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Genetic disruption of NAD\n                    <jats:italic>de novo<\/jats:italic>\n                    synthesis causes congenital NAD deficiency disorder (CNDD), characterized by multiple congenital malformations or death in utero. Patient outcomes are highly variable, likely due to differences in the availability of maternal NAD precursors vitamin B3 and tryptophan to the embryo and its extraembryonic tissues. Here, maternal plasma and yolk sac NAD metabolomes, embryonic NAD levels, and pregnancy outcomes were quantified in a CNDD mouse model to determine how maternal circulatory NAD precursor provision affects pregnancy outcome and to identify metabolic markers of CNDD risk. Maternal levels of nicotinamide positively correlated with embryonic NAD levels, highlighting its central role for embryonic NAD metabolism. Levels of nicotinamide\u2010derived excretion metabolites were the best predictors of adverse pregnancy outcome. NAD metabolomic analysis of pregnant women confirmed the relationship between dietary NAD precursor intake and circulatory nicotinamide and derived excretion product levels seen in mice, as women taking vitamin B3 supplements had elevated levels. Furthermore, mouse embryos with genetic disruption of NAD\n                    <jats:italic>de novo<\/jats:italic>\n                    synthesis (\n                    <jats:italic>Haao<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) were more susceptible to CNDD when maternal circulatory nicotinamide was limited, as their yolk sacs cannot generate NAD\n                    <jats:italic>de novo<\/jats:italic>\n                    from tryptophan. Metabolites originating from\n                    <jats:italic>Haao<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    embryos were detectable in maternal plasma, showing that embryonic NAD metabolism also affects maternal circulation. Together, our findings elucidate the complex interplay between NAD metabolism of mother and conceptus and identify metabolic markers in maternal circulation that predict risk of NAD deficiency\u2010related adverse pregnancy outcomes.\n                  <\/jats:p>","DOI":"10.1096\/fj.202500708rr","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T13:59:26Z","timestamp":1753106366000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Maternal Circulatory\n                    <scp>NAD<\/scp>\n                    Precursor Levels and the Yolk Sac Determine\n                    <scp>NAD<\/scp>\n                    Deficiency\u2010Driven Congenital Malformation Risk"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2910-7616","authenticated-orcid":false,"given":"Kayleigh","family":"Bozon","sequence":"first","affiliation":[{"name":"Victor Chang Cardiac Research Institute  Sydney New South Wales Australia"},{"name":"University of New South Wales  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1551-2354","authenticated-orcid":false,"given":"Hartmut","family":"Cuny","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute  Sydney New South Wales Australia"},{"name":"School of Clinical Medicine, Faculty of Medicine and Health University of New South Wales  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2658-7386","authenticated-orcid":false,"given":"Delicia Z.","family":"Sheng","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute  Sydney New South Wales Australia"},{"name":"University of New South Wales  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1948-6537","authenticated-orcid":false,"given":"Alena","family":"Sipka","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute  Sydney New South Wales Australia"},{"name":"School of Clinical Medicine, Faculty of Medicine and Health University of New South Wales  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4200-9295","authenticated-orcid":false,"given":"Antonia W.","family":"Shand","sequence":"additional","affiliation":[{"name":"Children's Hospital at Westmead Clinical School University of Sydney  Sydney New South Wales Australia"},{"name":"Department of Maternal Fetal Medicine Royal Hospital for Women  Sydney New South Wales Australia"},{"name":"Menzies Centre for Health Policy and Economics, Faculty of Medicine and Health University of Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3720-9655","authenticated-orcid":false,"given":"Natasha","family":"Nassar","sequence":"additional","affiliation":[{"name":"Children's Hospital at Westmead Clinical School University of Sydney  Sydney New South Wales Australia"},{"name":"Menzies Centre for Health Policy and Economics, Faculty of Medicine and Health University of Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2069-7349","authenticated-orcid":false,"given":"Sally L.","family":"Dunwoodie","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute  Sydney New South Wales Australia"},{"name":"School of Clinical Medicine, Faculty of Medicine and Health University of New South Wales  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399\u20100004.2009.01174.x"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ctdb.2015.12.010"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31665"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61847"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2023.0349"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1616361"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.03.018"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.97649"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/bies.10297"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092\u20108674(04)00416\u20107"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2019.12.006"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24211"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI174824"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.14328"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1916588117"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2021.114409"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae253"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.049647"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.5414\/cpp45448"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.EJ19\u20100313"},{"key":"e_1_2_9_22_1","unstructured":"Agricultural 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