Chronic Maternal Fluoxetine Infusion in Pregnant Sheep: Effects on the Maternal and Fetal Hypothalamic-Pituitary-Adrenal Axes

Abstract

Depression during pregnancy is frequently treated with the selective serotonin reuptake inhibitor, fluoxetine (FX). FX increases serotonergic neurotransmission and serotonin plays a role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. We have therefore investigated the effect of chronic administration of FX to the pregnant ewe on the maternal and fetal HPA axes. Nineteen late-gestation sheep were surgically prepared for chronic study of the fetus. FX (n ϭ 7, 98.5 g/kg/d) or sterile water (control, n ϭ 8) was administered to the ewe for 8 d by constant rate i.v. infusion with an initial FX bolus dose of 70 mg. Maternal and fetal plasma ACTH and cortisol concentrations were determined at 0700 h each day. Maternal plasma ACTH concentrations fell on infusion d 2, but no changes were observed in maternal plasma cortisol concentrations. Fetal plasma ACTH concentrations increased on infusion d 7, and fetal plasma cortisol concentrations increased on infusion d 6, 7, and 8 in the FX group. In addition, the regression coefficient for the relationship between fetal ACTH and cortisol levels was significantly greater in the FX group compared with the control group. Thus, maternal FX treatment increased fetal plasma cortisol concentration. These results are of particular interest in the context that exposure of the fetus to excess glucocorticoids at critical windows during development has been shown to increase the risk of poor health outcomes in later life. Clinical depression occurs in 5-15% of pregnant women (1). Treatment of depression during pregnancy is important to fetal outcome by preventing poor maternal self-care and nutrition, disturbed sleep, lack of prenatal care, increased exposure to alcohol and drugs, and a higher risk of suicide by the mother (1). Depression at 28 wk gestation is related to an increase in negative pregnancy outcome, including an increased risk of low-birth-weight newborns, preterm delivery, and small-forgestational-age newborns (2). FX is a SSRI that increases serotonergic neurotransmission and is prescribed clinically for the treatment of depression, obsessive-compulsive disorder, and bulimia (3). It and other SSRIs have become increasingly used for the treatment of depression in pregnancy because of their effectiveness and lower incidence of maternal side effects and wider safety margin compared with tricyclic antidepressants and monoamine oxidase inhibitors (4, 5). However, there have been several reports that use of these drugs during pregnancy can increase the incidence of adverse pregnancy outcomes, including preterm delivery, fetal growth restriction, and poor neonatal adaptation (5-8). There is also evidence for postnatal consequences of prenatal SSRI exposure, including reduced weight gain, slight delays in psychomotor development and motor movement control, and our own findings of reduced facial and heart rate responses to painful stimuli (9 -11). ABSTRACT40

Prenatal Antidepressant Exposure: Clinical and Preclinical Findings

“…Continuous infusion of fluoxetine in sheep via maternal femoral vein catheter yielded concentrations in maternal and fetal serum of ;150 and ;60 ng/ml, respectively; no measurements of norfluoxetine were obtained (Morrison et al, 2004). Similar results were found in mice: placental transfer of fluoxetine was 69%, whereas human placental transfer is 73% (Noorlander et al, 2008).…”

Third Trimester Fetal Heart Rate and Doppler Middle Cerebral Artery Blood Flow Velocity Characteristics During Prenatal Selective Serotonin Reuptake Inhibitor Exposure

“…To distinguish acute pharmacological effects from long-term sustained outcomes, we examined fetal blood flow and fHR variability measures before a typical morning SSRI dose (trough) and during an afternoon postdose (peak) session. Given, previous reports of neonatal cardiorespiratory and neurobehavioral disturbances in our sheep model after prenatal SSRI exposure (15)(16)(17), we expected blunted fetal brain blood flow indices and heart rate variability during late gestation would be present during both trough (predose) and peak (1-2 h postdose) drug conditions, reflecting sustained fetal effects rather than an acute pharmacological effect.…”

“…In pregnant sheep, an 8-d i.v. fluoxetine infusion resulted in initial transient reductions in uterine blood flow and fetal oxygenation, prolonged reduction in fetal rapid eye movement (REM) sleep, and augmented prepartum cortisol increase (15)(16)(17). Altered fetal REM sleep could affect cerebral blood flow and metabolism via changes between quiet and REM sleep which may in turn have long-term effects on brain growth and maturation (18).…”

Effect of Exposure to Selective Serotonin Reuptake Inhibitors In Utero on Fetal Growth: Potential Role for the IGF-I and HPA Axes

“…Some studies noted decreased values of these parameters (18 -21), whereas others did not (1,2,5). Growth attenuation accompanied by impaired growth hormone (GH) secretion was also reported in four children and adolescents treated with SSRIs for various psychiatric disorders (22).Insulin-like growth factor-I (IGF-I), a GH-dependent hormone, is known to play a major role in fetal growth (23,24), but there is limited information on the response of the fetal IGF-I/GH axis to maternal SSRI intake, or the response of the fetal hypothalamic-pituitary-adrenal (HPA) axis, which is involved in serotonin regulation of cortisol and adrenocorticotropic hormone (ACTH) secretion (25)(26)(27). In a sheep model, fetal plasma ACTH and cortisol significantly increased after chronic maternal fluoxetine administration (26), raising concerns of fetal exposure to excess glucocorticoids at critical periods during development.…”

“…In a sheep model, fetal plasma ACTH and cortisol significantly increased after chronic maternal fluoxetine administration (26), raising concerns of fetal exposure to excess glucocorticoids at critical periods during development. Human epidemiologic observations and animal studies have shown that under suboptimal in utero conditions, individual tissues and organ systems can be programmed, with adverse consequences for their function in later life (28 -30).…”