Single-nucleotide polymorphisms in dizygotic twin ovine fetuses are associated with discordant responses to antenatal steroid therapy
Abstract 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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-02-01
|
| Series: | BMC Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12916-025-03910-9 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823861961413099520 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Erin L. Fee |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-58ef3d71e46e454997898799091e6c5e |
| institution | Kabale University |
| issn | 1741-7015 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj-art-58ef3d71e46e454997898799091e6c5e2025-02-09T12:40:58ZengBMCBMC Medicine1741-70152025-02-0123111710.1186/s12916-025-03910-9Single-nucleotide polymorphisms in dizygotic twin ovine fetuses are associated with discordant responses to antenatal steroid therapyErin L. Fee0Haruo Usuda1Sean W. D. Carter2Hideyuki Ikeda3Tsukasa Takahashi4Yuki Takahashi5Yusaku Kumagai6Michael W. Clarke7Demelza J. Ireland8John P. Newnham9Masatoshi Saito10Sebastian E. Illanes11Binny Priya Sesurajan12Liang Shen13Mahesh A. Choolani14Gokce Oguz15Adaikalavan Ramasamy16Sara Ritchie17Andrew Ritchie18Alan H. Jobe19Matthew W. Kemp20Division of Obstetrics and Gynecology, Medical School, The University of Western AustraliaDivision of Obstetrics and Gynecology, Medical School, The University of Western AustraliaDepartment of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of SingaporeCentre for Perinatal and Neonatal Medicine, Tohoku University HospitalCentre for Perinatal and Neonatal Medicine, Tohoku University HospitalCentre for Perinatal and Neonatal Medicine, Tohoku University HospitalCentre for Perinatal and Neonatal Medicine, Tohoku University HospitalSchool of Biomedical Sciences, The University of Western AustraliaDivision of Obstetrics and Gynecology, Medical School, The University of Western AustraliaDivision of Obstetrics and Gynecology, Medical School, The University of Western AustraliaDivision of Obstetrics and Gynecology, Medical School, The University of Western AustraliaDepartment of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of SingaporeDepartment of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of SingaporeBiostatistics Unit, Yong Loo Lin School of Medicine, National University of SingaporeDepartment of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of SingaporeGenome Institute of Singapore. Agency for Science, Technology and Research (A*STAR)Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of SingaporeA8, DarkanA8, DarkanCincinnati Children’s Hospital Medical Centre, University of Cincinnati School of MedicineCentre for Perinatal and Neonatal Medicine, Tohoku University HospitalAbstract 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.https://doi.org/10.1186/s12916-025-03910-9BetamethasoneFetusFraternal twinsGlucocorticoidsAntenatal steroidsSheep |
| spellingShingle | 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 Single-nucleotide polymorphisms in dizygotic twin ovine fetuses are associated with discordant responses to antenatal steroid therapy BMC Medicine Betamethasone Fetus Fraternal twins Glucocorticoids Antenatal steroids Sheep |
| title | Single-nucleotide polymorphisms in dizygotic twin ovine fetuses are associated with discordant responses to antenatal steroid therapy |
| title_full | Single-nucleotide polymorphisms in dizygotic twin ovine fetuses are associated with discordant responses to antenatal steroid therapy |
| title_fullStr | Single-nucleotide polymorphisms in dizygotic twin ovine fetuses are associated with discordant responses to antenatal steroid therapy |
| title_full_unstemmed | Single-nucleotide polymorphisms in dizygotic twin ovine fetuses are associated with discordant responses to antenatal steroid therapy |
| title_short | Single-nucleotide polymorphisms in dizygotic twin ovine fetuses are associated with discordant responses to antenatal steroid therapy |
| title_sort | single nucleotide polymorphisms in dizygotic twin ovine fetuses are associated with discordant responses to antenatal steroid therapy |
| topic | Betamethasone Fetus Fraternal twins Glucocorticoids Antenatal steroids Sheep |
| url | https://doi.org/10.1186/s12916-025-03910-9 |
| work_keys_str_mv | AT erinlfee singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT haruousuda singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT seanwdcarter singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT hideyukiikeda singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT tsukasatakahashi singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT yukitakahashi singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT yusakukumagai singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT michaelwclarke singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT demelzajireland singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT johnpnewnham singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT masatoshisaito singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT sebastianeillanes singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT binnypriyasesurajan singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT liangshen singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT maheshachoolani singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT gokceoguz singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT adaikalavanramasamy singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT sararitchie singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT andrewritchie singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT alanhjobe singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy AT matthewwkemp singlenucleotidepolymorphismsindizygotictwinovinefetusesareassociatedwithdiscordantresponsestoantenatalsteroidtherapy |