New research from the University of Connecticut presents an intriguing hypothesis aiming to explain the causal mechanism that triggers premature birth. It's suggested a specific small protein, released by the immune system, could be a major cause of preterm birth, and inhibiting its release may prevent premature labor.

A baby born at fewer than 37 weeks of gestation is generally considered a preterm birth, and this is the most common cause of infant death worldwide. While we know of several risk factors that can contribute to the chances of a preterm birth (including smoking, diabetes, and stress), the underlying cause or mechanism that triggers such early labor is still unknown.

Prior research has revealed a high volume of cytokines in the amniotic fluid of women after premature births. Cytokines are important immunomodulating proteins produced in response to an infection, and are known to regulate the behavior of many different types of cells. The researchers wondered if premature birth was somehow triggered by an immune response that is usually suppressed during pregnancy.

"There's a lot of anti-inflammatory mechanisms that prevent the fetus from being rejected," says Anthony Vella, an immunologist working on the study. "So we thought maybe dangerous inflammation, that can break down the tolerance barrier, could mediate the start-up of birth."

In lab conditions, the researchers exposed mesenchymal stem cells, taken from amniotic fluid and the female reproductive tract, to bacteria. The goal was to observe what kind of cytokines were released by the cells in response.

The initial results were unexpected. High volumes of a very specific cytokine were identified. Called granulocyte-macrophage colony-stimulating factor (GM-CSF), this cytokine is known to specifically trigger cells to rapidly mature into macrophages, the immune system cells that consume foreign substances. It is unknown exactly what role macrophages play in the onset of labor, but they have been found to significantly increase in volume before a woman gives birth.

The last stage of the research was to examine whether inhibiting the production of GM-CSF actually prevented pre-term birth. Luckily, there are already drugs developed to block GM-CSF, particularly as a prospective treatment for rheumatoid arthritis. The experiment utilized mouse models where preterm birth could be triggered via the introduction of a dangerous bacteria. The results were quite impressive, with the rate of preterm births reducing from around 66 percent to just 25 percent in the mice treated with the GM-CSF inhibitor.

It is still much too early to clearly tell whether GM-CSF is a key causal agent in human premature birth, but the researchers are excited to move forward with the work and begin exploring human studies. One particular vein of examination will look at samples from women at early stages of their pregnancy to see if different early levels of GM-CSF can offer an indication of whether a pregnancy is more or less likely to reach full-term.

"We're hoping to do more immune mechanism studies in mice," says Christopher Nold, an obstetrician working on the research. "And in the not-too-distant future, we hope to start looking at human studies."

The new study was published in the journal Reproductive Sciences.