Fetal death: A condition with a dissociation in the concentrations of soluble vascular endothelial growth factor receptor-2 between the maternal and fetal compartments

Abstract

OBJECTIVE An anti-angiogenic state has been implicated in the pathophysiology of preeclampsia, fetal growth restriction and fetal death. Vascular endothelial growth factor (VEGF), an indispensible angiogenic factor for embryonic and placental development exerts its angiogenic properties through the VEGF receptor (VEGFR)-2. A soluble form of this protein (sVEGFR-2) has been recently detected in maternal blood. The aim of this study was to determine if fetal death was associated with changes in the concentrations of sVEGFR-2 in maternal plasma and amniotic fluid. STUDY DESIGN Maternal plasma was obtained from patients with fetal death (n=59) and normal pregnant women (n=134). Amniotic fluid was collected from 36 patients with fetal death and the control group consisting of patients who had an amniocentesis and delivered at term (n=160). Patients with fetal death were classified according to the clinical circumstances into the following groups: 1) unexplained; 2) preeclampsia and/or placental abruption; and 3) chromosomal and/or congenital anomalies. Plasma and amniotic fluid concentrations of sVEGFR-2 were determined by ELISA. Non-parametric statistics and logistic regression analysis were applied. RESULTS 1) Patients with a fetal death had a significantly lower median plasma concentration of sVEGFR-2 than normal pregnant women (p<0.001). The median plasma concentration of sVEGFR-2 in patients with unexplained fetal death and in those with preeclampsia/abruption, but not that of those with congenital anomalies, was lower than that of normal pregnant women (p=0.006, p<0.001and p=0.2 respectively); 2) the association between plasma sVEGFR-2 concentrations and preterm unexplained fetal death remained significant after adjusting for potential confounders (OR 3.2; 95% CI 1.4–7.3 per each quartile decrease in plasma sVEGFR-2 concentrations); 3) each subgroup of fetal death had a higher median amniotic fluid concentration of sVEGFR-2 than the control group (p<0.001 for each); 4) the association between amniotic fluid sVEGFR-2 concentrations and preterm unexplained fetal death remained significant after adjusting for potential confounders (OR 15.6; 95% CI 1.5–164.2 per each quartile increase in amniotic fluid sVEGFR-2 concentrations); and 5) among women with fetal death, there was no relationship between maternal plasma and amniotic fluid concentrations of sVEGFR-2 (Spearman Rho: 0.02; p=0.9). CONCLUSION Pregnancies with a fetal death, at the time of diagnosis, are characterized by a decrease in the maternal plasma concentration of sVEGFR-2, but an increase in the amniotic fluid concentration of this protein. While a decrease in sVEGFR-2 concentration in maternal circulation depends upon the clinical circumstances of fetal death, an increase in sVEGFR-2 concentration in amniotic fluid seems to be a common feature of fetal death. It remains to be determined if the perturbation in sVEGFR-2 concentrations in maternal and fetal compartments observed herein preceded the death of a fetus.

Maternal plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in patients presenting to the obstetrical triage area with the suspicion of preeclampsia

“…We have demonstrated that an imbalance of angiogenic/anti-angiogenic factor concentrations is not a unique characteristic of patients with PE since this perturbation can occur in isolated fetal growth restriction with abnormal uterine artery Doppler velocimetry [96], unexplained fetal death [160–163], twin-to-twin transfusion syndrome [164] and viral-induced hydrops fetalis [165,166] or Ballantynes syndrome [167]. Moreover, a subset of patients with spontaneous preterm labor with intact membranes also had an abnormal angiogenic/anti-angiogenic profile in maternal circulation prior to the diagnosis of preterm labor/delivery [168].…”

Placental bed disorders in preterm labor, preterm PROM, spontaneous abortion and abruptio placentae

“…In early pregnancy, a severe anti-angiogenic state is likely to lead to fetal death. 98–100 Why continue to invest maternal resources when there is not enough of an angiogenic drive to maintain the placenta and fetus? In milder cases of uteroplacental ischemia, isolated small-for-gestational-age fetus (SGA), SGA plus hypertension or late preterm labor could provide a solution.…”

Maternal plasma concentrations of angiogenic/antiangiogenic factors in the third trimester of pregnancy to identify the patient at risk for stillbirth at or near term and severe late preeclampsia

“…An imbalance of angiogenic/anti-angiogenic factors has been implicated in the pathophysiology of PE, 67–88 pregnancies with SGA neonates, 89–92 stillbirth, 93–95 and other obstetrical complications. 96–102 Changes in the concentrations of the angiogenic factor, placental growth factor (PlGF), and anti-angiogenic factors, soluble vascular endothelial growth factor receptor (sVEGFR)-1 [also known as soluble fms-like tyrosine kinase-1 (sflt-1)] and soluble endoglin (sEng) in maternal circulation, precede the clinical diagnosis of PE, 103–109 SGA 90,91 and stillbirth.…”