Impact of periconceptual vaginal microbiota on women's risk of preterm birth

围孕期阴道微生物群对女性早产风险的影响

• 批准号: 9342979
• 负责人: Raymond Scott McClelland
• 金额: $ 54.74万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9342979
• 关键词: 37 weeks gestation; Address; Anaerobic Bacteria; Antibiotic Therapy; Awareness; Bacteria; Bacterial Vaginosis; Biological Assay; Centers for Disease Control and Prevention (U.S.); Cervix Mucus; Child Mortality; Chronic; Clinic; Clinical Treatment; Clinical Trials; Cohort Studies; Communities; Conceptions; Country; Data; Detection; Development; Endometrium; Evaluation; Fetal Membranes; Funding; Goals; HIV; Histologic; Individual; Infant; Inflammation; International; Intervention; Laboratories; Lactobacillus; Lead; Link; Mediating; Medical; Membrane; Menstruation; Meta-Analysis; Methods; Microbiology; Molecular; Morbidity - disease rate; Neonatal; Outcome; Pathway interactions; Phenotype; Placenta; Polymerase Chain Reaction; Population; Pregnancy; Premature Birth; Public Health; Recruitment Activity; Regimen; Reproductive Health; Research; Research Infrastructure; Resources; Risk; Sampling; Specimen; Structure; Surface; Surgeon; Symptoms; Techniques; Term Birth; Testing; Thinking; Time; Training; Umbilical cord structure; United States National Institutes of Health; Uterine cavity; Uterus; Vagina; Vaginal delivery procedure; Woman; amniotic cavity; base; deep sequencing; epidemiology study; experience; high risk; innovation; intraamniotic infection; metabolic profile; microbial; microbiome; microbiota; mortality; multidisciplinary; novel; point of care; prevent; prospective; protective effect; public health relevance; rRNA Genes; reproductive tract; screening; sex; symposium

 DESCRIPTION (provided by applicant): Preterm birth occurs in an estimated 10% of pregnancies, causing high rates of morbidity and mortality in infants. This public health problem has led to domestic and international initiatives including the US Surgeon General's Conference on Preventing Preterm Birth and the Millennium Development Goals (Goal 4, Reduce Child Mortality). Spontaneous preterm birth (SPTB) accounts for 70-80% of preterm births, with the remainder being medically induced. Bacterial vaginosis (BV) is a common condition that has consistently been associated with SPTB. Many bacteria associated with BV remain difficult to detect using cultivation methods, but are easily detected using molecular methods. Despite the consistent association between BV and SPTB, treating BV during pregnancy has failed to reduce SPTB in numerous clinical trials, raising critical questions: Do key bacterial species mediate the risk of SPTB? Is treatment of BV during pregnancy too late to reduce SPTB? Our multidisciplinary team has been at the forefront in developing cutting-edge laboratory techniques and applying them in carefully conducted epidemiological studies to make important discoveries linking disruption of the vaginal microbiota to adverse reproductive health outcomes. In this proposal, we will test the overarching hypothesis that high-risk vaginal bacterial species present near the time of conception colonize the uterine cavity, causing sub-clinical inflammation, and leading to SPTB. We will leverage access to facilities, highly trained staff, and a population of Kenyan women attending preconception clinics supported with US CDC and NIH funding, to make this unique case-cohort study possible. Aim 1 will employ broad-range 16S ribosomal RNA gene polymerase chain reaction (PCR) and deep sequencing to compare vaginal bacterial community structure, diversity, richness, and the presence of key species near conception, in women with SPTB vs. term delivery. Aim 2 will use highly sensitive quantitative PCR (qPCR) assays to compare the presence and concentrations of key vaginal bacterial species near conception in women with SPTB vs. term birth, validating or refuting preliminary associations observed in Aim 1. Aim 3 will utilize fetal membrane and umbilical cord samples collected at delivery, combining species-specific qPCR assays and histological examination, to determine whether vaginal bacteria associated with SPTB in Aims 1 and 2 ascend to the upper genital tract and cause inflammation. In parallel, we will examine associations between key vaginal bacterial species during pregnancy and SPTB, allowing us to directly compare the risk of SPTB associated with vaginal bacteria identified in the peri-conception period vs. during pregnancy. Identification of strong relationships between bacterial species and communities present close to the time of conception and SPTB is expected to shift our paradigm for understanding how vaginal microbiota influences women's risk of SPTB. These data could inform development of targeted interventions based on elimination of high-risk species and promotion of low-risk vaginal bacterial communities in women planning a pregnancy, particularly after prior SPTB.

 描述（由申请人提供）：估计有 10% 的怀孕会发生早产，导致婴儿发病率和死亡率很高。这一公共卫生问题引发了国内和国际倡议，包括美国卫生局局长预防早产会议和会议。千年发展目标（目标 4，降低儿童死亡率） 自然早产 (SPTB) 占早产的 70-80%，细菌性阴道病 (BV) 是一种与 SPTB 相关的常见疾病，但使用培养方法仍然难以检测到，但使用分子方法很容易检测到。 BV 和 SPTB，在许多临床试验中，怀孕期间治疗 BV 未能减少 SPTB，这引发了关键问题：怀孕期间治疗 BV 是否会降低 SPTB 的风险？处于尖端实验室技术的最前沿，并将其应用于精心进行的流行病学研究中，以得出将阴道微生物群破坏与不良生殖健康结果联系起来的重要发现。在本提案中，我们将测试开发高风险阴道细菌的总体假设。接近受孕时存在的细菌种类会在子宫腔内定植，引起亚临床炎症，并导致 SPTB。我们将利用设施、训练有素的工作人员以及在美国疾病预防控制中心和美国疾病预防控制中心支持的孕前诊所就诊的肯尼亚妇女群体。 NIH 资助，使这项独特的病例队列研究成为可能，目标 1 将采用广泛的 16S 核糖体 RNA 基因聚合酶链反应 (PCR) 和深度测序来比较阴道细菌群落结构、多样性、丰富度和关键物种的存在。目标 2 将使用高灵敏度 PCR (qPCR) 检测来比较 SPTB 与足月分娩妇女在接近受孕时的关键阴道细菌种类的存在和浓度。驳斥目标 1 中观察到的初步关联。目标 3 将利用分娩时收集的胎膜和脐带样本，结合物种特异性 qPCR 检测和组织学检查，以确定目标 1 和 2 中与 SPTB 相关的阴道细菌是否上升到上生殖器与此同时，我们将检查怀孕期间关键阴道细菌种类与 SPTB 之间的关联，从而使我们能够直接比较与围孕期和怀孕期间发现的阴道细菌相关的 SPTB 风险。怀孕期间细菌种类和群落之间的密切关系有望改变我们了解阴道微生物群如何影响妇女患 SPTB 的风险。这些数据可以为基于消除 SPTB 的有针对性的干预措施的制定提供信息。高风险物种和促进低风险阴道细菌群落计划怀孕的妇女，特别是在既往 SPTB 后。