Prepregnancy Phenotype and Predisposition to Preeclampsia

描述(申请人提供)：1998年，我们提出了一种替代被广泛接受的与先兆子痫相关的“两阶段”病理生理学假说。与胎盘异常导致一种或多种胎盘毒素释放导致母体内皮细胞损伤和系统性疾病的观点相反，我们提出，当妊娠特有的生理适应叠加时，可识别的孕前生理表型容易发生先兆子痫。我们认为，孕前低血浆容量是高危人群的重要标志，而血容量扩张是关键的妊娠特异性生理应激源。从那时起，来自多项研究的重要证据支持了这样的假设，即孕前表型对先兆子痫的风险有重要影响，血浆容量减少是高危人群的预测。在我们最近完成的研究中，我们已经证明了孕前生理与妊娠合并先兆子痫的许多假定的病理生理后果之间存在显著的相关性，包括妊娠早期子宫血流减少，脉压增加，以及妊娠晚期血浆容量减少。我们在进度报告中总结了这项研究工作，目的是证明孕前生理对怀孕期间观察到的产妇生理有重要贡献。根据这些研究获得的初步数据，我们现在提出，孕前生理和妊娠独特的生理适应相结合有助于先兆子痫的发展及其相关的病理结果。检查有先兆子痫风险的妇女，并在怀孕前启动研究，我们将在三个具体目标中证明：1.妊娠前低血浆容量、低子宫血流量和动脉脉压升高与发生先兆子痫的风险增加及其病理生理相关。2.a)肾血流和肾素血管紧张素系统的变化反映出肾脏对妊娠的反应将是妊娠前血浆容量的函数。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期间肾血流量的变化和肾动脉切应力密切相关；这些反应将通过妊娠前的肾血管扩张能力来预测。3.正常妊娠易使妇女在妊娠晚期后部脑水肿增加，妊娠晚期全身血压升高会加重这种水肿。 公共卫生相关性：这项赠款的目标是检查孕前生理表型对先兆子痫发展的贡献。此外，我们希望了解妊娠特有的生理适应对一组有患先兆子痫风险的妇女的先兆子痫的病理生理相关性的影响。

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.