Prepregnancy Phenotype and Predisposition to Preeclampsia

描述（由申请人提供）：1998年，我们提出了一种替代广泛接受的与先兆子痫相关的“两阶段”病理生理学假设。相反的观点认为，异常胎盘的结果，在释放一种或多种胎盘毒素，导致母体内皮损伤和全身性疾病，我们提出了一个可识别的孕前生理表型易患先兆子痫时，妊娠特异性生理适应叠加。我们认为，低孕前血浆容量是一个重要的标志，为那些在风险和体积膨胀是关键的怀孕特定的生理应激。从那时起，来自多个调查线的重要证据支持了这一假设，即孕前表型对先兆子痫的风险有重要贡献，并且血浆体积减少可预测那些处于风险中的人。在我们最近完成的研究中，我们已经证明了孕前生理学与妊娠合并先兆子痫的许多假定病理生理学后果的显著相关性;包括妊娠早期子宫血流量减少，脉压增加和妊娠晚期血浆容量减少。我们的进展报告中总结了这项研究工作，目的是证明孕前生理学对怀孕期间观察到的母体生理学有重要贡献。基于这些研究中获得的初步数据，我们现在提出，孕前生理学和妊娠的独特生理适应的结合有助于先兆子痫及其相关病理结果的发展。检查有先兆子痫发展风险的妇女并在怀孕前启动研究，我们将证明三个具体目标：1。低血浆容量、低子宫血流量和动脉脉压增加与妊娠前发生先兆子痫的风险增加及其病理生理相关性有关。2. a）通过肾血流和肾素血管紧张素系统的变化反映的对妊娠的肾反应将是妊娠前血浆体积的函数。B）从妊娠前到妊娠晚期，血管内皮损伤标志物的变化与妊娠过程中肾血流量变化和肾动脉切应力密切相关;这些反应将通过孕前肾血管舒张能力预测。3.正常妊娠使妇女在妊娠晚期易患后部脑水肿，并且这种水肿在妊娠晚期与全身血压升高相关时加重。 公共卫生相关性：该基金的目的是研究孕前生理表型对先兆子痫发生的影响。此外，我们正在研究妊娠特异性生理适应对一组有先兆子痫风险的妇女先兆子痫病理生理学相关性的影响。

DESCRIPTION (provided by applicant): In 1998 we proposed an alternative to the broadly accepted "Two Stage" pathophysiologic hypothesis associated with preeclampsia. In contrast to the view that abnormal placentation results in the release of one or more placental toxins leading to maternal endothelial injury and systemic disease, we proposed that an identifiable prepregnancy physiologic phenotype predisposes to preeclampsia when pregnancy specific physiologic adaptations are superimposed. We suggested that low prepregnancy plasma volume was an important marker for those at risk and that volume expansion was the critical pregnancy specific physiologic stressor. Since that time significant evidence, from multiple lines of investigation, has supported the hypothesis that prepregnancy phenotype contributes importantly to the risk for preeclampsia and that reduced plasma volume is predictive of those at risk. In our recently completed studies we have demonstrated the significant association of prepregnancy physiology with many of the presumed pathophysiologic consequences of pregnancy complicated by preeclampsia; including reduced uterine blood flow in early pregnancy, increased pulse pressure, and reduced third trimester plasma volume. That research effort, summarized in our progress report, was aimed at demonstrating that prepregnancy physiology contributes importantly to maternal physiology observed during pregnancy. Based on preliminary data acquired in those studies we now propose that a combination of prepregnancy physiology and the unique physiologic adaptations of pregnancy contribute to the development of preeclampsia and its associated pathologic findings. Examining women at risk for the development of preeclampsia and initiating studies prior to pregnancy we will demonstrate, in three specific aims; 1. That low plasma volume, low uterine blood flow and increased arterial pulse pressure, prior to pregnancy, are associated with an increased risk of developing preeclampsia and its pathphysiologic associations. 2. a) That the renal response to pregnancy, reflected by changes in renal blood flow and the renin angiotensin system will be a function of plasma volume prior to pregnancy. b) That changes in markers of vascular endothelial injury, from prior to pregnancy through the third trimester, are strongly associated with volumetric renal blood flow changes and renal artery shear stress during the course of pregnancy; and these responses will be predicted by prepregnancy renal vasodilatory capacity. 3. That normal pregnancy predisposes women to increases in posterior cerebral edema in the third trimester and that this edema is exacerbated in association with elevated systemic blood pressure in late pregnancy. PUBLIC HEALTH RELEVANCE: The goal of this grant is to examine the contribution of prepregnancy physiologic phenotype to the development of preeclampsia. In addition, we are looking to understand the influence of pregnancy- specific, physiologic adaptations to the pathophysiologic associations of preeclampsia in a group of women at risk for developing preeclampsia.