Single-nucleotide polymorphisms in dizygotic twin ovine fetuses are associated with discordant responses to antenatal steroid therapy

Erin L Fee; Haruo Usuda; Sean W D Carter; Hideyuki Ikeda; Tsukasa Takahashi; Yuki Takahashi; Yusaku Kumagai; Michael W Clarke; Demelza J Ireland; John P Newnham; Masatoshi Saito; Sebastian E Illanes; Binny Priya Sesurajan; Liang Shen; Mahesh A Choolani; Gokce Oguz; Adaikalavan Ramasamy; Sara Ritchie; Andrew Ritchie; Alan H Jobe; Matthew W Kemp

doi:10.1186/s12916-025-03910-9

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Single-nucleotide polymorphisms in dizygotic twin ovine fetuses are associated with discordant responses to antenatal steroid therapy

Journal article

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Single-nucleotide polymorphisms in dizygotic twin ovine fetuses are associated with discordant responses to antenatal steroid therapy

Erin L Fee, Haruo Usuda, Sean W D Carter, Hideyuki Ikeda, Tsukasa Takahashi, Yuki Takahashi, Yusaku Kumagai, Michael W Clarke, Demelza J Ireland, John P Newnham, …

BMC medicine, Vol.23(1), 65

2025

DOI: https://doi.org/10.1186/s12916-025-03910-9

PMID: 39901164

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Abstract

Animals

Betamethasone - administration & dosage

Female

Fetus - drug effects

Injections, Intramuscular

Lung - drug effects

Male

Polymorphism, Single Nucleotide - genetics

Pregnancy

Premature Birth

Sheep

Twins, Dizygotic - genetics

Background Antenatal steroid (ANS) therapy is given to women at risk of preterm delivery to accelerate fetal lung maturation. However, the benefit of ANS therapy is variable and how maternal and fetal factors contribute to this observed variability is unknown. We aimed to test the degree of concordance in preterm lung function, and correlate this with genomic, transcriptomic, and pharmacokinetic variables in preterm dizygotic twin ovine fetuses. Methods Thirty-one date-mated ewes carrying twin fetuses at 123 ± 1 days’ gestation received maternal intramuscular injections of either (i) 1 × 0.25 mg/kg betamethasone phosphate and acetate (CS1, n = 11 twin pairs) or (ii) 2 × 0.25 mg/kg betamethasone phosphate and acetate, 24 h apart (CS2, n = 10 twin pairs) or (iii) 2 × saline, 24 h apart (negative control, n = 10 twin pairs). Fetuses were surgically delivered 24 h after their final treatment and ventilated for 30 min. Results ANS-exposed female fetuses had lower arterial partial pressure of carbon dioxide (PaCO2) values than male fetuses (76.5 ± 38.0 vs. 97.2 ± 42.5 mmHg), although the observed difference was not statistically significant (p = 0.1). Only 52% of ANS-treated twins were concordant for lung maturation responses. There was no difference in fetal lung tissue or plasma steroid concentrations within or between twin pairs. Genomic analysis identified 13 single-nucleotide polymorphisms (SNPs) statistically associated with ANS-responsiveness, including in the proto-oncogene MET and the transcription activator STAT1. Conclusions Twin fetal responses and ANS tissue levels were comparable with those from singleton fetuses in earlier studies. Twin ovine fetuses thus benefit from ANS in a similar manner to singleton fetuses, and a larger dose of betamethasone is not required. Assuming no difference in input from the placental or maternal compartments, fetal lung responses to ANS therapy in dizygotic twin preterm lambs are dependent on the fetus itself. These data suggest a potential heritable role in determining ANS responsiveness.

Details

Title: Single-nucleotide polymorphisms in dizygotic twin ovine fetuses are associated with discordant responses to antenatal steroid therapy
Authors/Creators: Erin L Fee - The University of Western Australia
Haruo Usuda - The University of Western Australia
Sean W D Carter - National University of Singapore
Hideyuki Ikeda - Tohoku University Hospital
Tsukasa Takahashi - Tohoku University Hospital
Yuki Takahashi - Tohoku University Hospital
Yusaku Kumagai - Duke-NUS Medical School
Michael W Clarke - The University of Western Australia
Demelza J Ireland - The University of Western Australia
John P Newnham - The University of Western Australia
Masatoshi Saito - Tohoku University Hospital
Sebastian E Illanes - IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
Binny Priya Sesurajan - National University of Singapore
Liang Shen - National University of Singapore
Mahesh A Choolani - National University of Singapore
Gokce Oguz - Agency for Science, Technology and Research
Adaikalavan Ramasamy - Duke-NUS Medical School
Sara Ritchie - A8, Darkan, WA, Australia
Andrew Ritchie - A8, Darkan, WA, Australia
Alan H Jobe - University of Cincinnati
Matthew W Kemp - Women and Children's Hospital, Chongqing Medical University, Chongqing, China
Publication Details: BMC medicine, Vol.23(1), 65
Publisher: BioMed Central Ltd unless otherwise stated. Part of Springer Nature; LONDON
Number of pages: 17
Grant note: Women and Infants Research Foundation
This work was supported by the Women and Infants Research Foundation.
Identifiers: 991005741591007891
Murdoch Affiliation: School of Veterinary Medicine
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.72 Obstetrics & Gynecology; 1.72.924 Preterm Birth Causes
Web Of Science research areas: Obstetrics & Gynecology
ESI research areas: Clinical Medicine