Prenatal corticosteroid (CS) therapy reduces mortality and morbidity from respiratory distress syndrome and intraventricular hemorrhage in small preterm infants. In experiments with animal models, the combination of CS with thyrotropin releasing hormone (TRH has additional beneficial effects on surfactant synthesis and release, the absorption of lung water, and the development of lung structure. There is recent evidence that the severity o respiratory distress syndrome (RDS) and the incidence of bronchopulmonary dysplasia (BPD) are significantly reduced for very low birthweight infants who receive a combination of TRH and CS. We are currently the Coordinating Center for a north American study comparing prenatal treatment with CS alone vs. TRH plus CS in infants who receive surfactant replacement as appropriate. This study is being done in 15 centers in North America and will enroll 1090 women who present in preterm labor at less than 30 weeks gestation. 475 women have been enrolled int he study as of June 30, 1995 and it is expected that enrollment in the study will be completed in December 1996. The sample size proposed is designed to provide 80% power to detect a reduction inn the risk of chronic lung disease from 13% to 7.5% in the overall intention-to-treat group and to have an 85% power to detect a reduction from 26% to 15% in a secondary analysis of the subgroup at higher risk for disease (infants delivered at lesser than 31.5 weeks gestation). No studies are currently being done on these infants to examine the mechanism(s) of action of combined hormonal therapy on lung development. In this project we propose to conclude data collection and analysis for the current TRH trial and to carry out follow-up of the infants. Additional infants will be enrolled and studied at selected centers and serial blood samples and bronchoalveolar lavage (BAL) samples will be obtained and made available to the other investigators ina the SCOR group. Lung specimens from infants who die early in their postnatal course will also be obtained. The large database allows correlation of the clinical course of infants with and without BPD with changes in inflammatory markers including cytokines and other indicators of oxidants stress as well as levels and distribution of surfactant proteins (Project I), IGF and IGF binding proteins (Project 3), and extracellular matrix proteins (Project iV). We hypothesize that these factors play a role in determining lung maturity at birth and/or its response to injury and healing, and that understanding these relationships will provide insights into the pathogenesis of BPD and suggest new strategies for prevention and therapy.
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