Scientists studying pregnancy haven’t yet solved the complex puzzle of what determines when labor begins, including the causes of preterm labor (delivery before 37 weeks). But a team led by researchers at Harvard Medical School, Beth Israel Deaconess Medical Center, and University of Texas Southwestern Medical Center has just slotted in another piece.
The team reported in Science that NAD+, a molecule best known for its role in cellular metabolism and aging, helps regulate the timing of labor.
The findings point to a potential new therapeutic target for protecting against preterm birth, which affects roughly 1 in 10 babies born in the United States and remains a leading cause of infant death and long-term disability.
Previous work from first author Erin Ciampa, HMS assistant professor of anaesthesia at Beth Israel Deaconess, and colleagues showed that the placenta exhibits signs of aging, including metabolic aging, over the course of a normal pregnancy. In addition, premature placental aging has been implicated in preterm birth, she said.
In the new study, “we wanted to understand how age-related metabolic changes in the placenta might influence the timing of labor,” Ciampa said.
Early drop in NAD+ levels linked to early labor
Ciampa and colleagues focused on a molecule called nicotinamide adenine dinucleotide, or NAD+, which is found in every cell in the body and plays a central role in helping cells convert nutrients into energy. Declining NAD+ levels are considered a hallmark of aging in many organs.
The researchers asked whether NAD+ levels in the placenta decline as gestation progresses and whether that drop helps determine when labor begins.
Examining placental tissue from healthy human and mouse pregnancies, they found that NAD+ levels indeed declined with gestational age.
The team then manipulated NAD+ levels in pregnant mice. Reducing placental NAD+ did 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, the study showed, these labor-promoting prostaglandins are free to take over.
This process appears to help initiate labor at the end of a healthy pregnancy. But the researchers found in a mouse model that when NAD+ levels drop prematurely, labor likewise begins early. When they experimentally induced inflammation — a well-established trigger of some cases of preterm labor — placental NAD+ levels dropped within hours and labor began early. Restoring placental NAD+ levels delayed labor onset and protected against preterm birth.
A new path to explore for optimizing labor timing
Taken together, the findings provide new insight into the complex biological processes that govern labor timing, bolstering evidence that the aging placenta — specifically, its metabolic aging — helps determine when birth begins.
The work suggests that developing interventions that act on NAD+ could help stave off preterm labor or, conversely, help induce labor when clinically indicated.
“These findings reveal potential therapeutic avenues for preterm labor,” the authors wrote. “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.”
Adapted from a Beth Israel Deaconess news release.
Authorship, funding, disclosures
Samir M. Parikh of UT Southwestern Medical Center is senior author. Additional co-authors include Luana M. Machado, Kathy J. Lee, Amanda J. Clark, Kyle Q. Vu, Nawal A. Khan, Sarah Kispert, Samantha Armstrong, Yunping Li, Ginger L. Milne, Ashley Solmonson, and S. Ananth Karumanchi.
This work was funded by the Foundation for Anesthesia Education and Research (MRTG-02-15-2022-Chiampa), the National Institutes of Health (grant 1K08HD117001-01A1; grant P30DK127984 through the UTSW Nutrition and Obesity Research Center), the Beth Israel Deaconess Department of Anesthesia, and the Leducq Foundation.
