Risk factors as predictors of ectopic pregnancy

描述(由申请人提供)：背景：异位妊娠(EP)是妊娠早期与妊娠有关的主要死亡原因，也是导致孕产妇发病率的主要因素。随着输卵管妊娠的进展，它会侵蚀血管，并可能导致大量腹内出血。目前用于诊断EP的策略存在局限性。即使使用系统地评估所有有EP风险的妇女的诊断算法，也只有50%的EP妇女可以在出现时被诊断出来。其余50%的患者的诊断是一个临床难题，可能需要长达6周的时间。如果EP的诊断延迟，可能会发生潜在的破裂，导致更大的发病率和死亡率。此外，体积较大的EP不能接受药物治疗，可能需要大手术(剖腹手术)而不是腹腔镜检查，即使在破裂前进行治疗，也可能对输卵管造成更大的损害(和更大的生育能力损害)。这项应用是一项竞争性的持续更新的ROI(预测异位妊娠的危险因素)。我们已经取得了实质性的进展，包括描述了危险因素作为预测因子的关联强度，开发了临床预测规则以帮助在出现症状时进行诊断，以及使用蛋白质组学方法初步开发了血清分子诊断。我们还重新定义了使用系列hCG测定来诊断有EP风险的妇女，这些妇女的诊断在临床上是不确定的。最后，我们确定了一种新的治疗异位妊娠妇女的药物治疗方案的安全性。这项申请的目标是在更大、更多样化和更独立的人群中进一步开发和验证这些发现，这些发现就是从这些发现发展而来的。具体目标和方法：我们计划将宾夕法尼亚大学医学中心对异位妊娠风险妇女的系统评估和血清收集扩展到另外两个中心(迈阿密大学和南加州大学)，使用修改后的现有电子数据库，该数据库记录了临床过程，并包含诊断测试的结果，用于明确诊断患有EP的风险妇女，但在出现时未被诊断出来。我们计划利用这些数据：1)利用a)临床因素，b)潜在的新血清标志物，以及c)两种方法的组合，优化(并验证)一种简单、准确、非侵入性的异位妊娠危及生命的诊断方法。2)确定构成我们的候选分子标记的蛋白质：3)验证基于hCG序列值的决策规则，该规则适用于在呈现时诊断不确定的女性。4)创建一种潜在的测试来预测那些将在异位妊娠的医疗处理方面取得最佳成功的人。这项应用是一个独特的机会，可以将流行病学和基础科学方法结合起来，了解和改进我们诊断具有重大公共健康后果的生殖疾病的能力方面的重要限制。我们认为，继续我们的转译研究有望增强我们对早期妊娠丢失科学的理解，并优化临床护理，潜在地降低发病率和死亡率，因此非常适合NIH路线图战略，以帮助跨学科开创性研究，帮助从工作台到床边和床边到实践的转换。

DESCRIPTION (provided by applicant): Background: Ectopic pregnancy (EP) is the leading pregnancy - related cause of death in the first trimester of pregnancy and a major contributor to maternal morbidity. As the tubal pregnancy progresses, it erodes into blood vessels and can cause massive intra-abdominal bleeding. There are limitations in the strategies currently employed to diagnose EP. Even with the use of diagnostic algorithms that systematically evaluate all women at risk for an EP, only 50 percent of women with an EP can be diagnosed upon presentation. Diagnosis in the remaining 50 percent represents a clinical conundrum and can take up to 6 weeks. If the diagnosis of EP is delayed potential rupture, resulting in greater risks of morbidity and mortality, can occur. Moreover, an EP of large size is not amenable to medical therapy, may require major surgery (laparotomy) instead of laparoscopy and can cause greater damage to fallopian tube (and greater impairment of fertility), even if treated before rupture. This application is a competitive continuing renewal of an ROI (Risk Factors as Predictors of Ectopic pregnancy). We have made substantial progress including delineation of the strength of association of risk factors as predictors, development of a clinical prediction rule to aid in diagnosis upon presentations, and preliminary development of a serum molecular diagnosis using a proteomic approach. We have also redefined the use of serial hCG determinations to diagnosis women at risk for EP whose diagnosis was uncertain at presentation. Finally we have established the safety of a novel medical management regimen for women with ectopic pregnancy. The goals of this application focus on further develop and validation of these finding in a larger, diverse and separate population from which they were developed. Specific Aims and Methods: We plan to extend the systematic evaluation of women at risk for ectopic pregnancy, and collection of serum, form The University of Pennsylvania Medical Center to include to two other centers (The Universities of Miami and Southern California) using a modified existing electronic database that chronicles the clinical course and contains the results of the diagnostic tests used to definitively diagnose women at risk for EP but not diagnosed upon presentation. We plan to use these data to: 1) optimize (and validate) a simple, accurate, non-invasive, diagnosis for the life-threatening condition of ectopic pregnancy using a) clinical factors, b) potential novel serum markers and c) the combination of the two approaches. 2) Identify the proteins that comprise our candidate molecular markers: 3) to validate a decision rule based on serial hCG values for women whose diagnosis was not definitive upon presentation. 4) create a potential test to predict those who will have optimal success with medical management of ectopic pregnancy. This application represents a unique opportunity to combine epidemiologic and basic science methodologies to understand and improve upon important limitations in our ability to diagnose a reproductive disorder with significant public health consequences. We feel that continuation of our translational research has promise to both enhance our understanding of the science of early pregnancy loss as well as to optimize clinical care with potential reduction of morbidity and mortality and therefore fits well into the NIH roadmap strategy to aide interdisciplinary pioneering research to aid in translation from bench to bedside and bedside to practice.