Preterm birth is a leading cause of both maternal and neonatal morbidity and mortality. It occurs in roughly one in every ten pregnancies, and at an even higher rate among Black Americans and residents of underdeveloped nations. Preterm birth can be initiated in response to a maternal or neonatal indication, or can occur spontaneously.
Though indications for the former may vary, the most frequent indication for indicated preterm birth is preeclampsia, a disorder of pregnancy marked by high blood pressure and systemic organ damage. While spontaneous preterm birth and preeclampsia account for a substantial fraction of the burden of prematurity, our understanding of the triggers for and pathogenesis of both diseases are lacking. As a result, we are not able to accurately identify women early in pregnancy who are at high risk of having a spontaneous preterm birth or of developing preeclampsia. There is mounting evidence that local and systemic inflammation, infection, and environmental exposures impact the vaginal ecosystem and may be triggers of spontaneous preterm birth and preeclampsia. In this thesis, I explore the role of vaginal microbes, metabolites, and immune factors in spontaneous preterm birth and preeclampsia.
After reviewing what is known about the vaginal ecosystem in spontaneous preterm birth and preeclampsia, I present a paired study of the vaginal microbiome and metabolome in a cohort of 232 women, 80 of whom delivered spontaneously preterm, and whose vaginal ecosystems were profiled during the second trimester of pregnancy. In this study I identify several metabolites strongly associated with spontaneous preterm birth, and suggest that many of these may be exogenous in origin. I also use metabolic models to investigate tyramine, a metabolite found to be associated with lower risk of spontaneous preterm birth. Finally, using predictive models I show that vaginal metabolite levels can be used to identify women at risk of spontaneous preterm birth months in advance.
I then present a second study of the vaginal microbiome and immune factors in a cohort of 124 women, 62 of whom developed severe preeclampsia, and whose vaginal ecosystems were profiled at the end of the first trimester. In this study, I demonstrate for the first time that the levels of vaginal microbes early in pregnancy as well as genomic variation in the vaginal microbiome are associated with the risk of developing preeclampsia. I also identify that many vaginal immune factors are significantly depleted in the vaginal ecosystem of women who develop severe preeclampsia. I then use predictive models to show that the levels of vaginal microbes are modestly predictive of preeclampsia risk, and that features from the vaginal ecosystem can be used to improve current methods for the identification of women at risk for severe preeclampsia. Finally, I show that the microbiome signature associated with severe preeclampsia replicates in an independent cohort, suggesting that the early pregnancy vaginal microbiome is robustly associated with the diagnosis of preeclampsia months later in pregnancy.
Overall, the microbial and molecular signatures that I identify in these studies contribute novel insight to our understanding of the signs and pathogenesis of both spontaneous preterm birth and preeclampsia, and in doing so, suggest novel approaches to intervention and diagnosis.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/hdgg-gg49 |
| Date | January 2024 |
| Creators | Kindschuh, William Francis |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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