Decoding the molecular landscape of the placenta in maternal diabetes: a systematic review of high-throughput data

Diabetes in pregnancy is associated with significant short- and long-term complications for both mothers and offspring, many of which are thought to result from altered placental development and function. Although numerous studies have reported molecular changes in the placenta in this context, findings are often heterogenous and the underlying mechanisms remain unclear. High-throughput transcriptomic and proteomic approaches provide powerful tools to interrogate placental molecular pathways; however no systematic synthesis of this literature has been undertaken.

We conducted a systematic review of placental omics studies comparing pregnancies complicated by diabetes with uncomplicated pregnancies. Fifty-six studies met the inclusion criteria, the majority focussing on gestational diabetes mellitus (GDM; n=52). Of these, 42 reported changes in RNA (n=30) or protein (n=12) abundance. Across studies, eight proteins and 189 RNA species were reported as altered in the same direction in at least two independent datasets. Functional enrichment analysis revealed dysregulation of immune, vascular, and developmental pathways. Integration of transcriptomics and proteomics data sets identified 98 molecules altered at both levels, of which 47 showed consistent directionality between studies, indicating convergence on core biological processes despite methodological heterogeneity.

Comparative analyses across diabetes types showed partial overlap of differentially expressed transcripts between GDM and type 1 diabetes (16 genes) and GDM and type 2 diabetes (34 genes), although no molecules were consistently altered across all diabetes types. Collectively, this systematic synthesis highlights recurrent molecular pathways associated with placental dysfunction in pregnancies complicated by maternal diabetes and provides a framework for future mechanistic studies, particularly in type 1 and type 2 diabetes.