Angiogenic factor levels across severity stages of fetal smallness with or without associated pre-eclampsia
Por:
Youssef L, Paolucci S, Crovetto F, Miranda J, Lobmaier S, Figueras-Retuerta F, Crispi F and Gratacós E
Publicada:
1 feb 2026
Ahead of Print:
1 ene 2026
Resumen:
Objective Angiogenic factors are elevated in fetal growth restriction (FGR), but their clinical value for assessing the severity of FGR and the potential influence of coexisting pre-eclampsia has scarcely been investigated. 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-eclampsia, and to investigate whether values of these angiogenic factors, such as placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and the sFlt-1/PlGF ratio, are helpful in determining the severity stage of fetal smallness. Methods This was a prospective cohort study of women with a singleton pregnancy diagnosed with fetal smallness (defined as birth weight < 10th centile) (n = 604) between October 2010 and December 2017, compared with a control group of pregnant women with an appropriate-for-gestational-age (AGA) singleton fetus (defined as birth weight >= 10th centile) (n = 424). 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-PI/UA-PI. Small fetuses were classified as: small-for-gestational age (SGA) if EFW >= 3rd and < 10th centile, with normal Doppler parameters; FGR Stage I if either EFW < 3rd centile, persistent MCA-PI < 5th centile, UA-PI > 95th centile, CPR < 5th centile or UtA-PI > 95th centile; FGR Stage II if there was absent end-diastolic flow in the UA; FGR Stage III if there was reversed end-diastolic flow in the UA or DV-PI >= 95th centile; or FGR Stage IV if there was non-reassuring cardiotocography or absent/reversed DV atrial flow. Maternal peripheral venous blood concentrations of PlGF and sFlt-1 were determined using enzyme-linked immunosorbent assay, and the sFlt-1/PlGF ratio was calculated. Linear trend of proportions was tested using the Mantel-Haenszel chi-square test. Results Among AGA controls (n = 424), SGA (n = 192), FGR Stage I (n = 380), FGR Stage II (n = 16) and FGR Stages III-IV (n = 16) fetuses, the proportion of cases with a sFlt-1/PlGF ratio > 95th centile was 12.7%, 7.8%, 30.8%, 43.8% and 62.5%, respectively (P = 0.0001), and the median multiples of the median (MoM) values for the sFlt-1/PlGF ratio were 0.55 (interquartile range (IQR), 0.19-2.00), 1.00 (IQR, 0.31-2.67), 3.03 (IQR, 0.91-8.20), 3.94 (IQR, 0.85-9.13) and 7.32 (IQR, 1.44-16.29), respectively (P = 0.24). Pre-eclampsia was diagnosed at any time between inclusion and delivery in 1.9% of controls, 3.6% of SGA, 21.1% of FGR Stage I, 37.5% of FGR Stage II and 50.0% of FGR Stages III-IV fetuses. Among all small fetuses with vs without pre-eclampsia, the proportion of pregnancies with sFlt-1/PlGF ratio > 95th centile was 56.9% vs 15.4% (P < 0.001) and the median MoM of the sFlt-1/PlGF ratio was 8.11 (IQR, 3.83-27.09) vs 1.59 (IQR, 0.52-5.04) (P = 0.18). Conclusions 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-eclampsia. However, absolute values of serum levels showed substantial overlap in both the presence and the absence of pre-eclampsia, making their use in determining the severity stage of fetal smallness challenging.
(c) 2026 International Society of Ultrasound in Obstetrics and Gynecology.
Filiaciones:
:
BCNatal, Barcelona Center for Maternal Fetal and Neonatal Medicine, Hospital Clínic and Hospital Sant Joan de Déu, IDIBAPS, University of Barcelona, Barcelona, Spain
Josep Carreras Leukaemia Research Institute, Hospital Clinic, University of Barcelona Campus, Barcelona, Spain
Paolucci S:
BCNatal, Barcelona Center for Maternal Fetal and Neonatal Medicine, Hospital Clínic and Hospital Sant Joan de Déu, IDIBAPS, University of Barcelona, Barcelona, Spain
Department of Obstetrics and Gynecology, Ospedale Filippo Del Ponte, University of Insubria, Varese, Italy
Crovetto F:
BCNatal, Barcelona Center for Maternal Fetal and Neonatal Medicine, Hospital Clínic and Hospital Sant Joan de Déu, IDIBAPS, University of Barcelona, Barcelona, Spain
Institut de Recerca Sant Joan de Déu (IRSJD), Fundació Sant Joan de Déu, Barcelona, Spain
:
BCNatal, Barcelona Center for Maternal Fetal and Neonatal Medicine, Hospital Clínic and Hospital Sant Joan de Déu, IDIBAPS, University of Barcelona, Barcelona, Spain
Department of Obstetrics and Gynecology, Faculty of Medicine, Grupo de Investigación en Cuidado Intensivo y Obstetricia (GRICIO), Universidad de Cartagena, Cartagena, Colombia
Department of Obstetrics and Gynecology, Centro Hospitalario Serena del Mar and Fundación Santa Fe de Bogotá, Bogotá, Colombia
Lobmaier S:
Technical University of Munich, Munich, Germany
TUM School of Medicine, Department Obstetrics and Gynecology, Munich, Germany
Figueras-Retuerta F:
BCNatal, Barcelona Center for Maternal Fetal and Neonatal Medicine, Hospital Clínic and Hospital Sant Joan de Déu, IDIBAPS, University of Barcelona, Barcelona, Spain
Crispi F:
BCNatal, Barcelona Center for Maternal Fetal and Neonatal Medicine, Hospital Clínic and Hospital Sant Joan de Déu, IDIBAPS, University of Barcelona, Barcelona, Spain
Centre for Biomedical Research on Rare Diseases (CIBER-ER), Madrid, Spain
Gratacós E:
BCNatal, Barcelona Center for Maternal Fetal and Neonatal Medicine, Hospital Clínic and Hospital Sant Joan de Déu, IDIBAPS, University of Barcelona, Barcelona, Spain
Institut de Recerca Sant Joan de Déu (IRSJD), Fundació Sant Joan de Déu, Barcelona, Spain
Centre for Biomedical Research on Rare Diseases (CIBER-ER), Madrid, Spain
Univ Barcelona, Hosp Clin, Barcelona Ctr Maternal Fetal & Neonatal Med,
BCNatal, Barcelona, Spain
Univ Barcelona, Hosp St Joan Deu, IDIBAPS, Barcelona, Spain
Univ Barcelona Campus, Hosp Clin, Josep Carreras Leukaemia Res Inst,
Barcelona, Spain
Univ Insubria, Osped Filippo Ponte, Dept Obstet & Gynecol, Varese, Italy
Fundacio St Joan Deu, Inst Recerca St Joan Deu IRSJD, Barcelona, Spain
Univ Cartagena, Grp Invest Cuidado Intens & Obstet GRICIO, Fac Med, Dept
Obstet & Gynecol, Cartagena, Colombia
Ctr Hosp Serena Mar, Dept Obstet & Gynecol, Bogota, Colombia
Fdn Santa Fe Bogota, Bogota, Colombia
Tech Univ Munich, Munich, Germany
TUM Sch Med, Dept Obstet & Gynecol, Munich, Germany
Ctr Biomed Res Rare Dis CIBER ER, Madrid, Spain
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