649 Despite recent advances in our understanding of the factors involved in the initiation of labor, preterm labor remains a significant problem in obstetric practice. Prostaglandins, particularly prostaglandin F 2α (PGF 2α ), form an essential link in the initiation of labor in many species, including human beings. 1 In sheep premature labor follows a rise in prostaglandin production that can also be induced by fetal glucocorticoid treatment. The in- duction of premature labor by glucocorticoid infusion in sheep has proved to be a useful model for the investiga- tion of new tocolytic treatments. 2 Prostaglandin endoper- oxidase H synthase (PGHS) catalyzes a key step in the prostaglandin synthetic pathway. An increase in the activ- ity of this enzyme is observed with advancing gestation in human amnion and ovine placental tissue, and there is a further increase with the onset of labor. 3, 4 Two PGHS iso- forms have been identified, PGHS-1 and PGHS-2. 5, 6 The expression of PGHS-1 is developmentally regulated and appears to perform maintenance functions in the fetus. Conversely, PGHS-2 expression is induced by several growth factors and cytokines in cells derived from gesta- tional tissues. 7 Studies with intrauterine tissues have From the Department of Physiology, Monash University. Supported by the National Health and Medical Research Council of Aus- tralia. Received for publication October 15, 1999; accepted February 17, 2000. Reprint requests: Peta L. Grigsby, BSc(Hons), Department of Physiology, Monash University, Clayton, Victoria, 3800, Australia. Copyright © 2000 by Mosby, Inc. 0002-9378/2000 $12.00 + 0 6/1/106584 doi:10.1067/mob.2000.106584 Inhibition of premature labor in sheep by a combined treatment of nimesulide, a prostaglandin synthase type 2 inhibitor, and atosiban, an oxytocin receptor antagonist Peta L. Grigsby, BSc(Hons), Kirsten R. Poore, PhD, Jonathan J. Hirst, PhD, and Graham Jenkin, PhD Melbourne, Victoria, Australia OBJECTIVE: The aim of this study was to compare the effects of the selective prostaglandin synthase type 2 inhibitor nimesulide, alone or in combination with the oxytocin receptor antagonist atosiban, on the pro- gression of glucocorticoid-induced premature labor in sheep. Effects on circulating maternal and fetal prosta- glandin concentrations and on fetal well-being were also examined. STUDY DESIGN: Premature labor was induced in ewes with long-term catheterized fetuses by infusion of dexamethasone (1 mg/d) starting at 138 ± 1 days’ gestation. Ewes also received an infusion of either nime- sulide and atosiban (20.0 and 4.12 mg/kg per day, respectively; n = 5), nimesulide alone (20.0 mg/kg per day; n = 5), or vehicle only (n = 9). Plasma 13,14-dihydro-15-keto-prostaglandin F 2α and prostaglandin E 2 concentrations were measured before and during infusions in plasma samples obtained from the maternal and fetal carotid arteries and the utero-ovarian vein. RESULTS: No fetuses from ewes treated with nimesulide and atosiban were delivered during treatment. These animals were killed electively 98.0 ± 6.8 hours after the commencement of dexamethasone induction. This was significantly longer than the delivery times for those ewes treated with nimesulide alone (71.2 ± 3.9 hours; n = 5) and for vehicle-treated ewes (51.4 ± 1.7 hours; n = 9). Both maternal and fetal plasma 13,14-di- hydro-15-keto-prostaglandin F 2α and prostaglandin E 2 concentrations in nimesulide and atosiban–treated ewes and in nimesulide-treated ewes decreased during treatment. In contrast, vehicle-treated ewes showed a significant increase in maternal and fetal plasma 13,14-dihydro-15-keto-prostaglandin F 2α and prosta- glandin E 2 concentrations during dexamethasone induction. Uterine electromyographic activity observed in nimesulide and atosiban–treated ewes was significantly suppressed with respect to activities in both vehicle- and nimesulide-treated ewes during the treatment period. All fetuses were alive at delivery or scheduled death. CONCLUSIONS: These results indicate that the combination of an inhibitor of prostaglandin endoperoxi- dase H synthase type 2 with an oxytocin receptor antagonist is more effective in inhibition of preterm labor than is treatment with a prostaglandin endoperoxidase H synthase type 2 inhibitor alone. The clinical use of atosiban to prevent the oxytocin-stimulated increase in uterine activity associated with labor in combination with nimesulide may permit reduction of the dose of nimesulide used to a level that has minimal impact on fetal well-being. (Am J Obstet Gynecol 2000;183:649-57.) Key words: Labor, nimesulide, oxytocin receptor antagonists, prostaglandin endoperoxidase H synthase inhibitors, sheep