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

项目摘要 约20%的临床确认妊娠的女性发生妊娠丢失。有过 流产代表了那些试图怀孕的人的很大一部分，但治疗仅限于广泛的 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 表明孕前低剂量阿司匹林治疗会增加有妊娠史妇女的出生率 当存在由C-反应蛋白确定的孕前慢性低度炎症时损失。有 迫切需要了解导致孕前慢性低度炎症的途径。这将 帮助确定更广泛的妇女群体，他们将受益于阿司匹林治疗，并告知阿司匹林的使用 在生殖医学方面。我们假设，先前暴露于常见的性传播感染（STI） 会导致长期免疫失调和组织修复缺陷。在那些有过 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 能从孕前抗炎治疗中获益流行且大多无症状的性传播感染， 因为沙眼衣原体和生殖支原体可以上升到上生殖道， 炎症、组织损伤和瘢痕形成。不幸的是，大多数女性在年轻时获得这些性传播感染， 他们不知道自己曾经被感染过。“训练的先天免疫”的概念假定先天免疫细胞 在通过表观遗传诱导的感染刺激后， 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不孕有关，但与 生殖力受损的其他措施是有限的。本提案的具体目标是：1）确定 沙眼衣原体和生殖支原体血清阳性影响妊娠时间， 有流产史的妇女的流产率和出生率，同时调整已知感染的其他性传播感染， 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 与血清反应阴性的女性相比。3)确定既往随机接受阿司匹林治疗的STI血清阳性女性 作为EAGeR试验的一部分的治疗（上述结果）改善了分娩结局。本研究将 包括来自EAGeR试验的1078名女性。所有妇女都有流产史，但没有不孕症史。 从极其详细的生殖结果研究中获得孕前数据是独一无二的。此外，本发明还 我们的团队包括STI诊断领域的世界领先者，可进行可靠的血清学测量。我们将 我还利用我们团队成员的专业知识，目前资助开发方法，以解决 推广性，将我们的结果传达给有流产史的美国女性目标人群 全国家庭成长调查。鉴于美国和欧洲的性传播感染患病率大幅上升， 流产的频率，这项研究和我们未来的工作可能会影响大量的妇女。

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.