Differential Effect of Vaginal Microbiota on Spontaneous Preterm Birth among Chinese Pregnant Women

Abstract

Objective: The effect of vaginal microbiota on spontaneous preterm birth (sPTB) has not been fully addressed, and few studies have explored the associations between vaginal taxa and sPTB in the gestational diabetes mellitus (GDM) and non-GDM groups, respectively. Study Design. To minimize external interference, a total of 41 pregnant women with sPTB and 308 controls (pregnant women without sPTB) from same regain were enrolled in this case-cohort study. Controls were randomly selected at baseline. With the exception of GDM, other characteristics were not significantly different between the two groups. Vaginal swabs were collected at early second trimester. Using 16S amplicon sequencing, the main bioinformatics analysis was performed on the platform of QIIME 2. Vaginal microbiota traits of the sPTB group were compared with controls. Finally, the effects of binary taxa on sPTB in the GDM group and the non-GDM group were analyzed, respectively.

Results: The proportion of GDM in the sPTB (19.51%) was higher than the controls (7.47%, P = 0.018). The vaginal microbiota of pregnant women with sPTB exhibited higher alpha diversity metrics (observed features, P = 0.001; Faith's phylogenetic diversity, P = 0.013) and different beta diversity metrics (unweighted UniFrac, P = 0.006; Jaccard's distance, P = 0.004), compared with controls. The presence of Lactobacillus paragasseri/gasseri (aOR: 3.12, 95% CI: 1.24-7.84), Streptococcus (aOR: 3.58, 95% CI: 1.68-7.65), or Proteobacteria (aOR: 3.39, 95% CI: 1.55-7.39) was associated with an increased risk of sPTB in the non-GDM group (P < 0.05). However, the relative abundance of novel L. mulieris (a new species of the L. delbrueckii group) was associated with a decreased risk of sPTB (false discovery rate, 0.10) in all pregnant women.

Conclusion: GDM may modify the association of vaginal taxa with sPTB, suggesting that maternal GDM should be considered when using vaginal taxa to identify pregnant women at high risk of sPTB.

Figure 1

The alpha and beta diversity metrics of vaginal microbiota between the sPTB and controls. The violin plots were applied to illustrate the alpha diversity metrics (a–d) between the two groups. P values in the violin plots were evaluated based on the Wilcoxon test. PCoA plots were applied to illustrate the beta diversity metrics (e–h) between the two groups, and P values in the plots were evaluated based on the Adonis analysis. The percentage on axis label was the proportion of variance explained by that axis.

Figure 2

Forest plots of vaginal bacterial traits associated with sPTB. The difference of the relative abundance of vaginal taxa between the sPTB and controls was evaluated using a zero-inflated negative binomial linear effect model. Shapes (red circles, FDR < 0.20; orange squares, raw P < 0.05; blue triangles, raw P ≥ 0.05) represent estimated coefficients, and lines show the 95% CIs of the coefficients.

Figure 3

Correlation between superpathway of hexitol degradation and significant taxa. (a) The difference of superpathway abundance of hexitol degradation between the sPTB and controls was evaluated using Welch's t-test (P < 0.05). (b) The relative abundance of taxa linked to sPTB was analyzed for covariation with superpathway of hexitol degradation using the Spearman test. Correlation effects were color-coded, from red (negative correlation) to blue (positive correlation). ^∗P < 0.05.

Figure 4

Cumulative hazard of sPTB among pregnant women in different strata. The taxa and GDM were treated as binary traits where 0 and 1 represented the absence and presence of vaginal taxa or GDM, respectively. P values were retained from log-rank analyses. (a) L. mulieris. (b) L. paragasseri/gasseri. (c) Streptococcus. (d) Proteobacteria.