Antenatal Betamethasone in Late Preterm Gestation Lambs

描述(申请人提供)：在过去十年中，晚产早产(定义为妊娠34 0/7周至36 6/7周出生)的发生率一直在稳步上升，约占所有早产的75%。过渡性疾病的呼吸道发病率，包括肺高压(肺血管扩张受损)、新生儿一过性呼吸急促(肺液清除不足)和呼吸窘迫综合征(表面活性物质产生和释放不足)，对晚期早产儿的影响比较高胎龄的婴儿更高。美国妇产科医师学会(ACOG)的实践指南建议妊娠34周以下的早产妇女使用宫缩和糖皮质激素。然而，超过34wk的努力不再针对延长妊娠或提高胎儿成熟度。此外，由于妊娠日期的内在不准确性，在妊娠晚期误差幅度高达3wk，引产和选择性剖宫产可能无意中导致晚期早产的发生率增加。足月剖宫产的产前类固醇研究报告称，两种剂量的倍他米松显著降低了择期剖宫产出生的37周婴儿的呼吸道发病率。对于早产的34周妊娠母亲，产前使用糖皮质激素无疑可以减少一些新生儿的发病率，包括呼吸窘迫和脑室出血。考虑到在一项单独的研究中对婴儿37周有希望的结果，评估34到36 6/7周之间早产的产前糖皮质激素对肺生理的影响和益处(或缺乏)的研究是重要的。我们建议在选择性剖宫产前给怀孕的母羊注射倍他米松，以获得这种洞察力。在开始产前类固醇疗程后48小时内可能无法阻止分娩。因此，我们计划测试两种方案：在该方案中，在分娩前24小时给予一剂倍他米松，在分娩前48小时和24小时给予两剂倍他米松。早产晚期羔羊(妊娠134 d，足月~145 d)，产前应用倍他米松2次、1次或不用药后，于出生时处死(用于评估肺血管反应性、肺液体状态、顺应性和表面活性物质的产生和释放)或用于评估肺血管阻力、氧合和机械通气6h，我们将研究出生时重要的肺转换介质如一氧化氮、β肾上腺素能药物、利钠肽和前列腺素的变化。我们推测，产前应用一次或两次倍他米松可促进剖宫产早产晚期羔羊的肺血管扩张、肺液体重吸收和肺表面活性物质的产生。这些研究可能会对产前使用类固醇的临床方案产生影响，改变目前的做法。与公共卫生相关：在北美，通过剖腹产分娩的妊娠34至37周的新生儿数量正在迅速增加，这通常被称为晚产早产。用倍他米松(一种类固醇)治疗分娩中的晚期早孕母亲可能会降低婴儿呼吸道并发症和死亡率的风险。我们打算将倍他米松用于晚期早孕母羊，以研究这种治疗在剖宫产胎羊中的益处和作用机制。

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.