Women with recurrent miscarriage had consistently higher concentrations of nicotinamide adenine dinucleotide (NAD) Salvage Pathway metabolites across plasma, blood, and urine, according to a prospective study published in Human Reproduction.
In this cohort of 88 non-pregnant women aged 20 to 40 years, 37 women with 2 or more consecutive miscarriages at less than 20 weeks gestation demonstrated elevated plasma 1-methylnicotinamide (151 vs 89 nM), N-methyl-2-pyridone-5-carboxamide (1.7 vs 1.1 µM), and N-methyl-4-pyridone-3-carboxamide (325 vs 206 nM) compared with 51 controls.
In plasma, every one-unit increase in 1MNA increased miscarriage odds by 2% after accounting for maternal age. Elevations in whole-blood NAD+, NAM, and NMN, as well as urinary NAM, NMN, 1MNA, 2PY, and 4PY were independent of vitamin B3 supplementation, maternal age, or time since miscarriage.
Metabolite correlations were strong across plasma, blood, and urine, indicating that each matrix, particularly spot urine, may be suitable for detecting NAD-related metabolic alterations.
Participants completed standardized health, diet, and supplement questionnaires before providing fasting blood and urine samples analyzed via ultra-high-performance liquid chromatography–tandem mass spectrometry.
The elevated NAD+, NAM, and NMN suggest increased precursor availability rather than deficiency and may reflect heightened NAD-consuming or methylation activity tied to inflammation or metabolic dysregulation. Machine-learning models integrating 1MNA, 2PY, 4PY, and age achieved high predictive accuracy, with an AUROC of 0.889.
Study limitations included single-site recruitment, small sample size, and metabolite measurements representing only a snapshot at time of collection rather than during pregnancy.
“There is an unmet need for biomarkers that allow identification of women at risk of miscarriage to enable early intervention prior to conception and in early pregnancy,” wrote lead authors Hartmut Cuny of Victor Chang Cardiac Research Institute, Sydney, NSW, Australia, Antonia W. Shand of School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia, and colleagues. “Given the numerous essential roles of NAD for embryonic development, further research into the role of NAD and related metabolites in miscarriage causation will improve our understanding towards preventative intervention strategies.”
The authors reported no conflicts of interest. The study was supported by funding from the National Health and Medical Research Council, New South Wales Health, and multiple philanthropic foundations.
Source: Human Reproduction