One percent of the clinical dose used for antenatal steroid therapy is sufficient to induce lung maturation when administered directly to the preterm ovine fetus

Author:

Fee Erin L.1ORCID,Takahashi Tsukasa12ORCID,Takahashi Yuki12,Carter Sean1,Furfaro Lucy1,Clarke Michael W.34,Milad Mark A.5,Usuda Haruo12,Newnham John P.1,Saito Masatoshi12,Jobe Alan H.16,Kemp Matthew W.1278

Affiliation:

1. Division of Obstetrics and Gynecology, Medical School, The University of Western Australia, Perth, Western Australia, Australia

2. Centre for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan

3. Metabolomics Australia, Center for Microscopy, Characterization and Analysis, The University of Western Australia, Perth, Western Australia, Australia

4. Faculty of Health and Medical Sciences, School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia

5. Milad Pharmaceutical Consulting LLC, Plymouth, Michigan

6. Cincinnati Children’s Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, Ohio

7. School of Veterinary Medicine, Murdoch University, Perth, Western Australia, Australia

8. Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Abstract

Antenatal steroids (ANSs) are routinely administered to women judged to be at imminent risk of preterm delivery. Their principal benefit is precocious functional maturation of the preterm fetal lung. Current dosing regimens expose the mother and fetus to high steroid levels that may be unnecessary, increasing the potential risks of disruption to the maternal and fetal hypothalamic-pituitary-adrenal (HPA) axis and glucose regulation, alterations in placental function, and reduced fetal growth. Using a sheep model of pregnancy, we tested the hypothesis that direct fetal administration of an ultra-low dose course of betamethasone phosphate (∼0.33 mg) would be sufficient to elicit functional maturation of the fetal lung. A jugular catheter was installed in singleton ovine fetuses at 122-day gestation under general anesthesia. Animals were randomized to receive either: 1) fetal intravenous betamethasone phosphate to target fetal plasma betamethasone mean levels of 2 ng/mL for 26 h (fetal treatment group; n = 16); 2) fetal intravenous saline for 26 h and two maternal intramuscular injections of 0.25 mg/kg betamethasone phosphate + betamethasone acetate, simulating a standard clinical treatment (maternal treatment group; n = 12); or 3) fetal intravenous saline only for 26 h (negative control group; n = 10). Fetuses were delivered 48 h after surgery, ventilated for 30 min to allow the collection of lung function and physiological data, and euthanized. Quantitative PCR and Western blots were used to assess markers of lung maturation. The average total betamethasone phosphate dose for the fetal treatment group was 1% (0.3 mg) of the maternal treatment group (31-mg betamethasone phosphate + betamethasone acetate). At 30 min of ventilation, arterial [Formula: see text], pH, heart rate, and ventilation efficacy index (VEI) were significantly ( P < 0.05) and equivalently improved in both the fetal treatment group and maternal treatment group, relative to the negative control group. Similarly, SP-A, SP-C, and AQ-5 mRNA expression was significantly higher in both the fetal treatment group and maternal treatment group, relative to negative control. Maternal steroid administration was not required to generate preterm fetal lung maturation in sheep. Using a low dose and targeting steroid treatments directly to the fetus has the potential to significantly reduce maternal exposures, while simultaneously reducing the potential risk of adverse outcomes associated with current clinical dosing regimens.

Funder

Stan Perron Charitable Foundation

Channel 7 Telethon Trust

Women and Infants Research Foundation

Publisher

American Physiological Society

Subject

Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology

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