[INTRODUCTION]: The intramuscular administration of antenatal steroids (ANS) to women at risk of preterm delivery achieves high maternal and fetal plasma steroid concentrations, which are associated with adverse effects and may reduce treatment efficacy. We have demonstrated that ANS efficacy is independent of peak materno-fetal steroid levels once exposure is maintained above a low threshold. [OBJECTIVES]: We aimed to test, using a sheep model of pregnancy, whether the low-dose ANS regimen

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... osed as part of the ACTION III Trial would achieve preterm lung maturation equivalent to that of the existing WHO dexamethasone treatment regimen, but with reduced risk of adverse outcomes. [STUDY DESIGN]: Following ethical review and approval, date-mated ewes with single fetuses received intramuscular injections of either: i) four x 6mg maternal intramuscular injections of dexamethasone phosphate q12h (n=22); or ii) four x 2 mg maternal intramuscular injections of betamethasone phosphate q12h (n=21); or ⅲ) four x 2mL maternal intramuscular injections of saline q12h (n=16). Forty-eight hours after first injection, (124±1 d), lambs were delivered, ventilated for 30 minutes, and euthanised for sampling. Arterial blood gas, respiratory, haematological and biochemical data were analysed for between-group differences with ANOVA according to distribution and variance, with p<0.05 taken as significant. [RESULTS]: After 30 minutes ventilation, lambs from both steroid-treated groups had significant and equivalent improvements in lung function relative to saline control (p<0.05). There was no significant difference in arterial blood pH, pO2, pCO2, lung compliance, ventilator efficiency index or lung volume at necropsy with a static pressure of 40cmH2O. The mRNA expression of surfactant protein (Sp)a, Spb, Spc, Spd, aquaporin (Aqp)1, Aqp5 and sodium channel epithelial 1 subunit beta (Scnn1b) was equivalent between both steroid groups. Maternal and fetal plasma neutrophil, glucose and fetal plasma c-peptide levels were significantly elevated in the dexamethasone group, relative to the betamethasone group. Fetal plasma IGF-1 was significantly reduced in the dexamethasone group compared to the betamethasone group (p<0.05). Fetal ACTH (r=0.53), maternal glucose value (r=-0.52) and fetal glucose values (r=-0.42) were correlated with maternal weight in Betamethasone Group (p<0.05) while fetal pCO2 and pO2 were not correlated. There were no significant differences between male and female lamb outcomes in any groups for any of the items evaluated. [CONCLUSIONS]: We report that, in preterm lambs, a low-dose treatment regimen of 8mg betamethasone achieves lung maturation equivalent to that of a 24mg dexamethasone-based regimen, but with smaller perturbations to the materno-fetal HPA axis. These data suggest that, given steroid pharmacokinetic differences between sheep and humans, a betamethasone dose of 2mg may remain above the minimum dose necessary for robust maturation of the preterm lung. Maternal weight-adjusted betamethasone doses might also be a key to reduce perturbations to the materno-fetal HPA axis.