PRC Scientists Find Early Pregnancy Immune Changes in Preterm Birth

Women who experience spontaneous preterm birth (sPTB) may experience a host of immune system changes as early as the first trimester that both set them apart from women who deliver on time and contribute to their early delivery risk, scientists at the March of Dimes Prematurity Research Center (PRC) at Stanford, in collaboration with those at University Medical Center Hamburg-Eppendorf in Germany, have discovered.

Recently published in Nature Communications, their findings detail 76 blood immune and serum protein features, including a group of stress-related features, that a Machine Learning (ML) algorithm has identified as predictive of early labor and that could one day lead to a test for sPTB risk.

By looking in-depth at immune features early in gestation and following their behavior across pregnancy — a unique characteristic of the study — the team was able to identify clusters of immune pathways that may give clues to the pathobiology of sPTB, which accounts for about 70% of all early births and largely remains a medical mystery.

One of the study’s most notable findings centered around stress, with researchers finding an elevated stress response in the immune cells of women who delivered early compared to those who delivered on time, suggesting women who experience a sPTB may have a heightened immune response to stress that could contribute to their risk for early labor.

The findings strengthen existing links between sPTB and maternal psychosocial stress perception both before and during pregnancy.

The paper, senior authored by Stanford PRC investigator Dr. Brice Gaudilliere and Drs. Petra Arck and Anke Diemert at the University of Hamburg, Germany, was co-first authored by Stanford PRC collaborator Dr. Ina Stelzer, now an Assistant Professor at the University of California San Diego’s Department of Pathology and a reproductive immunologist focused on the mind-body connection in pregnancy.

By studying blood samples across pregnancy from 70 women who delivered in Hamburg from 2012-2019, the team found that most of the 24 women who had a sPTB had a significantly different immune response in pregnancy compared to women who delivered term.

The changes, Dr. Stelzer said, were observed as early as 12-14 weeks gestation and indicative of a “general immune maladaptation to pregnancy.”

“This multi-omic study looked at many components of the immune system in pregnancy, and we found changes in all of them in the preterm group, which tells us the immune system in sPTB does not adapt to pregnancy in the same way as in term pregnancies,” she said.

The study’s stress findings resulted from exposing immune cells from the blood of women in both groups to a substance that mimics adrenaline, one of the body’s principal responses to physical and emotional stress. Using the ML algorithm, the team found that when the sPTB immune cells were stimulated with the adrenaline mimic, they exhibited distinct features whose activity was heightened compared to the term immune cells.

“This work is still in its early stages,” Dr. Stelzer said, “but our leading hypothesis is that women who experience spontaneous preterm birth may have an altered stress threshold that leads to a heightened, or more active, response to the presence of stress hormones, particularly adrenaline.”

“That altered threshold could have potentially contributed to their preterm birth and could give us clues into pathways that may lead to early labor.”

Dr. Stelzer emphasized that the link between stress and sPTB illustrated in the study was only an association, not causal; that the work still needed further study and validation; and that many questions remained about the connection.

Still, she hypothesized what may be behind it: an autonomic nervous system that leans toward a sympathetic, or ‘flight or fight’ state, instead of a parasympathetic, or ‘rest and digest’ state.

“Our nervous system is the primary responder and regulator of stress, and since we know that pregnancy thrives in a parasympathetic state, it’s plausible that women who spend more time — either over the course of their lives or during pregnancy — in the sympathetic survival state develop a lower threshold for stress and a higher stress response, which could contribute to preterm birth risk,” she said.

Dr. Stelzer added that stress is individual to each person, and that different ways of experiencing, perceiving, and coping with stress will affect the nervous system and the immune system differently.

“This is why we need more research,” she said, adding that a validation study was underway.

There were other discoveries as part of the paper. First, the study illuminated a separate difference in the blood of women who delivered preterm: a shift of CD4 T cells toward Th17 differentiation, a state previously associated with preeclampsia and, outside the context of pregnancy, with chronic psychosocial stress. Second, regulatory T cells, the CD4 T cell population responsible for maintaining tolerance to the genetically-foreign fetus (whose genes are half derived from the father), did not produce as much tolerizing factors in preterm compared to term pregnancies. Third, there were more fast-acting innate immune cells like granulocytes and monocytes in the blood throughout the later trimesters in preterm vs. term pregnancies, with granulocytes turning inflammatory toward the end of pregnancy. And finally, lower levels of proteins like circulating Vitamin D receptor and liver enzymes were observed in the preterm group, further indicating a metabolic shift.

Other than validation of the findings, Dr. Stelzer said next steps include narrowing down the larger group of immune and serum protein features characteristic of sPTB to a handful of the most predictive biomarkers using Stabl, an innovative new ML algorithm created by Dr. Gaudilliere and this team. Dr. Stelzer’s team will also investigate the shift of CD4 T immune cell states in preterm deliveries, with an eye toward identifying key maternal adaptation processes in pregnancy that could one day be targeted to delay or prevent preterm birth.

“We are very excited about this research,” Dr. Stelzer said. “There is a lot to uncover and a lot to be optimistic about.”