Wednesday, September 06, 2017
A massive DNA analysis of pregnant women has identified six gene regions that influence the length of pregnancy and the timing of birth. The findings, published today in the New England Journal of Medicine, may lead to new ways to prevent preterm birth and its consequences—the leading cause of death among children under age 5 worldwide.
The study, coordinated by Louis Muglia, MD, PhD, co-director of the Perinatal Institute at Cincinnati Children's and principal investigator of the March of Dimes Prematurity Research Center--Ohio Collaborative, together with Bo Jacobsson, MD, PhD, of Sahlgrenska Academy, University of Gothenburg, Sweden and the Norwegian Institute of Public Health, Oslo, involved data from more than 50,000 women.
The globe-spanning team included first author Ge Zhang, MD, PhD, of the Division of Human Genetics at Cincinnati Children’s, along with researchers from Norway, Denmark, Finland, Sweden, Yale University, University of Iowa, and the genetic testing company 23andMe. Vital funding was provided by the March of Dimes, the National Institutes of Health, The Research Council of Norway, Swedish Research Council and the Bill & Melinda Gates Foundation.
The March of Dimes Prematurity Research Center--Ohio Collaborative, launched in 2013, is responsible for the gene identification component of the network of five Prematurity Research Centers nationwide established by the March of Dimes to identify the unknown causes of preterm birth. Because preterm birth is a complex disorder with many possible causes, other Prematurity Research Centers are charged with exploring different aspects of preterm birth and how to prevent it. The centers work together on complementary investigations and share data and biosamples to accelerate progress.
Preterm birth is defined as any birth occurring before 37 weeks of pregnancy. In addition to the risk of death, babies who survive an early birth often face serious, lifelong health problems, including chronic lung disease, vision and hearing impairment, cerebral palsy, and neurodevelopmental disabilities. The scientific world has been hunting for the causes of preterm birth for decades.
“We have known for a long time that preterm birth is a combination of genetic and environmental factors. Previous research has suggested that about 30 to 40 percent of the risk for preterm birth is linked to genetic factors. This new study is the first to provide robust information as to what some of those genetic factors actually are,” says Dr. Muglia.
“This is a very exciting discovery that can be expected to lead to the development of new treatments to prevent pregnant women from going into labor too soon and to give more babies a healthy start in life,” says Stacey D. Stewart, president of the March of Dimes. She noted that identifying the biologic causes of preterm birth will be necessary for the United States to reach the March of Dimes goal to reduce the preterm birth rate to 5.5 percent by 2030.
Dr. Muglia notes that this study assembled extensive genomic data from at least five times as many pregnant women than had been gathered by any previous study of pregnancy and preterm birth. The findings are based heavily on data from more than 44,000 women who provided saliva samples to 23andMe. These women also answered questions about their past pregnancies and agreed that their genetic information could be analyzed, anonymously, for science.
The other crucial reference data set involved more than 8,000 Nordic women with the assistance of the Mother Child Cohort of Norway (MoBa); The Finnish Birth Cohort (FIN); and the Danish National Birth Cohort (DNBC).
“In the past year, there have been several successful large genome-wide association studies of reproductive behaviors; in that context, I think this study is particularly important because of the immediate clinical relevance of gestational timing,” says David Hinds, PhD, 23andMe Principal Scientist and Statistical Geneticist, who helped to co-author the paper. “This work shows that genetics can improve our understanding of variation in timing.”
“These are exciting findings that could play a key role in reducing newborn deaths and giving every child the chance to grow up smart and strong,” says Trevor Mundel, President of the Global Health Division of the Bill & Melinda Gates Foundation. “Not only did the study reveal several genes linked to pre-term birth, it also identified a simple, low-cost solution – selenium supplements for expectant mothers – that, if confirmed, could save thousands of lives. It’s a great example of the power of public-private partnership.”
Today’s breakthrough findings lead to several key implications:
In the months and years to come, much more research will be conducted to build upon today’s findings.
For example, work is underway to launch studies in Africa and Asia to determine how precisely the gene associations found in this study apply to non-European populations.
Planning work has started to conduct more-specific testing of selenium levels in pregnant women in low-income nations and areas within the United States.
Dr. Muglia noted that today’s findings will also be part of a March of Dimes Prematurity Research Center database that will allow researchers to study the importance of these genes not only in isolation but in context with other potential factors in preterm birth now under investigation, including:
The March of Dimes Prematurity Research Center--Ohio Collaborative partners are Cincinnati Children’s Hospital Medical Center, University of Cincinnati, The Ohio State University, Nationwide Children’s Hospital, Mount Carmel Health System, Case Western Reserve University, University MacDonald Women’s Hospital and Rainbow Babies & Children’s Hospital, and the MetroHealth System.
The other centers are located at Stanford University School of Medicine; Washington University in St. Louis; University of Pennsylvania Perelman School of Medicine; and University of Chicago-Northwestern University-Duke University.
Zhang, G, Feenstra B, Bacelis J, et al. Genetic Associations with Gestational Duration and Spontaneous Preterm Birth. N Engl J Med. DOI: 10.1056/NEJMoa1612665.
The paper appears free online beginning at 5:00 p.m. Eastern time, Wednesday, September 6 and will be in the September 21 printed issue of the New England Journal of Medicine.
Major funding and collaboration for the study were provided by the March of Dimes, White Plains, NY; Cincinnati Children’s Hospital Medical Center; 23andMe, Inc., Mountain View, CA; Bill & Melinda Gates Foundation, Seattle, WA; the National Institute of Child Health and Human Development, Bethesda, MD; The Finnish Birth Cohort (FIN); Mother Child Cohort of Norway (MoBa); and the Danish National Birth Cohort (DNBC).
Other partners in the study in the U.S. included Fifth Third Foundation, Cincinnati; The Broad Institute of MIT and Harvard, Cambridge, MA; Carver College of Medicine, University of Iowa, Iowa City, IA; Massachusetts General Hospital, Boston, MA; Stanford University School of Medicine, Stanford, CA; Wayne State University, Detroit, MI; and Yale University, New Haven, CT.
The March of Dimes is the leading nonprofit organization for pregnancy and baby health. For more than 75 years, moms and babies have benefited from March of Dimes research, education, vaccines, and breakthroughs. For the latest resources and health information, visit our websites marchofdimes.org and nacersano.org. If you have been affected by prematurity or birth defects, visit our shareyourstory.org community to find comfort and support. For detailed national, state and local perinatal statistics, visit peristats.org. You can also find us on Facebook or follow us on Instagram and Twitter.
For the first time, we have robust clues about the genetic pathways that can lead to a woman’s risk for preterm birth. This offers the potential to develop new ways to prevent preterm labor and spare babies from being born too soon.
This is just the beginning of the journey, but we think it leads to an exciting horizon where we can really make a difference in human pregnancy.
Infants born before 37 weeks of pregnancy are considered preterm. In the U.S., preterm births occur in 9.6 percent of all pregnancies.
More than 15 million babies worldwide are born preterm each year, and about one million of them die as a result. Preterm birth and its consequences are the leading cause of death for children under age 5. Infants that survive preterm birth often do so only after weeks, even months of tremendously expensive intensive care. Even so, some of the smallest, earliest born survivors grow up to face life-long health risks including chronic lung disease, vision and hearing impairment, cerebral palsy and other neurodevelopmental conditions.
Preterm birth also places enormous emotional and financial burdens on families, from the risk of uncovered health bills to weeks and months of lost time from work.
When babies are born as close to full-term as possible, everyone benefits.
By analyzing data from more than 50,000 women, the research team identified six gene areas, or loci, that were associated with gestational length and preterm birth.
These loci include EBF1, EEFSEC, and AGTR2, which were associated with both gestational length and preterm birth and WNT4, ADCY5 and RAP2C, which were associated with gestational length, but not with preterm birth (see #13 below for more information on these genes).
No. These are the gene associations that probably have the biggest effects. As we collect information from even more individuals, we may see other, less frequent gene associations that also may have an effect.
A wide variety of factors can be involved in early labor and preterm birth, including smoking, poor nutrition, chronic high blood pressure, diabetes, and a medical history of multiple miscarriages or previous preterm births. However, in more than 50 percent of preterm births, we do not know the cause. Doctors call these “spontaneous” preterm births.
Right now, doctors cannot predict which women are at risk. Knowing the genes associated with the length of pregnancy can help experts look for ways to detect early signs of preterm birth risk, and to begin developing ways to intervene.
Identifying a gene implies a pathway to pharmaceutical or other forms of treatment. However, even with these new findings, developing tests to predict risk or treatments to prevent preterm birth will require several more years of study.
A number of small studies over the years have suggested potential genetic links to preterm birth. But those findings have not stood up to further confirmation. This study is the first with enough participating women for scientists to feel confident about the findings.
Detecting the genes most responsible for length of gestation has been especially difficult because pregnancy and childbirth are enormously complicated processes, with multiple genes involved. In addition to numerous tissues and biological functions involved, two sets of genes may play a role—those of the mother and the developing fetus. All of these factors make conditions like preterm birth much harder to explain than single gene disorders.
Only in recent years has genomic technology advanced enough to allow scientists to look directly at human genetic data from large numbers of people at affordable costs.
For example, it took experts about 15 years to gather a crucial reference data set involving more than 8,000 Nordic women. By partnering with 23andMe, a direct to consumer genotyping company, the team gathered data from another 44,000 women in about two years.
One important aspect of this paper is that all six of the identified gene areas involve only the mother’s body. Also, for first time scientists have an idea of where the critical genetic variations are happening.
While previous research had focused on changes occurring in the uterus or the cervix, one of the genes detected in this study (WNT4) strongly suggests that the lining of the uterus—a unique type of tissue called the decidua—plays a driving role in preterm birth.
Looking at the decidua suggests a new way of thinking about preterm birth. Some of the risks may be occurring very early in pregnancy, just when implantation occurs.
Another gene association (EEFSEC) points to the possible role of micronutrients in a woman’s diet, including one nutrient that experts had not considered important to a healthy pregnancy: selenium.
Selenium is a common dietary mineral found in some nuts, certain green vegetables, liver and other meats. In the body, selenium is important for anti-inflammatory and antioxidant processes. Most people eating a healthy diet get plenty of this mineral. Selenium deficiencies are most likely to occur in people living in regions with low selenium in soil and diet, and people in the U.S. who live in low-income “food deserts.” The amount of selenium found in the soil varies widely around the world. Some European countries actually supplement soil with selenium to make sure foods contain a normal amount of the mineral.
However, it remains unclear whether some women face higher risk of preterm birth simply because they do not eat enough selenium-rich food, or whether their bodies do not properly absorb the mineral.
The U.S. recommended dietary allowance (RDA) of selenium is 55 micrograms per day. The safe upper limit is 400 micrograms per day. Taking more than this amount can be toxic.
Many multivitamins do contain selenium, but this study does not address how much a woman should have. More study is needed before experts can recommend a selenium target for healthy pregnancy.
We are launching a new study to build upon today’s findings. Experts plan to measure selenium levels during pregnancy in women throughout the world and investigate whether those levels are associated with risk for preterm birth.
Scientists also plan to extend the findings more precisely to Asian and African populations. The current findings primarily reflect women of European ancestry.
More research also is needed to explore potential new candidates for drug development. This study identified a cell receptor that seems to be involved in determining the length of gestation. However, much more work must be completed to develop a medication based on that finding.
Helping more preterm babies survive has been one of the great advances in pediatrics over the last 30 years. The future we see is someday putting ourselves out of the business of running neonatal intensive care units (NICUs) because understanding these genetic pathways helped us make preterm birth a problem of the past.