Cytogenetic signatures of recurrent pregnancy losses

ABSTRACT Objectives To investigate the incidence of chromosomal abnormalities in the products of conception (POC) of patients with spontaneous miscarriages (SM) and with recurrent pregnancy losses (RPL), and to determine biological mechanisms contributing to RPL. Design Retrospective cohort study. Setting University-affiliated medical center. Patients During a 20-years period, 12,096 POC samples underwent classical chromosome analysis as a part of standard clinical care. Interventions Cytogenetic findings were classified into six categories and compared between the SM and RPL cohorts. Main Outcome Measures RPL-specific cytogenetic abnormalities and sex bias in POCs with autosomal aneuploidy. Results Analysis of a large cohort of RPL patients has identified an increased incidence of inherited and de novo structural chromosome abnormalities, recurrent polyploid conceptions, and complex mosaic alterations. These abnormalities are the signature of genomic instability, posing a high risk of genetic abnormalities to offspring independent of maternal age. Predominance of male conceptions in the RPL cohort points toward X-linked etiology and gender-specific intolerance for certain genetic abnormalities. Conclusions Our study showed several possible genetic etiologies of RPL, including parental structural chromosome rearrangements, predisposition to meiotic nondisjunction and genomic instability in patients with karyotypically abnormal POCs. Loss of karyotypically normal fetuses might be attributed to defects in genes essential for fetal development and survival, as well as aberrations affecting the X chromosome structure or function. Molecular studies of parental and POC genomes will help to identify inherited defects in genes involved in meiotic divisions and DNA repair to confirm our hypotheses, and to discover novel fetal-essential genes.