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Prenatal Exposure to Fluoxetine Induces Fetal Pulmonary Hypertension in the Rat

¹ Lung Biology Research Group, Physiology and Experimental Medicine Program, Hospital for Sick Children, Toronto, Ontario, Canada; and Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to Jaques Belik, M.D., Division of Neonatology, University of Toronto Hospital for Sick Children, Room 3886, 555 University Avenue, Toronto, ON, M5G 1X8 Canada. E-mail: jaques.belik{at}sickkids.ca

Rationale: Fluoxetine is a selective serotonin reuptake inhibitor antidepressant widely used by pregnant women. Epidemiological data suggest that fluoxetine exposure prenatally increases the prevalence of persistent pulmonary hypertension syndrome of the newborn. The mechanism responsible for this effect is unclear and paradoxical, considering the current evidence of a pulmonary hypertension protective fluoxetine effect in adult rodents.

Objectives: To evaluate the fluoxetine effect on fetal rat pulmonary vascular smooth muscle mechanical properties and cell proliferation rate.

Methods: Pregnant rats were treated with fluoxetine (10 mg/kg) from Day 11 through Day 21 of gestation.

Measurements and Main Results: Fetuses were delivered by cesarean section. As compared with controls, fluoxetine exposure resulted in fetal pulmonary hypertension as evidenced by an increase in the weight ratio of the right ventricle to the left ventricle plus septum (P = 0.02) and by an increase in pulmonary arterial medial thickness (P < 0.01). Postnatal mortality was increased among experimental animals, and arterial oxygen saturation was 96 ± 1% in 1-day-old control animals and significantly lower (P < 0.01) in fluoxetine-exposed pups (79 ± 2%). In vitro, fluoxetine induced pulmonary arterial muscle contraction in fetal, but not adult, animals (P < 0.01) and reduced serotonin-induced contraction at both ages (P < 0.01). After in utero exposure to a low fluoxetine concentration the pulmonary arterial smooth muscle cell proliferation rate was significantly increased in fetal, but not adult, cells (P < 0.01).

Conclusions: In contrast to the adult, fluoxetine exposure in utero induces pulmonary hypertension in the fetal rat as a result of a developmentally regulated increase in pulmonary vascular smooth muscle proliferation.

Key Words: serotonin • selective serotonin reuptake inhibitor • newborn • lung

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Epidemiologic data suggest that antidepressants may increase the risk of neonatal pulmonary hypertension. What This Study Adds to the Field In contrast to the adult, fluoxetine exposure in utero induces pulmonary hypertension in the fetal rat as a result of a developmentally regulated increase in pulmonary vascular smooth muscle proliferation.

 

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