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Physiologic responses of the fetal lamb to eight day fluoxetine exposure during late gestation Morrison, Janna Leigh


Clinical depression is diagnosed in 10-15% of pregnancies frequently resulting in antidepressant therapy with selective serotonin reuptake inhibitors such as fluoxetine. Human studies have suggested that third trimester exposure to fluoxetine results in negative birth outcomes such as preterm delivery, low birth weight and increased admission to neonatal intensive care units. Based on these findings, we undertook an eight day maternal IV infusion of fluoxetine (FX, 98.5 µg/kg.d) in 14 chronically instrumented pregnant sheep during late gestation (125- 140 d, term = 147 d) with a control group of 15 animals receiving sterile water. In the FX group maternal and fetal plasma FX and norfluoxetine (NFX) concentrations were within the therapeutic range reported in humans. Maternal fluoxetine infusion increased plasma serotonin levels within 15 min of infusion associated with a 20% decrease in uterine artery blood flow. Both plasma serotonin levels and uterine artery blood flow returned to control values by 1 h after infusion. The transient decrease in uterine artery blood flow resulted in fetal hypoxemia during the first 24 h of infusion. Minor alterations in fetal blood gases continued throughout the eight-day infusion period. The incidences of low voltage electrocortical activity (EcoG), eye movements and fetal breathing movements were significantly reduced in the FX group while the incidence of high voltage ECoG was significantly increased during the first 6 h of maternal fluoxetine infusion. These alterations continued throughout the eight days of infusion to a lesser degree. Fetal ACTH and Cortisol plasma concentrations in the FX group increased on Infusion Days 7 and 8 more than in the control group. Late gestation infusion of fluoxetine in sheep did not alter birth weight or gestational age at delivery. In conclusions, late gestation exposure to FX in pregnant sheep transiently altered fetal blood gas status with greater effects on fetal behavioural state and neuroendocrine function. The longer term consequences of these in utero perturbations remains to be determined.

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