ABSTRACT Opioid abuse of pregnant women or women of childbearing age in general is an urgent public health concern. The number of women using opioids presenting at labor and delivery has more than quadrupled in the last decade. While the imminent effects of opioid use during pregnancy, namely neonatal opiate withdrawal syndrome, are well described, there is only limited knowledge about harmful effect of opioid abuse during pregnancy on maternal health, placental function, and the developing child. This proposal aims to investigate the effects of fentanyl use during pregnancy and its consequences on maternal physiology, stress reactivity, placental function, and offspring development using a translationally relevant approach in which rat dams self - administer fentanyl intravenously under extended-access conditions prior and throughout pregnancy. In three Aims we will test the hypotheses that fentanyl self-administration before and throughout pregnancy will 1) affect the maternal cardiovascular system, respiration and stress reactivity, 2) induce profound impairments in placental function, and 3) induces neonatal opioid withdrawal, impairs offspring development and increases stress reactivity in the offspring. We will assess comprehensively health, blood pressure, respiration rate, stress hormone levels and oxidative stress, and placental function in pregnant, fentanyl self-administering females. In the offspring, we will assess the overall health, occurrence and severity of neonatal opiate withdrawal and achievement of ag e-appropriate somatic and behavioral developmental milestones by the offspring. In comparison to yoked saline and sham control dams, we hypothesize that fentanyl self-administration of dams will lead to decreased blood pressure, respiratory depression and an increase in stress reactivity. We also expect a reduced sufficiency of the placenta, as well as neonatal opioid withdrawal symptoms, impairments in offspring development, and offspring stre ss reactivity. The results fromthe proposed studies will provide needed information regarding the effects of fentanyl on the pregnant female physiology and behavior and on offspring development. Ultimately, our studies should lead to knowledge that is vital for the identification of treatment opportunities, both pre- and postpartum.

NARRATIVE Opioid abuse in women of childbearing age or who are pregnant is a major public health threat. The number of women abusing opioids presenting at labor and delivery has more than quadrupled in recent years, with fentanyl abuse rising to an all-time high, putting the fetus at serious risk for opioid withdrawal, as well as developmental and behavioral impairments. The experiments proposed in this application aim to investigate the effects of fen- tanyl use during pregnancy on maternal physiology and stress, placental function, pregnancy outcome, and neonatal withdrawal, development, and stress markers in the offspring and these results will serve public health interests by providing knowledge, which may lead to the development of effective interventions to improve the well-being of drug abusing pregnant women and protect their highly vulnerable offspring. .