{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T14:40:38Z","timestamp":1774276838756,"version":"3.50.1"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2017,2,25]],"date-time":"2017-02-25T00:00:00Z","timestamp":1487980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>BACKGROUND<\/jats:title>\n                  <jats:p>Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by hypertension and proteinuria. The HELLP syndrome is the most severe form of PE. The aim of the present study was to determine different potential biomarkers that may help us perform an early diagnosis of the disease, assess on the severity of the disease, and\/or predict maternal or fetal adverse outcomes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>We measured serum levels of total and fetal circulating cell-free DNA (cfDNA), soluble endoglin, soluble form of vascular endothelial growth factor receptor, and placental growth factor in a healthy control group of pregnant women (n = 26), patients with mild (n = 37) and severe PE (n = 25), and patients with HELLP syndrome (n = 16).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>We observed a gradual and strong relationship between all the biomarkers mentioned and the range of severity of PE, with the highest levels in patients with HELLP syndrome. Nevertheless, only the values of total cfDNA were able to significantly differentiate severe PE and HELLP syndrome (20957 \u00b1 2784 vs. 43184 \u00b1 8647 GE\/ml, P = 0.01). Receiver operating characteristic (ROC) curves were constructed (i) for the healthy group with respect to the groups with PE and (ii) for patients with PE with respect to the group with HELLP syndrome; sensitivity and specificity values at different cutoff levels were calculated in each case. The maximum ROC area under the curve value for PE and HELLP syndrome (with respect to controls) was 0.91 (P &amp;lt; 0.001).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>The measured biomarkers of cell damage, angiogenesis, and antiangiogenesis may reflect the severity of PE, with higher levels in patients who develop HELLP syndrome. In addition, these biomarkers may also help predict adverse fetal and maternal outcomes.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ajh\/hpx024","type":"journal-article","created":{"date-parts":[[2017,2,15]],"date-time":"2017-02-15T08:56:05Z","timestamp":1487148965000},"page":"673-682","source":"Crossref","is-referenced-by-count":32,"title":["Total and Fetal Circulating Cell-Free DNA, Angiogenic, and Antiangiogenic Factors in Preeclampsia and HELLP Syndrome"],"prefix":"10.1093","volume":"30","author":[{"given":"Roc\u00edo","family":"Mu\u00f1oz-Hern\u00e1ndez","sequence":"first","affiliation":[{"name":"Laboratorio de Hipertensi\u00f3n Arterial e Hipercolesterolemia, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla 1 , Sevilla , Spain ;"},{"name":"Laboratorio de Investigaci\u00f3n cl\u00ednica y traslacional en enfermedades hep\u00e1ticas y digestivas. Instituto de Biomedicina de Sevilla (IBiS). Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla 2 , Sevilla , Spain ;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo","family":"Medrano-Campillo","sequence":"additional","affiliation":[{"name":"Laboratorio de Hipertensi\u00f3n Arterial e Hipercolesterolemia, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla 1 , Sevilla , Spain ;"},{"name":"Universidad Aut\u00f3noma de Chile 3 , Chile ;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria L.","family":"Miranda","sequence":"additional","affiliation":[{"name":"Laboratorio de Hipertensi\u00f3n Arterial e Hipercolesterolemia, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla 1 , Sevilla , Spain ;"},{"name":"Unidad Cl\u00ednico-Experimental de Riesgo Vascular (UCERV-UCAMI), Hospital Universitario Virgen del Roc\u00edo 4 , Sevilla , Spain ;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hada C.","family":"Macher","sequence":"additional","affiliation":[{"name":"Servicio de Bioqu\u00edmica Cl\u00ednica, Hospital Virgen del Roc\u00edo 5 , Sevilla , Spain ;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose Manuel","family":"Praena-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Unidad de Asesor\u00eda Estad\u00edstica, Metodolog\u00eda y Evaluaci\u00f3n de Investigaci\u00f3n, Fundaci\u00f3n P\u00fablica Andaluza para la Gesti\u00f3n de la Investigaci\u00f3n en Salud de Sevilla (FISEVI) 6 . Sevilla , Spain ;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio J.","family":"Vallejo-Vaz","sequence":"additional","affiliation":[{"name":"Laboratorio de Hipertensi\u00f3n Arterial e Hipercolesterolemia, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla 1 , Sevilla , Spain ;"},{"name":"School of Public Health, Imperial College London 7 . London , UK ;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda J.","family":"Dominguez-Simeon","sequence":"additional","affiliation":[{"name":"Laboratorio de Hipertensi\u00f3n Arterial e Hipercolesterolemia, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla 1 , Sevilla , Spain ;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Moreno-Luna","sequence":"additional","affiliation":[{"name":"Laboratorio de Fisiopatolog\u00eda Vascular, Hospital de parapl\u00e9jicos de Toledo 8 . Toledo , Spain ."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo","family":"Stiefel","sequence":"additional","affiliation":[{"name":"Laboratorio de Hipertensi\u00f3n Arterial e Hipercolesterolemia, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla 1 , Sevilla , Spain ;"},{"name":"Unidad Cl\u00ednico-Experimental de Riesgo Vascular (UCERV-UCAMI), Hospital Universitario Virgen del Roc\u00edo 4 , Sevilla , Spain ;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2017,2,25]]},"reference":[{"key":"2022112110393940400_CIT0001","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1136\/bmj.330.7491.576","article-title":"The pre-eclampsia community guideline (PRECOG): how to screen for and detect onset of pre-eclampsia in the community","volume":"330","author":"Milne","year":"2005","journal-title":"BMJ"},{"key":"2022112110393940400_CIT0002","first-page":"1122","article-title":"Report of the American College of Obstetricians and Gynecologists\u2019 Task Force on Hypertension in Pregnancy","volume-title":"Hypertension in Pregnancy","author":"The American college of Obstetricians and Gynecologists","year":"2013"},{"key":"2022112110393940400_CIT0003","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1146\/annurev-pathol-121808-102149","article-title":"Pathogenesis of preeclampsia","volume":"5","author":"Young","year":"2010","journal-title":"Annu Rev Pathol"},{"key":"2022112110393940400_CIT0004","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/0002-9378(93)90043-I","article-title":"Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome)","volume":"169","author":"Sibai","year":"1993","journal-title":"Am J Obstet Gynecol"},{"key":"2022112110393940400_CIT0005","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.preghy.2011.01.004","article-title":"The HELLP syndrome (hemolysis, elevated liver enzymes and low platelets): clinical characteristics and maternal-fetal outcome in 172 patients","volume":"1","author":"Miranda","year":"2011","journal-title":"Pregnancy Hypertens"},{"key":"2022112110393940400_CIT0006","doi-asserted-by":"crossref","first-page":"163","DOI":"10.3109\/10641950902968635","article-title":"Predictive value of clinical and laboratory indices at first assessment in women referred with suspected gestational hypertension","volume":"29","author":"Anumba","year":"2010","journal-title":"Hypertens Pregnancy"},{"key":"2022112110393940400_CIT0007","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1093\/ajh\/hpt187","article-title":"Role of circulating cell-free DNA levels in patients with severe preeclampsia and HELLP syndrome","volume":"26","author":"Miranda","year":"2013","journal-title":"Am J Hypertens"},{"key":"2022112110393940400_CIT0008","doi-asserted-by":"crossref","first-page":"98.e1","DOI":"10.1016\/j.ajog.2008.07.063","article-title":"Quantification of cell free fetal DNA in maternal plasma in normal pregnancies and in pregnancies with placental dysfunction","volume":"200","author":"Alberry","year":"2009","journal-title":"Am J Obstet Gynecol"},{"key":"2022112110393940400_CIT0009","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3109\/17482941.2010.513732","article-title":"Cell free DNA detected by a novel method in acute ST-elevation myocardial infarction patients","volume":"12","author":"Shimony","year":"2010","journal-title":"Acute Card Care"},{"key":"2022112110393940400_CIT0010","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1007\/s11239-010-0527-8","article-title":"Levosimendan reduces plasma cell-free DNA levels in patients with ischemic cardiomyopathy","volume":"31","author":"Zaravinos","year":"2011","journal-title":"J Thromb Thrombolysis"},{"key":"2022112110393940400_CIT0011","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.cca.2010.11.036","article-title":"The value of serial plasma nuclear and mitochondrial DNA levels in patients with acute ischemic stroke","volume":"412","author":"Tsai","year":"2011","journal-title":"Clin Chim Acta"},{"key":"2022112110393940400_CIT0012","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/j.cca.2010.05.017","article-title":"Association of cell-free plasma DNA with perioperative mortality in patients with suspected acute mesenteric ischemia","volume":"411","author":"Arnalich","year":"2010","journal-title":"Clin Chim Acta"},{"key":"2022112110393940400_CIT0013","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.cca.2009.09.011","article-title":"Circulating cell-free DNA levels in plasma increase with severity in experimental acute pulmonary thromboembolism","volume":"409","author":"Uzuelli","year":"2009","journal-title":"Clin Chim Acta"},{"key":"2022112110393940400_CIT0014","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1007\/s00408-010-9253-4","article-title":"Quantification of circulating cell-free DNA in the serum of patients with obstructive sleep apnea-hypopnea syndrome","volume":"188","author":"Ye","year":"2010","journal-title":"Lung"},{"key":"2022112110393940400_CIT0015","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1093\/ndt\/gfl439","article-title":"Soluble endoglin (sEng) joins the soluble fms-like tyrosine kinase (sFlt) receptor as a pre-eclampsia molecule","volume":"21","author":"Luft","year":"2006","journal-title":"Nephrol Dial Transplant"},{"key":"2022112110393940400_CIT0016","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.placenta.2008.03.006","article-title":"Circulating and placental endoglin concentrations in pregnancies complicated by intrauterine growth restriction and preeclampsia","volume":"29","author":"Jeyabalan","year":"2008","journal-title":"Placenta"},{"key":"2022112110393940400_CIT0017","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1186\/s13104-015-1506-0","article-title":"Difference of concentration of placental soluble fms-like tyrosine kinase-1(sFlt-1), placental growth factor (PlGF), and sFlt-1\/PlGF ratio in severe preeclampsia and normal pregnancy","volume":"8","author":"Gurnadi","year":"2015","journal-title":"BMC Res Notes"},{"key":"2022112110393940400_CIT0018"},{"key":"2022112110393940400_CIT0019","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/0002-9378(90)90376-I","article-title":"The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing?","volume":"162","author":"Sibai","year":"1990","journal-title":"Am J Obstet Gynecol"},{"key":"2022112110393940400_CIT0020","doi-asserted-by":"crossref","first-page":"2560","DOI":"10.1001\/jama.289.19.2560","article-title":"The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report","volume":"289","author":"Chobanian","year":"2003","journal-title":"JAMA"},{"key":"2022112110393940400_CIT0021","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1373\/clinchem.2006.074997","article-title":"Hypermethylated RASSF1A in maternal plasma: a universal fetal DNA marker that improves the reliability of noninvasive prenatal diagnosis","volume":"52","author":"Chan","year":"2006","journal-title":"Clin Chem"},{"key":"2022112110393940400_CIT0022","doi-asserted-by":"crossref","first-page":"941","DOI":"10.2353\/ajpath.2007.060641","article-title":"Hypermethylation of RASSF1A in human and rhesus placentas","volume":"170","author":"Chiu","year":"2007","journal-title":"Am J Pathol"},{"key":"2022112110393940400_CIT0023","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/S0025-7753(04)75317-8","article-title":"[Clinical and biological characteristics of a group of 54 pregnant women with HELLP syndrome]","volume":"122","author":"Vallejo Maroto","year":"2004","journal-title":"Med Clin (Barc)"},{"key":"2022112110393940400_CIT0024","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1111\/j.1749-6632.2001.tb03873.x","article-title":"Quantitative analysis of fetal DNA in maternal plasma in pathological conditions associated with placental abnormalities","volume":"945","author":"Smid","year":"2001","journal-title":"Ann N Y Acad Sci"},{"key":"2022112110393940400_CIT0025","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1093\/clinchem\/48.4.650","article-title":"Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome as a complication of preeclampsia in pregnant women increases the amount of cell-free fetal and maternal DNA in maternal plasma and serum","volume":"48","author":"Swinkels","year":"2002","journal-title":"Clin Chem"},{"key":"2022112110393940400_CIT0026","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/S1071-55760300155-2","article-title":"Inability to detect cell free fetal DNA in the urine of normal pregnant women nor in those affected by preeclampsia associated HELLP syndrome","volume":"10","author":"Li","year":"2003","journal-title":"J Soc Gynecol Investig"},{"key":"2022112110393940400_CIT0027","first-page":"779","article-title":"Role of VEGF receptor-1 (Flt-1) in mediating calcium-dependent nitric oxide release and limiting DNA synthesis in human trophoblast cells","volume":"76","author":"Ahmed","year":"1997","journal-title":"Lab Invest"},{"key":"2022112110393940400_CIT0028","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1161\/01.RES.0000147365.86159.f5","article-title":"Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia","volume":"95","author":"Ahmad","year":"2004","journal-title":"Circ Res"},{"key":"2022112110393940400_CIT0029","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/nm1429","article-title":"Soluble endoglin contributes to the pathogenesis of preeclampsia","volume":"12","author":"Venkatesha","year":"2006","journal-title":"Nat Med"},{"key":"2022112110393940400_CIT0030","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1161\/ATVBAHA.109.186742","article-title":"Inhibition of VEGF or TGF-{beta} signaling activates endothelium and increases leukocyte rolling","volume":"29","author":"Walshe","year":"2009","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2022112110393940400_CIT0031","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/s00404-015-3823-x","article-title":"Assessment of angiogenesis modulators in pregnant women with pre-eclampsia: a case-control study","volume":"293","author":"Mundim","year":"2016","journal-title":"Arch Gynecol Obstet"},{"key":"2022112110393940400_CIT0032","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1161\/HYPERTENSIONAHA.111.00754","article-title":"Circulating angiogenic factors and urinary prolactin as predictors of adverse outcomes in women with preeclampsia","volume":"61","author":"Lea\u00f1os-Miranda","year":"2013","journal-title":"Hypertension"},{"key":"2022112110393940400_CIT0033","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1002\/pd.3995","article-title":"Can detection of late-onset PE at triage by sflt-1 or PlGF be improved by the use of additional biomarkers?","volume":"32","author":"Kaufmann","year":"2012","journal-title":"Prenat Diagn"},{"key":"2022112110393940400_CIT0034","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1038\/hr.2010.92","article-title":"Circulating angiogenic factors determined by electrochemiluminescence immunoassay in relation to the clinical features and laboratory parameters in women with pre-eclampsia","volume":"33","author":"Molvarec","year":"2010","journal-title":"Hypertens Res"},{"key":"2022112110393940400_CIT0035","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s40291-015-0184-x","article-title":"Circulating maternal total cell-free DNA, cell-free fetal DNA and soluble endoglin levels in preeclampsia: predictors of adverse fetal outcome? A cohort study","volume":"20","author":"AbdelHalim","year":"2016","journal-title":"Mol Diagn Ther"},{"key":"2022112110393940400_CIT0036","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1002\/pd.2065","article-title":"Circulating soluble endoglin and placental abruption","volume":"28","author":"Signore","year":"2008","journal-title":"Prenat Diagn"},{"key":"2022112110393940400_CIT0037","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1002\/pd.1869","article-title":"Failure of second-trimester measurement of soluble endoglin and other angiogenic factors to predict placental abruption","volume":"27","author":"Tikkanen","year":"2007","journal-title":"Prenat Diagn"},{"key":"2022112110393940400_CIT0038","first-page":"49","article-title":"Assesment of plasma cell-free fetal DNA using hypermethylated RASSF1A in maternal plasma in cases of spontaneous preterm labor","volume":"12","author":"Bibers","year":"2013","journal-title":"Gynecol Obstet"},{"key":"2022112110393940400_CIT0039","first-page":"274","article-title":"Fetal fraction of cell-free DNA in maternal plasma in the prediction of spontaneous preterm delivery","volume":"34","author":"Quezada","year":"2014","journal-title":"Ultrasound Obstet Gynecol"},{"key":"2022112110393940400_CIT0040","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1002\/pd.1645","article-title":"Free fetal DNA is not increased before 20 weeks in intrauterine growth restriction or pre-eclampsia","volume":"27","author":"Crowley","year":"2007","journal-title":"Prenat Diagn"},{"key":"2022112110393940400_CIT0041","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1002\/pd.2372","article-title":"Increased free fetal DNA levels in early pregnancy plasma of women who subsequently develop preeclampsia and intrauterine growth restriction","volume":"29","author":"Illanes","year":"2009","journal-title":"Prenat Diagn"},{"key":"2022112110393940400_CIT0042","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"}],"container-title":["American Journal of Hypertension"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajh\/article-pdf\/30\/7\/673\/47160395\/ajh_30_7_673.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajh\/article-pdf\/30\/7\/673\/47160395\/ajh_30_7_673.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T10:40:27Z","timestamp":1669027227000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajh\/article\/30\/7\/673\/3052750"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,2,25]]},"references-count":42,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2017,2,25]]},"published-print":{"date-parts":[[2017,7,1]]}},"URL":"https:\/\/doi.org\/10.1093\/ajh\/hpx024","relation":{},"ISSN":["0895-7061","1941-7225"],"issn-type":[{"value":"0895-7061","type":"print"},{"value":"1941-7225","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,7]]},"published":{"date-parts":[[2017,2,25]]}}}