Clinical and Molecular differences of hypertensive disorders during pregnancy

Background: Hypertensive disorders of pregnancy (HDP) comprise a spectrum of four subtypes: chronic hypertension (cHTN), gestational hypertension (gHTN), preeclampsia (PE), and superimposed preeclampsia (siPE). Although often characterized as a spectrum of disease severity, there have been limited comparative studies of detailed clinical and molecular characteristics of these disorders. We hereby evaluate HDP subtypes using clinical, placental histopathological and molecular data to compare the similarities and differences between HDP subtypes. Methods: We utilize data from over 10-year-long pregnancy cohort with detailed clinical and placental pathology, as well as placental tissue RNA-sequencing. Clinical diagnosis was based on current ACOG criteria, and placental gross and histologic examination was based on the Amsterdam consensus statement. Results: Clinical data analysis showed cHTN and gHTN to be more likely to have normal placental pathology, while PE and siPE were more enriched in maternal vascular malperfusion (MVM). RNA-seq showed distinct gene expression signatures and pathway activation across our HDP subgroups. We could not identify any molecular evidence that preeclampsia (PE or siPE) was an advanced stage of hypertensive disorder (gHTN or cHTN), but rather identified distinct gene expression profiles between these entities, suggesting preeclampsia (PE or siPE) and hypertension (gHTN or cHTN) are distinct pathophysiological conditions. Finally, we found that, in the presence of MVM, siPE and PE share significant gene expression profiles and pathway activation. Conclusion: Our findings suggest that MVM specifically differentiates pregnancies that progress to PE and siPE. MVM is thought to initiate in early gestation, indicating the cascade to PE/siPE maybe differentiated from gHTN/cHTN early in pregnancy. Incorporating placental evaluation into patient care is essential, in order to probe the etiology of HDP.