MATERNAL DEHYDRATION--FETAL/AMNIOTIC FLUID HOMEOSTASIS

羊水(AF)是正常妊娠的必要伴随， 是胎儿运动、生长和发育所必需的。羊水过少， 或房颤体积减少，发生在所有怀孕的8%到38%。这个 大多数羊水过少患者没有可识别的医疗或 产前并发症，只有7%的病例与 胎儿畸形。然而，羊水过少往往与 慢性胎儿应激状态，如胎儿宫内发育 发育迟缓、先兆子痫和晚孕。这些条件， 再加上房颤体积减少的直接影响，导致 严重的围产期发病率和死亡率。增加自动对焦音量 然而，羊水过少的分娩患者改善了胎儿结局 这通常需要胎膜破裂。然而，我们的 研究表明，调节房颤的产生(胎儿尿流) 房颤吸收(胎儿吞咽和膜内血流)可能是 用于增加膜完整患者的房颤容量。我们 开发了一种新的模型来利用母体增加房颤体积 精氨酸加压素(AVP)抗利尿激动剂的应用 [去氨基，D-Arg8]-AVP(DDAVP)。我们对绵羊模型的研究表明 母体水合和DDAVP诱导母体和胎儿血浆 低钠血症，胎儿尿流量显著增加，胎儿减少 吞咽和扩张房颤体积。我们的人体研究支持 这些干预措施的临床效用。尽管有这些有希望的事情 结果，DDAVP治疗的有效性和安全性的关键问题 在临床使用之前，母亲和胎儿都必须得到解决。 首先，在疗效研究中，我们将确定最低水平的 引起并维持胎儿体液反应的母体低钠血症， 并检查胎盘渗透压变化的影响 渐变。长期研究将检验低钠血症的影响。 绵羊房颤体积、母体血浆体积及脐子宫的研究 羊水正常和羊水过少的绵羊妊娠时血液流动。 其次，在胎儿安全的研究中，我们将确定胎儿的大脑是否 低钠血症可引起脑水肿和/或脑组织电解质丧失。 由于AVP对胎儿体液和心血管有重要的调节作用， 我们将确定低钠血症对胎儿渗透压和非渗透压的影响。 渗透压刺激AVP分泌。最后，作为永久的印记 AVP的合成和分泌调节系统可能作为反应发生 新生大鼠的慢性紧张性改变，我们将检查 慢性紧张性改变对胎儿AVP转录和蛋白表达的影响 翻译。生理学评估将侧重于测量 胎儿体液交换和胎儿血浆及房颤的体积和成分。 内分泌和分子评估将包括液体的测定 调节激素与下丘脑AVP mRNA和垂体AVP 内容，利用我们新开发的绵羊130bpc DNA探针和 溶液和原位杂交技术。这个项目的目标是 是确定关键的疗效和胎儿安全问题 在人类广泛临床使用之前的母体DDAVP治疗 妊娠合并羊水过少。

Amniotic fluid (AF) is an essential accompaniment of normal pregnancy, necessary for fetal movement, growth and development. Oligohydramnios, or reduced AF volume, occurs in 8 to 38 percent of all pregnancies. The majority of oligohydramnios patients have no identifiable medical or antepartum complication and only 7 percent of cases have associated fetal malformations. However, oligohydramnios is often associated with conditions of chronic fetal stress, such as intrauterine growth retardation, preeclampsia and postterm pregnancy. These conditions, together with the direct effect of reduced AF volume, results in significant perinatal morbidity and mortality. Increasing AF volume in laboring patients with oligohydramnios improves fetal outcome, though this generally requires rupture of fetal membranes. However, our studies demonstrate that modulation of AF production (fetal urine flow) and AF resorption (fetal swallowing and intramembranous flow) may be utilized to increase AF volume in patients with intact membranes. We have developed a novel model to increase AF volume utilizing maternal administration of the arginine vasopressin (AVP) antidiuretic agonist [desamino, D-Arg8]-AVP (DDAVP). Our studies in the ovine model indicate that maternal hydration and DDAVP induces maternal and fetal plasma hyponatremia, marked increases in fetal urine flow, reduced fetal swallowing and expansion of AF volume. Our human studies have supported the clinical utility of these interventions. Despite these promising results, critical issues of efficacy and safety of DDAVP therapy for both the mother and fetus must be resolved prior to clinical use. Firstly, in studies of efficacy, we will determine the minimum level of maternal hyponatremia which induces and maintains fetal fluid responses, and examine the effects of alterations in placental osmolality gradients. Long term studies will examine the effects of hyponatremia on ovine AF volume, maternal plasma volume and umbilical and uterine blood flows in both normal and oligohydramnios ovine pregnancies. Secondly, in studies of fetal safety, we will determine if fetal brain edema and/or loss of brain electrolytes are induced by hyponatremia. As AVP has important fetal fluid and cardiovascular regulatory roles, we will determine the effect of hyponatremia on fetal osmotic and non- osmotic stimulated AVP secretion. Finally, as permanent imprinting of AVP synthesis and secretion regulatory systems may occur in response chronic tonicity alterations in newborn rats, we will examine the effects of chronic tonicity alterations on fetal AVP transcription and translation. Physiologic assessments will focus on measurements of fetal fluid exchange and fetal plasma and AF volume and composition. Endocrine and molecular assessments will include determination of fluid regulatory hormones and hypothalamic AVP mRNA and pituitary AVP contents, utilizing our newly developed ovine 130 bp cDNA probe and solution and in situ hybridization techniques. The goal of this project is to determine critical efficacy and fetal safety issues central to maternal DDAVP treatment, prior to widespread clinical use in human pregnancies with oligohydramnios.