Preterm birth (PTB) remains a major public health problem, complicating >10% of all deliveries, and itsassociated perinatal morbidity and mortality represents 30% of the total. The greatest single risk factor forPTB is a prior PTB. Early and accurate identification of at risk patients may permit targeted interventions.Despite great effort, the US PTB rate has actually increased over the past 30y. This failure reflects a poorunderstanding of the basic mechanisms initiating PTB coupled to a long held assumption that preterm labor(PL) is simply term labor ill timed. Ascending infection from the lower genital is a well-recognized as amechanism of upper tract inflammation, fetal inflammatory response syndrome, decidual hemorrhage,chorioamnionitis or combinations thereof. Yet, antibiotic therapy has failed to reduce the PTB rate. It is likelyother therapeutic strategies are necessary once the innate immunity of the lower genital tract isoverwhelmed and the inflammatory cascade established in the upper genital tract or fetal compartment. Wehypothesize that PTB reflects an alteration of oxygen independent (defensins and calgranulins) and oxygendependent (oxygen free radicals) defense mechanisms of the lower and upper genital tract, and that thesequestration of certain polymorphisms in genes regulating the inflammatory cascade among some ethnicgroups accounts in part for their risk of recurrent PTB (Specific Aim 1a). We hypothesize women destinedfor PTB express cervicovaginal biomarkers illustrative of altered innate immunity weeks or months beforeonset of PTB symptoms (cervical ripening, preterm labor contractions or pPROM) that can be reliablyidentified using proteomic tools (Specific Aim 1b). We hypothesize that the progesterone compoundsreported to decrease recurrent PTB affect maternal lower and upper genital tract defense mechanisms aswell as the fetal inflammatory response axis (Specific Aim 2). This proposal brings together an experiencedmultidisciplinary team who will test elements of these hypotheses in experiments performed over a 5y period.