This is the final published version. It originally appeared in Molecular Human Reproduction, at http://dx.doi.org/10.1093/molehr/gau105. ; Early human placental and embryonic development occurs in a physiologically low oxygen environment supported by histiotrophic secretions from endometrial glands. In this study, we compare the placental metabolomic profile in the first, second and third trimesters to determine whether the energy demands are adequately met in the first trimester.We investigated whether hypoxia-inducible factors, HIF-1a and/or HIF-2a, might regulate transcription during the first trimester. First and second trimester tissuewas collected using a chorionic villus sampling-like (CVS) technique. Part of each villus sample was frozen immediately and the remainder cultured under 2 or 21%O2+1 mMH2O2, and +the p38 MAPK pathway inhibitor, PD169316. Levels of HIF-1a were assessed by western blotting and VEGFA, PlGF and GLUT3 transcripts were quantified by RT?PCR. Term samples were collected from normal elective Caesarean deliveries. There were no significant differences in concentrations of ADP, NAD+, lactate, and glucose, and in the ATP/ADP ratio, across gestational age. Neither HIF-1a nor HIF-2a could be detected in time-zero CVS samples. However, culture under any condition (2 or 21% O2+1 mM H2O2) increased HIF-1a and HIF-2a. HIF-1a and HIF-2a were additionally detected in specimens retrieved after curettage. HIF-1a stabilization was accompanied by significant increases in VEGFA and GLUT3 and a decrease in PlGF mRNAs. These effects were suppressed by PD169316. In conclusion, our data suggest that first trimester placental tissues are not energetically compromised, and that HIF-1a is unlikely to play an appreciable role in regulating transcriptional activity under steady-state conditions in vivo. However, the pathway may be activated by stress conditions. ; This work was supported by the Wellcome Trust (084804/2/08/Z). Funding to pay the Open Access publication charges for this article was provided by theWellcome Trust.