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Further delineation of the clinical picture of trisomy for the distal segment of chromosome 13: report of three cases.

Three cases of partial trisomy for the distal segment of chromosome 13 are reported. Common clinical features included normal birth weight, postnatal asphyxia, convulsions, severe psychomotor retardation, normal growth, and a distinct pattern of dysmorphias consisting of trigonocephalic head with prominent metopic suture, long and markedly curved eyelashes, a stubby nose, increased distance between nose and upper lip, high-arched palate, misshapen ears with virtually absent lobules and prominent anthelices which are curved in a sharp angle, and hemangiomata. Features present in 2 cases were microcephaly, long and narrow fingers with convex nails, and hexadactyly. Two cousins were unbalanced offspring of a large family of carriers of a 9/13 translocation, whereas the third case exhibited a 13p+ chromosome which was formed de novo. The clinical features in the 3 patients are typical of the syndrome due to partial trisomy for the distal segment of chromosome 13 which shows selected and mitigated signs of full trisomy 13.

Abnormalities, Multiple↗

Fetal loss, twinning and birth weight after oral-contraceptive use.

To evaluate the effect of oral-contraceptive use on subsequent offspring, I reviewed information on the pregnancies of 19,887 women who indicated, in response to a mail questionnaire, that they had used oral contraceptives. The rates of spontaneous abortion and stillbirth were smaller for former users than for nonusers--a finding consistent with previous studies. Twinning was more frequent among births of infants conceived soon after cessation of oral contraceptives, the rate being approximately twice the expected value for women who had used oral contraceptives for more than six months (P = 0.1). The sex distribution of the twins indicated that the increase was mainly in dizygous twins (P = 0.02), in accordance with predictions about increased twinning after cessation of oral contraceptive use. No relation was evident between oral contraceptive use and birth weight.

Abortion, Spontaneous↗

Within birth cohort segregation analyses support recessive inheritance of body mass index in white and African-American families.

OBJECTIVE: We conducted segregation analyses of body mass index within birth cohort to determine whether previously reported support for recessive major gene inheritance in white and African-American families could have been due to higher rates of obesity in offspring than in parents, which are caused by temporal increases in obesity in recent decades. DESIGN: Segregation analysis of family data. MEASUREMENT: The body mass index (BMI), adjusted for effects of gender, linear and non-linear effects of age, education and occupation of head of household, and clinic from which family was ascertained. RESULTS: Segregation analysis results support a recessive mode of major gene inheritance of body mass index, even though we restricted our analysis to siblings born within the same post-1945 cohort. We also found support for substantial polygenic heritability of body mass index, which is consistent with a multigenic heritability. There was no significant heterogeneity between white and African-American families in support for a recessive mixed model. However, some differences in particular parameters were found, with higher gene frequency, lower polygenic heritability and a larger variance associated with the major gene model in African-Americans. CONCLUSION: Our present segregation analysis shows that the recessive pattern, whether due to single or multiple genes, cannot be explained by inter-generational differences in obesity prevalence or family correlation. There was suggestive evidence of a higher major gene frequency and larger gene effect size in African-American families.

Black People↗

Comparison of phenylketonuric and nonphenylketonuric sibs from untreated pregnancies in a mother with phenylketonuria.

Two children, one with phenylketonuria (PKU) and the other nonphenylketonuric, from untreated pregnancies in a mother with PKU provided the opportunity to compare the degree of damage from maternal PKU between these genotypically different fetuses. Both the phenylketonuric offspring and her nonphenylketonuric sib were microcephalic at birth and had congenital anomalies, esophageal atresia in the former and congenital dislocation of the hip in the latter. However, the phenylketonuric child also had intrauterine growth retardation while the nonphenylketonuric sib had normal weight and length at birth. Both children are mentally retarded with an IQ below 50 in the phenylketonuric child despite early dietary treatment for PKU and an IQ of 54 in the nonphenylketonuric sib. Both children also have hypoplasia of the corpus callosum and enlarged cerebral ventricles. This experience and review of the literature indicates that the residual liver phenylalanine hydroxylase activity of a nonphenylketonuric fetus offers little or no protection from damage in untreated maternal PKU. Consequently, the outcome in maternal PKU is likely to depend on control of the maternal biochemical abnormalities in the mother regardless of whether the fetus has or does not have PKU.

Abnormalities, Multiple↗

[Genetic risk after high dose radioiodine therapy with regard to gonadal dose].

AIM: The genetic risk for the offspring of patients treated with high doses of radioiodine was to be assessed with special regard to the gonadal dose caused by diagnostic and therapeutic procedures. METHODS: 41 young females (aged between 19 and 39 years) and four young males (aged 26 to 36 years) treated with radioiodine because of a thyroid carcinoma were interviewed by use of a questionnaire. The course of pregnancy and birth history could be documented as well as the congenital and developmental conditions of 56 children. RESULTS: The amount of radioactivity applied for therapy and whole body scans ranged over 4.144 and 35.15 GBq 1-131; the individual gonadal dose was calculated based on the MIRD model and ranged over 0.2 and 2.2 Sv (0.51 Sv at a mean). The period of time between the last radioiodine application and confinement was at least 9 months, not exceeding 14 years. As to the course of pregnancy and birth two early abortions, one extrauterine gravidity and one premature birth due to an insufficiency of the placenta were stated. In one case a chromosomal translocation 7/14 occurred as a genetic defect which lead to an interruption. The children's development was unconspicuous except of two cases of neurodermatitis as well as multiple allergies and an early closure of the anterior fontanelle in one child each. CONCLUSION: Although the genetic risk is supposed to increase with the gonadal dose achieved (doubling dose 1 Sv) and the increased risk of any congenital anomaly was calculated as about 13% at a mean in our patients, the rate of genetic determined diseases was not elevated (1.8% or 1/57). Thus, no increase of genetic defects or congenital malformations was reported in a total of 408 children described in the literature and in our group.

Abortion, Spontaneous↗

Risk estimates for balanced reciprocal translocation carriers--prenatal diagnosis experience.

An analysis was performed on 40 families at risk for an unbalanced rearrangement in the fetus because one of the parents is a reciprocal translocation carrier. The overall risk at second trimester prenatal diagnosis was 14% (8/57). The individual risk for unbalanced offspring at second trimester prenatal diagnoses and at birth were estimated using empirical data by Stengel-Rutkowski et al. (1988). The risks at birth ranged from 0%-21.6%. Most reciprocal translocations (22 or 55%) were at low risk. Without risk (7 or 17.5%), medium risk (6 or 15%) and high risk (5 or 12.5%) translocations were about equally represented and relatively infrequent. The analysis shows that the mode of ascertainment as well as the measurement of lengths of observed or probable imbalances cannot serve as a reliable risk predictor in individual counselling. In the translocations ascertained through spontaneous abortions the risk is frequently small or nonexistent, but remarkable exceptions to this rule are observed. Translocations discovered through unbalanced offspring were found to belong to different risk groups with the exception of the no risk group. Individual risk estimates have to be performed as a basis of genetic counselling before or during pregnancy so that parents with reciprocal translocations can make their choices regarding the available options.

Abnormalities, Multiple↗

Effect of high maternal blood phenylalanine on offspring congenital anomalies and developmental outcome at ages 4 and 6 years: the importance of strict dietary control preconception and throughout pregnancy.

OBJECTIVES: The Maternal Phenylketonuria Study was designed to determine the effect of a phenylalanine (Phe)-restricted diet in reducing the morbidity on the fetus. Congenital abnormalities were noted, with the focus on the effect of congenital heart defects (CHDs) and microcephaly (MICRO) on developmental outcome at 4 and 6 years of age. STUDY DESIGN: Women with blood Phe levels >240 micromol/L (n=526; to convert micromol/L to mg/dL, divide by 60) were enrolled; 382 contributed 572 pregnancies. The women had 413 offspring examined at birth and annually. At 4 years, the McCarthy General Cognitive Index was administered, and at 6 years, the Wechsler Intelligence Scale for Children Revised was administered. RESULTS: Microcephaly was noted in 137 (33%) of the offspring, and 32 (7.7%) had CHD. Maternal blood Phe levels were higher for infants with CHD and MICRO than for infants with CHD only (P=.02). Mean Phe levels at 4 to 8 weeks gestation predicted CHD (P<.0001). The McCarthy General Cognitive Index score was lower with CHD (P=.005) and MICRO (P=.0017), as was the Wechsler Intelligence Scale for Children Revised full-scale IQ score (P=.0002 for CHD and P=.0001 for MICRO). None of the subjects who had offspring with CHD had Phe control between 120 and 360 micromol/L during the first 8 to 10 weeks of gestation. CONCLUSIONS: Women with phenylketonuria need to be educated regarding diet for life. This should help improve diet control before conception and throughout pregnancy.

Abnormalities, Multiple↗

In-utero and early life exposures in relation to risk of breast cancer.

OBJECTIVES: In response to a hypothesis by Trichopoulos that risk of adult breast cancer is related to high estrogen exposure in utero, studies have been undertaken using proxy indicators of prenatal estrogens. The epidemiologic studies addressing these early factors will be reviewed, consistency with proposed biologic mechanisms will be addressed and recommendations for future research will be presented. METHODS: All studies identified in the literature addressing these in utero and early life factors related to adult breast cancer will be included in the review. The study results will be summarized by risk factor, followed by commentary on the findings. RESULTS: Review of epidemiologic studies suggests strong risks related to having been born of a twin pregnancy and reduced risks from a preeclamptic or eclamptic pregnancy. Birthweights greater than 4,000 grams have been associated with relative risks of 1.5-1.7 for breast cancer compared with normal birthweights (2,500-2,999 grams). Having been breastfed as an infant has been associated with a 20-35% reduction in risk of premenopausal breast cancer in four of six studies evaluating this factor. Some studies suggest an influence of older maternal age, perhaps only for firstborn offspring, but the data are not consistent. Smoking during the pregnancy does not seem to impart any risk for the daughter, severe nausea for two or three trimesters may be related to increased risk, and results are inconsistent for birth length, placental weight and gestational age. CONCLUSION: Although the results from epidemiologic studies assessing prenatal exposures are consistent with the hypothesis concerning estrogen exposure, the specific biologic mechanisms remain largely unknown. Relatively few epidemiologic studies have been published addressing these novel hypotheses; more studies with innovative research methods and analytic approaches are warranted to evaluate these exposures in the distant past.

Adult↗

Survival of triplets who are born to teen mothers in the United States.

OBJECTIVE: The purposes of this study were to assess survival among triplets who are born to teen mothers and to determine whether fetal number influences the mortality rates of the offspring of teen mothers when compared with the offspring of older women. STUDY DESIGN: A retrospective cohort study of 354 triplet births to teenage mothers and 6858 to young mature mothers (20-29 years) who were delivered from 1995 through 1998. We compared the occurrence of stillbirth and neonatal and infant mortality rates between the 2 categories by means of the generalized estimating equation. Similar analyses were conducted for singleton pregnancies and twin pregnancies. RESULTS: Triplets of teenage mothers experienced a higher level of stillbirth (odds ratio, 3.24; 95% CI, 1.44-7.24), neonatal mortality (odds ratio, 2.00; 95% CI, 1.11-3.61), and infant death (odds ratio, 1.66; 95% CI, 1.01-2.87). Moreover, as the plurality increased from singleton infant to triplet, the offspring of teenagers fared progressively worse ( P < .0001). CONCLUSION: This study confirms the association between teenage motherhood and feto-infant death and indicates that this mortality relationship varies in a dose-dependent fashion.

Adolescent↗

Limb anomalies following chorionic villus sampling: a registry based case-control study.

Using data from the Italian Multicentric Birth Defect Registry a case-control study was performed to verify if chorionic villus sampling (CVS) was associated with transverse limb defects (TLD), with or without features of oro-mandibular-limb hypogenesis complex (OMLHC), in the exposed offspring. The results show that the risk of TLD and OMLHC is increased following CVS, and is particularly high for CVS performed early in pregnancy, i.e., under 70 days of gestational age. These results, together with a review of other epidemiologic studies, biological data and clinical reports, strongly suggest a causative role of CVS as a risk factor for TLD and indicate that at this stage CVS before 70 days of gestational age should be discouraged as an option for prenatal diagnosis and that all patients wishing to undergo CVS should be informed about the possible risk of the procedure.

Abnormalities, Multiple↗

Prenatal phenytoin exposure and spatial navigation in offspring: effects on reference and working memory and on discrimination learning.

Previous research has shown that rats exposed to phenytoin (PHT) in utero demonstrate abnormal circling, decreased learning, hyperactivity, and delayed air righting reflex development. The effects of prenatal PHT on offspring learning have been found on multiple-T mazes (Biel and Cincinnati types) and on spatial navigation (Morris maze). However, the specificity of the latter effects is unknown. Herein, we tested the effects of prenatal PHT in a Morris maze using six different procedures: cued versus spatial reference memory-based learning, cued versus spatial working memory-based learning, and cued versus spatial discrimination learning. PHT-exposed offspring showed increased preweaning mortality, growth reduction, and abnormal circling as noted in previous studies. PHT offspring were separated into those exhibiting circling and those not. PHT noncircling offspring demonstrated impaired reference memory-based spatial learning (acquisition and reversal), but no other effects. By contrast, PHT circling offspring demonstrated not only impaired reference memory-based spatial learning, but also impaired cued platform learning, impaired spatial discrimination, and impaired working memory-based learning. These data confirm that prenatal PHT induces a specific reference memory-based spatial learning deficit even in asymptomatic (noncircling) offspring that is distinct from the impairment induced in littermates exhibiting the circling impairment.

Analysis of Variance↗

High rate of twins among offspring of mothers with the Järvi-Hakola-Nasu disease and with comments on disorders associated with twinning.

Finnish mothers with Jrvi-Hakola-Nasu disease, progressive dementia with lipomembranous polycystic osteodysplasia (McKusick 221770) have a high rate of twin maternities, 128.2/1000. The exact 99% confidence intervals are 28.7-322.2/1000, thus above the average twinning rate in Finland, i.e. 15/1000. This eightfold increase in twinning may be an indication of a disturbed cortico-hypothalmic-hypophyseal axis or an other premorbid hormonal imbalance. It is concluded that even if dizygotic twinning is as a rule an event in itself, not only iatrogenic factors, as ovulation inducers, etc., but also some genetic disorders may be associated with twinning. More studies are needed to elucidate the incidence of twinning in families with these disorders.

Birth Rate↗

The prevention of diabetes-associated birth defects.

Birth defects among infants of diabetic mothers convey a major financial and sociologic burden to society notwithstanding the psychologic impact to the patients and families. Epidemiologic, clinical, and experimental studies indicate that these malformations occur in early pregnancy, are influenced by the abnormal maternal metabolic milieu, and seem to result from a combination of more than one factor. Clinical and experimental studies, however, have demonstrated that optimal metabolic control achieved in the periconceptual period and maintained throughout the first trimester of pregnancy results in a significant reduction in the malformation rate among offspring of diabetic mothers. In this light, diabetic women contemplating pregnancy should be encouraged to delay conception until satisfactory metabolic control is achieved so that embryogenesis may occur in an optimal metabolic milieu. The experimental use of arachidonic acid in the prevention of diabetes-related embryopathy is a new and potentially valuable tool. It extends the spectrum of available methods for prevention and deserves further study as a potential agent for pharmacologic prophylaxis.

Abnormalities, Multiple↗

Follow-up of women with large-for-dates infants. Early insulin and C-peptide response to intravenous glucose, blood lipids and HLA-types.

In a previous study we determined the glucose disappearance rate (kt) in 129 newborn large-for-dates infants (LFD) born to mothers without known diabetes. Twenty-six infants (i.e. 20.6%) had elevated kt values similar to those in offspring of diabetic mothers. A follow-up study of 123 of these mothers was performed 7 years after delivery and included determination of early insulin and C-peptide response to intravenous glucose, plasma concentrations of 3-hydroxybutyrate, cholesterol, triglycerides, lipoproteins and HLA-typing. Two subjects had developed diabetes and altogether 14% had a kt below 1.0. Measures of the early insulin and C-peptide response to glucose were equally well correlated to maternal kt values (r = 0.40, P less than 0.001). Measures of the early insulin and C-peptide responses were significantly correlated (r = 0.64, P less than 0.001). The frequency distribution of HLA antigens were not different from normal and there was no association between HLA-B8 or B15 and impaired insulin response or glucose tolerance. Multiple regression and discriminate analysis of clinical and biochemical variables could not accurately identify women with high or low kt values. Multiple regression analysis using infant kt value as the dependent variable disclosed only a weak, but significant, inverse association to maternal insulin response to glucose at follow-up.

Adult↗

Unifying evolutionary dynamics: from individual stochastic processes to macroscopic models.

A distinctive signature of living systems is Darwinian evolution, that is, a propensity to generate as well as self-select individual diversity. To capture this essential feature of life while describing the dynamics of populations, mathematical models must be rooted in the microscopic, stochastic description of discrete individuals characterized by one or several adaptive traits and interacting with each other. The simplest models assume asexual reproduction and haploid genetics: an offspring usually inherits the trait values of her progenitor, except when a mutation causes the offspring to take a mutation step to new trait values; selection follows from ecological interactions among individuals. Here we present a rigorous construction of the microscopic population process that captures the probabilistic dynamics over continuous time of birth, mutation, and death, as influenced by the trait values of each individual, and interactions between individuals. A by-product of this formal construction is a general algorithm for efficient numerical simulation of the individual-level model. Once the microscopic process is in place, we derive different macroscopic models of adaptive evolution. These models differ in the renormalization they assume, i.e. in the limits taken, in specific orders, on population size, mutation rate, mutation step, while rescaling time accordingly. The macroscopic models also differ in their mathematical nature: deterministic, in the form of ordinary, integro-, or partial differential equations, or probabilistic, like stochastic partial differential equations or superprocesses. These models include extensions of Kimura's equation (and of its approximation for small mutation effects) to frequency- and density-dependent selection. A novel class of macroscopic models obtains when assuming that individual birth and death occur on a short timescale compared with the timescale of typical population growth. On a timescale of very rare mutations, we establish rigorously the models of "trait substitution sequences" and their approximation known as the "canonical equation of adaptive dynamics". We extend these models to account for mutation bias and random drift between multiple evolutionary attractors. The renormalization approach used in this study also opens promising avenues to study and predict patterns of life-history allometries, thereby bridging individual physiology, genetic variation, and ecological interactions in a common evolutionary framework.

Algorithms↗

BMP7 null mutation in mice: developmental defects in skeleton, kidney, and eye.

While generating bcl2 alpha transgenic mice, we found some F2 offspring of one of the transgenic lines which were very small and had closed eyes at the time of weaning. These pups died within 1 month after birth. In order to determine the molecular basis of this phenotype, we screened a genomic library of the above transgenic line with a transgene-specific probe and found that the Bmp7 gene, a member of the TGF beta superfamily, was inactivated by insertional mutagenesis due to transgene integration. The Bmp7 homozygous null condition in mice is a postnatal lethal mutation and is associated with various developmental defects: holes in the basisphenoid bone and the xyphoid cartilage, retarded ossification of bones, fused ribs and vertebrae, underdeveloped neural arches of the lumbar and sacral vertebrae, polydactyly of the hind limbs, a kinked tail, a reduced number of nephrons, polycystic kidney, lack of retinal pigmentation, and retarded lens development. These findings indicate that BMP7 is an important signaling molecule for normal development of the mammalian skeleton, kidney, and eye. Academic Press

Abnormalities, Multiple↗

Ultrasonic vocalizations as diagnostic tools in studies of developmental toxicity: an investigation of the effects of prenatal treatment with methylmercuric chloride.

Ultrasonic vocalizations were recorded during two tasks from four groups of neonatal CD rat pups. Groups 0, 2, 4 and 6 were the offspring from pregnant dams treated with 0, 2, 4 or 6 mg/kg methylmercuric chloride by gavage on gestation day 7. On the day of birth, Day 1, litters were randomly culled to 8 pups (4 males, 4 females). The pups were weighed on Days 1, 7, 14, 21 and 30, and no weight differences due to treatment were observed. At 5, 7, 9 and 11 days of age, ultrasonic vocalizations were recorded from the animals for 1 minute. Individual animals were placed in a small test chamber containing either soiled home cage bedding or clean bedding material. Half of the pups in each litter were tested in each "odor" condition, and the rate and duration of the vocalizations were measured for 1 minute. On days 8 and 9, pups were tested on a negative geotaxis incline during which time vocalizations were recorded. In both the "odor" and negative geotaxis tests, methylmercuric chloride affected vocalization rates in a nonlinear dose-response fashion. Regardless of treatment group, the pups vocalized at a higher rate and for a longer duration in the clean than in the soiled bedding test condition. These data showed the variability of the ultrasonic vocalization responses to be smallest for the animals tested at 11 days of age in the clean bedding condition. The results of this study suggest that the value of ultrasonic calls as dependent measures of toxicity may be strengthened by the use of multiple stimulus conditions in order to elicit a graded response pattern. This would facilitate the interpretation of potential nonlinear dose-response effects.

Age Factors↗

Maternal behavior toward premature twins: implications for development.

Assisted reproductive techniques and fertility enhancing therapies have increased multiple births and, therefore, the risk of prematurity and its developmental consequences. Parent intervention is an effective source of compensation for the cognitive effects of prematurity. We hypothesized that relative to parents of preterm singletons, parents of preterm twins are less able to provide such enhancing care, resulting in a developmental disadvantage for preterm twins. Maternal-infant interactions of premature singletons (n = 22; birth weight = 1668 +/- 350 g, gestational age = 32.3 +/- 2.1 weeks) and premature twins (n = 8; birth weight = 1618 +/- 249 g; gestational age = 32.0 +/- 2.6 weeks) with comparable demographic and medical status were observed at home at 1 and 8 months corrected age using a 30 min checklist of developmentally facilitative behavior. Mental (MDI) and psychomotor (PDI) indices of the Bayley Scales of Infant Development and Caldwell Home Observations for Measurement of the Environment (HOME) inventories were administered (18 months corrected age). Compared with mothers of premature singletons, mothers of premature twins exhibited fewer initiatives (P < 0.001) and responses (P < 0.01) and were less responsive to positive signals (P < 0.01) and crying (P < 0.01). Unprompted by the infant, twin mothers lifted or held (P < 0.05), touched (P < 0.01), patted (P < 0.05) or talked (P < 0.01) less. Singleton MDIs surpassed twins (119.4 +/- 7.7 vs 103.6 +/- 7.7; P < 0.01). Maternal verbal behavior and the acceptance of child factor (HOME), both favoring singletons, correlated with MDI (R-square = 0.46, P < 0.0002). Mothers of premature twins exhibited fewer initiatives and responses toward offspring than did mothers of premature singletons. Maternal behavior was predictive of cognitive development.

Adult↗