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

In patients with pre-eclampsia (PE) and fetal growth restriction (FGR), soluble Fms-like tyrosine kinase-1 (sFlt-1) is increased, while free placental growth factor (PlGF) is decreased, either due to sFlt-1 binding or decreased PlGF production.To distinguish increased sFlt-1 binding and decreased PlGF production, we calculated total PlGF from measured sFlt-1 and free PlGF in a prospective cohort study involving 407 pregnancies with suspected or confirmed PE, making a distinction between both early- and late-onset PE (gestational age <34 weeks vs. ≥34 weeks) and the presence or absence of a small for gestational age (SGA, to approximate FGR in the absence of biometry Doppler ultrasound) neonate.In early-onset PE, both women with and without SGA show lower free (19 and 45 pg/mL) and total PlGF levels (44 and 100 pg/mL) compared to 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 absolute changes were much more modest. Both SGA and PE individually increased sFlt-1, and in combination synergistically upregulated sFlt-1, thus resulting in the highest sFlt-1/free PlGF ratios in women with PE plus SGA. This occurred identically in early- and late-onset PE.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 imbalance. This article is protected by copyright. All rights reserved.