Development and validation of MR imaging methods for in vivo assessment of placental perfusion and oxygen transport

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PROJECT SUMMARY The capacity of the placenta to supply oxygen and nutrients from the maternal circulation, and eliminate waste products from the fetal circulation, is critical for fetal development and is dependent on adequate maternal- and fetal-placental perfusion. The clinical benefits of developing noninvasive tools for the in vivo assessment of placental function are tremendous. They include the proper diagnosis of placental insufficiency as a cause of fetal growth restriction, and detection of decreased fetal oxygen availability, allowing delivery to be expedited to prevent neurological damage. This proposal combines the strengths of two investigative teams with complementary methodologies, and builds upon our prior placental Magnetic Resonance Imaging (MRI) achievements. Specifically, our team’s use of the pregnant nonhuman primate (NHP) has allowed development of spatial modelling methods of placental function integrating dynamic contrast enhanced (DCE) MRI for validation of T2* relaxation mapping. Our team have also developed novel MR imaging and data modeling methods with simultaneous diffusion-encoded (IVIM-DWI) and multiecho spin-echo acquisitions. Initial clinical application of these methods showed the potential to separately interrogate the materno-placental and feto- placental circulations – this is a critical marker for identifying fetal hypoxia. The overall objective of this proposal is to develop multi-modal MRI and modelling approaches, validated in a clinically relevant NHP model, to provide robust quantitative methods for assessing placental health. The significance of our work derives from combining data generated from multiple contrast techniques that provide estimates of placental perfusion and oxygen saturation, with gold-standard measurement of oxygen level in the fetus and post-delivery measurement of the placental vascular structure in our translational NHP model. By leveraging established and new computational modeling of placental blood flow and function, our unique combination of advanced methods and rich data will let us measure the properties of oxygen transfer to the fetal vasculature (Aim 1). The physiological interpretation of these quantitative parameters will be further validated in studies subject to controlled changes in maternal oxygenation accompanied by measurement of fetal oxygenation (Aim 2). The combination of these methodologies will allow us to quantify and validate the variables that are of most interest to human placenta oxygen perfusion and transport over a range of relevant fetal oxygen levels. The validation of our modeling methods will significantly improve the discriminatory power of MRI in stratifying pregnancies where placental insufficiency and fetal hypoxia is suspected. Importantly, we have acquired preliminary data in our NHP model that demonstrates the feasibility of the approach we are proposing. Successful completion of the intended work will yield a set of novel non-contrast functional and structural MRI placental summary statistics, validated in an appropriate animal model, which can be translated to human studies for early identification of pregnancies at-risk for complications.