Microbial and human transcriptome in vaginal fluid at midgestation: Association with spontaneous preterm delivery.

BACKGROUND: Intrauterine infection and inflammation caused by microbial transfer from the vagina are believed to be important factors causing spontaneous preterm delivery (PTD). Multiple studies have examined the relationship between the cervicovaginal microbiome and spontaneous PTD with divergent results. Most studies have applied a DNA-based assessment, providing information on the microbial composition but not transcriptional activity. A transcriptomic approach was applied to investigate differences in the active vaginal microbiome and human transcriptome at midgestation between women delivering spontaneously preterm versus those delivering at term. METHODS: Vaginal swabs were collected in women with a singleton pregnancy at 18 + 0 to 20 + 6 gestational weeks. For each case of spontaneous PTD (delivery <37 + 0 weeks) two term controls were randomized (39 + 0 to 40 + 6 weeks). Vaginal specimens were subject to sequencing of both human and microbial RNA. Microbial reads were taxonomically classified using Kraken2 and RefSeq as a reference. Statistical analyses were performed using DESeq2. GSEA and HUMAnN3 were used for pathway analyses. RESULTS: We found 17 human genes to be differentially expressed (false discovery rate, FDR < 0.05) in the preterm group (n = 48) compared to the term group (n = 96). Gene expression of kallikrein-2 (KLK2), KLK3 and four isoforms of metallothioneins 1 (MT1s) was higher in the preterm group (FDR < 0.05). We found 11 individual bacterial species to be differentially expressed (FDR < 0.05), most with a low occurrence. No statistically significant differences in bacterial load, diversity or microbial community state types were found between the groups. CONCLUSIONS: In our mainly white population, primarily bacterial species of low occurrence were differentially expressed at midgestation in women who delivered preterm versus at term. However, the expression of specific human transcripts including KLK2, KLK3 and several isoforms of MT1s was higher in preterm cases. This is of interest, because these genes may be involved in critical inflammatory pathways associated with spontaneous PTD.

Effect of second-trimester sonographic cervical length on the risk of spontaneous preterm delivery in different risk groups: A prospective observational multicenter study.

INTRODUCTION: The aim of the study is to compare the effect of cervical length measured with transvaginal ultrasound in the second trimester on the risk of spontaneous preterm delivery (PTD) between different risk groups of asymptomatic women with a singleton pregnancy. MATERIAL AND METHODS: This is a pre-planned exploratory analysis of the CERVIX study, a prospective blinded multicenter diagnostic accuracy study. Asymptomatic women with a singleton pregnancy were consecutively recruited at their second-trimester routine ultrasound examination at seven Swedish ultrasound centers. Cervical length was measured with transvaginal ultrasound at 18-20 weeks (Cx1; n = 11 072) and 21-23 weeks (Cx2, optional; n = 6288). The effect of cervical length on the risk of spontaneous PTD and its discriminative ability was compared between women with: (i) previous spontaneous PTD, late miscarriage or cervical conization (high-risk group; n = 1045); (ii) nulliparae without risk factors (n = 5173); (iii) parae without risk factors (n = 4740). Women with previous indicated PTD were excluded (n = 114). Main outcome measures were: effect of cervical length on the risk of spontaneous PTD expressed as odds ratio per 5-mm decrease in cervical length with interaction analysis using logistic regression to test whether the effect differed between groups, area under the receiver operating characteristic curve (AUC), sensitivity, specificity, number needed to screen to detect one spontaneous PTD. RESULTS: The effect of cervical length at Cx2 on the risk of spontaneous PTD <33 weeks was similar in all groups (odds ratios 2.26-2.58, interaction p value 0.91). The discriminative ability at Cx2 was superior to that at Cx1 and was similar in all groups (AUC 0.69-0.76). Cervical length ≤25 mm at Cx2 identified 57% of spontaneous preterm deliveries <33 weeks in the high-risk group with number needed to screen 161. The number needed to screen for groups (ii) and (iii) were 1018 and 843. CONCLUSIONS: The effect of cervical length at 21-23 weeks on the risk of spontaneous PTD <33 weeks is similar in high- and low-risk pregnancies. The differences in number needed to screen should be considered before implementing a screening program.