A Reduction in Antenatal Steroid Dose Was Associated with Reduced Cardiac Dysfunction in a Sheep Model of Pregnancy

• Published in: Reproductive sciences (Thousand Oaks, Calif.) Calif.), 2023-11, Vol.30 (11), p.3222-3234
• Main Authors: Kumagai, Yusaku, Kemp, Matthew W., Usuda, Haruo, Takahashi, Tsukasa, Takahashi, Yuki, Hamada, Hirotaka, Schmidt, Augusto F., Hanita, Takushi, Watanabe, Shimpei, Sato, Shinichi, Ikeda, Hideyuki, Fee, Erin L., Furfaro, Lucy, Newnham, John P., Jobe, Alan H., Yaegashi, Nobuo, Saito, Masatoshi
• Format: Article
• Language: English
• Subjects: Adrenal Cortex Hormones; Animals; Betamethasone; Embryology; Female; Fetal Heart - diagnostic imaging; Fetal Organ Maturity; Heart Diseases - drug therapy; Maternal Fetal Medicine/Biology: Original Article; Medicine; Medicine & Public Health; Obstetrics/Perinatology/Midwifery; Pregnancy; Reproductive Medicine; Sheep; Steroids
• ISSN: 1933-7191; 1933-7205
• DOI: 10.1007/s43032-023-01264-2

Despite widespread use, dosing regimens for antenatal corticosteroid (ACS) therapy are poorly unoptimized. ACS therapy exerts a programming effect on fetal development, which may be associated with an increased risk of cardiovascular disease. Having demonstrated that low-dose steroid therapy is an efficacious means of maturing the preterm lung, we hypothesized that a low-dose steroid exposure would exert fewer adverse functional and transcriptional changes on the fetal heart. We tested this hypothesis using low-dose steroid therapy (10 mg delivered to the ewe over 36 h via constant infusion) and compared cardiac effects with those of a higher dose treatment (30 mg delivered to the ewe over 24 h by intramuscular injection; simulating currently employed clinical ACS regimens). Fetal cardiac function was assessed by ultrasound on the day of ACS treatment initiation. Transcriptomic analyses were performed on fetal myocardial tissue. Relative to saline control, fetuses in the higher-dose clinical treatment group had significantly lower ratios between early diastolic ventricular filling and ventricular filling during atrial systole, and showed the differential expression of myocardial hypertrophy-associated transcripts including βMHC, GADD45γ, and PPARγ. The long-term implications of these changes remain unstudied. Irrespective, optimizing ACS dosing regimens to maximize respiratory benefit while minimizing adverse effects on key organ systems, such as the heart, offers a means of improving the acute and long-term outcomes associated with this important obstetric therapy.