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PubMed2000

Reproductive factors, subfertility, and risk of neural tube defects: a case-control study based on the Oxford Record Linkage Study Register.

Periconceptual exposure to subfertility treatments is increasingly common, raising concerns about the possibility of malformations in the offspring. The authors conducted a case-control study to determine whether subfertility or its treatment was associated with increased risk of neural tube defects (NTDs). Cases were 694 women diagnosed with an NTD-affected pregnancy in Oxfordshire or West Berkshire, England, between 1970 and 1987. Cases were individually matched on maternal year of birth and year of index pregnancy to controls randomly selected from a computerized database. Data on demographic, reproductive, and obstetric factors were abstracted from patient hospital records. Overall, the period prevalences of subfertility and of subfertility treatment were 7% and 3%, respectively, No evidence was found that the risk of NTD-affected pregnancies was increased by either subfertility (odds ratio (OR) = 1.2, 95% confidence interval (CI): 0.7, 2.1) or its treatment (OR = 0.9, 95% CI: 0.4, 2.0). After adjustment, NTD-affected pregnancies were associated with female offspring (OR = 2.3, 95% CI: 1.8, 3.1), multiple birth (OR = 4.8, 95% CI: 1.2, 18.8), and higher numbers of pregnancies (p for trend = 0.005). The findings from this large, population-based study were wholly consistent with those from smaller studies that found no increased risk of NTD associated with exposure to fertility treatments but reported associations with various pregnancy outcomes.

Adult↗
PubMed1988

Diabetic embryopathy and fuel-mediated organ teratogenesis: lessons from animal models.

The growing recognition that faulty maternal metabolism during early organogenesis may be implicated in the increased incidence of birth defects in pregnancies complicated by diabetes has prompted worldwide efforts to institute improved preconceptional metabolic regulation. However, the failure to identify the periods of greatest risk for diabetic embryopathy, the mediating teratogen(s), and the underlying mechanisms have complicated attempts to establish precise therapeutic guidelines and targets. Some of the reported in vivo and in vitro experiences with rodent models have been reviewed to derive relevant insights. Substantial literature indicates that diabetes (experimental as well as spontaneous) in pregnant rats and mice is attended by retardation of growth and developmental delay during embryogenesis, and a variable incidence of birth defects. Poor metabolic regulation of the diabetic mother during early organogenesis may also be followed by subsequent resorption of the conceptus at the site of implantation. Vulnerability to diabetes-related resorptions and all other forms of embryopathy appears to begin during the early postimplantation period and is greatest near the onset of neurolation. Overall susceptibility is markedly influenced by genetic factors and may be modified by the antecedent metabolic exposures of the conceptus ("carry-over effects"). Mediation for the anomalous embryo development in pregnancies of diabetic rodents appears to be multifactorial; all the aberrant fuels and fuel-related components of "the diabetic state" (e.g. high glucose; ketones; somatomedin inhibitor(s); osmolality, etc.) which have been tested to date display dysmorphogenic potential ("fuel-mediated organ terato-genesis") in vitro. All tissues in the conceptus appear to be at risk. Dose-response relationships for the individual metabolic teratogens may be influenced by additive and synergistic interactions so that the integrated possibilities cannot be assessed fully by measurements confined to a single fuel or fuel-related component. In the context of the day-to-day variability in diabetes "control" of the poorly regulated mother, and the relatively longer duration of organogenesis, these multifactorial possibilities may account for the multiple birth defects that can occur in individual offspring, and the seemingly non-specific pattern of diabetic embryopathy. Insulin therapy diminishes the dysmorphogenic effects of "the diabetic state" in rodents with experimental or spontaneous diabetes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1998

Early development and spreading of autoantibodies to epitopes of IA-2 and their association with progression to type 1 diabetes.

Autoimmunity precedes clinical type 1 diabetes, and indicators of maturing autoimmune responses may be useful markers for disease prediction. To study this, epitope maturation of autoantibodies to the related protein tyrosine phosphatase (PTP)-like autoantigens IA-2 and IA-2beta was examined in sequential samples from birth in a cohort of 21 offspring developing multiple islet autoantibodies and a similar cohort of 48 relatives of patients with type 1 diabetes recruited at an older age. Initial reactivity in offspring was heterogeneous against the IA-2 juxtamembrane region (10/21) and PTP domains (13/21), and both specificity and extent of initial IA-2/IA-2beta autoantibodies were associated with HLA class II genotype. Intra-IA-2 epitope spreading and/or intermolecular spreading to IA-2beta epitopes were observed in seven offspring. In contrast, in older relatives, IA-2/IA-2beta Ab reactivity was stable and spreading rare. Development of diabetes in children was associated with the presence of Abs to the IA-2 juxtamembrane region (risk by age 5 yr, 52% vs 0% in those with PTP domain Abs only; p < 0.02), and 5 of 26 relatives who developed diabetes had IA-2 Abs only against the juxtamembrane region. The findings show that autoantibody reactivity to IA-2/IA-2beta is dynamic in the young, show that the juxtamembrane region of IA-2 is an early IA-2 autoantibody target, and suggest that these Abs are a risk factor for development of type 1 diabetes in infancy.

Adult↗
PubMed1983

Toxoplasma gondii--an environmental contaminant.

Toxoplasma gondii, the causal agent of toxoplasmosis, is a ubiquitous protozoan parasite which has the potential to infect man and all warm-blooded animals. It has as its definitive host the cat. Infections acquired by the human adult are generally subclinical. However, if acquired for the first time during pregnancy, the parasite can invade the developing foetus. Under these circumstances infection can result in abortion, stillbirth or production of live-born offspring with severe multiple organ involvement. Alternatively, offspring can be symptomless at birth but may manifest neurological and ocular sequelae of toxoplasmosis in later life. The degree of clinical involvement is thought to be dependent upon the time of acquisition of infection by the pregnant female. Recent investigations have been concerned with behavioural aspects of predator-prey relationships between cats and rodents. Since these aspects affect the spread of toxoplasmosis in the environment, they have strong epidemiological and ecological implications. Toxoplasma infection in the environment, they have strong epidemiological and ecological implications. Toxoplasma infection in mice is associated with subtle alterations in exploratory behaviour which are almost certainly maladaptive, rendering infected mice more susceptible to predation by cats. Consequently the behavioural abnormalities in mice associated with Toxoplasma infection would be of major importance for the continuation of the life-cycle of the parasite. Ingestion of Toxoplasma-infected mice leads to oocyst production in cats and this opens up the well-known pathway whereby Toxoplasma infection reaches the human species.

Animals↗
PubMed1979

Genital mycoplasmas and birth weight in offspring of primigravid women.

The relationship between colonization of pregnant women by Ureaplasma and Mycoplasma and the outcome of pregnancy in a study of 104 women is reported. There were eight abortions but no multiple births or stillbirths. Excluding abortions, the mean gestational length was 39.6 weeks and the corrected mean birth weight was 3.28 kilograms. There was no relationship between maternal colonization by genital mycoplasmas and reduction in birth weight of the offspring, but five of the eight women who aborted harbored Ureaplasma, suggesting an increased trend toward abortion in women harboring Ureaplasma.

Birth Weight↗
PubMed2006

Prediction of change in level of problem behavior among children of bipolar parents.

OBJECTIVE: To determine the effects of familial loading, birth weight, and family problems on change in parent-reported problems across a 14-month period among children of bipolar parents. METHOD: Emotional and behavioral problems in a sample of 140 offspring of bipolar parents and familial loading in first- and second-degree relatives were assessed at two measurements. Parents reported the birth weight of their offspring and completed a questionnaire on family problems. Multiple linear regression analyses were performed to assess associations of the three predictors with change in problem scores at follow-up. RESULTS: Familial loading of unipolar disorder was a unique predictor for an increase in problem scores from the first to the second measurement with beta-coefficients ranging from 0.17 to 0.25. Birth weight and family problems were not associated with change in problem scores across the two measurements. CONCLUSION: Familial loading of unipolar disorder predicted an increase in behavioral and emotional problems across the 14-month follow-up.

Adolescent↗
PubMed2006

Strain-specific induction of murine lung tumors following in utero exposure to 3-methylcholanthrene.

Fetal mice are more sensitive to chemical carcinogens than are adults. We previously demonstrated that resistant offspring of a DBA/2 x (C57BL/6 x DBA2) backcross exhibited a high incidence of lung tumors 12-13 mo after transplacental exposure to 3-methylcholanthrene (MC). We compared the effects of in utero treatment with MC on lung tumor incidence in the offspring of intermediately susceptible BALB/c (C), resistant C57BL/6 (B6), and reciprocal crosses between these strains. Pregnant mice were treated with 45 mg/kg of MC on day 17 of gestation and tumor incidence, multiplicity, and the Ki-ras mutational spectrum determined in the offspring 12-18 mo after birth. Tumor incidences in C mice and reciprocal crosses were 86% and 100%, respectively, while B6 mice demonstrated resistance to tumorigenesis, with a tumor incidence of 11%. Tumor multiplicities in C, B6C, CB6, and B6 mice were 3.3 +/- 3.2, 5.8 +/- 3.2, 5.0 +/- 2.7, and <0.1, respectively. Ki-ras mutations, which occurred chiefly in the K(s) allele (96%), were found in 79-81% of reciprocally crossed F1 mice, 64% of C mice, and 50% of B6 mice, with the Val(12), Asp(12), and Arg(13) mutations associated with more aggressive tumors. A subset of these mice was used to demonstrate the utility of computer tomography (CT) for the visualization and measurement of lung tumors in the submillimeter range in vivo. Based on known genetic differences in murine strains for lung cancer, our results suggest the presence of a previously unidentified genetic factor(s) which appears to specifically influence lung tumorigenesis following exposure to carcinogens during fetal development.

Animals↗
PubMed1987

Toward a theory of human multiple birthing: sociobiology and r/K reproductive strategies.

Using symbols from population biology, a continuum of reproductive strategies can be distinguished ranging from r, the production of large numbers of offspring provided with minimal care, to K, the production of few offspring nurtured intensively. While all humans are at the K end of the continuum, some are proposed to be more so than others. If multiple egg production is part of an r-reproductive strategy, certain facts may be ordered. Compared to mothers of singletons, for example, mothers of DZ twins have a lower age of menarche, a shorter menstrual cycle, a higher number of marriages, a higher rate of coitus, more illegitimate children, a closer spacing of births, a greater fecundity, more wasted pregnancies, a larger family, an earlier menopause, and an earlier mortality. Further, all twins have a shorter gestation period, a lower birth weight, and a greater incidence of infant mortality, with DZ twins having a greater frequency of health disorders, a higher mortality rate, and a lower rate of enrollment in volunteer registries. Multiple birthing also occurs more frequently in families of lower than of higher social status, and in those of African than of European and especially than of Oriental descent.

Animals↗
PubMed2004

Gene expression patterns in in vitro-produced and somatic nuclear transfer-derived preimplantation bovine embryos: relationship to the large offspring syndrome?

A considerable proportion of the offspring born from somatic nuclear transfer (sNT)-derived and in vitro-produced (IVP) embryos, particularly in ruminants and mice, is affected by multiple abnormalities of which a high birth weight is the predominant feature; a phenomenon that has been called "large offspring syndrome (LOS)". The underlying mechanisms are largely unknown at present, but changes in epigenetic modifications occurring during preimplantation development resulting in perturbed embryonic and fetal gene expression patterns are thought to be involved in the syndrome. This review summarizes results from studies comparing mRNA expression patterns from IVP and sNT-derived embryos to those of their in vivo counterparts, which are regarded as the "gold standard". Numerous aberrations have been observed ranging from suppression of expression to de novo overexpression or more frequently to a significant up- or down-regulation of a specific gene. These observations emphasize the need for further studies during preimplantation embryo development to gain insight in the molecular, preferentially epigenetic, mechanisms regulating embryonic and fetal development. Understanding these mechanisms will help to improve biotechnologies applied to early embryos in all species including humans.

Animals↗
PubMed1996

Mythos and logos in Hesiod's Theogony, circa 700 B.C.

Hesiod's Theogony, a completely preserved poem, is dated from about 700 B.C. It depicts partly a development, partly a situation that has arisen in the course of time in the world. It constitutes an attempt to understand the cosmos as the product of a genealogical evolution, which can be seen as a process of successive separation, differentiation, and hierarchization. In this attempted picture of the world myth and reality are inextricably interwoven. Observations of natural phenomena as far as of congenital malformations are accordingly exaggerated and undergone mythical transformation. Entities enumerated in this genealogical poem, no matter whether they stand for parts and concrete phenomena of the physical world or intellectual properties and abstract concepts, behave, think, and act, and are accordingly though of, in anthropomorphic terms. Monogamy, polygamy, endogamy, exogamy, asexual and sexual reproduction, multiple conceptions and births, dominantly and recessively inherited traits, normal and abnormal offspring, and perceptions and notions on cosmogony, isogamy, and teratogenesis could be observed in the writing of the Theogony and interpreted by rational modern concepts.

Genetics↗
PubMed1999

Determinants of bronchial responsiveness at school age in prematurely born children.

The bronchial challenge test using isocapnic hyperventilation of cold air (IHCA) was used to evaluate bronchial responsiveness in 63 offspring of multiple pregnancies when they were 8-15 years old. At birth, 27 (43%) children had had intrauterine growth retardation (IUGR, birth weight <-2 SD, or birth weight difference between twin pairs >1.3 SD). The median birth weight was 2,050 g (range, 800-3, 150), and the median gestational age was 35 weeks (range, 28-38). None of the children had asthma or suffered from asthma-like symptoms. In the interpretation of the IHCA test, a fall of 9% or more in the forced expiratory volume in 1 sec (FEV(1)) was considered as abnormal, and these children were classified as "cold air responders." The number of responders was 16 (25%); their baseline FEV(1)/forced vital capacity ratio (FEV(1)/FVC) and forced expiratory flow between 25-75% FVC (FEF(25-75)), but not FEV(1) were significantly lower than the corresponding values in nonresponders. No differences were found in perinatal or neonatal factors between responders or nonresponders. Eight (30%) of the 27 IUGR and 8 (22%) of the 36 appropriate for gestational age (AGA) children were IHCA responders. In particular, IUGR was not correlated with maximal FEV(1) falls following the IHCA test. Respiratory infections after the neonatal period were equally common in IUGR and AGA children; but infections were associated with subsequent IHCA responsiveness. Adenoidectomy, tonsillectomy, and/or myringotomy had been performed significantly more often in the responders than in the nonresponders. At least one of the above invasive procedures had been performed in 20 (32%) of the children; this group was termed the "ENT (ear, nose, throat) surgery group." Fifty-six percent of the responders, but only 26% of the nonresponders, belonged to the ENT surgery group (P = 0.02). We conclude that intrauterine growth retardation or prematurity is not associated with abnormal cold air responsiveness in the IHCA test.

Adolescent↗
PubMed2005

Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage.

Key research findings relative to the question of whether maternal use of folic acid before and during pregnancy reduces the chance that offspring will be born with a congenital heart defect or an orofacial cleft are reviewed in this paper. Observational studies in general support an association between maternal use of multivitamins containing folic acid and a reduction in the occurrence of congenital heart defects and orofacial clefts. Results from one randomized controlled trial (RCT) provide the strongest evidence that multivitamins prevent congenital heart defects, but this RCT did not provide evidence that multivitamins prevent orofacial clefts. In addition, most observational and interventional studies are not designed to detect an independent effect from folic acid. Early studies suggested that periconceptional multivitamin use was associated with an increased occurrence of both miscarriages and multiple births, which has resulted in a great deal of controversy about the safety of folic acid use during pregnancy. We also review reports that were designed to answer these questions with more definitive data. When more substantial evidence about the effect of periconceptional folic acid on the occurrence of congenital heart defects and orofacial clefts is reported, we will have additional support for promoting folic acid intervention programs. All women capable of becoming pregnant should continue to consume 400 mug/d of folic acid in addition to a healthy diet as advised.

Abortion, Spontaneous↗
PubMed2006

Maternal dietary exposure to fiber during pregnancy and mammary tumorigenesis among rat offspring.

Maternal diet during pregnancy has been proposed to modify female offspring's later susceptibility to develop breast cancer; however, most of the dietary factors identified thus far have led to increased risk. To identify dietary factors that might reduce offspring's breast cancer risk, pregnant rat dams were fed diets containing 6% fiber originating either from cellulose (control), or oat, whole wheat or defatted flax flour. At birth, dams were switched to the AIN93 semi-purified diet. Mammary tumor incidence and multiplicity, induced by administering the offspring 5 mg 7,12-dimethylbenz[a]anthracene (DMBA) at the age of 50 days, was reduced in the whole wheat flour-exposed offspring and increased in the defatted flax-exposed offspring. To identify the mechanisms mediating the effects of in utero dietary exposures, changes in mammary gland morphology and gene expression were assessed before puberty onset (3 weeks of age) and at the time rats are most susceptible to malignant transformation (8 weeks of age). The number of terminal end buds (TEBs), i.e., the targets of malignant transformation, was reduced in the mammary glands of whole wheat- and oat flour-exposed offspring, as compared to the controls. Further, the number of apoptotic epithelial cells (based on ISOL assay) was elevated in the whole wheat flour offspring, but no changes in cell proliferation (PCNA), estrogen receptor alpha (ER-alpha) or cyclin D1 mRNA or protein levels were seen. The mRNA and/or protein levels of BRCA1 and p53 were significantly increased in the mammary glands of whole wheat flour offspring. Further, the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA damage, were significantly reduced in these rats, suggesting that maternal dietary exposure to whole wheat during pregnancy may reduce offspring's breast cancer risk by improving DNA damage repair mechanisms.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2006

Boron workers in China: exploring work and lifestyle factors related to boron exposure.

This article describes the lifestyle patterns of boron mining and processing workers (N=936) and a comparison group (N=251) in northeast China, and explores relationships between boron exposure and reproductive health. An English version of an interview guide addressing areas of work and lifestyle relevant to boron exposure and metabolism was developed by an occupational health research team, translated to Chinese, and translated back, for clarity. Modifications incorporated suggestions from a local community advisory board and boron industry workers; the translation-back translation process was reapplied, and cultural and semantic equivalence was attained. Results from the interviews showed more than 64% of workers and comparison group participants smoked tobacco and more than 92% reported exposure to environmental tobacco smoke. Boron workers and the comparison group varied in their food intake and alcohol consumption, but not in their smoking habits. Thirty-four percent of boron workers reported eating in the contaminated work area. Nearly all boron workers (99%) showered or bathed after work, although approximately 10% redressed in their contaminated clothes. Reproductive health outcomes were explored, including delayed pregnancy, multiple births, spontaneous miscarriages, induced abortions, stillbirths, and an unusual ratio of male to female offspring. Implications for occupational health nurses and recommendations for future research are provided.

Adult↗
PubMed1989

Maternal thyroid disease and risk of birth defects in offspring: a population-based case-control study.

We investigated the relationship between maternal thyroid disease and the risk of birth defects in offspring using data from a large population-based, case-control study. Cases included 4904 stillborn and liveborn infants with major anomalies diagnosed in the first year of life and born to residents of metropolitan Atlanta between 1968 and 1980. Controls included 3027 normal babies, frequency-matched to cases by race, hospital of birth and quarter of birth. We compared mothers of cases and controls regarding history of physician-diagnosed hypothyroidism and hyperthyroidism before the infant's birth, age at diagnosis of thyroid condition, duration of illness, and intake of thyroid medications before and during pregnancy. Information obtained from maternal interviews was evaluated for concordance with hospital records. We adjusted for potentially confounding factors using conditional logistic regression analysis. Overall, there was no relationship between the risk of total birth defects and history of maternal hypothyroidism (odds ratio (OR) = 1.05, 95% C.I. 0.84-1.31), maternal hyperthyroidism (OR = 1.00, 95% C.I. 0.66-1.53), and intake of thyroid hormone and antithyroid drugs before and during pregnancy. In an analysis of 66 specific birth defects and defect groups, we found two statistically significant associations with hypothyroidism and three with hyperthyroidism which may reflect chance findings. In an evaluation of babies with multiple anomalies, we observed a two-fold increased risk with hypothyroidism but no discernible pattern of defects. The absolute risk of major birth defects in offspring of women with history of hypothyroidism can be estimated as 2.1%, a finding at odds with the 10-20% risk cited in the literature.

Abnormalities, Drug-Induced↗
PubMed1983

Induction of T cell hyporesponsiveness to Bebaru in mice, and abnormalities in the immune responses of progeny of hyporesponsive males.

Non-specific hyporesponsiveness of cytotoxic T cells to alphaviruses and alloantigens was induced in male mice by multiple, large injections, starting at birth, of gamma-inactivated alphavirus, stock-grown in outbred mouse brains. Offspring of matings between 2 out of 17 treated males and normal females also exhibited significant non-specific hyporesponsiveness (in comparison with normal control mice), without prior exposure to gamma-inactivated alphavirus stock.

Alphavirus↗