{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T04:48:35Z","timestamp":1782449315242,"version":"3.54.5"},"reference-count":56,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:00:00Z","timestamp":1781308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>L-citrulline is a non-protein amino acid with critical roles in perinatal and neonatal physiology through the intestinal\u2013renal arginine\u2013citrulline axis and nitric oxide (NO) production. During pregnancy, L-citrulline supports placental angiogenesis, vascular adaptation, and fetal growth through augmentation of arginine availability and endothelial NO production. In neonates, particularly preterm infants, developmental immaturity of citrulline and arginine synthesis contributes to hypoargininemia and may increase susceptibility to necrotizing enterocolitis, bronchopulmonary dysplasia with pulmonary hypertension, sepsis, and impaired intestinal function. Although L-citrulline has emerged as a promising modulator of NO bioavailability, prior reviews have largely focused on either adult cardiovascular disease or isolated neonatal applications, with limited integration of its mechanistic and translational relevance across the perinatal and neonatal continuum. Collectively, current evidence supports L-citrulline as a promising translational target in maternal\u2013fetal and neonatal medicine because of its central role in vascular, inflammatory, and metabolic regulation. However, adequately powered clinical trials are needed to define optimal dosing, timing, patient selection, and long-term outcomes before routine clinical implementation can be recommended. This review provides a comprehensive evaluation of L-citrulline metabolism and its therapeutic potential from pregnancy through neonatal life, with emphasis on the intestinal\u2013renal arginine\u2013citrulline axis, endothelial function, and NO-mediated vascular regulation. We specifically examine the role of citrulline in key pathophysiologic mechanisms underlying maternal and neonatal disease, including endothelial dysfunction, impaired NO bioavailability, inflammation, oxidative stress, and abnormal placental vascular remodeling.<\/jats:p>","DOI":"10.3390\/nu18121923","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T03:01:27Z","timestamp":1781492487000},"page":"1923","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["L-Citrulline in Maternal\u2013Fetal and Neonatal Health: Metabolic Mechanisms and Emerging Therapeutic Applications"],"prefix":"10.3390","volume":"18","author":[{"given":"Ana","family":"Collins-Smith","sequence":"first","affiliation":[{"name":"Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA"},{"name":"Division of Critical Care Medicine, Department of Anesthesia, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangeeta","family":"Jain","sequence":"additional","affiliation":[{"name":"Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0893-9840","authenticated-orcid":false,"given":"Sunil","family":"Jain","sequence":"additional","affiliation":[{"name":"Division of Perinatology, Department of Pediatrics, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s00726-005-0235-4","article-title":"Almost all about citrulline in mammals","volume":"29","author":"Curis","year":"2005","journal-title":"Amino Acids"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1016\/j.clnu.2017.10.009","article-title":"Citrulline in health and disease. Review on human studies","volume":"37","author":"Papadia","year":"2018","journal-title":"Clin. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1093\/advances\/nmz015","article-title":"Perspective: L-Arginine and L-Citrulline Supplementation in Pregnancy: A Potential Strategy to Improve Birth Outcomes in Low-Resource Settings","volume":"10","author":"Weckman","year":"2019","journal-title":"Adv. Nutr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.jnutbio.2003.11.010","article-title":"Arginine deficiency in preterm infants: Biochemical mechanisms and nutritional implications","volume":"15","author":"Wu","year":"2004","journal-title":"J. Nutr. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"E1348","DOI":"10.1152\/ajpendo.00399.2012","article-title":"De novo synthesis is the main source of ornithine for citrulline production in neonatal pigs","volume":"303","author":"Marini","year":"2012","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"E233","DOI":"10.1152\/ajpendo.00055.2017","article-title":"The intestinal-renal axis for arginine synthesis is present and functional in the neonatal pig","volume":"313","author":"Marini","year":"2017","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"F175","DOI":"10.1152\/ajprenal.00469.2019","article-title":"Developmental changes in the utilization of citrulline by neonatal pigs","volume":"318","author":"Mohammad","year":"2020","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e13572","DOI":"10.1111\/apha.13572","article-title":"Endogenous flux of nitric oxide: Citrulline is preferred to arginine","volume":"231","author":"Bahadoran","year":"2021","journal-title":"Acta Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s40272-020-00384-5","article-title":"Therapeutic Potential of Citrulline as an Arginine Supplement: A Clinical Pharmacology Review","volume":"22","author":"Rashid","year":"2020","journal-title":"Paediatr. Drugs"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7749","DOI":"10.1073\/pnas.90.16.7749","article-title":"Plasma arginine and citrulline kinetics in adults given adequate and arginine-free diets","volume":"90","author":"Castillo","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/S0002-9378(98)70437-5","article-title":"Plasma concentrations of asymmetric dimethylarginine in normal pregnancy and preeclampsia","volume":"178","author":"Holden","year":"1998","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/j.1365-3016.2012.01291.x","article-title":"Biological mechanisms for nutritional regulation of maternal health and fetal development","volume":"26","author":"Wu","year":"2012","journal-title":"Paediatr. Perinat. Epidemiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0143-4004(80)80012-9","article-title":"Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy","volume":"1","author":"Pijnenborg","year":"1980","journal-title":"Placenta"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1172\/JCI119388","article-title":"Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype","volume":"99","author":"Zhou","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.placenta.2009.02.009","article-title":"Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy","volume":"30","author":"Burton","year":"2009","journal-title":"Placenta"},{"key":"ref_16","first-page":"R441","article-title":"Nitric oxide and pregnancy","volume":"272","author":"Sladek","year":"1997","journal-title":"Am. J. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1139\/y02-016","article-title":"Regulation of human trophoblast migration and invasiveness","volume":"80","author":"Chakraborty","year":"2002","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1177\/1753944708092277","article-title":"The role of the L-arginine-nitric oxide pathway in preeclampsia","volume":"2","author":"Arenas","year":"2008","journal-title":"Ther. Adv. Cardiovasc. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nrneph.2011.31","article-title":"The role of asymmetric and symmetric dimethylarginines in renal disease","volume":"7","author":"Schwedhelm","year":"2011","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.nut.2012.07.002","article-title":"Citrulline: From metabolism to therapeutic use","volume":"29","author":"Bahri","year":"2013","journal-title":"Nutrition"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.bbrc.2014.10.029","article-title":"Oral supplementation with a combination of l-citrulline and l-arginine rapidly increases plasma l-arginine concentration and enhances NO bioavailability","volume":"454","author":"Morita","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1017\/S0007114507841110","article-title":"Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: The CITRUS study","volume":"99","author":"Moinard","year":"2008","journal-title":"Br. J. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"532","DOI":"10.3945\/jn.115.221267","article-title":"L-Citrulline Supplementation Enhances Fetal Growth and Protein Synthesis in Rats with Intrauterine Growth Restriction","volume":"146","author":"Bourdon","year":"2016","journal-title":"J. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3736","DOI":"10.1016\/j.clnu.2020.03.036","article-title":"Maternal supplementation with citrulline or arginine during gestation impacts fetal amino acid availability in a model of intrauterine growth restriction (IUGR)","volume":"39","author":"Bourdon","year":"2020","journal-title":"Clin. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1080\/14767058.2016.1229768","article-title":"Maternal citrulline supplementation enhances placental function and fetal growth in a rat model of IUGR: Involvement of insulin-like growth factor 2 and angiogenic factors","volume":"30","author":"Tran","year":"2017","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1111\/j.1742-7843.2006.pto_468.x","article-title":"Effects of oral L-arginine on fetal condition and neonatal outcome in preeclampsia: Preliminary report","volume":"99","author":"Rytlewski","year":"2006","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2217465","DOI":"10.1080\/14767058.2023.2217465","article-title":"L-Arginine supplementation in pregnancy: Systematic review of maternal and fetal outcomes","volume":"36","author":"Menichini","year":"2023","journal-title":"J. Matern. Fetal. Neonatal Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1111\/1471-0528.18070","article-title":"L-arginine and L-citrulline for prevention and treatment of preeclampsia: Systematic review and meta-analysis","volume":"132","author":"Makama","year":"2025","journal-title":"BJOG"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.1111\/bph.15783","article-title":"L-Citrulline ameliorates pathophysiology in a rat model of superimposed preeclampsia","volume":"179","author":"Man","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/978-3-031-32554-0_6","article-title":"Pathophysiology of Preeclampsia and L-Arginine\/L-Citrulline Supplementation as a Potential Strategy to Improve Birth Outcomes","volume":"1428","author":"Mosso","year":"2023","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1161\/HYPERTENSIONAHA.125.24785","article-title":"L-Citrulline Improves IGF-1 Signaling Pathway in Preeclampsia via Polyamines","volume":"82","author":"Man","year":"2025","journal-title":"Hypertension"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"R364","DOI":"10.1152\/ajpregu.00115.2020","article-title":"l-Citrulline supplementation during pregnancy improves perinatal and postpartum maternal vascular function in a mouse model of preeclampsia","volume":"321","author":"Gemmel","year":"2021","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/j.ajcnut.2024.12.001","article-title":"Oral citrulline supplementation in pregnancies with preeclampsia: A multicenter, randomized, double-blind clinical trial","volume":"121","author":"Winer","year":"2025","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1007\/s43032-023-01335-4","article-title":"CHERRY trial: Chronic hypertension and L-citrulline supplementation in pregnancy","volume":"31","author":"Ormesher","year":"2024","journal-title":"Reprod. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e1914171","DOI":"10.1001\/jamanetworkopen.2019.14171","article-title":"Effect of Combination l-Citrulline and Metformin Treatment on Motor Function in Patients with Duchenne Muscular DystrophyA Randomized Clinical Trial","volume":"2","author":"Hafner","year":"2019","journal-title":"JAMA Netw. Open."},{"key":"ref_36","unstructured":"(2026, May 01). AGREE: L-ArGinine to pRevent advErse prEgnancy Outcomes (AGREE), Available online: https:\/\/clinicaltrials.gov\/study\/NCT05934318."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0300-9084(83)80022-4","article-title":"Developmental changes of citrullinogenesis, mitochondrial N-acetylglutamate content and N-acetylglutamate synthetase in fetal and neonatal rats","volume":"65","author":"Rabier","year":"1983","journal-title":"Biochimie"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.earlhumdev.2011.11.008","article-title":"Plasma citrulline levels in preterm neonates with necrotizing enterocolitis","volume":"88","author":"Ioannou","year":"2012","journal-title":"Early Hum. Dev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1017\/S0007114511006660","article-title":"Urinary citrulline in very low birth weight preterm infants receiving intravenous nutrition","volume":"108","author":"Bourdon","year":"2012","journal-title":"Br. J. Nutr."},{"key":"ref_40","first-page":"345","article-title":"Enteral and Intravenous Supplementation of Arginine and Citrulline Fail to Prevent Necrotizing Enterocolitis in Preterm Neonatal Pigs","volume":"49","author":"Vonderohe","year":"2025","journal-title":"J. Parenter. Enter. Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1067\/mpd.2000.109145","article-title":"Reduced serum amino acid concentrations in infants with necrotizing enterocolitis","volume":"137","author":"Becker","year":"2000","journal-title":"J. Pediatr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"106402","DOI":"10.1016\/j.earlhumdev.2025.106402","article-title":"The Evidence for Neonatal Arginine Supplementation\u2014A Narrative Review","volume":"211","author":"Callaghan","year":"2025","journal-title":"Early Hum. Dev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"G638","DOI":"10.1152\/ajpgi.00198.2018","article-title":"Prematurity reduces citrulline-arginine-nitric oxide production and precedes the onset of necrotizing enterocolitis in piglets","volume":"315","author":"Robinson","year":"2018","journal-title":"Am. J. Physiol.-Gastrointest. Liver Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1002\/jimd.12810","article-title":"Potential Therapeutic Uses of L-Citrulline Beyond Genetic Urea Cycle Disorders","volume":"47","author":"Summar","year":"2024","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1203\/PDR.0b013e3181f90278","article-title":"L-Citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats","volume":"68","author":"Vadivel","year":"2010","journal-title":"Pediatr. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1038\/s41390-023-02684-1","article-title":"L-Citrulline Attenuates Lipopolysaccharide-Induced Inflammatory Lung Injury in Neonatal Rats","volume":"94","author":"Ivanovski","year":"2023","journal-title":"Pediatr. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s40272-022-00542-x","article-title":"Pharmacokinetics of L-Citrulline in Neonates at Risk of Developing Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension","volume":"25","author":"Fike","year":"2023","journal-title":"Paediatr. Drugs"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1038\/s41372-023-01809-y","article-title":"Multi-Dose Enteral L-Citrulline Administration in Premature Infants at Risk of Developing Pulmonary Hypertension Associated with Bronchopulmonary Dysplasia","volume":"44","author":"Fike","year":"2024","journal-title":"J. Perinatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"142","DOI":"10.3945\/ajcn.2007.25765","article-title":"Reduced citrulline production in sepsis is related to diminished de novo arginine and nitric oxide production","volume":"89","author":"Luiking","year":"2009","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e2115139119","DOI":"10.1073\/pnas.2115139119","article-title":"Beneficial effects of citrulline enteral administration on sepsis-induced T cell mitochondrial dysfunction","volume":"119","author":"Reizine","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e2250154","DOI":"10.1002\/eji.202250154","article-title":"Citrulline enteral administration markedly reduces immunosuppressive extrafollicular plasma cell differentiation in a preclinical model of sepsis","volume":"53","author":"Gauthier","year":"2023","journal-title":"Eur. J. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"109674","DOI":"10.1016\/j.jnutbio.2024.109674","article-title":"Citrulline Supplementation Exacerbates Sepsis Severity in Infected Preterm Piglets via Early Induced Immunosuppression","volume":"131","author":"Zhong","year":"2024","journal-title":"J. Nutr. Biochem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.earlhumdev.2015.09.004","article-title":"Reduced early dried blood spot citrulline levels in preterm infants with meconium obstruction of prematurity","volume":"91","author":"Woo","year":"2015","journal-title":"Early Hum. Dev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1002\/jpen.1671","article-title":"Plasma Citrulline Concentrations in Neonates with or Without Gastrointestinal Disease During Periods of Parenteral and Enteral Nutrition","volume":"43","author":"Herrera","year":"2019","journal-title":"JPEN J. Parenter. Enter. Nutr."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1002\/jimd.12100","article-title":"Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision","volume":"42","author":"Burlina","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/s41372-023-01761-x","article-title":"Enteral L-Citrulline Supplementation in Preterm Infants Is Safe and Effective in Increasing Plasma Arginine and Citrulline Levels\u2014A Pilot Randomized Trial","volume":"44","author":"Qasim","year":"2024","journal-title":"J. Perinatol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/12\/1923\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T04:14:09Z","timestamp":1782447249000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/12\/1923"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,13]]},"references-count":56,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["nu18121923"],"URL":"https:\/\/doi.org\/10.3390\/nu18121923","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,13]]}}}