A specific bacterial DNA signature in the vagina of Australian women in midpregnancy predicts high risk of spontaneous preterm birth (the Predict1000 study)

Abstract

BACKGROUND: Intrauterine infection accounts for a quarter of the cases of spontaneous preterm birth; however, at present, it is not possible to efficiently identify pregnant women at risk to deliver preventative treatments. OBJECTIVE: This study aimed to establish a vaginal microbial DNA test for Australian women in midpregnancy that will identify those at increased risk of spontaneous preterm birth. STUDY DESIGN: A total of 1000 women with singleton pregnancies were recruited in Perth, Australia. Midvaginal swabs were collected between 12 and 23 weeks' gestation. DNA was extracted for the detection of 23 risk-related microbial DNA targets by quantitative polymerase chain reaction. Obstetrical history, pregnancy outcome, and demographics were recorded. RESULTS: After excluding 64 women owing to losses to follow-up and insufficient sample for microbial analyses, the final cohort consisted of 936 women of predominantly white race (74.3%). The overall preterm birth rate was 12.6% (118 births); the spontaneous preterm birth rate at <37 weeks' gestation was 6.2% (2.9% at 34 weeks' gestation), whereas the preterm premature rupture of the membranes rate was 4.2%. No single individual microbial target predicted increased spontaneous preterm birth risk. Conversely, women who subsequently delivered at term had higher amounts of Lactobacillus crispatus, Lactobacillus gasseri, or Lactobacillus jensenii DNA in their vaginal swabs (13.8% spontaneous preterm birth vs 31.2% term; P¼.005). In the remaining women, a specific microbial DNA signature was identified that was strongly predictive of spontaneous preterm birth risk, consisting of DNA from Gardnerella vaginalis (clade 4), Lactobacillus iners, and Ureaplasma parvum (serovars 3 and 6). Risk prediction was improved if Fusobacterium nucleatum detection was included in the test algorithm. The final algorithm, which we called the Gardnerella Lactobacillus Ureaplasma (GLU) test, was able to detect women at risk of spontaneous preterm birth at <37 and 34 weeks' gestation, with sensitivities of 37.9% and 44.4%, respectively, and likelihood ratios (plus or minus) of 2.22 per 0.75 and 2.52 per 0.67, respectively. Preterm premature rupture of the membranes was more than twice as common in GLU-positive women. Adjusting for maternal demographics, ethnicity, and clinical history did not improve prediction. Only a history of spontaneous preterm birth was more effective at predicting spontaneous preterm birth than a GLU-positive result (odds ratio, 3.6). CONCLUSION: We have identified a vaginal bacterial DNA signature that identifies women with a singleton pregnancy who are at increased risk of spontaneous preterm birth and may benefit from targeted antimicrobial therapy.

Large-scale characterisation of the pregnancy vaginal microbiome and sialidase activity in a low-risk Chinese population

“…Despite these findings, we did not observe any relationship between L. iners dominance or any vaginal microbiota profile and subsequent risk of PTB in this cohort. This is in contrast to previous studies of predominantly Caucasian women by ourselves and others that have reported a relationship between L.iners and increased risk of PTB or cervical shortening, which is clinically used as a marker of PTB risk (6,7,12,48). Our data instead indicates that like Hispanic and African American women, L. iners does not appear to be risk factor for PTB in Chinese populations.…”

“…Dominance of the vaginal niche by commensal Lactobacillus species is often considered "optimal" due to their ability to prevent pathogen colonisation through competitive exclusion, in part achieved through the production of antimicrobial compounds and production of lactic acid (4,5). Recent studies have highlighted L. crispatus dominance as being protective against preterm birth (PTB) (2,(6)(7)(8)(9) and neonatal sepsis following preterm prelabour rupture of membranes (1). By contrast, colonisation by L.iners (7,(10)(11)(12) or Lactobacillus species depleted, high diversity compositions are associated with an increased risk of PTB (2,7,9,10,(13)(14)(15).…”

“…Recent studies have highlighted L. crispatus dominance as being protective against preterm birth (PTB) (2,(6)(7)(8)(9) and neonatal sepsis following preterm prelabour rupture of membranes (1). By contrast, colonisation by L.iners (7,(10)(11)(12) or Lactobacillus species depleted, high diversity compositions are associated with an increased risk of PTB (2,7,9,10,(13)(14)(15). Despite the majority of PTBs (60%) occurring in Asia (16), molecular based characterisation of the vaginal microbiota in pregnancy and its relationship with PTB has largely been restricted to Northern American and European populations.…”

Vaginal microbial profiling in a preterm birth high-risk cohort using shallow shotgun metagenomics

“…In 2-27% of pregnant women, the microbiome composition shifts to an increase in species diversity, leading to a dysbiotic vaginal microbiome associated with a disease state. Several studies have now show that an increase in bacterial diversity is linked to reproductive tract inflammation and increased risk of PTB [15][16][17][18][19] . Despite numerous studies investigating the predictive usefulness of vaginal microbiome analysis, the diagnostic utility of this approach remains elusive.…”

“…Despite numerous studies investigating the predictive usefulness of vaginal microbiome analysis, the diagnostic utility of this approach remains elusive. In a recent large study of low-risk Australian women, a high-risk microbial profile in the 2nd trimester was identified based on the presence/absence and combinations of known bacterial species 18 . Notwithstanding this study's clinical relevance to PTB management, it is important to point out that this particular work is based on analysis of a selected number of risk-associated bacteria, not the entire microbiome per se.…”