Trisomic Conceptions Research Articles

Infertility following trisomic pregnancies: A nationwide cohort study.

To study whether gynecologic or reproductive disorders show association with trisomic conceptions. This nationwide cohort study utilized the Registry of Congenital Malformations to identify women who had a trisomic pregnancy (n = 5784), either with trisomy 13 (T13; n = 351), trisomy 18 (T18; n = 1065) or trisomy 21 (T21; n = 4369) from 1987 to 2018. We used the Finnish Maternity cohort to match the cases to population controls (n = 34 422) on the age, residence, and timing of pregnancy. These data were cross-linked to the ICD-10 diagnoses of the national Care Registry for Health Care data on specialized health care in Finland during 1996 to 2019. Both inflammatory (ICD-10 diagnoses: N70-N77) and noninflammatory disorders of the genital tract (N80-N98) were studied. Crude odds ratios (ORs) with 95% CIs were calculated for associations between diagnoses and trisomic conceptions. The diagnosis of female infertility (N97) at any time was associated with trisomic conceptions (OR: 1.19, 95% CI: 1.08-1.32). In the subgroup analysis, this association was found for T18 (OR: 1.29, 95% CI: 1.03-1.61) and T21 (OR: 1.17, 95% CI: 1.04-1.32), but not for T13 (OR: 1.15, 95% CI: 0.75-1.72). When restricting the timing of the diagnosis of female infertility, an elevated OR was found only after the index pregnancy (OR: 1.81, 95% CI: 1.56-2.09). These increased odds for infertility after trisomic conceptions were observed both in women <35 years (T18 OR: 1.91, 95% CI: 1.21-3.00; T21 OR: 1.68, 95% CI: 1.31-2.14) and in women ≥35 years (T18 OR: 2.17, 95% CI: 1.40-3.33; T21 OR: 1.87; 95% CI: 1.47-2.39), but not after T13 conceptions. Our observational data suggest a link between trisomic conceptions and subsequent diagnoses of infertility but do not demonstrate causality. These data implicate that partially similar mechanisms might predispose to trisomy and infertility, regardless of maternal age.

Recurrence of Trisomic Pregnancies in Four Families: A Cytogenetic and Molecular Study

AbstractThe risk for recurrence of non disjunction trisomy 21 is conventionally considered to be less than 1%. Within a span of 3 years, we observed recurrence of non disjunction trisomies in four families. The objective of the present study was to determine low level mosaicism in either of the couple and to identify the parental origin of additional chromosome 21/18. The four couples who had recurrent trisomic conceptions were investigated for the underlying mosaicism by analysis of 100 cells from peripheral blood of the couple and the parental origin of supernumerary chromosome 21/18 were identified using microsatellite markers. Low level mosaicisms in peripheral lymphocytes of couple were ruled out for all four families. Microsatellite markers have shown maternal origin of chromosomal nondisjunction for all the families and defective first meiotic division as the most common mechanism for nondisjunction. This observation raises the need for discussing the option of invasive testing while counseling the couple with an affected child with non-disjunction trisomy as the risk for recurrence of trisomies in subsequent pregnancy might not be as low as 1%.

Biotin-deficient diet induces chromosome misalignment and spindle defects in mouse oocytes.

Increased abnormal oocytes due to meiotic chromosome misalignment and spindle defects lead to elevated rates of infertility, miscarriage, and trisomic conceptions. Here, we investigated the effect of biotin deficiency on oocyte quality. Three-week-old female ICR mice were fed a biotin-deficient or control diet (0, 0.004 g biotin/kg diet) for 21 days. On day 22, these mouse oocytes were analyzed by immunofluorescence. Due to biotin, undernutrition increased the frequency of abnormal oocytes (the biotin deficient vs. control: 40 vs. 16%). Next, the remaining mice in the biotin-deficient group were fed a control or biotin-deficient diet from day 22 to 42. Although biotin nutritional status in the recovery group was restored, the frequency of abnormal oocytes in the recovery group was still higher than that in the control group (48 vs. 18%). Our results indicate that steady, sufficient biotin intake is required for the production of high-quality oocytes in mice.

Miscarriage in contemporary maternal-fetal medicine: targeting clinical dilemmas

Miscarriage in contemporary maternal-fetal medicine: targeting clinical dilemmas

Germline mosaicism does not explain the maternal age effect on trisomy

A variety of hypotheses have been proposed to explain the association between trisomy and increasing maternal age in humans, virtually all of which assume that the underlying mechanisms involve meiotic errors. However, recently Hultén and colleagues [Hulten et al., 2010b] proposed a provocative model-the Oocyte Mosaicism Selection Model (OMSM)-that links age-dependent trisomy 21 to pre-meiotic errors in the ovary. Specifically, they propose that nondisjunctional events occur in a proportion of germ cells as they mitotically proliferate, resulting in mosaicism for trisomy 21. Assuming that the presence of an additional chromosome 21 delays meiotic progression, these cells would be ovulated later in reproductive life, resulting in an age-dependent increase in aneuploid eggs. Because this model has important clinical implications, we initiated studies to test it. We first analyzed oocytes from two trisomy 21 fetuses, combining immunostaining with FISH to determine the likelihood of detecting the additional chromosome 21 at different stages of meiosis. The detection of trisomy was enhanced during the earliest stage of prophase (leptotene), before homologs synapsed. Accordingly, in subsequent studies we examined the chromosome content of leptotene oocytes in seven second trimester female fetuses, analyzing three chromosomes commonly associated with human trisomies (i.e., 13, 16, and 21). In contrast to the prediction of the OMSM, we found no evidence of trisomy mosaicism for any chromosome. We conclude that errors in pre-meiotic germ cells are not a major contributor to human aneuploidy and do not provide an explanation for the age-related increase in trisomic conceptions.

Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies

Increased meiotic spindle abnormalities and aneuploidy in oocytes of women of advanced maternal ages lead to elevated rates of infertility, miscarriage, and trisomic conceptions. Despite the significance of the problem, strategies to sustain oocyte quality with age have remained elusive. Here we report that adult female mice maintained under 40% caloric restriction (CR) did not exhibit aging-related increases in oocyte aneuploidy, chromosomal misalignment on the metaphase plate, meiotic spindle abnormalities, or mitochondrial dysfunction (aggregation, impaired ATP production), all of which occurred in oocytes of age-matched ad libitum-fed controls. The effects of CR on oocyte quality in aging females were reproduced by deletion of the metabolic regulator, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). Thus, CR during adulthood or loss of PGC-1α function maintains female germline chromosomal stability and its proper segregation during meiosis, such that ovulated oocytes of aged female mice previously maintained on CR or lacking PGC-1α are comparable to those of young females during prime reproductive life.

Maternal age and chromosomally abnormal pregnancies: what we know and what we wish we knew.

The relationship between increasing maternal age and trisomy has been recognized for over 50 years and is one of the most important etiological factors associated with any human genetic disorder. Specifically, the risk of trisomy in a clinically recognized pregnancy rises from about 2-3% for women in their twenties to an astounding 30% or more for women in their forties. Thus, as women approach the end of their child-bearing years, errors of chromosome segregation represent the most important impediment to a successful pregnancy. Despite the clinical importance of this relationship, we do not understand how age affects the likelihood of producing a normal egg. Errors that affect chromosome segregation could occur at several stages during the development of the oocyte: in the fetal ovary, either during the mitotic proliferation of oogonia or the early stages of meiosis; in the 'dictyate' oocyte, during the 10-50-year period of meiotic arrest; or during the final stages of oocyte growth and maturation, when meiosis resumes and the meiotic divisions take place. Recent evidence from studies of human oocytes and trisomic conceptions and from studies in model organisms implicates errors at each of these stages. It seems likely that there are multiple causes of human age-related nondisjunction, complicating our efforts to understand - and, ultimately, to provide preventive measures for - errors associated with increasing maternal age.

Outcome of PGD for the indication of previous trisomic conception

OBJECTIVE: To determine the rate of aneuploidy and pregnancy outcome after preimplantation genetic diagnosis (PGD) in women with history of previous aneuploid conception. To determine the risk of a previous abnormality to occur again in embryos and after PGD.

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).

Ultrasound Manifestations of Unusual Trisomies-Excluding Trisomy 13, 18, and 21

Trisomy is the most commonly identified chromosome abnormality, occurring in at least 4% of all clinically recognized pregnancies (1). Most of the trisomies are associated with a single additional chromosome, although 2 other types of trisomic conceptions are occasionally observed, those with 2 additional chromosomes or double trisomy and those with both a normal and trisomic cell line or mosaic trisomies. The adverse effects of trisomy on the phenotype are well established. In this review article, we consider the prevalence of the unusual trisomies (excluding 13, 18, and 21) and present a review of their ultrasound findings.

Molecular cytogenetic characterisation of a mosaic add(12)(p13.3) with an inv dup(3)(q26.31 --> qter) detected in an autistic boy.

BackgroundInverted duplications (inv dup) of a terminal chromosome region are a particular subset of rearrangements that often results in partial tetrasomy or partial trisomy when accompanied by a deleted chromosome. Associated mosaicism could be the consequence of a post-zygotic event or could result from the correction of a trisomic conception. Tetrasomies of distal segments of the chromosome 3q are rare genetic events and their phenotypic manifestations are diverse. To our knowledge, there are only 12 cases reported with partial 3q tetrasomy. Generally, individuals with this genomic imbalance present mild to severe developmental delay, facial dysmorphisms and skin pigmentary disorders.ResultsWe present the results of the molecular cytogenetic characterization of an unbalanced mosaic karyotype consisting of mos 46,XY,add(12)(p13.3) [56]/46,XY [44] in a previously described 11 years old autistic boy, re-evaluated at adult age. The employment of fluorescence in situ hybridization (FISH) and multicolor banding (MCB) techniques identified the extra material on 12p to be derived from chromosome 3, defining the additional material on 12p as an inv dup(3)(qter → q26.3::q26.3 → qter). Subsequently, array-based comparative genomic hybridization (aCGH) confirmed the breakpoint at 3q26.31, defining the extra material with a length of 24.92 Mb to be between 174.37 and 199.29 Mb.ConclusionThis is the thirteenth reported case of inversion-duplication 3q, being the first one described as an inv dup translocated onto a non-homologous chromosome. The mosaic terminal inv dup(3q) observed could be the result of two proposed alternative mechanisms. The most striking feature of this case is the autistic behavior of the proband, a characteristic not shared by any other patient with tetrasomy for 3q26.31 → 3qter. The present work further illustrates the advantages of the use of an integrative cytogenetic strategy, composed both by conventional and molecular techniques, on providing powerful information for an accurate diagnosis. This report also highlights a chromosome region potentially involved in autistic disorders.

High viability of biopsied embryos using a new method of vitrification

OBJECTIVE: Preimplantation Genetic Diagnosis and Screening are used in an effort to decrease trisomic conceptions, decrease spontaneous miscarriage and to detect genetic disease. The impact of embryo biopsy on the ability to cryopreserve surplus embryos in PGS cycles needs to be considered, particularly since early reports described reduced viability. The purpose of this study is to demonstrate the effectiveness of the new S3-vitrification method on blastocysts derived from PGS. DESIGN: Retrospective analysis. MATERIALS AND METHODS: From January 2007 through February 2008, 28 patients had cryo-transfers of normal surplus blastocysts - that were vitrified using S3 vitrification during PGS cycles. Embryos were vitrified using several important modifications of regular vitrification. The new S3 approach uses a DMSO-free environment and standard sealable freezing straws. Pre-vitrification steps with this protocol allow for a three-fold duration of exposure time to cryoprotectants. Post-thaw survival was carefully observed. The average number of embryos transferred was 2.1 (range 1-3). RESULTS: All 28 patients had at least one embryo survive for cryotransfer. A total of 67 blastocysts were thawed and 63 of the these survived (94%). 18 of the patients had a positive pregnancy test and 16 of those had a clinical pregnancy (57%). There was one patient who had a spontaneous miscarriage (6.2%). The Implantation rate was 31.7%. We anticipate from this data that the incidence of birth will be in excess of 45%. CONCLUSIONS: This study clearly demonstrates the viability of blastocysts after biopsy on day three and PGS using S3-vitrification. The notion that such embryos do poorly after cryostorage can not be confirmed. The advantage of the new S3 approach is not only demonstrated in increased viability and pregnancy, but also in the shortened learning curve observed when embryologists unfamiliar with this technique were retrained.

Biological aging and the etiology of aneuploidy

A prevalent hypothesis concerning the cause of the rise in aneuploid conceptions with maternal age is that the changes that accompany normal ovarian aging increase the rate of meiotic errors in the oocyte. Biological aging of the ovary is accompanied by a decline in both the total oocyte pool and the number of antral follicles maturing per cycle, as well as changes in the levels of circulating reproductive hormones. The biological aging hypothesis predicts that aneuploidy rates should be higher in women with a prematurely reduced oocyte pool, and that women with trisomic conceptions should show signs of earlier ovarian aging than women of the same chronological age without trisomic conceptions. Comprehensive studies of aneuploidy in groups of women with known causes of premature ovarian failure remain to be done, though anecdotal evidence does suggest increased rates of pregnancy loss and aneuploidy. Smoking, which is a well-documented cause of earlier ovarian aging, is not associated with an increase in aneuploid conceptions. Evidence from women with unilateral ovariectomies is inconsistent. Support for the biological aging hypothesis was provided by one study showing that menopause occurred about a year earlier in women with a trisomic spontaneous abortion compared to women with chromosomally normal conceptions. Associations between high FSH and pregnancies with Down syndrome and chromosomally abnormal spontaneous abortions have also been reported. However, the most direct test of the hypothesis, which compared antral follicle counts and hormonal levels in women with trisomic pregnancies and those with chromosomally normal pregnancies, failed to find a difference in the expected direction. A prospective study of FSH levels in women with subfertility also failed to find an association with the rate of pregnancy loss. The bulk of evidence thus suggests that, if the processes of biological aging are indeed related to aneuploidy, they probably involve factors other than those measured by oocyte or antral follicle pool size and reproductive hormone levels.

Lower aneuploidy rate in spermatozoa selected for ICSI

Objective: We performed FISH on sperm from OAT patients to analyse the differences in aneuploidy rates between native and selected sperm collectives.Design: Several recent studies revealed the higher sperm aneuploidy frequencies among men suffering from oligoasthenoteratozoospermia. So far, chromosome 1, 7, 18, X and Y aneuploidy rates were examined in studies focused on the correlation between sperm morphology and non-disjunction. Moreover, these works analysed morphologically normal sperm irrespective of their motility. Our study was focused on subpopulation of spermatozoa selected according to their motility and morphology, used in practise for ICSI. On the one hand we checked the aneuploidy rate of chromosome 13 and 21, because sperms bearing a disomy of these autosomes may lead to viable trisomic conceptions (trisomie 21, Down syndrome and trisomie 13, Patau Syndrome). On the other hand we performed FISH with a specific probe for chromosome 16, as trisomy 16 is the commonest recognized trisomy in abortion.Materials/Methods: Twenty patients were included in this preliminary study. The inclusion criteria were: oligoasthenoteratozoospermia with sperm concentration lower than 10 × 10 6/ml, sperm motility <30% and normal sperm morphology <10%. Sperm selection was performed under 400x magnification, using Hoffman modulation contrast. FISH procedure was made by standard protocol, using probes for chromosome 13 and 21 (locus specific probes) and the probe for chromosome 16 (centromeric satellite probe). For each patient, we analysed 100–150 spermatozoa in both, native and selected sperm groups.Results: A significantly lower aneuploidy frequencies were observed in the selected group in comparison to native sperm population (2–4% vs. 4–33%). Incidence of disomy in native sperm ranged from 2% to 7%, from 2% to 10 % and from 1% to 4 % for chromosomes 13, 16 and 21, respectively. In the selected group, the rates of disomy ranged from 0.7% to 2%, from 0% to 0.7%, and from 0.7% to 1% for chromosomes 13, 16 and 21, respectively. The frequency of diploidy was 1–5% in native sperm, while no diploidy was detected in the selected group of sperms.Conclusions: Our results support the hypothesis of the positive correlation between abnormal sperm morphology and their aneuploidy rate. The selection of sperm using 400x magnification can significantly decrease their aneuploidy frequency. However, this method cannot exclude the incidence of aneuploid conceptuses of paternal origin.Supported by: No supports. Objective: We performed FISH on sperm from OAT patients to analyse the differences in aneuploidy rates between native and selected sperm collectives. Design: Several recent studies revealed the higher sperm aneuploidy frequencies among men suffering from oligoasthenoteratozoospermia. So far, chromosome 1, 7, 18, X and Y aneuploidy rates were examined in studies focused on the correlation between sperm morphology and non-disjunction. Moreover, these works analysed morphologically normal sperm irrespective of their motility. Our study was focused on subpopulation of spermatozoa selected according to their motility and morphology, used in practise for ICSI. On the one hand we checked the aneuploidy rate of chromosome 13 and 21, because sperms bearing a disomy of these autosomes may lead to viable trisomic conceptions (trisomie 21, Down syndrome and trisomie 13, Patau Syndrome). On the other hand we performed FISH with a specific probe for chromosome 16, as trisomy 16 is the commonest recognized trisomy in abortion. Materials/Methods: Twenty patients were included in this preliminary study. The inclusion criteria were: oligoasthenoteratozoospermia with sperm concentration lower than 10 × 10 6/ml, sperm motility <30% and normal sperm morphology <10%. Sperm selection was performed under 400x magnification, using Hoffman modulation contrast. FISH procedure was made by standard protocol, using probes for chromosome 13 and 21 (locus specific probes) and the probe for chromosome 16 (centromeric satellite probe). For each patient, we analysed 100–150 spermatozoa in both, native and selected sperm groups. Results: A significantly lower aneuploidy frequencies were observed in the selected group in comparison to native sperm population (2–4% vs. 4–33%). Incidence of disomy in native sperm ranged from 2% to 7%, from 2% to 10 % and from 1% to 4 % for chromosomes 13, 16 and 21, respectively. In the selected group, the rates of disomy ranged from 0.7% to 2%, from 0% to 0.7%, and from 0.7% to 1% for chromosomes 13, 16 and 21, respectively. The frequency of diploidy was 1–5% in native sperm, while no diploidy was detected in the selected group of sperms. Conclusions: Our results support the hypothesis of the positive correlation between abnormal sperm morphology and their aneuploidy rate. The selection of sperm using 400x magnification can significantly decrease their aneuploidy frequency. However, this method cannot exclude the incidence of aneuploid conceptuses of paternal origin. Supported by: No supports.

The Origin of Abnormalities in Recurrent Aneuploidy/Polyploidy

Recurrent miscarriage due to sporadic chromosomal abnormalities may simply be a consequence of the dramatic increase of trisomic conceptions with increased maternal age. However, it is also possible that some couples are at increased risk of abnormalities as a result of gonadal mosaicism, factors affecting chromosome structure and segregation, increased sperm aneuploidy in the male partner, or accelerated "aging" of the ovaries. We report cytogenetic and molecular findings from 122 spontaneous abortions (SAs) from 54 couples who were ascertained as having two or more documented aneuploid or polyploid SAs. The distribution of abnormalities in this group was similar to those from 307 SAs that involved chromosome abnormalities and were diagnosed at the same center but did not involve documented recurrent aneuploidy/polyploidy. Although recurrence of the same abnormality was observed in eight families, this number was equal to that expected by chance, indicating that gonadal mosaicism is rarely the explanation for recurrence. The origin of the abnormality was determined in 37 SAs from 23 of the couples in the study. A maternal meiotic origin was involved in 30 trisomies and in 1 triploid SA; 3 additional maternal trisomies were of possible somatic origin. A paternal origin was found in the remaining two trisomies and in one triploid SA. In addition, one double trisomy was the consequence of both a maternal and a paternal meiotic error. These results confirm that the etiology of trisomy is predominantly a result of meiotic errors related to increased maternal age, regardless of whether the couple has experienced one or multiple aneuploid SAs. Furthermore, this is true even when a second SA involves the same abnormality. Nonetheless, these data do not exclude some population variability in risk for aneuploidy.

Paternal Origin of Trisomy 21 Following Intracytoplasmic Sperm Injection (ICSI)

One important aspect in the debate on the genetic risks associated with intracytoplasmic sperm injection (ICSI) is the possible increased rate of chromosomal abnormalities in resulting pregnancies. ICSI was performed in a 27 year old man with asthenoteratozoospermia and his 25 year old wife. There was a spontaneous miscarriage at 9 weeks of gestation. Cytogenetic investigation revealed trisomy 21. Analysis of two polymorphic microsatellite markers showed that the additional chromosome was paternal. This is in contrast to the fact that the vast majority of trisomic concepti are maternal in origin. Identifying the parent of origin in trisomic conceptions achieved by ICSI may reveal whether ICSI is associated with an increased risk of paternally derived aneuploidy.

Confined placental mosaicism for trisomies 2, 3, 7, 8, 9, 16, and 22: their incidence, likely origins, and mechanisms for cell lineage compartmentalization.

Analysis of confined placental mosaicism (CPM) for trisomies 2, 3, 7, 8, 9, 16, and 22, in diagnostic chorionic villus sampling procedures, demonstrates apparent incidences of CPM for individual trisomies of between 9 and 91 cases per 100,000 pregnancies, with trisomy 7 being the most common. More detailed analysis of the percentage of aneuploid cells present, and the distribution of abnormality between the cytotrophoblast and extra-embryonic mesoderm cell lineages, shows a highly specific pattern for each chromosome. Theoretical considerations, in conjunction with direct observations, indicate that the overriding influence on the patterns of cell distribution seen in CPM is the distribution of aneuploid cells laid down during blastogenesis. This in turn reflects closely the origin of mosaicism from either correction of a trisomic conception or post-fertilization somatic error. The pattern of aneuploid cells for each trisomy, as seen at the end of the first trimester and later in pregnancy, can therefore be used to predict the relative contribution of meiotic and mitotic errors to CPM, and hence the likely incidences of uniparental disomy from this source, upd(16)mat being the most common (1 in 10,000 continuing pregnancies). In addition, CPM for trisomies 2, 3, and 8 shows strong evidence of a non-random distribution of aneuploid cells between the different extra-embryonic cell lineages. Analysis of comparable data from spontaneous abortion material repeats this non-random pattern for trisomies 2 and 3, and suggests that a similar phenomenon may also be occurring for trisomy 22. A non-random distribution could be attributable to selection for or against, or intolerance of, particular trisomic cells in certain lineages, but is more probably a result of either cell lineage-specific non-disjunction or consistent uneven compartmentalization of aneuploid cells during blastocyst development.

Pregnancy and lifestyle study: the long-term use of the contraceptive pill and the risk of age-related miscarriage.

Maternal ageing is a very important factor in aneuploidy. It is associated with an increased risk of a liveborn trisomy, especially Down's syndrome, and with a dramatic increase in trisomic conceptions, the majority of which miscarry. A total of 585 volunteer couples who were planning pregnancies participated in a prospective study of reproduction. The couples answered extensive questionnaires and early pregnancy tests (day 28) were conducted each month. The number of years of contraceptive pill use was correlated with pregnancy outcome. Lowered rates of miscarriage were found with increased years of pill use. The cut-off point for this positive effect appeared to be 9 years. Use of oral contraceptives for > or = 9 years was associated with a spontaneous abortion rate of 11.3%, which is about half the rate (23%) which was found in couples who had not used the pill. However, the effect of pill taking was correlated with female age, and when age was examined as an independent factor, the reduction in miscarriage was only statistically significant in women > 30 years old, where the rate of abortion reduced from 28 to 7%. Because age-related aneuploidy in humans probably occurs as a direct or an indirect result of follicle depletion, it is proposed that the long-term use of the oral contraceptive pill protects against abortion due to aneuploidy by preserving the number of follicles.

Increased parental ages and uniparental disomy 15: a paternal age effect?

Parental ages associated with both maternal and paternal uniparental disomy (UPD) of chromosome 15 are highly elevated in comparison to Zurich population-based controls, with mean maternal and paternal ages of 35.6 and 38.1, respectively for UPD patients (diagnosed in Zurich) and 28.0 and 31.0, in controls. The parental ages are also significantly higher than observed for trisomies of other chromosomes diagnosed in Zurich. The higher age of UPD cases may be due to the fact that two errors, both a gain and a loss of a chromosome 15, are necessary. We suggest that gamete complementation, zygote formation from two gametes one of which is nullisomic and the other disomic for the same chromosome, may be a major mechanism of UPD formation, as well as secondary loss of a chromosome in a trisomic conception, and that there is an association between increased paternal age and nondisjunction.

Reproductive potential in the older woman

There is a definite increase in the number of women bearing children in the 30- and 40-year-old age groups. The total number of women who are 35 to 40 years of age in the United States is projected to increase 42% and the percent births to this age group is projected to increase 37%. This is apparently because of a trend to postpone childbearing and first birth due to women's career priorities, advanced education, control over fertility, financial concerns, late and second marriages, and infertility. Associated with this is an increase in visits to the infertility specialist for older women who have an intrinsic decrease in fecundity with advancing age. Although, on the average, a woman will not experience menopause until about 50 years of age, her effective childbearing period may stop almost a decade earlier. A woman in her late 30s and, especially, early 40s is at some disadvantage in terms of conception delay, ability to carry a chromosomally normal fetus until term, and risk of trisomic conception. Certain endocrinologic parameters have been identified for the woman entering the transition to menopause. Biologic aging of the hypothalamic-pituitary-ovarian axis is intertwined with changes in the endocrine milieu of the perimenopause and preperimenopause. Despite a clear association of decreased fecundity in older women due to multiple biologic and social influences, so long as the individual has regular cycles and essentially normal endocrine parameters, she should be a candidate for an expedited infertility workup and ovulation induction, if not more aggressive treatment. Her obstetric profile is much improved, except for an increase in congenital anomalies and chromosomal defects. Chorionic villus biopsy study or amniocentesis is advised in all cases, regardless of therapy.