Vaginal Atopobium is Associated with Spontaneous Abortion in the First Trimester: a Prospective Cohort Study in China

Abstract

Spontaneous abortion (SA) has received more and more attention in light of its increasing incidence. However, the causes and pathogenesis of SA remain largely unknown, especially for those without any pathological features. In this study, we characterized the vaginal microbiota diversity and composition of pregnant women in their first trimester and evaluated the association between the vaginal microbiota and SA before 12 weeks of gestation. Participants' bacterial profiles were analyzed by 16S rRNA gene sequencing in the V3-V4 regions at 5-8 weeks of gestation. A total of 48 patients with SA at 12 weeks of gestation were included as the study group, while 116 women with normal pregnancies (NPs) were included as a control group. The results indicated that the richness of the vaginal microbiome in SA patients was higher (Chao1, P < 0.05) and different in composition relative to that of women with NPs (unweighted UniFrac, R = 0.15, P < 0.01; binary Jaccard, R = 0.15, P < 0.01). Furthermore, the genus Apotobium was significantly enriched in SA patients. An extreme gradient-boosting (XGBoost) analysis was able to classify Atopobium-induced SA more reliably (area under the receiver operating characteristic curve, 0.69; threshold, 0.01%). Moreover, after adjusting for potential confounders, the results showed a robust association between Apotobium and SA (as a categorical variable [<0.01%]; adjusted odds ratio, 2.9; 95% confidence interval, 1.3 to 6.5; P = 0.01). In conclusion, higher vaginal Apotobium levels were associated with SA in the first trimester. IMPORTANCE Spontaneous abortion (SA) is the most common adverse pregnancy outcome in the first trimester. The causal drivers of SA have become a substantial challenge to reveal and overcome. We hypothesize that vaginal microbial dysbiosis is associated with SA, as it was related to several female reproductive disorders in previous studies. In our study, we characterized the vaginal microbiota of patients with SA at 12 weeks of gestation as the study group, and women with normal pregnancies were enrolled as a control group. Generally, significant differences were discovered in the vaginal microbiota between the two groups. Our study also revealed that Apotobium may play an important role in the pathogenesis of SA. To our knowledge, this study is the first detailed elaboration of the vaginal microbiota composition and vaginal Apotobium in association with SA. We believe that our findings will inspire more researchers to consider dynamic changes in the vaginal microbiota as critical features for further studies of nosogenesis not only for SA but also other reproductive diseases.

Keywords: 16S rRNA; Apotobium; machine learning; spontaneous abortion; vaginal microbiota.

FIG 1

Vaginal taxonomic profiles of participants in the normal pregnancy and spontaneous abortion groups. (A) Phylum level. (B) Genus level. Bar charts showing the vaginal microbial taxa composition in mean values.

FIG 2

Different vaginal microbiota compositions of the normal pregnancy (NP) and spontaneous abortion (SA) groups. (A) Cladogram analyzed by linear discriminant analysis (LDA) by LEfSe. The nodes of the cladogram from the inner to the outer circles showed the abundant taxa from the kingdom (D0) level to the species (D6) level. Colors represented the groups in which differentially abundant taxa were enriched (red indicates NP, green indicates SA, yellow indicates non-significant), and the diameter of each node was proportional to the taxon’s abundance. The threshold on the logarithmic LDA score was 2.0. (B) The levels of relative abundance of Lactobacillus, Gardenerella, Atopobium, Prevotella, Streptococcus, Sneathia, Bifidobacterium, etc. were compared in individuals in the NP and SA groups. The P value was determined by the two-tailed Wilcoxon rank-sum test.

FIG 3

Screening the potential importance of the top 15 taxa at the genus level on the early pregnancy outcome by XGBoost. (A) XGBoost analysis was applied to assess the weight of different taxa at the genus level on the early pregnancy outcome. The analysis showed that the genus Atopobium was the one most related to SA. (B) Receiver operating characteristic (ROC) curve analysis was employed to evaluate the predictive value of Atopobium, Esherichia, and Prevotella. The black curve shows the average area under the ROC curve (AUC) of these taxa. The diagonal lines mark an AUC of 0.5. (Upper left) Summary ROC figure. Red indicates Atopobium, gray indicates Escherichia, and green indicates Prevotella. (Upper right) ROC of Atopobium (AUC, 0.686). (Lower left) ROC of Escherichia (AUC, 0.652). (Lower right) ROC of Prevotella (AUC, 0.515).