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PubMed1987

Inbreeding and prereproductive mortality in the Old Order Amish. II. Genealogic epidemiology of prereproductive mortality.

The effects of offspring and parental inbreeding on prereproductive mortality (death before age 20 years) in the historical population of the Lancaster County, Pennsylvania, Old Order Amish were investigated using the Amish genealogic registry, which contains information on 42,465 births dating to the time of the pioneer migrants in the 1700s. Inbreeding coefficients for offspring and parents were computed using the path method of tracing common ancestors in the multigenerational pedigrees. In this population, prereproductive mortality declined from about 15% in the late 1800s to about 5% after 1930. Offspring inbreeding was found to be an independent predictor of prereproductive mortality after multivariate adjustment for demographic risk factors for mortality. Moreover, the higher the coefficient, the higher the relative risk of prereproductive death, and the higher the risk of multiple deaths in the same sibship. There was no evidence of declining inbreeding effects over 10 generations of continuous inbreeding, nor of any significant parental inbreeding effects. Because of the high levels of inbreeding, it could be shown that inbreeding accounts for about 40% of all prereproductive deaths in the present population. Genetic load analysis showed an average of about 1.7 lethal equivalents and a mostly mutational load.

Adult↗

PubMed1995

Absent iris stroma, narrow body build and small facial bones: a new association or variant of SHORT syndrome?

We report four patients from two unrelated families with strikingly similar facial appearance, short stature, narrow body build and, in two of the patients, abnormalities of the iris stroma. The birth of an affected offspring suggests that this syndrome is likely to have autosomal dominant inheritance. The facial appearance and some of the features resemble the SHORT syndrome, the name being an acronym for Short stature, Hyperextensible joints, Ocular depression, Rieger anomaly and abnormalities of the Teeth. The relationship of the syndrome to the SHORT syndrome is discussed.

Abnormalities, Multiple↗

PubMed2002

Lessons from a recent adoption study to identify some of the service needs of, and issues for, donor offspring wanting to know about their donors.

This paper draws on some of the major findings of a recent large-scale study of over 400 adult adopted people, who either searched for origins information or were sought out by birth relatives, to identify the potential profile of donor offspring seeking origins information. It is predicted that more women than men will search, that people who search will be in their twenties or older, and that the age at which searching begins may be delayed by the effects of the social stigma attached to gamete donation and by the greater likelihood of accidental disclosure in adulthood resulting from the higher incidence of secrecy about donor assisted conception. Two of the single triggers for adopted people to begin searching (as opposed to multiple triggers) - becoming a parent and the death of adoptive parents - may also be among the triggers for donor offspring to begin searching. The search may be complicated further when undertaken after accidental disclosure. Finally, it is argued that some donor offspring will experience a normative urge for identity completion and seeking relationships similar to that experienced by adopted people. This urge may stem from the fact that some donor offspring attach an identity to their donor that extends beyond needing factual details about their physical characteristics (though not necessarily a desire to establish a relationship). Some donor offspring are likely to encounter a desire for face-to-face contact, regardless of whether a face-to-face meeting was the original intention. The need for services to help donor offspring, donors, family members and others affected by the situation is identified.

Adoption↗

PubMed2004

DNA repair gene polymorphisms, pre-natal factors and the frequency of somatic mutations in the glycophorin-A gene among healthy newborns.

This study investigates variation in somatic mutation frequency, as measured by the glycophorin-A (GPA) somatic mutation assay, in relation to polymorphic variation among 435 newborn babies in DNA repair genes XRCC1, XRCC3 and XRCC4 and gender, parental age, social class and smoking habits. The three polymorphisms under investigation were an Arg --> Gln substitution at codon 399 in exon 10 of XRCC1, a Thr --> Met substitution at codon 241 in exon 7 of XRCC3 and an Ile --> Thr substitution at codon 401 in exon 4 of XRCC4. The study population is an extension of that previously analysed for GPA mutations and XRCC1 polymorphisms. A significant difference was seen in the earlier work in the genotype distribution for the XRCC1 Arg399Gln polymorphism between the main population and the small number with extreme values for NN variant frequency and this was maintained in the larger study group (OR 3.20 [95% CI: 1.16, 8.81]) P = 0.043). No such association was seen for XRCC3 or XRCC4 polymorphisms. When adjustments were made for multiple testing, neither N0 nor NN variant frequencies in the main study population were found to be influenced by the polymorphisms in XRCC1, XRCC3, or XRCC4. In addition, neither maternal or paternal smoking, age or social class nor the gender of the offspring were found to affect variant frequencies nor were variant frequencies influenced by any interaction between any of these factors and genotype. It is concluded that the genotypic variation in DNA repair genes examined in this study has no discernable effect on the genesis of the somatic mutations observed at birth.

DNA Repair↗

PubMed2007

Condition dependence of reproductive strategy and the benefits of polyandry in a viviparous lizard.

Species in which males do not contribute to reproduction beyond the provision of sperm offer good opportunities to study the potential genetic benefits that females can obtain from polyandry. Here, we report the results of a study examining the relationships between polyandry and components of female fitness in the common lizard (Lacerta vivipara). We found that polyandrous females produce larger clutches than monandrous females. Polyandrous females also lose fewer offspring during the later stages of gestation and at birth, but we did not find any relationship between polyandry and physical characteristics of viable neonates. Our results were consistent with the predictions of the intrinsic male quality hypothesis, while inbreeding avoidance and genetic incompatibility avoidance might also explain some part of the variation observed in clutch size. Moreover, the benefits of polyandry appeared to depend on female characteristics, as revealed by an interaction between reproductive strategy and female length on reproductive success. Thus, all females did not benefit equally from mating with multiple males, which could explain why polyandry and monandry coexist.

Analysis of Variance↗

PubMed1998

Parental occupational exposures and risk of childhood cancer.

Occupational exposures of parents might be related to cancer in their offspring. Forty-eight published studies on this topic have reported relative risks for over 1000 specific occupation/cancer combinations. Virtually all of the studies employed the case-control design. Occupations and exposures of fathers were investigated much more frequently than those of the mother. Information about parental occupations was derived through interviews or from birth certificates and other administrative records. Specific exposures were typically estimated by industrial hygienists or were self-reported. The studies have several limitations related to the quality of the exposure assessment, small numbers of exposed cases, multiple comparisons, and possible bias toward the reporting of positive results. Despite these limitations, they provide evidence that certain parental exposures may be harmful to children and deserve further study. The strongest evidence is for childhood leukemia and paternal exposure to solvents, paints, and employment in motor vehicle-related occupations; and childhood nervous system cancers and paternal exposure to paints. To more clearly evaluate the importance of these and other exposures in future investigations, we need improvements in four areas: a) more careful attention must be paid to maternal exposures; b) studies should employ more sophisticated exposure assessment techniques; c) careful attention must be paid to the postulated mechanism, timing, and route of exposure; and d) if postnatal exposures are evaluated, studies should provide evidence that the exposure is actually transferred from the workplace to the child's environment.

Brain Neoplasms↗

PubMed2004

Parental age, family size, and risk of multiple sclerosis.

BACKGROUND: Family structure, such as having siblings, provides proxy measures for a variety of characteristics relevant to disease risk. The etiology of multiple sclerosis (MS) is not well defined and analysis of family structure may provide etiologic clues. We conducted a case-control study to examine possible associations. METHODS: Using the Swedish Inpatient Register, we identified 4443 patients with a diagnosis of MS. From the general Swedish population, using birth and death registers, we selected 24,194 controls with similar characteristics for year, county of birth, and survival until at least age at diagnosis of the matched cases. The Multi-Generation Register linked data on siblings and parents. The Census provided father's social class based on occupation. RESULTS: Having 3 or more younger siblings, compared with none, produced an adjusted odds ratio (OR) for MS (with 95% confidence interval) of 0.80 (0.70-0.92) (adjusting for number of siblings, twins, maternal and paternal age, parental MS, sex, father's social class, county and year of birth). With 3 or more older siblings, the adjusted OR was 0.83 (0.72-0.96). Different-sex twin pairs compared with singletons had an OR of 0.59 (0.37-0.95) for MS. The risk of MS increased steadily with father's age but not mother's age, up to 2.00 (1.35-2.96) for 51- to 55-year-old fathers (compared with 21- to 25-year-old fathers). CONCLUSIONS: Parents who have offspring with MS may have subtly impaired fertility. The unexpected association with paternal age may be the result of an increased risk of accumulating germ cell mutations among older men.

Adult↗

PubMed2001

Maternal and neonatal outcomes in pregestational and gestational diabetes mellitus, and the influence of maternal obesity and weight gain: the DEPOSIT study. Diabetes Endocrine Pregnancy Outcome Study in Toronto.

We prospectively studied pregnancy outcome in 428 women with gestational diabetes mellitus (DM) and 196 women with pregestational DM, with particular reference to the influence of maternal obesity and excessive weight gain. These were consecutive singleton pregnancies delivered in our institution over 5 years. After controlling for multiple risk factors, including maternal BMI and pregnancy weight gain, women with pregestational DM were at increased risk (compared to those with gestational DM) for Caesarean delivery (OR 3.6, 95%CI 2.3-5.6), shoulder dystocia or cephalopelvic disproportion (OR 2.2, 95%CI 1.3-3.6), and gestational hypertension or toxaemia (OR 3.0, 95%CI 1.7-5.4). The offspring of these women were also at increased risk for admission to the neonatal intensive care unit (OR 4.0, 95%CI 2.3-6.8), large-for-gestational-age birthweight (OR 3.5, 95%CI 2.2-5.6), and preterm birth before 37 weeks (OR 3.8, 95%CI 2.5-5.9). Maternal obesity, and, to a lesser degree, excessive weight gain, were also independent risk factors for all these adverse maternal and neonatal outcomes, regardless of the type of DM, except for shoulder dystocia/cephalopelvic disproportion.

Adult↗

PubMed1987

Emory University Project on Children of Disturbed Parents.

Young children (from birth to 5 years of age) of schizophrenic, depressed, and well mothers were studied to assess their intellectual, social, and neuropsychiatric functioning. The sample derived from predominantly black, low-income, single-parent families. An extensive battery of laboratory and home-based tests was administered three times, each 1 year apart, to test the stability of findings. Schizophrenic offspring, as a group, had more problems than others. They showed more deficits on social competence, had lower IQ's (the youngest children only), and were overrepresented in the group of children with multiple negative indices. However, both schizophrenic offspring and depressive offspring sometimes performed more poorly than children with well mothers (presence of symptoms of psychiatric disorder and certain categories of social behavior). In certain instances, the children of depressed mothers were worse off than either other group (small for age and showing less social competence at home). Deficits were found in the child-rearing environment provided by the disturbed mothers. Both schizophrenic and depressed mothers were rated as less affectively involved and less responsive than well mothers. Schizophrenic mothers were rated as providing the poorest overall environment: less play stimulation, fewer learning experiences, and less emotional and verbal involvement. The following possible protective factors were identified in the mothers: lesser severity of illness, older age, higher education, higher IQ, work experience, and presence of spouse, boyfriend, or other relative to help in child care.

Child↗

PubMed1982

Birth weight and birth defects in relation to maternal spermicide use.

The possible effects of maternal spermicide use on birth characteristics of offspring were examined in two studies. First, birth weight of offspring was examined in a cohort study of 302 women who reported using spermicides and 716 women who used no contraceptive methods in the year prior to pregnancy resulting in a 1974 live birth (without a malformation) in Upstate New York. There was no evidence that spermicide use prior to the last menstrual period (LMP) had an effect on mean birth weight or on the proportion of lower weights. Mean birth weight of female births was significantly lower in post-LMP spermicide users than in pre-LMP-only spermicide users and no-contraceptive users. In multiple linear regression analyses of birth weight among births to spermicide users, including maternal smoking during pregnancy and other variables, time of discontinuation of spermicide use was an important predictor of female (but not male) birth weight. In the second (case-control) study of 715 Upstate New York births with selected birth defects and 715 control births (matched on maternal age and race), no significantly increased relative risks were associated with maternal spermicide use prior to LMP or after LMP. Based on small numbers, relative risks for post-LMP spermicide use were greater than 1.00 for hypospadias (8/2 or 4.00, not significant) and for limb reduction defects (6/3 or 2.00, not significant).

Abnormalities, Drug-Induced↗

PubMed1998

Pregnancy after bone marrow transplantation.

PURPOSE: To evaluate the occurrence of pregnancy after bone marrow transplantation (BMT). DESIGN: Medline literature review of reported pregnancies in the BMT population published in the English language. RESULTS: Multiple case reports and a few series studies showed more than 250 offspring from BMT recipients. CONCLUSION: BMT patients receive high-dose chemotherapy and often radiation, as well. These agents are associated with gonadal dysfunction and the fertility of patients after BMT is of concern because BMT patients are often young people who wish to resume a normal quality of life, which for many patients involves the desire to have children. Our experience with the successful pregnancy of one of our BMT patients led to the investigation of reported cases that showed numerous other births. The issue of counseling BMT patients about fertility, pregnancy complications, and potential birth defects is becoming increasingly complex and warrants further investigation.

Bone Marrow Transplantation↗

PubMed1975

Maternal malnutrition, low birthweight and related phenomena in man. Physiological and behavioral interactions.

The variables producing lowered birthweight include prematurity, maternal genetic tendencies, low prepregnancy weight, low weight gain during pregnancy, pathologies of pregnancy, multiple births, maternal malnutrition, and intrauterine growth retardation. Reductions in intelligence related to low birthweight are distributed equally among different socioeconomic groups. However, when mental subnormality is used as the criterion of impairment, low socioeconomic status is a better predictor of poor outcome than low birthweight. Even when general intelligence is not impaired, low birthweight children show specific cognitive, perceptual and behavioral signs of organic brain damage. In the absence of frank congenital abnormality, absolute birthweight is a better predictor of impaired intelligence than intrauterine growth retardation. Maternal malnutrition during the period of pregnancy does not influence offspring intelligence. Malnutrition throughout the maternal and offspring lifespan does impair intelligence, especially when surrounding social conditions are counterproductive to its development.

Animals↗

PubMed1998

No paternal effect on monozygotic twinning in the Swedish Twin Registry.

Previous research has provided evidence for a genetic effect in monozygotic twinning, indicated by an increased risk for monozygotic women to have monozygotic offspring. However, since the biological mechanism for this trait is unknown, it is not clear if there exists a paternal inheritance. In this study we investigated twin pregnancies in offspring born in 1941-1996 to male twins in the Swedish Twin Registry and population controls born in 1926-1980. In total 4,225,331 offspring, of which 89,286 were twins, were studied. There was neither an increase in the probability for monozygotic men to have like-sexed twin offspring risk ratio (RR = 0.95; 95% CI = 0.77-1.13) nor an increase in the estimated number of monozygotic twin births. Thus, there is no evidence for a paternal effect on monozygotic twinning, suggesting that the gene(s) increasing the liability for division of the embryo are expressed in the mother and not in the fertilised egg.

Cohort Studies↗

PubMed1978

3-Hydroxyxanthine: transplacental effects and ontogeny of related sulfate metabolism in rats and mice.

The ontogeny of sulfate metabolism related to the metabolic activation of the carcinogenic purine N-oxide 3-hydroxyxanthine (3-OH-X) was studied in noninbred Sprague-Dawley rats. Sulfotransferase activity toward 3-OH-X was detectable in most fetal livers near term at about 25% of adult values and increased slowly after birth. This activity was also present in placentas. Compared to 3-OH-X sulfotransferase, sulfotransferase activity toward p-nitrophenol was lower in fetal livers and was not detected in placentas. Sulfohydrolase activity toward 3'-phosphoadenosine-5'-phosphosulfate was higher in fetal and newborn livers and in placentas than in adult liver. In a parallel transplacential carcinogenicity assay, a low but significant percentage of male rats exposed as fetuses to multiple high doses of 3-OH-X developed single liver carcinomas. After the lowest transplacental dose, the incidence of degenerative kidney disease in old male offspring was significantly higher than that in controls. In an assay with mice, (C57BL/6 X BALB/c)F1 mice exposed transplacentally to 3-OH-X experienced significantly greater perinatal morality and fewer lung adenomas among the surviviors at 20 months of age than did the controls.

Animals↗

PubMed1983

Body weight changes throughout pregnancy in the common marmoset Callithrix jacchus.

Adult female common marmosets were weighed weekly for periods of 6-30 months. Of 27 animals, 25 were pregnant at some stage of the investigation. Patterns of body weight change throughout singleton, twin and triplet pregnancies were obtained and compared. Maternal weight increase was dependent on the number of young in utero; however, little or no change in weight was observed during the first 13 weeks of gestation, irrespective of the number of offspring delivered subsequently. The overall maternal:fetal body weight ratio was 1.00:0.21, ranging from 1.00:0.11 for singleton to 1.00:0.26 for triplet pregnancies. Lactation had little or no effect on maternal body weight during the first 4 weeks postpartum.

Animals↗

PubMed1980

Nitrogen retention during late gestation in the rat in response to marginal zinc intake.

This study was conducted to characterize nitrogen retention in response to marginal dietary zinc during gestation. Long-Evans rats were randomly assigned to one of two dietary groups on day 1 of gestation. The dams were fed a basal diet supplemented with either restricted or control levels of zinc. Feces and urine were collected for 24 h on day 20 of pregnancy, and their nitrogen and zinc contents were determined. Urinary and fecal nitrogen excretions were similar for zinc-restricted and control dams, whereas fecal zinc excretions were depressed by feeding the zinc-restricted diet. Mean zinc and nitrogen retentions were negative for the zinc-restricted and positive for the control groups. Multiple stepwise regression analysis showed that nitrogen retention on day 20 depended on both dietary nitrogen and zinc intakes. Zinc-restricted offspring weighed 12% less and the maternal plasma zinc concentrations were reduced by 66% when compared with the control group values on day 22. Marginal dietary zinc and the associated anorexia limited fetal growth without causing excessive nitrogen excretion or severe weight loss.

Animals↗

PubMed2005

Analysis of multiple data sets reveals no association between the insulin gene variable number tandem repeat element and polycystic ovary syndrome or related traits.

CONTEXT: Variation at the insulin gene VNTR (variable number tandem repeat) minisatellite has been reported to be associated with polycystic ovary syndrome (PCOS), but findings have been inconsistent and all studies have featured small sample sizes. OBJECTIVE: To gain a robust understanding of the role of the INS-VNTR in PCOS susceptibility. DESIGN: Case-control, family-based association and quantitative trait analyses. SETTING AND PARTICIPANTS: A UK population comprising 255 parent-offspring trios, 185 additional cases, and 1062 control subjects (cases and controls all British/Irish) as well as 1599 women from a northern Finland population-based birth cohort characterized for PCO symptomatology and testosterone levels. VNTR class was inferred from genotyping of the -23HphI variant. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): INS-VNTR genotype frequencies between subject groups, body mass index, and testosterone levels by genotype. RESULTS: Case-control analyses in both UK and Finnish samples failed to confirm previously reported class III allele associations with PCOS (UK, P = 0.43, Finnish, P = 0.31; Kruskal-Wallis chi2). Transmission analysis in trios showed no excess transmission of either allele (P = 0.62), regardless of parent of origin (maternal: P = 0.73; paternal: P = 0.66). No association between genotype and testosterone levels was seen in any sample (UK PCOS subjects, P = 0.95; Finnish symptomatic cases, P = 0.38; Finnish control women, P = 0.58). CONCLUSIONS: Despite the strong biological candidacy and supportive data from previous studies, we conclude that variation at the INS-VNTR has no major role in the development of PCOS.

Adult↗

PubMed2004

Prenatal glucocorticoids and long-term programming.

Epidemiological evidence suggests that low birth weight is associated with an increased risk of cardiovascular, metabolic and neuroendocrine disorders in adult life. Glucocorticoid administration during pregnancy reduces offspring birth weight and alters the maturation of the lung and other organs. We hypothesised that prenatal exposure to excess glucocorticoids or stress might represent a mechanism linking foetal growth with adult pathophysiology. In rats, birth weight is reduced following prenatal exposure to the synthetic steroid dexamethasone, which readily crosses the placenta, or to carbenoxolone, which inhibits 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the physiological feto-placental 'barrier' to maternal glucocorticoids. As adults, the offspring exhibit permanent hypertension, hyperglycaemic, increased hypothalamic-pituitary-adrenal (HPA) axis activity and behaviour reminiscent of anxiety. Physiological variations in placental 11beta-HSD2 activity correlate directly with foetal weight. In humans, 11beta-HSD2 gene mutations cause low birth weight. Moreover, low-birth-weight babies have higher plasma cortisol levels throughout adult life, indicating HPA axis programming. The molecular mechanisms may reflect permanent changes in the expression of specific transcription factors, key among which is the glucocorticoid receptor (GR) itself. The differential programming of the GR in different tissues reflects effects upon one or more of the multiple tissue-specific alternate first exons/promoters of the GR gene. Overall, the data suggest that both pharmacological and physiological exposure prenatally to excess glucocorticoids programmes cardiovascular, metabolic and neuroendocrine disorders in adult life.

Animals↗