Prenatal Immunomonitoring in Spontaneous Preterm Birth Prevention (PROMIS)

PROJECT SUMMARY/ABSTRACT Every year, more than 15M babies are born too soon, resulting in more than 1M deaths. In fact, preterm birth (PTB) affects approximately 1 in 10 births across the globe, including 1 in 10 US births. Despite this, methods for the prediction and prevention of PTB are sorely lacking. Of note, more than 60% of PTBs are spontaneous (sPTBs), brought about by premature contractions or membrane rupture. The most common finding in sPTB is significant inflammation among the expectant mother. Yet, levels of circulating and even localized inflammatory markers during pregnancy fail to clinically predict who will versus will not progress to future sPTB. Similarly, antibiotics for asymptomatic infections and anti-inflammatories do not reduce risk for sPTB and are therefore not recommended for broad administration. To address such deficits, we developed a novel immunomonitoring method for use in prenatal care with the goal of predicting future sPTB and informing allocation of targeted, preventive interventions. In other words, we aimed to diagnose and address the immunopathologies driving sPTB risk. We have now shown that our novel prenatal immunomonitoring method can predict future birth timing in low-risk cohorts and future sPTB in moderate to high-risk cohorts, outperforming all available methods. In addition, our ex vivo experiments showed considerable inter-individual variation in the immunomodulatory effects of progesterone on immune function during pregnancy, which may explain why the drug is beneficial for some but not others. Thus, quantifying these immunomodulatory effects may provide a direct avenue toward targeted prevention of sPTB using a drug that is known to be safe during pregnancy. In the “Prenatal Immunomonitoring in Spontaneous Preterm Birth Prevention (PROMIS)” study, we propose to refine, expand, and clinically validate our prenatal immunomonitoring methods in a large, diverse clinical cohort. Our long-term goal is to save lives by predicting and preventing future sPTB. Our central hypothesis is that this can be accomplished using our novel prenatal immunomonitoring methods, which aim to diagnose and address the drivers of sPTB risk. To test this hypothesis, we’ll enroll a diverse cohort presenting for the prenatal care of singleton pregnancy, with early pregnancy patient-oriented data and biospecimen collection, mid-pregnancy cervical length measurement, and post-birth medical record review. We’ll test a prenatal immunomonitoring algorithm for the prediction of future sPTB. We’ll characterize the immunomodulatory effects of progesterone and examine the association between this profile and future sPTB. We expect the PROMIS study to produce novel insights into the pathogenesis, prediction, and prevention of sPTB. Importantly, risk prediction and targeted prevention go hand-in-hand, making advancements in one area dependent upon our capacity to advance the other. The potential impact of this study lies in its potential to identify sPTB risk using clinically feasible methods AND characterize risk phenotypes in a manner that allows us to address them. Thus, this project could provide unprecedented opportunity to predict AND prevent sPTB.