LAUSR

Background The progestogen 17‐&agr; hydroxyprogesterone caproate (17‐OHPC) is 1 of only 2 agents recommended for clinical use in the prevention of spontaneous preterm delivery, and studies of its efficacy have been conflicting. We have developed an in‐vitro model to study the fetal membrane weakening process that leads to rupture in preterm premature rupture of the fetal membranes (pPROM). Inflammation/infection associated with tumor necrosis factor‐&agr; (TNF‐&agr;) induction and decidual bleeding/abruption associated thrombin release are leading causes of preterm premature rupture of the fetal membranes. Both agents (TNF‐&agr; and thrombin) cause fetal membrane weakening in the model system. Furthermore, granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) is a critical intermediate for both TNF‐&agr; and thrombin‐induced fetal membrane weakening. In a previous report, we demonstrated that 3 progestogens, progesterone, 17‐alpha hydroxyprogesterone (17‐OHP), and medroxyprogesterone acetate (MPA), each inhibit both TNF‐&agr;– and thrombin‐induced fetal membrane weakening at 2 distinct points of the fetal membrane weakening pathway. Each block both the production of and the downstream action of the critical intermediate granulocyte‐macrophage colony‐stimulating factor. Objective The objective of the study was to characterize the inhibitory effects of 17‐OHPC on TNF‐&agr;– and thrombin‐induced fetal membrane weakening in vitro. Study Design Full‐thickness human fetal membrane fragments from uncomplicated term repeat cesarean deliveries were mounted in 2.5 cm Transwell inserts and cultured with/without 17‐alpha hydroxyprogesterone caproate (10–9 to 10–7 M). After 24 hours, medium (supernatant) was removed and replaced with/without the addition of tumor necrosis factor‐alpha (20 ng/mL) or thrombin (10 U/mL) or granulocyte‐macrophage colony‐stimulating factor (200 ng/mL). After 48 hours of culture, medium from the maternal side compartment of the model was assayed for granulocyte‐macrophage colony‐stimulating factor and the fetal membrane fragments were rupture strength tested. Results Tumor necrosis factor‐alpha and thrombin both weakened fetal membranes (43% and 62%, respectively) and increased granulocyte‐macrophage colony‐stimulating factor levels (3.7‐ and 5.9‐fold, respectively). Pretreatment with 17‐alpha hydroxyprogesterone caproate inhibited both tumor necrosis factor‐alpha– and thrombin‐induced fetal membrane weakening and concomitantly inhibited the induced increase in granulocyte‐macrophage colony‐stimulating factor in a concentration‐dependent manner. However, contrary to our prior reports regarding progesterone and other progestogens, 17‐alpha hydroxyprogesterone caproate did not also inhibit granulocyte‐macrophage colony‐stimulating factor–induced fetal membrane weakening. Conclusion 17‐Alpha hydroxyprogesterone caproate blocks tumor necrosis factor‐alpha– and thrombin‐induced fetal membrane weakening by inhibiting the production of granulocyte‐macrophage colony‐stimulating factor. However, 17‐alpha hydroxyprogesterone caproate did not also inhibit granulocyte‐macrophage colony‐stimulating factor–induced weakening. We speculate that progestogens other than 17‐alpha hydroxyprogesterone caproate may be more efficacious in preventing preterm premature rupture of the fetal membranes–related spontaneous preterm birth.