Research Collaborative Aims to Advance Understanding of Preterm Birth

Feb 2 2015

Research Collaborative Aims to Advance Understanding of Preterm Birth

preterm birthWhat causes preterm birth and how to prevent it remains a perplexing riddle in medical science. One in nine babies in the U.S. is born prematurely, according to the March of Dimes, and this rate has barely budged despite years of investigation.

Finding the solutions will require the ingenuity of researchers and physicians at The Children’s Hospital of Philadelphia who are part of a transdisciplinary team established by the new March of Dimes Prematurity Research Center at the Perelman School of Medicine at the University of Pennsylvania. They will apply sophisticated technology and methodology in molecular biology and genomics to help better understand the basis for preterm birth and eventually diminish the leading cause of newborn death in the U.S.

Babies born before 37 weeks are considered to be premature, and because their bodies and organ systems have not matured completely, they often need help breathing, eating, fighting infection, and staying warm. They can have long-term health problems, including cerebral palsy, cognitive impairments, and sensory disorders.

The March of Dimes announced in November that it will invest $10 million over the next five years to create the Prematurity Research Center, which is one of four launched by the foundation since 2011. The new center involves more than 40 investigators who will focus on three research themes that aim to generate important new discoveries regarding preterm birth: bioenergetics and genetics, cervical remodeling, and placental dysfunction.

“This kind of cooperation and collaboration is on a different scale than has ever been developed for preterm birth,” said Rebecca A. Simmons, MD, the project leader for the bioenergetics and genetics theme and an attending neonatologist at CHOP and the Hospital of the University of Pennsylvania. “It’s not only collaborative across our campus and many different departments within the Penn/CHOP system, but we also collaborate between centers, which is a very unique structure.”

The other transdisciplinary prematurity research centers include Stanford University School of Medicine in California; a partnership of Ohio research centers in Cincinnati, Columbus, and Cleveland; and Washington University in St. Louis.

At CHOP, the March of Dimes is particularly interested in researchers’ expertise in mitochondrial biology and biochemistry. Mitochondria are organelles often described as the body’s cellular power plants because they systematically extract energy from nutrient molecules (substrates) that is necessary to perform cells’ most basic and critical functions. Along with Marni Falk, MD, director of the Mitochondrial-Genetic Disease Clinic at CHOP, and Neal Sondheimer, MD, PhD, an attending physician at CHOP, Dr. Simmons will investigate how impaired cellular metabolism could result in power shortages in the reproductive tract that contribute to preterm labor.

“Reproductive tissues — the placenta, the uterus, the cervix — require a huge among of energy,” Dr. Simmons said. “But if for some reason the mitochondria aren’t able to utilize substrates normally, those reproductive tissues may not function properly.”

The study team will look at reproductive tissues from mice and humans with preterm birth to identify any patterns of mitochondrial dysfunction and then see if these disturbances interfere with the tissues’ ability to maintain bioenergetics and metabolic stability during pregnancy.

The Prematurity Research Center’s second theme ties into this hypothesis by exploring how the microbiome may influence cervical remodeling, which is a dynamic process during delivery that transforms the cervix from a rigid structure into a pliable passageway for a baby. The microbiome is a community of bacteria that normally inhabit the vagina and cervix. Preliminary studies suggest that the microbiome is different in women who experience preterm birth. The researchers will explore if abnormal bacteria cause mitochondrial distress and inflammation that accelerates cervical remodeling.

Michal Elovitz, MD, associate professor of Obstetrics and Gynecology and director of the Maternal and Child Health Research Program at the University of Pennsylvania, will lead the theme two projects. Samuel Parry, MD, associate professor of Obstetrics and Gynecology and chief of the Division of Maternal-Fetal Medicine at the University of Pennsylvania, is the project leader for theme three, which also will focus on mitochondrial deficiencies and an unhealthy microbiome as possible factors that disrupt metabolic processes in the placenta and lead to early labor.

“If we do find changes in the microbiome, those are targets for therapeutics that can be developed,” Dr. Simmons said. “We’ll look for strategies to either change the composition of the microbiome or change how the microbiome is functioning.”

Some of the answers to the medical mystery of preterm birth also may lie within complex gene-environment interactions that new research approaches could help to unravel. The study teams will explore the evolving field of epigenetics, which is the study of mechanisms that change how genes are expressed without altering the underlying DNA sequence.

They expect to gain insights into the multiple pregnancy-related risk factors — biological, behavioral, social, physical, and environmental — that could cause epigenetic modifications. For example, Dr. Simmons will explore in theme one how any abnormalities in the genes and biochemical pathways that regulate mitochondrial metabolic function could have a role in preterm birth.

“We think that if we can identify novel metabolic pathways, we can certainly design future interventions,” Dr. Simmons said.

As the Prematurity Research Center moves from the discovery phase to targeting and developing therapeutics, the researchers hope that their findings along the way will spark additional preterm birth studies. The Center will offer a series of pilot grants to investigators to encourage them to tackle this important health challenge. Dr. Simmons expects the first request for grant proposals to be issued in February.

Deborah A. Driscoll, MD, the Luigi Mastroianni Jr. Professor and Chair of the Department of Obstetrics and Gynecology at the Perelman School of Medicine at the University of Pennsylvania, is the director of the Prematurity Research Center, and Dr. Simmons, the Hallam Hurt Professor of Pediatrics, and Dr. Parry are the principal investigators.