|Year : 2012 | Volume
| Issue : 4 | Page : 281-286
Assessment of placental growth factor and soluble vascular endothelial growth factor receptor 1 in the prediction of pre-eclampsia
Maha Basuni1, Waleed M. Fathy1, Wail Gaber2
1 Department of Clinical Pathology, Faculty of Medicine, Menoufiya University, Egypt
2 Department of Obstetric and Gynecology, Faculty of Medicine, Menoufiya University, Egypt
|Date of Submission||29-May-2012|
|Date of Acceptance||25-Jun-2012|
|Date of Web Publication||21-Jun-2014|
Waleed M. Fathy
Department of Clinical Pathology, Faculty of Medicine, Menoufiya University, P.O. Box 32511
Source of Support: None, Conflict of Interest: None
Pre-eclampsia is a pregnancy-associated disease occurring in 5–8% of pregnancies and is a major cause of maternal and fetal morbidity and mortality. A potentially important process in the pathogenesis of pre-eclampsia is an imbalance between placenta-derived proangiogenic and antiangiogenic proteins. The proangiogenic proteins vascular endothelial growth factor (VEGF) and placental growth factor (PLGF) are involved in the regulation of placental vascular development and maternal endothelial function during pregnancy.
Aim of the study
The aim of this study is to assess the PLGF and soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) in the prediction of pre-eclampsia.
Materials and methods
This study included 88 pregnant women: 68 pregnant women with pre-eclampsia divided into two subgroups (mild and severe pre-eclampsia) and 20 healthy pregnant women matched for age and sex, who served as the control group. Laboratory investigations such as determination of complete blood count, blood urea, serum creatinine, aspartate aminotransferase, alanine transaminase, serum albumin, quantitative determination of total protein in urine, estimation of prothrombin time and concentration, serum PLGF concentration, and serum sVEGFR-1 concentrations were carried out by ELISA. BMI was estimated in this study.
The results showed that serum PLGF was highly significant decreased in women with pre-eclampsia when compared with the control group. There was a highly statistically significant difference between mild and severe cases, where the PLGF decreased with increased severity of pre-eclampsia (P<0.001). Serum sVEGFR-1 was highly significantly increased in women with pre-eclampsia when compared with the control group. There was a highly statistically significant difference between mild and severe cases, where the sVEGFR-1 increased with increased severity of pre-eclampsia (P<0.001). ROC study showed that the best cutoff value for sVEGFR-1 was 2075 pg/ml and the sensitivity was 75%, whereas the specificity was 85%. The cutoff value for PLGF was 151 ng/ml; the sensitivity was 75%, whereas the specificity was 72.1%. There was a highly statistically significant negative correlation between PLGF and sVEGFR-1.
Finally, it is concluded that high concentrations of sVEGFR-1 combined with low concentrations of PLGF may be used to predict the development of pre-eclampsia.
Keywords: placental growth factor, pre-eclampsia, vascular endothelial growth factor receptor 1
|How to cite this article:|
Basuni M, Fathy WM, Gaber W. Assessment of placental growth factor and soluble vascular endothelial growth factor receptor 1 in the prediction of pre-eclampsia. Egypt J Haematol 2012;37:281-6
|How to cite this URL:|
Basuni M, Fathy WM, Gaber W. Assessment of placental growth factor and soluble vascular endothelial growth factor receptor 1 in the prediction of pre-eclampsia. Egypt J Haematol [serial online] 2012 [cited 2020 Apr 10];37:281-6. Available from: http://www.ehj.eg.net/text.asp?2012/37/4/281/134978
| Introduction|| |
Pre-eclampsia is a pregnancy-associated disease occurring in 5–8% of pregnancies and a major cause of maternal and fetal morbidity and mortality. The disease is characterized by maternal symptoms that may occur from 20 weeks’ gestation onwards, and that consist of de-novo hypertension (diastolic blood pressure >90 mmHg with increment >20 mmHg from first-trimester diastolic blood pressure) and proteinuria (>300 mg/24 h) as defined by the Royal College of Obstetricians and Gynecologists 1.
The exact cause of pre-eclampsia is unclear, but this disease is known to be induced by a placental factor and it is hypothesized that oxidative stress may also contribute toward its pathogenesis 2.
The underlying mechanism for pre-eclampsia is believed to be impaired placentation because of inadequate trophoblastic invasion of the maternal spiral arteries, documented by the findings of both histological studies and Doppler ultrasound studies of the uterine arteries 3.
A potentially important process in the pathogenesis of pre-eclampsia is an imbalance between placenta-derived proangiogenic and antiangiogenic proteins. The proangiogenic proteins vascular endothelial growth factor (VEGF) and placental growth factor (PLGF) are involved in the regulation of placental vascular development and maternal endothelial function during pregnancy 4.
Incomplete widening of the maternal placental arteries results in insufficient blood supply to the developing fetus 5. The resulting reduced uteroplacental blood flow produces placental ischemia and hypoxia 6. The latter is associated with a maternal circulation containing reduced levels of angiogenic factors 7 and elevated levels of antiangiogenic factors 8, placental debris 9, and proinflammatory cytokines 10.
PLGF is a member of the VEGF subfamily. It is a key molecule in angiogenesis and vasculogenesis in particular during embryogenesis. The main source of PLGF during pregnancy is the placental trophoblast. PLGF is also expressed in many other tissues, including the villous trophoblast 11.
Soluble fms-like tyrosine kinase-1 (sFlt-1 or sVEGFR-1) is a tyrosine kinase protein that disables proteins that cause blood vessel growth. Soluble Flt-1 (sFlt-1) is a splice variant of VEGF receptor 1 (Flt-1) that is produced by a variety of tissues. These proteins act as a receptor of VEGF, a potent angiogenic growth factor 10.
VEGF and its soluble receptor (sVEGFR-1) are potent vasoactive factors, which are produced by the placenta 12,13. VEGF promotes neovascularization, reduces blood pressure, and is crucial in the formation and maintenance of the glomerular filtration barrier 14–16. Therefore, its deficiency could well explain the main clinical manifestations of pre-eclampsia (hypertension, proteinuria, and edema). sVEGFR-1 binds VEGF and is the most potent regulator of VEGF activity in vivo 10. It is known that sVEGFR-1 leaks from early trophoblasts into the maternal circulation as early as 30 days after conception 17.
Mild pre-eclampsia is defined as blood pressure of at least 140 mmHg systolic or at least 90 mmHg diastolic on at least two occasions and at least 4 to 6 h apart after the 20th week of gestation in women without pregnancy hypertension, with proteinuria (defined as ≥300 mg protein in a 24 h urine specimen) 18.
The classification of ‘severe’ pre-eclampsia varies, but one of the most commonly used criteria are either the blood pressure 160/110 mmHg or more and/or proteinuria 3–5 g or more during a 24-h collection 1,19.
| Aim of the work|| |
The aim of this study is to assess PLGF and sVEGFR-1 in the prediction of pre-eclampsia.
| Participants and methods|| |
The present study was carried out at the Clinical Pathology Department in collaboration with the Obstetrics and Gynecology Departments, Faculty of Medicine, Menoufiya University, in the period between October 2010 and July 2011. Eighty-eight pregnant women were included in this study and were divided into two groups:
Group I included 68 pre-eclamptic patients, ranging in age from 20 to 41 years and gestational age at sampling of 26–30 weeks.
The pre-eclamptic patients (group I) were further divided into two groups according to the severity of disease.
Group (Ia) – 49 women with mild pre-eclampsia, mean±SD 29.89±4.31 (range 25–41 years).
Group (Ib) – 19 women with severe pre-eclampsia, mean±SD 30.68±3.60 (range 25–39 years).
Group II included 20 apparently healthy pregnant women matched for age (mean±SD 28.55±4.12, range 20–38 years) and sex, and served as the control group.
The exclusion criteria were a history of chronic hypertension, diabetes mellitus, and renal insufficiency.
Patients’ data including age, parity, vomiting, headache, convulsions, blurring of vision, history of pre-eclampsia, and history of chronic diseases, weight, height, and calculation of BMI according to the equation BMI=weight (kg)/height (m2) were determined.
All patients underwent a full clinical evaluation, with a focus on blood pressure measurement and fundus examination.
Blood sample: 9 ml of venous fasting blood sample was collected from each woman under a complete aseptic condition by a sterile vein puncture without venous stasis and was divided as follows: 2 ml of blood collected in EDTA for assay of complete blood count, 2 ml of blood collected in a citrated tube for estimation of prothrombin time and concentration, 3 ml was collected, left to clot, serum was separated, and used for an immediate assay of kidney and liver function tests, and fasting blood sugar and 2 ml were collected, left to clot, serum was separated, and kept at −80°C for assay of PLGF and sVEGFR-1.
Urine sample: 24 h urine collection from each woman for the estimation of total protein.
Complete blood count was determined using a Sysmex automated hematology analyzer (ABX, Montpellier, France).
Estimation of prothrombin time and concentration by STA-Compact, Diagnostica Stago (Parsippany, New Jersey, USA).
Blood urea, serum creatinine, fasting blood glucose, aspartate aminotransferase, alanine transaminase, and serum albumin were determined on Synchron Cx9 (Backman Instrument Inc., Fullerton, California, USA). Quantitative determination of total protein in urine was carried out.
The serum PLGF concentration was measured using the ELISA kit supplied by R&D Systems Inc. (Minneapolis, Minnesota, USA) 20.
Serum sVEGFR-1 concentrations were determined using the ELISA kit supplied by R&D Systems 21.
The data collected were tabulated and analyzed by SPSS (statistical package for the social science software) (SPSS Inc., Chicago, Illinois, USA) version II on an IBM compatible computer.
Quantitative data were expressed as mean±SD (X±SD) and analyzed using a t-test for a comparison of two groups of normally distributed variables and the Mann–Whitney test and U-test for non-normally distributed ones.
Qualitative data were expressed as n (%) and analyzed using the χ2-test. Pearson’s correlation (r) was used to measure the association between two quantitative variables.
All tests were used as tests of significance at P value less than 0.05.
| Results|| |
[Table 1] shows a comparison between the maternal characteristics of group I (patients) and group II (controls) in terms of parity, previous history of pre-eclampsia, BMI, and age. There was no statistically significant difference in age and parity between group I and group II (P>0.05); in contrast, there was a highly statistical significant difference in BMI (P<0.001) and previous history of pre-eclampsia (P<0.01), with higher levels in patients compared with controls.
|Table 1: Baseline maternal characteristics among patients and control groups|
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[Table 2] shows a highly significant increase in urea and creatinine in the patient group compared with the control group (P<0.01 and P<0.001, respectively). In terms of the amount of protein in 24 h urine, a highly significant increase was detected (P<0.001). Serum albumin showed a highly significant decrease (P<0.001).
The prothrombin concentration showed a highly significant decrease in patients compared with the control group (P<0.001).
[Table 3] shows a highly significant decrease in the platelet count in the patient group compared with the control group (P<0.01). In terms of serum PLGF and serum sVEGFR-1 levels, a highly significant decrease and increase were detected in the patient group compared with the control group (P<0.001).
|Table 3: Platelets, soluble vascular endothelial growth factor receptor 1 and placental growth factor in serum among patients and control groups|
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[Table 4] shows significant and highly significant differences in serum sVEGFR and serum PLGF when comparing mild and severe pre-eclampsia (P<0.05 and P<0.001, respectively). As the severity of pre-eclampsia increases, serum sVEGFR and PLGF decrease.
|Table 4: Statistical comparison between patients with mild and severe pre-eclampsia in terms of soluble vascular endothelial growth factor receptor 1 and placental growth factor|
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[Table 5] shows a highly significant negative correlation between PLGF and systolic, diastolic blood pressure, urea, creatinine, and protein in 24 h urine collection and a positive correlation between PLGF and the level of serum albumin (P<0.001). In terms of sVEGFR-1, highly significant positive correlations were detected between sVEGFR-1 and systolic, diastolic blood pressure, and protein in 24 h urine collection and a negative significant correlation between sVEGFR-1 and the level of serum albumin, gestational age at labor, prothrombin concentration, and platelet number (P<0.001).
|Table 5: Pearson’s linear correlation between placental growth factor in serum and soluble vascular endothelial growth factor receptor 1 and other parameters (in all studied groups)|
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[Table 6] shows a stepwise multiple regression model for the relationship between the parameters studied and PLGF in serum. There was significant regression between PLGF, age, and diastolic blood pressure (P<0.01).
|Table 6: Stepwise multiple regression model for the relationship between the studied parameters and placental growth factor in serum|
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[Table 7] shows a stepwise multiple regression model for the relationship between the parameters studied and serum sVEGFR-1 and a strong negative stepwise multiple regression between the sVEGFR-1 level and albumin and between the serum sVEGFR-1 level and blood platelets.
|Table 7: Stepwise multiple regression models for the relationship between the studied parameters and plasma soluble vascular endothelial growth factor receptor 1|
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[Table 8] shows the correlation between sVEGFR-1 and PLGF in all the studied groups; there was a statistically significant negative correlation between PLGF and sVEGFR-1 [Figure 1] and [Figure 2].
|Table 8: Spearman correlation between soluble vascular endothelial growth factor receptor 1 and placental growth factor (in all studied groups)|
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|Figure 1: ROC curve of placental growth factor in serum of patients and control groups. Area under the curve=0.872 (<0.001), 95% CI (0.781–0.962) at a cutoff point of 151, sensitivity=75.0%, specificity=72.1%, positive predictive value=44.1%, negative predictive value=90.7%, accuracy of the test=72.7%.|
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|Figure 2: ROC curve of soluble vascular endothelial growth factor receptor 1 in serum of patients and control groups. Area under the curve=0.883, 95% CI (0.804–0.962) at a cutoff point of 2075, sensitivity=75%, specificity=85.0%, positive predictive value=94.4%, negative predictive value=50.0%, accuracy of the test=77.3%.|
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| Discussion|| |
Pre-eclampsia is a major cause of maternal morbidity and mortality, especially in the developing countries and worldwide. It is one of the leading contributors to adverse perinatal outcomes, such as prematurity and intrauterine growth retardation 22,23. On the basis of the different pathophysiological phenomena associated with pre-eclampsia, several circulating biochemical markers, showing placental and endothelial dysfunction, activation of coagulation, or inflammation, have been tested for their ability to predict the disease. Among many others, such markers include fibronectin, fetal DNA, hemoglobin or hematocrit, hCG, estriol, leptin, plasminogen activator, PLGF, and uric acid 24,25.
The present study aimed to assess the serum concentration of PLGF and sVEGFR-1 among pregnant women with pre-eclampsia in comparison with healthy pregnant women especially after 20 weeks of gestation to evaluate their role in the prediction of pre-eclampsia.
In agreement with previous reports 26–29, the present study found that women with pre-eclampsia, when compared with the healthy control group, showed significantly higher BMI, systolic and diastolic blood pressure, and the blood pressure also increased significantly with increased severity of pre-eclampsia.
In the current study, women with pre-eclampsia had significantly higher urea and creatinine levels than the healthy control group. These results are in agreement with those of Szarka et al. 30, who found that there was a highly statistically significant difference between pre-eclamptic women and healthy women in kidney function tests.
In the present study, there was a highly statistically significant difference between the pre-eclamptic group and the healthy control group in terms of serum albumin and platelet count. Markedly decreased levels were found in severe than mild pre-eclamptic cases. These results are in agreement with those of Benoit and Rey 31, who found that women with severe pre-eclampsia had a significantly lower albumin level (23.5±2.8 g/l) than women with mild pre-eclampsia (25.5±2.8 g/l; P<0.05), and also in agreement with the results of Mohapatra et al. 32, who found that the mean value of the platelet count was significantly decreased in patient with pre-eclampsia.
In agreement with Laivuori 33, there was a highly statistically significant difference between the pre-eclamptic group and the healthy control group in terms of the total protein in 24 h urine collection, which was highly elevated in cases compared with the control group, and this elevation was clearer in the severe than the mild group.
In the present study, the mean values of PLGF in serum were significantly lower in group I (patient with pre-eclampsia) than in group II (control). It also showed considerably decreased levels in severe than the mild pre-eclamptic cases. These results are in agreement with those of Kim et al. 34, who found that PLGF levels were significantly lower in the pre-eclamptic women than in normal controls (median 86, range 29–232 vs. median 146, range 68–380; P<0.001), and also in agreement with Shaker and Shehata 35 and Teixeira et al. 36, who found that the concentration of PLGF was 12-fold lower in pre-eclampsia vs. non-pre-eclampsia pregnancies.
In the present study, in women with pre-eclampsia, there was a highly statistically significant negative correlation between PLGF and systolic (r=−0.688) and diastolic (r=−0.640) blood pressure and protein in 24 h (r=−0.595; P<0.001).
These results are similar to those obtained by Varughese et al. 35, who reported that there was a negative correlation between the serum concentrations of PLGF and blood pressure (systolic blood pressure, r=–0.739, and diastolic blood pressure, r=–0.739, and protein in 24 h in women with pre-eclampsia; P<0.0001).
In the present study, the mean values of sVEGFR-1 in serum were significantly higher in group I (patients with pre-eclampsia) than in group II (control). It also showed considerably increased levels in severe than in mild pre-eclamptic cases, and this is in agreement with Shaker and Shehata 35, and Sunderji et al. 37.
In the present study, in women with pre-eclampsia, there was a highly statistically significant negative correlation between sVEGFR-1 and albumin and platelet count (P<0.001).
These results are similar to those obtained by Maynard et al. 20, who reported that excess serum sFlt-1 concentration may contribute toward endothelial dysfunction, hypertension, and proteinuria in pre-eclampsia.
The mechanisms responsible for the alternation of maternal plasma sFlt-1 and PLGF concentrations in women with pre-eclampsia remain unknown. In-vitro studies have shown that PLGF is decreased 38 and sFlt-1 is increased 39 in trophoblast cells under conditions of reduced oxygen tension. It appears that PLGF deficiency and sFlt-1 excess may result from placental hypoxia associated with incomplete remodeling of maternal spiral arteries.
Finally, it was concluded that the serum sVEGFR-1 concentration showed a highly significant increase and serum PLGF showed a highly significant decrease in women with pre-eclampsia compared with healthy pregnant women. Also, there were significant negative correlations between circulating sFlt-1 and PLGF levels in pre-eclamptic women. The serum level of sVEGFR-1 and PLGF can serve as a marker for pre-eclampsia and aid in the early prediction of patients with severe pre-eclampsia.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]