Prepregnancy Phenotype and Predisposition to Preeclampsia

描述（由申请人提供）：1998年，我们提出了与子痫前期相关的广泛接受的“两阶段”病理生理假说的替代方案。与异常胎盘导致一种或多种胎盘毒素释放导致母体内皮损伤和全身性疾病的观点相反，我们提出，当妊娠特异性生理适应叠加时，可识别的孕前生理表型易导致先兆子痫。我们认为，孕前血浆容量低是高危人群的重要标志，血浆容量增大是妊娠期重要的生理应激源。从那时起，来自多种调查的重要证据支持了孕前表型对子痫前期风险有重要影响的假设，血浆量减少预示着这些风险。在我们最近完成的研究中，我们已经证明了妊娠前生理与妊娠合并子痫前期的许多假定的病理生理后果的显著关联；包括妊娠早期子宫血流量减少，脉压升高，妊娠晚期血浆量减少。我们在进度报告中总结了这项研究工作，其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。基于这些研究中获得的初步数据，我们现在提出，孕前生理和怀孕的独特生理适应的结合有助于先兆子痫的发展及其相关的病理结果。检查有患先兆子痫风险的妇女并在怀孕前开始研究我们将在三个具体目标中证明；1. 妊娠前低血浆量、低子宫血流量和动脉脉压升高与子痫前期发病风险增加及其病理生理关联有关。2. a)肾脏对妊娠的反应，反映在肾血流和肾素血管紧张素系统的变化上，将是妊娠前血浆容量的函数。b)从怀孕前到妊娠晚期，血管内皮损伤标志物的变化与妊娠期间肾血流容量变化和肾动脉剪切应力密切相关；这些反应可以通过孕前肾脏血管舒张能力来预测。3. 正常妊娠易使妇女在妊娠晚期后脑水肿增加，并且这种水肿在妊娠后期随着全身血压升高而加剧。

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.