Increased Lipoprotein associated phospholipase A (LpPLA) has been associated with inflammatory pathologies, including Type 2 Diabetes. Studies on LpPLA and Gestational Diabetes Mellitus (GDM) are rare, and have focused mostly on maternal outcome. In the present study, we investigated whether LpPLA activity on foetal lipoproteins is altered by maternal GDM and/or obesity (a major risk factor for GDM), thereby contributing to changes in lipoprotein functionality. We identified HDL as the major carrier of LpPLA activity in the foetus, which is in contrast to adults. We observed marked expression of LpPLA in placental macrophages (Hofbauer cells; HBCs) and found that LpPLA activity in these cells was increased by insulin, leptin, and pro-inflammatory cytokines. These regulators were also increased in plasma of children born from GDM pregnancies. Our results suggest that insulin, leptin, and pro-inflammatory cytokines are positive regulators of LpPLA activity in the foeto-placental unit. Of particular interest, functional assays using a specific LpPLA inhibitor suggest that high-density lipoprotein (HDL)-associated LpPLA exerts anti-oxidative, athero-protective functions on placental endothelium and foetus. Our results therefore raise the possibility that foetal HDL-associated LpPLA might act as an anti-inflammatory enzyme improving vascular barrier function.