Antenatal Betamethasone in Late Preterm Gestation Lambs

描述（由申请人提供）：晚期早产（定义为妊娠34 0/7至36 6/7周出生）的发生率在过去十年中稳步上升，占所有早产的75%左右。由过渡性疾病引起的呼吸系统疾病，包括肺动脉高压（肺血管舒张受损）、新生儿短暂性呼吸急促（肺液体清除不足）和呼吸窘迫综合征（表面活性剂产生和释放不足）对晚期早产儿的影响高于更高龄的婴儿。美国妇产科医师学会（ACOG）的实践指南推荐对妊娠34周以下的早产妇女使用溶胎和糖皮质激素。然而，超过34周的努力不再针对延长妊娠或提高胎儿成熟度。此外，由于妊娠日期固有的不准确性，在妊娠晚期的误差范围可达3周，在“推定足月”进行引产和选择性剖宫产可能会无意中增加晚期早产的发生率。足月剖宫产的产前类固醇研究报道，两种剂量的产前倍他米松可显著降低选择性剖宫产出生的bb0 ~ 37周婴儿的呼吸系统发病率。对妊娠< 34周的早产母亲使用产前糖皮质激素无疑可以减少新生儿的一些发病率，包括呼吸窘迫和脑室内出血。考虑到在一项研究中婴儿出生年龄为0至37周的有希望的结果，评估产前糖皮质激素对34至36 6/7周早产儿的肺生理影响和益处（或缺乏）的研究是重要的。我们建议通过在选择性剖宫产前给怀孕母羊使用倍他米松来获得这样的见解。产前类固醇疗程开始后48小时内可能无法预防分娩。因此，我们计划测试两种方案：在分娩前24小时给药一剂倍他米松，在分娩前48小时和24小时给药两剂。通过选择性剖宫产分娩的晚期早产羔羊（妊娠134天，足月~ 145天），在产前使用两剂、一剂或不使用倍他米松后，要么在出生时处死（用于评估肺血管反应性、肺液状态、顺应性和表面活性剂的产生和释放），要么用仪器评估肺血管阻力。我们将研究出生时肺过渡重要介质的变化，如一氧化氮、β肾上腺素能剂、利钠肽和前列腺素，这些介质是产前糖皮质激素使用的继发因素。我们假设产前给予一剂或两剂倍他米松会增强剖宫产晚期早产羔羊的肺血管舒张、肺液体重吸收和表面活性剂的产生。这些研究可能会对产前类固醇使用的临床方案产生影响，改变目前的做法。公共卫生相关性：在北美，通过剖宫产在妊娠34至37周分娩的人数（通常称为晚期早产）正在迅速增加。用倍他米松（一种类固醇）治疗分娩中的晚期早产孕妇可以降低其婴儿呼吸系统并发症和死亡率的风险。我们打算给晚期早产母羊使用倍他米松，以研究这种治疗在剖宫产胎羊羔中的益处和机制。

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.