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Am J Obstet Gynecol

Title:		Low-dose antenatal betamethasone treatment achieves preterm lung maturation equivalent to that of the World Health Organization dexamethasone regimen but with reduced endocrine disruption in a sheep model of pregnancy
Author(s):		Usuda H; Fee EL; Carter S; Furfaro L; Takahashi T; Takahashi Y; Newnham JP; Milad MA; Saito M; Jobe AH; Kemp MW;
Address:		"Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Western Australia, Australia; Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan. Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Western Australia, Australia. Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Western Australia, Australia; School of Veterinary and Life Sciences, Murdoch University, Western Australia, Australia. School of Veterinary and Life Sciences, Murdoch University, Western Australia, Australia. Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan. Milad Pharmaceutical Consulting LLC, Plymouth, MI. Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Western Australia, Australia; Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan; Neonatology and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati Medical School, Cincinnati, OH; Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Queenstown, Singapore. Electronic address: kemma@nus.edu.sg"
Journal Title:		Am J Obstet Gynecol
Year:		2022
Volume:		20220702
Issue:		6
Page Number:		903 -
DOI:		10.1016/j.ajog.2022.06.058
ISSN/ISBN:		1097-6868 (Electronic) 0002-9378 (Linking)
Abstract:		"BACKGROUND: The intramuscular administration of antenatal steroids 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 antenatal steroid efficacy is independent of peak maternofetal steroid levels once exposure is maintained above a low threshold. OBJECTIVE: This study aimed to test, using a sheep model of pregnancy, whether the low-dose antenatal steroid regimen proposed as part of the Antenatal Corticosteroids for Improving Outcomes in Preterm Newborns trial would achieve preterm lung maturation equivalent to that of the existing World Health Organization 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 (1) four 6-mg maternal intramuscular injections of dexamethasone phosphate every 12 hours (n=22), (2) 4 2-mg maternal intramuscular injections of betamethasone phosphate every 12 hours (n=21), or (3) 4 2-mL maternal intramuscular injections of saline every 12 hours (n=16). Of note, 48 hours after first injection, (124+/-1 day), lambs were delivered, ventilated for 30 minutes, and euthanized for sampling. Arterial blood gas, respiratory, hematological, and biochemical data were analyzed for between-group differences with analysis of variance according to distribution and variance, with P<.05 taken as significant. RESULTS: After 30 minutes of ventilation, lambs from both steroid-treated groups had significant and equivalent improvements in lung function relative to saline control (P<.05). There was no significant difference in arterial blood pH, pO(2), pCO(2), lung compliance, ventilator efficiency index, or lung volume at necropsy with a static pressure of 40 cmH(2)O. The messenger RNA 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 insulin-like growth factor 1 was significantly reduced in the dexamethasone group compared with the betamethasone group (P<0.05). Fetal adrenocorticotropic hormone (r=0.53), maternal glucose value (r=-0.52), and fetal glucose values (r=-0.42) were correlated with maternal weight in the betamethasone group (P<.05), whereas fetal pCO(2) and pO(2) were not correlated. There was no significant difference between male and female lamb outcomes in any groups for any of the items evaluated. CONCLUSION: This study reported that in preterm lambs, a low-dose treatment regimen of 8 mg betamethasone achieves lung maturation equivalent to that of a 24-mg dexamethasone-based regimen, but with smaller perturbations to the maternofetal hypothalamic-pituitary-adrenal axis. These data suggested that given steroid pharmacokinetic differences between sheep and humans, a betamethasone dose of 2 mg 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 reducing perturbations to the maternofetal hypothalamic-pituitary-adrenal axis"
Keywords:		"Sheep Female Animals Infant, Newborn Male Pregnancy Humans *Hypothalamo-Hypophyseal System *Pituitary-Adrenal System Betamethasone Glucocorticoids Lung/metabolism Dexamethasone World Health Organization Glucose/pharmacology antenatal corticosteroid betame;"
Notes:		"MedlineUsuda, Haruo Fee, Erin L Carter, Sean Furfaro, Lucy Takahashi, Tsukasa Takahashi, Yuki Newnham, John P Milad, Mark A Saito, Masatoshi Jobe, Alan H Kemp, Matthew W eng Research Support, Non-U.S. Gov't 2022/07/07 Am J Obstet Gynecol. 2022 Dec; 227(6):903.e1-903.e16. doi: 10.1016/j.ajog.2022.06.058. Epub 2022 Jul 2"