A decline in the levels of the coenzyme nicotinamide adenine dinucleotide (NAD+) in the placenta may help trigger labor by allowing prostaglandins to accumulate, raising the possibility of new strategies to identify and prevent preterm birth.

NAD+ may play a central role in the onset of labor. A study published in Science found that placental NAD+ levels decline toward the end of pregnancy and that labor begins once concentrations fall below a critical threshold. According to lead author Erin J. Ciampa, MD, anesthesiologist in the Department of Anesthesia at Beth Israel Deaconess Medical Center in Boston, the findings suggest that placental metabolism may be an important regulator of pregnancy duration and a potential target for preventing preterm birth.

Mouse and Human Studies

The researchers conducted most of their experiments in mice but also analyzed human placental samples. They found that NAD+ concentrations declined in placental tissue before the onset of labor in both mice and humans.

The researchers then used additional mouse experiments to investigate the mechanism underlying this irreversible decline. They found that NAD+ synthesis became impaired as maternal stores of NAD+ precursors diminished, and the placental machinery responsible for NAD+ production developed a bottleneck.

NAD+ is an essential coenzyme for 15-hydroxyprostaglandin dehydrogenase, an enzyme that helps prevent preterm labor by breaking down prostaglandins, which promote uterine contractions.

The researchers noted that prostaglandins are only one part of the complex process that initiates labor. Hormonal changes, including declining progesterone levels, rising estrogen levels, and fetal signals originating from the fetus, also contribute to the onset of labor.

When researchers administered an NAD+ precursor to pregnant mice, the onset of labor was delayed. Researchers highlighted the potential therapeutic value of targeting this pathway to prevent preterm birth.

Critical Role

Speaking with the Science Media Center Germany, Sandra M. Blois, MD, PhD, director of the Laboratory of Glycoimmunology and Reproduction at the Center for Obstetrics, Pediatrics and Adolescent Medicine at the University Medical Center Hamburg-Eppendorf, Hamburg, Germany, said, “The study shows that a natural decline in placental nicotinamide adenine dinucleotide (NAD+) late in pregnancy plays a critical role in the initiation of labor.”

Alexandra Gellhaus, MD, PhD, head of obstetrics research at University Hospital Essen, Essen, Germany, described the study as convincing. “The findings show that placental NAD+ dynamically influences the duration of pregnancy by regulating prostaglandin accumulation, which triggers labor,” Gellhaus said.

Jarmila Zdanowicz, MD, head of the Maternity Unit and specialist in obstetrics and gynecology at Bern University Hospital in Bern, Switzerland, noted the findings contribute to a better understanding of the biological processes involved in labor. At the same time, she cautioned that it remains unclear whether the mechanisms identified in the study can be directly translated to humans.

Gellhaus noted that NAD+ deficiency has already been implicated in preeclampsia. “Reduced NAD+ levels have been observed in the placentas of women with inflammation-related preeclampsia, which contributes to mitochondrial dysfunction,” she said.

According to Blois, the results show that there is a “metabolic brake” on labor: If the placenta has sufficient NAD+, it keeps prostaglandin levels under control. When NAD+ levels decrease, this brake is released. “The study supports the view that preterm labor should, in some cases, be regarded as a disruption of the placenta’s metabolic health and opens up new avenues beyond traditional tocolytics or progesterone supplementation,” Blois said.

Gellhaus emphasized that the relevance of these findings in humans must now be confirmed in clinical studies. “The basic idea — that NAD+ availability influences prostaglandin-dependent labor — could also be relevant in humans,” she said.

Future studies are needed to examine maternal NAD+ or nicotinamide adenine dinucleotide and hydrogen concentrations, placental NAD+ levels, timing of delivery, and the role of NAD+ in human trophoblast cells. “We need to determine whether NAD+ levels in humans actually decline before labor begins, whether this decline plays a causal role in labor initiation, and whether it can be modified through a safe intervention,” Gellhaus said.

If confirmed in humans, the findings could have several clinical implications according to Blois. “NAD+ metabolites in the blood and placenta could be used as new biomarkers to identify women at risk for preterm labor. Similarly, the preventive or therapeutic administration of NAD+ precursors could support placental function and prolong pregnancy,” Gellhaus said.

Gellhaus suggested that supplementation with NAD+ precursors, such as vitamin B3, could eventually become one option. However, she emphasized that safe and effective NAD+ supplementation during pregnancy has not been established and that long-term effects remain unknown. “Targeted NAD+ manipulation would have to be extremely well regulated and evidence-based to avoid risks.” This includes, for example, the impact on other NAD+-dependent processes. Only then can this approach be considered a potential treatment for preterm birth by maintaining or optimizing placental NAD+ levels.

This story was translated from Medscape’s German edition.