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

Chromosome aneuploidyis 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 miscarriagedemonstrates that trisomies arise mainly in female meiosisand 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 zygotesin women of advanced maternal ageundergoing IVF, using microarray comparative genomichybridisation (array CGH). Analysis of the segregation patterns underlying the copy number changes reveals that premature predivision of chromatidsrather than non-disjunction of whole chromosomes causes almost all errors in the first meiotic division and unlike natural conception, over half of aneuploidiesresult from errors in the second meiotic division. Furthermore, most abnormal zygoteshad multiple aneuploidies. These differences in the aetiology of aneuploidyin IVF compared with natural conception may indicate a role for ovarian stimulation in perturbing meiosisin ageing oocytes.