the VAGINAL MICROBIOME AND PRETERM BIRTH                            

There are two major projects ongoing in the laboratory that explore the role of the vaginal microbiome in preterm birth. The first project is a collaboration with Dr. Mary Regan, at the University of Maryland School of Nursing and the second project is a collaboration with Dr. Michal Elovitz at the University of Pennsylvania School of Medicine. 

Influence of Modifiable Factors on the Vaginal Microbiota and Preterm Birth

Preterm birth (PTB) is the leading cause of infant mortality and incurs billions of dollars per year in avoidable health costs. The causes of preterm birth are not well understood but are thought to originate from complex demographic, biological and behavioral factors. More recently vaginal dysbiosis - disruptions in the vaginal microbiota - have been shown to be associated with PTB. Studies have also shown that the composition and the frequency and duration of dysbiosis in the vaginal microbiota may be affected by the same demographic, biological and behavioral factors that are known predictors of preterm birth. This proposed study will examine the contribution that social and bio-behavioral factors known to be associated with PTB have on the composition of the vaginal microbiota as well as the frequency and duration of vaginal dysbiosis. The overall goal of this study is to elucidate the relationship between social and bio-behavioral factors, the vaginal microbiota and birth gestation. Specific aims include characterizing the effect of social and bio-behavioral factors on birth gestation (Aim 1) and on the vaginal microbiota (Aim 3), characterizing the effect of the microbiota on birth gestation (Aim 2) and quantifying the role of the vaginal microbiota in the relationship between social and bio-behavioral factors and birth gestation (Aim 4). In this prospective cohort study, 400 women will be followed from 20 weeks gestation through to birth. By recruiting pregnant women from neighborhoods in Baltimore City with higher than average PTB rates we expect that at least 16% of the cohort will experience premature birth. Weekly self-collected mid-level vaginal swabs will be obtained using a validated protocol. Diet information, vaginal and prenatal health behavior data will be collected via a web- based application specifically designed for this study. Structural equation modeling and mixed effects models will be used to test the hypotheses. The sample for Aims 1, 3, and 4 will include the full cohort while Aims 2-4 will use a subsample of cases that deliver preterm and age-matched controls. Vaginal swabs and pH for the women that experience PTB and the age-matched control will be analyzed using r16S culture-independent techniques. Findings will provide essential knowledge about the influence that modifiable social and bio- behavioral factors have on the composition and frequency and duration of vaginal dysbiosis during pregnancy the PTB.

This research reported is supported by the National Institute of Nursing Research, of the National Institutes of Health under award R01NR014826.

REVEALING THE ROLE OF THE CERVICO-VAGINAL MICROBIOME IN SPONTANEOUS PRETERM BIRTH

Worldwide, 13 million infants are born preterm each year. In the United States, approximately 1 in 8 live births are preterm. The economic burden from prematurity is enormous costing over 28 billion dollars a year. These costs are not just for immediate neonatal care but also for long term care of these preterm children who are at increased risk for a spectrum of medical and neurobehavioral disorders. Currently, we have no effective strategies to predict or to prevent the majority of preterm births (PTBs). Based on the current model, key events in the pathogenesis of PTB are uterine infection and contractility. Assuming this model to be valid, the only strategies to decrease the risk for PTB are to monitor for increased uterine contractility and/or to treat the presumed underlying infectious process. Unfortunately, clinical trials attempting to treat or prevent uterine contractions and/or to treat infections have failed. Based in part on new findings linking, for example, dysbiosis of microbial communities (microbiota) inhabiting the human gastrointestinal tract to disease states through immune responses at the mucosal barriers, we propose a revised paradigm for the pathogenesis of PTB. Whereas PTB result from microbiota dysbiosis in the cervicovaginal (CV) compartment leading to a local immune response and altered tissue (cervix) homeostasis. The dysregulated immune response, mediated by the CV epithelial barrier, promotes changes in the cervix which leads to PTB. Furthermore, we propose that certain factors (e.g. behavior, social, environmental) known to mildly increase the risk for PTB, actually serve to alter the CV microbiota; thus, contributing to the pathogenesis of PTB. We hypothesize that microbial communities in the CV space will be stably composed of Lactobacillus spp. throughout pregnancy in women who are destined to have a term delivery. However, we propose that microbial communities will be less stable and enter states depleted of Lactobacillus spp. in women destined to have a PTB. Furthermore, specific microbial communities will induce an unfavorable immune response from the CV mucosal barrier; thus, microbial communities will be found to play a mechanistic role in PTB. This new paradigm will dramatically alter clinical care by allowing the identification, through the characterization of the CV microbiota, of the majority of women at risk-months prior to a clinical event- thus, providing opportunities for low-risk, feasible interventions. We have assembled an interdisciplinary team of experts in the field of reproductive medicine, microbiology, and perinatal nursing. We propose to assemble a prospective cohort, enriched with women with a prior PTB, that will allow for 3 longitudinal assessments during the 2nd and early 3rd trimester. At each study time point, we will determine the CV microbiota, the CV host immune response and determine if there are any molecular changes in the cervix consistent with premature cervical remodeling. In addition, we will comprehensively assess if behavioral, social and/or environmental factors modify the CV microbiota and/or its association with PTB.

This research reported is supported by the National Institute of Nursing Research, of the National Institutes of Health under award R01NR014784.