Mitigating Placental Inflammation is Necessary for Improved Fetal Outcomes following Maternal H1N1 Infection 2327794

Abstract Introduction Influenza infection during pregnancy poses significant risks to maternal and fetal health, including increased hospitalization, ICU admission, and mortality, as well as long-term neurodevelopmental deficits in offspring. Maternal H1N1 infection induces COX-1—mediated arachidonic acid pathway activation in the lungs (site of infection) and placenta. Placentas from infected dams show increased infiltration of proinflammatory immune cells, including macrophages and T cells, with elevated frequencies of IFNγ, GZB+, and IL-17+ CD8+ T cells and IFNγ-producing γδ T cells. These markers of placental inflammation were associated with reduced expression of neural growth factors in fetuses from H1N1-infected dams. As H1N1 does not replicate outside the respiratory tract, identifying mechanisms for mitigating placental inflammation will be critical for improved outcomes. Methods To distinguish the contributions of viral replication and maternal immune activation, infected pregnant CD1 dams were treated with oseltamivir and/or low-dose acetylsalicylic acid (LDA), beginning 2 days post-infection and continuing until euthanasia at 6 days post-infection. Results OST reduced lung viral burden and maternal morbidity but had limited impact on placental immune and endocrine dysregulation. In contrast, LDA reduced systemic IFNγ, reduced COX-1 activation, and partially mitigated placental cytokine dysregulation. While all treatments reduced placental IFNγ, only combination therapy simultaneously reduced pulmonary viral replication and normalized placental endocrine and inflammatory profiles, including suppression of GZB+ CD8+ T cells and IFNγ γδ T cells. Combination therapy fully rescued fetal growth, demonstrating that targeting maternal inflammation is required in addition to antiviral therapy to prevent adverse fetal outcomes. Conclusion Given that OST and LDA are approved for use during pregnancy, these findings highlight their combined therapeutic potential for treating influenza infection in pregnancy. Funding Source 5T32AI007417-29 Topic Categories Viral Immunology (VIR)