FETAL MATURATION IN A MODEL SYSTEM

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This is a proposal to evaluate new clinically relevant strategies to improve postnatal outcome of the preterm. The goal is to test the efficacy and safety of potential maturational agents given 24 hr. before preterm delivery of baboons at 125 days gestational age, a point in gestation that will just permit survival with the combined use of surfactant therapy and intensive care. The treatment interval of 24 hr. and the gestational age at delivery are selected based on information being collected using a preterm sheep model funded separately and are selected to focus the studies on the questions most relevant to treatment of humans at risk of preterm labor. The fetal baboons will initially be treated with a single dose of intramuscular betamethasone using fetal ultrasound to direct the injections. The initial experiment will permit the selection of a corticosteroid dose using physiologic measures of efficacy over 24 hr. after delivery followed by measurements of corticosteroid effects in a variety of tissues. T(4) then will be evaluated when used in conjunction with corticosteroids. We then will perform 10 day postnatal studies of animals treated with the corticosteroid alone, corticosteroid plus T4 and a control group. These studies will be followed in later years by evaluations of other effector molecules as well as by changes in the timing of delivery after fetal treatment. Following fetal treatment and preterm delivery, each newborn will be extensively studied in terms of performance as a newborn by evaluating lung function, cardiovascular performance, neuroendocrine adaptation and kidney function. Tissues then will be collected for focused studies of effects of the fetal treatments. Lung tissue will be used to evaluate selected aspects of surfactant lipid and protein metabolism. Kidney tissue will be used to evaluate receptor systems and Na+K+ATPase activity. Plasma samples will be processed for hormone levels, for provocative tests of the thyroid axis and the adrenal axis, and tissues will be collected for measurements of receptor systems. The experimental goal is to combine physiologic with biochemical and molecular indicators of maturation for a number of organ systems to characterize how the fetus will perform as a newborn and what changes occur as a result of the fetal therapy.