Trisomic Pregnancies 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.

O-153 Clinical utility of preimplantation genetic testing for aneuploidy origin (PGT-AO) to enhance embryo selection for monogenic disorders: a retrospective pan-country integrative genomic and clinical study

Abstract Study question What is PGT-AO’s impact on implantation and pregnancy rate per embryo transfer, by determining the prevalence and effect of (mosaic) aneuploidies and their segregational origin? Summary answer PGT-AO potentially enhances the efficiency of PGT and increases the pregnancy rate per embryo transfer by minimizing transfers with poor outcomes and improving implantation rates. What is known already Demographic factors such as advanced parental age increases risk of aneuploid offspring, driving demand for advanced PGT. Randomized controlled trials revealed that PGT-A does not increase live birth rates after IVF. PGT-A, the most frequent form of PGT, overlooks the mosaic nature and segregational origin of aneuploidies in IVF embryos. This possibly leads to avoiding the transfer of mosaic embryos and reduces the pregnancy rate per cycle. Prompting this study, five embryos transferred based on PGT-M, led to trisomic pregnancies terminated following invasive prenatal diagnosis. Subsequent genome haplarithmisis revealed that these embryos carried (meiotic) trisomies not previously detected by PGT-M. Study design, size, duration In this retrospective study, we included 1944 embryos (816 PGT-M embryos, 323 couples, 224 indications). Currently, 284 have been processed by genome haplarithmisis-based PGT-AO and analyzed to assess if (mosaic) aneuploidies and segregational origin would have altered transfer decisions and subsequent clinical outcomes. We evaluated our novel PGT- A approach, termed PGT-AO, providing a nuanced understanding of early embryonic development in clinical practice and more responsible PGT-A, potentially leading to viable mosaic embryo transfer. Participants/materials, setting, methods The couples were counseled by clinical geneticists at Dutch University Medical Centers (UMCs), in Maastricht, Amsterdam, Utrecht, and Groningen, and enrolled in the diagnostic PGT-M procedure after signing an informed consent form. Embryos (n = 816) eligible for transfer based on absence of the monogenic aberration of interest by PGT-M were analyzed by haplarithmisis-based PGT-AO including parental information. This information allows for the detection of (mosaic) chromosomal abnormalities and their parental and segregational origin. Main results and the role of chance Of 816 included embryos (323 couples, 224 indications), 284 were found to be suitable for transfer by PGT-M and were analyzed by PGT-AO. Of these, 183 were transferred. Of the transferred embryos, 65 (35.5%) had a positive HCG and 48 (26.3%) resulted in a liveborn. 14.6% (7/48) carried abnormalities following our PGT-AO approach. These abnormalities consisted of mitotic mosaic trisomies, mosaic monosomies, and mosaic duplications and a deletion. Of the transferred embryos, 132 (72.1%) did not result in a liveborn and 115 (62.8%) had negative HCG tests. Of the transferred embryos with negative HCG, 38.3% (44/115) contained a total of 90 abnormalities, consisting of 37 monosomies, 35 trisomies, 12 deletions, 2 duplications, 2 UPD and 1 ring chromosome. The 35 trisomies occurred in 20 embryos, of which 9 were of meiotic origin and 5 of mitotic origin, 1 of both meiotic and mitotic, and 5 could not be determined. Based on these preliminary results, PGT-AO can avoid the transfer of embryos with aneuploidy of meiotic origin and non-mosaic status. In contrast, embryos with aneuploidy of mitotic origin are often mosaic and the abnormality may not be uniformly distributed throughout the blastocyst and could potentially be considered for transfer. Limitations, reasons for caution Haplarithmisis relies on the inclusion of parental DNA to phase the embryonic genome and thus determine the segregational origin of aberrations. Additionally, mitosis and meiosis II trisomies cannot be discerned where a crossover event is absent for a chromosome with trisomy. Wider implications of the findings Implementation of PGT-AO will re-define the current embryo selection system. This enhances PGT by increasing pregnancy rate per embryo transfer and minimizing transfers with poor outcomes, disposal of potentially viable embryos, spontaneous pregnancy losses, and termination of aneuploid pregnancies. This reduces the emotional and financial burdens on families and healthcare. Trial registration number Not applicable

Integrative analyses of maternal plasma cell-free DNA nucleosome footprint differences reveal chromosomal aneuploidy fetuses gene expression profile

BackgroundChromosomal aneuploidy is the most common birth defect. However, the developmental mechanism and gene expression profile of fetuses with chromosomal aneuploidy are relatively unknown, and the maternal immune changes induced by fetal aneuploidy remain unclear. The inability to obtain the placenta multiple times in real-time is a bottleneck in research on aneuploid pregnancies. Plasma cell-free DNA (cfDNA) carries the gene expression profile information of its source cells and may be used to evaluate the development of fetuses with aneuploidy and the immune changes induced in the mother owing to fetal aneuploidy.MethodsHere, we carried out whole-genome sequencing of the plasma cfDNA of 101 pregnant women carrying a fetus with trisomy (trisomy 21, n = 42; trisomy 18, n = 28; trisomy 13, n = 31) based on non-invasive prenatal testing (NIPT) screening and 140 normal pregnant women to identify differential genes according to the cfDNA nucleosome profile in the region around the transcription start sites (TSSs).ResultsThe plasma cfDNA promoter profiles were found to differ between aneuploid and euploid pregnancies. A total of 158 genes with significant differences were identified, of which 43 genes were upregulated and 98 genes were downregulated. Functional enrichment and signaling pathway analysis were performed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases found that these signal pathways were mainly related to the coordination of developmental signals during embryonic development, the control of cell growth and development, regulation of neuronal survival, and immune regulation, such as the MAPK, Hippo, TGF-β, and Rap1 signaling pathways, which play important roles in the development of embryonic tissues and organs. Furthermore, based on the results of differential gene analysis, a total of 14 immune-related genes with significant differences from the ImmPort database were collected and analyzed. These significantly different immune genes were mainly associated with the maintenance of embryonic homeostasis and normal development.ConclusionsThese results suggest that the distribution characteristics of cfDNA nucleosomes in maternal plasma can be used to reflect the status of fetal development and changes of the immune responses in trisomic pregnancies. Overall, our findings may provide research ideas for non-invasive detection of the physiological and pathological states of other diseases.

Assessment of a Simplified Cell-Free DNA Method for Prenatal Down Syndrome Screening.

Prenatal screening for common trisomies via cell-free (cfDNA) is usually implemented by technologies utilizing massively parallel sequencing, stringent environmental controls, complex bioinformatics, and molecular expertise. An alternative and less complex methodology utilizes rolling circle amplification (RCA). Further evaluation of its performance and related requirements are warranted. At 16 sites, women at 10 to 20 weeks gestation provided informed consent, relevant information, and 2 to 3 blood samples. Samples shipped for testing were processed and stored. Women were enrolled at primary cfDNA screening, or following such screening at referral for diagnostic testing. RCA testing occurred post-enrollment, over 11 months. Diagnostic results and delivery notes determined clinical truth. Detection rates were based on confirmed trisomic pregnancies; false-positive rates were based on unaffected pregnancies from the general population. Detection rate for the common trisomies was 95.9% (117/122, 95% CI, 90.5%-98.5%); overall false-positive rate was 1.00% (22/2,205, 0.65%-1.51%). Test failure rate after repeat testing was 0.04%. When assay standard deviations were below pre-specified levels, the overall false-positive rate was much lower at 0.30% (P < 0.001). Fetal sex calls were correct for 99.7%. One technician analyzed 560 samples over 2 weeks, a rate of 14 000/year. Our assessment of this simplified cfDNA-based system for prenatal screening for common trisomies performed in a prenatal screening laboratory is encouraging. Improved detection, low failure rates and rapid reporting can be achieved by collecting 2 samples. Future priorities should include achieving higher run precision using a single collection tube. NCT03087357.

Ovulation suppression protects against chromosomal abnormalities in mouse eggs at advanced maternal age

The frequency of egg aneuploidy and trisomic pregnancies increases with maternal age. To what extent individual approaches can delay the "maternal age effect" is unclear because multiple causes contribute to chromosomal abnormalities in mammalian eggs. We propose that ovulation frequency determines the physiological aging of oocytes, a key aspect of which is the ability to accurately segregate chromosomes and produce euploid eggs. To test this hypothesis, ovulations were reduced using successive pregnancies, hormonal contraception, and a pre-pubertal knockout mouse model, and the effects on chromosome segregation and egg ploidy were examined. We show that each intervention reduces chromosomal abnormalities in eggs of aged mice, suggesting that ovulation reduction delays oocyte aging. The protective effect can be partly explained by retention of chromosomal Rec8-cohesin that maintains sister chromatid cohesion in meiosis. In addition, single-nucleus Hi-C (snHi-C) revealed deterioration in the 3D chromatin structure including an increase in extruded loop sizes in long-lived oocytes. Artificial cleavage of Rec8 is sufficient to increase extruded loop sizes, suggesting that cohesin complexes maintaining cohesion restrict loop extrusion. These findings suggest that ovulation suppression protects against Rec8 loss, thereby maintaining both sister chromatid cohesion and 3D chromatin structure and promoting production of euploid eggs. We conclude that the maternal age effect can be delayed in mice. An implication of this work is that long-term ovulation-suppressing conditions can potentially reduce the risk of aneuploid pregnancies at advanced maternal age.

Most noninvasive prenatal screens failing due to inadequate fetal cell free DNA are negative for trisomy when repeated.

We aimed to test for an association between the amount of circulating fetal cell-free DNA and trisomy, and whether NIPS failure due to low fetal fraction indicates trisomy risk. Maternal BMI, maternal age, fetal sex, gestational age, fetal cfDNA fraction, and NIPS results was collected on 2374 pregnancies. Additional clinical information was available for 1180 research consented patients. We investigated associations between fetal fraction and available variables and determined the success rate of repeat NIPS testing. Fetal trisomy was marginally associated with decreased fetal fraction (P = .067). However, the proportions of trisomy events were not significantly increased in women who had failed NIPS due to low fetal fraction (<4%) (OR = 1.37 [0.3-7.4]; P = .714). 66% of repeated NIPS after a second blood draw were successful. Failure to meet the clinical cutoff of 4% fetal fraction established for NIPS accuracy did not suggest increased risk for trisomy in our cohort. Because repeat testing was successful in the majority of cases and most failures were explained by high BMI and low gestational age, a redraw may be an appropriate next step before invasive screening due to concerns for trisomic pregnancies.

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%.

Clinical application of embryo aneuploidy testing by next-generation sequencing.

We review here the evolution in the field of embryo aneuploidy testing over the last 20 years, from the analysis of a subset of chromosomes by fluorescence in situ hybridisation to the transition toward a more comprehensive analysis of all 24 chromosomes. This current comprehensive aneuploidy testing most commonly employs next-generation sequencing (NGS). We present our experience in over 130 000 embryo biopsies using this technology. The incidence of aneuploidy was lower in trophectoderm biopsies compared to cleavage-stage biopsies. We also confirmed by NGS that embryo aneuploidy rates increased with increasing maternal age, mostly attributable to an increase in complex aneuploid embryos. In contrast, the number of MII oocytes retrieved or the use of oocyte vitrification did not affect aneuploidy rates. Similarly, neither maternal age, oocyte number, nor oocyte vitrification affected the incidence of mosaicism. Analysis of clinical outcomes, indications, and potential benefits of embryo aneuploidy testing revealed advanced maternal age as the most favored group, with some evidence of improved delivery rate per transfer as well as decreased miscarriage rates and time to pregnancy. Other indications are: recurrent miscarriage, repetitive implantation failure, severe male factor, previous trisomic pregnancy, and good prognosis patients mainly undergoing single embryo transfer, with the latter indication used to reduce the occurrence of multiple pregnancies without compromising cycle outcome. In conclusion, NGS has become the most appropriate technology for aneuploidy testing in trophectoderm biopsies, with accurate results, high throughput, and cost efficiency. This technology can be also applied to the analysis of the embryonic cell free DNA released to the culture media at blastocyst stage. This is a promising approach towards a non-invasive preimplantation genetic testing of aneuploidy.

EP07.05: A case of double Trisomy (T21 and T18)

It is estimated that as much as 60% of first-trimester pregnancy losses are chromosomally abnormal and that single trisomies comprise the majority of these. In comparison, the occurrence of double aneuploidy in the same individual is a relatively rare phenomenon, and estimated to occur in only 0.21 to 2.8% of karyotyped spontaneous abortions. Pregnancy losses with double trisomies are reported to occur at an earlier gestational age and at an older maternal age than single trisomic losses. Various combinations of double trisomy in more than fifty cases have been described in the literature. The common double trisomies were the combinations of 48,XXY, +21 and 48,XXX,+18; 20 and 16 cases were reported, respectively. There was only one case report published by Grosse and Schwanitz [1977] regarding a liveborn female with double trisomy of the autosomes 18 and 21 (48,XX,+18,+21), exhibiting the clinical features of mongolism. We describe a case of double trisomy of the autosomes 18 and 21 (48,XX,+18,+21) noted from the cytogenetic studies of products of conception. A 42-year-old lady G1P0 was referred to the fetal medicine unit at approximately 11 weeks gestation with cystic hygroma. She had NIPT which showed high risk for T13 and T18. Unfortunately, she had spontaneous miscarriage, and subsequently had evacuation of retained products of conception. The cytogenetic studies of the products of conceptions showed 48,XX,+18,+21. Recurrence risk following a single trisomic pregnancy is approximately 1%. Currently, the recurrence risk following double trisomy is unknown. Case control studies are needed to determine recurrence risk following double or triple trisomic pregnancies. A significantly greater recurrence risk than that for single trisomy would have implications for genetic counselling.

Does decreasing AMH correlate with increasing frequency of aneuploid miscarriage in patients with recurrent early pregnancy loss?

Anti-Mullerian hormone (AMH) is an established serum marker of ovarian reserve and predictor of fertility treatment success. Its association with other reproductive disorders, such as recurrent pregnancy loss, is controversial. It is well documented that advancing maternal age is associated with an increased frequency of trisomic pregnancies, usually leading to miscarriage of less than 10 weeks size. The purpose of this study is to determine the whether serum AMH is associated with the frequency of aneuploidy miscarriage in a cohort of women with recurrent early pregnancy loss (RPL). An observational cohort study at an academic RPL Program. Inclusion criteria for this RPL cohort included having 2 or more pregnancy losses at less than 10 weeks and having chromosome results for one or more pregnancy losses. The RPL Biorepository contains prospectively collected biospecimens and clinical data is stored within a RPL Database1. Cryopreserved serum samples were analyzed for serum AMH and analysis performed to assess the correlation of serum AMH to probability of live birth, miscarriage, and miscarriage due to chromosome errors in each patient’s subsequent pregnancy. Data were analyzed by two-way ANOVA and chi-square where appropriate, with p<0.05 considered as significant. A total of 130 patients were included for analysis. For the cohort, the mean age was 35.5 (SD 4.3), BMI 25.8 (SD 5.6) and mean AMH 4.59 ng/ml (SD 3.94, range < 0.76 - 18.9). The cohort was stratified by AMH into 3 groups (AMH ≥2; AMH 1-2; AMH < 1) for analysis. The mean AMH (SD) for the 3 groups are 6.44 (3.61) ; 1.56 (0.33) ; and 0.52 (0.30). The mean ages (SD) for the 3 groups are 34.4 (3.7) ; 37.0 (4.7) ; and 38.1 (4.6) p < 0.0001. The number of cycles to conceive was not significantly different between the 3 groups (2.5, 2.5, 2.6 cycles respectively). The probability of live birth in the subsequent pregnancy was not significantly different between the different AMH groups (p = 0.63). Out of 72 miscarriages analyzed, 63 (88%) had confirmed chromosomal analysis results. When stratified by AMH, there was no significant difference in the rate of euploid and non euploid pregnancy losses among miscarriages with confirmed chromosomal analysis results (p=0.665) [Table 1] Our results show that serum AMH does not correlate with aneuploidy miscarriage in a cohort of women with RPL.Tabled 1AMH and miscarriage chromosome results in index pregnancy (n=63)AMH > 2 (n=44)AMH 1-2 (n=8)AMH < 1 (n=11)p value 0.665Euploid Miscarriages24 (54%)3 (38%)6 (54%) 46,XX1013 46,XY1423Non Euploid Miscarriages20 (46%)5 (62%)5 (46%) Open table in a new tab

Low oocyte yield during IVF treatment and the risk of a trisomic pregnancy

A low number of antral follicles may result in the selection of suboptimal oocytes that are prone to meiotic errors. The aim of this case-control study was to evaluate women receiving IVF treatment with low oocyte yield (defined as three or fewer oocytes retrieved after ovarian stimulation) who are at an increased risk of a trisomic pregnancy. Data were obtained from Danish and Dutch medical registries between 1983 and 2011. Analyses were carried out in 105 cases and 442 controls matched by age and year of IVF treatment. Cases were women with a trisomic pregnancy (trisomies 13, 18 or 21) resulting from fresh IVF treatment and confirmed by karyotyping. Cases were included regardless of pregnancy outcome. Controls were women with a live born child without a trisomy, resulting from fresh IVF treatment. Low oocyte yield was observed in 6.6% (29/440) of the women, of which 8.4% (7/83) were cases and 6.2% (22/357) controls. Low oocyte yield in IVF treatment was not associated with a higher risk of trisomic pregnancy (OR 1.43, 95% CI 0.64 to 3.19). Stratification for female age, adjustment for history of ovarian surgery, and gonadotrophin-releasing hormone protocol used did not change the results.

Effect of extended oral contraception use on the prevalence of fetal trisomy 21 in women aged at least 35 years.

To study factors influencing the number of ovulations in reproductive life as risk factors for common trisomies. The present observational study examined data from genetic counseling sessions performed at the 1st Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary, between September 1, 2013, and September 1, 2015, and retrieved data on patients of advanced maternal age (≥35years) who had fetal trisomy 21, 18, or 13 confirmed. Consecutive patients of advanced maternal age with genetic amniocentesis-confirmed healthy fetal karyotypes were also included as a control group. Medical record details were confirmed through telephone interviews with patients; the estimated ovulation number was calculated and compared among patients, as were factors contributing to the number of ovulations each patient had. Data from 12776 genetic counseling situations were examined; 35 patients with fetal trisomies and 100 patients in the control group were interviewed. Shorter mean length of oral contraceptive pill use before trisomic pregnancy (P<0.001) and a higher estimated ovulation number (P=0.012) were identified among patients with pregnancies with fetal trisomies. Fewer ovulatory cycles, potentially resulting from longer oral contraceptive pill use, was associated with healthy fetal karyotypes among patients of advanced reproductive age.

A rare occurrence of three consecutive autosomal trisomic pregnancies in a couple without offspring

Background: Trisomies are the most common chromosomal abnormalities, being a major cause of pregnancy loss in the first trimester. Data from preimplantation embryos support the concept of recurrent aneuploidy in women with recurrent abortion. Case: The authors report a rare case with three different consecutive trisomic pregnancies: 47,XY,+21, 47,XX,+9, and 47,XX,+18. All pregnancies resulted from the same relationship and no consanguinity was present. Standard clinical cytogenetic analysis indicated that both members had normal peripheral blood karyotype, with no evidence of mosaicism in either patient or her partner. Conclusion: The present report supports the hypothesis that some women have a higher risk for nondisjunction than others of the same age. Counseling a couple with recurrent trisomies is difficult and future research on genetics of cell division are required to assist them.

Aneuploidy screening by array comparative genomic hybridization improves success rates of in vitro fertilization: A multicenter Indian study.

OBJECTIVE:To evaluate the usefulness of preimplantation genetic screening (PGS) using array comparative genomic hybridization (aCGH) in the Indian population.MATERIALS AND METHODS:This is a retrospective, multicenter study including 235 PGS cycles following intracytoplasmic sperm injection performed at six different infertility centers from September 2013 to June 2015. Patients were divided as per maternal age in several groups (<35, 35–36, 37–38, 39–40, and >40 years) and as per indication for undergoing PGS. Indications for performing PGS were recurrent miscarriage, repetitive implantation failure, severe male factor, previous trisomic pregnancy, and advanced maternal age (≥35). Day 3 embryo biopsy was performed and analyzed by aCGH followed by day 5 embryo transfer in the same cycle or the following cycle. Outcomes such as pregnancy rates (PRs)/transfer, implantation rates, miscarriage rates, percentage of abnormal embryos, and number of embryos with more than one aneuploidy and chaotic patterns were recorded for all the treated subjects based on different age and indication groups.RESULTS:aCGH helped in identifying aneuploid embryos, thus leading to consistent implantation (range: 33.3%–42.9%) and PRs per transfer (range: 31.8%–54.9%) that were obtained for all the indications in all the age groups, after performing PGS.CONCLUSION:Aneuploidy is one of the major factors which affect embryo implantation. aCGH can be successfully employed for screening of aneuploid embryos. When euploid embryos are transferred, an increase in PRs can be achieved irrespective of the age or the indication.

Activin Decoy Receptor ActRIIB:Fc Lowers FSH and Therapeutically Restores Oocyte Yield, Prevents Oocyte Chromosome Misalignments and Spindle Aberrations, and Increases Fertility in Midlife Female SAMP8 Mice.

Women of advanced maternal age (AMA) (age ≥ 35) have increased rates of infertility, miscarriages, and trisomic pregnancies. Collectively these conditions are called "egg infertility." A root cause of egg infertility is increased rates of oocyte aneuploidy with age. AMA women often have elevated endogenous FSH. Female senescence-accelerated mouse-prone-8 (SAMP8) has increased rates of oocyte spindle aberrations, diminished fertility, and rising endogenous FSH with age. We hypothesize that elevated FSH during the oocyte's FSH-responsive growth period is a cause of abnormalities in the meiotic spindle. We report that eggs from SAMP8 mice treated with equine chorionic gonadotropin (eCG) for the period of oocyte growth have increased chromosome and spindle misalignments. Activin is a molecule that raises FSH, and ActRIIB:Fc is an activin decoy receptor that binds and sequesters activin. We report that ActRIIB:Fc treatment of midlife SAMP8 mice for the duration of oocyte growth lowers FSH, prevents egg chromosome and spindle misalignments, and increases litter sizes. AMA patients can also have poor responsiveness to FSH stimulation. We report that although eCG lowers yields of viable oocytes, ActRIIB:Fc increases yields of viable oocytes. ActRIIB:Fc and eCG cotreatment markedly reduces yields of viable oocytes. These data are consistent with the hypothesis that elevated FSH contributes to egg aneuploidy, declining fertility, and poor ovarian response and that ActRIIB:Fc can prevent egg aneuploidy, increase fertility, and improve ovarian response. Future studies will continue to examine whether ActRIIB:Fc works via FSH and/or other pathways and whether ActRIIB:Fc can prevent aneuploidy, increase fertility, and improve stimulation responsiveness in AMA women.

An FSH-lowering activin disrupting therapy prevents egg chromosome and spindle misalignments that predispose to aneuploidy, and increases fertility, in a mouse model of midlife reproductive aging

Women of advanced maternal age women (AMA, >age 35) have increased risk of oocyte & embryo aneuploidy, infertility, miscarriages, and trisomic pregnancies (collectively “egg infertility.”). Egg infertility increases markedly with age due to elevated rates of egg aneuploidy. It is a significant public health problem, with 1 in 5 US women now attempting her first pregnancy after 35. Elevated FSH is one of the first signs of ovarian aging. We hypothesize that high FSH is a cause of egg infertility, that elevating FSH activity for the period of oocyte growth will increase egg infertility, and that lowering FSH for the period of oocyte growth will prevent egg infertility.

How oocytes try to get it right: spindle checkpoint control in meiosis.

The generation of a viable, diploid organism depends on the formation of haploid gametes, oocytes, and spermatocytes, with the correct number of chromosomes. Halving the genome requires the execution of two consecutive specialized cell divisions named meiosis I and II. Unfortunately, and in contrast to male meiosis, chromosome segregation in oocytes is error prone, with human oocytes being extraordinarily "meiotically challenged". Aneuploid oocytes, that are with the wrong number of chromosomes, give rise to aneuploid embryos when fertilized. In humans, most aneuploidies are lethal and result in spontaneous abortions. However, some trisomies survive to birth or even adulthood, such as the well-known trisomy 21, which gives rise to Down syndrome (Nagaoka et al. in Nat Rev Genet 13:493-504, 2012). A staggering 20-25% of oocytes ready to be fertilized are aneuploid in humans. If this were not bad enough, there is an additional increase in meiotic missegregations as women get closer to menopause. A woman above 40 has a risk of more than 30% of getting pregnant with a trisomic child. Worse still, in industrialized western societies, child birth is delayed, with women getting their first child later in life than ever. This trend has led to an increase of trisomic pregnancies by 70% in the last 30years (Nagaoka et al. in Nat Rev Genet 13:493-504, 2012; Schmidt et al. in Hum Reprod Update 18:29-43, 2012). To understand why errors occur so frequently during the meiotic divisions in oocytes, we review here the molecular mechanisms at works to control chromosome segregation during meiosis. An important mitotic control mechanism, namely the spindle assembly checkpoint or SAC, has been adapted to the special requirements of the meiotic divisions, and this review will focus on our current knowledge of SAC control in mammalian oocytes. Knowledge on how chromosome segregation is controlled in mammalian oocytes may help to identify risk factors important for questions related to human reproductive health.

Screening Performance and Costs of Different Strategies in Prenatal Screening for Trisomy 21

Objective: Cell-free fetal DNA (cffDNA) testing has opened new options in prenatal screening for trisomy 21. Due to the higher costs of cffDNA testing there is an ongoing debate on how to combine different screening strategies. Methods: For this study, a model-based approach was used to evaluate all births in Germany in 2012 together with the percentage of euploid and trisomic pregnancies. Detection rates (DR), false positive rates (FPR), the costs of different screening strategies for trisomy 21 and combinations of these strategies were compared. The number of fetuses with trisomy 21 at 12 + 0 weeks of gestation was estimated based on maternal age distribution. We examined the screening performance of a screening strategy based on maternal age, first trimester screening (FTS) and cffDNA testing as well as the combinations “maternal age and cffDNA” and “FTS and cffDNA”. Results: In 2012 673 544 children were born. Median maternal age at delivery was 30.2 years (25th–75th quartile: 27.0–34.0). Based on maternal age distribution the expected number of fetuses with trisomy 21 at 12 weeksʼ gestation was 1788. Our study population therefore consisted of 675 332 pregnancies. Screening based only on maternal age or FTS or cffDNA resulted in detection rates of 63.3 %, 92.2 % and 99.0 % and false positive rates of 21.8 %, 8.0 % and 0.1 %, respectively. When maternal age was combined with cffDNA, cffDNA testing was only offered to women over a certain age; if a cut-off of 30 years was used, this resulted in a DR of 85.2 % and a FPR of 1.7 %. If primary screening consisted of FTS with cffDNA testing only done when the risk was between 1 : 10 and 1 : 1000, the detection rate was 96.7 % and the false positive rate was 1.2 %. Conclusion: In this model-based study we showed that prenatal screening for trisomy 21 can be improved even more by combining FTS and cffDNA. Further studies are necessary to examine whether these results can be reproduced in reality.

First-trimester contingent screening for trisomies 21, 18 and 13 by fetal nuchal translucency and ductus venosus flow and maternal blood cell-free DNA testing

Objective To examine performance of screening for major trisomies by a policy of first-line assessment of risk according to maternal age, fetal nuchal translucency thickness (NT) and ductus venosus pulsatility index for veins (DV-PIV) followed by cell-free DNA (cfDNA) testing in pregnancies with an intermediate risk. Methods We estimated the distribution of risks based on maternal age, fetal NT and DV-PIV in a dataset of 86 917 unaffected and 491 trisomic pregnancies undergoing prospective screening for trisomies. Performance of screening for trisomies by cfDNA testing was derived from a meta-analysis of clinical validation studies. We estimated performance and cost of screening for trisomies using different combinations of ultrasound screening and cfDNA testing.

Screening Performance and Costs of Different Strategies in Prenatal Screening for Trisomy 21.

Objective: Cell-free fetal DNA (cffDNA) testing has opened new options in prenatal screening for trisomy 21. Due to the higher costs of cffDNA testing there is an ongoing debate on how to combine different screening strategies. Methods: For this study, a model-based approach was used to evaluate all births in Germany in 2012 together with the percentage of euploid and trisomic pregnancies. Detection rates (DR), false positive rates (FPR), the costs of different screening strategies for trisomy 21 and combinations of these strategies were compared. The number of fetuses with trisomy 21 at 12 + 0 weeks of gestation was estimated based on maternal age distribution. We examined the screening performance of a screening strategy based on maternal age, first trimester screening (FTS) and cffDNA testing as well as the combinations "maternal age and cffDNA" and "FTS and cffDNA". Results: In 2012 673 544 children were born. Median maternal age at delivery was 30.2 years (25th-75th quartile: 27.0-34.0). Based on maternal age distribution the expected number of fetuses with trisomy 21 at 12 weeks' gestation was 1788. Our study population therefore consisted of 675 332 pregnancies. Screening based only on maternal age or FTS or cffDNA resulted in detection rates of 63.3 %, 92.2 % and 99.0 % and false positive rates of 21.8 %, 8.0 % and 0.1 %, respectively. When maternal age was combined with cffDNA, cffDNA testing was only offered to women over a certain age; if a cut-off of 30 years was used, this resulted in a DR of 85.2 % and a FPR of 1.7 %. If primary screening consisted of FTS with cffDNA testing only done when the risk was between 1 : 10 and 1 : 1000, the detection rate was 96.7 % and the false positive rate was 1.2 %. Conclusion: In this model-based study we showed that prenatal screening for trisomy 21 can be improved even more by combining FTS and cffDNA. Further studies are necessary to examine whether these results can be reproduced in reality.