In utero and lactational exposure to the Selective Serotonin Reuptake Inhibitor fluoxetine compromises pup bones at weaning

Abstract

Selective Serotonin Reuptake Inhibitors (SSRIs) such as fluoxetine are widely prescribed to pregnant and breastfeeding women, yet the effects of peripartum SSRI exposure on neonatal bone are not known. In adult populations, SSRI use is associated with compromised bone health, and infants exposed to in utero SSRIs have a smaller head circumference and are shorter, suggesting possible effects on longitudinal growth. Yet no study to date has examined the effects of peripartum SSRIs on long bone growth or mass. We used microCT to determine the outcomes of in utero and lactational SSRI exposure on C57BL6 pup bone microarchitecture. We found that peripartum exposure to 20 mg/kg fluoxetine reduced femoral bone mineral density and bone volume fraction, negatively impacted trabecular and cortical parameters, and resulted in shorter femurs on postnatal day 21. Although SSRIs are considered the first-choice antidepressant for pregnant and lactating women due to a low side effect profile, SSRI exposure may compromise fetal and neonatal bone development.

Figure 1

Pups exposed to in utero and lactational fluoxetine have compromised trabecular femoral bone. Dams were injected intraperitoneally with either saline or 20 mg/kg fluoxetine from day 0 of pregnancy through day 21 of lactation. At weaning, femurs were extracted from n = 4 and n = 8 female pups of saline dams and n = 6 male and n = 8 female pups of fluoxetine dams and subjected to microCT analysis. (A) Bone volume/tissue volume. (B) 3D reconstruction images of distal femur trabecular bone. The scale bar represents 100 microns. (C) Trabecular number (mm⁻¹). (D) Trabecular thickness (μm). (E) Trabecular spacing (μm). (F) Trabecular bone mineral density (mgHg/cm³). Data were analyzed with a Student’s t-test and are presented as mean ± SEM.

Figure 2

Pups exposed to in utero and lactational fluoxetine have compromised cortical femoral bone and shorter femurs. Dams were injected intraperitoneally with either saline or 20 mg/kg fluoxetine from day 0 of pregnancy through day 21 of lactation. At weaning, femurs were extracted from n = 4 and n = 8 female pups of saline dams and n = 6 male and n = 8 female pups of fluoxetine dams and subjected to microCT analysis. (A) Cortical thickness (mm). (B) Cortical porosity (%). (C) Cortical bone mineral density (mgHg/cm³). (D) Femur length (mm). (E,F) Isolated femurs from saline-treated (left) and fluoxetine-treated (right) mice are shown. Scale bar in mm. Males are shown in (E) and females are shown in (F). Data were analyzed with a Student’s t-test and are presented as mean ± SEM.