A role of the anti-angiogenic factor sVEGFR-1 in the 'mirror syndrome' (Ballantyne's syndrome)

Abstract

Background: 'Mirror syndrome' (Ballantyne's syndrome) refers to the association of fetal hydrops with placentomegaly and severe maternal edema. Preeclampsia occurs in approximately 50% of these cases. Soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), an anti-angiogenic factor, has been implicated in the pathophysiology of preeclampsia (PE).

Objective: The objective of this study was to determine if the maternal plasma concentration of sVEGFR-1 is elevated in patients with mirror syndrome.

Study design: This case-control study included patients with uncomplicated pregnancies (n = 40) and those with mirror syndrome (n = 4) matched for gestational age. Mirror syndrome was defined as fetal hydrops and severe maternal edema. Maternal plasma sVEGFR-1 concentrations were determined using specific enzyme-linked immunosorbent assays. Immunohistochemistry of sVEGFR-1 on villous trophoblasts was also performed in samples from one patient with mirror syndrome and compared with those from a patient with spontaneous preterm delivery matched for gestational age. Non-parametric statistics were used for analysis (p < 0.05).

Results: (1) The median maternal plasma concentration of sVEGFR-1 was significantly higher in patients with mirror syndrome than in the control group (median: 3974 pg/mL, range: 3083-10 780 vs. median: 824 pg/mL, range: 260-4712, respectively; p < 0.001). (2) All patients with mirror syndrome had sVEGFR-1 concentrations above the 95th percentile for gestational age. Syncytiotrophoblast, especially syncytial knots, showed strong staining with antibodies against sVEGFR-1 in placental samples from the patient with mirror syndrome, but not in those from the patient with spontaneous preterm delivery.

Conclusion: High maternal plasma concentrations of sVEGFR-1 were observed in mirror syndrome. We propose that this anti-angiogenic factor may participate in the pathophysiology of this syndrome. Thus, maternal plasma determination of sVEGFR-1 may help to identify the hydropic fetus that places the mother at risk for preeclampsia.

Figure 1.

Maternal plasma concentration of sVEGFR-1 in patients with “Mirror Syndrome” and in those with uncomplicated pregnancies. The lower and upper lines represent the 5th and 95th percentiles of the plasma sVEGFR-1 concentrations among patients with normal pregnancies.

Figure 2.

Histological examination of placental samples with Hematoxylin and Eosin (H&E) demonstrated immature intermediate villi with edematous changes (Figure 2a) and increased syncytial knots, increased intervillous fibrin, and multifocal villous calcifications (Figure 2b). In contrast, examination of the placental samples from the spontaneous delivery case did not show these histological findings (Figure 2c).

Figure 3.

Syncytiotrophoblast, especially syncytial knots, showed strong staining with antibodies against sVEGFR-1 in the placental samples from a patient with “Mirror Syndrome” (Figure 3a and 3B), but not in those from the patient with spontaneous preterm delivery (Figure 3c).