Large-scale proteomics in early pregnancy and timing of onset of hypertensive disorders of pregnancy

Hypertensive disorders of pregnancy (HDP) may first be diagnosed antepartum, during labor, or postpartum. We utilized untargeted large-scale proteomics to identify pathways associated with HDP based on timing of onset.

We performed a nested case-control study comparing differential protein expression, from the SomaScan 7K platform, based on timing of onset of HDP (categorized as antepartum, intrapartum, postpartum) versus controls (referent) using first-trimester plasma samples from the NuMoM2b-Heart Health Study, a multi-site prospective cohort that followed nulliparous individuals from the first trimester through postpartum. Associations of individual proteins with timing of onset of HDP, adjusted for co-variates, were assessed using logistic regression q value-based false discovery rates and pathway enrichment and differential expression analysis were conducted.

Of 1628 individuals included, 678 had a HDP, of which 67% initially manifested antepartum (AP), 29% intrapartum (IP), and 3% postpartum (PP). After adjusting for co-variates, compared to controls, 698 proteins, 39 proteins, and 144 proteins were differentially expressed in those with HDP according to AP, IP, PP onset, respectively. There was little overlap in individual protein expression based on timing of HDP diagnosis, with pathway enrichment analysis and graphical summary analysis suggesting distinct processes. Specifically, there was downregulation of angiogenic proteins in AP HDP, downregulation of immune-related proteins in IP HDP, and upregulation of complement activation promoting fibrotic and inflammatory changes leading to cardiac dysfunction in PP HDP.

There are differences in first-trimester protein expression based on whether HDP first manifests AP, IP or PP. This raises the possibility that there may be distinct mechanistic phenotypes that could uniquely inform diagnostic and therapeutic targets for HDP.