Multiple meiotic errors caused by predivision of chromatids in women of advanced maternal age undergoing in vitro fertilisation

Abstract

Chromosome aneuploidy is a major cause of pregnancy loss, abnormal pregnancy and live births following both natural conception and in vitro fertilisation (IVF) and increases exponentially with maternal age in the decade preceding the menopause. Molecular genetic analysis following natural conception and spontaneous miscarriage demonstrates that trisomies arise mainly in female meiosis and particularly in the first meiotic division. Here, we studied copy number gains and losses for all chromosomes in the two by-products of female meiosis, the first and second polar bodies, and the corresponding zygotes in women of advanced maternal age undergoing IVF, using microarray comparative genomic hybridisation (array CGH). Analysis of the segregation patterns underlying the copy number changes reveals that premature predivision of chromatids rather than non-disjunction of whole chromosomes causes almost all errors in the first meiotic division and unlike natural conception, over half of aneuploidies result from errors in the second meiotic division. Furthermore, most abnormal zygotes had multiple aneuploidies. These differences in the aetiology of aneuploidy in IVF compared with natural conception may indicate a role for ovarian stimulation in perturbing meiosis in ageing oocytes.

Reproductive outcome of women 43 years and beyond undergoing ART treatment with their own oocytes in two Connecticut university programs

“…However, the main challenge for aged women seeking infertility treatment, are higher cancellation rates and difficulties in getting enough available embryos which makes it more difficult for them to succeed when using embryo biopsy and chromosomal testing for their ART treatment. A possible deleterious effect when stimulating older women could also further compound their treatment [8].…”

The Role of Aneuploidy Screening in Human Preimplantation Embryos

“…There is conflicting evidence on the frequency of errors in both the first and second meiotic division with groups showing errors in both the first meiotic division-MI (Kuliev et al 2003) and more recently in the second meiotic division-MII (Fragouli et al 2011;Handyside et al 2012) occurring more frequently. This discrepancy may be due in part to differences in www.intechopen.com patient maternal age of the study groups and the difference in resolution of the cytogenetic techniques used.…”

“…While biopsy of PB1 alone and a combined PB1 and PB2 strategy have been used clinically for PGS, it is becoming increasingly evident that PB1 alone has limited applicability to PGS as only errors in MI can be detected and even MI chromatid segregation errors may not all be detected without analysis of both polar bodies. Indeed, as much as 30% of aneuploidy of maternal origin will not be diagnosed if only PB1 is sampled (Handyside et al 2012). It is therefore the authors opinion that biopsy of both first and second polar body is essential for optimal detection of oocyte aneuploidy if used as an embryo selection tool.…”

Preimplantation Genetic Screening

“…With the development of a complete platform including library-based WGA such as Sureplex® in combination with arrays especially developed for single cell work [17,41,42], PGS with aCGH became accessible to most PGS centres. Handyside et al [18] examined 105 aCGH sets of two polar bodies and the corresponding zygote resulting from a pilot study to evaluate the feasibility of a randomized controlled trial for PGS on polar bodies in patients with AMA [17,43]. During the pilot study, it was found that 72% of the oocytes analysed had one or more aneuploidies in either one or both polar bodies.…”

“…The simultaneous biopsy has as advantage that the oocyte needs to be manipulated only once; however, it takes some skill and training to differentiate the first from the second polar body [17]. This is important to obtain an accurate diagnosis: the first polar body normally contains 23 chromosomes and 46 chromatids, but can display abnormalities both at the level of the chromosomes, caused by non-disjunction, as of the chromatids, caused by premature predivision, while the second polar body is a fully haploid cell with 23 chromosomes/chromatids [18].…”