A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate

Abstract

Introduction: Accumulating evidence suggests that an imbalance between pro-angiogenic (i.e., vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)) and anti-angiogenic factors (i.e., soluble VEGF receptor-1 (sVEGFR-1, also referred to as sFlt1)) is involved in the pathophysiology of preeclampsia (PE). Endoglin is a protein that regulates the pro-angiogenic effects of transforming growth factor beta, and its soluble form has recently been implicated in the pathophysiology of PE. The objective of this study was to determine if changes in maternal plasma concentration of these angiogenic and anti-angiogenic factors differ prior to development of disease among patients with normal pregnancies and those destined to develop PE (preterm and term) or to deliver a small for gestational age (SGA) neonate.

Methods: This longitudinal nested case-control study included 144 singleton pregnancies in the following groups: (1) patients with uncomplicated pregnancies who delivered appropriate for gestational age (AGA) neonates (n = 46); (2) patients who delivered an SGA neonate but did not develop PE (n = 56); and (3) patients who developed PE (n = 42). Longitudinal samples were collected at each prenatal visit, scheduled at 4-week intervals from the first or early second trimester until delivery. Plasma concentrations of soluble endoglin (s-Eng), sVEGFR-1, and PlGF were determined by specific and sensitive ELISA.

Results: (1) Patients destined to deliver an SGA neonate had higher plasma concentrations of s-Eng throughout gestation than those with normal pregnancies; (2) patients destined to develop preterm PE and term PE had significantly higher concentrations of s-Eng than those with normal pregnancies at 23 and 30 weeks, respectively (for preterm PE: p < 0.036 and for term PE: p = 0.002); (3) patients destined to develop PE (term or preterm) and those who delivered an SGA neonate had lower plasma concentrations of PlGF than those with a normal pregnancy throughout gestation, and the maternal plasma concentration of this analyte became detectable later among patients with pregnancy complications, compared to normal pregnant women; (4) there were no significant differences in the plasma concentrations of sVEGFR-1 between patients destined to deliver an SGA neonate and those with normal pregnancies; (5) patients destined to develop preterm and term PE had a significantly higher plasma concentration of sVEGFR-1 at 26 and 29 weeks of gestation than controls (p = 0.009 and p = 0.0199, respectively); and (6) there was no significant difference in the increment of sVEGFR-1 between control patients and those who delivered an SGA neonate (p = 0.147 at 25 weeks and p = 0.8285 at 40 weeks).

Conclusions: (1) Changes in the maternal plasma concentration of s-Eng, sVEGFR-1, and PlGF precede the clinical presentation of PE, but only changes in s-Eng and PlGF precede the delivery of an SGA neonate; and (2) differences in the profile of angiogenic and anti-angiogenic response to intrauterine insults may determine whether a patient will deliver an SGA neonate, develop PE, or both.

Figure 1

Maternal plasma concentration of soluble endoglin [log(1+s-Eng)] in normal pregnancies. The solid line represents the mean plasma concentration of s-Eng and the dotted lines the 95% confidence interval.

Figure 2

Maternal plasma concentration of placental growth factor [log(1+PlGF)] in normal pregnancies. The solid line represents the mean plasma concentration of PlGF and the dotted lines the 95% confidence interval.

Figure 3

Maternal plasma concentration of soluble vascular endothelial growth factor receptor-1 [log(1+sVEGFR-1)] in normal pregnancies. The solid line represents the mean plasma concentration of sVEGFR-1 and the dotted lines the 95% confidence interval.

Figure 4

Forward analysis of the maternal plasma concentration of endoglin soluable (s-Eng) in patients with normal pregnancies and those with pregnancy complications. Patients who delivered an SGA neonate had a significantly higher plasma concentration of s-Eng from ten weeks of gestation onwards than controls (p<0.0001). The increment in plasma s-Eng in patients destined to develop preterm PE surpassed that of patients with normal pregnancies at 13 weeks and became significant at 23 weeks. In patients destined to develop PE at term, the maternal plasma concentration of s-Eng became significantly higher that that of normal patients at 30 weeks.

Figure 5

Backward analysis of the maternal plasma concentration of soluble endoglin (s-Eng) in patients with normal pregnancies and those with pregnancy complications. Patients destined to deliver an SGA neonate had a significantly higher plasma s-Eng concentration than controls up to 30 weeks before delivery.

Figure 6

Forward analysis of the maternal plasma concentration of placental growth factor (PlGF) in patients with normal pregnancies and those with pregnancy complications. Patients destined to develop PE (term or preterm) and those who delivered an SGA neonate had lower plasma concentration of PlGF throughout gestation than controls. These differences were statistically significant at ten weeks of gestation for SGA and term PE and at 11 weeks for preterm PE.

Figure 7

Backward analysis of the maternal plasma concentration of placental growth factor (PlGF) in patients with normal pregnancies and those with pregnancy complications. Backward analysis indicated that patients destined to develop preterm PE, term PE and those destined to deliver an SGA neonate had a significantly lower plasma PlGF concentration 20, 12 and 16 weeks before the clinical presentation of the disease when compared to controls.

Figure 8

Forward analysis of the maternal plasma concentration of soluable vascular endothelial growth factor receptor-1 (sVEGFR-1) in patients with normal pregnancies and those with pregnancy complications. Patients destined to develop preterm term and term PE had a significantly higher plasma concentrations of sVEGFR-1 at 26 and 29 weeks of gestation, respectively, than controls. However, there was no difference in the increment of sVEGFR-1 between control patients and those who delivered an SGA neonate.

Figure 9

Backward analysis of the maternal plasma concentration of sVEGFR-1 in patients with normal pregnancies and those with pregnancy complications. Patients who developed preterm and term PE had a significantly higher plasma sVEGFR-1 concentration 7 and 11 weeks before the clinical diagnosis of the disease.

Figure 10

Mean and 95% confidence interval of the maternal plasma concentration of each analyte [log(1+analyte)] in patients who developed PE (term and preterm) as well as those who delivered an SGA neonate. The mean analyte concentration of the normal pregnancy group (solid green line) was added to each plot for comparison.