Gestational age-dependent decrease in fetal Hofbauer cells in placentas from pregnancies exposed to wildfire smoke in California

Abstract OBJECTIVE Wildfires are more common over the last decade and the frequency of wildfire events has been accelerated by climate change. The existing body of literature suggests that exposure to wildfire smoke during pregnancy contributes to adverse perinatal outcomes such as preterm birth and fetal growth restriction. We hypothesize that exposures to wildfire smoke and its constituents triggers a fetal inflammatory response which contributes to pathological changes that underlie these adverse pregnancy outcomes. In this study, we quantified the presence of fetal macrophages (i.e., Hofbauer cells) in human placentas obtained between 2018 and 2020 to assess the relationship between fetal immune status and wildfire exposure. STUDY DESIGN We collected placentas from pregnancies from two hospitals in San Francisco over a two-year period that included two severe major wildfires. The average particulate matter < 2.5 μm (PM 2.5 ) or wildfire specific PM 2.5 levels were estimated over the gestational duration of each sample. Immunostaining against CK7 and CD68 was performed to identify intravillous fetal Hofbauer cells. We assessed the gestational-age dependent relationship between placental CD68+ cell density and mean daily PM 2.5 or wildfire-specific PM 2.5 via linear regression and Welch’s t-test. Additionally, we compared placental CD68+ cell density with estimated peak wildfire exposures during the gestation to determine if timing of exposure during pregnancy may influence the occurrence of Hofbauer cells in the placenta. RESULTS The gestational ages ranged from 7-41 weeks (n = 67). The majority of samples were collected during one of two major wildfire events in Northern California (70%; n = 47). In general, we observed a significant inverse relationship between placental CD68 density and PM2.5 or wildfire specific PM2.5, however, these associations were only observed in first or second trimester samples, and not in term samples. For example, among first trimester samples (n=22), we observed lower mean CD68 density among samples likely to be exposed to wildfire events ( mean = 1.42, SD = 0.8) as compared to those not exposed ( mean = 3.73, SD = 1.983) ( p = 0.0015). Based on our linear regression model results, we predicted that a one μg/m 3 increase in daily mean wildfire PM 2.5 was associated with a 0.457 decrease in CD68 density (ß =-0.457; 95% CI: -0.722, -0.193). This association was also significant for daily mean overall PM 2.5 , though smaller in magnitude (ß = -0.139; 95% CI: -0.218, -0.059). CONCLUSIONS Our results suggest that wildfire smoke exposures are associated with decreased presence of fetal Hofbauer cells in first and second trimester placentas, suggesting exposure may lead to impaired placental function via altered presence of fetal Hofbauer cells and changes in immune status.