Womb With a (New) View
The ultimate source of comfort might not be what we thought
The womb has long been thought of as the ultimate safe harbor – a nurturing incubator from which we’re thrust into the harsh environs of the outside world.
But more recently, scientists have discovered that the uterus isn’t always the pristine sanctuary previously thought. For some babies, in fact, it becomes a hostile place from which they are forced to beat a hasty retreat.
Those are the infants born before 28 weeks gestation – some 50,000 of them a year – and they account for as much as 70 percent of neonatal mortality. Alan Jobe, MD, PhD, a Cincinnati Children’s neonatologist, is working to learn more about the effects of the uterine environment on preterm birth.
Sterile? Not So Much
“Historically, preterm labor was looked at as an acute event that occurred during an abnormal pregnancy,” Jobe says. “We now think that, for some pregnancies, the uterine environment is probably not sterile but is in fact an environment harboring low-grade commensal organisms that have been growing for weeks or months - or perhaps even since before conception.”
For some fetuses, this low-grade intrauterine infection is enough to trigger preterm labor and delivery. “We think that a lot of the women who deliver very early gestational age fetuses have actually been carrying infectious organisms for a considerable period of time, in the endometrium, the membranes or the amniotic fluid,” Jobe says.
The women at risk are unaware of their infection because they have no symptoms and many of the organisms at fault are not detectable by traditional culturing methods. They are identifiable only by a molecular test known as a polymerase chain reaction (PCR) analysis for bacterial rDNA.
“It’s not a traditional infection, it’s a colonization that depends on the maternal or fetal inflammatory response to recognize it and precipitate preterm labor,” Jobe says. He attributes some 50 to 60 percent of the pregnancies that deliver before 32 weeks to this chronic, low-grade infection.
Why Some and Not Others?
Yet not all women who have the infection deliver early. To understand what’s different about these pregnancies, Jobe and his colleagues are studying the infectious organism most commonly associated with preterm delivery, ureaplasma. “We know from sampling the amniotic fluid of women for genetic abnormalities – normal, healthy women - that about 15 percent of them carry ureaplasma or mycoplasma in the amniotic fluid. But only a few percent actually deliver preterm.”
In fact, Jobe says, many of these pregnancies go on to be late preterm (32 - 36 weeks) or fullterm deliveries, even when the same infection may be present.
He is working with researchers in Australia to replicate in sheep the same low-grade infection that occurs in the human womb. Sheep are the best animals to study because their 150-day gestation allows researchers to better follow the progression of the infection – and its impact on the fetus. Scientists inject live ureaplasma into the amniotic fluid 50-60 days into gestation and follow what happens.
What they’ve found is similar to what they see in humans. The fetus and the amniotic fluid become colonized with the organism, which elicits a low-grade inflammatory response, but few of the animals go into preterm labor.
Upping the Ante
To further understand why some fetuses withstand infection better than others, the researchers are also conducting experiments with more potent inflammatory agents. The team is using the pro-inflammatory mediators lipopolysaccharide (LPS) and the cytokine IL-1 to induce inflammation in the sheep’s uterine environment.
What they have seen so far is that a single dose of LPS causes a strong inflammatory response in the sheep fetus, while a second dose appears to do little or nothing – a phenomenon called endotoxin tolerance.
“The fetuses are very clever about how they cope with inflammation and infection,” Jobe says. “They appear to have the ability to cope with inflammatory stimuli, tolerize to it and actually develop in spite of it.”
Understanding inflammatory response is tricky, says Jobe, particularly in the fetal environment, where it has been largely unexplored. But he and his team hope that the work they are doing will shed some light on the process and ultimately lead to anti-inflammatory treatments that could be delivered in utero.
“The point of all this is that our immune system is really complicated,” he says. “And when you’re a fetus, it has to be stimulated and programmed. We think that by studying fetal responses to intrauterine inflammation, we will learn a lot about how the developing immune system might be programmed. These studies will also help us understand how exposure to intrauterine inflammation might impact allergic diseases in postnatal life.”
Alan Jobe, MD, PhD, is director, Perinatal Biology and professor, Department of Pediatrics, University of Cincinnati College of Medicine.
