BIDMC Researchers Uncover New Clues to How Labor Begins
BIDMC Study Could Yield New Therapeutic Target
Researchers at Beth Israel Deaconess Medical Center (BIDMC) have uncovered a new clue to one of pregnancy's enduring mysteries: what determines when labor begins? In a study published in Science, the investigators found that a molecule best known for its role in cellular metabolism and aging also helps regulate the timing of labor. The findings offer new insight into the causes of preterm birth and point to a potential new therapeutic target.
Preterm birth — delivery before 37 weeks of pregnancy — affects roughly 1 in 10 babies born in the United States and remains a leading cause of infant death and long-term disability. Yet many of the biological signals that trigger labor remain poorly understood.
"Our previous work showed that the placenta exhibits signs of aging over the course of a normal pregnancy, even in healthy mothers," said corresponding author Erin Ciampa, MD, PhD, of the Department of Anesthesia, Critical Care and Pain Medicine at BIDMC. "Because premature placental aging has been implicated in preterm birth, we wanted to understand how age-related metabolic changes in the placenta might influence the timing of labor."
Ciampa, who is also an assistant professor of anaesthesia at Harvard Medical School, and colleagues focused on a molecule called nicotinamide adenine dinucleotide, or NAD+, which plays a central role in helping cells convert nutrients into energy. Found in every cell in the body, declining NAD+ levels are considered a hallmark of aging in many organs. Building on their previous findings that the placenta ages over the course of a healthy pregnancy, they asked whether NAD+ levels in the placenta also decline as gestation progresses, and whether the resulting drop in NAD+ helps determine when labor begins.
To find out, the investigators manipulated NAD+ levels in a rodent model. In pregnant mice, reducing placental NAD+ did indeed trigger earlier labor, while boosting NAD+ prolonged pregnancy and protected against preterm birth.
Further experiments revealed why. The researchers found that NAD+ acts as a biochemical brake, suppressing the activity of other chemicals called prostaglandins, which are known to help initiate labor. As NAD+ levels decline, these labor-promoting prostaglandins are free to take over.
While this process appears to help initiate labor at the end of a healthy pregnancy, the researchers found that declining NAD+ levels may also contribute to preterm birth. In a mouse model, experimentally induced inflammation — a well-established trigger of some cases of preterm labor — caused placental NAD+ levels to drop within hours and labor to begin early.
Furthermore, the investigators found that restoring placental NAD+ levels in mice could delay labor onset and protect against preterm birth.
Taken together, the findings provide new insight into the complex biological processes that govern labor timing, suggesting that the aging placenta may help determine when birth begins. The work also points to potential new strategies for preventing preterm labor.
“These findings reveal potential therapeutic avenues for preterm labor,” Ciampa and collaborators write. “Our findings identify a metabolic component of the physiology of labor, further highlighting the distinct metabolic demands of pregnancy and pinpointing powerful elements of NAD+ biology in the placenta.”
Co-authors included Luana M. Machado, Kathy J. Lee, Sarah Kispert, Samantha Armstrong, Yunping Li of BIDMC; Amanda J. Clark and Kyle Q. Vu of University of Texas Southwestern Medical Center and Children’s Medical Center; Samir M. Parikh, Nawal A. Khan, and Ashley Solmonson of University of Texas Southwestern Medical Center; Ginger L. Milne of Vanderbilt University Medical Center; and S. Ananth Karumanchi of Cedars- Sinai Medical Center.
This work was funded by the Foundation for Anesthesia Education and Research (MRTG- 02- 15- 2022- Ciampa to E.J.C.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (1K08HD117001- 01A1 to E.J.C.), the BIDMC Department of Anesthesia internal support (E.J.C.), the National Institute of Diabetes and Digestive and Kidney Diseases (P30DK127984 to A.S. through the UTSW Nutrition and Obesity Research Center), and the Leducq Foundation (S.A.K.). The authors declare that they have no competing interests.
About Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center is a leading academic medical center, where extraordinary care is supported by high-quality education and research. BIDMC is a teaching affiliate of Harvard Medical School, and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is the official hospital of the Boston Red Sox.
Beth Israel Deaconess Medical Center is a part of Beth Israel Lahey Health, a healthcare system that brings together academic medical centers and teaching hospitals, community and specialty hospitals, more than 4,700 physicians and 39,000 employees in a shared mission to expand access to great care and advance the science and practice of medicine through groundbreaking research and education.
