Evaluating the intersection between sexually transmitted infections, inflammation and reproductive success

评估性传播感染、炎症和生殖成功之间的交叉点

• 批准号: 10338181
• 负责人: Brandie DePaoli Taylor
• 金额: $ 45.56万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10338181
• 关键词: Address; Adverse event; Age; Anti-Inflammatory Agents; Aspirin; Biological Assay; Birth; Birth Rate; Blood; Blood Platelets; C-reactive protein; Cells; Chlamydia; Chlamydia trachomatis; Chronic; Cicatrix; Clinical; Conceptions; Couples; Data; Decidual Cell Reactions; Defect; Diagnosis; Diagnostic; Disease; Dose; Endometrial; Epigenetic Process; Epithelial Cells; Event; Exposure to; Family; Fertility; Frequencies; Funding; Future; Goals; Growth; High Prevalence; IL6 gene; IL8 gene; Immune; Immune signaling; Immunologic Receptors; Infection; Infertility; Inflammation; Interleukin-15; Laboratories; Lead; Legal patent; Link; Live Birth; Measurement; Measures; Mediating; Menstrual cycle; Metadata; Methods; Mission; Morbidity - disease rate; Mycoplasma; Mycoplasma genitalium; Natural Immunity; Nature; Neisseria gonorrhoeae; Outcome; PGF gene; PTGS2 gene; Pathogenesis; Pathology; Pathway interactions; Phenotype; Placebos; Placentation; Plasma; Population; Pregnancy; Pregnancy Histories; Pregnancy loss; Prevalence; Prevention; Prostaglandins; Public Health; Randomized; Recording of previous events; Reproduction; Reproductive Health; Reproductive Medicine; Research; Research Support; Risk; Route; STI prevention; Serology; Seroprevalences; Serum; Services; Sexually Transmitted Diseases; Sterility; Stimulus; Subfecundity; Surveys; Target Populations; Thromboxane A2; Time; Tissues; Training; Trichomonas vaginalis; Tube; United States National Institutes of Health; Variant; Vascular Endothelial Growth Factors; Woman; Women' s Group; Work; adverse event risk; adverse outcome; angiogenesis; cytokine; early pregnancy loss; fetal; high risk; high risk population; histone modification; human disease; improved; improved outcome; inflammatory marker; innovation; insight; interest; member; obstetric care; pathogen; reproductive; reproductive morbidity; reproductive outcome; reproductive success; reproductive tract; seropositive; subfertility; time-to-pregnancy; tissue repair; trying to conceive; tubal infertility; young adult

PROJECT SUMMARY ABSTRACT Pregnancy loss occurs in ~20% of women with a clinically recognized pregnancy. Couples with histories of pregnancy loss represent a large portion of those trying to conceive, but treatment is limited to widely inaccessible fertility services. Data from the Effects of Aspirin in Gestation and Reproduction (EAGeR) Trial has shown that preconception low-dose Aspirin therapy increases birth rates in women with histories of pregnancy loss when preconception chronic low-grade inflammation, determined by C-reactive protein, is present. There is a critical need to understand pathways that result in preconception chronic low-grade inflammation. This would help to identify a broader group of women whom would benefit from aspirin therapy and inform the use of aspirin in reproductive medicine. We hypothesize that prior exposure to common sexually transmitted infections (STIs) can lead to long-term immune dysregulation and defective tissue repair. Among women with histories of pregnancy loss, STI serology may indicate subsequent risk of adverse events or represent a group of women who would benefit from preconception anti-inflammatory therapy. Prevalent and mostly asymptomatic STIs such as Chlamydia trachomatis and Mycoplasma genitalium can ascend to the upper genital tract causing endometrial inflammation, tissue damage and scarring. Unfortunately, most women acquire these STIs as young adults, but do not know they were ever infected. The concept of “trained innate immunity” posits that innate immune cells can develop a long-term proinflammatory phenotype following infectious stimuli induced through epigenetic changes to immune and epithelial cells. Indeed, these STIs are linked to tubal infertility but associations with other measures of impaired fecundity are limited. The specific aims of this proposal will: 1) determine if seropositivity to Chlamydia trachomatis and Mycoplasma genitalium influences time-to-pregnancy, pregnancy loss and birth rates in women with histories of pregnancy loss while adjusting for other STIs known to infect the upper genital tract. 2) Determine if STI seropositive women have a unique blood immune and angiogenic profile compared to seronegative women. 3) Determine if STI seropositive women previously randomized to Aspirin therapy as part of the EAGeR trial (results described above) have improved birth outcomes. This study will include 1078 women from the EAGeR trial. All women have histories of pregnancy loss but no history of infertility. Access to preconception data from a study with extremely detailed reproductive outcomes is unique. Additionally, our team includes a world-leader in STI diagnostics, which allows for robust serological measurements. We will also leverage the expertise of our team members, currently funded to develop methods to address generalizability, to transport our results to our target population of US women with histories of pregnancy loss using the National Survey of Family Growth. Given the profound increase in STI prevalence in the U.S. and the frequency of pregnancy loss, this study and our future work could impact a large number of women.

项目概要 摘要 约 20% 经临床确认怀孕的女性会发生流产。有历史的夫妇 尝试怀孕的人中很大一部分是流产，但治疗仅限于广泛 无法获得生育服务。阿司匹林对妊娠和生殖的影响 (EAGeR) 试验的数据 研究表明，孕前低剂量阿司匹林治疗可提高有妊娠史的女性的出生率 当存在由 C 反应蛋白确定的孕前慢性低度炎症时，就会丧失。有 迫切需要了解导致孕前慢性低度炎症的途径。这会 帮助确定更多可以从阿司匹林治疗中受益的女性群体，并告知阿司匹林的使用 在生殖医学领域。我们假设之前接触过常见性传播感染 (STI) 可能导致长期的免疫失调和有缺陷的组织修复。在有以下病史的女性中 妊娠丢失、STI 血清学可能表明随后发生不良事件的风险或代表一组女性 谁会受益于孕前抗炎治疗。普遍且大多无症状的性传播感染，例如 因为沙眼衣原体和生殖支原体可以上升到上生殖道，引起子宫内膜异位症。 炎症、组织损伤和疤痕。不幸的是，大多数女性在年轻时都会感染这些性传播感染，但是 不知道他们曾经被感染过。 “训练有素的先天免疫”的概念认为，先天免疫细胞 在通过表观遗传诱导的感染刺激后可以形成长期的促炎表型 免疫细胞和上皮细胞的变化。事实上，这些性传播感染与输卵管性不孕有关，但与 其他衡量生育能力受损的措施是有限的。该提案的具体目标将： 1) 确定是否 沙眼衣原体和生殖支原体血清阳性影响怀孕时间、妊娠 有流产史的妇女的流产率和出生率，同时调整其他已知感染性病的性传播感染 上生殖道。 2) 确定 STI 血清阳性女性是否具有独特的血液免疫和血管生成特征 与血清阴性女性相比。 3) 确定 STI 血清阳性女性之前是否被随机分配服用阿司匹林 作为 EGeR 试验一部分的治疗（结果如上所述）改善了出生结局。这项研究将 包括来自 EGeR 试验的 1078 名女性。所有女性都有流产史，但没有不孕史。 从具有极其详细的生殖结果的研究中获得孕前数据是独一无二的。此外， 我们的团队包括 STI 诊断领域的世界领先者，可以进行可靠的血清学测量。我们将 还利用我们团队成员的专业知识，目前资助开发方法来解决 普遍性，将我们的结果传达给有流产史的美国女性目标人群 使用全国家庭成长调查。鉴于美国性传播感染流行率大幅上升 流产的频率、这项研究和我们未来的工作可能会影响大量女性。