Epigenetic and Transcriptomic Signatures of Maternal and Neonatal Risk for Adverse Pregnancy Outcomes Open Access

Abstract

Pregnancy and delivery complications are remarkably common and put both the mother and the neonate at increased risk for both acute and chronic adverse health outcomes. Despite these well-known risks, the underlying etiology of most pregnancy and delivery complications is not clear. The first step in understanding these etiologies is to examine changes over uncomplicated, full term pregnancies. We identify patterns of gene expression changes over pregnancy that are consistent with physiological changes, including changes in oxygen transport, immune factors, and response to microbes. In complicated pregnancies, we identify DNA methylation changes predictive of fetal intolerance of labor, a common pregnancy complication that may indicate the need for a Cesarean section. Thus, understanding the gene expression and gene regulatory changes associated with pregnancy can allow for better prediction of maternal risk.

In addition to maternal DNA methylation changes, neonatal DNA methylation can also serve as a proxy for neonatal risk. We developed a predictor of gestational age at birth based on DNA methylation data from neonatal blood spots and cord blood. The difference between predicted age and clinically estimated gestational age, termed gestational age acceleration, is associated with a variety of factors related to developmental maturity. We show that neonates requiring oxygen, steroids, and surfactant in the neonatal intensive care unit have a lower developmental maturity than those who do not. Additionally, neonates with a lower developmental maturity are more likely to develop bronchopulmonary dysplasia. Gestational age acceleration, therefore, is a useful tool for both clinical and research applications to better quantify neonatal risk. 

Table of Contents

Chapter 1: Maternal and Neonatal Risk Associated with Pregnancy 1

Complications

Introduction 2

Physiological Changes Over Pregnancy 2

Adverse Health Outcomes Associated with Pregnancy Complications 4

Genetic, Epigenetic, and Transcriptomic Signatures of Pregnancy Complications 6

Conclusions 12

References 15

Chapter 2: Characterization of Gene Expression Changes Over Healthy Term Pregnancies 34

Introduction 35

Methods 36

Results 40

Discussion 42

References 54

Chapter 3: SLC9B1 Methylation Predicts Fetal Intolerance of Labor 60

Introduction 61

Methods 62

Results 67

Discussion 69

References 81

Chapter 4: Predicting Neonatal Gestational Age Using DNA Methylation 88

Introduction 89

Methods 90

Results 99

Discussion 105

References 126

Chapter 5: Predicting Perinatal Risk Using DNA Methylation 137

Introduction 138

Methods 139

Results 142

Discussion 144

References 158

Chapter 6: Conclusions and Recommendations for Future Studies 163

References 169 

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Genetics Health Sciences, Obstetrics and Gynecology
Keyword	Epigenetics Genetics Neonatal Pregnancy Methylation
Committee Chair / Thesis Advisor	Alicia K Smith, Emory University
Committee Members	Karen N Conneely, Emory University Anne L Dunlop, Emory University Paula M Vertino, Emory University Jennifer G Mulle, Emory University

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