Abstract
Study question
To investigate the vaginal microbial composition and the local immune response in chromosomally normal and abnormal miscarriages and compare this to uncomplicated pregnancies delivering at term.
Summary answer
We show that euploid miscarriage is associated with a significantly higher prevalence of Lactobacillus spp. deplete vaginal microbial communities compared to aneuploid miscarriage.
What is known already
Emerging evidence supports the role of the vaginal microbiota in adverse pregnancy outcome, but the underlying mechanisms are poorly understood. A dominance of Lactobacillus spp. in pregnancy provides protection against pathogenic bacteria by producing lactic acid and antimicrobial compounds. A depletion in Lactobacillus spp. is often linked to adverse pregnancy outcomes.Current work also implicates the reproductive tract microbiota as a key modulator of local inflammatory and immune pathways. We have previously shown that miscarriage is associated with vaginal dysbiosis but without knowledge of the cytogenetic status of those miscarriages or the local immune profile.
Study design, size, duration
This study was a prospective observational cohort study based at Queen Charlotte’s & Chelsea Hospital, Early Pregnancy Unit, London between March 2014-February 2019. Vaginal swabs were collected from the posterior vaginal fornix of 167 patients.
Participants/materials, setting, methods
We used 16S rRNA gene based metataxonomics to interrogate the vaginal microbiota in a cohort of 167 women, 93 miscarriage patients (54 euploid and 39 aneuploid using molecular cytogenetics) and 74 women who delivered at term and correlate this with the aneuploidy status of the miscarriages. We also measured the concentrations of IL-2, IL-4, IL-6, IL-8, TNF-α, IFN-γ, IL-1β, IL-18 and IL-10 in cervical vaginal fluid using Human Magnetic Luminex Screening Assay (8-plex).
Main results and the role of chance
We show that euploid miscarriage is associated with a significantly higher prevalence of Lactobacillus spp. deplete vaginal microbial communities compared to aneuploid miscarriage (P=0.008). In women having Lactobacillus spp. deplete vaginal microbial communities, euploid miscarriage associates with higher concentrations of pro-inflammatory cytokines IL-1β, IL-8, IL-6 (P<0.001, P=0.01 and P<0.001 respectively) and lower concentrations of anti-inflammatory cytokines IL10 (P<0.001) when compared to viable term pregnancy. We identified Prevotella bivia and Streptococcus as particularly common in euploid miscarriage and as drivers of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α). Co-occurrence network analyses revealed low levels of co-occurrence between Lactobacillus crispatus and other organisms and strong co-occurrence between Streptococcal species. Our data show a combination of both an adverse vaginal microbiota and a cytokine response to it influences early pregnancy outcome. Although this may be a reflection of intrinsic maternal immune response, it appears that the cytokine response is largely driven by the bacterial taxa present in the vagina, which presents an opportunity for specific, directed intervention. The negative co-occurrence between L.crispatus and all other organisms suggests a possible therapeutic role for probiotics containing this organism. The influence of Streptococci also suggests a potential benefit of targeted antibiotics with probiotics for some patients.
Limitations, reasons for caution
There were no longitudinal samples in this cohort and our results are based on the assumption that the vaginal microbial composition is stable throughout the first trimester.Future longitudinal studies with larger sample sizes are needed to corroborate these findings and provide insights to the mechanisms that trigger the inflammatory response.
Wider implications of the findings
These findings support the hypothesis that the vaginal microbiota plays an important aetiological role in euploid miscarriage and may represent a target to modify the risk of pregnancy loss.
Trial registration number
n/a
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