Direct assessment of human placental blood oxygenation can provide valuable information about placental function and, potentially, detect dysfunction. Currently however, no bedside tools exist for noninvasive monitoring of placental oxygenation. Here we report a continuous, non-invasive in vivo method to probe placental oxygen hemodynamics using deep penetrating Frequency Domain Diffuse Optical Spectroscopy (FD-DOS) with concurrent ultrasound (US) imaging. This multi-modal instrument facilitates assessment of placental oxygenation properties from image reconstruction algorithms that integrate anatomical US information about layer morphology with information from optics about functional hemodynamics. Tissue phantom experiments, simulations, and human subject studies validate the approach and demonstrate sensitivity to placental tissue located 5 cm below the surface. In a pilot study (n=24), human placental oxygen hemodynamics are measured non-invasively during maternal hyperoxia. Initial results suggest placental response to maternal hyperoxia may serve as a tool to detect placenta-related adverse pregnancy outcome and maternal vascular malperfusion of placenta, weeks before delivery.Abnormal placental development is widely accepted as the cause of common adverse pregnancy outcomes (APOs) such as hypertensive disorders, fetal growth restriction, and stillbirth. Moreover, placental dysfunction has been associated with morbidities in offspring, including perinatal mortality and long-term neurodevelopmental and cardiovascular consequences 1-3 . To better understand human placental dysfunction associated with these APOs, non-invasive methods that measure placental oxygen dynamics are needed. Ultrasound (US) imaging is the primary clinical modality used for assessing pregnancy; it can provide indirect information about flow resistance in large blood vessels but is used primarily to derive morphological information. Thus, clinical US guidelines do not include direct functional assessment of the placenta 4 . Current knowledge about placental biology has been gleaned largely from ex-vivo tissue and from animal research 5,6 , which have limitations as models for dynamic changes in placental pathophysiology during pregnancy 7,8 . Similarly, the reference literature on placental oxygenation is derived largely from decades-old sheep studies, and from scant human data using invasive sampling techniques that have yielded varying results 7,9 . Lastly, even MRI tools for assessing placental oxygenation 10,11 are poorly suited for bedside monitoring and generally rely on indirect signals 12 .