Ann Kinney

Trisomic Pregnancy and Earlier Age at Menopause

We tested the hypothesis that the connection between advanced maternal age and autosomal trisomy reflects the diminution of the oocyte pool with age. Because menopause occurs when the number of oocytes falls below some threshold, our hypothesis is that menopause occurs at an earlier age among women with trisomic pregnancies than it does among women with chromosomally normal pregnancies. To determine their menstrual status, we interviewed women from our previous study of karyotyped spontaneous abortions who, in 1993, were age >/=44 years. Premenopausal women completed interviews every 4-5 mo, until menopause or until the study ended in 1997. The primary analyses compare 111 women whose index pregnancy was a trisomic spontaneous abortion with two groups: women whose index pregnancy was a chromosomally normal loss (n=157) and women whose index pregnancy was a chromosomally normal birth (n=226). We used a parametric logistic survival analysis to compare median ages at menopause. The estimated median age at menopause was 0.96 years earlier (95% confidence interval -0.18 to 2.10) among women with trisomic losses than it was among women with chromosomally normal losses and chromosomally normal births combined. Results were unaltered by adjustment for education, ethnicity, and cigarette smoking. Our results support the hypothesis that trisomy risk is increased with decreased numbers of oocytes. Decreased numbers may indicate accelerated oocyte atresia or fewer oocytes formed during fetal development.

Chromosomal differences in susceptibility to meiotic aneuploidy

A basic question concerning the origins of germ cell aneuploidy is whether the same mechanisms operate for all chromosomes, or whether there are chromosome‐specific factors influencing the susceptibility to nondisjunction. Although selective loss of some trisomies in early gestation may contribute to the observed differences in trisomy frequency, data from spontaneous abortions, early embryos and gametes strongly suggest that there are real differences in the frequency with which different trisomies arise. In particular the preponderance of trisomy 16 and acrocentric trisomy appears to be present at conception. Maternal and paternal age relationships also differ among trisomies, as do the extent of maternal and paternal contributions, and the relative frequency of meiosis I and meiosis II errors. Recombination patterns associated with nondisjunction also show chromosomal differences. Chromosomal differences in length, centromere position, pericentromeric and other repetitive sequences, recombination patterns and chromatin characteristics might all be related to a differential susceptibility to aneuploidy, but no current explanation accounts for the excess of maternally derived trisomy 16. The existence of chromosome‐specific factors makes extrapolation from observations on one chromosome to all aneuploidy unwise, both for investigations into the causes of aneuploidy, and for surveillance of aneuploidy frequency.

Caffeine And Spontaneous Abortion Of Known Karyotype

We tested associations of caffeine from beverages with spontaneous abortions of known karyotype. Spontaneous abortions (cases) were classified as chromosomally normal (n = 510) or chromosomally aberrant (n = 389) and, within the latter category, by type of aberration (237 trisomies, 54 monosomies X, 49 triploidies, 49 others). Controls registered for prenatal care before 22 weeks gestation and delivered at 28 weeks or later (n = 1,423). Caffeine intake in the perifertilization period did not differ among case groups and controls. For the highest category, 225+ mg/day, odds ratios (OR), adjusted for payment group and maternal age, were 1.0 for chromosomally normal cases, 0.9 for trisomies, 1.6 for monosomies X, and 0.8 for triploidies. Caffeine intake during pregnancy was tested for associations with chromosomally normal loss using the chromosomally aberrant cases to provide a robust comparison group. Although the proportion of subjects with intake of 225+ mg/day of caffeine was higher in cases than in controls, it was similar for those with chromosomally normal and aberrant losses (OR = 1.2). We infer that caffeine intake in the perifertilization period does not influence the risk of chromosomally normal loss or trisomy. For monosomy X and triploidy, no strong associations were observed, but numbers were insufficient to rule out moderate effects. For caffeine intake during pregnancy, we found little evidence to support an influence on chromosomally normal loss.

Trisomic pregnancy and elevated FSH: implications for the oocyte pool hypothesis

BACKGROUND Some studies, but not all, support the hypothesis that trisomy frequency is related to the size of the oocyte pool, with the risk increased for women with fewer oocytes (older ovarian age). We tested this hypothesis by comparing hormonal indicators of ovarian age among women who had trisomic pregnancy losses with indicators among women with non-trisomic losses or chromosomally normal births. The three primary indicators of advanced ovarian age were low level of anti-Müllerian hormone (AMH), high level of follicle-stimulating hormone (FSH) and low level of inhibin B. METHODS The analysis drew on data from two hospital-based case-control studies. Data were analyzed separately and the evidence from the two sites was combined. We compared 159 women with trisomic pregnancy losses to three comparison groups: 60 women with other chromosomally abnormal losses, 79 women with chromosomally normal losses and 344 women with live births (LBs) age-matched to women with losses. We analyzed the hormone measures as continuous and as categorical variables. All analyses adjust for age in single years, day of blood draw, interval in storage and site. RESULTS AMH and inhibin B did not differ between women with trisomic losses and any of the three comparison groups. Mean ln(FSH) was 0.137 units (95% confidence interval (CI): 0.055, 0.219) higher for trisomy cases compared with LB controls; it was also higher, though not significantly so, for trisomy cases compared with women with other chromosomally abnormal losses or chromosomally normal losses. The adjusted odds ratio in relation to high FSH (≥ 10 mIU/ml) was significantly increased for trisomy cases versus LB controls (adjusted odds ratio (OR): 3.8, 95% CI: 1.6, 8.9). CONCLUSIONS The association of trisomy with elevated FSH is compatible with the oocyte pool hypothesis, whereas the absence of an association with AMH is not. Alternative interpretations are considered, including the possibility that elevated FSH may disrupt meiotic processes or allow recruitment of abnormal follicles.

Menopausal transition: predicting time to menopause for women 44 years or older from simple questions on menstrual variability.

Objective To assess whether menstrual variability predicts time to menopause. Design Analyses drew on 326 menstruating women, aged 44 to 56, who were followed until they reached menopause or the study ended. The women provided data on their menstrual characteristics at intake. We evaluated the utility of six definitions of menstrual variability for predicting time to ascertained menopause (final menstrual period + 12 months): (1) more than 90 days since the most recent menstrual period (n = 20); (2) 60 or more days of amenorrhea during the previous year (n = 71); (3) cycle lengths that varied by 19 or more days (n = 106); (4) cycle lengths too variable to report a usual length (n = 29); (5) cycles less regular than they had been at age 40 (n = 107); and (6) change in the duration or heaviness of menstrual flow compared with age 40 (n = 255). In addition, we evaluated hot flashes or night sweats during the previous week (n = 50) and age 50 or more years (n = 60) as predictors. Results Definitions 1 to 5 predicted time to menopause; definition 6 did not. Definition 1 had the highest positive predictive value for ascertained menopause within 2 years and within 4 years; definitions 2 and 4 had low to moderate positive predictive values for ascertained menopause within 2 years but good positive predictive values for ascertained menopause within 4 years. For ascertained menopause within 2 years, definition 2 showed the best balance of sensitivity (94%) and specificity (91%). Conclusion Simple questions about menstrual variability elicit information that is informative about proximity to menopause.

Skewed X Chromosome Inactivation and Trisomic Spontaneous Abortion: No Association

Several studies suggest that highly skewed X chromosome inactivation (HSXI) is associated with recurrent spontaneous abortion. We hypothesized that this association reflects an increased rate of trisomic conceptions due to anomalies on the X chromosome that lead both to HSXI and to a diminished oocyte pool. We compared the distribution of X chromosome inactivation (XCI) skewing percentages (range: 50%-100%) among women with spontaneous abortions in four karyotype groups-trisomy (n = 154), chromosomally normal male (n = 43), chromosomally normal female (n = 38), nontrisomic chromosomally abnormal (n = 61)-to the distribution for age-matched controls with chromosomally normal births (n = 388). In secondary analyses, we subdivided the nontrisomic chromosomally abnormal group, divided trisomies by chromosome, and classified women by reproductive history. Our data support neither an association of HSXI with all trisomies nor an association of HSXI with chromosomally normal male spontaneous abortions. We also find no association between HSXI and recurrent abortion (n = 45).

Intermediate CGG repeat length at the FMR1 locus is not associated with hormonal indicators of ovarian age.

ObjectivePremutation and intermediate CGG repeat length at the fragile X mental retardation 1 (FMR1) locus have been associated with premature ovarian failure. We tested whether intermediate length is associated with indicators of ovarian age in a sample of fertile women. Our primary measures of ovarian age were antimüllerian hormone (AMH) and follicle-stimulating hormone (FSH) levels. MethodsThe cross-sectional sample comprised 258 women with karyotyped spontaneous abortions (140 trisomic spontaneous abortions and 118 chromosomally normal spontaneous abortions or spontaneous abortions with anomalies other than trisomy) and 325 women with recent live births (LBs). We analyzed data from the total sample and data from LBs only. We defined CGG repeat length by the length (both continuous and categorical) on the longer allele. ResultsCGG repeat length was not significantly associated with either hormone measure. A repeat length of 35 to 54 CGG, versus the modal category of 30 CGG, was associated with an approximately 7% increase in median AMH level and a 3% increase in median FSH level. Results were unaltered when analyses were limited to LBs. Analyses of hormone levels using cutpoints to define older ovarian age showed no associations with repeat length. Among 10 women with repeat lengths of 35 to 54 CGG analyzed for AGG sequences, the uninterrupted CGG length was not significantly longer among women with hormonal indicators of “old” versus “young” ovarian age. ConclusionsOur data do not support an association between intermediate CGG repeat length and levels of AMH or FSH among fertile women.

Copy number changes on the X chromosome in women with and without highly skewed X-chromosome inactivation.

Aim: To test the hypothesis that microdeletions or microduplications below the resolution of a standard karyotype may be a significant cause of highly skewed X-inactivation (HSXI) in women without a cytogenetically detected X-chromosome anomaly. Methods: Cases were women with HSXI, defined as ≥85% of cells in a blood sample with the same active allele at the HUMARA locus. The skewing in controls ranged from 50 to <75%. We performed an SNP microarray analysis using the Affymetrix 6.0 platform for 45 cases and 45 controls. Results: Cases and controls did not differ in the frequency of X-chromosome copy number changes ≥100 kb or in the frequency of copy number changes that contained genes. However, one woman with HSXI >90% in blood and left and right buccal smears had a 5.5-Mb deletion in Xp22.2p22.1. This deletion could affect the viability of male conceptions and may have led to the dysmorphology found in female carriers. Conclusion: HSXI in a blood sample is rarely due to X-chromosome copy number changes detectable by microarray.

Alzheimer's disease in the parents of women with trisomic spontaneous abortions.

We tested whether familial aggregation of Down syndrome and Alzheimers disease (AD) is present for trisomies of other autosomes. We compared rates of Alzheimer-like dementia in the parents of women with trisomic pregnancy losses (n = 109) with those in parents of women with chromosomally normal losses (n = 151) and births (n = 216). Relative risks of Alzheimer-like dementia in parents of women with trisomic losses were 1.2 (95% Cl 0.6, 2.2) and 0.9 (95% Cl 0.5, 1.5) in comparison to parents of women with chromosomally normal losses and births, respectively. Associations were similar among women whose index pregnancy occurred before age 35 or later. Our data do not support an association between the occurrence of AD and trisomy of all autosomal chromosomes. They raise the possibility that familial aggregation with AD is specific to trisomy 21.

NO MATERNAL AGE RELATIONSHIP FOR POLYPLOIDY

Department of Genetics and Development, Columbia University, New York, NY 10032, USA 2 Department of Pediatrics, Columbia University, New York, NY 10032, USA 3 New York State Psychiatric Institute, Sergievsky Center and School of Public Health, Columbia University, New York, NY 10032, USA 4 School of Public Health, Columbia University and Research Foundation for Mental Hygiene, New York Psychiatric Institute, New York, NY 10032, USA