Born too soon
Can evolution guide the search for genes involved in preterm birth?
We humans are a big-headed lot. We need the space for our large brains – they’re what make us human, after all. But our outsized pates are not so optimal when it comes to being born and fitting through the female pelvis, narrowed by our fondness for walking on two legs.
It usually works – we’re born before our heads get too big to fit. Evolution finessed the parameters to get it right, posits Louis Muglia, M.D., Ph.D.
“We think that human pregnancy had to adapt and push the time of birth to the earliest compatible with optimal survival for both the mom and the fetus,” says Muglia, Edward Claiborne Stahlman Professor and vice chair for Research Affairs in the Department of Pediatrics at Vanderbilt University Medical Center .
Yet there is a problem: This year more than half a million babies in the United States will be born too soon – before 37 weeks of the usual 40 week term. The nation’s preterm rate, 12.8 percent, is among the highest in the Western world. It also has been increasing rapidly, by 10 percent during each of the past four decades, for reasons that are not well understood.
That’s why Muglia and others have been thinking about the evolutionary “push” in human birth. It could point to the genes that control the biology of birth timing – and which might participate in causing birth to occur too early.
Premature babies spend their first days, weeks and even months in a neonatal intensive care unit (NICU). They face an increased risk of death and serious medical complications, including chronic lung disease, cerebral palsy (prematurity is the main cause of cerebral palsy), learning delays and other neurological, digestive, vision and hearing problems.
The cost of these complications is enormous – an estimated $26 billion a year in the United States. But Muglia says that’s an underestimate. “You really can’t put a price on some of the very long term functional deficits these children have,” he says. “The strain on families and society, both emotionally and financially, is tremendous.”
Prematurity also appears to increase a person’s susceptibility to diseases like diabetes, obesity and cardiovascular disease in adulthood.
Some babies are delivered early for medical reasons – our increased ability to monitor fetal well-being enables us to detect and deliver a baby that is in distress. Medical indications account for about 25 percent of all preterm births.
The remaining 75 percent are spontaneous preterm births. About half of these can be linked to a factor known to increase risk for premature birth – such as infection, maternal drug use or multiple gestation. Assisted reproductive technologies, such as in vitro fertilization, and women having children later in life both have contributed to an increase in the number of twin pregnancies.
The other half, representing nearly 40 percent of all preterm births, has no known cause.
Doctors currently are ill-equipped to stop preterm birth. Once labor begins, it can be delayed for perhaps two days – long enough to administer steroids that can help fetal lung maturation, but not long enough to change the frequency of adverse outcomes.
“I think the question of birth timing is one of the most important questions in reproductive biology right now,” Muglia says. “Only by preventing the early life adverse outcome of premature birth can we block acute and later adult problems as well.”
For Muglia, who came to Vanderbilt in 2009 from Washington University in St. Louis, the problems of prematurity resonated during the six months he spent as a pediatrics resident in the NICU at Children's Hospital Medical Center in Boston.
He was struck by the fact that the infant in the “enormous facility filled with isolettes and heating tables and sophisticated equipment of many kinds” were not sick because there was anything wrong with their developmental programs, but simply because they had been born too soon.
The biology fascinated him. “Who’s responsible for the timing of pregnancy – is it the mom, is it the baby, is it both? And how do we go about unraveling that biology?” he wondered.
To begin to get at these questions, Muglia and his Washington University colleagues turned to animal models – a common approach for exploring the physiology and genetics of biological processes. They studied various genetically altered mouse models, and they made good progress, Muglia says, in elucidating the pathway that is essential for birth timing in mice.
The investigators know that mice (and other animals) experience a precipitous drop in the pregnancy-supporting hormone progesterone just before they deliver. And they know that an increase in inflammatory molecules causes the ovary to stop making progesterone. They were also able to pinpoint what makes the inflammatory molecules, and where they’re made.
The problem? In human pregnancy, the drop in progesterone that’s so essential to birth timing in the mouse doesn’t happen.
“So all those steps in mice that lead up to that fall in progesterone don’t predict what’s going to happen in humans,” Muglia says.
The studies did point to conserved pathways, Muglia points out. If progesterone falls during human pregnancy, the pregnancy will terminate; inflammatory molecules (prostaglandins) can be used to accelerate birth timing; and anti-inflammatory therapies can delay the progression of preterm labor (by blocking prostaglandin-mediated uterine contraction).
But which conserved molecules are most important, where they are produced, and whether the signals are fetal, maternal, or both, are open questions, he says.
“We feel that the signals in birth timing and the physiological pathways are poorly enough known right now that we want to take an open-ended approach to understanding the critical determinants of regular pregnancy, and which of those are disrupted that lead to preterm birth,” Muglia says.
Muglia suggests two general “models” for prematurity.
In one model, something acute (like an infection) triggers a baby to be born too early.
In the other model, genetic programming sets a variable window for birth timing, and some women are genetically predisposed to having a relatively earlier birth. Muglia and colleagues opted to pursue the second model – to look for the genes that set the birth timer.
But first they needed to probe the likelihood of this explanation: could genetic influences determine a risk for prematurity?
In initial studies, the researchers examined the recurrence of preterm birth to an individual mother. They used a database of 1.5 million births in Missouri between 1978 and 1997 that included all births to a given mother and a number of risk factors.
Their analysis suggested that mothers who had already had a preterm birth had two to three times greater risk of having a preterm birth in a subsequent pregnancy than women who had a term birth in a first pregnancy.
An interesting finding from the study was that when mothers had a recurrent preterm birth, it was usually within the same week of gestation as the first preterm birth.
“If you thought there was a random environmental influence, you wouldn’t expect it to cause the timing to repeat across pregnancies,” Muglia says.
The investigators also have examined birth timing in twins – births to identical twin sisters compared to non-identical twin or non-twin sisters. Twin studies allow the team to model genetic factors, shared environmental factors and unique environmental factors.
“We can show that there’s no way to generate the patterns that are observed unless there is a significant genetic component to maternal birth timing.”
To probe the genetic contribution of the fetus, Muglia’s group performed a similar twins versus siblings study focused on the fathers.
They found no evidence for a strong paternal genetic contribution to birth timing, which suggests there may not be a strong fetal contribution, though the studies didn’t rule out genes from the mother that might be expressed by the fetus, Muglia notes.
These and other studies have supported the notion that maternal genes (expressed either in the mother or in the fetus) are key determinants for preterm birth. Muglia estimates that 30 percent to 40 percent of the variation in birth timing is due to genetic factors.
Now at Vanderbilt, Muglia’s team is one of many searching for genes that will predict whether a woman has an increased risk of having a preterm infant.
For the past several years, investigators including Scott Williams, Ph.D., an investigator in the Vanderbilt Center for Human Genetics Research, have assessed variations in so-called “candidate genes” – genes with roles in biological pathways that are hypothesized to increase risk for preterm birth (such as infection- and inflammation-related pathways).
And although they have found compelling associations for certain genes and preterm birth in some study groups, corroborating these findings in other groups of women has been difficult.
“One of the problems with the genetic studies to date is that preterm birth clearly falls into multiple, heterogeneous sub-phenotypes,” Williams points out.
Sub-grouping preterm births based on characteristics such as preterm rupture of membranes, presence of infection or week of gestation (early, mid or late preterm), he says, might improve investigators’ ability to find genetic culprits. But such sub-grouping comes at a cost in numbers, and genetic studies rely on very large groups of patients in order to have the statistical power to find small but biologically important differences.
As a next step in the gene chase, the field is banding together to conduct “genome wide association studies” (GWAS) – analyses that search for common genetic variation that increases susceptibility for preterm birth. Common genetic variants are spots in the genome where a variable “letter” of the DNA code is present in at least 5 percent of the population. Williams is one of the leaders of an international consortium (the Preterm Birth Genome Project) that is contributing DNA samples to a combined dataset for analysis.
Muglia’s team also is pursuing GWAS studies. But he’s most excited about his team’s analysis of rapidly evolving genes. These are the genes that differ most between humans and chimps – our closest living relatives – and other animal species. And these are the genes that might have changed, Muglia proposes, to move birth timing earlier to accommodate our large heads.
The relative immaturity of a human baby at birth also appears to support an evolutionary push to earlier birth times. A newborn chimp has normally developed vision (can fix on an object and follow it), good motor coordination and nearly erupted teeth. Human infants can’t “fix and follow,” have very little motor control and won’t have a first tooth for about six months. Cross-species comparisons of measured traits like gestational duration and body size (“allometric scaling”) predict that human gestation should last 11 to 12 months (rather than the usual 9 months), again supporting evolutionary pressure for early birth.
In collaboration with Justin Fay, Ph.D., a comparative genomic biologist and assistant professor of Genetics at Washington University, Muglia and additional colleagues at Vanderbilt and Washington University have used computational methods to compare the human genome to the chimp, rhesus, cow, dog, rat and mouse genomes. With this approach, they have identified about 200 genes that specifically changed in humans.
The investigators have now examined these rapidly evolving genes for a role in preterm birth, and they have identified “some very interesting prospects that look like they’re associated with preterm birth,” Muglia says. They are working to validate these findings in other larger populations.
“What we’re hoping is that genetic variants we detect – in this relatively non-biased way – will give us insight into biomarkers for preterm birth and improve our ability to predict who is at increased risk and should be followed more closely.”
The genes might suggest ways to intervene – such as a nutritional supplement analogous to folic acid for the prevention of neural tube defects, he adds.
Muglia is keeping mum about exactly which genes are looking interesting. He estimates that within a year or two, his team will know if the prospects hold up.
But for now, it’s too early to say.
See related story on the "placental clock."
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