Scientists take aim at a novel target to reduce preterm birth

A research team at the Medical University of South Carolina reports in Cells that the complement system, part of the body’s natural immune defenses, is a key driver of inflammatory responses that contribute to fetal brain inflammation and preterm birth, the latter of which is the leading cause of complications and death in newborns. The study, led by Eliza McElwee, M.D., an assistant professor of Obstetrics and Gynecology, focuses on finding the root cause of preterm birth itself, rather than just treating the complications left in its wake.

A major health concern

Preterm birth, or delivery before 37 weeks, affects about 12% of pregnancies in the U.S. and is linked to serious complications, such as brain hemorrhage, cerebral palsy, sepsis and death. South Carolina ranks fifth in the nation for preterm deliveries, highlighting a significant public health concern for the Lowcountry.

A few options are available to mitigate preterm birth once it has already begun. “We have some strategies and medications that have a goal of stopping preterm labor after it’s happening,” McElwee explained. However, there are limited therapies that prevent preterm birth by addressing its root cause. “As a result, rates of preterm delivery remain high in the U.S.”

Looking for root causes

Previous studies have shown a link between inflammation brought on by infection in the amniotic fluid and preterm birth, but the source of the inflammation remained unknown. Using a well-studied animal model, McElwee and her team set out to pinpoint what causes the inflammation associated with preterm birth. They focused on the complement system, an area of expertise for Stephen Tomlinson, Ph.D., professor of Pharmacology and Immunology, whose lab supported the study. Often referred to simply as complement, this group of proteins in the blood helps to defend the body against infection and plays an important role in immunity.

When activated, complement enlists leukocytes — white blood cells — to respond. These cells create and sustain inflammation, which can lead to weakening of the cervix. The cervix can be thought of as the gateway of the pregnancy, keeping the baby safely inside until birth, when it thins and dilates to allow the baby’s passage. When weakened by inflammation, the cervix can’t guard the gates effectively, leading to the baby being delivered prematurely.

To investigate complement's role in preterm birth, researchers used a mouse model that simulates a uterine infection-induced inflammation in pregnant women. They found increased complement activation and leukocyte infiltration in the cervix as early as one hour after inducing inflammation, with a marked rise at nine hours, and that these immune changes were associated with preterm delivery. Team member Devin Hatchell, a trainee in the South Carolina Clinical and Translational Research Institute’s TL1 predoctoral training program, helped to perform these experiments and analyze the data.

The results strongly support the team’s theory that complement is a key factor in preterm birth. “We found that complement activation is increased in inflammatory-mediated preterm birth,” explained McElwee.

“I am never surprised to find that complement plays a significant role in a disease process,” Tomlinson said.

Setting the stage for potential new therapies

The team then went a step further - showing that these changes could be prevented in this animal model by administering a drug called a complement inhibitor, which blocks complement activation and limits its ability to recruit leukocytes. Compared to mice receiving a placebo, pregnant mice induced for preterm birth and treated with the complement inhibitor saw reduced inflammation in both the maternal uterus and the fetal brain. This treatment also reduced leukocyte infiltration and decreased levels of pro-inflammatory cytokines associated with fetal brain inflammation. Pregnant mice treated with the complement inhibitor carried their babies longer and gave birth to more viable offspring.

The hope is that these findings could provide the scientific groundwork for a new therapeutic approach. “By targeting complement with a complement inhibitor, we could decrease rates of preterm birth and reduce fetal neural inflammation,” McElwee said.

Hatchell, whose research before joining the McElwee team focused on developing therapies to reduce brain hemorrhages in premature babies, says what stood out most for him about the results is the possibility of using complement inhibitors in mothers as a preventive therapy. “All the therapy was given to the mother,” he said. “This suggests that we can take care of the mother as well as take care of the offspring at the same time.”

In other words, treating mothers during pregnancy with complement inhibitors could stop preterm birth before it happens and prevent serious complications for both mother and child. “Healthy pregnancies mean healthy babies,” McElwee added.

Several drugs that block complement are in clinical trials, including one with a similar mechanism of action to the mouse complement inhibitor used in the study. However, very few have been approved for medical use — and none is approved for preventing preterm birth or fetal brain inflammation. Still, this study’s findings offer hope for future treatments of preterm birth and beyond.

“This study by Dr. McElwee certainly paves the way for expanding the investigation of complement inhibitors as potential therapies for infection-induced preterm birth, and it is noteworthy that many new complement inhibitors are in clinical development,” said Tomlinson.

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The South Carolina Clinical & Translational Research (SCTR) Institute is the catalyst for changing the culture of biomedical research, facilitating the sharing of resources and expertise and streamlining research-related processes to bring about large-scale change in the clinical and translational research efforts in South Carolina. Our vision is to improve health outcomes and quality of life for the population through discoveries translated into evidence-based practice. To learn more, visit https://research.musc.edu/resources/sctr