The World Health Organization Antenatal CorTicosteroids for Improving Outcomes in preterm Newborns (ACTION-III) trial—rationale for the selected lower steroid dose

Antenatal corticosteroids (ACS), most commonly administered as betamethasone or dexamethasone, remain a cornerstone of care for women at risk of preterm birth. However, the standard 24-mg regimen introduced more than five decades ago has not undergone formal dose-finding evaluation. Emerging concerns regarding possible dose-related adverse effects, particularly among late preterm infants subsequently born at term, have renewed interest in optimizing corticosteroid exposure. Experimental data across species, supported by human pharmacokinetic analyses, indicate that fetal lung maturation is driven by sustained low corticosteroid concentrations rather than high peak levels. This commentary summarizes key experimental, pharmacokinetic, and modelling evidence that informed the selection of the lower-dose betamethasone phosphate regimen evaluated in the WHO ACTION-III trial and explains the scientific rationale for this dosing strategy. Pharmacokinetic modeling indicates that 2 mg betamethasone phosphate administered intramuscularly every 12 h for four doses achieves fetal concentrations within the 1 to 4 ng/mL range identified in experimental studies, while avoiding the supratherapeutic peaks observed with conventional regimens. The ACTION-III trial will evaluate whether this lower dose ACS regimen, chosen on the basis of carefully developed models and clinical studies, maintains clinical efficacy while potentially reducing unnecessary systemic corticosteroid exposure in women at risk of late preterm birth. Trial registration: ISRCTN11434567, registered on 7 June 2021. https://www.isrctn.com/ISRCTN11434567?q=ACTION-III&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10.