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 .

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Journal
Trials
Published
2026-07-24
DOI
https://doi.org/10.1186/s13063-026-09903-0
Primary Topic
Neonatal Respiratory Health Research
Type
article
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article

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

Tina Lavin, Shabina Ariff, Nitya Wadhwa, Ebunoluwa A. Adejuyigbe et al.
Trials
Neonatal Respiratory Health Research
article

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

Tina Lavin, Shabina Ariff, Nitya Wadhwa, Ebunoluwa A. Adejuyigbe, Adejumoke Idowu Ayede, Olubukola Adesina, Lumaan Sheikh, Nicole Minckas, Ayesha De Costa, Oluwafemi Kuti, Yeshita V. Pujar, Saleha Begum Chowdhury, John Kinuthia, Soofi SB, Rajiv Bahl, Shivaprasad S. Goudar, Shuchita Gupta, A A Baqui, My Huong Nguyen, Mohammod Shahidullah, Jyotsna Suri, Fred Were, Joshua P. Vogel, Harish Chellani, Sangappa M. Dhaded, Olufemi T. Oladapo, Zahida P. Qureshi, Mark A. Milad, Suman P. N. Rao, Salahuddin Ahmed, The WHO ACTION Trials Collaborators, Alan H. Jobe
article en

Abstract

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 .

TrialsVol. 27(1)
Aga Khan University (PK), University of Nairobi (KE), Johns Hopkins University (US), Burnet Institute (AU), The University of Melbourne (AU), Vardhman Mahavir Medical College & Safdarjung Hospital (IN), University of Ibadan (NG), University College Hospital, Ibadan (NG), Bangladesh Shishu (Children) Hospital & Institute (BD), Translational Health Science and Technology Institute (IN), Kenyatta National Hospital (KE), Indian Council of Medical Research (IN), Society for Applied Studies (IN), World Health Organization (CH), KLE Academy of Higher Education and Research (IN), Biomedical Research Foundation (BD), Obafemi Awolowo University (NG), University of Cincinnati (US)
Good health and well-being
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Neonatal Respiratory Health Research
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