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In this study, our aim was to investigate the profile of maternal angiogenic factors across severity stages of fetal smallness compared with controls, analyzed overall and stratified by the presence or absence of pre\u2010eclampsia, and to investigate whether values of these angiogenic factors, such as placental growth factor (PlGF), soluble fms\u2010like tyrosine kinase\u20101 (sFlt\u20101) and the sFlt\u20101\/PlGF ratio, are helpful in determining the severity stage of fetal smallness.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n This was a prospective cohort study of women with a singleton pregnancy diagnosed with fetal smallness (defined as birth weight <\u200910\n th<\/jats:sup>\n \u2009centile) (\n n<\/jats:italic>\n \u2009=\u2009604) between October 2010 and December 2017, compared with a control group of pregnant women with an appropriate\u2010for\u2010gestational\u2010age (AGA) singleton fetus (defined as birth weight \u2265\u200910\n th<\/jats:sup>\n \u2009centile) (\n n<\/jats:italic>\n \u2009=\u2009424). At diagnosis, ultrasound was performed to assess estimated fetal weight (EFW) and Doppler pulsatility indices (PI) of the uterine artery (UtA), umbilical artery (UA), fetal middle cerebral artery (MCA) and ductus venosus (DV), and these parameters were monitored regularly until delivery. Cerebroplacental ratio (CPR) was calculated as MCA\u2010PI\/UA\u2010PI. Small fetuses were classified as: small\u2010for\u2010gestational age (SGA) if EFW \u2265\u20093\n rd<\/jats:sup>\n and <\u200910\n th<\/jats:sup>\n \u2009centile, with normal Doppler parameters; FGR Stage\u2009I if either EFW <\u20093\n rd<\/jats:sup>\n \u2009centile, persistent MCA\u2010PI <\u20095\n th<\/jats:sup>\n \u2009centile, UA\u2010PI >\u200995\n th<\/jats:sup>\n \u2009centile, CPR <\u20095\n th<\/jats:sup>\n \u2009centile or UtA\u2010PI >\u200995\n th<\/jats:sup>\n \u2009centile; FGR Stage\u2009II if there was absent end\u2010diastolic flow in the UA; FGR Stage\u2009III if there was reversed end\u2010diastolic flow in the UA or DV\u2010PI \u2265\u200995\n th<\/jats:sup>\n \u2009centile; or FGR Stage\u2009IV if there was non\u2010reassuring cardiotocography or absent\/reversed DV atrial flow. Maternal peripheral venous blood concentrations of PlGF and sFlt\u20101 were determined using enzyme\u2010linked immunosorbent assay, and the sFlt\u20101\/PlGF ratio was calculated. Linear trend\u00a0of proportions was tested using the Mantel\u2013Haenszel chi\u2010square test.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among AGA controls (\n n<\/jats:italic>\n \u2009=\u2009424), SGA (\n n<\/jats:italic>\n \u2009=\u2009192), FGR Stage\u2009I (\n n<\/jats:italic>\n \u2009=\u2009380), FGR Stage\u2009II (\n n<\/jats:italic>\n \u2009=\u200916) and FGR Stages\u2009III\u2013IV (\n n<\/jats:italic>\n \u2009=\u200916) fetuses, the proportion of cases with a sFlt\u20101\/PlGF ratio >\u200995\n th<\/jats:sup>\n \u2009centile was 12.7%, 7.8%, 30.8%, 43.8% and 62.5%, respectively (\n P<\/jats:italic>\n \u2009=\u20090.0001), and the median multiples of the median (MoM) values for the sFlt\u20101\/PlGF ratio were 0.55 (interquartile range (IQR), 0.19\u20132.00), 1.00 (IQR, 0.31\u20132.67), 3.03 (IQR, 0.91\u20138.20), 3.94 (IQR, 0.85\u20139.13) and 7.32 (IQR, 1.44\u201316.29), respectively (\n P<\/jats:italic>\n \u2009=\u20090.24). Pre\u2010eclampsia was diagnosed at any time between inclusion and delivery in 1.9% of controls, 3.6% of SGA, 21.1% of FGR Stage\u2009I, 37.5% of FGR Stage\u2009II and 50.0% of FGR Stages\u2009III\u2013IV fetuses. Among all small fetuses with\n vs<\/jats:italic>\n without pre\u2010eclampsia, the proportion of pregnancies with sFlt\u20101\/PlGF ratio >\u200995\n th<\/jats:sup>\n \u2009centile was 56.9% vs 15.4% (\n P<\/jats:italic>\n \u2009<\u20090.001) and the median MoM of the sFlt\u20101\/PlGF ratio was 8.11 (IQR, 3.83\u201327.09)\n vs<\/jats:italic>\n 1.59 (IQR, 0.52\u20135.04) (\n P<\/jats:italic>\n \u2009=\u20090.18).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Serum levels of angiogenic factors became more abnormal as the severity stage of fetal smallness increased. This association with severity was stronger in the presence of pre\u2010eclampsia. However, absolute values of serum levels showed substantial overlap in both the presence and the absence of pre\u2010eclampsia, making their use in determining the severity stage of fetal smallness challenging. \u00a9 2026 International Society of Ultrasound in Obstetrics and Gynecology.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/uog.70156","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T21:48:20Z","timestamp":1767908900000},"page":"147-154","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Angiogenic factor levels across severity stages of fetal smallness with or without associated pre\u2010eclampsia"],"prefix":"10.1002","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0554-5507","authenticated-orcid":false,"given":"L.","family":"Youssef","sequence":"first","affiliation":[{"name":"BCNatal, Barcelona Center for Maternal Fetal and Neonatal Medicine, Hospital Cl\u00ednic and Hospital Sant Joan de D\u00e9u, IDIBAPS 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":"S.","family":"Paolucci","sequence":"additional","affiliation":[{"name":"BCNatal, Barcelona Center for Maternal Fetal and Neonatal Medicine, Hospital Cl\u00ednic and Hospital Sant Joan de D\u00e9u, IDIBAPS University of Barcelona Barcelona Spain"},{"name":"Department of Obstetrics and Gynecology, Ospedale Filippo Del Ponte University of Insubria Varese Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0140-7411","authenticated-orcid":false,"given":"F.","family":"Crovetto","sequence":"additional","affiliation":[{"name":"BCNatal, Barcelona Center for Maternal Fetal and Neonatal Medicine, Hospital Cl\u00ednic and Hospital Sant Joan de D\u00e9u, IDIBAPS University 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