Prenatal Glucocorticoid Therapy Reverses Pulmonary Immaturity in Congenital Diaphragmatic Hernia in Fetal Sheep

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Abstract
Objective To assess the feasibility of conducting clinical trials of prenatal steroid therapy for congenital diaphragmatic hernia (CDH) in humans, the authors tested whether prenatal glucocorticoid, currently the standard treatment to minimize respiratory distress syndrome in premature infants, might improve the pulmonary immaturity in severe CDH in a large animal model. Summary Background Data The authors have used the nitrofen-induced rat model of CDH, which demonstrates immature lungs by biochemical, morphometric, and molecular biologic criteria. They also have shown that the lethally immature lungs of the full-term CDH rats can be improved by biochemical, morphometric, physiologic, and molecular criteria by treating the mothers with parenteral steroids at doses extrapolated from the current therapy used to accelerate lung development of premature human babies. Methods During a 3-year period in 88 fetal sheep, 1) left-sided diaphragmatic hernias were created surgically at varying gestational ages (day 78-90; term = 142-145 days) and size to maximize severity (n = 45), 2) placement and design of indwelling fetal intravenous catheters were optimized (n = 13), and 3) timing and dosage of cortisol administration were determined (n = 17). As a result, diaphragmatic hernias were created on day 80, intravenous catheters were placed on day 120, and twice-daily intravenous cortisol injections (n = 8) or saline as the control (n = 5) were administered (days 133-135). Lambs were delivered on day 136 via cesarean section to avoid steroid-induced abortion; vascular access was obtained, and the fetuses were ventilated at standard settings. Physiologic data were collected, and lungs were harvested for biochemical and histologic analysis. Results Significant improvements were measured in postductal arterial oxygen pressure ([PaO2] 38 ± 6 mmHg after cortisol therapy compared with 20 ± 3 mmHg for saline controls; p = 0.002) and in dynamic compliance (0.42 ± 0.05 mL/cm H2O vs. 0.29 ± 0.01 mL/cm H2O; p = 0.01). Lung glycogen levels in the right lung of the cortisol group were significantly better than controls (4.6 ± 0.3 mg/g lung vs. 6.8 ± 0.4 mg/g; p = 0.002), as were protein/DNA levels (8.3 ± 0.9 mg/mg vs. 14.5 ± 2.9 mg/mg; p < 0.05). Striking morphologic maturation of airway architecture was observed in the treated lungs. Conclusions Prenatal glucocorticoids correct the pulmonary immaturity of fetal sheep with CDH by physiologic, biochemical, and histologic criteria. These data, combined with previous small animal studies, have prompted the authors to initiate a prospective phase I/II clinical trial to examine the efficacy of prenatal glucocorticoids to improve the maturation of hypoplastic lungs associated with CDH.