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Cardiovascular, metabolic, endocrine and behavioral aspects of development in postnatal lambs in relation to age, sex, lamb number and acute fluoxetine administration Nguyen, Tuan-Anh Thi


Human newborns exposed in utero to maternally administered SSRIs such as fluoxetine (FX) have an increased risk of adverse pregnancy outcomes including poor neonatal adaptation. This comprises respiratory difficulty, jitteriness, cyanosis when feeding and persists for several days after birth. Several potential mechanisms underlying these symptoms have been proposed: 1) acute toxicity to the drugs (i.e. serotonin syndrome), 2) withdrawal syndrome due to the sudden discontinuation of maternal-fetal placental drug transfer at birth or 3) an SSRIs-elicited alteration in fetal brain development. However, the actual mechanism has not been elucidated. In addition, the safety of SSRIs for the treatment of depression in children and adolescents is uncertain. Thus, we conducted experiments in which acute i.v FX (1mg/kg) and sterile water were given to FX and control groups in the lambs at ~ 3,10 days, 1,3,6 and 12 months of age. In another cohort, daily 50mg FX was given i.v to 5 pregnant ewes via implanted catheters during late gestation (131-132d, term = 147d) for 2 weeks. Plasma FX concentrations in the newborn acute FX group were within the range measured in human infants at the same age. There was a lack of significant acute FX effects on cardiovascular-respiratory, behavioral and endocrine functions in ~ 4 day old lambs. In the lambs exposed to FX prenatally, plasma FX at birth and postnatal day (PND) 2 were low and undetectable on PND 5,10,14. However, prenatal FX-exposed lambs were hyperactive during PND 4 to 14 and their heart rate variability (HRV) was significantly lower than control lambs on PND 2. Results suggested that SSRI toxicity and withdrawal are unlikely to be the mechanism underlying poor neonatal adaptation in human exposed to FX in utero. However, acute FX effects were seen in some, but not all, age groups. No acute FX effects were observed in the young lambs (10d and 3 months of age). However, hypoactivity, transient hypoxemia, hypertension and increased HRV occurred after acute FX administration in the older lambs (1,6 and 12 months of age). Hypoxemia and hypertension effects were more profound in males. No changes in HPA axis function were observed

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