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

项目总结摘要 在临床确认怀孕的妇女中，约20%会发生妊娠丢失。有婚姻历史的夫妇 妊娠丢失占试图怀孕的人的很大一部分，但治疗仅限于广泛 难以获得的生育服务。阿司匹林对妊娠和生殖的影响(EARGE)试验的数据已经 有孕产史的妇女中，先入为主的小剂量阿司匹林治疗会增加出生率 当先入为主的慢性低度炎症(由C-反应蛋白确定)时的损失。的确有 迫切需要了解导致先入为主的慢性低度炎症的途径。这将会 帮助确定将从阿司匹林治疗中受益的更广泛的妇女群体，并告知阿司匹林的使用 在生殖医学方面。我们假设之前接触过常见性传播感染(STI) 会导致长期免疫失调和组织缺陷修复。有吸毒史的女性中 妊娠丢失、性传播感染血清学检测可能提示后续不良事件的风险或代表一组妇女 谁将从先入为主的抗炎治疗中受益。流行且大多无症状的性传播疾病，如 由于沙眼衣原体和生殖支原体可以上升到上生殖道，导致子宫内膜 炎症、组织损伤和疤痕形成。不幸的是，大多数女性在年轻时就感染了这些性传播疾病，但 不知道他们曾经被感染过。“训练有素的先天免疫”的概念假定先天免疫细胞 可在通过表观遗传诱导的感染刺激后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症有关，但与 其他衡量生育能力受损的指标也是有限的。这项提案的具体目标将：1)确定 沙眼衣原体和生殖支原体血清阳性对妊娠时间的影响 有妊娠流失史的妇女的失败率和出生率，同时调整了其他已知的感染 上生殖道。2)确定STI血清阳性妇女是否具有独特的血液免疫和血管生成特征 与血清阴性的女性相比。3)确定之前随机使用阿司匹林的STI血清阳性妇女 作为急切试验的一部分的治疗(结果如上所述)改善了分娩结果。这项研究将 包括来自急切试验的1078名女性。所有女性都有流产史，但没有不孕史。 从一项具有极其详细的生育结果的研究中获得先孕数据是独一无二的。另外， 我们的团队包括一位STI诊断领域的世界领先者，这使得强大的血清学测量成为可能。我们会 还利用我们团队成员的专业知识，目前他们被资助开发方法来解决 概括性，将我们的结果传递给我们的目标人群--有妊娠流产史的美国女性 使用全国家庭成长调查。鉴于性传播感染在美国和美国的发病率大幅上升 妊娠丢失的频率，这项研究和我们未来的工作可能会影响大量女性。

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.