The Role Of Subclinical Infection And Cytokines In Preterm Parturition

亚临床感染和细胞因子在早产中的作用

基本信息

批准号：
8941476
负责人：
ROBERTO ROMERO
金额：
$ 2048.67万
依托单位：
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8941476
关键词：
Acute Adrenergic beta-Agonists Affect Amniotic Fluid Anaerobic Bacteria Antibiotic Therapy Bacteria Bacterial Vaginosis Base Sequence Bedside Testings Biological Assay Birth Calcium Channel Blockers Cervix Uteri Communities Control Groups Detection Development Diagnosis Diagnostic Disease Ecology Ecosystem Electrons Endometritis Endotoxins Enzymes Equation Frequencies Future Gardnerella Generations Genetic Genital system Genome Genomics Gestational Age Goals Gram-Negative Bacteria Histologic Hour Human body Immune response Individual Infant Infection Infection of amniotic sac and membranes Inflammation Inflammatory Inflammatory Response Injury Interleukin-6 Intervention Lactobacillus Lesion Light Mass Spectrum Analysis Mechanics Meconium Meconium Aspiration Membrane Meta-Analysis Methods Microbe Mobiluncus Modeling Molecular Morbidity - disease rate Mucous Membrane Nitroglycerin Oropharyngeal Pathogenesis Pathologic Processes Patients Perinatal Perinatology Phospholipase A2 Placenta Predisposing Factor Predisposition Pregnancy Pregnant Women Premature Birth Premature Labor Prevention Prevotella Procedures Relative (related person)Reporting Research Risk Risk Factors Role Sampling Series Staining method Stains Structure Suction Surveys Syndrome Taxon Techniques Technology Testing Time Tocolysis Tocolytic Agents Trichomonas vaginalis United States Vagina Virus Woman clinical risk cost cytokine fetal gene environment interaction human disease improved indexing intraamniotic infection ionization microbial microorganism mortality neonatal sepsis neonate pregnant premature prevent pyrosequencing rRNA Genes rapid diagnosis systematic review tool uterine contractility vaginal fluid

项目摘要

A central question is why some women develop an ascending intra-amniotic infection, while whereas most do not. The relationship between the mucosa of the lower genital tract (vagina and cervix) and the microbial ecosystem appears to be a key factor predisposing to ascending infection. Bacterial vaginosis a change in the microbial ecosystem in which there is proliferation of anaerobic bacteria confers risk for intra-amniotic infection and spontaneous preterm delivery. Similarly, trichomonas vaginalis infection is a risk factor for preterm delivery. However, antibiotic treatment of asymptomatic women with bacterial vaginosis or trichomonas vaginalis has not reduced the rate of preterm delivery. A comprehensive understanding of microbial ecology, genetic factors that control susceptibility to infection and the inflammatory response is required, particularly in light of evidence that gene-environment interactions may predispose to preterm labor (2). Characterization of the microbial composition of ecological niches in the human body, including the vagina, using culture-independent techniques, is now possible. This year, we reported a study which showed that the composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women. This included non-pregnant women (N=32) and pregnant women who delivered at term (38-42 weeks) without complications (n = 22). Serial samples of vaginal fluid were collected from both non-pregnant and pregnant patients. A 16S rRNA gene sequence-based survey was conducted using pyrosequencing to characterize the structure and stability of the vaginal microbiota. Linear mixed effects models and generalized estimating equations were used to identify the phylotypes whose relative abundance was different between the two study groups. The vaginal microbiota of normal pregnant women was different from that of non-pregnant women (higher abundance of Lactobacillus vaginalis, L. crispatus, L. gasseri and L. jensenii and lower abundance of 22 other phylotypes in pregnant women). Bacterial community state type (CST) IV-B or CST IV-A characterized by high relative abundance of species of genus Atopobium as well as the presence of Prevotella, Sneathia, Gardnerella, Ruminococcaceae, Parvimonas, Mobiluncus and other taxa previously shown to be associated with bacterial vaginosis were less frequent in normal pregnancy. The stability of the vaginal microbiota of pregnant women was higher than that of non-pregnant women; however, during normal pregnancy, bacterial communities shift almost exclusively from one CST dominated by Lactobacillus spp. to another CST dominated by Lactobacillus spp.(3). We then conducted a study to determine whether the vaginal microbiota of pregnant women who subsequently had a spontaneous preterm delivery is different from that of women who had a term delivery. We included a control group of pregnant women who had a term delivery and those who had a spontaneous preterm delivery before 34 weeks of gestation (cases). Samples of vaginal fluid were collected longitudinally and stored at −70C until assayed. A microbial survey using pyrosequencing of V1-V3 regions of 16S rRNA genes was performed, and we tested the hypothesis of whether the relative abundance of individual microbial species (phylotypes) was different between women who had a term versus preterm delivery. The findings were that: the composition of the vaginal microbiota during normal pregnancy changed as a function of gestational age, with an increase in the relative abundance of four Lactobacillus spp., and decreased in anaerobe or strict-anaerobe microbial species as pregnancy progressed; however, no change in the relative abundance of bacterial taxa was observed between women who had a spontaneous preterm delivery and those who delivered at term. The same was the case for the frequency of the vaginal community state types (CST I, III, IV-B). These early findings suggest that changes in the vaginal microbiota are not easily detected in women who subsequently have a spontaneous preterm delivery. Future studies need to take into consideration the indices of the maternal immune response and functional aspects of the vaginal microbiota (4). Meconium-stained amniotic fluid (MSAF) affects 5-20% of all pregnancies (400,000-600,000 deliveries per year in the United States alone), and is a risk factor for meconium aspiration syndrome (MAS); however, only 5% of infants with MSAF develop MAS. A critical question is why some neonates exposed to meconium develop this syndrome, and others do not. Attempts to prevent MAS with mechanical methods such as oropharyngeal, nasopharyngeal and tracheal suctioning and amnioinfusion have been attempted, but none have proven effective. Patients with MSAF are at increased risk for clinical chorioamnionitis, puerperal endometritis, neonatal sepsis, and intra-amniotic infection. Therefore, we conducted a series of studies to determine if MSAF was associated with the presence of bacteria in the amniotic fluid or bacterial products such as endotoxin. We found that 19% of patients with MSAF have microorganisms detected by culture, and there were frequently gram-negative bacteria. Endotoxin was detected in 46% of patients with MSAF, and these patients were also more likely to have intra-amniotic inflammation (an elevation in AF IL-6). In a separate study, we found that MSAF containing bacterial endotoxin also had a higher concentration of secreted phospholipase A2, an enzyme implicated in the pathogenesis of MAS. Studies are now in progress to determine if fetal systemic inflammation may be a predisposing factor for the development of MAS (5). The mainstay for the treatment of preterm labor remains arresting uterine contractility (tocolysis). We previously reported systematic reviews and meta-analyses of calcium-channel blockers for this indication. This year, we reported a systematic review and meta-analysis of transdermal nitroglycerin for the treatment of preterm labor. We found that, although transdermal nitroglycerin appears to be more effective than beta adrenergic receptor agonists, the current evidence does not support its routine use as a tocolytic agent for the treatment of preterm labor (6).

一个核心问题是，为什么有些女性会出现上升的肿瘤内感染，而大多数女性则没有。下生殖道（阴道和子宫颈）和微生物生态系统的粘膜之间的关系似乎是易受上升感染的关键因素。细菌性阴道病的一种微生物生态系统的变化，其中厌氧细菌的增殖赋予了肿瘤内感染和自发早产的风险。同样，阴道感染是早产的危险因素。然而，对无症状的细菌性阴道病或阴道的抗生素治疗尚未降低早产率。需要对微生物生态学的全面理解，控制感染易感性和炎症反应的遗传因素，尤其是鉴于证据表明基因 - 环境相互作用可能会易于早产（2）。现在可以使用独立的技术来表征人体生态壁细分市场的微生物组成，包括阴道。今年，我们报道了一项研究表明，正常孕妇阴道菌群的组成和稳定性与非怀孕妇女的组成和稳定性不同。这包括未怀孕的妇女（n = 32）和孕妇在学期（38-42周）中分娩而没有并发症（n = 22）。从非妊娠和孕妇收集阴道液的系列样品。使用焦磷酸测序进行了基于16S rRNA基因序列的调查，以表征阴道微生物群的结构和稳定性。线性混合效应模型和广义估计方程用于识别两个研究组之间相对丰度不同的系统型。正常孕妇的阴道菌群与非孕妇的阴道菌群不同（阴道乳酸乳杆菌的丰度较高，Crispatus L. crispatus，L。Gasseri和L. jensenii以及孕妇其他22种其他系统型）。细菌群落状态类型（CST）IV-B或CST IV-A的特征是，其特征在于，肥大属的物种相对丰度以及Prevotella，Sneathia，Gardnerella，Gardnerella，Ruminococcaceae，Parvimonas，Mobiluncus，Mobiluncus和其他先前显示出与细菌性阴道病的频率更少有关。孕妇阴道菌群的稳定性高于非孕妇的稳定性。但是，在正常怀孕期间，细菌群落几乎完全从一个由乳杆菌属于乳杆菌的CST转移。到另一个由乳酸杆菌属属于（3）的CST。然后，我们进行了一项研究，以确定随后自发早产的孕妇的阴道菌群是否与递送期限的妇女不同。我们包括了一个对照组的孕妇，这些孕妇的期限分娩和那些在妊娠34周之前自发早产的孕妇（病例）。纵向收集阴道流体的样品，并以-70C储存，直到测定。进行了16S rRNA基因的V1-V3区域的旋转测序的微生物测量，我们测试了在术语与早产递送的妇女之间的单个微生物物种（系统型）相对丰度（系统型）是否不同的假设。研究结果是：正常怀孕期间阴道菌群的组成随胎龄的作用而变化，随着妊娠的相对丰度增加，厌氧菌或严格的虫害微生物物种的相对丰度随着妊娠的进展而减少；但是，在自发早产的妇女和任期交付的女性之间，没有观察到细菌分类单群的相对丰度。阴道群落状态类型的频率也是如此（CST I，III，IV-B）。这些早期发现表明，在随后自发早产的女性中，阴道微生物群的变化不容易被发现。未来的研究需要考虑到阴道菌群的母体免疫反应和功能方面的指标（4）。胎粪染色的羊水（MSAF）会影响所有怀孕的5-20％（仅在美国，每年400,000-600,000次分娩），这是胎粪吸入综合征（MAS）的危险因素；但是，只有5％的MSAF婴儿发展为MAS。一个关键的问题是，为什么一些暴露于胎粪的新生儿发展了这种综合征，而另一些则没有。已经尝试使用机械方法来预防MAS，例如口咽，鼻咽和气管吸收和羊膜输液，但已尝试使用，但没有证明有效。 MSAF患者患临床绒毛膜炎，胸膜子宫内膜炎，新生儿败血症和肿瘤内感染的风险增加。因此，我们进行了一系列研究，以确定MSAF是否与羊水或细菌产物（例如内毒素）中的细菌存在有关。我们发现，有19％的MSAF患者患有培养物检测到的微生物，并且经常患有革兰氏阴性细菌。在46％的MSAF患者中检测到内毒素，这些患者也更有可能患有肿瘤内炎症（AF IL-6升高）。在另一项研究中，我们发现含有细菌内毒素的MSAF也具有更高浓度的分泌磷脂酶A2，这是一种与MAS发病机理有关的酶。现在正在进行研究以确定胎儿全身性炎症是否可能是MAS发展的诱人因素（5）。早产治疗的主要手段仍然会阻止子宫收缩力（吞噬）。我们先前报道了该指示的钙通道阻滞剂的系统评价和荟萃分析。今年，我们报道了对透皮硝基甘油的系统综述和荟萃分析，以治疗早产。我们发现，尽管经皮硝酸甘油似乎比β肾上腺素能受体激动剂更有效，但目前的证据不支持其作为早产劳动治疗的溶剂溶剂的常规用途（6）。