Imaging Innovations for Placental Assessment in Response to Environmental Pollution (PARENTs)

Many epidemiological studies have associated exposure to traffic-derived air pollution from motor vehicles, air toxins from industry and other environmental toxins by pregnant women with measures of poor birth outcomes including preeclampsia (PE), preterm birth (PTB) and intra-uterine growth restriction (IUGR). Preeclampsia, preterm labor and IUGR, collectively known as ischemic placental disease, are strongly correlated with infant morbidity and a host of adult diseases ranging from coronary artery disease to cancer. Although it is widely believed that the pathophysiological mechanisms leading to complications of ischemic placental disease and placental insufficiency have similar biological origins, starting as early as defective placental implantation, to date there are no predictive studies that prospectively examine placental structure and/or function. This may be related to existing technologies, routinely employed in clinical decision-making, such as ultrasonography and certain biomarkers, lacking precision in the first trimester, and adequate sensitivity and specificity in the second to third trimesters. Thus, assessment and prediction of normalcy versus aberrancy of placental function are lacking. Therefore, the overarching objective of this proposal is to develop and evaluate a suit of cutting-edge multi-parametric magnetic resonance imaging (mp-MRI) technologies (primary predictor), and translate these novel placental imaging modalities to assessing the impact of environmental pollution exposure on prediction of the composite of placental aberrancy/insufficiency and related outcomes (PE, PTB and IUGR) (primary outcome).

Our central hypothesis is that chronic exposure to high rates of environmental pollution, independent of socio-economic status (SES), increases the risk of placental insufficiency due to early gestational development of adverse placental structure/function as detected by mp-MRI technological advances.

To test this hypothesis, our interdisciplinary research team at UCLA will first develop non-contrast freebreathing placental mp-MRI, consisting of multi-delay pseudo-continuous arterial spin labeling (pCASL) perfusion and high-resolution multi-contrast structural MRI, which will provide reproducible measures of placental perfusion and tissue microstructure (AIM 1). The novel mp-MRI techniques will be compared to the uterine artery Doppler ultrasound through pregnancy and validated ultimately by the gold standard histological pathology and vascularity of the post-parturient placenta (AIM 2). Lastly, the investigators will perform in-depth analyses of recruited subjects for exposure to environmental pollution and correlate their rates of exposure to extensively collected pregnancy outcomes, towards building a predictive model (AIM 3). Our specific aims are:

AIM 1: Develop non-contrast free-breathing placental mp-MRI techniques that can non-invasively characterize the in vivo placental perfusion and microstructure through all trimesters.

1. Develop a free-breathing multi-delay pCASL sequence using background-suppressed localized-volume 3D GRASE imaging for quantitative measurement of placental perfusion within a 5-10 min scan (1.5x1.5x2 mm3 resolution).
2. Develop a free-breathing high-resolution golden-angle 3D stack-of-radial sequence with self-navigation and retrospective motion compensation using compressed sensing for mapping placental microstructure within a 5-10 min scan (1x1x1 mm3 isotropic resolution).

AIM 2: Evaluate placental mp-MRI by longitudinal comparison with uterine artery Doppler ultrasound through gestation as a predictive marker of placental insufficiency.

1. Conduct a 3-year prospective cohort study of pregnant women, performing newly developed mp-MRI (AIM1) in the 1st and 2nd trimesters in parallel to ultrasound measurement of uterine artery Doppler, to assess mp-MRI prediction capability versus ultrasound.
2. Collect detailed pregnancy outcome data of prospective cohort, including diagnosis, neonatal outcome, and placenta for pathological and histological analysis to ascertain risk factors for placental insufficiency as a response to environmental exposures (AIM 3).

AIM 3: Perform in-depth analyses in recruited subjects to determine associations of environmental pollution exposures and both placental mp-MRI measurements and concomitant pregnancy outcomes.

1. Perform in-depth analyses to measures of modeled environmental pollution exposure in our recruited subjects to assess associations with mp-MRI measures of placental structure and perfusion throughout gestation, taking into account multiple confounding factors such as maternal age at delivery, race/ethnicity, and SES.
2. Correlate mp-MRI measures of placental structure and perfusion throughout gestation with pregnancy outcomes, post-parturient assessment of placental weight, pathology, and neonatal outcomes. These studies will establish the impact of environmental pollution on placental structure and function, and related pregnancy outcomes, with obstetric and neonatal practices embracing surveillance tactics based on the residential location of pregnant women and their offspring. In addition, the proposed research will establish the potential for early recognition of placental insufficiency, thereby staging future strategies of preventive and interventional therapies targeting reversal before encountering detrimental consequences.