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...