PRENATAL CORTICOSTEROIDS IN INFANTS WITH CONGENITAL DIAPHRAGMATIC HERNIA

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。大约每2500名活产儿中就有一人患有先天性隔膜疝气(CDH)，产前诊断时死亡率为30-70%。尽管在出现早发性严重呼吸衰竭的CDH婴儿中使用了积极的支持来维持足够的气体交换，但传统治疗的失败率仍然很高。似乎有充分的证据表明，患有CDH的动物和人类婴儿的肺部显示出表面活性物质缺乏的肺部疾病的证据。随着产前超声在评估胎儿健康状况和确定合适胎龄方面的使用越来越多，越来越多的婴儿在分娩前被诊断为CDH。孕期母体类固醇通过促进肺成熟和加速肺表面活性物质的产生，从而改善新生儿结局，已被证明对早产儿有明显的益处。这种治疗似乎需要至少24小时才能改善肺功能，这与蛋白质合成或酶诱导所需的时间一致。在氮鼠CDH模型中，现在有证据表明，产前类固醇逆转了许多不成熟的组织学和生化指标。在这一模型中，产前类固醇也显示出氧合和肺顺应性的改善。虽然从这些观察来看，出生后使用表面活性物质治疗似乎是合乎逻辑的，但事实上，只有轶事支持将其用于患有CDH的婴儿，没有一项是前瞻性随机试验的结果。怀孕第三十四周后，由于正常的肺部已经足够成熟，所以不会广泛使用类固醇。鉴于先前对CDH胎儿肺不成熟的观察，以及在CDH胎儿模型中注意到的积极作用，我们提出了一项前瞻性的多中心研究，以评估母亲应用糖皮质激素对诊断为CDH的胎儿的影响。假设：这项研究的假设是，与未经治疗的诊断为CDH的胎儿相比，对怀有CDH的孕妇进行产前类固醇治疗将显著降低此类胎儿的死亡率。具体目的：1.明确产前类固醇是否能提高CDH的存活率。2.探讨产前激素对先天性心脏病患儿肺功能的改善作用。3.确定CDH患儿有效的产前预后预测指标。研究设计：所有胎儿产前诊断为CDH的母亲将被纳入并被要求参与这项研究。在知情同意后，母亲将随机接受倍他米松12.5 mg或安慰剂，从怀孕34周开始，两次剂量将相隔24小时给予。在妊娠35周和36周时再给一剂倍他米松或生理盐水安慰剂。来自28个围产期中心的284名患者将参加这项研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Congenital diaphragmatic hernia (CDH) occurs in approximately one out of every 2500 live births and has a mortality of 30-70% when diagnosed prenatally. Despite the aggressive support used to maintain adequate gas exchange in infants with CDH who present with early-onset severe respiratory failure, there is still a high failure rate with conventional management. There appears to be ample evidence that the lungs of animals and human infants with CDH show evidence of surfactant-deficient lung disease. With the increased use of prenatal ultrasound to evaluate fetal well being and establish appropriate gestational age, an increasing proportion of infants with CDH are diagnosed before delivery. Antenatal maternal steroids have been shown to be clearly beneficial for premature fetuses, by improving lung maturation and accelerating lung production of surfactant, thereby improving neonatal outcome. Such treatment appears to require at least 24 hours to produce an improvement in lung function, consistent with the time required for protein synthesis or enzyme induction. In the nitrogen rat model of CDH, there is now evidence that antenatal steroids reverse many of the histological and biochemical indices of immaturity. Improvements in oxygenation and lung compliance have also been shown with antenatal steroids in this model. While post-natal treatment with surfactant appears logical from these observations, in fact there is only anecdotal support for its use in infants with CDH, none of which has been the result of prospective randomized trials. Steroids are not widely administered after the thirty-fourth week of pregnancy since the normal lung is sufficiently mature at that time. In view of the previously described observations of fetal lung immaturity in CDH and the positive effects noted in fetal models of CDH, we propose a prospective, multicenter study to evaluate the effect of maternally administered corticosteroids to fetuses with diagnosed CDH. Hypothesis: The hypothesis of this study is that the administration of antenatal steroids to women carrying fetuses with proven CDH will significantly reduce the mortality for such fetuses compared to untreated fetuses with diagnosed CDH. Specific Aims: 1. To determine if prenatal steroids improve survival in CDH. 2. To determine if prenatal steroids improve lung function in infants with CDH. 3. To determine valid prenatal predictors of outcome for infants with CDH. Study Design: All mothers with fetuses diagnosed with CDH antenatally will be enrolled and asked to participate in the study. Following informed consent, mothers will be randomized to receive Betamethasone 12.5 mg or placebo beginning at 34 weeks gestation when 2 doses will be given 24 hours apart. An additional single dose of Betamethasone or saline placebo will be given at 35 weeks gestation and again at 36 weeks gestation. A total of 284 patients from 28 perinatal centers will be enrolled in the study.