The mechanisms of deficient placentation in the first trimester remain poorly understood although apoptosis, hypoxia and oxidative stress have all been implicated. High uterine artery Doppler (UtAD) resistance indices (RI), indicative of poor uterine blood flow, have been shown to be predictive of placental complications of pregnancy such as pre-eclampsia (PE), fetal growth restriction (FGR) and stillbirth. We investigated these pathways in placental tissue from first trimester pregnancies characterised by their risk of developing placental complications. We provide evidence that, even in the first trimester, pregnancies with high UtAD RI demonstrate alterations in placental gene and protein expression. Illumina gene microarray analysis demonstrated that first trimester pregnancies with high RI have differentially regulated placental gene expression in pathways relating to immune and inflammatory response, cell motility, cell cycle and apoptosis compared with normal RI pregnancies. Apoptotic markers are significantly higher in high RI placental tissue as determined by western blot analysis of cleaved PARP and caspase 3. Protein expression of the trophoblast survival factor IGF2 is significantly lower. Both high RI and normal RI placental tissue show evidence of hypoxia and oxidative stress, with expression ofHIFla and 2a, HSP 70, presence ofnitrotyrosine residues and lipid peroxidation. We found no exaggerated placental hypoxia or oxidative stress associated with high RI pregnancies, in fact there was significantly lower HIFla protein in these cases. High RI placental tissue demonstrates an altered balance of antioxidant enzyme activity in response to this oxidative stress with significantly lower glutathione peroxidase activity and higher superoxide dismutase activity when compared with normal RI placental tissue. Hypoxia and oxidative stress appear to be a physiological state in early pregnancy, with our data not supporting the concept these are associated with deficient placentation in the first trimester. Higher levels of apoptosis, reduced IGF2 expression and altered antioxidant defences may contribute to abnormal placentation and the later development of pregnancy complications such as PE, FGR and stillbirth.