Evidence in support of a role for anti-angiogenic factors in preterm prelabor rupture of membranes

Abstract

Objective: Vaginal bleeding, placental abruption, and defective placentation are frequently observed in patients with preterm prelabor rupture of membranes (PROM). Recently, a role of vascular endothelial growth factor (VEGF) and its receptor, VEGF receptor (VEGFR)- 1 has been implicated in the mechanisms of membrane rupture. The purpose of this study was to determine whether the soluble form of VEGFR-1 and -2 concentrations in amniotic fluid (AF) change with preterm PROM, intra-amniotic infection/inflammation (IAI), or parturition.

Study design: This cross-sectional study included 544 patients in the following groups: (1) midtrimester (MT) (n = 48); (2) preterm labor (PTL) leading to term delivery (n = 143); (3) PTL resulting in preterm delivery with (n = 72) and without IAI (n = 100); (4) preterm PROM with (n = 46) and without IAI (n = 42); (5) term in labor (n = 48); and (6) term not in labor (n = 45). The concentrations of sVEGFR-1 and sVEGFR-2 were determined by ELISA. Non-parametric statistics and logistic regression analysis were applied.

Results: (1) Preterm PROM (with and without IAI) had a lower median AF concentration of sVEGFR-1 than patients with PTL who delivered at term (p < 0.001 for each comparison); (2) A decrease in AFsVEGFR-1 concentrations per each quartile was associated with PROM after adjusting for confounders (OR 1.8; 95%CI 1.4-2.3); (3) IAI, regardless of the membrane status, was not associated with a change in the median AF concentrations of sVEGFR-1 and sVEGFR-2 (p > 0.05 for each comparison); and (4) Spontaneous term and PTL did not change the median sVEGFR-1 and sVEGFR-2 concentrations (p > 0.05 for each comparison).

Conclusion: (1) This is the first evidence that preterm PROM is associated with a lower AF concentration of sVEGFR-1 than patients with PTL intact membranes. These findings cannot be attributed to gestational age, labor, or IAI; and (2) AF concentrations of sVEGFR-2 did not change with preterm PROM, IAI, or labor at term and preterm.

Figure 1

Amniotic fluid concentrations of sVEGFR-1 in normal pregnant women at midtrimester, patients with preterm labor (PTL) with intact membranes who delivered at term, and women at term without labor. Patients with PTL who delivered at term (median: 101 ng/ml; range 0.1–595.6 ng/ml) had a significantly higher median sVEGFR-1 concentration in amniotic fluid than women in the midtrimester (median: 33 ng/ml; range: 10.7–74.3 ng/ml; p<0.001) and than those at term not in labor (median: 64 ng/ml; range: 10.6–373.4 ng/ml; p=0.01). Women at term not in labor had a significantly higher median amniotic fluid concentration of sVEGFR-1 than those in the midtrimester (p<0.001). LOD: limit of detection. *: p<0.05

Figure 2

Amniotic fluid concentrations of sVEGFR-2 in normal pregnant women at midtrimester, patients with PTL with intact membranes who delivered at term, and women at term without labor. Patients with PTL who delivered at term (median: 0.7 ng/ml; range: 0–3.7 ng/ml) had a significantly higher median amniotic fluid concentration of sVEGFR-2 than women in midtrimester (median: 0.4 ng/ml; range: 0.1–1.5 ng/ml; p=0.002) and than women at term not in labor (median: 0.5 ng/ml; range: 0.1–9.3 ng/ml; p=0.03). There was no significant difference in the median amniotic fluid concentration of sVEGFR-2 between normal pregnant women at term not in labor and those in the midtrimester (p=0.4). LOD: limit of detection. *: p<0.05

Figure 3

Amniotic fluid concentrations of sVEGFR-1 in patients with preterm labor (PTL) and intact membranes who delivered at term, and in those with preterm prelabor rupture of membranes (PROM) with and without intra-amniotic infection/inflammation (IAI). Patients with preterm PROM with (median: 45 ng/ml; range:1.4–255.6 ng/ml) and without IAI (median: 56 ng/ml; range: 8.9–398.2 ng/ml) had a significantly lower median amniotic fluid concentration of sVEGFR-1 than those with PTL who delivered at term (median: 101 ng/ml; range: 0.1–595.6 ng/ml) (p<0.001 and p=0.002; respectively). Amniotic fluid sVEGFR-1 concentrations did not change with the presence of IAI (p=0.3). LOD: limit of detection. *: p<0.05

Figure 4

Amniotic fluid concentrations of sVEGFR-2 in patients with preterm labor (PTL) and intact membranes who delivered at term, and in those with preterm prelabor rupture of membranes (PROM) with and without intra-amniotic infection/inflammation (IAI). There were no significant differences in the median amniotic fluid sVEGFR-2 concentrations between patients with PTL who delivered at term (median: 0.7 ng/ml; range: 0.0–3.7 ng/ml) and those with preterm PROM without IAI (median: 0.7 ng/ml; range: 0.1–2.0 ng/ml; p=0.8) and between patients with PTL and those with preterm PROM with IAI (median: 0.6 ng/ml; range: 0.1–3.7 ng/ml; p=0.5). LOD: limit of detection.

Figure 5

Amniotic fluid concentrations of sVEGFR-1 among women with spontaneous preterm labor (PTL) and intact membranes. There were no significant differences in the median amniotic fluid sVEGFR-1 concentrations among the subgroups of patients with PTL (PTL with term delivery: median: 101 ng/ml; range: 0.1–595.6 ng/ml; PTL who delivered preterm without IAI: median: 99.4 ng/ml; range: 0.7–459 ng/ml; PTL who delivered preterm with IAI: median: 98.7 ng/ml; range: 2.0–544.8 ng/ml; all p>0.05). LOD: limit of detection.

Figure 6

Amniotic fluid concentrations of sVEGFR-2 among women with spontaneous preterm labor (PTL) and intact membranes. There were no significant differences in the median amniotic fluid sVEGFR-2 concentrations among the subgroups of patients with PTL (PTL with term delivery: median: 0.7 ng/ml; range: 0.0–3.7 ng/ml; PTL who delivered preterm without IAI: median: 0.6 ng/ml; range: 0.2–3.3 ng/ml; PTL who delivered preterm with IAI: median: 0.8 ng/ml; range: 0.1–3.9 ng/ml; all p>0.05). LOD: limit of detection.

Figure 7

Amniotic fluid concentrations of sVEGFR-1 in normal pregnant women at term with and without labor. There was no significant difference in the median amniotic fluid sVEGFR-1 concentrations between patients with spontaneous labor and those not in labor (term in labor: median: 65 ng/ml; range: 4.7–243.8 ng/ml; vs. term not in labor: median: 64 ng/ml; range: 10.6-373.4 ng/ml; p=0.6). LOD: limit of detection.

Figure 8

Amniotic fluid concentrations of sVEGFR-2 in normal pregnant women at term with and without labor. There was no significant difference in the median amniotic fluid sVEGFR-2 concentrations between patients with spontaneous labor at term and those at term not in labor (term in labor: median: 0.7 ng/ml; range: 0.0-7.9 ng/ml; vs. term not in labor: median: 0.5 ng/ml; range: 0.1-9.3 ng/ml; p=0.5). LOD: limit of detection.