*3.4. PP13 and Preeclampsia*

Preeclampsia, a severe life-threatening complication of pregnancy characterized by hypertension, proteinuria and organ failure [57–60] is mainly attributed to impaired placentation [61,62]. It a ffects ten million pregnan<sup>t</sup> women globally, and is often accompanied by fetal loss and major newborn disabilities ([63]—www.preeclampsia.org). The hunting for serum markers to predict the risk to develop this pregnancy complication was a major challenge in the first decade of the 21st century [64]. We explored the potential use of PP13 as a biomarker for predicting the risk to develop preeclampsia. The availability of the purified native and recombinant PP13 have stimulated the generation of various poly- and monoclonal antibodies, followed by the development of an ELISA immune-diagnostic kit [50]. With these tools in hands, a comparative analysis of PP13 levels in maternal blood was conducted in multiple studies [65–68].

The studies have shown reduced concentrations of maternal blood PP13 in the first trimester in pregnancies that subsequently developed early, preterm and term preeclampsia with and without fetal growth restriction (FGR) [66,69–78]. Longitudinal studies have shown that in preeclampsia there is a sharp increase of PP13 between the first to the third trimester with the slope of change predicting the severity of the subsequent complication [42,75]. Such PP13 increase also predicts severe hemorrhage after delivery [79]. Interestingly, in twin pregnancies that subsequently develop preeclampsia, the level is very high already in the first trimester, indicating accelerated processes of impaired placentation in multiple pregnancy, corresponding with their higher frequency of the disorder [68].

In studies where term placentas were obtained after delivery, the mRNA levels of PP13 were 3.5-fold lower in women who developed PE and the related HELLP syndrome [45,65]. Additional studies have shown that the reduced PP13 mRNA can be determined already in the first trimester in patients who subsequently developed preeclampsia [80–82]. Unlike the protein level that tends to increase near the time of disease, low PP13 mRNA was detected throughout pregnancy. It was subsequently discovered by in-vitro placental explant studies that in a normal pregnancy the release of PP13 from a single placental villus is decreased from the first to the third trimester. During the first trimester of normal pregnancy the level of PP13 in maternal blood increases from 200–300 pg/mL to 400–600 pg/mL [42] due to the increase in the total number of villi during pregnancy [83]. In contrast, villi of preeclamptic placentas showed an elevated PP13 release at the time of disease [83]. It is estimated that aponecrotic release of PP13 from the large number of damaged villi accounts for the sharp slope of the PP13 level in maternal blood during the etiology of preeclampsia [36].

In a meta-analysis of 18 studies that investigated maternal blood levels of PP13 during the first trimester, reduced PP13 levels were found in women who subsequently developed preeclampsia about 20 weeks later. If evaluated in the first trimester as a single biomarker PP13 provided 83% detection rate for 10% false positive rate for early preeclampsia ( <34 weeks), 66% for preterm preeclampsia (<37 weeks), and 47% for all cases of preeclampsia [66]. PP13 combined with first trimester Doppler pulsatility index of the blood flow through the maternal uterine arteries and the use of additional markers provides higher detection rates of preeclampsia in the first trimester [66,84].
