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Impact of preconception vaginal microbiota on women's risk of spontaneous preterm birth: protocol for a prospective case-cohort study.

ABSTRACT: INTRODUCTION:Bacterial vaginosis (BV) and vaginal microbiota disruption during pregnancy are associated with increased risk of spontaneous preterm birth (SPTB), but clinical trials of BV treatment during pregnancy have shown little or no benefit. An alternative hypothesis is that vaginal bacteria present around conception may lead to SPTB by compromising the protective effects of cervical mucus, colonising the endometrial surface before fetal membrane development, and causing low-level inflammation in the decidua, placenta and fetal membranes. This protocol describes a prospective case-cohort study addressing this hypothesis. METHODS AND ANALYSIS:HIV-seronegative Kenyan women with fertility intent are followed from preconception through pregnancy, delivery and early postpartum. Participants provide monthly vaginal specimens during the preconception period for vaginal microbiota assessment. Estimated date of delivery is determined by last menstrual period and first trimester obstetrical ultrasound. After delivery, a swab is collected from between the fetal membranes. Placenta and umbilical cord samples are collected for histopathology. Broad-range 16S rRNA gene PCR and deep sequencing of preconception vaginal specimens will assess species richness and diversity in women with SPTB versus term delivery. Concentrations of key bacterial species will be compared using quantitative PCR (qPCR). Taxon-directed qPCR will also be used to quantify bacteria from fetal membrane samples and evaluate the association between bacterial concentrations and histopathological evidence of inflammation in the fetal membranes, placenta and umbilical cord. ETHICS AND DISSEMINATION:This study was approved by ethics committees at Kenyatta National Hospital and the University of Washington. Results will be disseminated to clinicians at study sites and partner institutions, presented at conferences and published in peer-reviewed journals. The findings of this study could shift the paradigm for thinking about the mechanisms linking vaginal microbiota and prematurity by focusing attention on the preconception vaginal microbiota as a mediator of SPTB.

SUBMITTER: Lokken EM

PROVIDER: S-EPMC7045118 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Impact of preconception vaginal microbiota on women's risk of spontaneous preterm birth: protocol for a prospective case-cohort study.

Lokken Erica M EM Mandaliya Kishorchandra K Srinivasan Sujatha S Richardson Barbra A BA Kinuthia John J Lannon Sophia S Jaoko Walter W Alumera Hudson H Kemoli Arthur A Fay Emily E John-Stewart G G Fredricks David N DN McClelland R Scott RS

BMJ open 20200225 2

<h4>Introduction</h4>Bacterial vaginosis (BV) and vaginal microbiota disruption during pregnancy are associated with increased risk of spontaneous preterm birth (SPTB), but clinical trials of BV treatment during pregnancy have shown little or no benefit. An alternative hypothesis is that vaginal bacteria present around conception may lead to SPTB by compromising the protective effects of cervical mucus, colonising the endometrial surface before fetal membrane development, and causing low-level i ...[more]

PMID: 32102825

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Project description:BackgroundThe bacterial community present in the female lower genital tract plays an important role in maternal and neonatal health. Imbalances in this microbiota have been associated with negative reproductive outcomes, such as spontaneous preterm birth (sPTB), but the mechanisms underlying the association between a disturbed microbiota and sPTB remain poorly understood. An intrauterine infection ascending from the vagina is thought to be an important contributor to the onset of preterm labour. Our objective was to characterize the vaginal microbiota of pregnant women who had sPTB (n = 46) and compare to those of pregnant women who delivered at term (n = 170). Vaginal swabs were collected from women at 11-16 weeks of gestational age. Microbiota profiles were created by PCR amplification and pyrosequencing of the cpn60 universal target region.ResultsProfiles clustered into seven community state types: I (Lactobacillus crispatus dominated), II (Lactobacillus gasseri dominated), III (Lactobacillus iners dominated), IVA (Gardnerella vaginalis subgroup B or mix of species), IVC (G. vaginalis subgroup A dominated), IVD (G. vaginalis subgroup C dominated) and V (Lactobacillus jensenii dominated). The microbiota of women who experienced preterm birth (< 37 weeks gestation) had higher richness and diversity and higher Mollicutes prevalence when compared to those of women who delivered at term. The two groups did not cluster according to CST, likely because CST assignment is driven in most cases by the dominance of one particular species, overwhelming the contributions of more rare taxa. In conclusion, we did not identify a specific microbial community structure that predicts sPTB, but differences in microbiota richness, diversity and Mollicutes prevalence were observed between groups.ConclusionsAlthough a causal relationship remains to be determined, our results confirm previous reports of an association between Mollicutes and sPTB and further suggest that a more diverse microbiome may be important in the pathogenesis of some cases.

Project description:ObjectiveThe 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.ResultsThe 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.ConclusionGDM 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.

Project description:Previous studies have investigated the associations between the vaginal microbiome and preterm birth, with the aim of determining whether differences in community patterns meaningfully alter risk and could therefore be the target of intervention. We report on vaginal microbial analysis of a nested case-control subset of the Pregnancy, Infection, and Nutrition (PIN) Study, including 464 White women (375 term birth and 89 spontaneous preterm birth, sPTB) and 360 Black women (276 term birth and 84 sPTB). We found that the microbiome of Black women has higher alpha-diversity, higher abundance of Lactobacillus iners, and lower abundance of Lactobacillus crispatus. However, among women who douche, there were no significant differences in microbiome by race. The sPTB-associated microbiome exhibited a lower abundance of L. crispatus, while alpha diversity and L. iners were not significantly associated with sPTB. For each order of magnitude increase in the normalized relative abundance of L. crispatus, multivariable adjusted odds of sPTB decreased by approximately 20% (odds ratio, 0.81; 95% confidence interval, 0.70, 0.94). When we considered the impact of douching, associations between the microbiome and sPTB were limited to women who do not douche. We also observed strong intercorrelations between a range of maternal factors, including poverty, education, marital status, age, douching, and race, with microbiome effect sizes in the range of 1.8 to 5.2% in univariate models. Therefore, race may simply be a proxy for other socially driven factors that differentiate microbiome community structures. Future work will continue to refine reliable microbial biomarkers for preterm birth across diverse cohorts. IMPORTANCE Approximately 10% of all pregnancies in the United States end in preterm birth, and over 14% of pregnancies end in preterm birth among Black women. Knowledge on the associations between vaginal microbiome and preterm birth is important for understanding the potential cause and assessing risk of preterm birth. Our study is one of the largest studies performed to date to investigate the associations between vaginal microbiome and spontaneous preterm birth (sPTB), with stratified design for Black and White women. We found that the vaginal microbiome was different between Black and White women. The vaginal microbiome was associated with sPTB, and a lower abundance of L. crispatus increased the risk of sPTB independent of racial differences in microbial community structures. Furthermore, we also found that vaginal douching obscured the associations between vaginal microbiome, race, and preterm birth, suggesting that vaginal douching is an important factor to consider in future studies.

Project description:BackgroundA processed diet, high in fat and low in fiber, is associated with differences in the gut microbiota and adverse health outcomes in humans; however, little is known about the diet-microbiota relation and its impact on pregnancy. Spontaneous preterm birth (SPTB), a pregnancy outcome with serious short- and long-term consequences, occurs more frequently in black and in obese women in the United States.ObjectivesIn a prospective, case-control sample matched for race and obesity (cases = 16, controls = 32), we compared the fecal gut microbiota, fecal and plasma metabolites, and diet in the late second trimester. We hypothesized that a Western diet would be associated with reduced microbiota richness and a metabolic signature predicting incidence of SPTB.MethodsThe fecal microbiota was characterized by 16S-tagged sequencing and untargeted metabolomics was used to analyze both plasma and fecal metabolites. Wilcoxon's rank-sum test was used for the comparison of microbiota genera, α-diversity, fecal and plasma metabolites, and dietary variables between term and SPTB. β-Diversity was analyzed using permutational multivariate ANOVA, and metabolite associations were assessed by module analysis.ResultsA decrease in α-diversity was strongly associated with the development of SPTB, especially in the taxonomic class of Betaproteobacteria. Of 824 fecal metabolites, 22 metabolites (mostly lipids) differed between cases and controls (P < 0.01), with greater DHA (22:6n-3) and EPA (20:5n-3) in cases [false discovery rate (FDR) < 0.2]. The most significant fecal metabolite module (FDR-adjusted P = 0.008) was dominated by DHA and EPA. Dietary saturated fat (primarily palmitate) intake was greater in cases (31.38 ± 7.37 compared with 26.08 ± 8.62 g, P = 0.045) and was positively correlated with fecal DHA and EPA (P < 0.05).ConclusionsReduced α-diversity of the gut microbiota and higher excretion of omega-3 (n-3) fatty acids in stool may provide a novel biomarker signature predicting SPTB in women with a low-fiber, high-fat diet. Further investigation of these markers in a larger sample is needed for validation.

Project description:BackgroundPreterm birth (PTB) remains a leading cause of neonatal mortality and long-term morbidity. Individual factors have been linked to PTB risk. The impact of a healthy lifestyle, with multiple modifiable prenatal factors, remains unknown.ObjectivesWe aimed to examine the associations of preconceptional and early-pregnancy low-risk modifiable factors (individually and in combination) with PTB risk.MethodsThis prospective cohort study included 2449 women with singleton pregnancies in the Pregnancy Environment and Lifestyle Study. PTB was defined as ultrasound-confirmed obstetric estimate-based gestational age at delivery <37 wk. A set of low-risk modifiable factors were identified: healthy weight (prepregnancy BMI: 18.5-24.9 kg/m2) based on clinical measurements and high-quality diet (Alternate Healthy Eating Index-Pregnancy score ≥75th percentile) and low-to-moderate stress during early pregnancy (Perceived Stress Scale score <75th percentile) assessed at gestational weeks 10-13. Poisson regression estimated adjusted relative risk (aRR) of PTB in association with individual and combined low-risk modifiable prenatal factors, adjusting for sociodemographic, clinical, and other prenatal factors.ResultsOne hundred and sixty women (6.5%) delivered preterm. Risk of PTB was lower among women who had a healthy weight (aRR: 0.58; 95% CI: 0.39, 0.86), high-quality diet (aRR: 0.68; 95% CI: 0.39, 0.99), and low-to-moderate stress (aRR: 0.60; 95% CI: 0.41, 0.88). Women with 1, 2, or 3 low-risk modifiable prenatal factors compared with none had a 38% (aRR: 0.72; 95% CI: 0.45, 1.16), 51% (aRR: 0.49; 95% CI: 0.29, 0.84), or 70% (aRR: 0.30; 95% CI: 0.13, 0.70) lower PTB risk, respectively. Associations of having ≥1 low-risk factor with PTB risk were more pronounced for medically indicated than for spontaneous PTB and for late than for early or moderate PTB. Associations also varied by race or ethnicity, although with overlapping 95% CIs.ConclusionsA healthy prenatal lifestyle with multiple low-risk modifiable factors was associated with lower risk of PTB. Our findings may inform multicomponent preconceptional or early-pregnancy prevention strategies to mitigate PTB risk.

Project description:A major challenge in preventing preterm birth (PTB) is identifying women at greatest risk. This pilot study prospectively examined the differences in vaginal microbiota and metabolite profiles of women who delivered prematurely compared to their term counterparts in a cohort of asymptomatic (studied at 20-22, n = 80; and 26-28 weeks, n = 41) and symptomatic women (studied at 24-36 weeks, n = 37). Using 16S rRNA sequencing, the vaginal microbiota from cervicovaginal fluid samples was characterized into five Community State Types (CST) dominated by Lactobacillus spp.: CSTI (Lactobacillus crispatus), CSTII (Lactobacillus gasseri), CSTIII (Lactobacillus iners), CSTV (Lactobacillus jensenii); and mixed anaerobes-CSTIV. This was then related to the vaginal metabolite profile and pH determined by 1H-Nuclear Magnetic Resonance spectroscopy and pH indicator paper, respectively. At 20-22 weeks, the term-delivered women (TDW) indicated a proportion of CSTI-dominated microbiota >2-fold higher compared to the preterm-delivered women (PTDW) (40.3 vs. 16.7%, P = 0.0002), and a slightly higher proportion at 26-28 weeks (20.7 vs. 16.7%, P = 0.03). CSTV was >2-fold higher in the PTDW compared to TDW at 20-22 (22.2 vs. 9.7%, P = 0.0002) and 26-28 weeks (25.0 vs. 10.3%, P = 0.03). Furthermore, at 26-28 weeks no PTDW had a CSTII-dominated microbiome, in contrast to 28% of TDW (P < 0.0001). CSTI-dominated samples showed higher lactate levels than CSTV at 20-22 weeks (P < 0.01), and 26-28 weeks (P < 0.05), while CSTII-dominated samples indicated raised succinate levels over CSTV at 26-28 weeks (P < 0.05). These were supported by Principal coordinates analysis, which revealed strong clustering of metabolites according to CST. In addition, the CSTI-dominated samples had an average pH of 3.8, which was lower than those of CSTII-4.4, and CSTV-4.2 (P < 0.05). Elevated vaginal lactate and succinate were associated with predominance of CSTI and II over CSTV in women who delivered at term compared with their preterm counterparts. This suggests that L. jensenii-dominance and decreased lactate and/or succinate could increase the risk of PTB, while L. crispatus/gasseri may confer some protection against inflammation-associated PTB and highlight the need for further study in this area.

Dataset Information

Impact of preconception vaginal microbiota on women's risk of spontaneous preterm birth: protocol for a prospective case-cohort study.

Publications

Impact of preconception vaginal microbiota on women's risk of spontaneous preterm birth: protocol for a prospective case-cohort study.

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