Significance: Nicotinamide adenine dinucleotide (NAD) is an important molecule synthesized from tryptophan or vitamin B3 and involved in numerous cellular reactions. NAD deficiency during pregnancy causes congenital NAD deficiency disorder (CNDD) characterized by multiple congenital malformations and/or miscarriage. Studies in genetically engineered mice replicating mutations found in human patient cases show that CNDD can be prevented by dietary supplements.

Recent Advances: A growing number of patient reports show that biallelic loss-of-function of genes involved in NAD de novo synthesis (KYNU, HAAO, NADSYN1) cause CNDD. Other factors that limit the availability of NAD precursors, for example, limited dietary precursor supply or absorption, can cause or contribute to NAD deficiency and result in CNDD in mice. Molecular flux experiments allow quantitative understanding of NAD precursor concentrations in the circulation and their usage by different cells. Studies of NAD-consuming enzymes and contributors to NAD homeostasis help better understand how perturbed NAD levels are implicated in various diseases and adverse pregnancy outcomes.

Critical Issues: NAD deficiency is one of the many known causes of adverse pregnancy outcomes, but its prevalence in the human population and among pregnant women is unknown. Since NAD is involved in hundreds of diverse cellular reactions, determining how NAD deficiency disrupts embryogenesis is an important challenge.

Future Directions: Furthering our understanding of the molecular fluxes between the maternal and embryonic circulation during pregnancy, the NAD-dependent pathways active in the developing embryo, and the molecular mechanisms by which NAD deficiency causes adverse pregnancy outcomes will provide direction for future prevention strategies. Antioxid. Redox Signal. 39, 1108–1132.