Grand Challenges in Global Health: Preventing Preterm Birth
Determinants of Preterm Birth Associated with Bacterial Trafficking from the Lower Genital Tract
David A Eschenbach, MD, Principal Investigator; Kristina Adams Waldorf, MD, and Florian Hladik, MD, PhD, Co-Investigators
Preterm birth (PTB) and stillbirth (SB) contribute directly and indirectly to an estimated 3.3 million deaths worldwide every year. Preterm birth is the 2nd leading cause of neonatal death. The situation is especially prevalent in the developing world where 99% of the ~4 million perinatal deaths occur. Sub-Saharan Africa and South Asia, in particular, have the highest maternal, fetal and neonatal mortality rates and the lowest use of hospitals for delivery or newborn care. In these regions, the adoption of other potentially life-saving interventions aimed at the mother or infant are equally low. While investments in infrastructure, transportation and other basic health services can overcome some of these barriers, there is an opportunity to create the next generation of medical technologies to save lives at the frontline of care. The particular need for better understanding of the etiologies of PTB and SB and novel interventions is further supported by multiple studies suggesting that even if existing preventive interventions were fully scaled, fewer than 20% of PTB and 35% of SB would be prevented. This initiative addresses the urgent need for a broad range of scientific studies to illuminate the root causes, underlying molecular pathways and potential targets for future interventions to improve pregnancy, fetal and newborn outcomes. Furthermore, such studies must be integrated and coordinated to reflect the dynamic processes that result in a continuum of maternal, fetal and neonatal health outcomes, especially in the context of populations where adverse outcomes are prevalent. The goals of the Preventing Preterm Birth (PPB) initiative are to 1) explore underlying mechanisms leading to preterm birth or stillbirth (associated with preterm birth), with emphasis on the role of infection, inflammation and poor nutrition; and 2) initiate studies that within three to four years provide critical discoveries and evidence to guide development and testing of new interventions or refine the application of existing interventions. It is expected that studies funded in this inititive will illuminate potential targets based on basic causes and mechanisms for new intervention development focused on prevention in future clinical trials.
Funding Source: Seattle Children's Hospital Research Institute/Bill & Melinda Gates Foundation
End Date: 6-30-16
Global Alliance to Prevent Prematurity and Stillbirth: Specimen Respository Network
David A Eschenbach, MD, Principal Investigator
The Washington State Prematurity Research Network (WSPRN) is a new and innovative statewide network that collects prospective data and specimens from a cohort of pregnant women to promote the discovery of preterm birth causes and interventions. This coalition of hospitals, providers, and researchers focuses on preventing preterm birth by facilitating new research and improving the quality of prenatal care. Specimens and data will be processed and stored at the GAPPS Repository, which is part of the Seattle Children's Research Institute (SCRI). This critical research resource will allow investigators to answer a broad range of scientific questions about maternal, fetal and newborn health. This effort is led by the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS), an initiative of Seattle Children's that is leading a collaborative, global effort to increase awareness and accelerate innovative research and interventions to improve maternal, newborn and child health outcomes.
Funding Source: Seattle Children's Hospital Research Institute/Gates Foundation
End Date: 12-31-15
GBS-Mediated In Utero Fetal Injury
Kristina M Adams Waldorf, MD, Co-Principal Investigator with Lakshmi Rajagopal, PhD
Morbidity and mortality of human newborns are significant public health concerns. Predominant risk factors for neonatal morbidity and mortality are invasive bacterial infections and the ensuing severe inflammatory response, which mainly begin in utero. Group B Streptococci (GBS) are a significant cause of preterm births, stillbirths and early onset neonatal disease. Factors that facilitate ascending GBS infection from the lower genital tract to the fetus are not understood. Our studies indicate that upregulation of virulence factors facilitate GBS invasion of placental membranes, in vitro. Using human placental membranes and a nonhuman primate model, the objective of this proposal is to mechanistically define how virulence factors enable ascending in utero GBS infection and subsequent fetal lung and brain injury.
Funding Source: National Institutes of Health/ (NIH/NIAID)
End Date: 6-30-17
Environmental Signals that Regulate GBS Virulence
Kristina M Adams Waldorf, MD, Co-Investigator, with Lakshmi Rajagopal, PhD, Principal Investigator
Morbidity and mortality of human newborns are significant public health concerns. Group B Streptococci (GBS) are a significant cause of preterm births, stillbirths and early onset sepsis in human newborns. Although GBS normally reside as commensals in the lower genital tract (LGT) of healthy women, the events that promote transmission of GBS from the LGT to the fetus are unknown. Using human placenta and a guinea pig model of intrauterine infection, the objective of this proposal is to define environmental signals that activate virulence gene expression for ascending GBS infection and fetal injury.
Funding Source: National Institutes of Health (NIH/NIAID)
End Date: 11-30-15
Targeting Leukocyte Activation to Prevent Preterm Labor
Kristina M Adams Waldorf, MD, Co-Investigator, with Stephen Lye, PhD, Principal Investigator (University of Toronto)
The objectives of this proposal are 1) to determine whether peripheral leukocyte activation is associated with labor, 2) analyze how cytokines produced by laboring myometrium activate leukocytes, and 3) use a unique, chronically catheterized, nonhuman primate model of preterm labor to determine whether blockade of this peripheral leukocyte activation and the consequent uterine inflammation through administration of a broad spectrum chemokine inhibitor can prevent infection-induced preterm labor.
Funding Source: Burroughs-Wellcome Fund
End Date: 5-30-18