{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T14:55:57Z","timestamp":1781535357720,"version":"3.54.5"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Vitamin D is key in immunoregulation and impacts critical care outcomes. With a high prevalence of neonatal Vitamin D deficiency (VDD), we aim to evaluate its association with clinical outcomes in the neonatal intensive care unit (NICU).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Systematic search of PubMed, EMBASE, Web of Science and Scopus was conducted. Primary outcomes included mortality and incidence of sepsis, while secondary outcomes were length of stay (LOS), incidence of bronchopulmonary dysplasia (BPD), and need for mechanical ventilation (MV). Eligible studies included preterm and term NICU neonates with 25-hydroxyvitamin D levels reported on admission. Definition of VDD was based on individual studies due to significant inter-study heterogeneity, however further sub-analyses with VDD definitions of \u2264 30\u202fng\/mL and Vitamin D sufficient (VDS)\u202f&amp;gt;\u202f30\u202fng\/mL were performed to evaluate possible dose\u2013response relationships. Pooled estimates were calculated with random-effects model due to study heterogeneity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 2,735 articles, 18 studies met predefined inclusion criteria (\n                      <jats:italic>n<\/jats:italic>\n                      =\u202f1981 patients). VDD was associated with increased incidence of sepsis [odds ratio (OR) 2.31, 95%CI 1.50\u20133.57], length of hospital stay (mean difference 4.52\u202fdays, 95% CI 1.66\u20137.37) and need for MV (OR 1.67, 95%CI 1.09\u20132.55), in comparison to VDS neonates. Further subgroup analyses for preterm (OR 2.05, 95%CI 1.04\u20134.04) and term neonates (OR 3.96, 95%CI 1.68\u20139.35) continued to show significant association between VDD and sepsis. No differences were observed between both groups for mortality and incidence of BPD. Further subgroup analyses based on Vitamin D levels found that those \u2264 30\u202fng\/mL had no significant difference (mean difference 0\u202fdays, 95%CI -1.89 - 1.89) in terms of length of hospital stay.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>VDD in critically ill neonates is significantly associated with increased odds of sepsis, need for MV, and longer LOS. However, these findings are limited by significant heterogeneity across studies. This warrants further interventional studies, involving both term and preterm neonates, to examine the potential of optimization of Vitamin D levels to improve critical care outcomes in NICU.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2026.1770536","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T14:45:10Z","timestamp":1781534710000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A systematic review and meta-analysis of Vitamin D status and clinical outcomes in critically ill neonates"],"prefix":"10.3389","volume":"13","author":[{"given":"Nowel","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Paediatrics, KK Women\u2019s and Children\u2019s Hospital","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charmaine Shi Mei","family":"Lee","sequence":"additional","affiliation":[{"name":"Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirena","family":"Beh","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, KK Women\u2019s and Children\u2019s Hospital","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darolyn Jia Lin","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, KK Women\u2019s and Children\u2019s Hospital","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruther Teo","family":"Zheng","sequence":"additional","affiliation":[{"name":"Endocrinology Service, Department of Paediatrics, KK Women\u2019s and Children\u2019s Hospital","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, KK Women\u2019s and Children\u2019s Hospital","place":["Singapore, Singapore"]},{"name":"Endocrinology Service, Department of Paediatrics, KK Women\u2019s and Children\u2019s Hospital","place":["Singapore, Singapore"]},{"name":"Duke-NUS Medical School","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1056\/NEJMra070553","article-title":"Vitamin D deficiency","volume":"357","author":"Holick","year":"2007","journal-title":"N Engl J Med"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1097\/CCM.0b013e31822d74f3","article-title":"Low serum 25-hydroxyvitamin D at critical care initiation is associated with increased mortality","volume":"40","author":"Braun","year":"2012","journal-title":"Crit Care Med"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1024\/0300-9831\/a000733","article-title":"Sources of vitamin D for humans","volume":"92","author":"Benedik","year":"2022","journal-title":"Int J Vitamin Nutr Res"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"2924","DOI":"10.3390\/ijms24032924","article-title":"Vitamin D deficiency: an underestimated factor in Sepsis?","volume":"24","author":"Delrue","year":"2023","journal-title":"Int J Mol Sci"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.nut.2018.11.001","article-title":"Vitamin D in the ICU: more sun for critically ill adult patients?","volume":"61","author":"Langlois","year":"2019","journal-title":"Nutrition"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s13613-015-0102-8","article-title":"Vitamin D deficiency and length of pediatric intensive care unit stay: a prospective observational study","volume":"6","author":"Sankar","year":"2016","journal-title":"Ann Intensive Care"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e27966","DOI":"10.1097\/MD.0000000000027966","article-title":"Association between vitamin D deficiency at one month of age and bronchopulmonary dysplasia","volume":"100","author":"Byun","year":"2021","journal-title":"Medicine"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1007\/s00431-018-3210-2","article-title":"Severe vitamin D deficiency in preterm infants: maternal and neonatal clinical features","volume":"58","author":"Park","year":"2015","journal-title":"Korean J Pediatr"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1007\/s00431-018-3210-2","article-title":"Prevalence of vitamin D deficiency in cord blood of newborns and the association with maternal vitamin D status","volume":"177","author":"Ariyawatkul","year":"2018","journal-title":"Eur J Pediatr"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4103\/2249-4847.151155","article-title":"Vitamin D and the neonate: an update","volume":"4","author":"Aly","year":"2015","journal-title":"J Clin Neonatol"},{"key":"ref11","volume-title":"Vitamin D Deficiency-. New Insights","author":"Ghahremani","year":"2022"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1038\/jp.2015.88","article-title":"Maternal\/neonatal vitamin D deficiency: a risk factor for bronchopulmonary dysplasia in preterms?","volume":"35","author":"\u00c7etinkaya","year":"2015","journal-title":"J Perinatol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1002\/fsn3.2003","article-title":"Effects of vitamin D on neonatal sepsis: a systematic review and meta-analysis","volume":"9","author":"Bitew","year":"2020","journal-title":"Food Sci Nutr"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1038\/pr.2017.329","article-title":"Vitamin D ameliorates neonatal necrotizing enterocolitis via suppressing TLR4 in a murine model","volume":"83","author":"Shi","year":"2018","journal-title":"Pediatr Res"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1093\/qjmed\/hcs014","article-title":"Vitamin D deficiency is associated with poor outcomes and increased mortality in severely ill patients","volume":"105","author":"Arnson","year":"2012","journal-title":"QJM"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvaf053","article-title":"Vitamin D deficiency and clinical outcomes in critically ill pediatric patients: a systematic review and meta-analysis","volume":"9","author":"Tan","year":"2025","journal-title":"J Endocr Soc"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1001\/jama.2014.13204","article-title":"Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial","volume":"312","author":"Amrein","year":"2014","journal-title":"JAMA"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1186\/s13063-024-08461-7","article-title":"Rapid normalization of vitamin D deficiency in PICU (VITdALIZE-KIDS): study protocol for a phase III, multicenter randomized controlled trial","volume":"25","author":"O\u2019Hearn","year":"2024","journal-title":"Trials"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"99","DOI":"10.18502\/jfrh.v15i2.6450","article-title":"Serum vitamin D deficiency in NICU hospitalized neonates and its association with neonatal outcomes","volume":"15","author":"Mosayebi","year":"2021","journal-title":"J Family Reprod Health"},{"key":"ref20","article-title":"C. Covidence","year":""},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1164\/ajrccm.163.7.2011060","article-title":"Bronchopulmonary dysplasia","volume":"163","author":"Jobe","year":"2001","journal-title":"Am J Respir Crit Care Med"},{"key":"ref22","doi-asserted-by":"publisher","DOI":"10.1007\/s10654-010-9491-z","article-title":"Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses","volume":"25","author":"Stang","year":"2010","journal-title":"Eur J Epidemiol"},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.1111\/jre.13405","article-title":"Risk of bias evaluation of cross-sectional studies: adaptation of the Newcastle-Ottawa scale","author":"Carra","year":"2025","journal-title":"J Periodontal Res"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: a revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"777","DOI":"10.7326\/M14-2385","article-title":"The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations","volume":"162","author":"Hutton","year":"2015","journal-title":"Ann Intern Med"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/sj.ejcn.1602960","article-title":"Association of subclinical vitamin D deficiency in newborns with acute lower respiratory infection and their mothers","volume":"63","author":"Karatekin","year":"2009","journal-title":"Eur J Clin Nutr"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"128","DOI":"10.5958\/0976-5506.2018.01327.X","article-title":"Vitamin D levels in late pre-term neonates and its association with sepsis","volume":"9","author":"Prasad","year":"2018","journal-title":"Indian J Public Health Res Dev"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1080\/20469047.2018.1477388","article-title":"Association of vitamin D deficiency with an increased risk of late-onset neonatal sepsis","volume":"38","author":"Dhandai","year":"2018","journal-title":"Paediatr Int Child Health"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1186\/s13052-024-01665-2","article-title":"Association of low vitamin D level and full-term early-onset neonatal sepsis; a case-control study","volume":"50","author":"Mohamed","year":"2024","journal-title":"Ital J Pediatr"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1002\/ppul.25813","article-title":"Effects of early vitamin D supplementation on the prevention of bronchopulmonary dysplasia in preterm infants","volume":"57","author":"Ge","year":"2022","journal-title":"Pediatr Pulmonol"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"e650","DOI":"10.5001\/omj.2024.89","article-title":"Unveiling the novel impact of vitamin D injections at birth on the prognosis of newborns: a double-blind study","volume":"39","author":"Boskabadi","year":"2024","journal-title":"Oman Med J"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1016\/j.jpeds.2015.01.055","article-title":"Association of vitamin D status with acute respiratory morbidity in preterm infants","volume":"166","author":"Onwuneme","year":"2015","journal-title":"J Pediatr"},{"key":"ref33","volume-title":"Does vitamin D Deficiency affect placental Inflammation or Infections among very low Birth Weight Infants?J. Maternal-Fetal Neonatal Med","author":"Puthuraya","year":"2018"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"437","DOI":"10.4314\/ahs.v20i1.50","article-title":"Vitamin D deficiency and its effect on respiratory distress syndrome in premature infants: results from a prospective study in a tertiary care Centre","volume":"20","author":"Dogan","year":"2020","journal-title":"Afr Health Sci"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.clnesp.2021.06.009","article-title":"The potential effects of vitamin D deficiency on respiratory distress syndrome among preterm infants","volume":"44","author":"Al-Matary","year":"2021","journal-title":"Clin Nutr ESPEN"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"152","DOI":"10.4103\/jcn.jcn_30_21","article-title":"25-hydroxy vitamin D deficiency \u2013 a potential risk factor neonatal sepsis correlation with biochemical markers and neonatal sequential organ failure assessment score","volume":"10","author":"Mahmoud","year":"2021","journal-title":"J Clin Neonatol"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1562","DOI":"10.1080\/14767058.2020.1762560","article-title":"Severe vitamin D deficiency in preterm infants: possibly no association with clinical outcomes?","volume":"35","author":"Matejek","year":"2022","journal-title":"J Matern Fetal Neonatal Med"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"32","DOI":"10.34172\/aim.2022.06","article-title":"Association between vitamin D insufficiency and respiratory problems in premature neonates - PubMed","volume":"25","author":"Jafari","year":"2022","journal-title":"Arch Iran Med"},{"key":"ref39","article-title":"To investigate the correlation between acute respiratory distress syndrome (ARDS) and serum 25 (OH) vitamin D3 levels in pediatric patients","volume":"12","author":"Saggi","year":"2023","journal-title":"Int J Life Sci Biotechnol Pharma Res"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"45","DOI":"10.5472\/marumj.1380019","article-title":"The association of serum 25-hydroxyvitamin D levels with early neonatal morbidity and mortality in late preterm infants monitored in the neonatal intensive care unit","volume":"37","author":"Cet\u0131n","year":"","journal-title":"Marmara Med J"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1038\/jp.2017.18","article-title":"Maternal\/neonatal vitamin D deficiency: a new risk factor for necrotizing enterocolitis in preterm infants?","volume":"37","author":"Cetinkaya","year":"2017","journal-title":"J Perinatol"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"166","DOI":"10.3345\/kjp.2018.06632","article-title":"Association between vitamin D level at birth and respiratory morbidities in very-low-birth-weight infants","volume":"62","author":"Kim","year":"2019","journal-title":"Korean J Pediatr"},{"key":"ref43","volume-title":"Country Classifications by Income level for 2024\u20132025","year":""},{"key":"ref44","doi-asserted-by":"publisher","first-page":"791","DOI":"10.7499\/j.issn.1008-8830.2016.09.001","article-title":"Relationship between vitamin D deficiency and early-onset neonatal sepsis","volume":"18","author":"Yang","year":"2016","journal-title":"Zhongguo dang dai er ke za zhi"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"3065","DOI":"10.1080\/14767058.2017.1363731","article-title":"Effect of different doses of vitamin D supplementation on preterm infants - an updated meta-analysis","volume":"31","author":"Yang","year":"2018","journal-title":"J Matern Fetal Neonatal Med"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1186\/s13054-014-0660-4","article-title":"Vitamin D deficiency as a risk factor for infection, sepsis and mortality in the critically ill: systematic review and meta-analysis","volume":"18","author":"de Haan","year":"2014","journal-title":"Crit Care"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1186\/s12887-023-04205-9","article-title":"A phase II dose evaluation pilot feasibility randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study)","volume":"23","author":"O'Hearn","year":"2023","journal-title":"BMC Pediatr"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1038\/ncpendmet0716","article-title":"Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity","volume":"4","author":"Adams","year":"2008","journal-title":"Nat Clin Pract Endocrinol Metab"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1002\/eji.200425995","article-title":"Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns","volume":"36","author":"Sadeghi","year":"2006","journal-title":"Eur J Immunol"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1210\/me.2013-1252","article-title":"Vitamin D is a regulator of endothelial nitric oxide synthase and arterial stiffness in mice","volume":"28","author":"Andrukhova","year":"2014","journal-title":"Molecular Endocrinol"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s13052-023-01415-w","article-title":"The association of serum vitamin D level and neonatal respiratory distress syndrome","volume":"49","author":"Liu","year":"2023","journal-title":"Ital J Pediatr"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"L587","DOI":"10.1152\/ajplung.00117.2014","article-title":"The impact of vitamin D on fetal and neonatal lung maturation. A systematic review - PubMed","volume":"308","author":"Lykkedegn","year":"2015","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1007\/s00408-016-9939-3","article-title":"Inhaled vitamin D: a novel strategy to enhance neonatal lung maturation","volume":"194","author":"Taylor","year":"2016","journal-title":"Lung"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.jand.2022.06.012","article-title":"Safety and efficacy of early vitamin D supplementation in critically ill extremely preterm infants: an ancillary study of a randomized trial","volume":"123","author":"Aristizabal","year":"2023","journal-title":"J Acad Nutr Diet"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"300060520926890","DOI":"10.1177\/0300060520926890","article-title":"Effects of a single dose of vitamin D in septic children: a randomized, double-blinded, controlled trial","volume":"48","author":"Wang","year":"2020","journal-title":"J Int Med Res"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"e45374","DOI":"10.1097\/MD.0000000000045374","article-title":"Birth weight status of newborns and its relationship with other anthropometric parameters","volume":"104","author":"Basnet","year":"2025","journal-title":"Medicine"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1210\/jc.2015-2175","article-title":"Global consensus recommendations on prevention and management of nutritional rickets","volume":"101","author":"Munns","year":"2016","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1770536\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T14:45:13Z","timestamp":1781534713000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1770536\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,15]]},"references-count":57,"alternative-id":["10.3389\/fnut.2026.1770536"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2026.1770536","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,15]]},"article-number":"1770536"}}