Gestational diabetes (GDM) may be controlled with diet, but requires medication if symptoms are severe; however, what leads to severe GDM in some at risk women but not others is unclear. To investigate potential placental involvement in GDM, we determined if the placental stress-response is altered in GDM compared to healthy pregnancies and is distinct between mild (diet treated) and severe (medication treated) GDM pregnancies. To investigate if related changes can be detected during pregnancy, we also profiled maternal circulating antioxidant capacity and microRNA expression.

Placental villous tissue (≥37 week’s gestation) and maternal plasma (26–28 week’s gestation) was collected from control (no complications), GDM diet treated (GDMD), and GDM medication (insulin and/or metformin) treated (GDMM) pregnancies (n≥8 per group). Groups were matched for delivery mode, maternal age, maternal BMI, and infant weight. Placental expression of 239 genes was measured by qPCR. Antioxidant capacity was measured by activity assay. Maternal circulating expression of 800 microRNAs was measured using the nCounter system.

Twenty placental genes had potentially biologically meaningful changes. Eight genes were down-regulated and four genes were up-regulated in GDM compared to control. Eight genes were up-regulated in GDMD but down-regulated in GDMM. Placental antioxidant capacity was decreased in male GDMD and female GDMM, and increased in female GDMD, relative to controls. Circulating antioxidant capacity was reduced in GDMM compared to GDMD and controls. The circulating expression of 16 microRNAs was different between GDM and controls. Nine microRNAs were upregulated in GDMD, and five in GDMM, compared to controls.

The placenta may not be adapting successfully in severe GDM cases. There was lower expression of genes involved in antioxidant systems, metabolic pathways, and drug processing in placentae from medication treated GDM, suggesting that these placentae have a dampened response to stimuli. This response at the gene level may relate to an overall lowered antioxidant capacity in GDM in both placental and maternal compartments. Circulating antioxidant capacity and microRNA profiles may be effective in distinguishing which women are likely to require medication. Differences in the placental stress response in GDM may underlie why some women can be managed with diet while others require medication, or may be placental effects of GDM medication.