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Birth order and breast cancer risk.

It has been hypothesized that prenatal exposure to maternal estrogens may be a risk factor for breast cancer in the offspring. In two recent studies, maternal estradiol levels in the first pregnancy have been compared to those in the second, and in both studies levels were higher in the first pregnancy. If both the hypothesis and the reported findings were true, women born as their mother's second child would be expected to have lower risk for breast cancer than first-born women. Data from 1,468 cases of breast cancer and 4,175 hospital controls from three previously published studies were modelled through multiple logistic regression to evaluate this possibility. The size of the woman's sibship was not related to breast cancer risk. On the other hand, second-born women had, as predicted, lower breast cancer risk than first-born women, although the difference was nominally significant only among premenopausal women. The relative risk for breast cancer, contrasting second-born to first-born women, and the corresponding 95 per cent confidence intervals, were 0.71 (0.54-0.94) among premenopausal women, 0.94 (0.76-1.17) among postmenopausal women, and 0.86 (0.73-1.02) among all women, controlling for menopausal status.

Birth Order↗

Griseofulvin: a teratogenic study.

Griseofulvin, a fungistatic agent, was administered in oral doses of 125 to 1500 milligrams per kilogramn per day to pregnant rats during organogenesis. Evaluation of the offspring from dams treated with the largest doses, 63 and 75 times a therapeutic dose in man, indicated decreased survival rates and a syndrome of malformations.

Abnormalities, Drug-Induced↗

Urogenital carcinogenesis in female CD1 mice induced by in utero arsenic exposure is exacerbated by postnatal diethylstilbestrol treatment.

Transplacental inorganic arsenic carcinogenicity, together with postnatal exposure to diethylstilbestrol or tamoxifen, was studied. Pregnant CD1 mice received 85 ppm arsenic in the drinking water from gestation days 8 to 18 and were allowed to give birth. Groups (n = 35) of female offspring were injected s.c. on postpartum days 1 through 5 with diethylstilbestrol (2 microg/pup/d) or tamoxifen (10 microg/pup/d) and observed for 90 weeks. Arsenic alone induced some urogenital system tumors, including mostly benign tumors of the ovary and uterus, and adrenal adenoma. Diethylstilbestrol alone induced some tumors (primarily cervical) but when given after in utero arsenic, it greatly enhanced urogenital tumor incidence, multiplicity, and progression. For instance, compared with the incidence of urogenital malignancies in the control (0%), arsenic alone (9%), and diethylstilbestrol alone (21%) groups, arsenic plus diethylstilbestrol acted synergistically, inducing a 48% incidence of malignant urogenital tumors. Of the urogenital tumors induced by arsenic plus diethylstilbestrol, 80% were malignant, and 55% were multiple site. Arsenic plus diethylstilbestrol increased ovarian, uterine, and vaginal tumors, and urinary bladder proliferative lesions, including three transitional cell carcinomas. Tamoxifen alone did not increase urogenital tumors or affect arsenic-induced neoplasia but did increase arsenic-induced uroepithelial proliferative lesions. Uterine and bladder carcinoma induced by arsenic plus diethylstilbestrol greatly overexpressed estrogen receptor-alpha (ER-alpha) and pS2, an estrogen-regulated gene. In neonatal uteri, prenatal arsenic increased ER-alpha expression and enhanced estrogen-related gene expression induced by postnatal diethylstilbestrol. Thus, arsenic acts with estrogens to enhance production of female mouse urogenital cancers.

Animals↗

Pregnancy complications and the risk of asthma among Norwegians born between 1967 and 1993.

BACKGROUND: Fetal life events may affect the development of the immune and/or respiratory system and increase the risk of asthma and allergic diseases. The objective of this study was to test the hypothesis that pregnancy complications are associated with the risk of developing asthma in the off-spring. METHODS: The study population comprised Norwegian live births 1967-1993 (n = 1,548,429) linking the Medical Birth Registry of Norway (MBRN) (exposure variables) and the National Insurance Administration Register (NIAR) (outcome variables), which covers all Norwegians. The MBRN variables included pregnancy complications, pregnancy outcomes and diseases of the mother. The NIAR provided data on all Norwegians who had received cash benefit for treatment of asthma from 1967 to 1996 (n = 5938, 3.9/1000 persons). RESULTS: In multiple logistic regression analysis, pregnancy complications (International Classification of Diseases (ICD)-8-codes: 630-634) were associated with the risk of asthma (odds ratio 1.82, 95% confidence interval: 1.67-1.98). This was also the case if analyses were performed in different strata according to year of birth, plurality, maternal atopy, geographical district of birth, and maternal education. CONCLUSIONS: Pregnancy complications may represent risk factors for the development of asthma in the offspring or express early signs of increased risk for developing the disease.

Adolescent↗

Association between prepregnancy maternal body mass index and the risk of having an infant with a congenital diaphragmatic hernia.

BACKGROUND: A previous study observed that women who are underweight prior to conception were significantly more likely to have infants affected by congenital diaphragmatic hernia (CDH). The objective of the current study was to examine the association between maternal body mass index and the risk of a CDH-affected offspring based on a larger number of cases of CDH. METHODS: A case control study was conducted using data collected by the Boston University Slone Epidemiology Center Birth Defects Study, which identifies infants with major malformations who are born in the metropolitan area surrounding Boston, Massachusetts; Philadelphia, Pennsylvania; and Toronto, Ontario, Canada. Control infants were selected from infants without malformations who were born in the same areas. The study included 85 cases of CDH and 655 controls delivered between 1993 and 1997. RESULTS: After adjustment for maternal education and maternal age, we observed that women who were thin or underweight for their height (body mass index < or = 19.0 kg/m2) had an increased risk of having an infant with isolated CDH (OR = 1.9; 95% CI = 0.92-4.1), but no increase in the risk of having a CDH infant with multiple defects (OR = 0.86; 95% CI = 0.29-2.6) compared with all other women. CONCLUSIONS: Although our finding for isolated CDH was not statistically significant (P = 0.08), it suggests that the offspring of thin or underweight women may have an increased risk of isolated CDH. This finding requires confirmation. If it is confirmed, further research on factors associated with being underweight should be explored such as diet, exercise, and use of drugs.

Body Mass Index↗

Course and outcome of IVF pregnancies and spontaneous conceptions within an IVF setting.

The study determines mortality and morbidity levels during pregnancy and the perinatal period in those conceiving through IVF in the Republic of Ireland in comparison with other parts of the world and a peer infertile group conceiving spontaneously whilst on the IVF clinic books. Six hundred and sixty couples had 187 IVF pregnancies from whom 220 babies were born to 151 deliveries. There were also 78 spontaneous conceptions which produced 78 offspring from 73 deliveries. The majority had trouble free pregnancies. The incidence of all complications was less than has been reported elsewhere. Of the IVF group, 16.5% aborted completed as did 5% of the spontaneous conceptions. A further 7% and 3.8%, respectively, aborted one sac of a multiple pregnancy. Of the IVF deliveries, 35.8% were multiple as were 6.8% of the spontaneous conceptions. Higher order multiple presence detrimentally influenced delivery mode, gestational age and birth weights in the IVF group. Of IVF patients, 55.7% were section deliveries as were 10.9% of the spontaneous conceptions. Incidence of IVF-group significant congenital abnormality was 1.8%. The perinatal mortality rate was 4.2 per 1000 births. This series suggests the final take-home baby outlook of 81% from conception by IVF is not as poor as previously portrayed. However, attention should be given to abortion, section and multiple pregnancy rates.

Adult↗

Intracytoplasmic injection of spermatozoa and spermatogenic cells: its biology and applications in humans and animals.

Intracytoplasmic sperm injection (ICSI) has become the method of choice to overcome male infertility when all other forms of assisted fertilization have failed. Animals in which ICSI has produced normal offspring include many species. Success rate with normal spermatozoa is well above 50% in the mouse but ICSI success rates in other animals have been low, ranging from 0.3 to 16.5%. Mouse ICSI revealed that spermatozoa that cannot participate in normal fertilization can produce normal offspring by ICSI, provided their nuclei are genomically intact. Human ICSI using infertile spermatozoa has been highly successful perhaps because of the intrinsic instability of human sperm plasma membrane. The health of children born after ICSI and other assisted fertilization techniques is of major concern. Careful analyses suggest that higher incidences of congenital malformations and/or low birth weights after assisted fertilization are largely attributable to parental genetic background and increased incidence of multiple births, rather than to the techniques of assisted fertilization. Since the physiological and nutritional environments of developing embryos may cause persisting alteration in DNA methylation, extreme caution must be exercised in handling gametes and embryos in vitro. In the mouse, round spermatid injection (ROSI) has been routinely successful but its use in humans is controversial. Whether human ROSI and assisted fertilization involving younger spermatogenic cells are medically safe must be the subject of further investigations.

Animals↗

Prenatal alcohol and offspring development: the first fourteen years.

This report summarizes findings from a prospective longitudinal study of the effects of prenatal alcohol exposure on a birth cohort of 500 offspring selected from 1,529 consecutive pregnant women in prenatal care by mid-pregnancy at two representative community hospitals. Effects of prenatal alcohol observable on size measures at birth were insignificant after 8 months. Morphometric analysis of facial features identified effects only at the very highest alcohol exposure levels. By contrast, dose-dependent effects on neurobehavioral function from birth to 14 years have been established using partial least squares (PLS) methods jointly analysing multiple measures of both alcohol dose and outcome. Particularly salient effects included problems with attention, speed of information processing, and learning problems, especially arithmetic.

Adolescent↗

The risk of preterm birth across generations.

OBJECTIVE: To examine the risk of preterm birth for mothers who themselves were born before term. METHODS: Data were taken from a linked data base of birth certificates composed of two cohorts: 1) a parental cohort of women born between 1947 and 1957 and 2) their offspring born between 1970 and 1992. "Preterm mothers" were women in the parental cohort who were born at less than 37 weeks' gestation. "Term mothers" were women in the parental cohort born at or after 38 weeks' gestation. Preterm mothers and term mothers were matched for birth year, county of birth, marital status, parity, and age. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the risk of preterm delivery in preterm mothers. Multiple logistic regression was used to assess the interaction of concomitant variables with the risk of premature delivery. RESULTS: The risk of preterm birth was significantly higher in preterm mothers than in term mothers (OR 1.18; 95% CI 1.02, 1.37). The risk increased as the gestational age at the mothers' birth decreased (less than 30 weeks'; OR 2.38; 95% CI 1.37, 4.16). The interaction between maternal age and parity increased the risk of preterm delivery at less than 34 weeks in some age and parity strata. CONCLUSION: An increased risk of preterm delivery exists for women who themselves were born before 37 weeks' gestation. The risk is inversely correlated with the maternal gestational age at birth and is influenced by maternal age and parity.

Adolescent↗

Integrated perinatal health framework. A multiple determinants model with a life span approach.

BACKGROUND: Despite great strides in improving prenatal care utilization among American women, key perinatal indicators have remained stagnant or worsened in the past decade, and the United States continues to rank near the bottom compared to other developed countries. A new approach is needed if we are to achieve improvements in perinatal health. METHODS: To propose a new framework that integrates a "life span" approach with a multiple determinants model. RESULTS: We recognize that (1) powerful influences on outcome occur long before pregnancy begins; (2) pregnancy outcome is shaped by social, psychological, behavioral, environmental, and biological forces; and (3) the demography of pregnancy has changed dramatically in the last few decades with more women delaying their first birth. Approaches that simultaneously consider the entire life span as well as multiple determinants may need to be adopted. We propose a framework that integrates these approaches and is supported by the research literature. The life span perspective focuses attention toward the preconceptional and interconceptional periods as targets for intervention in improving perinatal health. The multiple determinants model distinguishes among concepts of disease, health and functioning, and well-being for both women and their offspring. CONCLUSIONS: Our intent is to influence how policymakers, public health professionals, clinicians, and researchers approach perinatal health.

Family Planning Services↗

Perinatal exposure to the fungicide prochloraz feminizes the male rat offspring.

Prochloraz is a commonly used fungicide that has shown multiple mechanisms of action in vitro. It antagonizes the androgen and the estrogen receptors, agonizes the Ah receptor, and inhibits aromatase activity. In vivo prochloraz acts antiandrogenically in the Hershberger assay by reducing weights of reproductive organs, affecting androgen-regulated gene expressions, and increasing luteinizing hormone (LH) levels. The purpose of this study was to investigate reproductive toxic effects after exposure during gestation and lactation to prochloraz alone and a mixture of five pesticides (deltamethrin, methiocarb, prochloraz, simazine, and tribenuron-methyl). Prochloraz (30 mg/kg/day) or the mixture (20 mg/kg/day) was dosed to pregnant Wistar dams from gestational day (GD) 7 until postnatal day (PND) 16. Some dams were taken for cesarean section at GD 21, and others were allowed to give birth. Results showed that prochloraz and the mixture significantly reduced plasma and testicular testosterone levels in GD 21 male fetuses, whereas testicular progesterone was increased. Gestational length was increased by prochloraz. Chemical analysis of the rat breast milk showed that prochloraz was transferred to the milk. In males a significant increase of nipple retention was found, and the bulbourethral gland weight was decreased, whereas other reproductive organs were unaffected. In addition cytochrome P450 (CYP)1A activities in livers were induced by prochloraz, possibly as a result of Ah receptor activation. Behavioral studies showed that the activity level and sweet preference of adult males were significantly increased. Overall these results strongly indicate that prochloraz feminizes the male offspring after perinatal exposure, and that these effects are due, at least in part, to diminished fetal steroidogenesis.

Animals↗

Aspirin and acetaminophen use by pregnant women and subsequent child IQ and attention decrements.

In a longitudinal prospective study of 1,529 women pregnant in 1974-1975, aspirin and acetaminophen were the two medications most frequently taken during the first half of pregnancy (46 and 41%, respectively). In a selected cohort of 421 offspring of these women, examined at 4 years of age, maternal aspirin use during the first half of pregnancy was significantly related to IQ and attention decrements in the exposed children. Multiple regression analyses were used to statistically adjust for a variety of potentially confounding factors including demographic characteristics, child characteristics, other exposures, and lifestyle/environmental variables. Continuous dose-response and step-function parameterizations of aspirin exposure were both statistically significant and not clearly distinguishable from each other. The estimated aspirin effect is significantly greater for girls than boys. Aspirin effects on offspring function were found in the absence of effects on physical size both at birth and at 4 years. Maternal acetaminophen use was not significantly related to child IQ or attention. As this exploratory research originated from observations of a data set gathered for other purposes, it would be desirable to have these findings replicated in other studies. Further follow-up of the children at a later age is planned.

Acetaminophen↗

Prenatal corticosterone increases spontaneous and d-amphetamine induced locomotor activity and brain dopamine metabolism in prepubertal male and female rats.

Recently, both glucocorticoid receptor immunoreactivity and glucocorticoid receptor messenger RNA levels were found in multiple brain areas, especially in the neuroepithelium during the late prenatal development of the rat brain. To better understand the potential influence of stress on fetal brain development by release of maternal adrenocortical steroids, we have investigated the effects of corticosterone administration to pregnant rats on the locomotor activity of their prepubertal offspring. On day 16 of pregnancy female rats were implanted with either placebo or corticosterone pellets (release of 2.4 mg/day for seven days). After birth their offspring were nursed by foster mothers to avoid any postnatal effects of the corticosterone pellets. At three weeks of age, the offspring were tested for spontaneous motor behaviours. Both male and female offspring from corticosterone treated mothers showed significantly increased spontaneous ambulation, motility and rearing compared to placebo treated groups. No significant sex differences were found in locomotor activity between male and female offspring from placebo groups. Following d-amphetamine (1.5 mg/kg) treatment, a preferential dopamine releasing agent, we observed a significant increase in ambulation, motility and rearing activity in the male offspring treated with corticosterone. In the female offspring, only the rearing activity was significantly higher after d-amphetamine treatment in the prenatal corticosterone group compared with the placebo treated group. Basal dopamine metabolism (dihydroxyphenylacetic acid/dopamine ratio) was increased in the dorsal striatum and ventral striatum of male and female offspring from corticosterone-treated dams. In the male offspring, corticosterone treatment was associated with a disappearance of the right side dominance of dopamine metabolism in the dorsal striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

Women with schizophrenia: pregnancy outcome and infant death among their offspring.

Schizophrenia in the mother may imply an increased risk of adverse pregnancy outcome. However, inconclusive findings, unknown pathological mechanisms and possible confounding by social factors and smoking requests further explorations. The aim of this study were to (1) examine non-optimal pregnancy outcome using data from a population-based cohort, controlling for covariates known to influence fetal growth; and (2) perform separate analyses of women diagnosed before childbirth and women hospitalized for schizophrenia during pregnancy. The study sample comprised 2096 births by 1438 mothers diagnosed with schizophrenia (of whom 696 mothers were antenatal diagnosed and 188 admitted during pregnancy) and 1,555,975 births in the general population. We found significantly increased risks for stillbirth, infant death, preterm delivery, low birth weight, and small-for-gestational-age among the offspring of women with schizophrenia. Women with an episode of schizophrenia during pregnancy had the highest risks (e.g., low birth weight; OR 4.3, 95% CI 2.9-6.6 and stillbirth; OR 4.4, 95% CI 1.4-13.8). Controlling for a high incidence of smoking during pregnancy among schizophrenic women (51% vs. 24% in the normal population) and other maternal factors (single motherhood, maternal age, parity, maternal education, mothers' country of birth and pregnancy-induced hypertensive diseases) in a multiple regression model, reduced the risk estimates markedly. However, the risks for adverse pregnancy outcomes were even after adjustments generally doubled for women with an episode of schizophrenia during pregnancy compared to women in the control group (e.g., low birth weight; OR 2.3, 95% CI 1.5-3.5, preterm delivery; OR 2.4, 95% CI 1.5-3.8 and stillbirth; OR 2.5, 95% CI 0.8-7.9). The risks for preterm delivery and low birth weight were significantly elevated throughout the analyses. We conclude that schizophrenia in the mother implies an increased risk for poor perinatal outcome, not fully explained by maternal factors, and a need to consider a common familial (probably genetic) vulnerability for pre- and perinatal stress and schizophrenia.

Adult↗

[Correlation between maternal age, social class and smoking, and birth weight].

An epidemiological survey was carried out in Ribeirão Preto, Brazil, from June 1978 to May 1979. Interviews were held with mother of singleton live borne children, delivered in hospitals, which accounted for 98% of all births in the area. The higher percentages of low birthweight children related to the offspring of smokers, young mother and women belonging to the working class. The majority of young women were found in the working class and the prevalence of smoking was higher in the group of women below 20 years of age. There was no statistical difference in the smoking habit as between different social classes. A larger number of low birthweight children were observed in nonsmoking women of the working class than among women smokers of the middle class. A log model was adjusted to the data in order to study the possible multiple association of smoking, maternal age and social class with birthweight. The results indicated that maternal smoking, maternal age and social class had independent effects on birthweight. The was no interaction between them. These findings suggest that the higher prevalence of low birthweight in nonsmoking mothers of the working class in relation to smoking mothers of the middle class probably reflects clustering of other risk factors-such as poor education inadequate prenatal care, high parity and differences in reproductive behavior in women of the working class.

Adult↗

Campomelia, cervical lymphocele, polycystic dysplasia, short gut, polysplenia.

An aborted fetus, the offspring of consanguineous parents, had the unusual combination of campomelia, cervical lymphocele, polycystic kidneys, pancreas, and liver, short gut, and polysplenia. Births of earlier similarly affected fetuses suggest an autosomal recessive inheritance. Skeletal, lymphatic, and renal lesions were seen at 26 weeks' gestation by ultrasonography, but not at 16 weeks.

Abnormalities, Multiple↗

Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation.

We have observed over 25 different mutations in the diastrophic dysplasia sulphate transporter gene (DTDST) in association with the recessive disorders achondrogenesis 1B, atelosteogenesis 2, and diastrophic dysplasia. The c862t (R279W) transition is the most common mutation in non-Finnish patients, but in these disorders it is usually combined with other DTDST mutations. We had not seen a case of homozygosity for c862t (R279W) until we analysed DNA from a 36 year old male with tall-normal stature (180 cm) who asked for genetic counselling for suspected multiple epiphyseal dysplasia. He was treated for club foot and hip dysplasia at birth. Skeletal changes consistent with multiple epiphyseal dysplasia, with the peculiar finding of a double layered patella, were recognised during childhood. Cleft palate, swelling of the ear pinna, and hitch hiker thumb were absent. He was found to be homozygous, and both healthy parents heterozygous, for the R279W mutation in DTDST, and his fibroblasts showed a sulphate incorporation defect typical of DTDST disorders. Counselling was given for a recessive disorder, thereby considerably reducing the probability of affected offspring. Multiple epiphyseal dysplasia is more frequently caused by dominant mutations in the COMP (EDM1, McKusick 132400) and COL9A2 genes (EDM2, McKusick 600204). A few other patients and families with features similar to our proband have been described previously and considered to have autosomal recessive MED (EDM4, McKusick 226900). This observation confirms the existence of this entity and assigns it to the phenotypic spectrum associated with mutations at the DTDST locus.

Adult↗

[Roberts-SC phocomelia syndrome: cytogenetic findings and clinical variability in three brothers].

Three sibs with Roberts syndrome SC-phocomelia are presented. The first one, a nine years old girl, with a malformative syndrome consistent with SC-phocomelia: symmetrical reductive malformations of the upper limbs; flexion contractures of both knee joints; multiple minor anomalies, including hemangioma of the face, hypoplastic nose, dysplastic ears and scanty, silvery blond hair; intrauterine and extrauterine growth retardation; psychomotor and mild mental retardation. Cytogenetic study reveals a centromeric abnormality consistent with an unusual sister chromatid disjunction in all metaphases, that can also be a useful tool in prenatal diagnosis. Next two sibs were males and offspring of a twin pregnancy and were found to have a malformative syndrome consistent with Roberts syndrome: low birth weight; dysplastic ears; hypertelorism, exophthalmos and cloudy corneas; bilateral cleft lip and cleft palate; severe reductive defects in both upper limbs and only syndactylia in the lower ones. Both sibs died soon after delivery. Autosomic recessive pattern of inheritance of this disorder, presentation in the same sibship of Roberts and SC-phocomelia syndromes, as different degrees of expression of the same disorder, and relationship of cytogenetic findings with cell division are discussed.

Child↗