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; (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 < 0.001 and 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); (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. Although 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.

Figure 1

Plasma concentrations of sVEGFR-2 in normal pregnant women and patients with fetal death. Women with fetal death had a significantly lower median plasma concentration of sVEGFR-2 than normal pregnant women (median 8.8 ng/ml, range 3.4–13.6 ng/ml vs. median 10.6 ng/ml, range 3.4–24.7 ng/ml; respectively; p<0.001).* p<0.05

Figure 2

Plasma concentrations of sVEGFR-2 in normal pregnant women, unexplained fetal death, fetal death with preeclampsia and/or placental abruption, and fetal death with chromosomal or congenital anomalies. The median plasma concentration of sVEGFR-2 in unexplained fetal death was lower than that of the normal pregnancy group (median 8.9 ng/ml, range 5.9–13.6 ng/ml vs. median 10.6 ng/ml, range 3.4–24.7 ng/ml; respectively; p=0.006), but higher than that of fetal death with preeclampsia and/or placental abruption (median 6.1 ng/ml, range 3.4–12.4 ng/ml; p=0.001). There was no significant difference in the median plasma sVEGFR-2 concentration between women with a fetal death with major chromosomal and/or congenital anomalies (median 10.1 ng/ml, range 6.4–12.1 ng/ml) and those with a normal pregnancy (median 10.6 ng/ml, range 3.4–24.7 ng/ml; p=0.2). * p<0.05

Figure 3

Plasma concentrations of sVEGFR-2 in normal pregnant women at preterm gestation and unexplained preterm fetal death. Unexplained preterm fetal death had a significantly lower median plasma sVEGFR-2 concentration than normal pregnant women at preterm gestation (median 8.9 ng/ml, range 5.9–13.6 ng/ml vs. median 12.8 ng/ml, range 5.9–24.7 ng/ml; respectively; p<0.001). * p<0.05

Figure 4

Plasma concentrations of sVEGFR-2 in normal pregnant women at term gestation and unexplained term fetal death. There was no significant difference in the median plasma concentration of sVEGFR-2 between patients with unexplained fetal death at term and women at term without labor (median 8.8 ng/ml, range 6.5–11.6 ng/ml vs. median 9.3 ng/ml, range 3.4–20.2 ng/ml; respectively; p=0.7).

Figure 5

Amniotic fluid concentrations of sVEGFR-2 in patients with fetal death and women in the control group. The median amniotic fluid concentration of sVEGFR-2 was significantly higher in women with a fetal death than that of women in the control group (median 2.6 ng/ml, range 0.3–8.1 ng/ml vs. median 0.6 ng/ml, range 0–9.3 ng/ml; respectively; p<0.001). Two patients in the control group had amniotic fluid concentrations of sVEGFR-2 below the limit of detection (LOD). * p<0.05

Figure 6

Amniotic fluid concentrations of sVEGFR-2 in the control group, unexplained fetal death, fetal death with preeclampsia and/or placental abruption, and fetal death with chromosomal or congenital anomalies. Women with unexplained fetal death (median 2.4 ng/ml, range 0.4–8.1 ng/ml), those with fetal death with preeclampsia and/or placental abruption (median 2.1 ng/ml, range 0.5–5.8 ng/ml), and those with fetal death and major chromosomal/congenital anomalies (median 2.8 ng/ml, range 0.3–6.3 ng/ml) had a significantly higher median amniotic fluid concentration of sVEGFR-2 than women in the control group (median 0.6 ng/ml, range 0–9.3 ng/ml; p<0.001, p=0.03 and p=0.005; respectively; see Figure 6). Two patients in the control group had amniotic fluid concentrations of sVEGFR-2 below the limit of detection (LOD). * p<0.05

Figure 7

Amniotic fluid concentrations of sVEGFR-2 of women in the control group and those with unexplained fetal death at preterm gestation. Unexplained preterm fetal death had a significantly higher median amniotic fluid sVEGFR-2 concentration than the control group (median 2.6 ng/ml, range 0.4–8.1 ng/ml vs. median 0.6 ng/ml, range 0–3.7 ng/ml; respectively; p<0.001). Two patients in the control group had amniotic fluid concentrations of sVEGFR-2 below the limit of detection (LOD). * p<0.05

Figure 8

Amniotic fluid concentrations of sVEGFR-2 in the control group and those with unexplained fetal death at term gestation. There was no significant difference in the median amniotic fluid concentration of sVEGFR2 in patients with unexplained fetal death at term and women at term without labor (median 0.5 ng/ml, range 0.4–3.0 ng/ml vs. median 0.5 ng/ml, range 0.1–9.3 ng/ml; respectively; p=0.2).