The Influence of Fetal Sex on Antepartum Treatments in a Murine Model of Preterm Birth [ID: 2369702]

INTRODUCTION: Preterm neonates exposed to magnesium sulfate (MgSO 4 ) and corticosteroids such as betamethasone (BMTZ) in utero have a lower incidence of neurodevelopmental disability, specifically cerebral palsy. The efficacy of MgSO 4 /BMTZ remains poor, particularly in male offspring. The mechanisms by which MgSO 4 /BMTZ confer “neuroprotection” in only some patients and in relation to fetal sex, remain unknown. Our objective was to examine sex-specific responses to MgSO 4 /BMTZ in a murine model of fetal neuroinflammatory injury. METHODS: Utilizing an established murine model of preterm birth, dams were injected intrauterine with either phosphate-buffered saline or bacterial endotoxin (lipopolysaccharide [LPS]) on embryonic day 15.5 to induce fetal inflammation. Thereafter, dams received MgSO 4 /BMTZ or the vehicle. Fetal brains and placentas were collected 6 hours postinjection for gene expression analysis of key inflammatory cytokines: Il1b, Il6, and Tnf. RESULTS: Irrespective of sex, LPS exposure up-regulated all three cytokines. With MgSO 4 /BMTZ, Il1b expression was significantly lower in female, but not male brains. In contrast, MgSO 4 /BMTZ lowered Il6 expression in placentas from males, but not females. No sex differences were observed with Tnf expression. CONCLUSION: Within the context of LPS-mediated in utero inflammation, fetal sex influenced the efficacy of MgSO 4 /BMTZ. The anti-inflammatory effect of MgSO 4 /BMTZ also appeared tissue specific, with protection shown in female brains and male placentas. These results suggest that the neuroprotective effects of MgSO 4 /BMTZ are more robust in females, whereas placental inflammation is more affected in males. Further investigation is warranted to determine whether these sex-specific patterns govern fetal outcomes.