Chromosomally normal miscarriage is associated with vaginal dysbiosis and local inflammation

Abstract

Background Emerging evidence supports an association between vaginal microbiota composition and risk of miscarriage; however, the underlying mechanisms are poorly understood. We aim 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. Methods We used 16S rRNA gene based metataxonomics to interrogate the vaginal microbiota in a cohort of 167 women, 93 miscarriages (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. Results We show that euploid miscarriage is associated with a significantly higher prevalence of Lactobacillus spp. deplete vaginal microbial communities compared to aneuploid miscarriage (P = 0.01). Integration of matched cervicovaginal fluid immune-profiles showed that Lactobacillus spp. depleted vaginal microbiota associated with pro-inflammatory cytokine levels most strongly in euploid miscarriage compared to viable term pregnancy (IL-1β; P < 0.001, IL-8; P = 0.01, IL-6; P < 0.001). Conclusions Our data suggest the vaginal microbiota plays an important aetiological role in euploid miscarriage and may represent a target to modify risk of pregnancy loss.

Analysis of Vaginal Microbiome in Women with or Without Episodes of Spontaneous Abortion in Eastern Nigeria

“…Most of the genera we found to be exclusive to SA (i.e. Sneathia, Megaphaera, Dialister, Peptostreptococcus, Gardnerella, and other facultative anaerobes encountered) have previously been associated with vaginal dysbiosis by other authors (22,26). Also, the facultative anaerobes identified (exclusively or more abundantly in SA) in this study included: Anaerococcus, Gardnerella, Peptostreptococcus Megasphaera, Dialister, Prevotella, and Peptoniphilus, among others.…”

“…Earlier reports (21,22) suggested that significant differences exist in average microbial diversity between women who experienced SA and those who successfully carried the pregnancy to term. In our study, we noted that the Shannon diversity index was much higher among SA samples, compared with non-SA (t=147.13703; p<0.001), showing that the vagina of SA patients had significantly more diversity of bacterial genera and species.…”

“…Based on this study, it can be concluded that SA is associated with reduced Lactobacillus levels and increased diversity of vaginal microbiota. This is possibly due to the fact that a reduced level of vaginal Lactobacilli may predispose the vagina to colonization by diverse groups of bacterial genera and species, which may, in turn, induce immunological pressures that could result in the premature ejection of the developing fetus -before the fetus attains viability; this could be attributed to the fact that presence of infecting organisms can lead to consequent activation of pattern-recognition receptors (PPRs) and release of inflammatory mediators that could ultimately stimulate uterine contractions, leading to the eventual ejection of the unviable fetus (22,24).…”

Cohort profile: the Swedish Maternal Microbiome project (SweMaMi) – assessing the dynamic associations between the microbiome and maternal and neonatal adverse events

“…27 35 Vaginal dysbiosis has also been associated with miscarriage, preterm birth, preeclampsia, gestational diabetes and excessive gestational weight gain, which are all common gestational complications. [36][37][38][39][40] Some specific bacterial species linked to vaginal dysbiosis such as BVAB1, Sneathia spp, Gardnerella vaginalis and Prevotella spp, have been associated with increased risks of spontaneous preterm birth, yet may be linked to ethnogeographical differences. 37 38 41 Two recent studies (one with Chinese women and one mixed cohort with mostly Hispanic women) failed to identify associations between specific vaginal bacterial species and preterm birth highlighting the pathogenic complexity.…”

“…Vaginal dysbiosis, and particularly the presence of anaerobic bacteria, has been associated with higher risks of sexually transmitted infections,33 poor fertility treatment outcome,34 human papillomavirus infection and gynaecological cancers 27 35. Vaginal dysbiosis has also been associated with miscarriage, preterm birth, preeclampsia, gestational diabetes and excessive gestational weight gain, which are all common gestational complications 36–40. Some specific bacterial species linked to vaginal dysbiosis such as BVAB1, Sneathia spp, Gardnerella vaginalis and Prevotella spp, have been associated with increased risks of spontaneous preterm birth, yet may be linked to ethno-geographical differences 37 38 41…”