Dose-response effects of betamethasone on maturation of the fetal sheep lung

Abstract

Objective: Glucocorticoid administration to women in preterm labor improves neonatal mortality and morbidity. Fetal exposure to glucocorticoid levels higher than those appropriate to the current gestational stage has multiple organ system effects. Some, eg, fetal hypertension, are maximal at lower than the clinical dose. We hypothesized that the clinical dose has supramaximal lung maturational effects.

Study design: We evaluated the full, half, and quarter clinical betamethasone dose (12 mg/70 kg or 170 microg/kg intramuscularly twice 24 hours apart) on fetal sheep lung pressure volume curves (PVC) after 48 hours' exposure at 0.75 gestation. We measured key messenger RNAs and protein products that affect lung function and total lung dipalmitoyl phosphatidyl choline.

Results: Full and half doses had similar PVC and total lung dipalmitoyl phosphatidyl choline effects. Messenger RNA for surfactant proteins A, B, and D and elastin increased in a dose-dependent fashion.

Conclusion: Half the clinical betamethasone dose produces maximal PVC improvement in fetal sheep at 0.75 gestation.

Figure 1. Pressure-volume relationships in fetal sheep lungs removed from fetuses of ewes treated with a single injection of betamethasone adjusted to maternal weight

(0 μg/kg [C: control], N=7 (3,4); 42.5 μg/kg, N=7 (2,5); 85 μg/kg, N=8 (2,6); 170 μg/kg, N=8 (3,5)) at 8.00 AM on day 110 and again at 8.00 AM on day 111. The fetus was delivered by Cesarean Section and the lungs evaluated 48 h after the first dose. A deflation arm of the pressure-volume relationship (symbols for doses as indicated); B area under the curve for each BM dose; • average of twins; ○ singletons; C mean area under the curve for each BM dose. M ± SEM. * p<0.05 comparison to control.

Figure 2. Correlations between maternal weight adjusted betamethasone dose and mRNA of surfactant proteins, elastin and glucocorticoid receptor

• average of twins; ○ singletons. SP-A r = 0.50 p = 0.005; SP-B r = 0.37 p = 0.046; SP-C r = 0.14 p = 0.469; SP-D r = 0.38 p=0.038; Elastin r = 0.39 p = 0.032; GR r = −.20 p= 0.301.

Figure 3. Surfactant protein (SP) in fetal sheep lungs removed from fetuses of ewes treated with a single injection of either vehicle or betamethasone (BM)

A SP-A; B SP-B; and C SP-C relative to E-actin in fetal sheep lungs removed from fetuses of ewes treated with a single injection of either vehicle C or BM adjusted to maternal weight (0 μg/kg [C: control], N=7 (3,4); 42.5 μg/kg, N=7 (2,5); 85 μg/kg, N=8 (2,6); 170 μg/kg, N=8 (3,5)) at 8.00 AM on day 110 and again at 8.00 AM on day 111. The fetus was delivered by Cesarean Section and the lungs evaluated for protein content by Western analysis 48 h after the first dose. There were no differences between groups.

Figure 4. Fetal whole lung disaturated phophatidyl choline (DPPC)

DPPC in fetuses of pregnant ewes treated with different doses of betamethasone (BM) adjusted to maternal body weight (0 μg/kg [C: control], N=7 (3,4); 42.5 μg/kg, N=7 (2,5); 85 μg/kg, N=7 (1,6); 170 μg/kg, N=7 (2,5)). Mean ± SEM. Regression function: DPPC = −11.9 ln(BM) + 190. r = 0.993.