The impact of maternal glucose fluctuations in gestational diabetes on placental development

Background: Gestational diabetes (GDM) affects around 13% of pregnancies and is associated with an increased risk of infants being born large-for-gestational-age (LGA). LGA can lead to birth complications and infants are predisposed to developing future cardiometabolic disease. The prevalence of LGA remains high even when glycaemia is well controlled and continuous glucose monitoring (CGM) has demonstrated that women with GDM who deliver LGA infants have temporal periods of mild hyperglycaemia. It is unclear how this causes LGA, but LGA has been linked to altered placental development and function. Aim: To determine whether temporal periods of mild hyperglycaemia associated with LGA in GDM impact on placental development and function. Methods: Placental explants from uncomplicated pregnancies were cultured in glucose fluctuations mimicking in vivo levels in GDM. Further RNA sequencing, bioinformatics, immunohistochemistry and ELISAs were performed to predict the functional consequence. Two models were employed to assess the impact of glucose fluctuations on placental vascular development; endothelial-lineage differentiation of placental mesenchymal stromal cells (pMSCs) isolated from term placentae, and a perfusable ‘on-a-chip’ model of placental microvessels. Differentiation potential and microvessel function were assessed by RT-qPCR, and functional assays. Results: Mild hyperglycaemia altered the placental transcriptome and differentially expressed genes (DEGs) were predicted to be associated with vascular development and an anti-inflammatory response. ELISAs and RT-qPCR confirmed downregulation of pro-inflammatory mediators and showed trends towards increased levels of vascular-regulatory M2-polarised placental macrophages (Hofbauer Cells; HBCs). Culture of pMSCs in mild hyperglycaemia had minimal impact on their endothelial lineage differentiation, however vessel development and permeability were altered by glucose fluctuations in the microvessel model. Conclusion: Fluctuations in maternal glucose in GDM can alter the placental transcriptome and may contribute to placental vascular dysfunction, directly and/or via HBCs. This may impact the ability of the placenta to transfer nutrients and gases to the fetus, resulting in LGA.