{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T04:41:50Z","timestamp":1760848910218,"version":"build-2065373602"},"reference-count":24,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003123","name":"Fetal Medicine Foundation","doi-asserted-by":"crossref","award":["1037116"],"award-info":[{"award-number":["1037116"]}],"id":[{"id":"10.13039\/501100003123","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Gestational diabetes mellitus (GDM) is associated with subclinical alterations in fetal cardiac morphology and function. Ursodeoxycholic acid (UDCA), widely used in pregnancy for intrahepatic cholestasis, has demonstrated cardioprotective properties in experimental fetal models, preventing conduction abnormalities and improving myocardial function. Whether UDCA modifies fetal or neonatal cardiac adaptation in GDM pregnancies has not been previously investigated. The objective was to evaluate the effect of ursodeoxycholic acid (UDCA) on fetal and neonatal cardiac function in pregnancies complicated by gestational diabetes mellitus (GDM). Methods: In this randomized, placebo-controlled study, 113 women with GDM were enrolled, of whom 56 received UDCA and 57 the placebo. After measurement of maternal blood UDCA concentrations, 43 participants in the treatment group had levels \u22650.5 \u00b5mol\/L and were included in the per-protocol analysis. Echocardiographic and Doppler-derived cardiac indices were assessed at baseline, 36 weeks\u2019 gestation, and postpartum. Comparisons were performed using univariable tests and mixed-effects multivariable models accounting for time and treatment. Results: In the treatment group, compared to the placebo group, there were no significant differences in cardiac indices at 36 weeks\u2019 gestation or postpartum when assessed individually. However, in the mixed-effects longitudinal analysis, a significant treatment-by-time interaction was observed. Specifically, in the postpartum period, mitral A-wave velocity (MV-A) was higher in the treatment group compared to that under the placebo (9.58, 95% CI 2.29\u201316.87; p = 0.010), reflecting a more pronounced increase in the atrial contribution to left ventricular filling over time. Similarly, aortic peak velocity (Ao_Vm\u00e1x) was significantly higher in the treatment group compared to that under the placebo in the postpartum period (7.97, 95% CI 0.19\u201315.75; p = 0.045), indicating a greater augmentation in left ventricular outflow dynamics. Conclusions: In pregnancies complicated by GDM, UDCA did not lead to significant cross-sectional differences in fetal or neonatal cardiac indices at 36 weeks or postpartum. However, longitudinal modeling indicated that UDCA was associated with a greater increase in the atrial contribution to ventricular filling (MV-A) and aortic peak velocity (Ao_Vm\u00e1x) in the postpartum period compared to that under the placebo. These findings suggest that while UDCA does not broadly alter cardiac function, it may modulate specific aspects of diastolic filling and systolic outflow dynamics during late gestation and early neonatal adaptation.<\/jats:p>","DOI":"10.3390\/jcm14207366","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T14:29:17Z","timestamp":1760711357000},"page":"7366","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Impact of Ursodeoxycholic Acid on Fetal Cardiac Function in Women with Gestational Diabetes Mellitus: A Randomized Controlled Study (GUARDS Trial)"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3653-4069","authenticated-orcid":false,"given":"Ana Maria","family":"Company Calabuig","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Hospital Cl\u00ednico Universitario Virgen de la Arrixaca, El Palmar, 30120 Murcia, Spain"},{"name":"Faculty of Medicine, Universidad de Murcia, 30107 Murcia, Spain"},{"name":"Biomedical Research Institute of Murcia Pascual Parrilla\u2014IMIB, 30120 Murcia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0511-3533","authenticated-orcid":false,"given":"Jose Eliseo Blanco","family":"Carnero","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Hospital Cl\u00ednico Universitario Virgen de la Arrixaca, El Palmar, 30120 Murcia, Spain"},{"name":"Faculty of Medicine, Universidad de Murcia, 30107 Murcia, Spain"},{"name":"Biomedical Research Institute of Murcia Pascual Parrilla\u2014IMIB, 30120 Murcia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5895-6887","authenticated-orcid":false,"given":"Christos","family":"Chatzakis","sequence":"additional","affiliation":[{"name":"Harris Birthright Research Centre for Fetal Medicine, King\u2019s College London, London SE5 8BB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Williamson","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Developmental Biology, Department of Metabolism, Digestion & Reproduction, Imperial College London, London W12 0NN, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kypros H.","family":"Nicolaides","sequence":"additional","affiliation":[{"name":"Harris Birthright Research Centre for Fetal Medicine, King\u2019s College London, London SE5 8BB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marietta","family":"Charakida","sequence":"additional","affiliation":[{"name":"Harris Birthright Research Centre for Fetal Medicine, King\u2019s College London, London SE5 8BB, UK"},{"name":"School of Biomedical Engineering and Imaging Sciences, King\u2019s College London, London SE1 7EH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catalina","family":"De Paco Matallana","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Hospital Cl\u00ednico Universitario Virgen de la Arrixaca, El Palmar, 30120 Murcia, Spain"},{"name":"Faculty of Medicine, Universidad de Murcia, 30107 Murcia, Spain"},{"name":"Biomedical Research Institute of Murcia Pascual Parrilla\u2014IMIB, 30120 Murcia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e19","DOI":"10.1210\/clinem\/dgae709","article-title":"Gestational Diabetes: An Update 60 Years After O\u2019Sullivan and Mahan","volume":"110","author":"McIntyre","year":"2024","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5156","DOI":"10.1093\/eurheartj\/ehae706","article-title":"Gestational Diabetes and Future Cardiovascular Diseases: Associations by Sex-Specific Genetic Data","volume":"45","author":"Zhang","year":"2024","journal-title":"Eur. Heart J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"574.e1","DOI":"10.1016\/j.ajog.2020.04.019","article-title":"Paired Maternal and Fetal Cardiac Functional Measurements in Women with Gestational Diabetes Mellitus at 35\u201336 Weeks\u2019 Gestation","volume":"223","author":"Aguilera","year":"2020","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1002\/uog.22148","article-title":"Impact of Gestational Diabetes Mellitus on Fetal Cardiac Morphology and Function: Cohort Comparison of Second- and Third-Trimester Fetuses","volume":"57","author":"Yovera","year":"2021","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1001\/jamapediatrics.2023.1174","article-title":"Fetal Cardiac Function at Midgestation in Women Who Subsequently Develop Gestational Diabetes","volume":"177","author":"Huluta","year":"2023","journal-title":"JAMA Pediatr."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Borges Manna, L., Papacleovoulou, G., Flaviani, F., Pataia, V., Qadri, A., Abu-Hayyeh, S., McIlvride, S., Jansen, E., Dixon, P., and Chambers, J. (2020). Ursodeoxycholic Acid Improves Feto-Placental and Offspring Metabolic Outcomes in Hypercholanemic Pregnancy. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-67301-1"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Reilly-O\u2019Donnell, B., Ferraro, E., Tikhomirov, R., Nunez-Toldra, R., Shchendrygina, A., Patel, L., Wu, Y., Mitchell, A.L., Endo, A., and Adorini, L. (2024). Protective Effect of UDCA against IL-11-Induced Cardiac Fibrosis Is Mediated by TGR5 Signalling. Front. Cardiovasc. Med., 11.","DOI":"10.3389\/fcvm.2024.1430772"},{"key":"ref_8","first-page":"792","article-title":"A Protective Antiarrhythmic Role of Ursodeoxycholic Acid in an In Vitro Rat Model of the Fetal Heart","volume":"54","author":"Miragoli","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_9","first-page":"617","article-title":"Effect of Maternal Ursodeoxycholic Acid Treatment on Fetal Atrioventricular Conduction in Patients with Intrahepatic Cholestasis of Pregnancy","volume":"51","author":"Eyisoy","year":"2024","journal-title":"Fetal Diagn. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.pbiomolbio.2016.01.003","article-title":"The Protective Effect of Ursodeoxycholic Acid in an In Vitro Model of the Human Fetal Heart Occurs via Targeting Cardiac Fibroblasts","volume":"120","author":"Schultz","year":"2016","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Adeyemi, O., Alvarez-Laviada, A., Schultz, F., Ibrahim, E., Trauner, M., Williamson, C., Gliukhov, A.V., and Gorelik, J. (2017). Ursodeoxycholic Acid Prevents Ventricular Conduction Slowing and Arrhythmia by Restoring T-Type Calcium Current in the Fetal Heart. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183167"},{"key":"ref_12","first-page":"cvaf133","article-title":"Protective Effect of Ursodeoxycholic Acid upon the Post-Myocardial Infarction Heart","volume":"12","author":"Ferraro","year":"2025","journal-title":"Cardiovasc. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"101732","DOI":"10.1016\/j.ajogmf.2025.101732","article-title":"Randomized, Controlled Trial of the Impact of Ursodeoxycholic Acid on Glycemia in Gestational Diabetes Mellitus: The GUARDS Trial","volume":"7","author":"Matallana","year":"2025","journal-title":"Am. J. Obstet. Gynecol. MFM"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Schulz, K.F., Altman, D.G., Moher, D., and CONSORT Group (2010). CONSORT 2010 statement: Updated guidelines for reporting parallel group randomised trials. PLoS Med., 7.","DOI":"10.2427\/5718"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/uog.19066","article-title":"Ultrasonographic Estimation of Fetal Weight: Development of New Model and Assessment of Performance of Previous Models","volume":"52","author":"Hammami","year":"2018","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1002\/uog.19073","article-title":"Fetal Medicine Foundation Fetal and Neonatal Population Weight Charts","volume":"52","author":"Nicolaides","year":"2018","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1159\/000338003","article-title":"Fetal Cardiac Function: Technical Considerations and Potential Research and Clinical Applications","volume":"32","author":"Crispi","year":"2012","journal-title":"Fetal Diagn. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/uog.1959","article-title":"A Modified Myocardial Performance (Tei) Index Based on the Use of Valve Clicks Improves Reproducibility of Fetal Left Cardiac Function Assessment","volume":"26","author":"Carreras","year":"2005","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_19","unstructured":"R Core Team (2025). R: A Language and Environment for Statistical Computing, Version 2.15.1, R Foundation for Statistical Computing. Available online: https:\/\/www.r-project.org\/."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1016\/j.jhep.2020.11.038","article-title":"Fetal Cardiac Dysfunction in Intrahepatic Cholestasis of Pregnancy Is Associated with Elevated Serum Bile Acid Concentrations","volume":"74","author":"Vasavan","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1111\/1471-0528.18010","article-title":"Fetal Heart Rate Analysis in Pregnancies Complicated by Gestational Diabetes Mellitus: A Prospective Multicentre Observational Study","volume":"132","author":"Chivers","year":"2025","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1002\/uog.22163","article-title":"Effect of Maternal Diabetes on Fetal Heart Function on Ultrasound and Fetal Echocardiography: Systematic Review and Meta-Analysis","volume":"57","author":"Depla","year":"2021","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Skovsgaard, J., Haugaard, M., Iversen, K.K., Hjortdal, V.E., and Bech, B.H. (2024). Cardiac Function in Offspring of Mothers with Diabetes in Pregnancy: A Systematic Review. Front. Pediatr., 12.","DOI":"10.3389\/fped.2024.1404625"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"100952","DOI":"10.1016\/j.ajogmf.2023.100952","article-title":"Intrahepatic Cholestasis of Pregnancy and Fetal Cardiac Dysfunction: A Systematic Review and Meta-Analysis","volume":"5","author":"Zhan","year":"2023","journal-title":"Am. J. Obstet. Gynecol. 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