Maternal plasma cell-free RNA as a predictive test for fetal lung maturation
Abstract Background A lack of tests to assess fetal development impacts decision making around antenatal steroid use in women at risk of preterm birth. We analyzed the expression of 21 cfRNA targets related to human fetal lung maturation. Discovery studies were performed using maternal and fetal she...
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2025-07-01
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| Online Access: | https://doi.org/10.1186/s12916-025-04256-y |
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| author | Sean W. D. Carter Kay Yi Michelle Seah Si En Poh Winston Koh Haruo Usuda Erin L. Johnson Yusaku Kumagai Tsukasa Takahashi Lara J. Monteiro Reyna Peñailillo Gino Nardocci Hannah R. S. Watson Masatoshi Saito Mahesh A. Choolani Sebastián E. Illanes Matthew W. Kemp |
| author_facet | Sean W. D. Carter Kay Yi Michelle Seah Si En Poh Winston Koh Haruo Usuda Erin L. Johnson Yusaku Kumagai Tsukasa Takahashi Lara J. Monteiro Reyna Peñailillo Gino Nardocci Hannah R. S. Watson Masatoshi Saito Mahesh A. Choolani Sebastián E. Illanes Matthew W. Kemp |
| author_sort | Sean W. D. Carter |
| collection | DOAJ |
| description | Abstract Background A lack of tests to assess fetal development impacts decision making around antenatal steroid use in women at risk of preterm birth. We analyzed the expression of 21 cfRNA targets related to human fetal lung maturation. Discovery studies were performed using maternal and fetal sheep plasma, with results compared to fetal lung mRNA expression. These findings were then validated in first, second, and third trimester human maternal plasma samples. Methods Discovery studies utilized a preterm sheep model of pregnancy. Date mated ewes received saline (control n = 6), or antenatal steroids (dexamethasone n = 12) (betamethasone n = 11) prior to delivery and ventilation. We analyzed the expression of 21 human cfRNA targets related to lung maturation in maternal and fetal sheep plasma and compared this to mRNA expression in fetal lung tissue. Findings were first validated in a separate cohort of sheep exposed to betamethasone (n = 8), intraamniotic LPS endotoxin for lung maturation (n = 6), or untreated term animals (n = 6). Findings were further validated in maternal plasma from a human cohort of uncomplicated term pregnancies (n = 10). Delivery and ventilation data were analyzed with ANOVA, Tukey HSD, and Dunnett T3 tests. A Random Forest algorithm identified genes that separated mature from immature fetal lung subgroups and determined AUC values for maternal and fetal cell-free RNA (cfRNA) feature sets to predict fetal lung maturation. Results We demonstrate that the analysis of 21 human cfRNA targets in maternal plasma is highly predictive of fetal lung maturation status across antenatal steroid induced (Dexamethasone AUC = 0.93; Betamethasone AUC = 1) and physiological (AUC = 1) lung development models. Maternal plasma cfRNA expression in the dexamethasone antenatal steroid group closely resembled direct fetal lung tissue mRNA expression. These findings were then validated in human maternal plasma samples (1st vs. 3rd trimester AUC = 0.96; 2nd vs. 3rd trimester AUC = 1). Conclusions Further development of this technology may provide a rapid, minimally invasive, and cost-effective clinical tool to optimize patient selection for initial and repeat courses of antenatal steroids, along with insights into the molecular mechanisms underlying fetal lung development. Graphical Abstract Graphical abstract illustrating the potential future application of maternal plasma cell-free RNA analysis. Created in https://BioRender.com . |
| format | Article |
| id | doaj-art-b5ad7f36e21e4e109e6db537c881f1c5 |
| institution | Kabale University |
| issn | 1741-7015 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| series | BMC Medicine |
| spelling | doaj-art-b5ad7f36e21e4e109e6db537c881f1c52025-08-20T03:43:22ZengBMCBMC Medicine1741-70152025-07-0123112010.1186/s12916-025-04256-yMaternal plasma cell-free RNA as a predictive test for fetal lung maturationSean W. D. Carter0Kay Yi Michelle Seah1Si En Poh2Winston Koh3Haruo Usuda4Erin L. Johnson5Yusaku Kumagai6Tsukasa Takahashi7Lara J. Monteiro8Reyna Peñailillo9Gino Nardocci10Hannah R. S. Watson11Masatoshi Saito12Mahesh A. Choolani13Sebastián E. Illanes14Matthew W. Kemp15Department 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 SingaporeInstitute of Bioengineering and Bioimaging, Agency for Science, Technology and ResearchInstitute of Bioengineering and Bioimaging, Agency for Science, Technology and ResearchDivision of Obstetrics and Gynaecology, University of Western AustraliaDivision of Obstetrics and Gynaecology, University of Western AustraliaDepartment of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of SingaporeDivision of Obstetrics and Gynaecology, University of Western AustraliaReproductive Biology Program, Center for Biomedical Research and Innovation, Universidad de los AndesReproductive Biology Program, Center for Biomedical Research and Innovation, Universidad de los AndesIMPACT, Center of Interventional Medicine for Precision and Advanced Cellular TherapyDivision of Obstetrics and Gynaecology, University of Western AustraliaCentre for Perinatal and Neonatal Medicine, Tohoku University HospitalDepartment 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 SingaporeDepartment of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of SingaporeAbstract Background A lack of tests to assess fetal development impacts decision making around antenatal steroid use in women at risk of preterm birth. We analyzed the expression of 21 cfRNA targets related to human fetal lung maturation. Discovery studies were performed using maternal and fetal sheep plasma, with results compared to fetal lung mRNA expression. These findings were then validated in first, second, and third trimester human maternal plasma samples. Methods Discovery studies utilized a preterm sheep model of pregnancy. Date mated ewes received saline (control n = 6), or antenatal steroids (dexamethasone n = 12) (betamethasone n = 11) prior to delivery and ventilation. We analyzed the expression of 21 human cfRNA targets related to lung maturation in maternal and fetal sheep plasma and compared this to mRNA expression in fetal lung tissue. Findings were first validated in a separate cohort of sheep exposed to betamethasone (n = 8), intraamniotic LPS endotoxin for lung maturation (n = 6), or untreated term animals (n = 6). Findings were further validated in maternal plasma from a human cohort of uncomplicated term pregnancies (n = 10). Delivery and ventilation data were analyzed with ANOVA, Tukey HSD, and Dunnett T3 tests. A Random Forest algorithm identified genes that separated mature from immature fetal lung subgroups and determined AUC values for maternal and fetal cell-free RNA (cfRNA) feature sets to predict fetal lung maturation. Results We demonstrate that the analysis of 21 human cfRNA targets in maternal plasma is highly predictive of fetal lung maturation status across antenatal steroid induced (Dexamethasone AUC = 0.93; Betamethasone AUC = 1) and physiological (AUC = 1) lung development models. Maternal plasma cfRNA expression in the dexamethasone antenatal steroid group closely resembled direct fetal lung tissue mRNA expression. These findings were then validated in human maternal plasma samples (1st vs. 3rd trimester AUC = 0.96; 2nd vs. 3rd trimester AUC = 1). Conclusions Further development of this technology may provide a rapid, minimally invasive, and cost-effective clinical tool to optimize patient selection for initial and repeat courses of antenatal steroids, along with insights into the molecular mechanisms underlying fetal lung development. Graphical Abstract Graphical abstract illustrating the potential future application of maternal plasma cell-free RNA analysis. Created in https://BioRender.com .https://doi.org/10.1186/s12916-025-04256-yCell-free RNAPreterm birthLung maturationAntenatal corticosteroidsPredictive testGene expression |
| spellingShingle | Sean W. D. Carter Kay Yi Michelle Seah Si En Poh Winston Koh Haruo Usuda Erin L. Johnson Yusaku Kumagai Tsukasa Takahashi Lara J. Monteiro Reyna Peñailillo Gino Nardocci Hannah R. S. Watson Masatoshi Saito Mahesh A. Choolani Sebastián E. Illanes Matthew W. Kemp Maternal plasma cell-free RNA as a predictive test for fetal lung maturation BMC Medicine Cell-free RNA Preterm birth Lung maturation Antenatal corticosteroids Predictive test Gene expression |
| title | Maternal plasma cell-free RNA as a predictive test for fetal lung maturation |
| title_full | Maternal plasma cell-free RNA as a predictive test for fetal lung maturation |
| title_fullStr | Maternal plasma cell-free RNA as a predictive test for fetal lung maturation |
| title_full_unstemmed | Maternal plasma cell-free RNA as a predictive test for fetal lung maturation |
| title_short | Maternal plasma cell-free RNA as a predictive test for fetal lung maturation |
| title_sort | maternal plasma cell free rna as a predictive test for fetal lung maturation |
| topic | Cell-free RNA Preterm birth Lung maturation Antenatal corticosteroids Predictive test Gene expression |
| url | https://doi.org/10.1186/s12916-025-04256-y |
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