Steep drop in metabolic coenzyme could trigger preterm labor

by UT Southwestern Medical Center

edited by Lisa Lock, reviewed by Robert Egan

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Declining placental concentrations of a molecule that plays a key role in metabolism appear to trigger the end of pregnancy and hasten labor and delivery, suggesting a study co-led by researchers at UT Southwestern Medical Center. The findings, published in Science, could lead to new ways to predict when pregnant women might give birth and who might be at risk for premature delivery.

"A normal length of pregnancy is vital to the health of the child. Our findings identify a metabolic mechanism that may influence the length of pregnancy in both health and disease," said Samir Parikh, M.D., chair and professor of internal medicine and professor of pharmacology at UT Southwestern. Parikh co-led the study with first author Erin Ciampa, M.D., Ph.D., assistant professor of anesthesia at Harvard Medical School and attending anesthesiologist at Beth Israel Deaconess Medical Center.

Healthy mammalian pregnancies tend to be approximately the same length within species. For example, human pregnancies average about 40 weeks and mouse pregnancies about 18.5 days, with little variation. Scientists have long known labor is activated by molecules called prostaglandins—lipids with hormone-like actions that are often used to induce labor. But what signals reproductive tissues to produce prostaglandins, and why this typically occurs after an average length of pregnancy, has been unknown.

A metabolic clock in the placenta

To answer these questions, Parikh, Ciampa and their colleagues examined the concentrations of different molecules present in mouse placentas as they progressed from the second trimester to full-term pregnancies. They immediately homed in on nicotinamide adenine dinucleotide (NAD+), a coenzyme that plays a pivotal role in helping cellular organelles called mitochondria generate energy from nutrients and facilitates hundreds of chemical reactions in every cell. As pregnancy neared its end, placental levels of NAD+ and precursor molecules used to generate this coenzyme dropped precipitously.

When the researchers examined placentas from women who gave birth via cesarean section at different points during pregnancy before labor started, they found a similar phenomenon: Levels of NAD+ and its precursors also fell close to the time natural labor would have taken place.

How NAD+ loss sets off labor

To determine whether NAD+ plays a role in signaling the end of pregnancy, the researchers depleted this molecule in mouse placentas using either a drug that reduced NAD+ levels or genetic alterations that did the same. In both cases, decreasing NAD+ shortened pregnancy by more than a day on average, a significant length for mouse pregnancies. Conversely, supplementing a mouse model of preterm birth with NAD+ precursors lengthened pregnancy by nearly a day. These results suggested NAD+ is key to sustaining pregnancy, and its loss kick-starts labor.

A closer look revealed the loss of NAD+ affected the activity of another placental enzyme called 15-PGDH, which uses NAD+ as a coenzyme to degrade prostaglandins produced by the placenta throughout pregnancy. The team's results suggest that when NAD+ levels drop at the end of pregnancy, 15-PGDH can no longer degrade prostaglandins, allowing their concentrations to rise and trigger labor.

The sudden fall in NAD+ levels seems to be a tipping point in the nutritional balance between the mother and fetus that exists throughout pregnancy, Parikh explained. When the metabolic demands of the fetus outweigh those of the mother, NAD+ drops and labor starts.

Clues for timing and risk

By monitoring components of the NAD+-prostaglandin pathway, researchers may be able to detect who might be at risk for preterm labor or give full-term mothers a better idea of when they might deliver. In addition, supplementing gestating mothers at risk for preterm births with NAD+-augmenting precursors might prolong pregnancy to a healthier length, while depleting it could represent a new way to induce labor when necessary.

Publication details

Erin J. Ciampa et al, Placental nicotinamide adenine dinucleotide modulates the timing of labor, Science (2026). DOI: 10.1126/science.adz1624

Journal information: Science

Key medical concepts

NADProstaglandinsPreterm Labor15-hydroxyprostaglandin dehydrogenase

Clinical categories

Obstetrics & gynecologyPregnancyReproductive health Provided by UT Southwestern Medical Center Who's behind this story?

Lisa Lock

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