Prenatal serotonin reuptake inhibitor exposure and maternal depression symptoms are associated with altered fetal brain and placental development

Maternal mental health is associated with fetal neurodevelopment. Identifying effective treatments for maternal psychiatric conditions is a public health priority. SRIs (SSRIs and SNRIs) are commonly prescribed for prenatal mental health conditions; however, their impact on fetal brain development remains understudied. In this observational cohort study, we compared fetal brain and placental structures between SRI-exposed and unexposed pregnancies divided by categories of maternal depressive symptom severity from the Edinburgh Postnatal Depression Scale (EPDS). Pregnant women treated with SRIs and controls without mental illness or antidepressant exposure underwent fetal MRI studies between 20-40 weeks' gestation. Fetal brain motion correction and 3D reconstructions were performed using slice-to-volume registration. Fetal brain volumes (cortical gray matter, white matter, deep gray matter, cerebellum, brainstem, and hippocampi) were quantified using deep learning-based segmentation with manual correction. Cerebral cortical folding measures included local gyrification index, sulcal depth, curvedness, and surface area. Placental volume and microstructure were assessed with T2-weighted and diffusion-weighted MRI, respectively. EPDS scores were categorized as low ( ≤ 4), moderate (5-9), and high ( ≥ 10). A total of 182 pregnant women were included [62 SRI-exposed (59 SSRIs, 3 SNRIs); 120 controls]. Notably, 29% of SRI-exposed women continued to report elevated depression. SRI-exposed fetuses had smaller hippocampal volumes and reduced cortical gyrification, curvedness, and surface area. Subgroup analysis of stratification by EPDS scores revealed that SRI-exposed fetuses had reduced hippocampal volumes compared to unexposed fetuses with low and moderate, but not high, EPDS scores, and reduced cortical curvedness compared to unexposed subgroups. Among unexposed subgroups, fetuses exposed to high maternal EPDS scores had smaller hippocampal volumes compared to those with low scores. Placenta volume and microstructural diffusion were increased in the SRI-exposed compared to the unexposed group. Larger placental volume was associated with larger total fetal brain volume, and higher placental diffusion was associated with larger fetal white matter and cerebellar volumes in the SRI-exposed group. These findings suggest that prenatal SRI exposure may be associated with altered fetal hippocampal volumes, cerebral cortical maturation, and placental volume and microstructural diffusion. The clinical significance and long-term neurodevelopmental consequences of these structural alterations remain unknown and are currently under study.