TRH AND THE PREVENTION OF CHRONIC LUNG DISEASE

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Prenatal corticosteroid (CS) therapy reduces mortality and the incidence of respiratory distress syndrome (RDS) in small preterm infants but is not always effective. In experimental systems, the combination of thyroid hormone and CS further accelerates surfactant synthesis and release, resorption of lung water, and the development of lung structure. We recently completed a multicenter trial (1986-89) of prenatal treatment with thyrotropin-releasing hormone (TRH) plus CS vs CS alone. The incidence of chronic lung disease (CLD) was significantly reduced for VLBW (less than 1500 grams) infants who received full treatment with TRH + CS (17.6%) compared to the group who received only CS (43.9%, p is less than 0.01). However, none of the infants in the study received surfactant replacement, which has now been shown to reduce mortality and morbidity from RDS and is accepted clinical practice. The clinical trial proposed in this application will test the response to TRH among infants treated antenatally with CS and postnatally with surfactant replacement (Exosurf), evaluating both benefit and possible adverse effects. In addition, possible mechanisms by which antenatal treatment with TRH + CS reduces chronic lung disease will be investigated. Twelve hundred women in five cooperating centers who are at risk of delivering a preterm infant at less than 30 weeks gestation will be randomly assigned to 2 groups. The treatment group will receive TRH + CS, and the control group will receive placebo + CS. After birth, Exosurf will be administered according to standard clinical criteria. The sample size proposed will provide 90% power to detect a reduction of the risk of CLD from 18% to 9% in the overall intention-to-treat group. A supplemental analysis of the subgroup at risk (approximately 720 VLBW infants delivered at less than 31.5 weeks and weighing less than 1500 grams) will have 95% power to detect a reduction of the risk of CLD from 26% to 15%. Data will also be collected to study several factors involved in the evolution of CLD and indicators of outcome. We will assay surfactant proteins A and B and indicators of inflammatory response in bronchoalveolar lavage and determine concentrations of thyroid hormones and cortisol in plasma. Pulmonary function measurements (including compliance, resistance and FRC) and studies of the ductus arteriosus will be made over the first month of life. Long term follow-up of study infants will be performed. We hypothesize that antenatal TRH added to CS and postnatal surfactant replacement will result in lower incidence of CLD, decreased severity of RDS, shorter hospital stays and better long-term outcome.