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However, to date, no studies have simultaneously explored the relationships between maternal stress, placental expression and methylation of\n HSD11\u03b22<\/jats:italic>\n , and fetal cortisol metabolites according to fetal growth. The aim of the present study was to evaluate the association between perceived antenatal maternal stress, the expression and methylation of the placental\n HSD11\u03b22<\/jats:italic>\n gene, fetal cortisol metabolites in amniotic fluid and birth weight.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n This nested case\u2013control study, which was part of a large prospective cohort study, was conducted at two maternofetal medicine units in Barcelona, Spain (BCNatal: Hospitals Clinic and Sant Joan de D\u00e9u). We enrolled singleton pregnancies and classified neonates as small\u2010for\u2010gestational age (SGA) if their birth weight was below the 10\n th<\/jats:sup>\n percentile (\n n<\/jats:italic>\n \u2009=\u2009343) or as appropriate\u2010for\u2010gestational\u2010age (AGA) controls (\n n<\/jats:italic>\n \u2009=\u2009399). The Perceived Stress Scale (PSS) and the State\u2013Trait Anxiety Inventory (STAI) scores were obtained to assess maternal stress and anxiety levels. We analyzed placental\n HSD11\u03b22<\/jats:italic>\n RNA expression (\n n<\/jats:italic>\n \u2009=\u200944 SGA and\n n<\/jats:italic>\n \u2009=\u200928 AGA) and DNA methylation levels (\n n<\/jats:italic>\n \u2009=\u200989 SGA and\n n<\/jats:italic>\n \u2009=\u200934 AGA), and fetal cortisol metabolites and the activity of metabolizing enzymes in amniotic fluid (\n n<\/jats:italic>\n \u2009=\u2009135 SGA and\n n<\/jats:italic>\n \u2009=\u200978 AGA) using liquid chromatography\u2010tandem mass spectrometry.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Median maternal perceived stress (PSS, 23 (interquartile range (IQR), 17\u201328)\n vs<\/jats:italic>\n 20 (IQR, 15\u201326);\n P<\/jats:italic>\n \u2009<\u20090.001) and median anxiety state (STAI\u2010state, 19.0 (IQR, 14.0\u201329.0)\n vs<\/jats:italic>\n 16.0 (IQR, 11.0\u201324.0);\n P<\/jats:italic>\n \u2009<\u20090.001) scores were significantly higher in the SGA group compared with the control group. SGA cases showed lower median placental\n HSD11\u03b22<\/jats:italic>\n RNA expression (\u0394 Ct, 50.5 (IQR, 21.6\u2013106.0)\n vs<\/jats:italic>\n 92.7 (IQR, 62.3\u2013118.0);\n P<\/jats:italic>\n \u2009=\u20090.013) with similar DNA methylation levels (mean\u2009\u00b1\u2009SD, 10.7\u2009\u00b1\u20093.0%\n vs<\/jats:italic>\n 11.0\u2009\u00b1\u20092.8%;\n P<\/jats:italic>\n \u2009=\u20090.648) compared with AGA controls. Analysis of amniotic fluid revealed altered cortisol metabolism in SGA fetuses, with increased median 5\u03b1\u2010tetrahydrocortisol concentration (SGA, 0.09% (IQR, 0.06\u20130.15%)\n vs<\/jats:italic>\n controls, 0.07% (IQR, 0.05\u20130.11%);\n P<\/jats:italic>\n \u2009=\u20090.020) and activity of its related enzyme (5\u03b1\u2010reductase activity in SGA, 0.19% (IQR, 0.14\u20130.31%)\n vs<\/jats:italic>\n controls, 0.17% (IQR, 0.12\u20130.22%);\n P<\/jats:italic>\n \u2009=\u20090.007), together with a decrease in median 6\u2010hydroxycortisol concentration (SGA, 0.09% (IQR, 0.06\u20130.11%)\n vs<\/jats:italic>\n controls, 0.11% (IQR, 0.08\u20130.12%);\n P<\/jats:italic>\n \u2009<\u20090.001) and activity of its related enzyme (CYP3A7 activity in SGA, 0.19% (IQR, 0.11\u20130.25%)\n vs<\/jats:italic>\n controls, 0.24% (IQR, 0.17\u20130.33%);\n P<\/jats:italic>\n \u2009<\u20090.001).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n SGA pregnancy is associated with high perceived maternal stress and dysregulated fetoplacental cortisol metabolism. These results deepen our understanding of the pathophysiology of SGA and highlight the potential benefit of intervention to mitigate maternal stress. \u00a9 2025 The Author(s).\n Ultrasound in Obstetrics & Gynecology<\/jats:italic>\n published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/uog.29238","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T06:30:23Z","timestamp":1747981823000},"page":"738-748","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Maternal stress and fetoplacental cortisol regulation in small\u2010for\u2010gestational\u2010age newborns"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0372-8374","authenticated-orcid":false,"given":"J.","family":"Miranda","sequence":"first","affiliation":[{"name":"BCNatal\u00a0\u2013\u00a0Barcelona Center for Maternal\u2010Fetal and Neonatal Medicine (Hospital Cl\u00ednic and Hospital Sant Joan de Deu) University of Barcelona Barcelona Spain"},{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine Universidad de Cartagena Cartagena Colombia"},{"name":"Department of Obstetrics and Gynecology, Centro Hospitalario Serena del Mar, Cartagena Colombia y Fundaci\u00f3n Santa Fe de Bogota Bogota Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Benitez","sequence":"additional","affiliation":[{"name":"BCNatal\u00a0\u2013\u00a0Barcelona Center for Maternal\u2010Fetal and Neonatal Medicine (Hospital Cl\u00ednic and Hospital Sant Joan de Deu) University of Barcelona Barcelona Spain"},{"name":"Institut d'Investigacions Biom\u00e8diques August Pi I Sunyer (IDIBAPS)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Mac\u00edas\u2010Redondo","sequence":"additional","affiliation":[{"name":"Instituto Aragon\u00e9s de Ciencias de la Salud (IACS) and Placental Pathophysiology & Fetal Programming Research Group Zaragoza Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Paules","sequence":"additional","affiliation":[{"name":"BCNatal\u00a0\u2013\u00a0Barcelona Center for Maternal\u2010Fetal and Neonatal Medicine (Hospital Cl\u00ednic and Hospital Sant Joan de Deu) University of Barcelona Barcelona Spain"},{"name":"Institut d'Investigacions Biom\u00e8diques August Pi I Sunyer (IDIBAPS)"},{"name":"Instituto Aragon\u00e9s de Ciencias de la Salud (IACS) and Placental Pathophysiology & Fetal Programming Research Group Zaragoza Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Gomez\u2010Gomez","sequence":"additional","affiliation":[{"name":"Applied Metabolomics Research Group Hospital del Mar Research Institute (IMIM) Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Basso","sequence":"additional","affiliation":[{"name":"BCNatal\u00a0\u2013\u00a0Barcelona Center for Maternal\u2010Fetal and Neonatal Medicine (Hospital Cl\u00ednic and Hospital Sant Joan de Deu) University of Barcelona Barcelona Spain"},{"name":"Department of Obstetrics and Gynecology, ASST Lecco A.Manzoni Hospital Lecco Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Crovetto","sequence":"additional","affiliation":[{"name":"BCNatal\u00a0\u2013\u00a0Barcelona Center for Maternal\u2010Fetal and Neonatal Medicine (Hospital Cl\u00ednic and Hospital Sant Joan de Deu) University of Barcelona Barcelona Spain"},{"name":"Institut de Recerca Sant Joan de D\u00e9u, Esplugues de Llobregat Spain"},{"name":"Primary Care Interventions to Prevent Maternal and Child Chronic Diseases of Perinatal and Development Origin, RD21\/0012\/0003 Instituto de Salud Carlos III Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Youssef","sequence":"additional","affiliation":[{"name":"BCNatal\u00a0\u2013\u00a0Barcelona Center for Maternal\u2010Fetal and Neonatal Medicine (Hospital Cl\u00ednic and Hospital Sant Joan de Deu) University of Barcelona Barcelona Spain"},{"name":"Josep Carreras Leukaemia Research Institute Hospital Clinic\/University of Barcelona Campus Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O. 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