Advanced MRI for Uteroplacental Flow, Perfusion, Oxygenation & Inflammation

Decreased uteroplacental perfusion is a recognized antecedent event in pregnancies that ultimately results in adverse outcomes like fetal growth restriction (FGR), preeclampsia (PE) and/or preterm birth. This concept is well supported clinically by identification of spiral artery vascular lesions called acute atherosis. Current literature suggests that these events occur very early which is why we are using multiple techniques related to flow at early time points. We are studying individuals with either poor maternal vascular response and/or inadequate spiral artery remodeling with resultant inadequate placentation will have a reduced uteroplacental perfusion. Given that the spiral arteries draw the vast majority of the blood flow in a gravid state, poor placentation would be reflected in the total uteroplacental blood flow (UPBF), and early detection would allow both design and then routine initiation of novel preventive therapies early in gestation to improve pregnancy outcome.

The goal of this research is to develop an arsenal of advanced ultrasound (U/S) and magnetic resonance imaging (MRI) techniques that are compatible to be run simultaneously or sequentially to probe uteroplacental health and overcome the limitations posed by obesity and motion. While safety concerns remain with MRI, particularly in the first trimester, we will front-load developmental and optimization studies in primate models as "proof of principle" before translating to humans; this conservative approach is key to our achieving paradigm shifting outcomes. A pilot study was completed prior to the main study to evaluate U/S Doppler and 2D PC MRI for UPBF measures that including contributions from the ovarian arteries in addition to the uterine arteries. The pilot study is now complete as the pilot data was evaluated after the enrolled pilot subjects completed the U/S and 2D PC MRI visits.

We are matching all imaging measures with clinical data and blood and urine sample post-hoc analyses for cytokines and tissue-specific metalloproteases, these correlations will further inform a differential diagnosis of distinct disease mechanisms that may otherwise show common imaging outcomes. At the end of the studies on both lean and obese women, we will inevitably have outcomes categorized as FGR, hypertensive and/or PE, perhaps preterm and/or rarely stillbirth outcomes. Using this combination of approaches we will determine: 1) an optimal combination of imaging methods that is practical and sufficiently safe to use in humans; 2) if new data so derived is informative beyond that currently available clinically; 3) at what point in gestation an abnormality may be detected by these new methods relative to current standard clinical measures and/or diagnoses; and 4) if imaging outcomes can predict specific complications, or only warn of a higher risk of general complications.

The primary objective of the ferumoxytol research, conducted under the pending Investigational New Drug Application, is to demonstrate homing of macrophages in vivo in the decidua of pregnancies with reduced uteroplacental blood-flow and perfusion. The secondary objective is to develop a test of placenta function in on-going pregnancies in subjects with reduced uteroplacental blood flow and perfusion. To evaluate these objectives, subjects with and without reduced total uterine blood-flow and possible reduced placental perfusion will receive Ferumoxytol (Feraheme®) prior to dynamic sequences magnetic resonance.