Elucidating the Microbiome in Patients With Recurrent Pregnancy Loss Vs. Patients Without Gynecological or Obstetrical Conditions

Aims The aim of the current study is to evaluate vaginal and intrauterine microbiota in women with recurrent pregnancy loss (RPL) as compared to normal controls. Ultimately we would like to assess whether women with RPL have a characteristic microbiome which may be significantly different microbiota of healthy patients in our study population. This could later lead to treatment with a tailored microbiota transplantation approach involving healthy vaginal microbiota for the treatment of patients with RPL and implement it in a prospective randomized controlled trial in order to modulate the reproductive tract microbiota and achieve and improved pregnancy outcome.

Background

A rapidly growing field in biologic research of human health and disease is that of microbiome research. The microbiome inhabiting the female reproductive tract has long been suspected to play an important role in health and disease. Current theories suggest that altered microbiota even without clinical infection may trigger an inflammatory response in the endometrium. It affects the success of embryo implantation and future development of pregnancy.5 Most studies deal with genital tract microbiome in patients with repeated implantation failure in IVF, however, some studies have also found altered microbiome in patients with recurrent pregnancy loss (RPL)6 Vaginal and endometrial microbiotas might be independent. Endometrial microbiota has a richer alpha diversity than vaginal microbiota, and dysbiosis of vaginal or endometrial microbiota can cause implantation failure. Unlike previous reports, Ichiyama et al reports that the Lactobacillus rate in the vagina, but not the endometrium, may be a biomarker for repeated implantation failure7 Small studies showed association between spontaneous abortion and abnormal vaginal microbiome( 60% intermediate flora, 20% BV condition), with higher levels of selected metabolites in the vaginal environment (e.g., inosine, fumarate, xanthine, benzoate, ascorbate)8 Recurrent pregnancy loss (RPL) is defined American Society for Reproductive medicine as two or more spontaneous miscarriages before gestational week 22 (not necessarily consecutive) The role of vaginal infections in RPL is controversial and screening for infections is not routinely recommended in patients with RPL9

Major immune cells in the human endometrium include uterine Natural Killer (uNK) cells, macrophages, dendritic cells (DCs) and T cells. Each of these cell populations demonstrated a specific role. uNK are involved in the success of implantation and maintenance of pregnancy through their ability both to interact through inhibitor receptors with HLA-G, HLA-E and HLA-C expressed on trophoblast cells and to produce angiogenic factors Kuon et al in their small study described that RPL patients with elevated pNK suffer more often from colonization by Gardnerella vaginalis and gram-negative anaerobes . This might indicate an association between the vaginal microbiota, local inflammation, changes in immune parameters and miscarriage.10 Like the vaginal microbiome, the endometrial microbiome is usually dominated by Lactobacilli. 11 A recent studies illustrated that the presence of a non-Lactobacillus-dominating microbiome in endometrial fluid of IVF patients was associated with significantly lower implantation, pregnancy and live birth rates 12 13 According to researches microbiota composition in endometrial fluid does not fully reflect that in endometrial tissue.14 However, only few studies have directly probed the microbes within the uterine environment and how these microbes could influence in implantation , the majority of them in IVF cycles.

First trimester miscarriage can be associated with reduced prevalence of Lactobacillus spp. and with changes in the relative abundance of several bacterial genera, including Fam_Finegoldia, Lac_Coprococcus_3, and Lac_Roseburia 15 16