Maternal markers and prediction of preeclampsia

描述(申请人提供)：先兆子痫是世界上母婴发病率和死亡率的主要原因。这种特定于妊娠的综合征通常在怀孕20周后发生，并可能导致主要的孕产妇发病或死亡。与此同时，胎盘血流量减少会导致胎儿生长受限、母体或胎儿指征早产，以及胎儿发病率和死亡率。目前，还没有得到证实的预防先兆子痫的干预措施。这项研究的总体目标将是确定怀孕前三个月有更高风险在怀孕后期发展为先兆子痫的妇女。该项目的具体目标是：(1)比较妊娠早期抑制素A、PP13、激活素A和ADAM12的水平与对照妇女的水平，以及(2)利用这些早期妊娠母血清标记物结合我们数据库中记录的一组母体特征，开发一个预测先兆子痫的多变量模型。嵌套病例对照研究将从科罗拉多大学妇产科数据库和马里兰大学产科、妇科和生殖科学系数据库中包含的现有数据中选择先兆子痫患者和对照(未患先兆子痫的女性)患者。通过合并这两个中心的数据，我们将获得全面的临床数据，包括4,000例妊娠的产妇特征和结局(截至2008年12月，每个地点约有2,000名妇女)。从这些怀孕9至14周的患者身上提取的血液样本已储存在这两家机构的样本储存库中，并将可用于化验。这项研究将利用成熟的研究团队、预先存在的和特征良好的数据、获得PP13和ADAM12分析，以及与经验丰富的专家合作，设计不良围产期结局的预测模型。NIH妇女健康研究协调委员会研究小组委员会于2007年11月发布的一份文件中，将拟议研究的目标确定为2008年NIH妇女健康研究优先事项。该文件特别鼓励“在早期发现和治疗方面的研究，包括开发新的工具来识别和验证与疾病风险有关的生物标记物”。这项研究意义重大，因为子痫前期是全球胎儿和产妇死亡的主要原因，而对子痫前期的早期预测将促进和加速寻找预防和治疗先兆子痫的药物。此外，识别先兆子痫的早期标志物将导致对高危妊娠的更密切的审查，并可能提供关于疾病机制的信息。 公共卫生相关性：改善对患有先兆子痫的妇女的护理的一个关键目标是在疾病明显之前识别处于危险中的妇女。在怀孕早期识别这些女性的能力，可以在短期内进行更密切的监测，从长远来看，可能会导致未来试验有希望的药物或技术，这些药物或技术可能会预防甚至预防这种疾病。实现这两个目标中的任何一个都将导致降低母亲和婴儿的发病率和死亡率。

DESCRIPTION (provided by applicant): Preeclampsia is the leading cause of maternal and fetal morbidity and mortality in the world. This pregnancy- specific syndrome generally develops after the twentieth week of gestation, and can lead to major maternal morbidity or death. At the same time, reduced placental blood flow can lead to fetal growth restriction, premature delivery for maternal or fetal indications, and fetal morbidity and mortality. At the present time there are no proven interventions to prevent preeclampsia. The overall goal of this research will be to identify women in the first trimester who are at increased risk of developing preeclampsia later in pregnancy. The specific aims of this project are: (1) To compare first trimester levels of inhibin A, PP13, activin A and ADAM12 from women who subsequently developed preeclampsia to levels seen in control women, and (2) To develop a multivariate prediction model for preeclampsia using these first trimester maternal serum markers in combination with a panel of maternal characteristics as recorded in our database. The nested case control study will select preeclamptic and control (women who did not develop preeclampsia) patients from existing data contained in the University of Colorado Department of OB-GYN Database and a database from the Department of Obstetrics, Gynecology and Reproductive Sciences at the University of Maryland. By merging data from these two centers we will have access to comprehensive clinical data including maternal characteristics and outcomes from 4,000 pregnancies (approximately 2,000 women from each site as of December, 2008). Blood samples drawn from these patients between 9 and 14 weeks gestation have been stored in sample repositories at both institutions, and will be available for assay. The study will make use of a well established research team, preexisting and well-characterized data, access to PP13 and ADAM12 assays, and collaboration with accomplished experts in devising prediction modeling in adverse perinatal outcome. The aims of the proposed study have been identified as a 2008 NIH Research Priority for Women's Health in a document issued by the Research Subcommittee of the NIH Coordinating Committee on Research on Women's Health in November, 2007. This document specifically encouraged research "in early detection and treatment, including the development of novel tools to identify and validate biomarkers in relation to disease risk". The study is significant because preeclampsia is a leading cause of fetal and maternal death worldwide, and first trimester prediction of preeclampsia will have the effect of promoting and accelerating the search for prophylactic and therapeutic agents for preeclampsia. In addition identification of early markers of preeclampsia would lead to closer scrutiny of at risk pregnancies and may provide information regarding the mechanism of the disease. PUBLIC HEALTH RELEVANCE: A critical goal in improving the care of women with preeclampsia is to identify women at risk even before the disease is manifest. The ability to identify these women early in their pregnancy would allow closer monitoring in the short term, and in the longer term could lead to future trials of promising drugs or techniques that might forestall or even prevent the disease. Accomplishing either of these objectives would lead to reduced morbidity and mortality of both mothers and babies.