• The Genetic Connection

    Keys to prematurity may hide in 'experiments of nature'

    After decades of research and continued puzzlement over the causes of preterm birth, the answers are likely closer than we think – although well hidden inside us.

    Uncovering those answers is the impetus behind a new comprehensive study into the human genetics of prematurity – a collaborative, multi-institutional effort led by Louis Muglia, MD, PhD, Director of the Center for Prevention of Preterm Birth and Co-Director of the Perinatal Institute at Cincinnati Children’s.

    “I don’t want to give the impression that we think genetic variations drive the majority of preterm births, but we think genet­ics will allow us to get a handle on the molecular pathways and processes of prematurity,” Muglia explains.

    This is not the first time researchers have analyzed how genes might affect birth timing and particularly, the timing of premature birth. Plenty of effort has gone into trying to understand this health challenge, but with fairly modest results. Mainly because of changes in obstetric practices, the US preterm birth rate has declined slightly in the past few years. Still, preterm birth rates remain nearly 30 per­cent higher than 20 years ago, Muglia says.

    Going Big and Bold

    In hopes of turning the tide, the new genetics study will gather a large and well-characterized group of research participants. These new participants will be added to a list of about 2,000 families Mug­lia has recruited since 2004 in research collaborations involving the University of Iowa, Washington University, Vanderbilt University and the University of Helsinki in Finland.

    Attracting a larger complement of participants – especially members of families prone to preterm birth – will help strengthen the study’s statistical and informational power, according to Emily DeFranco, DO, a maternal-fetal medicine specialist at the Univer­sity of Cincinnati and Cincinnati Children’s who is collaborating on the project.

    “Because the study is an avenue to give us a better perspective of the genetic influences of prematurity, we will invite the participation of families who have multiple members affected by prematurity,” DeFranco says.

    What makes the new study different from past efforts is the sheer magnitude of the scientific and human resources that research­ers will assemble – locally, statewide and beyond.

    Clinic to Focus on Family History

    On the local level, a new Familial Preterm Birth Clinic will open at Cincinnati Children’s this fall. The clinic will enlist women with family histories of preterm birth to participate in the study, whether they are planning a pregnancy, are currently pregnant, or have had an earlier preterm birth.

    They will receive a comprehensive medical evaluation, be made aware of preventive interventions, and have the opportunity to par­ticipate in the genetic research studies. Using the latest genetic se­quencing and analysis technology, Muglia will attempt to identify genes associated with preterm birth and look for variations between normal populations and those prone to prematurity. The goal is to find strong genetic associations for preterm birth, then use this in­formation to feed studies linking genetic indicators to environmental factors such as lifestyle, health influences and socioeconomic traits

    Starting with the Basics

    Muglia says it makes sense to start by looking first at the genetics of families prone to preterm birth for no apparent reason, who have no obvious contributing lifestyle or other strong risk factors. Focus­ing on women who have risk factors highly associated with preterm birth could create too many potential variables.

    Researchers believe families who lack obvious risks might serve as proverbial “canaries in the coal mine” – their genetic indications might rise to the surface more clearly.

    Scientists then plan to see if genes identified in these families might also apply to Cincinnati’s and Ohio’s populations at high risk for preterm birth – especially those in Ohio’s inner cities.

    Although earlier studies by Muglia and others have identified a few candidate genes for preterm birth, researchers enter the new study with a more or less blank slate.

    “The thing about modern genomic approaches is we don’t have to restrict ourselves or hedge our bets to what we think may most likely be involved,” Muglia says. “We’ll let the information we find tell us. What we are doing is focusing on experiments of nature – identifying and studying families that have multiple instances of children born prematurely for no reason we can identify.”

    Working with Community Obstetricians

    Multi-institutional collaboration will be critical to the study’s suc­cess. Cincinnati Children’s will collaborate with obstetrical provid­ers throughout Cincinnati. Muglia says the Familial Preterm Birth Clinic will not replace a woman’s current pregnancy care provider. “We just want to understand why some families are at such high risk,” he says.

    The clinic will obtain DNA samples for research, get the family medical history related to preterm birth, and offer perinatal health counseling that might be beneficial to the women, according to DeFranco.

    “The majority of women who come to the clinic will probably be those who have had spontaneous preterm births, where they just go into labor early for no apparent reason,” she says. “Those are the preterm births that tend to cluster in families,”

    DeFranco says she expects research participation rates to be high among this group of women, who tend to be proactive about their reproductive health. She also believes it will yield useful information.

    “We hope the study will help increase awareness and we will gain a lot of knowledge that will help us find potential interventions to reduce prematurity.”

  • Dr. Louis Muglia.

    Genes could be one of the many possible causes of preterm birth, says Dr. Louis Muglia. A new genetics study will add to a growing body of research on women with family histories of preterm birth.

  • Prematurity: Is It All in the Family?

    Linda Cyr’s four children were all born prematurely. So was she. She still has questions about why the births happened the way they did. Now that her kids range in age from 13 to 21, Linda considers her family fortunate, but continues to look for answers.

    “I have no idea why this happened,” she says. “If there is any thinking that it could be a genetic issue, I wish I’d known. I could have been a lot more prepared.”

    Now almost 50, Linda was born a month before she was due.

    “They never really did tell my mother why,” she says. “My father tells me my moth­er would go to the grocery store and pick up chickens and cry because I weighed less than the chickens.”

    When Linda and her husband, Billy, decided to have their own family, both were type-A Princeton graduates who planned ev­erything meticulously. They even researched how to have a healthy pregnancy.

    Most of the first pregnancy went smoothly, until contractions started com­ing early. Their son Britt was born a month ahead of schedule.

    With her second child, doctors put Linda on bed rest for two weeks to delay de­livery. But daughter Peppar arrived 13 weeks premature. Linda credits steroid shots for helping Peppar’s lungs develop quickly. After three months in the hospital, Peppar came home with no major health complications.

    With her third and fourth babies, Linda had her cervix sewn shut to try to prevent more early deliveries. But Tigar’s traumatic birth came at 35 weeks, and a car accident prompted Tindar, her fourth child, to arrive early as well.

    Each early birth carried its own set of worries, including an emergency blood transfusion, jaundice, breathing and heart­beat scares, pneumonia, concerns about eye­sight, hearing and balance, signs of autism – and with one child, even mild cerebral palsy.

    The experience left Linda feeling that more needs to be done to advance research. Daughter Peppar, now 19, hopes to study medicine and work on finding those an­swers.

    “Even though my family has come out of this with positive outcomes, we see it as an important thing to have research going,” Peppar says. “Just because you have positive outcomes doesn’t mean you should be bank­ing on that.”

    Visit the Cincinnati Children's YouTube channel to learn more about the Cyr family’s experience.