Placental and intra-amniotic inflammation are associated with altered fetal immune responses at birth

Introduction
High-grade placental inflammation is associated with preterm birth and poor neonatal outcomes. Recent reports suggest that low-grade placental inflammation is common in uncomplicated pregnancies. The relationship between placental inflammation and innate immune anti-microbial responses is unknown. In this study we sought to identify any association between placental inflammation and fetal immune responses.
Methods
Cord blood samples collected from late preterm and full-term Caesarean section deliveries (n = 44) were exposed to various immune challenges (resiquimod, LPS, PGN, poly (I:C), cGAMP, and 5′ppp-dsRNA) and production of inflammatory mediators (G-CSF, IFN-γ, IL-1β, IL-6, IL-8, IL-10, and TNF-α) was measured by multiplex assay. Hospital histology reports were used to assess the extent of inflammation in the placenta.
Results
Almost half (47.7%) of placentae examined here showed histological evidence of inflammation. Resiquimod, LPS, and PGN elicited strong inflammatory responses in neonatal cord blood, while poly (I:C), cGAMP, and 5′ppp-dsRNA elicited weaker responses. Fetuses with evidence of chorioamnionitis and fetal inflammatory reaction in their placentae had significantly increased immune responses to cGAMP and 5′ppp-dsRNA (ligands for STING and RIG-I, respectively) and significantly decreased immune responses to poly (I:C) (a TLR3 agonist). Interestingly, STING, RIG-I, and TLR3 are all involved in viral response pathways, suggesting that fetuses exposed to chorioamnionitis or fetal inflammatory reaction might respond differently to viruses postnatally.
Conclusion
Our data suggest that low-level placental inflammation is associated with altered innate cytokine responses at birth.