Preterm labour, a common pregnancy complication, has long been a mystery to scientists. But a new study from the University of California, San Francisco, in the US shows one of the causes of preterm labour may be the fetal immune system “waking up” too early and beginning to reject the mother, causing the uterus to start preterm contractions.

The researchers think the fetal immune system becomes triggered in a case of mistaken identity. An initial infection in the mother can result in inflammation and arouse the fetal immune system. Much like the rejection of a donated organ, the fetal immune cells then confuse the mother’s cells for an invader and mount an attack, in the form of inflammatory chemicals. These chemicals then trigger preterm contractions, leading to premature labour, the leading cause of infant mortality.

“The dogma has always been that the fetus has a very immature immune system, and as a result, people haven’t really considered its possible role in pregnancy complications,” said senior author Dr. Tippi MacKenzie, an associate professor in the UCSF division of pediatric surgery and the fetal treatment center. “We showed that in patients who have preterm labour as a result of some kind of infection or inflammation — the most common cause of preterm labour — the fetal immune system awakens prematurely and may trigger labour.”

In the new study, published in Science Translational Medicine, the researchers tested umbilical cord blood, which contains fetal cells, along with blood taken from 89 women who had healthy pregnancies and 70 who went into preterm labour. But the scientists saw no signs of an immune response in the mother’s blood. Instead, they detected activation in two types of immune cells in the cord blood of preterm infants. The researchers also found greater numbers of the mother’s cells circulating in the cord blood of preterm infants.

During pregnancy, cells from the mother and the fetus travel back and forth through the umbilical cord, across the placenta barrier. Just as in an organ transplant, the immune systems of the mother and the fetus have to tolerate one another, so the fetus is not rejected. This tolerance is governed by immune cells known as regulatory T cells, which dampen the immune system by keeping the other types of T cells in check.

However, during preterm labour the infant’s immune system was found to be activated specifically to attack the mother’s cells. The researchers detected higher levels of both dendritic cells and effector T cells in the cord blood of preterm infants; dendritic cells present foreign substances to the T cells to signify they are a potential threat, and T cells — the primary fighter cells of the immune system — then mount an attack by releasing inflammatory chemicals.

T cells from preterm infants made significantly higher levels of these inflammatory chemicals those from full-term infants, and in a laboratory model of uterine contraction, the researchers discovered that these chemicals induced contraction of uterine cells.

“If you’re a fetus and your immune system is developing in a healthy environment, it’s in your best interest to keep things quiet so that you can develop and be born at a normal time,” said the study’s first author Michela Frascoli, PhD, a former postdoctoral researcher in MacKenzie’s lab, now an adjunct assistant professor at the University of Massachusetts Medical School. “But if you encounter trouble in the form of an infection or inflammation, then that can trigger your dendritic cells and T cells to wake up. Ultimately, it could be a defense mechanism to exit a hostile uterine environment.”

MacKenzie has long studied the fetal immune system in the context of fetal stem cell transplants. She became interested in premature labour during her own pregnancy, when she experienced a long period of bed rest because she was at risk of delivering her baby early.

“The medicines we use to treat preterm labour right now are just aimed at stopping the uterus from contracting. But at that point, the horse is out of the barn,” MacKenzie said. “What we really have to do is diagnose and treat fetal immune activation, which is probably starting weeks before the patient comes in with the uterine contractions.”

Her lab is now pursuing biomarkers in the mother’s blood that can identify whether the fetal immune system is activated and increasing risk for preterm labour.