The reproductive tract microbiota and miscarriage

Abstract

Early miscarriage (pregnancy loss before 12 weeks) occurs in 20 % of pregnancies of which half are due to aneuploidy. However, the mechanisms that drive euploid miscarriage are poorly understood and, despite its prevalence, there are no interventions that prevent sporadic miscarriage. Emerging evidence supports the role of the vaginal microbiota in adverse pregnancy outcome. Our group has previously shown that miscarriage is associated with vaginal dysbiosis but the cytogenetic status of those miscarriages was unknown. The existence and origin of an early pregnancy placental niche and the interaction between the rectal and vaginal microbiota in early pregnancy loss has not been addressed. Bacterial 16S rRNA gene based metataxonomic analysis was used to interrogate the vaginal microbiota in women who miscarried compared to term healthy pregnancies. The same approach was used to compare the trophoblast and rectal microbiota of miscarriage patients with termination of pregnancy patient controls. I have shown that, compared to aneuploid miscarriage, euploid miscarriage is associated with a significantly higher prevalence of Lactobacillus spp. deplete vaginal microbial communities. In women with Lactobacillus spp. deplete vaginal microbial communities, euploid miscarriage associates with higher concentrations of pro-inflammatory cytokines (measured using the Human Magnetic Luminex Screening 8-plex Assay) when compared to viable term pregnancy. Prevotella bivia and Streptococcus were identified as particularly common in euploid miscarriage and as drivers of proinflammatory cytokines. This shows that it is a combination of an adverse vagina microbiota and the maternal local immune response to it that predicts miscarriage. I have also demonstrated that there is a bacterial signal in trophoblast above the background contamination control, but it was difficult to account for cross contamination via the vaginal niche due to sample collection methods. In those that had an adverse vaginal microbiota significant rectal dysbiosis was seen in euploid compared to aneuploid miscarriage. Furthermore, a healthy gut microbiome appears to dampen the cervicovaginal immune response to Lactobacillus spp. deplete vaginal microbiota. Overall the findings presented in this thesis support the hypothesis that the vaginal microbiota plays an important aetiological role in euploid miscarriage and that the rectal or gut microbiota may modulate the inflammatory reaction to vaginal dysbiosis. These findings suggest that modulation of the vaginal and or rectal/gut microbiota, using prebiotics or live biotherapeutics may reduce the risk of miscarriage.