craniofacial skeleton, heart, and thymus. Our prior studies with retinoic acid have established that gestational day (gd) 9 is a sensitive embryonic age in the mouse for inducing craniofacial and thymic defects. Methods: We exposed pregnant mice to variable doses of vitamin A (retinyl acetate) on gd 9 and embryos were evaluated for changes in developing pharyngeal arch and pouch morphology, neural crest cell migration and marker gene expression. Additionally, we investigated whether a single organ system was more sensitive to low doses of vitamin A and could potentially be used as an indicator of vitamin A exposure during early gestation. Results: High (100 mg/kg) and moderate (50 and 25 mg/kg) doses of vitamin A resulted in significant craniofacial, cardiac outflow tract and thymic abnormalities. Low doses of vitamin A (10 mg/kg) produced craniofacial and thymic abnormalities that were mild and of low penetrance. Exposed embryos showed morphologic changes in the 2nd and 3rd pharyngeal arches and pouches, changes in neural crest migration, abnormalities in cranial ganglia, and altered expression of Hoxa3. Conclusions: These animal studies, along with recent epidemiologic reports on human teratogenicity with vitamin A, raise concerns about the potential for induction of defects (perhaps subtle) in offspring of women ingesting even moderate to low amounts of supplemental vitamin A during the early gestational period.

Intelligence and physical features of children of women with epilepsy.

Abstract: The teratogenicity of maternal epilepsy has been attributed to several factors, including the antiepileptic drugs taken to prevent seizures during pregnancy, the occurrence of seizures during pregnancy, and the factors in the mother that caused her to have epilepsy. We have addressed the hypothesis that the children of women who have a history of epilepsy (seizure history), but who took no antiepileptic drugs (AED) and had no tonic-clonic seizures in pregnancy, have an increased risk of malformations and diminished intelligence. The frequency of cognitive dysfunction was determined in 57 seizure history and 57 matched control children aged 6–l6 years. The masked evaluation of the children included a physical and neurologic examination and testing with the Wechsler Intelligence Scale for Children-Revised (WISC-R) and a systematic physical examination for the features of the fetal AED syndrome. The evaluation of both parents of each child included a test of reasoning (Ravens Progressive Matrix) and a physical examination. There were no differences between the two groups of children in either IQ scores or physical features; none of the seizure history children was judged to have the “anticonvulsant face” or digit hypoplasia. This study had 80% power to rule out a difference of seven or more IQ points between the two groups, based on a two-sided test at a 5% level of significance. Our confidence in concluding that there was no difference between seizure history and control infants was strengthened by the fact that no statistically significant differences were observed with respect to multiple outcomes, including eight related measures of intelligence. Thirty (53%) of the seizure history mothers resumed taking AED after the birth of the child we evaluated. Additional studies are needed to address the teratogenicity of the antiepileptic drugs as monotherapy. Teratology 61:196–202, 2000. © 2000 Wiley-Liss, Inc.

Hypothesis: Folate-responsive neural tube defects and neurocristopathies

Abstract: Background What accounts for the wide spectrum of folate-responsive dysmorphogeneses? Both embryonic and fetal cells are entirely dependent on maternal folate to support their requirement for precisely timed proliferative bursts during gestation. Folate receptors (FRs) mediate transport into cells and are central to transplacental maternal-to-fetal folate transport. FRs are also critical for neural tube and neural crest development because recent murine “knock-out” and “knock-down” of FRs results in a high percentage of folate-responsive neural tube defects (NTDs) and neurocristopathies. Hypothesis Central to our hypothesis is the fact that folate deficiency is accompanied by a reduction in the proliferative capacity of highly mitotic neural tube or neural crest cells. Therefore, depending on when in pregnancy various cohorts of highly proliferative cells are deprived of folate, and the origin of the affected cells will determine the type of developmental dysmorphogenesis. Thus, selective folate deficiency in early pregnancy of only highly proliferative neural tube or neural crest cells predisposes to NTDs or gross dysmorphogenesis, respectively. Folate deficiency that compromises placental development will predispose to small-for-date babies due to an overall nutrient deficiency, and the development of folate insufficiency later in pregnancy could predispose to more subtle midline birth defects involving atresia of neural crest cell-derived structures. Finally, a congenital folate transport defect would only be corrected by suprapharmacological doses of folate, which ensures passive diffusion. Conclusion This hypothesis can explain the results of several earlier and more recent clinical trials on folate supplementation in pregnancy, but it also raises the possibility that there may be several as yet undiscovered neurocristopathies that are folate responsive. Teratology 62:42–50, 2000. Published 2000 Wiley-Liss, Inc.

Neonatal thyroid-stimulating hormone level and perchlorate in drinking water.

Abstract: Background The effect of perchlorate in drinking water on neonatal blood thyroid-stimulating hormone (thyrotropin; TSH) levels was examined for Las Vegas and Reno, Nevada. Methods The neonatal blood TSH levels in Las Vegas (with up to 15 μg/L (ppb) perchlorate in drinking water) and in Reno (with no perchlorate detected in the drinking water) from December 1998 to October 1999 were analyzed and compared. The study samples were from newborns in their first month of life (excluding the first day of life) with birth weights of 2,500–4,500 g. A multivariate analysis of logarithmically transformed TSH levels was used to compare the mean TSH levels between Las Vegas and Reno newborns, with age and sex being controlled as potential confounders. Results This study of neonatal TSH levels in the first month of life found no effect from living in the areas with environmental perchlorate exposures of ≤15 μg/L (P = 0.97). Conclusions This study, which was sensitive enough to detect the effects of age and gender on neonatal blood TSH levels, detected no effect from environmental exposures to perchlorate. Teratology 62:429–431, 2000. © 2000 Wiley-Liss, Inc.

Patterns of infant mortality caused by major congenital anomalies

Abstract: Background: We assessed the impact of recent advances in perinatal care on infant mortality due to congenital anomaly. Methods: Analysis of trends in congenital anomaly-attributed infant mortality, using the 1981-1995 Statistics Canada's birth and death records, with a total of 2,878,826 live births, 21,883 infant deaths, and 6,908 infant deaths due to congenital anomalies. Results: Infant mortality due to major congenital anomaly decreased from 3.11 per 1,000 live births in 1981 to 1.89 per 1,000 live births in 1995. Cause-specific infant mortality rates for anencephaly, spina bifida, other central nervous system anomalies, cardiovascular system anomalies, respiratory system anomalies, digestive system anomalies, certain musculoskeleton anomalies, urinary system anomalies, chromosomal anomalies, and multiple congenital anomalies were 0.20, 0.23, 0.27, 1.04, 0.24, 0.08, 0.22, 0.16, 0.22, and 0.13 per 1,000 live births, respectively, in 1981-1983, whereas corresponding rates were 0.07, 0.07, 0.18, 0.73, 0.25, 0.03, 0.12, 0.12, 0.26, and 0.06 per 1,000 live births, respectively, in 1993-1995. Conclusions: Recent Canadian data show that infant deaths caused by major congenital anomalies have decreased significantly, but reductions varied substantially according to specific forms of anomalies.

Nonspecific stimulation of the maternal immune system. II. Effects on gene expression in the fetus.

Abstract: BACKGROUND Maternal immune stimulation reduces malformations caused by chemical teratogens. Mechanisms for this effect are not known. Altered expression of regulatory molecules (e.g., transforming growth factor [TGF-beta], tumor necrosis factor-alpha [TNF-alpha]) has been reported in fetuses from immunostimulated mice, which may affect gene expression. Expression of selected genes that function to control proliferation, differentiation, or apoptosis was evaluated in chemical-exposed fetuses, with or without maternal immunostimulation. METHODS Ethyl carbamate (urethane) was given to pregnant ICR mice on day 10 of gestation to induce cleft palate. Before teratogen administration, the immune system of the female mice was stimulated by footpad injection with Freund's complete adjuvant (FCA) or by intraperitoneal injection with interferon-gamma (IFN-gamma). RESULTS Maternal immunostimulation with interferon-gamma (IFN-gamma) decreased severity of the cleft palate lesion caused by urethane, while FCA decreased both incidence and severity of cleft palate. Gestation day 14 fetuses from urethane-exposed mothers displayed decreased expression of cell cycle/apoptotic genes bcl2alpha, bcl2beta, pkCalpha, and p53 in fetal heads. Immune stimulation with IFN-gamma-normalized expression of bcl2alpha, bcl2beta, and pkCalpha to control levels. Urethane also decreased the ratio of expression of bclalpha/p53, bclbeta/p53, and pkCalpha/p53, while maternal injection with IFN-gamma restored these expression ratios to control levels. Maternal immunization with FCA also significantly increased bcl2alpha/p53, bcl2beta/p53, and pkCalpha/p53 gene expression ratios. CONCLUSIONS These results suggest that (1) the maternal immune system may possess heretofore unrecognized regulatory activity in fetal development, and (2) protection against urethane-induced cleft palate may be mediated through maternal immune regulation of fetal gene expression.

Large-scale double-staining of rat fetal skeletons using Alizarin Red S and alcian blue.

Abstract: A critical component in the conduct of a prenatal developmental toxicity study is the evaluation of fetal skeletal development. As the developing rodent fetus is typically evaluated at gestation day 20, at a time when ossification of the skeleton is incomplete, a thorough assessment of skeletal development would include both ossified and cartilaginous structures. Current methods to double-stain the fetal skeleton using Alizarin Red S and Alcian Blue are typically described for small sample sizes or using time allotments for each processing step that are unsuitable for industry. In an industrial setting, there is a need for an effective means to double-stain fetal skeletons on a large scale (i.e., hundreds of fetuses simultaneously). This article describes a method used in our laboratory to stain both fetal bone and cartilage using solutions and procedures on an industrial scale.

Myelocystocele-cloacal exstrophy in a pedigree with a mitochondrial 12S rRNA mutation, aminoglycoside-induced deafness, pigmentary disturbances, and spinal anomalies.

Abstract: A large Filipino-American family with progressive matrilineal hearing loss, premature graying, depigmented patches, and digital anomalies was ascertained through a survey of a spina bifida clinic for neural crest disorders. Deafness followed a matrilineal pattern of inheritance and was associated with the A1555G mutation in the 12S rRNA gene (MTRNR1) in affected individuals as well as unaffected maternal relatives. Several other malformations were found in carriers of the mutation. The proband had a myelocystocele, Arnold-Chiari type I malformation, cloacal exstrophy, and severe early-onset hearing loss. Several family members had premature graying, white forelock, congenital leukoderma with or without telecanthus, somewhat suggestive of a Waardenburg syndrome variant. In addition to the patient with myelocystocele, two individuals had scoliosis and one had segmentation defects of spinal vertebrae. The syndromic characteristics reported here are novel for the mitochondrial A1555G substitution, and may result from dysfunction of mitochondrial genes during early development. However, the mitochondrial A1555G mutation is only rarely associated with neural tube defects as it was not found in a screen of 218 additional individuals with spina bifida, four of whom had congenital hearing loss.

Expression of the Sonic Hedgehog gene in human embryos with neural tube defects

Abstract: Background: To estimate the rate of malformations observed during early human development, a series of 38,913 first-trimester abortions were studied. Neural tube defects (NTD) were found in 57 cases. Methods: A histological study of serial sections performed in 25 embryos revealed a spectrum of axial structure abnormalities. Expression of the SHH gene was studied by in situ hybridization in one case of CRS and in two cases of SB. Results: A cervical notochord duplication was always found in craniorachischisis (CRS, n = 8), but not in spina bifida (SB, n = 10) or diplomyelia (split cord malformation, n = 3). In the embryo with CRS, expression of SHH was found in both domains, corresponding to the duplicated part of the notochord, whereas a single signal was observed in the nonduplicated part. This expression was associated at the cervical level of the open neural tube with a broad SHH expression domain and with two or even three domains in its lumbar region, suggesting multiple functional floor plates. Similarly, in two embryos with SB, two domains of SHH expression were found in the ventral neural tube. Conclusions: Our findings suggest that notochord splitting in the cervical region might be involved in the pathogenesis of CRS. Interestingly, similar notochord abnormality and altered expression of the shh gene are observed in Lp mice with NTD. This suggests that the Lp gene could be a candidate gene for human CRS. Further studies are needed to establish the primary event responsible for the notochord splitting and for the abnormal expression of the SHH gene in the floor plate in embryos with CRS and SB.

Collecting and interpreting birth defects surveillance data by hispanic ethnicity : A comparative study

Abstract: RUSSELL KIRBY, JOANN PETRINI, CAROLINE ALTER, and THE HISPANIC ETHNICITY BIRTH DEFECTS WORKGROUP Department of Obstetrics and Gynecology, Milwaukee Clinical Campus, University of Wisconsin Medical School, Milwaukee Wisconsin 53201-0342. Perinatal Data Center, Office of the Medical Director, March of Dimes Birth Defects Foundation, White Plains, New York 10605. Members of the Hispanic Ethnicity Birth Defects Workgroup include: Arizona Department of Health Service, Birth Defects Monitoring Program: Timothy J. Flood, MD, Thomas E. Hughes, MA; California Birth Defects Monitoring Program: Kamala Deosaransingh, MPH, Jackie White Wynne, BA; Colorado Responds to Children with Special Needs: Lisa Miller, MD, Heather Orton, Russel Rickard, MS; New Jersey Birth Defects Registry and Special Needs Registry: Leslie M. Beres, MS; New Mexico Birth Defects Prevention and Surveillance System: Mary Olguin, EdD; New York State Congenital Malformations Registry: Charlotte Druschel, MD, MPH, Jeffrey P. Hughes, MPH; Texas Birth Defects Monitoring Division: Mark Canfield, PhD; March of Dimes Birth Defects Foundation: Donald Mattison, MD, MPH. The assistance of Larry D. Edmonds, MSPH, and Paula Yoon, PhD, Division of Birth Defects and Pediatric Genetics, National Center for Environmental Health, Centers for Disease Control and Prevention, is gratefully acknowledged.

Appropriate use of animal models in the assessment of risk during prenatal development: An illustration using inorganic arsenic

Abstract: Background Assessing risks to human development from chemical exposure typically requires integrating findings from laboratory animal and human studies. Methods Using a case study approach, we present a program designed to assess the risk of the occurrence of malformations from inorganic arsenic exposure. We discuss how epidemiological data should be evaluated for quality and criteria for determining whether an association is causal. In this case study, adequate epidemiological data were not available for evaluating the potential effect of arsenic on development. Consequently, results from appropriately designed, conducted, and interpreted developmental toxicity studies, which have been shown to be predictive of human risk under numerous scenarios, were used. In our case study, the existing animal data were not designed appropriately to assess risk from environmental exposures, although such studies may be useful for hazard identification. Because the human and animal databases were deficient, a research program comprising modern guideline toxicological studies was designed and conducted. Results The results of those studies in rats, mice, and rabbits indicate that oral and inhalational exposures to inorganic arsenic do not cause structural malformations, and inhalational exposures produced no developmental effects at all. The new study results are discussed in conjunction with considerations of metabolism, toxicokinetics, and maternal toxicity. Conclusions Based on the available experimental data, and absent contrary findings from adequately conducted epidemiological studies, we conclude that exposure to inorganic arsenic by environmentally relevant routes poses no risk of the occurrence of malformations and little risk of other prenatal developmental toxicity in developing humans without concomitant and near-lethal toxicological effects in mothers. Teratology 62:51–71, 2000. © 2000 Wiley-Liss, Inc.

Comparison of cleft palate induction by Nicotiana glauca in goats and sheep

Abstract: The induction of cleft palate by Nicotiana glauca (wild tree tobacco) during the first trimester of pregnancy was compared between Spanish-type goats and crossbred western-type sheep. Cleft palate was induced in 100% of the embryonic/fetal goats when their pregnant mothers were gavaged with N. glauca plant material or with anabasine-rich extracts from the latter, during gestation days 32-41. Seventy-five percent of newborn goats had cleft palate after maternal dosing with N. glauca during gestation days 35-41, while no cleft palates were induced when dosing periods included days 36-40, 37-39, or day 38 only. The induced cleft palates were bilateral, involving the entire secondary palates with complete detachment of the vomer. Eleven percent of the newborn goats from does gavaged during gestation days 32-41 had extracranial abnormalities, most often contractures of the metacarpal joints. Most of these contractures resolved spontaneously by 4-6 weeks postpartum. One newborn kid also had an asymmetric skull due to apparent fetal positioning. No cleft palates were induced in lambs whose mothers were gavaged with N. glauca plant or anabasine-rich extracts during gestation days 34-41, 35-40, 35-41, 36-41, 35-51, or 37-50. Only one of five lambs born to three ewes gavaged with N. glauca plant material during gestation days 34-55 had a cleft palate, but all five of these lambs had moderate to severe contractures in the metacarpal joints. The slight to moderate contracture defects resolved spontaneously by 4-6 weeks postpartum, but the severe contractures resolved only partially. Embryonic/fetal death and resorption (determined by ultrasound) occurred in 25% of pregnant goats fed N. glauca compared to only 4% of pregnant sheep. Nicotiana glauca plant material contained the teratogenic alkaloid anabasine at 0.175% to 0.23%, dry weight, demonstrating that Spanish-type goats are susceptible to cleft palate induction by the natural toxin anabasine, while crossbred western-type sheep are resistant. However, clinical signs of toxicity were equally severe in goats and sheep, even though maternal alkaloid tolerance was generally lower in sheep. We postulate that an alkaloid-induced reduction in fetal movement during the period of normal palate closure is the cause of the cleft palate and multiple flexion contractures. Teratology 61:203-210, 2000. Published 2000 Wiley-Liss, Inc.

Nonspecific stimulation of the maternal immune system. I. Effects On teratogen-induced fetal malformations.

Abstract: Background Maternal immune stimulation has reported, but unconfirmed, efficacy for reducing chemical-induced morphologic defects in mice. Methods Teratogenic chemicals (2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], ethyl carbamate [urethane], methylnitrosourea [MNU], or valproic acid [VA]) were given to pregnant mice to induce cleft palate (TCDD, urethane), digital defects (urethane, MNU), or exencephaly (VA). Before teratogen administration, the immune system of female mice was stimulated by intraperitoneal (IP) administration of pyran copolymer or attenuated bacillus Calmette Guerin (BCG), or by footpad injection with Freund's complete adjuvant (FCA). Results Fetal defects caused by all four chemicals studied were reduced by maternal immunostimulation, sometimes dramatically. In addition to reducing VA-induced exencephaly, immunostimulation with FCA resulted in fetal mice displaying anury (absence of tails). Activated maternal immune cells could not be detected in fetal circulation using flow cytometry and a fluorescent cell-tracking probe. Conclusions For the chemicals tested, maternal immune stimulation has efficacy in reducing fetal defects. Immune protection against teratogenesis may be an indirect effect of maternal immune cell activation. Teratology 62:413–419, 2000. © 2000 Wiley-Liss, Inc.

Prenatal ages and stages-measures and errors.

Abstract: Background: The confusing term gestational age is generally either not defined or is used for menstrual age, postovulatory age, or postfertilizational age. The designation (post)menstrual weeks and/or days is very useful in obstetrics but, because prenatal age extends from fertilization to birth, menstrual age is a misnomer. The term stage has a specific morphological meaning in embryology and should not be used either for ages or for lengths. Methods: Embryonic age is best assessed, when possible, from the 23 internationally recognized morphological stages. A morphological staging system is not available for the fetal period, and fetal age is assessed mainly from measurements. Results: Among these, the unsatisfactory designation crown-rump length (CRL) should be replaced, in ultrasonic biometry as well as in embryology, by the greatest length (GL), exclusive of the lower limbs. These points are discussed in detail, and justification for the views expressed is provided. Conclusions: The continuing confusion concerning prenatal age is shown to be unnecessary once the ambiguous and superfluous term gestational age is abandoned.

Spina bifida phenotypes in infants or fetuses of obese mothers

Abstract: Background: A twofold or greater risk of neural tube defect (NTD)-affected pregnancy has been associated with prepregnant obesity, where obesity was defined as body mass index (BMI) of >29 kg/m 2 . Risks have been more elevated for spina bifida than for anencephaly. Methods: We investigated whether finer phenotypic classifications of spina bifida, in combination with other factors, were associated with a BMI of >29 kg/m 2 . Data were derived from a case-control study of fetuses and infants with NTDs among 1989-1991 California births. Interviews were conducted with mothers of 277 spina bifida cases and 517 nonmalformed controls. Results: Women with a BMI of >29 kg/m 2 compared with those ≤29 kg/m 2 revealed an odds ratio (OR) of 2.2 (95% confidence interval [95% Cl] = 1.4-3.3) for spina bifida in their infants and fetuses. Elevated risks were observed for each spina bifida subphenotype, and risks varied by subphenotype: open spina bifida, OR = 2.0 (1.2-3.1); closed (skin-covered), 3.3 (1.4-7.5); isolated, 2.2 (1.4-3.4); nonisolated, 1.9 (0.9-4.2); high, 4.5 (2.1-9.6); low, 1.9 (1.2-2.9); open/ isolated/high, 7.1 (2.8-18.1); and open/isolated/low, 1.8 (1.1-3.1). Risks were higher among female infants/fetuses and foreign-born Latinas, and for some phenotypes the risks were quite large, e.g., OR = 8.3 (2.9-23.6) for closed spina bifida among female infants/fetuses whose mothers were >29 kg/m 2 compared with males whose mothers were ≤29 kg/m 2 . Maternal periconceptional vitamin use was not observed to influence risk as greatly across phenotypes. Conclusions: The observed pathogenetic heterogeneity of prepregnant obesity and spina bifida risks suggests that there are likely to be several biologic mechanisms underlying the association.

Interrupted aortic arch: An epidemiologic study

Abstract: Background: Interruption of the aortic arch (IAA) is a rare but severe anomaly associated with major intracardiac defects and with multisystem noncardiac malformations, recently linked to chromosome deletion of 22q11.2. Methods: The Baltimore-Washington Infant Study (1981-1989), a population-based epidemiologic study of cardiovascular malformations, evaluated 53 infants with IAA in comparison with 3,572 controls. Risk factors for the anatomic subtypes were evaluated in 14 cases of IAA type A and 32 cases of IAA type B, but no molecular genetic tests were available. The distribution of associated cardiac defects was similar for both types. Results: DiGeorge syndrome (DGS) occurred more frequently in IAA type B. Case-control comparisons demonstrated that infants in both groups were growth retarded at birth. A family history of noncardiac defects occurred only in IAA type B cases and included relatives with cleft lip and/or cleft palate. Candidate risk factors were associated only in type B cases and differed for those with (n = 10) and for those without (n = 19) DGS: a family history of noncardiac defects (odds ratio [OR] = 7.2, 95% confidence interval [CI] = 1.5-39.2) and maternal use of aspirin during the critical period (OR = 4.8, 95% Cl = 1.3-25.4) occurred with DGS, while previous stillbirth (OR = 9.4, 95% Cl = 1.3-53.1), bleeding during pregnancy (OR = 3.7, 95% Cl = 1.4-11.4), and maternal exposure to arts/crafts paints (OR = 4.8, 95% Cl = 1.3-17.4) were associated in those without DGS. Conclusions: These findings confirm the heterogeneity of IAA and of the type B subtype. Risk factors specific for cases with DGS may open a window to further investigations of the etiology of IAA and of the associated molecular genetic abnormalities.

Birth defects prevalence among infants of Persian Gulf War veterans born in Hawaii, 1989-1993.

Abstract: Background: Gulf War veterans (GWVs) have expressed concern about possible teratogenic exposures. However, epidemiologic studies on birth defects prevalence among their progeny have been limited to military hospitals, anomalies diagnosed among newborns, or self-reported data. To measure the prevalence of selected birth defects among infants of GWVs and nondeployed veterans (NDVs) in Hawaii, using birth defects surveillance records. Methods: Personal identifiers of 684,645 GWVs and 1,587,102 NDVs and their families were matched against birth certificate records of 99,545 live births reported to the State of Hawaii Department of Health between 1989 and 1993 to identify births to military personnel. These births were matched with records from the Hawaii Birth Defects Program. Results: A total of 17,182 military infants (3,717 GWV infants and 13,465 NDV infants) were identified. Of these, 367 infants (2.14/100 live births) were identified with one or more of 48 major birth defects diagnoses. The prevalence of the 48 birth defects were similar for GWV and NDV infants during the prewar and postwar periods, and among GWV infants who were conceived before and after the Gulf war. Conclusions: The results must be interpreted with caution because of the small number of affected infants in each birth defects category. This study demonstrated the feasibility of measuring birth defects prevalence among military infants through multiple data linkage. Further, it included live births to parents who had separated from the military, births in civilian hospitals, and birth defects diagnosed through the first year of life.

Mini-review: history of organized teratology information services in North America.

Abstract: A history of the Organization of Teratology Information Services (OTIS) is presented in context of the history of teratology information services. During the late 1970s, teratology information services grew out of the need for current and accurate information about fetal effects of environmental exposures in pregnancy. Over the next decade, teratology information services networked and collaborated, developing their own professional organization. A description of the activities of OTIS is described.

Free Radicals, Oxidants, and Antioxidants

Abstract: Free radicals are species with one or more unpaired electrons. The unpaired electron results in a species that is often highly reactive. Free radicals have a wide range of reactions; two broad classes of reactions are electron transfer and addition reactions resulting in covalent bond formation. Free radicals can be classified as reducing (donating an electron to an acceptor) or oxidizing (accepting an electron from a donor). Because of the wide range of reactivities of radicals, there is a thermodynamic hierarchy or pecking order for electron transfer reactions (Buettner, '93). Table 1 is arranged with the most oxidizing radicals at the top and most reducing at the bottom. This pecking order predicts the flow of electrons. This thermodynamic hierarchy helps to predict which species might react with each other. In general, the radical species higher in the pecking order steal electrons from the reduced species lower in the pecking order. The pecking order predicts that peroxyl radicals will react with vitamin E (tocopherol):

Are oral clefts a consequence of maternal hormone imbalance? evidence from the sex ratios of sibs of probands.

Abstract: Background: The causes of oral clefts (cleft lip with or without cleft palate, CL/P, and cleft palate alone, CP) have not been established. However, maternal intrauterine hormone profiles have been suspected of being involved. There is now substantial evidence that maternal hormone concentrations around the time of conception partially control the sexes of offspring. It is possible that the hormone profiles that control sex of offspring share features of the profiles suspected of causing clefts. This can be tested by examining the sex ratios (proportions male) of the unaffected sibs of probands. If these sex ratios are skewed in the same direction as that of probands, that suggests, ex hypothesi, maternal hormonal involvement in the causation of clefts. Methods: Accordingly, a search was made for data on the sex ratios of the unaffected sibs of probands with clefts. For reasons given in the text, this search was informal rather than based on electronic data retrieval systems. Nine papers were located giving sex ratios of sibs of probands with CL/P and CP. Results: Published data suggest that the sibs of probands with CL/P have a significantly higher sex ratio than the sibs of probands with CP. Thus the sib sex ratios are skewed in the same direction as those of the probands themselves. In other words, parents (mothers) of CL/P patients apparently have a tendency to produce boys, and parents of CP patients to produce girls. Conclusion: Accordingly, it is suggested that maternal hormone profiles may partially explain the unusual sex ratios (of probands and their sibs), as well as the malformations.