| Summary: | Recurrent miscarriage (RM), defined as 3 or more consecutive spontaneous losses of pregnancy before 20 weeks gestation, affects 1-2% of couples and has a complex etiology. Half of miscarriages from RM cases are caused by chromosomal abnormalities in the embryo and while there are several associated maternal factors, underlying causes and clinically relevant biomarkers have been elusive. I hypothesized that genetic and/or epigenetic factors associated with maternal meiotic non-disjunction, reproductive aging and endocrinological profile, or placental functioning will contribute to the etiology of RM. In these case-control studies, I investigated the association between RM and 1) maternal mutations in synaptonemal complex protein 3 (SYCP3), 2) maternal telomere lengths, 3) maternal polymorphisms in genes in the hypothalamus-pituitary-ovarian (HPO) axis and 4) placental DNA methylation patterns. The findings suggest that maternal mutations in SYCP3 and polymorphisms in HPO axis genes may not contribute significantly to risk for RM. No mutations in SYCP3 were identified in women with RM with at least one trisomic conception. While associations between polymorphisms within the estrogen receptor β, activin receptor 1, prolactin receptor and glucocorticoid receptor genes and RM were identified, these were not significant after correction for multiple comparisons. Aspects of chromosomal biology may be important factors in the etiology of RM. Women with RM had significantly shorter telomeres compared to controls, suggesting altered rates of biological aging. In the placental villi of RM samples, there were few differences in DNA methylation at targeted sites when compared to isolated miscarriages and elective terminations. However, gene ontology analysis showed that imprinted genes and immune response pathways were overrepresented among those sites differentially methylated between RM and elective termination placentas. The RM group additionally had an increase in the number of outlier cases at a select number of imprinted loci. Furthermore, several placental samples from both cases and controls showed aberrant DNA methylation profiles at many loci investigated, suggesting these samples may have global dysregulation of DNA methylation and/or differences in placental composition/functioning. These studies have improved our understanding of mechanisms involved in RM and will contribute to the direction of future research. === Medicine, Faculty of === Medical Genetics, Department of === Graduate
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