Fetal behavioural state changes following maternal fluoxetine infusion in sheep

Morrison, Janna L.; Chien, Caly; Gruber, Nancy; Rurak, Dan; Riggs, Wayne

doi:10.1016/s0165-3806(01)00255-3

Cited by 49 publications

(53 citation statements)

References 46 publications

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“…Previously we have reported that maternal FX infusion reduces the incidence of low-voltage/rapid eye movement (LV/REM) behavioral state in the fetal lamb, and that this effect persists for the entire 8-d infusion period (29). Thus, FX exposure alters the level of activation of both the HPA axis and fetal behavior (13) and these alterations could underlie some of the postnatal consequences observed in human infants exposed prenatally to SSRIs (7, 9 -11).…”

Section: Discussionmentioning

confidence: 97%

“…A midline incision in the maternal abdomen allowed access to the uterus to expose the fetus for implantation of polyvinyl catheters (Tygon, Akron, OH, U.S.A.) in the trachea, femoral arteries, lateral tarsal vein, and amniotic cavity. As previously reported (12,29), animals were instrumented for measurement of fetal behavioral state and uterine artery blood flow.…”

Section: Methodsmentioning

confidence: 99%

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

Morrison¹,

Riggs

Chien

et al. 2004

Pediatr Res

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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

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Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

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

Morrison¹,

Riggs

Chien

et al. 2004

Pediatr Res

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“…In an animal model, i.v. fluoxetine administration to pregnant ewes resulted in transient fetal hypoxemia and reduced uterine blood flow (15), reflecting a transient increase in blood serotonin (37) and serotonin's action as a potent uterine vasoconstrictor (38).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 82%

“…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).…”

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confidence: 99%

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

et al. 2011

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Prenatal selective serotonin reuptake inhibitor (SSRI) exposure increases the risk for adverse neonatal behavioral outcomes; although it is unknown whether altered brain function is present before birth. We investigated fetal vascular and heart rate changes at 36-wk gestation in SSRI-treated women with mood disorders (n ϭ 29) [exposed (EXP)] and controls (n ϭ 45) [non-EXP (NEXP)]. Fetal middle cerebral artery (MCA) flow parameters and heart rate characteristics were obtained during pre-SSRI dose morning and postdose afternoon sessions. Maternal mood and cord Hb and hematocrit were measured. Basal fetal heart rate (fHR) did not differ between groups or across the day. The fHR short-and long-term variations, accelerations, and duration of high variability episodes remained lower and did not change across the day in EXP, whereas all increased significantly in NEXP. In both groups, MCA flow velocity and volume flow increased significantly across the day. EXP MCA pulsatility index was significantly lower, as was MCA cross-sectional area. EXP cord Hb and hematocrit were significantly increased. Prenatal SSRI exposure reduced fetal MCA flow resistance and fHR variability, before and after an SSRI dose, controlling for maternal mood. These changes and the SSRI-related increased red cell indices suggest possible fetal hypoxia. (Pediatr Res 70: 96-101, 2011) I ncreasing use of selective serotonin reuptake inhibitor (SSRI) antidepressants to manage maternal mood disturbance during pregnancy has raised concerns about the longterm effects of increased central serotonergic tone during fetal development (1-3). Widespread observations of neonatal neurobehavioral disturbances (4,5), altered infant stress regulation (6,7), and increased risk for neonatal persistent pulmonary hypertension (8) have been reported. Although persistent pulmonary hypertension in neonates has been supported by findings of increased pulmonary arterial wall thickness, associated with lower oxygen saturation and a higher mortality in fluoxetine-exposed (EXP) newborn rats (9), a subsequent human report did not replicate the earlier human reports (10). Such adverse consequences may reflect the effects of SSRI-related increased levels of the neurotransmitter serotonin during fetal development (3,11). SSRIs primarily act by blocking the serotonin transporter thereby increasing extracellular serotonin levels, and because SSRIs readily cross the placenta and the blood-brain barrier, it is conceivable that they alter early brain development via increased central serotonin levels (12). It remains unclear, however, what mechanisms underlie these disturbances and whether the effects of prenatal SSRI exposure are apparent before birth, long before ongoing antenatal medication exposure ends.To date, very little is known about SSRI effects on the human fetal physiologic functions (13). In a single report, fetal middle cerebral artery (MCA) Doppler blood flow velocities increased by 18.5% over an expected clinical level in two fetuses of depressed SSRI-treated...

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Neonatal Outcomes After Prenatal Exposure to Selective Serotonin Reuptake Inhibitor Antidepressants and Maternal Depression Using Population-Based Linked Health Data

Oberlander¹,

Warburton²,

Misri³

et al. 2006

Arch Gen Psychiatry

485

443

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Fetal behavioural state changes following maternal fluoxetine infusion in sheep

Cited by 49 publications

References 46 publications

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

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

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

Neonatal Outcomes After Prenatal Exposure to Selective Serotonin Reuptake Inhibitor Antidepressants and Maternal Depression Using Population-Based Linked Health Data

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