{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:16:23Z","timestamp":1789042583242,"version":"build-2803163510"},"reference-count":28,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background\/Objectives: To investigate maternal serum Isthmin-1 (ISM1) levels in pregnancies complicated by fetal growth restriction (FGR) and to evaluate its potential discriminatory performance for FGR. Methods: This prospective cross-sectional study included 44 pregnant women with late-onset FGR and 43 gestational age-matched healthy controls. FGR was diagnosed according to one of two criteria: (1) estimated fetal weight (EFW) below the 3rd percentile, or (2) EFW between the 3rd and 10th percentile with at least one abnormal Doppler finding (Umbilical Artery Pulsatility Index (UA-PI), Middle Cerebral Artery Pulsatility Index (MCA-PI), or Cerebroplacental Ratio (CPR). Maternal serum ISM1 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Ultrasonographic parameters, Doppler indices, and perinatal outcomes were compared between groups. Correlation and receiver operating characteristic (ROC) analyses were performed to assess diagnostic performance. Results: Maternal ISM1 levels were significantly lower in the FGR group compared with controls [10.63 (9.95\u201312.10) vs. 12.40 (10.75\u201313.25) ng\/mL, p = 0.003]. ISM1 correlated negatively with FGR presence (r = \u22120.318, p = 0.003) and positively with EFW percentile (r = 0.235, p = 0.028). ROC analysis showed moderate diagnostic accuracy Area Under the Curve (AUC) = 0.684, 95% CI: 0.575\u20130.779) with 70.5% sensitivity and 72.1% specificity at a cut-off \u226411.5 ng\/mL. No significant association was found between ISM1 and composite adverse perinatal outcomes. Conclusions: Levels of ISM1 in maternal serum were found to be significantly lower in pregnancies complicated by FGR, supporting a potential association between ISM1 and impaired fetal growth. However, its moderate diagnostic performance and lack of association with adverse perinatal outcomes indicate that ISM1 should currently be regarded as a promising exploratory biomarker rather than a standalone diagnostic or prognostic marker. Further studies are needed to validate these findings and to determine whether ISM1 provides additional value when combined with established Doppler and angiogenic markers.<\/jats:p>","DOI":"10.3390\/jcm15187018","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T11:38:39Z","timestamp":1789040319000},"page":"7018","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Maternal Serum Isthmin-1 as a Novel Biomarker for Late-Onset Fetal Growth Restriction"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1134-9950","authenticated-orcid":false,"given":"\u00d6zge","family":"\u00d6zt\u00fcrk","sequence":"first","affiliation":[{"name":"Department of Perinatology, Etlik City Hospital, Ankara 06170, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6570-1006","authenticated-orcid":false,"given":"Recep Taha","family":"A\u011fao\u011flu","sequence":"additional","affiliation":[{"name":"Department of Perinatology, Etlik City Hospital, Ankara 06170, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3352-0195","authenticated-orcid":false,"given":"Gunel","family":"Aliyeva","sequence":"additional","affiliation":[{"name":"Department of Perinatology, Etlik City Hospital, Ankara 06170, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3993-2402","authenticated-orcid":false,"given":"Mesut","family":"\u015eim\u015fek","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Etlik City Hospital, Ankara 06170, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3182-4312","authenticated-orcid":false,"given":"Kadriye","family":"Yakut Y\u00fccel","sequence":"additional","affiliation":[{"name":"Department of Perinatology, Etlik City Hospital, Ankara 06170, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/uog.15884","article-title":"Consensus definition of fetal growth restriction: A Delphi procedure","volume":"48","author":"Gordijn","year":"2016","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_2","doi-asserted-by":"crossref","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":"ref_3","doi-asserted-by":"crossref","unstructured":"American College of Obstetricians and Gynecologists (2021). Fetal growth restriction: ACOG Practice Bulletin No. 227. Obstet. Gynecol., 137, e16\u2013e28.","DOI":"10.1097\/AOG.0000000000004251"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/ijgo.13522","article-title":"FIGO (International Federation of Gynecology and Obstetrics) initiative on fetal growth: Best practice advice for screening, diagnosis, and management of fetal growth restriction","volume":"152","author":"Melamed","year":"2021","journal-title":"Int. J. Gynecol. Obstet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1002\/uog.22134","article-title":"ISUOG Practice Guidelines: Diagnosis and management of small-for-gestational-age fetus and fetal growth restriction","volume":"56","author":"Lees","year":"2020","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_6","unstructured":"Royal College of Obstetricians and Gynaecologists (2024). Investigation and Care of the Small-for-Gestational-Age Fetus and a Growth Restricted Fetus (Green-Top Guideline No. 31), RCOG. Available online: https:\/\/www.rcog.org.uk\/media\/t3lmjhnl\/gtg_31.pdf."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1016\/S0140-6736(14)62049-3","article-title":"2 year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): A randomised trial","volume":"385","author":"Lees","year":"2015","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1136\/bmj.301.6761.1111","article-title":"The fetal and infant origins of adult disease","volume":"301","author":"Barker","year":"1990","journal-title":"BMJ"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1056\/NEJMra0708473","article-title":"Effect of In Utero and Early-Life Conditions on Adult Health and Disease","volume":"359","author":"Gluckman","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S745","DOI":"10.1016\/j.ajog.2017.11.577","article-title":"Pathophysiology of placental-derived fetal growth restriction","volume":"218","author":"Burton","year":"2018","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1056\/NEJMoa1414838","article-title":"Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia","volume":"374","author":"Zeisler","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1161\/HYPERTENSIONAHA.113.01787","article-title":"New Gestational Phase\u2013Specific Cutoff Values for the Use of the Soluble fms-Like Tyrosine Kinase-1\/Placental Growth Factor Ratio as a Diagnostic Test for Preeclampsia","volume":"63","author":"Verlohren","year":"2014","journal-title":"Hypertension"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Shakhawat, H.M., Hazrat, Z., and Zhou, Z. (2022). Isthmin\u2014A Multifaceted Protein Family. Cells, 12.","DOI":"10.3390\/cells12010017"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1007\/s12079-023-00732-3","article-title":"Advances in research of biological functions of Isthmin-1","volume":"17","author":"Li","year":"2023","journal-title":"J. Cell Commun. Signal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e153","DOI":"10.1038\/cddis.2011.37","article-title":"Isthmin exerts pro-survival and death-promoting effect on endothelial cells through alphavbeta5 integrin depending on its physical state","volume":"2","author":"Zhang","year":"2011","journal-title":"Cell Death Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1038\/cdd.2014.3","article-title":"Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction","volume":"21","author":"Chen","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1111\/j.1582-4934.2009.00961.x","article-title":"Isthmin is a novel secreted angiogenesis inhibitor that inhibits tumour growth in mice","volume":"15","author":"Xiang","year":"2011","journal-title":"J. Cell. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1016\/j.cmet.2021.07.010","article-title":"Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis","volume":"33","author":"Jiang","year":"2021","journal-title":"Cell Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1083\/jcb.201801081","article-title":"ISM1 regulates NODAL signaling and asymmetric organ morphogenesis during development","volume":"218","author":"Wu","year":"2019","journal-title":"J. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2271624","DOI":"10.1080\/14767058.2023.2229931","article-title":"Investigation of serum isthmin 1 concentration in pregnant women diagnosed with gestational diabetes mellitus; a case-control study","volume":"36","author":"Kale","year":"2023","journal-title":"J. Matern.-Fetal Neonatal Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e05096","DOI":"10.1016\/j.heliyon.2020.e05096","article-title":"Isthmin 2 is decreased in preeclampsia and highly expressed in choriocarcinoma","volume":"6","author":"Martinez","year":"2020","journal-title":"Heliyon"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"156423","DOI":"10.1016\/j.cyto.2023.156423","article-title":"Isthmin: A multifunctional secretion protein","volume":"173","author":"Liang","year":"2024","journal-title":"Cytokine"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1089\/jir.2013.0137","article-title":"Isthmin 1 Is a Secreted Protein Expressed in Skin, Mucosal Tissues, and NK, NKT, and Th17 Cells","volume":"34","author":"Burkhardt","year":"2014","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e002972","DOI":"10.1136\/bmjdrc-2022-002972","article-title":"Serum isthmin-1 levels are positively and independently correlated with albuminuria in patients with type 2 diabetes mellitus","volume":"10","author":"Wang","year":"2022","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1186\/s12933-023-02075-0","article-title":"Isthmin-1 (ISM1), a novel adipokine that reflects abdominal adipose tissue distribution in individuals with obesity","volume":"22","author":"Casamayor","year":"2023","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.ajog.2021.11.1357","article-title":"The diagnosis and management of suspected fetal growth restriction: An evidence-based approach","volume":"226","author":"Lees","year":"2022","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1111\/1471-0528.12172","article-title":"Novel biomarkers for predicting intrauterine growth restriction: A systematic review and meta-analysis","volume":"120","author":"Papageorghiou","year":"2013","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"105854","DOI":"10.1016\/j.ebiom.2025.105854","article-title":"Reduced circulating NrCAM as a biomarker for fetal growth restriction","volume":"118","author":"Bartho","year":"2025","journal-title":"EBioMedicine"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/18\/7018\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T11:51:10Z","timestamp":1789041070000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/18\/7018"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":28,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["jcm15187018"],"URL":"https:\/\/doi.org\/10.3390\/jcm15187018","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,10]]}}}