Early in normal human pregnancy, maternal plasma osmolality decreases and plasma volume increases. A failure to achieve adequate plasma volume expansion is associated with adverse pregnancy outcomes, including reduced amniotic fluid (AF) volume (oligohydramnios). Oligohydramnios occurs in 8 to 38 percent of all pregnancies and is associated with significant perinatal morbidity and mortality. Our recent experiments confirm the central role of placental osmotic gradients in the modulation of fetal fluid acquisition. We have established that maternal DDAVP and oral water administration induces maternal and fetal physiologic responses which increase AF volume. Specifically, ovine maternal and fetal plasma hypo-osmolality expands maternal plasma volume and increases fetal fluid acquisition, fetal urine production and thus AF volume. We have developed a conceptual model based on existing literature and our studies, temporally linking the resetting of maternal plasma osmolality and arginine vasopressin (AVP) secretory thresholds, maternal plasma volume expansion and AF volume. Our preliminary studies indicate that a fasting, morning plasma osmolality/sodium may be utilized as a simplified "index" of the maternal plasma osmolality threshold for AVP secretion, permitting repeated determinations of threshold setpoints throughout gestation. These hypotheses will be addressed in a stepwise series of human investigations. Firstly, we will establish the utility of a simplified index of the plasma osmolality/sodium setpoint for AVP secretion in nonpregnant patients and will confirm this index in a cross- sectional study of pregnant patients throughout gestation. Secondly, gestational changes and population distributions of plasma osmolality setpoint will be correlated with maternal plasma volume, fetal urine flow and AF volume in a longitudinal study of pregnant patients. Thirdly, we will determine the degree of maternal to fetal DDAVP transfer in pregnant subjects. Finally, the effects of DDAVP-induced plasma hypo-osmolality on fetal urine flow, AF volume and maternal plasma volume will be examined in patients with reduced AF volume, while determining the effects of DDAVP on maternal coagulation. These studies will potentially support a future study of chronic DDAVP-induced plasma-osmolality for pregnant patients with evidence of elevated plasma osmolality (i.e., failure to reset osmolality threshold). This proposal will aid in the development of markers of prediction and therapeutic approaches to the prevention and treatment of human oligohydramnios.

R01HD035947

1999-05-05

2003-04-30