MATERNAL DEHYDRATION--FETAL/AMNIOTIC FLUID HOMEOSTASIS

羊水（AF）是正常妊娠的基本伴随物， 对胎儿的运动、生长和发育是必要的。羊水过少， 或房颤体积减少，发生在所有怀孕的8%至38%。 的 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 胎儿畸形 然而，羊水过少往往与 慢性胎儿应激的条件，如宫内生长 发育迟缓、先兆子痫和过期妊娠。 这些条件， 与AF体积减少的直接效果一起，导致 围产期发病率和死亡率很高。 增加AF体积， 尽管羊水过少的分娩患者可以改善胎儿结局， 这通常需要胎膜破裂。 但我们的 研究表明调节AF产生（胎儿尿流） 和AF再吸收（胎儿吞咽和膜内血流）可能是 用于增加膜完整患者的AF体积。 我们 开发了一种新的模型，利用母体 精氨酸加压素（AVP）抗利尿剂激动剂的施用 [脱氨基，D-Arg 8]-AVP（DDAVP）。 我们对绵羊模型的研究表明， 母体水合作用和DDAVP诱导母体和胎儿血浆 低钠血症，胎儿尿流量明显增加，胎儿尿量减少 吞咽和扩大AF体积。 我们的人体研究支持了 这些干预措施的临床效用。 尽管有这些有希望 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，必须解决母亲和胎儿的问题。 首先，在疗效研究中，我们将确定最低水平的 母体低钠血症诱导并维持胎儿体液反应， 并检测胎盘渗透压的改变 梯度。 长期研究将检查低钠血症的影响 对绵羊AF体积、母体血浆体积以及脐带和子宫的影响 正常和羊水过少绵羊妊娠期的血液流动。 其次，在胎儿安全的研究中，我们将确定胎儿大脑是否 水肿和/或脑电解质损失由低钠血症引起。 由于AVP具有重要的胎儿体液和心血管调节作用， 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发生反应 新生大鼠的慢性张力改变，我们将研究 慢性张力改变对胎儿AVP转录的影响 翻译. 生理评估将侧重于测量 胎儿液体交换和胎儿血浆以及AF体积和组成。 内分泌和分子评估将包括测定液体 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130 bp cDNA探针， 溶液和原位杂交技术。 这个项目的目标 是确定关键的疗效和胎儿安全问题， 母体DDAVP治疗，在人类临床广泛使用之前 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.