We used pregnant sheep and their fetuses as well as newborn lambs (with and without severe respiratory distress due to prematurity) to study the differences in plasma clearance rate, production rate, and circulating concentrations of immunoreactive PGE₂. Fetal PGE₂ concentrations were significantly higher than simultaneous maternal concentrations. After delivery by cesarean section, all newborn animals were paralyzed and mechanically ventilated. The PGE₂ concentrations fell in those lambs that required only minimal ventilatory support (FI_O²<0.25) and were similar to maternal concentrations by two to three hours. Newborn lambs that developed severe respiratory distress (FI_O²>0.55) continued to have concentrations that were even greater than fetal concentrations. The elevated PGE₂ concentrations in severely distressed lambs were due not only to a decreased plasma clearance rate but also to an increased production rate of PGE₂. Since PGE₂ appears to maintain the patency of the ductus arteriosus in the fetus and preterm neonate, we examined the patency of the ductus arteriosus in 3-hour-old newborn lambs by radioactive microsphere injections. The ductus was more widely patent in lambs with higher concentrations of PGE₂. The increased circulating concentrations of PGE₂ in newborn lambs with severe respiratory distress may contribute to the pathogenesis of patent ductus arteriosus by exerting an additional vasodilatory effect on the vessel.