Antenatal Betamethasone in Late Preterm Gestation Lambs

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DESCRIPTION (provided by applicant): The incidence of late preterm births (defined as births at 34 0/7 to 36 6/7 wk gestation) have been steadily increasing over the past decade and account for the ~ 75% of all preterm births. Respiratory morbidity from disorders of transition including pulmonary hypertension (impaired pulmonary vasodilation), transient tachypnea of newborn (inadequate lung liquid clearance) and respiratory distress syndrome (inadequate surfactant production and release) affect late preterm infants at a higher rate than infants of more advanced gestational age. Practice guidelines of the American College of Obstetricians and Gynecologists (ACOG) recommend tocolysis and glucocorticoids to women in preterm labor up to 34 wk gestation. However, beyond 34 wk efforts are no longer directed at prolonging pregnancy or enhancing fetal maturity. Moreover, because of the inherent inaccuracy of pregnancy dating with margins of error up to 3 wk in the third trimester, inductions of labor and elective cesarean section performed at "presumed term" might inadvertently contribute to the increasing incidence of late preterm birth. The Antenatal Steroids for Term Cesarean Section study reported that two doses of antenatal betamethasone significantly reduced respiratory morbidity in > 37 wk infants born by elective cesarean section. Administration of antenatal glucocorticoids to < 34 wk gestation mothers in preterm labor undoubtedly reduces a number of neonatal morbidities including respiratory distress and intraventricular hemorrhage. Given the promising results in infants > 37 wk in a single study, research evaluating the pulmonary physiological effects and benefits (or lack there of) of antenatal glucocorticoids for preterm labor between 34 and 36 6/7 wk is important. We propose to gain such insight by administering betamethasone to pregnant ewes prior to elective cesarean section. It may not be possible to prevent delivery for 48 h after initiation of an antenatal steroid course. Hence we plan to test two protocols: one dose of betamethasone administered 24 h prior to delivery and two doses administered 48 h and 24 h prior to delivery in this proposal. Late preterm lambs (134 d gestation, term ~ 145 d) delivered by elective cesarean section following two, one or no doses of antenatal betamethasone will either be sacrificed at birth (for evaluation of pulmonary vascular reactivity, lung liquid status, compliance and surfactant production and release) or instrumented for evaluation of pulmonary vascular resistance, oxygenation and ventilation for 6 h. We will study the changes in important mediators of pulmonary transition at birth such as nitric oxide, beta adrenergic agents, natriuretic peptides and prostaglandins secondary to antenatal glucocorticoid use. We hypothesize that antenatal administration of either one or two doses of betamethasone will enhance pulmonary vasodilation, lung liquid reabsorption and surfactant production in late preterm lambs delivered by cesarean section. These studies are likely to have an impact on the clinical protocol for use of antenatal steroids, changing current practice. PUBLIC HEALTH RELEVANCE: The number of births at 34 to 37 weeks of gestation, often referred to as late preterm births, delivered by cesarean section is rapidly increasing in North America. Treating late preterm pregnant mothers in labor with betamethasone (a steroid) may reduce the risk of respiratory complications and mortality in their infants. We intend to administer betamethasone to late preterm gestation ewes to study the benefit and mechanism of this treatment in fetal lambs delivered by cesarean section.