Review
Prediction of preeclampsia using angiogenic and antiangiogenic factors
2013 Volume 1 Issue 2 Pages 66-70
Details
2013 Volume 1 Issue 2 Pages 66-70
Angiogenic factors play important roles in the regulation of placental vasculogenesis, and placental vascular development may be regulated by a local balance between angiogenic and antiangiogenic factors. Vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) are potent angiogenic growth factors capable of inducing proliferation, migration, and activation of endothelial cells. Soluble vascular endothelial growth factor receptor 1 (sVEGFR1) functions as an antagonist of both VEGF and PlGF. In this review, we survey literature on the use of peripheral blood PlGF levels or the sFlt-1/PlGF ratio to predict preeclampsia. While peripheral blood PlGF levels may not be clinically useful for predicting preeclampsia, the sFlt-1/PlGF ratio is a promising tool for assessing the risk of early-onset preeclampsia, although the sFlt-1/PlGF ratio does not perform well as a screening test for preeclampsia.
Angiogenic factors play important roles in the regulation of placental vasculogenesis. Placental vascular development may be regulated by a local balance between angiogenic and antiangiogenic factors.
Vascular endothelial growth factor (VEGF) plays an important role in the stabilization of endothelial cells in mature blood vessels.1) Pregnancies complicated by preeclampsia have been shown to exhibit low peripheral blood levels of free VEGF.1)
Placenta growth factor (PlGF), a homolog of VEGF, is a potent angiogenic growth factor capable of inducing proliferation, migration, and activation of endothelial cells,2) and its abundant expression is restricted to the placenta.3) PlGF exhibits many structural and functional similarities with VEGF. The PlGF gene has seven exons and resides on chromosome 14. There are three known isoforms of PlGF that arise via alternative splicing (i.e., PlGF-1, PlGF-2, and PlGF-3). The biological activity of PlGF-2 is greater than that of PlGF-1. Very little is known about the function of PlGF-3. PlGF may also accelerate placental villous proliferation.4) PlGF expression in normal trophoblasts is significantly downregulated by hypoxia, whereas VEGF expression is upregulated under these conditions.5) PlGF homodimers can bind fms-like tyrosine kinase-1 (Flt-1), but not KDR or Flk-1.
Soluble vascular endothelial growth factor receptor 1 (sVEGFR1) (soluble fms-like tyrosine kinase-1: sFlt-1) is a truncated splice variant of the membrane-bound VEGF receptor which functions as an antagonist of both VEGF and PlGF, binding to them in the circulation and preventing interaction with their endogenous receptors.1)
VEGF and PlGF are produced in moderate amounts in normal pregnancy, and free forms of these growth factors may play a role in trophoblast proliferation and vascular formation. However, in preeclampsia, sVEGFR1 is produced abundantly, and the levels of VEGF and free PlGF decrease. This disturbs trophoblast proliferation and vascular formation, and results in hypertension via disturbances in physiological vasodilatation (Figure 1).6)
Changes of VEGF, PlGF, and sVEGFR1 and pathophysiology in normal pregnancy and preeclampsia.
In this review, we consider the possibility of using PlGF levels or the sFlt-1/PlGF ratio to predict preeclampsia.
Maternal PlGF levels reportedly increase during normal pregnancy from the first trimester to the late second trimester, and subsequently decline from 30 weeks of gestation to delivery. Moreover, PlGF levels are low in pregnancies complicated by preeclampsia.7) Ohkuchi et al. established reference range values for plasma levels of sFlt-1 and PlGF and the sFlt-1/PlGF ratio in Japanese pregnant women using Elecsys sFlt-1 and Elecsys PlGF. Plasma samples were collected from 144 normal pregnant women at 19–25, 27–31, and 34–38 weeks of gestation and from 34 women with preeclampsia. The most appropriate reference range curves for plasma levels of sFlt-1 and PlGF and the sFlt-1/PlGF ratio were presented as quadratic curves after logarithmic transformation. A cutoff value of 45 for the sFlt-1/PlGF ratio was found to result in the best sensitivity and specificity for diagnosing all preeclampsia cases.8)
Maynard et al. and Koga et al. reported that sVEGFR1 (sFlt-1) levels increase in the serum of women with preeclampsia.9,10) Levine et al. measured serum sFlt-1 levels throughout pregnancy and preeclamsia, and found that the levels increased gradually throughout normal pregnancy.11) These changes occurred earlier and were more pronounced in women who developed preeclampsia later on in pregnancy; sFlt-1 levels increased from approximately five weeks before the onset of preeclampsia.
Levine et al. performed a nested case-control study in which each woman with preeclampsia was matched to one normotensive control. For specimens obtained during the second trimester or the early stages of the third trimester, the lowest quartile of PlGF levels was associated with an increased risk of preterm preeclampsia (at<37 weeks of gestation; odds ratio for specimens from 13 weeks to 20 weeks, 7.4; 95 percent confidence interval, 1.8 to 30.2; odds ratio for specimens from 21 weeks to 32 weeks, 7.9; 95 percent confidence interval, 2.9 to 21.5). The lowest quartile of P1GF levels, however, was not a significant predictor of preeclampsia with an onset at term (≥37 weeks).11)
Levine et al. also attempted to predict preeclampsia using urinary PlGF levels in a nested case-control study. One hundred twenty pairs of women were randomly chosen for analysis of serum and urine specimens obtained before labor. Mean urinary PlGF in women with preeclampsia was 32 pg/ml, compared with 234 pg/ml in controls with fetuses of similar gestational age. The adjusted odds ratio for the risk of preeclampsia to begin at<37 weeks of gestation for specimens obtained at 21 to 32 weeks, which were in the lowest quartile of control PlGF levels (<118 pg/ml), compared with all other quartiles, was 22.5. The authors concluded that decreased urinary PlGF levels at mid-gestation is strongly associated with the early development of preeclampsia.12)
Romero et al. reported on a longitudinal nested case-control study which included 144 singleton pregnancies.13) The study population consisted of: (1) patients with uncomplicated pregnancies who delivered appropriate for gestational age (AGA) neonates (n=46); (2) patients who delivered small for gestational age (SGA) neonates but did not develop preeclampsia (n=56); and (3) patients who developed preeclampsia (n=42). Longitudinal samples were collected at each prenatal visit, which was scheduled at 4-week intervals from the first trimester or early second trimester until delivery. Plasma PlGF levels were determined by ELISA. Patients destined to develop preeclampsia and those who delivered SGA neonates had lower plasma PlGF levels than those who had normal pregnancies throughout gestation.
Espinoza et al. assessed the utility of the combined use of uterine artery Doppler velocimetry (UADV) and maternal plasma PlGF and sVEGFR-1 levels in the second trimester to identify patients at risk for severe and/or early onset preeclampsia.14) A prospective cohort was designed to examine the relationship between abnormal UADV and plasma levels of PlGF and sVEGFR-1 in 3,348 pregnant women. Plasma samples were obtained between 22 and 26 weeks of gestation at the time of ultrasound examination. The combination of abnormal UADV and a maternal plasma PlGF level<280 pg/ml was associated with an odds ratio (OR) of 43.8 for the development of early onset preeclampsia, an OR of 37.4 for the development of severe preeclampsia, and an OR of 8.6 for the development of preeclampsia. The authors concluded that in a low-risk population, the combination of abnormal UADV and a maternal plasma PlGF level<280 pg/ml in the second trimester is associated with a high risk for preeclampsia and early onset and/or severe preeclampsia. Using abnormal UADV and a maternal plasma PlGF level<280 pg/ml, they were able to identify patients who experienced early onset and/or severe preeclampsia.
Sibai et al. analyzed serum obtained from 704 patients with previous preeclampsia and/or chronic hypertension (CHTN).15) One hundred four developed preeclampsia: 27 at≥37 weeks and 77 at<37 weeks (9 at<27 weeks). None of the markers were associated with preeclampsia at≥37 weeks. Significant associations were observed between preeclampsia at<37 weeks and reduced PlGF levels at baseline and follow-up and elevated inhibin A and sFlt-1 levels at follow-up. At 75% specificity, sensitivities ranged from 38% to 52%; using changes in markers from baseline to follow-up, sensitivities were 52–55%. Associations were observed between baseline markers and preeclampsia at<27 weeks; sensitivities were 67–89%, but positive predictive values (PPVs) were only 3.4–4.5%. Levels of inhibin A and circulating angiogenic factors obtained at 12 weeks 0 day to 19 weeks 7 days were significantly associated with the onset of preeclampsia at<27 weeks, and levels obtained at 24–28 weeks were significantly associated with the onset of preeclampsia at<37 weeks. The authors concluded that these markers might not be clinically useful for predicting preeclampsia in women with previous preeclampsia and/or CHTN because the corresponding sensitivities and/or PPVs were low.
Savvidou et al. also reported that urinary PlGF levels and the PlGF/creatinine ratio did not predict preeclampsia when these samples were taken from 11 weeks to 13 weeks.16)
Levine et al. reported that increased sFlt-1 levels and reduced PlGF levels predict the subsequent development of preeclampsia.11) A few years later, Roche introduced new automated assays that allowed for fast and easy assessment of sFlt-1 and PlGF levels for clinical use, with the assays requiring only 18 min to obtain results.
Verlohren et al. evaluated a newly developed Elecsys assay (Roche, Penzberg, Germany) for sFlt-1 and PlGF and tested the predictive value of the sFlt-1/PlGF ratio for preeclampsia.17) Maternal serum levels of sFlt-1 and PlGF significantly separated healthy women and women with preeclampsia. The sFlt-1/PlGF ratio had an AUC of 0.95. A cutoff ratio of 85 resulted in a sensitivity of 82% and a specificity of 95%. The best performance with this cutoff was obtained in the identification of early-onset preeclampsia (AUC, 0.97), with a sensitivity of 89% and a specificity of 97%. The authors proposed that levels of sFlt-1 and PlGF and the sFlt-1/PlGF ratio may have predictive value for preeclampsia and in the differential diagnosis of patients with atypical presentations of preeclampsia, and perhaps in the differential diagnosis of women with chronic hypertension who are suspected to develop superimposed preeclampsia.
Moore et al. reported that 78 of 276 women with suspected preeclampsia developed maternal or neonatal complications.18) A higher sFlt-1/PlGF ratio was associated with an increased probability of developing complications among women presenting prior to 37 weeks. A multivariable model combining the sFlt-1/PlGF ratio with clinical variables was more predictive of complications (AUC, 0.91) than a model using clinical variables alone (AUC, 0.82). Angiogenic biomarkers were associated with maternal and neonatal complications in women with suspected preeclampsia, and thus may be useful for risk stratification.
Stepan et al. studied 63 second trimester pregnant women (from 19 weeks to 24 weeks of gestation) with abnormal uterine perfusion.19) An sFlt-1/PlGF ratio cutoff of 3.15 predicted subsequent preeclampsia with a sensitivity of 62% and a specificity of 51%. Moreover, this cutoff predicted subsequent early onset preeclampsia with a sensitivity of 67% and a specificity of 51% (Table 1).
| Study | Number of patients with PE (control) | Patients | Sensitivity (%) | Specificity (%) | ||
|---|---|---|---|---|---|---|
| Stepan et al. (2007) | 12 (38) | 19–24 weeks | Cutoff 3.15 | All patients | 62 | 51 |
| 9 (38) | 19–24 weeks | Cutoff 3.15 | Early-onset PE | 67 | 51 | |
| Kim et al. (2007) | 46 (100) | 14–23 weeks | All patients | 80.4 | 78 | |
| Cutoff log (sFlt-1/PlGF)=1.4 | ||||||
| Crispi et al. (2008) | 38 (76) | 24 weeks | Early-onset PE | 84.2 | 90 | |
| Diab et al. (2008) | 33 (108) | 23 week abnormal Doppler | All PEs | 100 | 85 | |
| 8 (108) | Early-onset PE | 90 | 90 | |||
| De Vivo et al. (2008) | 52 (52) | 24–28 weeks | All patients | 88.5 | 88.5 | |
| Kusanovic et al. (2009)* | 62 (1,560) | 6–15 weeks, 20–25 weeks | All patients | 40.3 | 78.5 | |
| 9 (1,613) | Early-onset PE | 100 | 89.1 | |||
Kim et al. determined whether sFlt-1 and PlGF levels changed during the second trimester (from 14 weeks to 23 weeks) in the plasma of women who subsequently develop preeclampsia.20) The receiver operating characteristic curve revealed a specificity of 78% with a diagnostic sensitivity of 80.4%; the optimal cut-off value of the log[sFlt-1/PlGF] ratio was 1.4. Preeclampsia was strongly associated with increased sFlt-1 levels and decreased PlGF levels in second trimester maternal plasma. The authors concluded that the sFlt-1/PlGF ratio may allow for the early prediction of subsequent preeclampsia.
Crispi et al. examined the predictive value of second trimester uterine artery Doppler examination and measurement of maternal serum PlGF and sFlt-1 levels for preeclampsia and/or intrauterine growth restriction.21) Subsequent early onset preeclampsia was predicted with a sensitivity of 80.4% and a specificity of 90%.
Diab et al. measured sFlt-1/PlGF ratios for 108 pregnant women with abnormal uterine perfusion using Doppler velocimetry at 23 weeks of gestation. The prediction of subsequent preeclampsia using a cutoff value of 3.92 had a sensitivity of 100% and a specificity of 85%.22) The prediction of subsequent early onset preeclampsia using a cutoff value of 7.775 had a sensitivity of 100% and a specificity of 90%.
De Vivo et al. used the sFlt-1/PlGF ratio to predict preeclampsia,23) and found that the prediction of subsequent preeclampsia using a cutoff of 38.47 had a sensitivity of 88.5% and a specificity of 88.5%.
Kusanovic et al. investigated the predictive value of the PlGF/sFlt-1 ratio for preeclampsia by screening 1,622 consecutive pregnancies in the general population. Using early pregnancy specimens (6–15 weeks of gestation), a cutoff<0.033 predicted preeclampsia with a sensitivity and specificity of 93.5% and 22.2%, respectively. Using mid-trimester specimens (20–25 weeks of gestation), a cutoff<0.12 predicted preeclampsia with a sensitivity and specificity of 40.3% and 78.5%, respectively.24) The prediction of early-onset preeclampsia with mid-trimester specimens using a cutoff<0.082 had a sensitivity and specificity of 100% and 89.1%, respectively. The authors concluded that the sFlt-1/PlGF ratio is a promising tool for assessing the risk of developing early-onset preeclampsia, although the ratio did not perform well as a screening test for preeclampsia.
Collectively, the studies reviewed herein suggest that while PlGF alone was not useful for predicting preeclampsia, the sFlt-1/PlGF ratio shows some predictive value, particularly for early-onset preeclampsia.
I have no relationships with companies that may have a financial interest in the information contained in the manuscript.
