Buprenorphine Induces Human Fetal Membrane Sterile Inflammation

Abstract

Opioid-use disorder (OUD) during pregnancy has increased in the United States to critical levels and is a leading cause of maternal morbidity and mortality. Untreated OUD is associated with pregnancy complications in particular, preterm birth. Medications for OUD, such as buprenorphine, are recommended with the added benefit that treatment during pregnancy increases treatment post-partum. However, the rate of preterm birth in individuals using illicit opioids or being treated with opioid agonist therapeutics is double that of the general population. Since inflammation in the placenta and the associated fetal membranes (FM) is a common underlying cause of preterm birth, we sought to determine if the opioid, buprenorphine, induces sterile inflammation in human FMs and to examine the mechanisms involved. Using an established in vitro human FM explant system, we report that buprenorphine significantly increased FM secretion of the inflammatory cytokine IL-6; the neutrophilic chemokine IL-8; and the inflammasome-mediated cytokine IL-1{beta}, mirroring the inflammatory profile commonly seen at the maternal-fetal interface in preterm birth. Other factors that were elevated in FMs exposed to buprenorphine included the mediators of membrane weakening, prostaglandin E2 (PGE2), and matrix metalloproteinases, MMP1 and MMP9. Furthermore, this sterile inflammatory and weakening FM response induced by buprenorphine was mediated in part by innate immune Toll-like receptor 4 (TLR4), the NLRP3 inflammasome, the -opioid receptor, and downstream NF{kappa}B and ERK/JNK/MAPK signaling. This may provide the mechanistic link between opioid use in pregnancy and the elevated risk for preterm birth. Since there are adverse consequences of not treating OUD, our findings may help identify ways to mitigate the impact opioids have on pregnancy outcomes while allowing the continuation of maintenance therapy.