The maternal plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated in SGA and the magnitude of the increase relates to Doppler abnormalities in the maternal and fetal circulation

Abstract

Objectives: The soluble form of vascular endothelial growth factor receptor-1 (sVEGFR-1), an antagonist to vascular endothelial growth factor and placental growth factor, has been implicated in the pathophysiology of preeclampsia. Preeclampsia and pregnancy complicated with small for gestational age (SGA) fetuses share some pathophysiologic derangements, such as failure of physiologic transformation of the spiral arteries, endothelial cell dysfunction, and leukocyte activation. The objectives of this study were to: (1) determine whether plasma concentrations of sVEGFR-1 in mothers with SGA fetuses without preeclampsia at the time of diagnosis are different from those in patients with preeclampsia or normal pregnant women, and (2) examine the relationship between plasma concentrations of sVEGFR-1 and Doppler velocimetry in uterine and umbilical arteries in patients with preeclampsia and those with SGA.

Study design: A cross-sectional study was conducted to determine the concentrations of the soluble form of VEGFR-1 in plasma obtained from normal pregnant women (n = 135), women with SGA fetuses (n = 53), and patients with preeclampsia (n = 112). Patients with SGA fetuses and those with preeclampsia were sub-classified according to the results of uterine and umbilical artery Doppler velocimetry examinations. Plasma concentrations of sVEGFR-1 were determined by an ELISA. Since these concentrations change with gestational age, differences among various subgroups were statistically estimated with the delta value, defined as the difference between the observed and expected plasma sVEGFR-1 concentration. The expected values were derived from regression analysis of plasma sVEGFR-1 concentrations in normal pregnancy. Regression analysis and univariate and multivariate analysis were employed.

Results: (1) Mothers with SGA fetuses had a mean plasma concentration of sVEGFR-1 higher than normal pregnant women (p < 0.001), but lower than patients with preeclampsia (p < 0.001). (2) Among patients with SGA fetuses, only those with abnormal uterine artery Doppler velocimetry had a mean plasma sVEGFR-1 concentration significantly higher than normal pregnant women (p < 0.001). (3) Among mothers with SGA fetuses in whom Doppler velocimetry was performed (n = 41), those with abnormalities in both the uterine and umbilical artery velocimetry had the highest mean delta of sVEGFR-1 plasma concentration (mean +/- standard deviation (SD): 0.69 +/- 0.29). Conversely, patients who had normal Doppler velocimetry in both uterine and umbilical arteries had the lowest mean delta (mean +/- SD: 0.09 +/- 0.29) of sVEGFR-1 plasma concentrations (ANOVA; p < 0.001). (4) Among patients with preeclampsia in whom Doppler velocimetry was performed (n = 69), those with abnormalities in both the uterine and umbilical artery velocimetry had the highest mean delta sVEGFR-1 plasma concentration (mean +/- SD: 1.01 +/- 0.22) among all groups classified (ANOVA; p < 0.001). (5) Among patients with SGA and those with preeclampsia, there was a relationship (Chi-square for trend p < 0.001 for both) between the severity of Doppler velocimetry abnormalities and the proportion of patients who had high delta sVEGFR-1 plasma concentrations (defined as a concentration two standard deviations (2SD) above the mean delta of normal pregnant women). (6) Multiple regression analysis suggested that the diagnostic category (e.g., SGA or preeclampsia), Doppler abnormalities, and gestational age at blood sampling were associated with an increase in plasma sVEGFR-1 concentrations (p < 0.001).

Conclusions: These observations provide support for the participation of the soluble receptor of vascular endothelial growth factor in the pathophysiology of SGA with abnormal uterine artery Doppler velocimetry and preeclampsia. An excess of sVEGFR-1 is released into the maternal circulation of patients with preeclampsia and those with SGA fetuses, as abnormalities of impedance to blood flow involve uterine and umbilical circulation.

Figure 1.

Plasma sVEGFR-1 concentrations of normal pregnant women increased as a function of gestational age according to the equation: log (sVEGFR-1 + 1) = 0.026 (gestational age in weeks) + 2.172 (r² = 0.34; p < 0.001).

Figure 2.

The mean plasma sVEGFR-1 concentrations of normal pregnant women, patients with SGA, and those with preeclampsia. Patients with preeclampsia (mean ± SD: 7,958 ± 9,170 pg/mL) and those with SGA (mean ± SD: 3,603 ± 6,740 pg/mL) had a higher mean plasma concentrations of sVEGFR-1 than normal pregnant women (mean ± SD: 1,445 ± 865 pg/mL; p < 0.001 for both). However, patients with preeclampsia had a higher mean plasma sVEGFR-1 concentration than those with SGA (p < 0.001). The comparisons were performed after logarithmic transformation (log sVEGFR-1 + 1). The statistical test used was ANOVA with Bonferroni correction for multiple comparisons. The vertical axis in the figure is in the logarithmic scale. *p < 0.05.

Figure 3.

The mean plasma sVEGFR-1 concentrations of normal pregnant women and patients with SGA who had normal uterine artery Doppler velocimetry and those who had abnormal uterine artery Doppler velocimetry. Patients with abnormal uterine artery Dopplervelocimetry (mean ± SD: 5359 ± 9945 pg/mL) had a higher mean plasma sVEGFR-1 concentration than those with normal uterine artery Doppler (mean ± SD: 2100 ± 1540 pg/mL) and normal pregnant women (mean ± SD: 1445 ± 865 pg/mL; p = 0.04 and p < 0.001, respectively). In contrast, there was no significant difference in the mean delta plasma sVEGFR-1 concentration between patients with SGA who had normal uterine artery Doppler and normal pregnant women (p = 0.09). The comparisons were performed after logarithmic transformation (log sVEGFR-1 + 1). The statistical test used was ANOVA with post hoc Dunnett’s T3. The vertical axis in the figure is in the logarithmic scale. *p < 0.05.

Figure 4.

The mean delta plasma concentrations of normal pregnant women and patients with SGA fetuses (n=41) sub-classified according to the results of uterine and umbilical artery Doppler velocimetry. Patients with SGA fetuses who had abnormalities in both the uterine and umbilical artery Doppler velocimetry had the highest mean delta plasma sVEGFR-1 concentration (mean ± SD: 0.69 ± 0.29) among all groups. Patients who had normal Doppler velocimetry in both uterine and umbilical arteries had the lowest mean delta plasma sVEGFR-1 concentration (mean ± SD: 0.09 ± 0.29; ANOVA; p < 0.001). Patients with abnormal uterine, but normal umbilical artery, Doppler had a mean delta plasma sVEGFR-1 concentration higher than normal pregnant women (mean ± SD: 0.31 ± 0.52 vs. mean±SD: 0.01 ± 0.21). However, the difference did not reach statistical significance (p = 0.4; ANOVA post hoc Dunnett’s T3). The means ± SD of plasma sVEGF-R1 concentrations in each group are displayed in the figure. *p < 0.05.

Figure 5.

The mean delta plasma concentrations of normal pregnant women and patients with preeclampsia (n=69) sub-classified according to the results of uterine and umbilical artery Doppler velocimetry. Patients with preeclampsia who had abnormalities in both the uterine and umbilical artery Doppler velocimetry had the highest mean delta plasma sVEGFR-1 concentration (mean ± SD: 1.01 ± 0.22) among all groups. Patients who had normal Doppler velocimetry in both uterine and umbilical arteries had the lowest mean delta plasma sVEGFR-1 concentration (mean ± SD: 0.37 ± 0.31; ANOVA; p < 0.001). Patients with abnormal uterine, but normal umbilical artery, Doppler velocimetry had a mean delta plasma sVEGFR-1 concentration higher than normal pregnant women (mean ± SD: 0.80 ± 0.40 vs. mean ± SD: 0.01 ± 0.21; p<0.001; ANOVA post hoc Dunnett’s T3). The means ± SD of plasma sVEGF-R1 concentrations in each group are displayed in the figure. *p < 0.05.