Before their time
To what extent do genetic variations account for preterm births?
Nearly one in eight babies in the United States is born too early — three or more weeks before the estimated due date. Because these infants are born before their bodies and organ systems have fully matured in the womb, they have an increased risk of heart and lung problems, vision and hearing loss, infections and physical or learning disabilities.
Although there are known risk factors for preterm birth — including having a prior preterm birth or being pregnant with multiple babies, smoking, diabetes, high blood pressure, lack of prenatal care or some infections — for more than half of women who deliver early there is no explanation. And while researchers have made tremendous strides in treating premature infants to ensure their survival, there has been little progress in preventing preterm birth.
Louis J. Muglia, MD, PhD, Alumni Endowed Professor of Pediatrics, and Justin C. Fay, PhD, assistant professor of genetics, suspect underlying genetic changes that have occurred over time may help to explain why some women give birth early and others do not. They are studying these changes through a grant from the Children's Discovery Institute, using new technology to look for genetic variations that may influence the timing of birth.
Muglia and Fay began by comparing DNA from blood samples of 200 mothers who gave birth too early and from 200 women who gave birth at full-term. Their research team is testing individual genes to find those associated with premature birth and looking for genetic variations common in women who have had full-term babies, which might show a protective effect against premature birth.
By looking at genes in both mothers who have had full- and preterm babies, the researchers may uncover a combination of variations powerful enough to initiate preterm birth. Through their studies, they hope to define critical molecular pathways involved in preterm birth and their influence on risk factors such as nutrition and infection, which also may contribute to early delivery.
Their work has progressed more quickly than anticipated partly due to the use of high-throughput DNA genotyping machines recently made available through the laboratory of Thomas M. Morgan, MD, assistant professor of pediatrics. Morgan is using CDI funding to look for the genetic causes of congenital heart disease.
"This state-of-the-art genotyping platform looks at the samples and genotypes of 1 million SNPs (single nucleotide polymorphisms) and several hundred thousand copy number variants," Muglia says. "It allows us to essentially define 1.8 million traits in the human genome looking at the data output from the microarrays."
The research team is among the first to use the high-tech machines, Fay says. During the process, they expect to narrow the field of key genes involved in preterm birth from 25,000 in the whole human genome to 10 that may be present in racially diverse nuclear families in the United States with recurrent preterm birth.
"We are sitting on the most exciting point of a two-year project," Fay says. "Now is the interesting part where we get to look at the data and figure out what genes might be involved in the timing."
As humans evolved from primates, brain size increased and walking upright reshaped the pelvis — changes that made it more difficult for babies to be delivered through the birth canal. Preterm birth ensures that babies will be born before their heads grow too large, but there's a limit to how early babies can be born without health risks.
"Human brain and head size are much larger than those of most other higher primates for a given body size," Muglia explains. "To accommodate this size difference, we suspect there was selective pressure put on genes to push the birth process to the earliest possible time compatible with good fetal survival."
To target genes potentially linked to premature birth, the researchers are scanning the genomes of humans, non-human primates such as chimpanzees and rhesus monkeys, dogs and mice to identify human genes that have accumulated significant changes. Such variations in the DNA code are of interest because they would indicate that a gene has acquired a new function.
The research team expects to spend most of 2008 pinpointing genetic markers that may help doctors predict which women are likely to give birth early. Once they narrow the field, they will test the genes to confirm their results. Eventually, they plan to study the genes of full-term and preterm babies as well to determine any differences.
"These initial studies will allow us to identify genes that are associated with the risk of preterm birth and are viewed as high-priority targets for an even larger international analysis," Muglia said. "If these are confirmed in subsequent validation, they have the potential to determine a woman's risk for preterm birth prior to becoming pregnant and give enormous biological insight into the actual molecular mechanisms in preterm birth."
Finding genetic markers that determine early birth would have a significant impact on child health and premature birth, which results in more than $26 billion in health care costs each year in the United States. The markers could provide a way to identify women who are at risk, to develop new drugs that could treat active preterm labor, to detect premature labor early enough to treat it and potentially to provide a way to prevent preterm birth altogether.
"The goal really is not just to understand the science, but to solve the problem," Fay says. "If we had a biomarker that identified someone at risk for preterm birth, physicians could monitor the mother throughout the pregnancy. If they knew a week or two in advance that the mother was going to deliver early, that would be remarkable."