In this prospective cohort study, we found that the BMI and MAP of pregnant women who developed HDP were significantly higher than that of normotensive, which indicates that the risk of HDP is greater in women with high BMI and MAP. The research is consistent with Rahman [11]. In addition, the pregnancy method and previous SLE history of pregnant women also suggested that it would affect the occurrence of HDP. Whether other clinical features have an impact on HDP needs further research.
Although the etiology of PE is not fully understood, its development is believed to be mainly related to the superficial invasion of the maternal decidua and spiral artery by extravillous trophoblast(EVT). Hoffmann et al. found that EG-VEGF inhibits the migration and invasion of HTR-8 cells (extravillous trophoblast cell line) and the EVT in the early pregnancy villous explant culture system, and proved that EG-VEGF inhibits HTR-8 cell tissue from entering the tubular structure [10]. The data strongly suggests that EG-VEGF can act as an inhibitor of the differentiation of trophoblasts into an aggressive phenotype. EG-VEGF controls the migration and invasion of trophoblast cells, suggesting that these proteins locally control the process of spiral artery remodeling and fetal-maternal circulation establishment. Our previous studies have shown that during normal pregnancy, EGVEGF peaks in the proliferation and differentiation of placental trophoblasts and early angiogenesis (8–10 + 6 weeks), and then drops to a lower level to maintain until the end of placental recasting (11–20 weeks). This clinical finding suggests that the secretion level of EGVEGF is consistent with its physiological function: high levels of EGVEGF in the first trimester mainly exercise its pro-angiogenic function, and then effectively withdraw (low levels) to avoid inhibiting the normal invasion of EVT cells. In the normal placenta model, the down-regulation of EG-VEGF expression at around 11 weeks of gestation promotes EVT differentiation. In our study, we found that compared with the normotensive group, the persistently high levels of EG-VEGF that can be observed in the first trimester of HDP patients. We speculated that the high expression of EG-VEGF at 11–13 weeks’ gestation may make EVT invade too shallow and lead to insufficient spiral artery recasting and cause pregnancy-induced hypertension. Sergent et al. have shown that in a mouse model, maintaining EG-VEGF levels more than 11.5 days of pregnancy, which is equivalent to the first trimester of pregnancy, can lead to the development of the pathogenesis of HDP [12]. EG-VEGF has been described as a new actor in human fertility and plays a major role in the development of the uterus, placenta, and ovaries. During pregnancy, PROK1 can not only promote the development of chorionic villi, but also regulate placental angiogenesis [8, 10, 13–15]. Its deregulation has been reported to be related to various placental pathologies, such as fetal growth restriction and PE[10, 15]. More interestingly, EG-VEGF has recently been confirmed to be involved in the development of tumors in multiple reproductive organs such as testes, prostate [16]. EG-VEGF can promote apoptosis via regulating PI3K/AKT/mTOR pathway [17] and may be involved in the ability of tumor cells to invade other organs[18]. As PROK1 is a well-known actor in cell proliferation and survival [19], one could speculate that PROK1 might then participate with other factors to the development of HDP. However, the exact mechanism by which EG-VEGF causes HDP is unclear, and we still need to make further study.
Since 2012, the focus of biomarker research has been on the prediction accuracy of sFlt-1, PlGF and sFlt-1/PlGF ratio. Previous studies have suggested that in pregnant women who develop HDP the concentration of pro-angiogenic factor PIGF decreases, and the concentration of anti-angiogenic factor sFlt-1 increases [20, 21], which is consistent with our research. Although elevated sFlt-1 and low PlGF are described as predictors of GHD, the predictive validity of these parameters is still worth exploring. The detection rate of PIGF in the first trimester is 41–59% in early-onset PE and 33% in late-onset PE [22]. A recent study of 4,212 singleton pregnancies showed that PlGF cannot improve the screening performance of early-onset preeclampsia [23]. A study by Boucoiran et al. found that sFlt-1 has a specificity of 90% and a sensitivity of 25% [24]. In a multi-center clinical study conducted, it is reported that the DR of the PGF/sFlt-1 ratio is 82%, and the FPR is 5%, which is especially high for EO-PE (the detection rate is 89%) [22]. Therefore, we hope to compare EG-VEGF with PIGF and sFlt-1 to evaluate its predictive value in this study. Our study found that when EG-VEGF ≥ 227.83 pg/ml, the sensitivity, specificity, positive predictive value, and negative predictive value of EG-VEGF for HDP screening were higher than those of PIGF (43% vs. 33%; 93% vs. 70%; 52% vs. 86 %; 51% vs. 62%). In addition, the positive predictive value of EG-VEGF is also higher than that of sFlt-1 (86% vs. 59%). In this study, EG-VEGF is more specific than PIGF and sFlt-1. This shows that this indicator has a better ability to correctly diagnose it as a non-patient in people who are not actually sick, reducing the waste of medical resources, and alleviating the patients' unprovoked panic and anxiety. The higher positive predictive value allows more people who screen positive to benefit from preventive interventions, reducing unnecessary exposure of the population.
The current guidelines recommend that preventive use of low-dose aspirin before 16 weeks for pregnant women at high risk of preeclampsia can reduce the risk of early-onset PE by more than 60%[25]. The same aspirin intervention after 20 weeks will not be as effective as the first trimester[26]. Therefore, in order to calculate individualized risks, the current trend in screening involves combining the presence or absence of multiple risk factors at 11–13 + 6 weeks. The prediction model we established in the first trimester include maternal BMI, MAP, and EG-VEGF, with an AUC of 0.8861 (95%CI: 0.7905–0.9818), which is better than using EG-VEGF alone (AUC: 0.66). This suggests that the combination of maternal characteristics of pregnant women and EG-VEGF can improve the effectiveness of the current prediction model. Our research supplements the existing evidence that during pregnancy, the maternal characteristics routinely measured in clinical practice, combined with the biochemical marker EG-VEGF, can be used to screen the risk of gestational hypertension and preeclampsia in low-risk populations.
This research has the following advantages: In this study, for the first time, EG-VEGF was included in the prediction model of HDP, and the prediction model showed good predictive performance (AUC: 0.886); all measurements were carried out by trained personnel using recognized standardized methods, enabling the comparison of our findings with previous reports; both patients and care providers were blinded to HDP risk calculation, so as not to affect further management.
The potential limitations of this study as follows: first, it is a single-center retrospective study. We hope but have no chance to verify the most suitable model among external populations from more races, different regions, and different geographic regions. There is still a lack of evidence for clinically practice. Therefore, a larger scale multi-center prospective study is still needed to further verify the role of the examined markers in assessing the severity of PE and pregnancy outcome.Second, the combination of the mentioned thresholds of biomarkers as a biomarker test is only a preliminary suggestion. The level of all biomarkers may vary with race,gestational age, and may also depend on parity and smoking status. Therefore, further research is needed to reduce the bias caused by confounding factors.