Prematurity is the leading cause of neonatal morbidity and mortality in the United States. The 8% of neonates born prematurely account for 70% of all perinatal deaths hot attributed to congenital malformations. A growing body of evidence suggests that intrauterine infections are an important, and potentially treatable cause of prematurity. However, the mechanisms by which infection leads to prematurity remain speculative and treatment strategies untested largely because humans cannot be longitudinally studied following infection. We propose to use chronically instrumented pregnant rhesus monkeys (n: 36) at 120-130 days gestation with experimental intrauterine infection, as previously described (Gravett et al, Am J Obstet & Gynecol; 171:1660-1667,1994) to study the temporal and quantitative relationships among infection, cytokines, prostaglandins, lipoxygenase derivatives, steroid hormones, cytokine antagonists, and preterm labor in order to develop effective interventional strategies. After postoperative stabilization in a tether, we will (1) infuse proinflammatory cytokine IL-1beta into the amniotic cavity through previously placed indwelling catheters in the absence of infection (n=16); (2) inoculate Group 8 streptococci (GBS) into the amniotic fluid to establish intrauterine infection and preterm labor (n=20). Uterine contractility will be continuously monitored and periodic samples of amniotic fluid and maternal and fetal blood (1-4 cc) will be obtained for assays of eicosanoids, steroid hormones, cytokines, complement and heat-shock proteins, and for microbial studies. Prior to infusion of IL-1beta in the absence of infection, potent inhibitors of proinflammatory cytokine production (dexamethasone, interleukin-10) or prostaglandin production (indomethacin) will be used to ascertain the most effective intervention to down-regulate the cytokine/prostaglandin cascade and associated uterine activity. The immunosuppressants or prostaglandin synthase inhibitor will be similarly studied in combination with antibiotics in the setting of experimental intrauterine infection with GBS. Samples of the decidua, placenta, and fetal tissue will be obtained at cesarean section for microbiologic, histopathologic, and studies for cytokine mRNA localization and quantitation. The fetus is pre-viable and will be euthanized. Postpartum, the mother will be treated with appropriate antibiotics to eradicate the GBS from the genital tract and returned to the colony. These studies will clarify the pathophysiology of infection-associated preterm labor and will suggest effective interventional strategies.
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