Miscarriage is considered the most common kind of pregnancy loss. Up to 25 percent of all known first-trimester pregnancies end in miscarriage, and that number may be even higher for pregnancies that happen so briefly women don’t even know they are pregnant.

For years, researchers have struggled to find an answer, ranging from theories of disease to chromosomal abnormalities in the embryos, with no hard conclusion. Now, teams at the University of Warwick (UoW) in the UK along with University Hospitals Coventry and Warwickshire NHS Trust have found a link between recurrent miscarriage (three or more) and a lack of stem cells in the uterine lining. Their research was recently published in the journal Stem Cells [PDF].

Study co-author Jan Brosens, a professor of obstetrics and gynecology at UoW, has been studying miscarriage for years. Brosens tells mental_floss that in most women, there has been no obvious cause for the recurring loss of pregnancies. “For decades we have been screening for clotting abnormalities and immune disorders, and so on. We started to realize that in the vast majority of women you can test until you are blue in the face and you will find nothing.” The only correlation they did find was that women with obesity were more likely to have a lower number of stem cells.

Determining that the cause of miscarriage was most likely not an underlying illness, they pursued studying “the pathways that lead to miscarriage” and the process of implantation itself, especially since many women with recurrent miscarriage, he says, “will tell you they conceive with great ease.”

They examined uterine tissue samples from 183 women being treated at the hospital’s Implantation Research Clinic. “We were looking for methylation changes,” Brosens says. DNA methylation is an epigenetic mechanism used by cells to control gene expression. It’s also the way embryonic stem cells differentiate into different types of body tissue. Changes in methylation can suggest a problem. “We discovered a big epigenetic signature, which you normally only find in stem cells, was lacking in the culture of patients with recurrent miscarriages,” he says.

Stem cells are what make the endometrium—or uterine lining—sensitive to the chemical signals of an embryo. When an embryo attempts to implant into the uterine lining, the stem cells interpret the embryo’s signals to determine whether the embryo is viable or not, and will make a decision to “invest” in the embryo and accept implantation, or to discard it in the next menstrual cycle.

In women with recurrent miscarriage, the study found that this lack of stem cells causes “premature aging of the tissue of the uterine lining,” says Brosens. “It becomes excessively inflamed.” The inflammatory stage is conducive to conception, but hostile to implantation, because the endometrium then fails to send out the hormone signals that will begin the formation of a placenta to nourish the developing embryo.

There is, however, good news in this equation: “Each time you become pregnant, you become pregnant with a unique embryo and also a unique lining of the womb," Brosens says. "It makes you adaptable.” He adds that most women with recurrent miscarriage will, eventually, sustain a pregnancy if they can persevere. He stresses, though, that “not all miscarriages are bad, because you need to have a process of selection and quality control.”

Even better news is that this research is the first step in creating a predictive test that can screen a woman’s risk of miscarriage without her ever having been pregnant. “I’m confident that using sequencing of the endometrium, we’ll be able to identify markers that will be predictive of risk,” Brosens says.

From there they’re pursuing four aspects of research and treatment: one, to understand how the embryo signals its potential to the uterine lining; two, to learn how to control and maintain the stem cell population in the endometrium; three, to look for the predictive signature in the endometrium that can help assess a woman’s risk of miscarriage; and four, to develop therapies to increase the stem cell supply. For the latter, there is an existing drug that will soon be tested in a randomized, double-blind trial on human subjects.