Proteomics Analysis of Human Chorionic Villi Reveals Dysregulated Pathways That Contribute to Recurrent Pregnancy Loss

PurposeRecurrent pregnancy loss (RPL) represents a common disorder with consequences on family and society. As more than half of the RPL cases do not have a clearly identified cause, uncovering the mechanisms behind the idiopathic RPL is urgently needed.Experimental DesignUsing label-free data-independent LC-MS/MS acquisition coupled with ion mobility, we compared the proteome of chorionic villi from 13 RPL cases with 10 age and gestational week-matched elective pregnancies. Transcriptional levels of selected candidate biomarkers were determined in chorionic villi of 35 RPL cases and 25 controls using quantitative polymerase chain reaction (qPCR).ResultsStatistically significant difference in abundance (Benjamini-Hochberg [B-H] p <= 0.05) and fold change >= 1.5 showed 128 proteins. Bioinformatics analysis identified complement and coagulation cascades, platelet activation, tricarboxylic acid cycle (TCA) cycle, and ferroptosis as pathways with the highest significance. Correlation with transcriptome datasets revealed a weak statistically significant positive correlation with 45% of the co-differentially expressed proteins/genes displaying the same regulation trend. The transcription levels of neurofilament light polypeptide (NEFL), dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex_mitochondrial (DLST), nitric oxide synthase 3 (NOS3), and ceruloplasmin (CP) were significantly increased in the RPL, consistent with the proteomics findings.Conclusions and Clinical RelevanceOur data suggests alteration of several pathways as potential causes of idiopathic RPL from the fetal side and opens the way for investigations concerning clinical management.