"Investigating Placental Inflammation as a Mediator of Maternal Obesity and Risk of Preterm Birth" 

Public Health/Epidemiology

Committee: 
James M. Roberts, Department of Obstetrics, Gynecology & Reproductive Sciences, Department of Epidemiology
Jennifer J. Adibi, Department of Epidemiology, Department of Obstetrics, Gynecology & Reproductive Sciences
Marnie Bertolet, Departments of Epidemiology and Biostatistics and the Clinical and Translational Sciences Institute

Abstract: 
Preterm birth (<37 weeks’ gestation) is the leading cause of infant mortality worldwide. Pre-pregnancy obesity is the most prevalent and potentially modifiable risk factor of preterm birth, which may partially be attributed to placental inflammation. However, evidence of a pro-inflammatory effect of obesity on the placenta in pregnancy has been conflicting due to limited tissue level biomarkers of the placenta and bias attributed to study inclusion criteria. My dissertation uses a combination of placental histopathology and transcriptomic data to address these limitations and determine how pre-pregnancy obesity predisposes women to preterm birth through placental dysfunction.

My first paper leverages placental histopathology reports from a large, contemporary US birth cohort to evaluate if pre-pregnancy obesity increases the risk of acute and chronic placental inflammation in term pregnancies. Obesity was associated with a lower risk of acute placental inflammation, but a higher risk of chronic placental inflammation. After accounting for selection bias, obesity was still associated with risk of chronic but not acute placental inflammation. In my second paper, we performed a cluster analysis of placental features extracted from histopathology reports to classify early (<32 weeks’ gestation) and late (32 to <37 weeks’ gestation) preterm births into placental pathological phenotypes. We found that pre-pregnancy obesity may predispose women to preterm birth through placental vascular impairment and that obesity mainly affects placental health in more severe, early preterm births. In the third paper, we analyzed placental transcriptomic data from two pregnancy cohorts to elucidate inflammatory and non-inflammatory molecular pathways contributing to placental dysfunction in preterm births. Applying high-dimensional mediation analyses, we observed the interleukin 1 receptor-like 1 gene to be a mediator of a positive association between pre-pregnancy BMI and higher gestational age. Interleukin 1 receptor-like 1 is a known inhibitory gene of acute inflammatory pathways.

Contrary to our hypothesis, obesity may predispose women to preterm birth through mechanisms other than acute placental inflammation. We applied various analytic methods to identify preterm birth subtypes most susceptible to the adverse effects of obesity and have characterized nuanced relationships between obesity and placental inflammation to inform future preterm interventions.