**6.1 PIGF (placental growth factor)**

PlGF belongs to the VEGF family, is secreted by trophoblast cells, and has proangiogenic function. Preeclampsia occurs due to an impaired placentation with subsequent ischemia triggers which raised secretion of antiangiogenic factors such as soluble Fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) in the circulation of maternity. This process creates a course of antagonizing the angiogenic factors such as PlGF [45].

PIGF was in an early focus of the research groups in the search for a suitable prediction factor. It turned out that the concentration of PlGF in a preeclamptic pregnancy did not increase to the extent as would be expected in a normal pregnancy [46, 47]. Others could show that in the first trimester, there are already significant differences between PlGF concentrations in maternal blood of pregnant women with normal pregnancy and those that develop preeclampsia during pregnancy [34, 48–50]. Since 2011, the first conventional test of the company Alere allows the quantitative detection of PIGF in anticoagulated EDTA plasma in the first trimester with fluorescence immunoassay (sensitivity and specificity 95%). The detection rate of preeclampsia using PlGF alone for the early-onset preeclampsia is between 41 and 59% and for late-onset preeclampsia 33% [51].

The latest studies show a strong connection between changed levels of PlGF and sVEGF R1 in preeclamptic pregnancy, as well as in those who will eventually develop the condition later in pregnancy. These reports are based on the findings that sVEGF R1 levels increase earlier and to a greater extent in women who eventually develop preeclampsia compared to women with normal pregnancies. In contrast, free PlGF levels in women who develop preeclampsia (compared to women with normal pregnancies) are meaningfully lower. Latest data indicate these markers to be convincing in the differential examinations of hypertensive diseases of pregnancy [52, 53].

#### **Figure 2.**

*An excessive production of sFlt-1 is known in patients with preeclampsia. As an antagonist, it binds with high affinity to free PIGF in maternal serum. Thereby, proangiogenic effects by binding of PIGF to membranous sFlt-1 receptors (a vascular endothelial growth factor) are inhibited and are thought to be responsible for endothelial dysfunction.*

#### **6.2 sFlt-1/PlGF ratio**

Researches show that sFlt-1 is an antiangiogenic molecule and therefore seems to be involved importantly in the pathogenesis of preeclampsia. High levels of circulatings sFlt-1 in early pregnancy are associated with the later commencement of preeclampsia. An in vitro research shows that sFlt-1 inhibits tube formation of endothelial cells from human umbilical vein. In essential cytotrophoblast cell culture, sFlt-1 production and mRNA expression are related inversely to oxygen saturation. A twofold elevation in the level of sFlt-1 was also observed when normal villous explants were exposed to a hypoxic state (1% oxygen), compared with physiologic exposure to 5% oxygen. Therefore, it is reasonable that the hypoxic placenta releases an excess of sFlt-1 into the maternal circulation, which induces maternal endothelial dysfunction and clinical symptoms of preeclampsia. There is also a tendency that an excess of sFlt-1 production can trigger events in the pathogenesis of preeclampsia [55].

Especially, the sFlt-1/PlGF ratio connects to the clinical condition of the disease, differentiates between healthy and preeclamptic pregnancies, and gives a shortterm prediction of disease development. Consequently, the estimation of sFlt-1 and PlGF was measured in clinical routine as a reliable and meaningful tool in examining and monitoring PE [56].

Research on antiangiogenesis factors such as sFlt-1 failed to convince as the exclusive marker for the prediction of preeclampsia in the first trimester [51]. Verlohren et al. showed that the combination of angiogenesis and antiangiogenesis factors, at least in the second and third trimesters, may offer the possibility of a risk classification by an sFlt-1/PlGF ratio. It was found that patients with preeclampsia

**27**

[72, 73].

**6.9 Adiponectin**

*Risk Factor and Biomarker of Preeclampsia DOI: http://dx.doi.org/10.5772/intechopen.85173*

pregnancy [16, 57, 58] (**Figure 2**).

**6.4 Inhibin A and activin A**

maternal circulation [60, 68–70].

**6.8 IGFBP-1 and IGFBP-3**

**6.3 PAPP-A**

**6.5 PP13**

**6.6 PTX3**

**6.7 P-selectin**

had a significantly increased sFlt-1/PlGF ratio compared to patients with a normal

Pregnancy-associated plasma protein A (PAPP-A), an insulin-like growth factor-

binding protein protease, is secreted by the syncytiotrophoblast. As part of the first-trimester screening, it has long been used in risk calculation for chromosomal abnormalities. We could show that patients with decreased levels of PAPP-A in maternal blood during the first trimester develop preeclampsia [54], especially an

Both glycoprotein hormones are produced by the fetoplacental unit. Several studies exhibited that both inhibin A and activin A are increased in the first trimester in maternal blood of patients who later develop preeclampsia compared to pregnant women with normal pregnancies [60, 61]. However, no association is found between impaired trophoblast invasion and subsequent endothelial dysfunc-

The placental protein 13 plays a role in physiological placentation. Because of impaired placentation in the presence of preeclampsia, there is an increased secre-

Pentraxin 3 is a secreted protein as part of an inflammatory immune response and is increased as an acute phase protein molecule [62]. Both with manifestations of PE and before clinical symptoms, there is an increased secretion of PTX 3 in the

As a cell adhesion molecule, P-selectin plays a role in endothelial dysfunction. The consequence of placental ischemia in the context of preeclampsia is endothelial dysfunction and thus increased secretion of P-selectin [71]. This is already detect-

Both insulin-like growth factor-binding proteins are the focus of new research. Both in early- and late-onset preeclampsia, IGFBP-1 is decreased in the first trimester. Such changes are detected by secretion of IGFBP-3 only in late-onset preeclampsia. In both cases, there is no correlation to a disturbed trophoblast invasion

In the case of early-onset PE, adiponectin levels are higher than in the first trimester compared to normal controls. This does not apply to late-onset PE. There

early-onset preeclampsia as revealed also by others [34, 59, 60, 74].

tion and increased concentration of activin A [62].

tion of PP13 in the first trimester of pregnancy [63–67].

able in the first trimester of pregnancy [60, 69, 70].

had a significantly increased sFlt-1/PlGF ratio compared to patients with a normal pregnancy [16, 57, 58] (**Figure 2**).
