Preeclampsia is one of the hypertensive disorders of pregnancy, defined by the onset of hypertension and proteinuria after 20 weeks of gestation. It affects 2-8% of all pregnant women and, despite advances in diagnosis and treatment, remains a major cause of maternal and perinatal morbidity and mortality. Research has shown that preeclampsia is most likely the result of abnormal remodelling of the spiral arteries in the placenta caused by genetic, immune and environmental factors in the first trimester of pregnancy. Reduced blood supply and oxygenationreperfusion injury to the placenta lead to morphological changes in the placenta and the release of inflammatory, antiangiogenic, immune, oxidative and vasoconstrictive factors into the maternal circulation, which in turn cause endothelial dysfunction and other characteristics of preeclampsia. The same aetiopathogenesis can also be observed in intrauterine growth restriction, which is a frequent but not necessary accompaniment of preeclampsia. The aim of our study was to use biochemical markers, biophysical parameters and their combinations to elucidate the changes in placental function in preeclampsia and to determine their association with the likelihood of individual and combined complications in pregnancy. We intended to test three hypotheses: 1. In preeclampsia, when the augmentation index (AIx) is elevated and the reactive hyperemia index (RHI) is reduced, placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) levels are reduced, concentrations of soluble fms-like tyrosine kinase (sFlt-1), inhibin A, placental protein 13 (PP13), soluble endoglin (sEng) and tumor necrosis factor alpha (TNF-α) were elevated. 2. An elevated sFlt-1/PlGF ratio in pregnant women with preeclampsia is associated with elevated levels of PP13, sEng and inhibin A, which is probably due to insufficient blood supply and hypoxia in the placental tissue. 3. An elevated sFlt-1/PlGF ratio in pre-eclampsia is associated with an increased augmentation index and an increased degree of endothelial dysfunction. To this end, we compared biochemical markers and biophysical parameters between different groups of subjects with pregnancy complications and a control group of women with normal pregnancies. The study included 36 healthy pregnant women, 30 pregnant women with preeclampsia without intrauterine growth restriction (PE), 43 pregnant women with preeclampsia and intrauterine growth restriction (PE+IUGR) and 16 pregnant women with intrauterine growth restriction only (IUGR). Serum samples were assayed for VEGF, PlGF, sFlt-1, sEng, PP13, inhibin A and TNF-α, and urine samples were used to determine the protein concentrations. Uterine artery blood flow indices were measured by Doppler ultrasound and reactive hyperemia index (RHI) and augmentation index (AIx) by peripheral arterial tonometry. In the first part of the study, where we compared a group of healthy pregnant women with a group with preeclampsia with or without intrauterine growth restriction, we found statistically significantly higher values of sFlt-1 (p < 0.001), sEng (p < 0.001), inhibin A (p = 0.001), sFlt-1/PlGF ratio (p < 0.0001), pulsatility index (PI) (p < 0.001), resistance index (RI) (p < 0.001) and the presence of bilateral notch (p < 0.001). Statistically significant lower values were found for PlGF (p < 0.001) and in the ratio PlGF/(sFlt-1+sEng) (p < 0.0001). Among the individual markers, sFlt-1 (AUC = 0.92) and sEng (AUC = 0.92) and the marker combination (sFlt-1/PlGF)+PI+RI (AUC = 0.97) showed the highest diagnostic accuracy of the test for the diagnosis of PE irrespective of intrauterine growth reastriction. In the second part of the study, when comparing the group of healthy pregnant women with the groups with PE, IUGR and PE+IUGR, we reached similar findings as in the first part of the study. In addition, when comparing between groups of subjects with pregnancy complications, we found statistically significantly higher sFlt-1 and sEng values in the PE+IUGR group compared with the IUGR group (p < 0.001; p < 0.001), as well as higher PI and RI values in the IUGR group compared with the PE group (p < 0.001; p < 0.001), and in the PE+IUGR group compared with the PE group (p < 0.001; p < 0.001). The highest diagnostic accuracy of the test was demonstrated by sEng (AUC = 0.92) in the PE group, sFlt-1 (AUC = 0.95) in the PE+IUGR group and PI (AUC = 0.98) in the IUGR group. The best discrimination between the control group and the PE group was shown by the ratio (sFlt-1/PlGF)+PI+RI (AUC = 0.93), in the IUGR and PE+IUGR groups it was PlGF/(sFlt-1+sEng)+PI+RI (AUC = 0.98; AUC = 0.99). The tests with the highest diagnostic accuracy for PE diagnosis were sEng (AUC = 0.92) and the combination (sFlt-1/PlGF)+PI+RI (AUC = 0.93); for the diagnosis of PE+IUGR, sFlt-1 (AUC = 0.95) and the combinations (sFlt-1/PlGF)+PI+RI (AUC = 0.98) and PlGF/(sFlt-1+sEng)+PI+RI (AUC = 0.98); and for the diagnosis of IUGR, PI (AUC = 0.98) and the combination PlGF/(sFlt-1+sEng)+PI+RI (AUC = 0.99). In the last part of the study, we compared a smaller number of cases with PE pregnancies with or without intrauterine growth restriction (n = 26) with healthy pregnant women (n = 26) and detected similar statistically significant differences in biochemical markers and biophysical parameters measured by Doppler. We also detected statistically higher AIx (p = 0.002) and RHI (p = 0.0138) in the PE group with or without intrauterine growth restriction. In this group, sEng (AUC = 0.91) and the combination PlGF/(sFlt-1+sEng)+PI+RI (AUC = 0.97) had the highest diagnostic accuracy. With our results, we were able to partially confirm all 3 hypotheses, thus using biochemical markers and biophysical measurements to explain the changes in placental function in PE. In this way, we have contributed to a better understanding of the mechanism of preeclampsia and/or intrauterine growth restriction in pregnant women with PE.
|
