Morphological And Vascular Changes In The Placenta And Its Association With Maternal Plasma Levels Of Selected Biomarkers In Normal Pregnancy And Pregnancy Induced Hypertension (Pih).

Abstract

Hypertensive disorders in Pregnancy contributes to about 12% of maternal deaths in Malaysia and similarly worldwide. Early detection and adequate management are preventable strategies. Biochemical markers of abnormal placentation would be more specific in early detection than the traditional clinical tools used. The aim of this study is to estimate maternal PlGF and sFlt-1 in PIH and to compare these values with normotensive pregnancies. As a corollary, the study also aimed to determine correlation between these biomarkers and morphometry and histopathology. The study examined three core modalities in relation to the investigation of PIH, viz. plasma concentrations of PlGF and sFlt-1 using commercially available test kits, morphometric evaluation and histopathology of the placenta. Statistical comparisan were performed using ANOVA, Spearmans Rank Correlation and Pearson Correlation tests (SPSS version 15.0). PlGF levels were found to be lower in PIH women in comparison to normotensive during antepartum and intrapartum period whereas sFlt-1 was elevated in PIH when compared to normotensives during the same stages of pregnancy. An inverse relationship between these two biomarkers was observed and strengthened by correlation analysis. It was noted that sFlt-1 remained significantly higher in PIH when compared to normotensives in the postpartum period. There were no differences among ethnic group, parity and maternal age. Unlike normotensive women where sFlt-1 level peaks at delivery and yet remain lower than PIH women, sFlt-1 levels in PIH women were much higher than normotensive women and continued to remain high during both antepartum and intrapartum period. PlGF was observed to have significant inverse correlation with total villous surface area of the placental periphery (TCsa – C) and villous capillarisation of the placental periphery (VC – C). Villous capillarisation and intervillous space it was generally observed that PIH women had higher villous capillarisation in comparison to normotensive women in all groups but statistically was not significant. Histopathological scorings by two independent pathologists revealed no significant difference between PIH, normotensive and HPT placentas. When correlating biomarker and histopathology scoring it was observed that when sFlt-1 intraprtum level increases, placental histopathological scoring becomes worse From the findings in this study, several conclusions can be drawn. Firstly, some of the biomarkers (sFlt-1 in particular) are useful and reliable in differentiating normotensive and PIH women. This also directly indicates that sFlt-1 is associated with the occurrence of PIH in women and it is possible that the longer one is exposed to sFlt-1 influence, the higher the likelihood of PIH development. Second, it is likely that the development of PIH in women assessed in this study is related to defective capillarisation since we have shown that there is an inverse relationship between the pro-angiogenic factor PlGF and the anti-angiogenic factor sFlt-1. Third, while morphometric and histopathologic changes were identified in this study, the assessment done using these two techniques showed that these two modalities were unable to distinguish between normotensive, PIH and HPT women, as no significant correlations were observed. However the correlation observed with TCsa – C and VC – C and PlGF indicate possible capillarisation defect, and thus warrants further investigation with a larger sample size in a multi-centric study. This study definitely provides evidence that plasma biomarkers and placental morphometry should remain a mainstay in PIH research and large scale clinical trials using these biomarkers should be conducted to help elucidate the complex mechanism of pregnancy induced hypertension.