Maternal markers and prediction of preeclampsia

描述（由申请人提供）：先兆子痫是世界上孕产妇和胎儿发病率和死亡率的主要原因。这种妊娠特异性综合征通常在妊娠20周后发生，可导致产妇主要发病或死亡。同时，胎盘血流减少可导致胎儿生长受限、产妇或胎儿指征早产以及胎儿发病率和死亡率。目前还没有证实的干预措施来预防先兆子痫。这项研究的总体目标是确定怀孕前三个月的妇女在怀孕后期患先兆子痫的风险增加。该项目的具体目的是：(1)比较随后发生子痫前期妇女的妊娠早期抑制素A、PP13、激活素A和ADAM12水平与对照组妇女的水平；(2)利用这些妊娠早期母体血清标志物结合我们数据库中记录的母体特征，建立子痫前期的多变量预测模型。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妇产科和生殖科学系数据库中现有数据中选择子痫前期和对照组（未发生子痫前期的妇女）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4000例妊娠的产妇特征和结果（截至2008年12月，每个中心约有2000名妇女）。从这些患者妊娠9至14周抽取的血液样本已储存在两家机构的样本库中，并将用于分析。该研究将利用一个成熟的研究团队，预先存在和特征明确的数据，获得PP13和ADAM12检测，并与有成就的专家合作设计围产期不良结局的预测模型。2007年11月，美国国立卫生研究院妇女健康研究协调委员会研究小组委员会发布了一份文件，确定了拟议研究的目标为2008年美国国立卫生研究院妇女健康研究优先事项。该文件特别鼓励“早期检测和治疗方面的研究，包括开发识别和验证与疾病风险相关的生物标志物的新工具”。这项研究意义重大，因为先兆子痫是全世界胎儿和孕产妇死亡的主要原因，而先兆子痫的妊娠早期预测将促进和加速寻找先兆子痫的预防和治疗药物。此外，确定子痫前期的早期标记将导致对高危妊娠的更密切审查，并可能提供有关该疾病机制的信息。

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.