{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T13:20:19Z","timestamp":1772803219232,"version":"3.50.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T00:00:00Z","timestamp":1682640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["\u00a0"],"award-info":[{"award-number":["\u00a0"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008666","name":"Fundaci\u00f3 La Marat\u00f3 de TV3","doi-asserted-by":"publisher","award":["\u00a0"],"award-info":[{"award-number":["\u00a0"]}],"id":[{"id":"10.13039\/100008666","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p>Previous reports suggest that cord blood biomarkers could serve as a prognostic tool for conotruncal congenital heart defects (CHD). We aimed to describe the cord blood profile of different cardiovascular biomarkers in a prospective series of fetuses with tetralogy of Fallot (ToF) and D-transposition of great arteries (D-TGA) and to explore their correlation with fetal echocardiography and perinatal outcome.<\/jats:p><jats:sec><jats:title>Methods<\/jats:title><jats:p>A prospective cohort study (2014\u20132019), including fetuses with isolated ToF and D-TGA and healthy controls, was conducted at two tertiary referral centers for CHD in Barcelona. Obstetric ultrasound and fetal echocardiography were performed in the third trimester and cord blood was obtained at delivery. Cord blood concentrations of N-terminal precursor of B-type natriuretic peptide, Troponin I, transforming growth factor\u03b2 (TGF\u03b2), placental growth factor, and soluble fms-like tyrosine kinase-1 were determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thirty-four fetuses with conotruncal-CHD (22 ToF and 12 D-TGA) and 36 controls were included. ToF-fetuses showed markedly increased cord blood TGF\u03b2 (24.9\u2005ng\/ml (15.6\u201345.3) vs. normal heart 15.7\u2005ng\/ml (7.2\u201324.3) vs. D-TGA 12.6\u2005ng\/ml (8.7\u201337.9); <jats:italic>P<\/jats:italic>\u2009=\u20090.012). These results remained statistically significant even after adjusting for maternal body mass index, birth weight and mode of delivery. TGF\u00df levels showed a negative correlation with the pulmonary valve diameter <jats:italic>z<\/jats:italic>-score at fetal echocardiography (<jats:italic>r<\/jats:italic>\u2009=\u2009\u22120.576, <jats:italic>P<\/jats:italic>\u2009=\u20090.039). No other differences were found in the rest of cord blood biomarkers among the study populations. Likewise, no other significant correlations were identified between cardiovascular biomarkers, fetal echocardiography and perinatal outcome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study newly describes increased cord blood TGF\u03b2 concentrations in ToF compared to D-TGA and normal fetuses. We also demonstrate that TGF\u03b2 levels correlate with the severity of right ventricle outflow obstruction. These novel findings open a window of research opportunities on new prognostic and potential preventive strategies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fped.2023.1151814","type":"journal-article","created":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T05:59:07Z","timestamp":1682661547000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Cord blood cardiovascular biomarkers in tetralogy of fallot and D-transposition of great arteries"],"prefix":"10.3389","volume":"11","author":[{"given":"Olga","family":"G\u00f3mez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Nogu\u00e9","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iris","family":"Soveral","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Guirado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nora","family":"Izquierdo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam","family":"P\u00e9rez-Cruz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Narc\u00eds","family":"Masoller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Clara","family":"Escobar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joan","family":"Sanchez-de-Toledo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josep Maria","family":"Mart\u00ednez-Crespo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar","family":"Bennasar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F\u00e0tima","family":"Crispi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,4,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1002\/uog.12403","article-title":"ISUOG practice guidelines (updated): sonographic screening examination of the fetal heart","volume":"41","author":"Carvalho","year":"2013","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1136\/hrt.2005.061143","article-title":"Tetralogy of fallot: from fetus to adult","volume":"92","author":"Shinebourne","year":"2006","journal-title":"Heart"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2183","DOI":"10.1161\/01.cir.0000437597.44550.5d","article-title":"Diagnosis and treatment of fetal cardiac disease: a scientific statement from the American heart association","volume":"129","author":"Donofrio","year":"2014","journal-title":"Circulation"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1559","DOI":"10.1016\/j.jacc.2005.11.064","article-title":"Cardiac expression of placental growth factor predicts the improvement of chronic phase left ventricular function in patients with acute myocardial infarction","volume":"47","author":"Iwama","year":"2006","journal-title":"J Am Coll Cardiol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"9267","DOI":"10.1073\/pnas.88.20.9267","article-title":"Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor","volume":"88","author":"Maglione","year":"1991","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B6","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1093\/eurheartj\/eht389","article-title":"Maternal and foetal angiogenic imbalance in congenital heart defects","volume":"35","author":"Llurba","year":"2014","journal-title":"Eur Heart J"},{"key":"B7","doi-asserted-by":"publisher","first-page":"7119","DOI":"10.3390\/jcm11237119","article-title":"Cord blood cardiovascular biomarkers in left-sided congenital heart disease","volume":"11","author":"Soveral","year":"2022","journal-title":"J Clin Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1053\/j.semtcvs.2007.07.013","article-title":"The molecular basis of congenital heart disease","volume":"19","author":"Mitchell","year":"2007","journal-title":"Semin Thorac Cardiovasc Surg"},{"key":"B9","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1093\/eurheartj\/ehq456","article-title":"Troponin elevation in coronary vs. non-coronary disease","volume":"32","author":"Agewall","year":"2011","journal-title":"Eur Heart J"},{"key":"B10","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1002\/pd.4787","article-title":"Prenatal prediction of neonatal death in single ventricle congenital heart disease","volume":"36","author":"Lee","year":"2016","journal-title":"Prenat Diagn"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1080\/14767058.2019.1632285","article-title":"Evaluation of cord blood creatine kinase (CK), cardiac troponin T (cTnT), N-terminal-pro-B-type natriuretic peptide (NT-proBNP), and s100B levels in nonreassuring foetal heart rate","volume":"34","author":"Irmak","year":"2021","journal-title":"J Matern Fetal Neonatal Med"},{"key":"B12","doi-asserted-by":"publisher","first-page":"273.e1","DOI":"10.1016\/j.ajog.2008.10.009","article-title":"Biochemical tissue-specific injury markers of the heart and brain in postpartum cord blood","volume":"200","author":"Kocylowski","year":"2009","journal-title":"Am J Obstet Gynecol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"110289","DOI":"10.1016\/j.cbi.2022.110289","article-title":"Transforming growth factor-\u03b2 signaling: from tissue fibrosis to therapeutic opportunities","volume":"369","author":"Ren","year":"2023","journal-title":"Chem Biol Interact"},{"key":"B14","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1038\/s41598-018-36458-1","article-title":"Circulating transforming growth factor-\u03b2 and aortic dilation in patients with repaired congenital heart disease","volume":"9","author":"Cheung","year":"2019","journal-title":"Sci Rep"},{"key":"B15","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1007\/s00380-013-0326-1","article-title":"Progressive aortic dilation and aortic stiffness in children with repaired tetralogy of fallot","volume":"29","author":"Seki","year":"2014","journal-title":"Heart Vessels"},{"key":"B16","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1111\/j.1471-0528.1979.tb10804.x","article-title":"The accuracy of radiological estimates of gestational age using early fetal crown-rump length measurements by ultrasound as a basis for comparison","volume":"86","author":"Robinson","year":"1979","journal-title":"Br J Obstet Gynaecol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1002\/uog.17365","article-title":"Descriptive analysis of different phenotypes of cardiac remodeling in fetal growth restriction","volume":"50","author":"Rodr\u00edguez-L\u00f3pez","year":"2017","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"2427","DOI":"10.1161\/CIRCULATIONAHA.110.937995","article-title":"Fetal growth restriction results in remodeled and less efficient hearts in children","volume":"121","author":"Crispi","year":"2010","journal-title":"Circulation"},{"key":"B19","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1097\/00003081-200606000-00009","article-title":"Adult consequences of fetal growth restriction","volume":"49","author":"Barker","year":"2006","journal-title":"Clin Obstet Gynecol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1007\/s00246-015-1242-1","article-title":"Troponin T and NT ProBNP levels in gestational, type 1 and type 2 diabetic mothers and macrosomic infants","volume":"37","author":"Mert","year":"2016","journal-title":"Pediatr Cardiol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1002\/uog.20187","article-title":"Perinatal changes in fetal cardiac geometry and function in diabetic pregnancy at term","volume":"54","author":"Patey","year":"2019","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1097\/QAD.0000000000001066","article-title":"Zidovudine treatment in HIV-infected pregnant women is associated with fetal cardiac remodelling","volume":"30","author":"Garc\u00eda-Otero","year":"2016","journal-title":"AIDS"},{"key":"B23","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1159\/000357592","article-title":"Update on the diagnosis and classification of fetal growth restriction and proposal of a stage-based management protocol","volume":"36","author":"Figueras","year":"2014","journal-title":"Fetal Diagn Ther"},{"key":"B24","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1046\/j.1469-0705.2001.00414.x","article-title":"Examination of the fetal heart by five short-axis views: a proposed screening method for comprehensive cardiac evaluation","volume":"17","author":"Yagel","year":"2001","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1002\/uog.2677","article-title":"Cardiac screening examination of the fetus: guidelines for performing the \u201cbasic\u201d and \u201cextended basic\u201d cardiac scan","volume":"27","author":"Lee","year":"2006","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1002\/uog.12396","article-title":"ISUOG Practice guidelines: use of Doppler ultrasonography in obstetrics","volume":"41","author":"Bhide","year":"2013","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1046\/j.1469-0705.1994.04050381.x","article-title":"Reference ranges for fetal venous and atrioventricular blood flow parameters","volume":"4","author":"Hecher","year":"1994","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1016\/0002-9378(87)90365-6","article-title":"Estimating fetal age using multiple parameters: a prospective evaluation in a racially mixed population","volume":"156","author":"Hadlock","year":"1987","journal-title":"Am J Obstet Gynecol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.ejogrb.2006.12.015","article-title":"Customized birthweight standards for a Spanish population","volume":"136","author":"Figueras","year":"2008","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1002\/uog.20","article-title":"The cerebroplacental Doppler ratio revisited","volume":"21","author":"Baschat","year":"2003","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1002\/uog.23127","article-title":"Reference ranges for fetal cardiac, ventricular and atrial relative size, sphericity, ventricular dominance, wall asymmetry and relative wall thickness from 18 to 41 gestational weeks","volume":"58","author":"Garc\u00eda-Otero","year":"2021","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1159\/000494838","article-title":"Nomograms of fetal cardiac dimensions at 18\u201341 weeks of gestation","volume":"47","author":"Garc\u00eda-Otero","year":"2020","journal-title":"Fetal Diagn Ther"},{"key":"B33","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1002\/uog.2597","article-title":"Development of z-scores for fetal cardiac dimensions from echocardiography","volume":"26","author":"Schneider","year":"2005","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1002\/uog.12374","article-title":"Value of annular M-mode displacement vs tissue Doppler velocities to assess cardiac function in intrauterine growth restriction","volume":"42","author":"Cruz-Lemini","year":"2013","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1042\/BJ20101490","article-title":"Hypoxia down-regulates sFlt-1 (sVEGFR-1) expression in human microvascular endothelial cells by a mechanism involving mRNA alternative processing","volume":"436","author":"Ikeda","year":"2011","journal-title":"Biochem J"},{"key":"B36","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.placenta.2021.07.297","article-title":"Placenta morphology and biomarkers in pregnancies with congenital heart disease - A systematic review","volume":"112","author":"Snoep","year":"2021","journal-title":"Placenta"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2177","DOI":"10.1161\/CIRCULATIONAHA.109.884866","article-title":"B-type natriuretic peptides and cardiovascular risk: systematic review and meta-analysis of 40 prospective studies","volume":"120","author":"Di Angelantonio","year":"2009","journal-title":"Circulation"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1548","DOI":"10.1055\/s-0041-1722944","article-title":"Cord-blood high-sensitivity troponin-I reference interval and association with early neonatal outcomes","volume":"29","author":"Mondal","year":"2022","journal-title":"Am J Perinatol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.ijgo.2007.08.007","article-title":"Cord blood cardiac troponin I, fetal Doppler velocimetry, and acid base status at birth","volume":"100","author":"Alexandre","year":"2008","journal-title":"Int J Gynaecol Obstet"},{"key":"B40","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1159\/000484315","article-title":"Cord blood biomarkers of cardiac dysfunction and damage in term growth-restricted fetuses classified by severity criteria","volume":"44","author":"Perez-Cruz","year":"2018","journal-title":"Fetal Diagn Ther"},{"key":"B41","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1038\/cr.2008.326","article-title":"TGF-beta signaling in vascular biology and dysfunction","volume":"19","author":"Goumans","year":"2009","journal-title":"Cell Res"},{"key":"B42","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1016\/j.yjmcc.2010.10.033","article-title":"Transforming growth factor (TGF)-\u03b2 signaling in cardiac remodeling","volume":"51","author":"Dobaczewski","year":"2011","journal-title":"J Mol Cell Cardiol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.7863\/ultra.15.08017","article-title":"Quantitative cardiac assessment in fetal tetralogy of fallot","volume":"35","author":"Jatavan","year":"2016","journal-title":"J Ultrasound Med"},{"key":"B44","doi-asserted-by":"publisher","first-page":"H1649","DOI":"10.1152\/ajpheart.00235.2018","article-title":"Human fetal hearts with tetralogy of fallot have altered fluid dynamics and forces","volume":"315","author":"Wiputra","year":"2018","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1002\/dvdy.20029","article-title":"Development-related changes in the expression of shear stress responsive genes KLF-2, ET-1, and NOS-3 in the developing cardiovascular system of chicken embryos","volume":"230","author":"Groenendijk","year":"2004","journal-title":"Dev Dyn"},{"key":"B46","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1002\/uog.23707","article-title":"MRI Characterization of hemodynamic patterns of human fetuses with cyanotic congenital heart disease","volume":"58","author":"Sun","year":"2021","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B47","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1038\/nrcardio.2009.191","article-title":"Cellular and molecular mechanisms of thoracic aortic aneurysms","volume":"6","author":"El-Hamamsy","year":"2009","journal-title":"Nat Rev Cardiol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"2441","DOI":"10.1016\/j.ijcard.2013.03.033","article-title":"Circulating transforming growth factor-\u03b2 as a prognostic biomarker in Marfan syndrome","volume":"168","author":"Franken","year":"2013","journal-title":"Int J Cardiol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.pedneo.2016.05.004","article-title":"Developmental changes in aortic mechanical properties in normal fetuses and fetuses with cardiovascular disease","volume":"58","author":"Taketazu","year":"2017","journal-title":"Pediatr Neonatol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"676994","DOI":"10.3389\/fped.2021.676994","article-title":"Prevalence of growth restriction at birth for newborns with congenital heart defects: a population-based prospective cohort study EPICARD","volume":"9","author":"Ghanchi","year":"2021","journal-title":"Front Pediatr"},{"key":"B51","doi-asserted-by":"publisher","first-page":"299","DOI":"10.3390\/antiox11020299","article-title":"Brain oxygen perfusion and oxidative stress biomarkers in fetuses with congenital heart disease-A retrospective, case-control pilot study","volume":"11","author":"Escobar-Diaz","year":"2022","journal-title":"Antioxidants"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2023.1151814\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T05:59:11Z","timestamp":1682661551000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2023.1151814\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,28]]},"references-count":51,"alternative-id":["10.3389\/fped.2023.1151814"],"URL":"https:\/\/doi.org\/10.3389\/fped.2023.1151814","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,28]]},"article-number":"1151814"}}