Trisomic Pregnancies Research Articles

Chromosomal drive and the evolution of meiotic nondisjunction and trisomy in humans.

Trisomy is a genetic abnormality of considerable medical importance. The most familiar example is trisomy 21, which causes Down Syndrome [Cummings, M. R. (1988) Human Heredity: Principles and Issues (West Publishing Company, New York)]. In a classic paper, Axelrod and Hamilton [Axelrod, R. & Hamilton, W. D. (1981) Science 211, 1390-1396] offered a chromosomal drive (CD) hypothesis based on the game iterated prisoner's dilemma (IPD) to explain the evolution of an increased frequency of trisomic pregnancies with maternal age. In this paper we explore this hypothesis and its predictions in detail. On closer examination we find that IPD does not provide an adequate model for the CD hypothesis. Therefore, we develop a more suitable model and explore the conditions necessary for it to explain maternal age-dependent trisomy. Our results demonstrate that a relationship between the decay of a female's reproductive potential and chromosomal drive must exist for the CD hypothesis to work. With appropriate parameter values, a comparison of model predictions with empirical estimates for the age-dependence of trisomy reveals a striking correspondence. We point out a close correspondence between other predictions made by the CD hypothesis and empirical observations, as well.

Recurrence risk of a serious, noninherited chromosomal abnormality

Objective: To investigate the recurrence risk of a serious, noninherited chromosomal abnormality. Design: Prospective and retrospective analysis. Setting: University-based prenatal diagnosis clinic. Patient(s): Data on 240 pregnancies in 165 couples after a pregnancy with a serious chromosomal abnormality. Result(s): Autosomic trisomic pregnancy had occurred in 133 families. In these families, there were 193 new pregnancies, 132 in women under 35 years and 61 in women over 35 years. The recurrence rate was 2.3% in the women under 35 years and 8.2% in the women over 35 years. Pregnancy had occurred in 18 families with a sex-chromosomal abnormality. In these families, there were 24 new pregnancies, 21 in women under 35 years and 3 in women over 35 years. All pregnancies were chromosomally normal. Some other serious chromosomal abnormality had occurred in 14 families. In these families, there were 23 new pregnancies. Chromosomal abnormality recurred in two families: in a woman under 35 years and in a woman over 35 years. Conclusion(s): The high recurrence rate of chromosomal abnormalities even in women under 35 years warrants fetal chromosomal investigation in new pregnancies.

The maternal insulin-like growth factor (IGF) and IGF-binding protein response to trisomic pregnancy during the first trimester: a possible diagnostic tool for trisomy 18 pregnancies.

Many lines of evidence point to an important role for the insulin-like growth factors (IGFs) in embryonic and fetal growth in human pregnancy. The bioavailability of IGFs is modulated by IGF-binding proteins (IGFBP-1 to -6), whose permissive or inhibitory actions are regulated in part by posttranslational modification. In second and third trimester pregnancies, maternal IGFBP-1 is elevated in preeclampsia and intrauterine growth retardation. In the first trimester, trisomic pregnancies result in derangement of maternal serum levels of peptides, including hCG beta and pregnancy-associated plasma protein A. Trisomy 18 is characterized by growth failure in the first trimester, whereas trisomy 21 is not; thus, if maternal serum levels of IGFs and IGFBPs reflect fetal growth, changes specific to trisomy 18 may be expected. We report maternal serum levels of IGF-I, IGF-II, and IGFBP-1,-2, and -3; IGFBP-1 phosphorylation; and IGFBP-3 proteolysis in pregnancies (n = 139) complicated by trisomy 18 or trisomy 21 compared with those in normal controls. Maternal IGF-I, IGF-II, and IGFBP-3 showed no significant difference between fetuses with a normal karyotype and those with trisomy 18 or 21. The mean IGFBP-1 level was significantly higher and the mean IGFBP-2 level was lower in fetuses with trisomy 18 compared with normal fetuses [108.8 +/- 6.1 vs. 36.7 +/- 1.9 micrograms/L (P = 0.0001) and 81.2 +/- 5.5 vs. 206.1 +/- 10.2 micrograms/L (P = 0.0001), respectively]. There was no significant difference between the trisomy 21 and normal groups. The reduction in IGFBP-2 was confirmed by Western ligand and immunoblotting, and there was no evidence of variation in lower mol wt products to suggest differential proteolysis. IGFBP-1 phosphoforms and IGFBP-3 proteolysis were not significantly different between groups. The finding of altered maternal serum levels of IGFBP-1 and IGFBP-2 specific to pregnancies complicated by trisomy 18 suggests that these binding proteins may be important mediators of fetal growth in the first trimester, and the clear differences in the ratio of IGFBP-1 to -2 may serve as an additional diagnostic marker for trisomy 18 pregnancies.

The Maternal Insulin-Like Growth Factor (IGF) and IGF-Binding Protein Response to Trisomic Pregnancy during the First Trimester: A Possible Diagnostic Tool for Trisomy 18 Pregnancies

The Maternal Insulin-Like Growth Factor (IGF) and IGF-Binding Protein Response to Trisomic Pregnancy during the First Trimester: A Possible Diagnostic Tool for Trisomy 18 Pregnancies

Fetal hepatic alpha-fetoprotein mRNA expression in fetuses with trisomy 21 and 18 at 12-15 weeks gestation.

In this study we examined alpha-fetoprotein (AFP) mRNA expression in fetal liver at 12-15 weeks of gestation in trisomy 21 (n = 13), trisomy 18 (n = 5) and control fetuses (n = 24). No significant difference was found in the steady-state level of fetal liver AFP mRNA levels in either of the two trisomy groups studied. These findings suggest that the decrease in maternal serum AFP concentration found in trisomic pregnancies is unlikely to be the consequence of impaired transcription of the AFP gene by the fetal liver.

Gene expression of human pregnancy-associated plasma protein-A in placenta from trisomic pregnancies

Placental pregnancy-associated plasma protein-A (PAPP-A) mRNA expression, placental PAPP-A protein concentration and maternal serum levels of PAPP-A were examined in pregnancies affected by trisomy 21 (n=8), trisomy 18 (n=7) and 15 normal controls at 12-15 weeks of gestation. The maternal serum concentration of PAPP-A in the trisomic group of pregnancies was significantly lower than in the normal controls. However there were no significant differences between the three groups in PAPP-A mRNA expression or PAPP-A protein concentration in the placental tissues. There was no significant association between the level of placental mRNA and either placental protein or maternal serum PAPP-A concentrations in the normal or trisomic pregnancies. There was however a significant association between placental protein and maternal serum PAPP-A concentrations in the normal and trisomy 21 pregnancies but not in those affected by trisomy 18. These findings suggest that the decrease in maternal serum PAPP-A in trisomic pregnancies is due to alternations in post-translational events such as protein stability, alterations in the release mechanism of the protein, impaired protein transport across the placenta or modified serum stability of PAPP-A.

Placental mRNA expression of pregnancy-associated plasma protein a (PAPP-A) in trisomic pregnancies

Placental mRNA expression of pregnancy-associated plasma protein a (PAPP-A) in trisomic pregnancies

A prenatal trisomy 21 screening program using α-fetoprotein, human chorionic gonadotropin, and free estriol assays on maternal dried blood

OBJECTIVE: The feasibility of large-scale Down syndrome maternal screening with dried blood samples and nonradioactive methods was examined. STUDY DESIGN: A prospective observation study was performed on a nonselected population of 11,241 pregnant women sampled between January 1991 and September 1992, between 14 and 24 weeks' gestation (ultrasonographic scanning available for 91.6%), through a multicenter collaborative network. Enzyme-linked immunosorbent assays for α-fetoprotein, human chorionic gonadotropin, and free estriol were performed on dried blood samples. Risk determination was made with an in-house software implementing the multivariate gaussian log likelihood method. RESULTS: A total of 10,450 samples were eligible for the study. Mean age at term was 27.9 years. A total of 6.84% of the patients were ≥35 years old with a prior risk of trisomy 21 > 1:350. The general positive rate of our sample ws 8.15%. After calculation 31.7% with prior risk >1:350 were still in the high-risk group; 6.36% of the low-risk group were found to be at high risk for Down syndrome. Fifteen trisomic pregnancies were observed, of which 11 had a calculated risk higher than the selected cutoff value (1:350). The overall detection rate was 73%, specificity was 92%, and positive predictive power was 1.2%. CONCLUSION: Our pilot study has shown performances within the range of conventional serum screening programs. Dried blood assays are a handy alternative to serum assays. Blot paper cards represent a simple method of sampling, well fitted for large population screening. Combined with nonradioactive methods, this method appears to be both low cost and effective. The current work apparently is the first large-scale Down screening program performed with dried blood.

Trisomy and age at menopause: predicted associations given a link with rate of oocyte atresia.

The association of trisomy with advancing maternal chronological age suggests that some aspect of physiological aging is accelerated in women with trisomic pregnancies. This paper develops a quantitative theoretical model based on the hypothesis that trisomy risk is primarily a function of the size of the oocyte pool and, in particular, that risk is increased in women with accelerated rates of oocyte atresia and hence smaller pools at given chronological ages. Since the rate of oocyte atresia is a determinant of age at menopause, this hypothesis leads to the prediction that women who have had trisomic pregnancies reach menopause earlier than women who have not. We used data relating chronological age to oocyte number, trisomy and menopause to deduce the distribution of oocyte atresia rates in all women and in women with trisomic pregnancies. Given certain simplifying assumptions, we predict that associations between trisomy and age at menopause will vary with a woman's age at the time of trisomy such that trisomies at 34-43 years will be associated with a 1-3.4 year earlier onset of menopause, while trisomies at younger or older ages will have no or little association with age at menopause. This model, while vulnerable to the uncertainties that attend its assumptions, provides a testable prediction that permits separation of one aspect of physiological age from chronological age.

Trisomic pregnancies have normal human chorionic gonadotropin bioactivity

Sera from women carrying either chromosomally normal or aneuploid fetuses in the first half of pregnancy were assayed for human chorionic gonadotropin (hCG) bioactivity in order to determine whether differences might provide the basis for a useful antenatal screen for aneuploidy. A mouse uterine weight assay was used to assess hCG bioactivity in sera from 35 patients undergoing chorionic villus sampling (12 normal pregnancies and 23 trisomic pregnancies) and in sera from 18 patients undergoing elective second-trimester abortion (12 presumed normal pregnancies, 3 trisomic pregnancies, and 3 pregnancies with neural tube defects). The hCG bioactivity to immunoactivity (B:I) ratio of normal pregnancies progressively decreased from 7.7 +/- 1.3 at 4-5 menstrual weeks, to 4.7 +/- 0.4 at 9-12 menstrual weeks, to 3.3 +/- 0.5 at 16-20 menstrual weeks. There were no significant differences in the B:I ratios between normal and aneuploid pregnancies in either the first-trimester (4.7 +/- 0.4 versus 5.2 +/- 0.3) or the second-trimester samples (3.3 +/- 0.5 versus 2.6 +/- 0.3), despite significantly greater hCG concentrations in the trisomic pregnancies. We conclude that while aneuploid pregnancies display dysfunctional regulation of hCG expression, the bioactivity of their hCG is normal and does not appear to form the basis for a useful screen for aneuploidy.