Angiogenic imbalance in pre‐eclampsia and fetal growth restriction: enhanced soluble fms‐like tyrosine kinase‐1 binding or diminished production of placental growth factor?

Objectives: To assess levels of total placental growth factor (PlGF), soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and free PlGF in women with pre‐eclampsia (PE) with or without a small‐for‐gestational‐age (SGA) neonate in order to establish whether low free PlGF levels associated with PE and SGA are due to enhanced sFlt‐1 binding or decreased PlGF production. Methods: This was a secondary analysis of a prospective multicenter cohort study involving 407 pregnancies with suspected or confirmed PE, in which total PlGF levels were calculated from measured sFlt‐1 and free PlGF levels. The control group included women who were suspected to have PE at a certain point in pregnancy but did not develop PE. The analysis was stratified according to whether PE was early‐ or late‐onset (gestational age < 34 weeks vs ≥ 34 weeks) and according to the presence of SGA at birth, which was used as a proxy of fetal growth restriction in the absence of Doppler ultrasound and biometric data. Results: In early‐onset PE, both women with and those without SGA had lower free (19 and 45 pg/mL) and total (44 and 100 pg/mL) PlGF levels compared with women without PE (free and total PlGF, 300 and 381 pg/mL, respectively). SGA alone did not affect free and total PlGF in this condition (free and total PlGF, 264 and 352 pg/mL, respectively). Observations in women with late‐onset PE were similar, although the changes were more modest. Both SGA (gestational age < 34 weeks) and PE were individually associated with increased sFlt‐1 and, in women with both PE and SGA, the upregulation of sFlt‐1 occurred in a synergistic manner, thus resulting in the highest sFlt‐1/free PlGF ratio in this group. This occurred in both early‐ and late‐onset PE. Conclusions: Particularly in pregnancies with early‐onset PE and SGA, diminished PlGF production is an important cause of low free PlGF levels. Under such conditions, sFlt‐1 lowering is unlikely to restore the angiogenic balance. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]