Circulating EGFL7 distinguishes between IUGR and PE: an observational case\u2013control study

Micol Massimiani,Heidi Stuhlmann,Herbert Valensise,Silvia Salvi,Antonio Lanzone,Luisa Campagnolo,Grazia M Tiralongo,Sascia Moresi

doi:10.1038/s41598-021-97482-2

Abstract

Isolated intrauterine growth restriction (IUGR) and preeclampsia (PE) share common placental pathogenesis. Differently from IUGR, PE is a systemic disorder which may also affect liver and brain. Early diagnosis of these conditions may optimize maternal and fetal management. Aim of this study was to assess whether Epidermal Growth Factor-Like domain 7 (EGFL7) dosage in maternal blood discriminates between isolated IUGR and PE. A total of 116 women were enrolled in this case–control study: 12 non-pregnant women, 34 healthy pregnant women, 34 women presenting with isolated IUGR and 36 presenting with PE. Levels of circulating EGFL7 and other known pro- and anti-angiogenic factors were measured by ELISA at different gestational ages (GA). Between 22–25 weeks of gestation, EGFL7 levels in early-onset PE (e-PE) plasma samples were significantly higher than those measured in controls or isolated IUGR samples (69.86 ± 6.17 vs. 19.8 ± 2.5 or 18.8 ± 2.8 µg/ml, respectively). Between 26–34 weeks, EGFL7 levels remained significantly higher in e-PE compared to IUGR. At term, circulating and placental EGFL7 levels were comparable between IUGR and late-onset PE (l-PE). In contrast, circulating levels of PlGF were decreased in both IUGR- and PE- complicated pregnancies, while levels of both sFLT-1 and sENDOGLIN were increased in both conditions. In conclusion, EGFL7 significantly discriminates between isolated IUGR and PE.

Highlights

Isolated intrauterine growth restriction (IUGR) and preeclampsia (PE) share common placental pathogenesis
By principal component analysis (PCA), we demonstrated that Epidermal Growth Factor-Like domain 7 (EGFL7) distributes as a separate factor with respect to the three well-known angiogenic factors Placental Growth Factor (PlGF), soluble fms-like tyrosine kinase 1 and soluble Endoglin, indicating that it may represent an additional independent diagnostic marker of P E24
We show that maternal circulating levels of EGFL7, a secreted protein whose function is crucial for proper placental development, are increased in PE, but not in isolated IUGR21,29,30

Summary

Introduction

Isolated intrauterine growth restriction (IUGR) and preeclampsia (PE) share common placental pathogenesis. Aim of this study was to assess whether Epidermal Growth Factor-Like domain 7 (EGFL7) dosage in maternal blood discriminates between isolated IUGR and PE. Between 22–25 weeks of gestation, EGFL7 levels in early-onset PE (e-PE) plasma samples were significantly higher than those measured in controls or isolated IUGR samples (69.86 ± 6.17 vs 19.8 ± 2.5 or 18.8 ± 2.8 μg/ml, respectively). We have previously demonstrated that EGFL7 is expressed in human placental villi by endothelial cells, as well as by cytotrophoblast and syncytiotrophoblast cells, and that it regulates trophoblast migration and invasion[21,22], suggesting a potential involvement in placental development. In pregnant women affected by PE placental levels of EGFL7 are down-regulated[21,25], whereas its levels are significantly increased in the maternal circulation at term (i.e., 35–40 weeks of gestation)[24]. By principal component analysis (PCA), we demonstrated that EGFL7 distributes as a separate factor with respect to the three well-known angiogenic factors Placental Growth Factor (PlGF), soluble fms-like tyrosine kinase 1 (sFLT-1) and soluble Endoglin (sENDOGLIN), indicating that it may represent an additional independent diagnostic marker of P E24

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