MON-139 - Maternal Serotonin Selective Reuptake Inhibitor (SSRI) Exposure Disrupts Placental Development and Function Alongside Offspring Development

Selective serotonin reuptake inhibitor (SSRI) use during pregnancy is increasingly prevalent, yet its combined effects on placental vascular function and fetal programming remain poorly understood. We investigated the effect of serotonin transporter (SERT) inhibition on placental structure, perfusion, and offspring outcomes using complementary mouse models and human placental analyses.
Pregnancies were established in 3-month-old female mice using pharmacological SSRI (fluoxetine) exposure. On embryonic day 17, Doppler ultrasound revealed that SSRI exposure reduced maternal and placental blood flow volume, flow velocity, and heart rate, while fetal blood flow parameters were increased, consistent with compensatory fetal cardiovascular response to impaired placental perfusion. These in utero hemodynamic disturbances were associated with lasting postnatal consequences as SSRI-exposed offspring exhibited a significant, non-sex-specific reduction in average body weight (p=0.00269) and adipose tissue mass from postnatal day (PND) 0 through PND21. Growth restriction was further exacerbated while adipose tissue development normalized with increasing gestation number (weight p= < 0.001; adipose: p=0.17), indicating that consecutive pregnancies impact offspring development.
To determine whether altered placental function could mechanistically link impaired perfusion to postnatal growth deficits, we performed RNA sequencing on placentas collected from genetic SERT knockout mice at E13 and E17 to capture mid- and late-gestation molecular adaptations to SERT inhibition. Transcriptomic profiling revealed upregulation of the immune response, host defenses, and tissue remodeling at both timepoints, suggesting sustained placental stress or maladaptive remodeling state that may compromise nutrient exchange and endocrine signaling.
We next assessed whether these placental alterations are conserved in humans. Histological analysis of placentas from SSRI-treated cesarean deliveries revealed marked hypervascularization of the chorionic villi compared with controls. Immunohistochemistry further demonstrated increased SERT expression across placental layers in SSRI-exposed human samples, with particularly elevated expression in the chorionic villi, a pattern not observed in controls.
Together, these findings support a model in which maternal SSRI exposure disrupts placental vascular development and function, leading to impaired maternal-placental perfusion, compensatory fetal hemodynamic changes, and persistent deficits in early postnatal growth. This conserved placental vascular phenotype across species highlights the placenta as a central mediator of SSRI-associated impact on development.

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