The placenta is a vital specialized organ connecting the mother and the fetus and plays an important role in the healthy normal pregnancy. The key role of villous trophoblasts in the development of PAS is well-known. The molecular mechanism of PAS is not clearly described.
For the placental development, there should be coordination between the angiogenic and anti-angiogenic growth factors and their receptors. The Antenatal diagnosis of placenta accreta spectrum provides an opportunity to coordinate a multi-disciplinary team for managing the placenta accreta in a tertiary center. Pre-operative diagnosis and planned managements decrease the maternal and neonatal morbidity and mortality.
In Iran, the rate of C/S is much higher than the world health standards. It includes 50–60% of total deliveries and 90% of which occurs in the cities and private hospitals [25].
Most of the studies have investigated the placental level of the angiogenic and antiangiogenic factors while the studies on the serum level of these factors are considerably low. According to the results of this study, the maternal serum levels of angiogenic factors could be have predictive value for the prenatal diagnosis of PAS.
In the present study, the value of VEGF and PLGF in predicting PAS was investigated. The maternal serum level of the PLGF in pregnancy was found to be accurate in diagnosing the PAS, whereas maternal serum level of the VEGF had no diagnostic accuracy. Also, though the maternal serum level of the VEGF was lower in the PAS group, the difference was not statistically significant and the level of the PLGF was not affected by the depth of invasion.
In the present study, the gravidity, number of C/S, and age in the accreta group were significantly higher than the normal group that is similar to previous studies [18].
Overall, the present findings indicated that the maternal serum of the VEGF is not an accurate predictor of PAS, whereas the PLGF has more accuracy and might be suitable for the diagnosis of the PAS in pregnancy.
The PAS is a multifactorial complex: abnormal decidualization, abnormal maternal vascular remodeling and increased trophoblastic invasion are the important cause of the PAS[2]. Decidua is the source of the VEGF and PLGF and with the paracrine mechanism regulate the trophoblastic invasion[18].
Both VEGF and PLGF are glycoproteins. These factors with 4 isoforms have an important ‘role in the angiogenesis, decidual vascularization, growth, differentiation and trophoblastic invasion. The VEGF has 3 receptors and is bound to both receptor 1 and 2 with high affinity. The VEGFR-1 is a kinase insert domain-containing receptor (KDR) and the VEGFR-2 is Fms-like tyrosine kinase receptor (Flt-1). The PLGF only exhibit the high affinity binding to the Flt-1 receptor [26].
In vitro and in normoxic conditions, in term of the placenta, the level of the PLGF was higher than the VEGF and in hypoxic condition, the VEGF expression was upregulated, while the PLGF expression was decreased. Thus, according to the oxygen tension, the level of these factors could be changed [26].
The Soluble Flt-1 is the Antagonist of the VEGF. The hypoxia leads to a decrease in the sFlt-1 and hyperperfusion can increase the expression of the sFlt-1in the villous trophoblasts [20].
The PAS has tumoral behavior with epithelial mesenchymal transition in trophoblasts [27]. With the excessive neovascularization, it upregulates the angiogenic factors such as VEGF and angiopoietin 2 (Ang-2) and downregulates the antiangiogenic factors such as sFlt-1 and VEGFR-2 in syncytiotrophoblast [22].
Compromised oxygenation in the scars of C/S is the cause of excessive trophoblastic invasion to the myometrium. Thus, in the PAS, maternal serum level of the total oxidative stress decreases and the total antoxidative stress increases [28]. In this study, the placenta previa was relatively associated with the placenta percreta indicating the implantation in the area with the lesser blood supply results in hypoxia and further more placental invasion.
Several studies revealed that the expression of angiogenic factors such as VEGF, PLGF, ICAM-1, EGF, and TGF- β increase in the placenta and myometrium of the patients with the placenta accrete and expression of VEGF-R decreases[21–23, 28].
These studies did not evaluate the maternal serum level of the angiogenic factors. In a study by Hacer Uyanıkoğlu et al, the maternal serum level of the VEGF, PLGF, and sFlt-1, compared to the control group, was lower in the patients with the placenta percreta [29].
Wehrum et al analyzed the maternal serum level of the VEGF, PLGF, and sFlt-1 between patients with and without complete placenta previa He found that the serum level of the VEGF decreases in the patients with the placenta previa and accrete, while only placenta previa did not affect the serum level of these 3 factors and also, serum level of sFLt-1and PLGF in both group were similar.
Also, placenta level of the VEGF was high in the patients with the PAS[6]. In another study by Biberglu et al, it was found that maternal serum level of VEGF, PLGF and sFLt-1 have not statistical difference between patients with and without PAS and theses angiogenic factors has not the predictive value for the diagnosis of the PAS [30]. In the present study, the low serum levels of the VEGF were detected which were not statistically significant.
The serum level of the VEGF in the PAS may be decrease due to various causes: consumption of the VEGF in the placenta or the increase in the serum level of the sFlt-1 which is binding to VEGF; however, in this study the serum level of sFlt-1 has not checked.
Lack of the decidualization and consequently a decrease in the production of the VEGF in decidua could be another cause of the low serum level of the VEGF.
In hypoxic conditions such as preeclampsia, VEGFR-1 increases and causes a decrease in the serum level of the PLGF in the patients.
In concordance to present study, in the hypervascularity conditions such ass placenta accreta, the anti angiogenic factor including VEGFR-1 decreases leading to decrease attachment of PLGF to its receptor .the final consequence of this phenomenon is increased serum level of PLGF [22, 31, 32].
There were some limitations in the present study, including inability to check the maternal serum levels of the angiogenic factors in the first trimester, in implantation time, and serial evaluation in each trimester. The study also did not check the placenta levels of the angiogenic factors and their receptors in placenta .
Though the age, gravidity, and the number of C/S in both groups were different, there was no correlation between these factors and the level of the VEGF and PLGF. However, the study had some strength points including the evaluation of the correlation between the age, gravidity, and the number of C/S with the rate of the placenta accreta. Also, the blood sampling in the control group was performed before 34th weeks. Another strength point was the large sample size of the PAS group, while the previous studies had a more limited sample size. Besides, the present study excluded the patients with the comorbidities that could affect the angiogenic factors.
In conclusion, regardless of the depth of the myometrial invasion, the maternal serum level of the PLGF was found to be the most accurate accreta predictor of the PAS and the VEGF showed a low diagnostic accuracy. It seems that there need further studies for evaluating these angiogenic factors as new targets in the diagnosis and management of the PAS.