Preventing Preterm Birth Initiative yields promising research discoveries

Nov. 17, 2016 – In 2011, the Bill & Melinda Gates Foundation committed $20 million to the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS), an initiative of Seattle Children’s, to fund the Preventing Preterm Birth initiative (PPB).

The PPB is part of the Grand Challenges in Global Health, and seeks to discover biological mechanisms that lead to preterm births and develop novel interventions to prevent them. In the five years since its launch, GAPPS has overseen 13 projects funded through the PPB and tremendous strides have been made in preterm birth research.

More than 15 million babies are born too soon every year, and preterm birth is the leading cause of death in all children under 5 worldwide. Despite this high global burden, few strategies have been found that can identify women at risk or prevent preterm birth.

GAPPS was asked to develop the PPB to evaluate if investment in a consortium of innovative investigators could advance the science of pregnancy and preterm birth and identify novel targets for preterm birth prevention. By bringing together experts from a variety of scientific disciplines and creating a collaborative research program, the PPB has yielded promising discoveries in pregnancy health.

"The strength of the PPB consortium is its ability to bring together a cadre of established investigators, both within and outside the reproductive biology community, who regularly question and critique each other’s work and direct ongoing activities to improve project outcomes,” said Dr. Eve Lackritz. “Collaborations among investigators have continued to expand, and increased communication among researchers has benefitted the program as a whole. We’re proud of the investigators and their innovation and accomplishments, which have more than fulfilled the vision of the PPB."

Highlights of the PPB include:

• Seven awards for sophisticated biomolecular investigations of mechanisms of preterm birth, biomarkers, and identification of novel targets for prevention.
• Two awards to field sites with extensive expertise in monitoring pregnant women and collecting biological samples in low- and middle-income countries.
• A pilot project examining a targeted drug delivery system to delay the onset of labor.
• Three awards to researchers using a systems biology approach to harness big data to investigate the complex and interrelated root causes of preterm birth.

The research projects funded through the PPB have identified novel targets for translational opportunity. These include:

• Dr. Sam Mesiano from Case Western Reserve University, who accelerated his production and investigation of candidate SPRMs (Selective Progesterone Receptor Modulators), developed an in-silico 3D modeling technique for selection of candidate compounds, and developed at least one key molecule to move forward in a development pipeline. Progesterone is critical in maintaining pregnancy and these SPRMs potentially could reduce the risk of preterm birth among at-risk women.
• Dr. David Olson from the University of Alberta has identified lead cytokine candidate antagonists for further testing. These include short peptides known as peptidomimetics that potentially could be given orally in low-resource settings. The most promising compound, Rytvela-COOH, was found to block uterine contractility in mouse ex vivo experiments and block preterm delivery in mice.
• Dr. Kevin Kain, from the University Health Network and the University of Toronto, has identified Complement- and Angiogenic- mediated pathways important to malaria-associated preterm birth and stillbirth that potentially could be addressed through micronutrient supplementation in subSaharan Africa.
• Dr. David Aronoff from Vanderbilt University Medical Center has identified dramatic differences in Group B streptococcus (GBS) strains in their capacity to be killed by neutrophils, stimulate inflammatory responses by macrophages, to cause disease, and to form bacterial biofilms that conceal bacteria from the immune system and have recently been implicated in infectioninduced preterm birth. In addition to advancing preventive strategies for bacterial trafficking and preterm birth pathogenesis, the identification of strain differences in pathogenicity has important relevance to the development of selective GBS vaccines for use in pregnant women.
• Dr. Margaret Hostetter from Cincinnati Children’s Hospital Medical Center demonstrated in vitro mechanisms for effects of Candida sp. colonization on the balance of Tregs and Th17 and inflammatory mediators. Vaginal candidiasis, associated with prematurity in several studies, is one of the most common genital tract infections in pregnancy, and could be readily diagnosed and treated in low-income settings.

Highlights from international research sites

The PPB also funded investigators working in Bangladesh and Zambia to implement and develop rigorous, standardized systems for the prospective collection of data and specimens among pregnant women and newborns in low- and middle-income countries. The sites emphasize accurate gestational age dating and characterization of maternal complications and preterm phenotypes. Their work has helped strengthen biorepository systems to accelerate preterm birth research both within the PPB consortium and to the research community more broadly. To date more than 2,600 pregnant women in Bangladesh and more than 800 pregnant women in Zambia have participated in the cohort, and new collaborations are underway. Utilizing the preterm birth field infrastructure and established biorepositories will accelerate discovery, reduce costs, and improve efficiencies in preterm birth research.

Using big data to predict and prevent preterm birth

High-dimensional systems biology technologies such as proteomics, transcriptomics, metabolomics, and metagenomics represent a novel approach to the study of complex biologic processes. Yet these techniques have not been widely used to study determinants of healthy and abnormal pregnancy. When they are utilized, most investigators have utilized a single platform (e.g., proteomics), an approach that has not allowed for an understanding of inter-relationships and pathways that contribute to pregnancy outcomes. The PPB made three awards to investigations utilizing multiple analytic tools and platforms, coupled with computational analysis. Through these projects, multiple biologic fluids collected throughout pregnancy undergo proteomic, metabolomic, and lipidomic analysis, and the vaginal microbiome will be characterized. The projects will serve as a collaborative consortium of investigators, sharing specimens and data, to identify potential biomarkers for healthy pregnancy and for preterm birth.

GCAPR: Advancing visibility and investment to accelerate global preterm birth research The PPB also facilitated the development of the Global Coalition to Advance Preterm birth Research (GCAPR), in partnership with the Gates Foundation, NICHD, and March of Dimes, to advance investment, communication, and coordination of preterm research among funding organizations. GAPPS serves as the coalition’s Secretariat, and priority projects have been selected, including strategies to harmonize preterm birth research studies and accelerate data sharing. Progress in this particular area represents a critical step in building visibility and resources for the generally underrecognized field of preterm birth research.