{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:44:38Z","timestamp":1792788278261,"version":"4.5.0"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":3,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Lund University","id":[{"id":"https:\/\/ror.org\/012a77v79","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Ital J Pediatr"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Caffeine is widely used in preterm infants, yet the optimal administration strategy remains unclear. This systematic review aims to evaluate different caffeine administration approaches, including route, frequency, dose modifications, and co-administration with surfactant in preterm infants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We searched three databases and two trial registries up to October 2024. Data collection and analysis followed Cochrane methodology; certainty of evidence was assessed using GRADE; and reporting followed PRISMA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Three RCTs were identified, two provided data for analyses: one study (38 infants) on route of administration (intravenous versus oral caffeine) and one study (40 infants) on frequency of administration (once versus twice daily). The evidence is very uncertain about the effects of intravenous versus oral administration on: mortality (RR 0.14, 95% CI 0.01\u20132.59); mechanical ventilation duration (MD 1.00, 95% CI -8.05 to 10.05); hospital stay (MD 8.00, 95%CI -5.35-21.35); severe intraventricular hemorrhage (RR 1.00, 95%CI 0.29\u20133.43); and chronic lung disease (RR 5.00, 95%CI 0.26\u201397.70). The evidence is very uncertain about the effects of twice-daily versus once-daily caffeine on: mortality (RR 1.00, 95%CI 0.29\u20133.45); ventilation duration (MD 0.81, 95%CI -7.56-9.18); and hospital stay (MD -2.70, 95%CI -8.12-2.72). We found no studies on caffeine dose modifications and co-administration with surfactant. Two trials on adjusting caffeine dose and route of administration are ongoing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Although caffeine clearly benefits preterm infants, evidence guiding optimal administration strategies, such as route, frequency, and dose modifications, is limited. High-quality studies are urgently needed to inform clinical practice and guidelines.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13052-026-02344-0","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T07:44:55Z","timestamp":1789976695000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Strategies for caffeine administration in preterm infants: route, dosing, monitoring, and adjunctive interventions - a systematic review"],"prefix":"10.1186","volume":"52","author":[{"given":"Alaa A. M.","family":"Osman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Russo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Rojas-Reyes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franciszek","family":"Borys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Fiander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Soll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4775-872X","authenticated-orcid":false,"given":"Matteo","family":"Bruschettini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greta","family":"Sibrecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"issue":"11","key":"2344_CR1","doi-asserted-by":"publisher","first-page":"e2445871","DOI":"10.1001\/jamanetworkopen.2024.45871","volume":"7","author":"AM Ahmed","year":"2024","unstructured":"Ahmed AM, Grandi SM, Pullenayegum E, McDonald SD, Beltempo M, Premji SS. Short-Term and Long-Term Mortality Risk After Preterm Birth. JAMA Netw Open. 2024;7(11):e2445871.","journal-title":"JAMA Netw Open"},{"issue":"6","key":"2344_CR2","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1891\/0730-0832.19.6.17","volume":"19","author":"K Theobald","year":"2000","unstructured":"Theobald K, Botwinski C, Albanna S, McWilliam P. Apnea of prematurity: diagnosis, implications for care, and pharmacologic management. Neonatal Netw. 2000;19(6):17\u201324.","journal-title":"Neonatal Netw"},{"issue":"6","key":"2344_CR3","first-page":"319","volume":"43","author":"CY Lee","year":"2002","unstructured":"Lee CY, Su BH, Lin TW, Lin HC, Li TC, Wang NP. Risk factors of extubation failure in extremely low birth weight infants: a five year retrospective analysis. Acta Paediatr Taiwan. 2002;43(6):319\u201325.","journal-title":"Acta Paediatr Taiwan"},{"issue":"10","key":"2344_CR4","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1164\/rccm.202105-1150OC","volume":"204","author":"EA Jensen","year":"2021","unstructured":"Jensen EA, Whyte RK, Schmidt B, Bassler D, Vain NE, Roberts RS. Association between Intermittent Hypoxemia and Severe Bronchopulmonary Dysplasia in Preterm Infants. Am J Respir Crit Care Med. 2021;204(10):1192\u20139.","journal-title":"Am J Respir Crit Care Med"},{"issue":"5","key":"2344_CR5","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1016\/j.survophthal.2018.04.002","volume":"63","author":"SJ Kim","year":"2018","unstructured":"Kim SJ, Port AD, Swan R, Campbell JP, Chan RVP, Chiang MF. Retinopathy of Prematurity: A Review of Risk Factors and their Clinical Significance. Surv Ophthalmol. 2018;63(5):618\u201337.","journal-title":"Surv Ophthalmol"},{"key":"2344_CR6","doi-asserted-by":"publisher","unstructured":"Marques KA, Bruschettini M, Roehr CC, Davis PG, Fiander M, Soll R. Methylxanthine for the prevention and treatment of apnea in preterm infants. Cochrane Database Syst Rev. 2023;(10). https:\/\/doi.org\/10.1002\/14651858.CD013830.pub2.","DOI":"10.1002\/14651858.CD013830.pub2"},{"key":"2344_CR7","doi-asserted-by":"publisher","first-page":"3840124","DOI":"10.1155\/2020\/3840124","volume":"2020","author":"S Endesfelder","year":"2020","unstructured":"Endesfelder S, Strau\u00df E, Bendix I, Schmitz T, B\u00fchrer C. Prevention of oxygen-induced inflammatory lung injury by caffeine in neonatal rats. Oxid Med Cell Longev. 2020;2020:3840124.","journal-title":"Oxid Med Cell Longev"},{"issue":"3","key":"2344_CR8","first-page":"133","volume":"58","author":"I Gillot","year":"1990","unstructured":"Gillot I, Gouyon JB, Guignard JP. Renal effects of caffeine in preterm infants. Biol Neonate. 1990;58(3):133\u20136.","journal-title":"Biol Neonate"},{"issue":"18","key":"2344_CR9","doi-asserted-by":"publisher","first-page":"1893","DOI":"10.4155\/bio-2016-0127","volume":"8","author":"M Bruschettini","year":"2016","unstructured":"Bruschettini M, Barco S, Romantsik O, Risso F, Gennai I, Chinea B. DBS-LC-MS\/MS assay for caffeine: validation and neonatal application. Bioanalysis. 2016;8(18):1893\u2013902.","journal-title":"Bioanalysis"},{"issue":"6","key":"2344_CR10","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1097\/FTD.0b013e3181898b6f","volume":"30","author":"BG Charles","year":"2008","unstructured":"Charles BG, Townsend SR, Steer PA, Flenady VJ, Gray PH, Shearman A. Caffeine citrate treatment for extremely premature infants with apnea: population pharmacokinetics, absolute bioavailability, and implications for therapeutic drug monitoring. Ther Drug Monit. 2008;30(6):709\u201316.","journal-title":"Ther Drug Monit"},{"key":"2344_CR11","doi-asserted-by":"publisher","unstructured":"Bruschettini M, Brattstr\u00f6m P, Russo C, Onland W, Davis PG, Soll R. Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity. Cochrane Database Syst Rev. 2023;4 https:\/\/doi.org\/10.1002\/14651858.CD013873.pub2.","DOI":"10.1002\/14651858.CD013873.pub2"},{"issue":"1","key":"2344_CR12","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/S0095-5108(18)31165-5","volume":"6","author":"JV Aranda","year":"1979","unstructured":"Aranda JV, Turmen T. Methylxanthines in apnea of prematurity. Clin Perinatol. 1979;6(1):87\u2013108.","journal-title":"Clin Perinatol"},{"issue":"6","key":"2344_CR13","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1016\/S0009-9236(97)90097-7","volume":"61","author":"TC Lee","year":"1997","unstructured":"Lee TC, Charles B, Steer P, Flenady V, Shearman A. Population pharmacokinetics of intravenous caffeine in neonates with apnea of prematurity. Clin Pharmacol Ther. 1997;61(6):628\u201340.","journal-title":"Clin Pharmacol Ther"},{"issue":"3","key":"2344_CR14","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1111\/apa.14586","volume":"108","author":"P Brattstr\u00f6m","year":"2019","unstructured":"Brattstr\u00f6m P, Russo C, Ley D, Bruschettini M. High-versus low dose caffeine in preterm infants: a systematic review and meta-analysis. Acta Paediatr. 2019;108(3):401\u201310.","journal-title":"Acta Paediatr"},{"key":"2344_CR15","unstructured":"Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions version 6.4 (updated August 2023). Cochrane. 2023. Available https:\/\/www.trainingcochraneorghandbook"},{"key":"2344_CR16","doi-asserted-by":"publisher","first-page":"l4898","DOI":"10.1136\/bmj.l4898","volume":"366","author":"JA Sterne","year":"2019","unstructured":"Sterne JA, Savovi\u0107 J, Page MJ, Elbers RG, Blencowe NS, Boutron I. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898.","journal-title":"BMJ"},{"key":"2344_CR17","unstructured":"Sch\u00fcnemann H, Bro\u017cek J, Guyatt G, Oxman A, editors. editor(s). Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach (updated October 2013). GRADE Working Group; 2013. Available Httpsgdtgradeproorgapphandbookhandbookhtml."},{"key":"2344_CR18","doi-asserted-by":"publisher","first-page":"n71","DOI":"10.1136\/bmj.n71","volume":"372","author":"MJ Page","year":"2021","unstructured":"Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.","journal-title":"BMJ"},{"issue":"1","key":"2344_CR19","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1007\/s40272-022-00541-y","volume":"25","author":"C Dani","year":"2023","unstructured":"Dani C, Cecchi A, Ciarcia M, Miselli F, Luzzati M, Remaschi G, et al. Enteral and Parenteral Treatment with Caffeine for Preterm Infants in the Delivery Room: A Randomised Trial. Paediatr Drugs. 2023;25(1):79\u201386.","journal-title":"Paediatr Drugs"},{"issue":"1","key":"2344_CR20","first-page":"46","volume":"9","author":"F Faramarzi","year":"2018","unstructured":"Faramarzi F, Shiran M, Rafati M, Farhadi R, Salehifar E, Nakhshab M. The efficacy and safety of two different doses of caffeine in respiratory function of preterm infants. Casp J. 2018;9(1):46\u201353.","journal-title":"Casp J"},{"issue":"1","key":"2344_CR21","doi-asserted-by":"publisher","first-page":"124","DOI":"10.3126\/jnps.v42i1.37173","volume":"42","author":"F Syed","year":"2022","unstructured":"Syed F, Kini S, Majeed A. The Efficacy and Safety of Once Daily versus Twice Daily Dosing of Caffeine Citrate in Apnea of prematurity: a Randomised Control Trial. J Nepal Paediatr Soc. 2022;42(1):124\u20138.","journal-title":"J Nepal Paediatr Soc"},{"issue":"12","key":"2344_CR22","doi-asserted-by":"publisher","first-page":"EVIDoa2300183","DOI":"10.1056\/EVIDoa2300183","volume":"2","author":"A Katheria","year":"2023","unstructured":"Katheria A, Ines F, Banerji A, Hopper A, Uy C, Chundu A, et al. Caffeine and Less Invasive Surfactant Administration for Respiratory Distress Syndrome of the Newborn. NEJM Evid. 2023;2(12):EVIDoa2300183.","journal-title":"NEJM Evid"},{"issue":"10","key":"2344_CR23","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1038\/jp.2017.82","volume":"37","author":"NR Dobson","year":"2017","unstructured":"Dobson NR, Rhein LM, Darnall RA, Corwin MJ, Heeren TC, Eichenwald E, et al. Caffeine decreases intermittent hypoxia in preterm infants nearing term-equivalent age. J Perinatol. 2017;37(10):1135\u201340.","journal-title":"J Perinatol"},{"key":"2344_CR24","unstructured":"Srinivasan P, Katz S, DeCristofaro J. Increased caffeine levels do not reduce the frequency of clinical cardiopulmonary events in neonates with apnea of prematurity following repeat bolus therapy. A randomized placebo controlled study. Neonatology - abstract book. 2002; p 420A."},{"key":"2344_CR25","unstructured":"CTRI\/2023\/07\/055443. To determine if apnea episodes(cessation of breathing in premature newborns) occur less frequently in infants whose caffeine(drug used for treatment of apnea) doses are increased for weight gain. https:\/\/trialsearch.who.int\/Trial2.aspx?TrialID=CTRI\/2023\/07\/055443. 2023."},{"key":"2344_CR26","unstructured":"CTRI\/2023\/09\/057903. Effect of increasing caffeine intake compared to usual maintenance dose in preterm neonates: a Randomised Controlled Trial. https:\/\/trialsearch.who.int\/Trial2.aspx?TrialID=CTRI\/2023\/09\/057903. 2023."},{"key":"2344_CR27","doi-asserted-by":"publisher","unstructured":"Moresco L, Sj\u00f6gren A, Marques KA, Soll R, Bruschettini M. Caffeine versus other methylxanthines for the prevention and treatment of apnea in preterm infants. Cochrane Database Syst Rev. 2023;(10). https:\/\/doi.org\/10.1002\/14651858.CD015462.pub2","DOI":"10.1002\/14651858.CD015462.pub2"},{"issue":"5","key":"2344_CR28","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1007\/s11096-022-01437-0","volume":"44","author":"WZ Yun","year":"2022","unstructured":"Yun WZ, Kassab YW, Yao LM, Khairuddin N, Ming LC. Effectiveness and safety of early versus late caffeine therapy in managing apnoea of prematurity among preterm infants: a retrospective cohort study. Int J Clin Pharm Int J Clin Pharm. 2022;44(5):1140\u20138.","journal-title":"Int J Clin Pharm Int J Clin Pharm"},{"issue":"3","key":"2344_CR29","first-page":"253","volume":"26","author":"A Rebentisch","year":"2021","unstructured":"Rebentisch A, Kovey K, Denslow S. An Evaluation of Twice-Daily Dosing of Caffeine for Apnea of Prematurity. J Pediatr Pharmacol Ther. 2021;26(3):253\u20137.","journal-title":"J Pediatr Pharmacol Ther"},{"issue":"6","key":"2344_CR30","doi-asserted-by":"publisher","first-page":"101178","DOI":"10.1016\/j.siny.2020.101178","volume":"25","author":"V Saroha","year":"2020","unstructured":"Saroha V, Patel RM. Caffeine for preterm infants: Fixed standard dose, adjustments for age or high dose? Semin Fetal Neonatal Med. 2020;25(6):101178.","journal-title":"Semin Fetal Neonatal Med"},{"issue":"6","key":"2344_CR31","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/jp.2014.226","volume":"35","author":"P Alur","year":"2015","unstructured":"Alur P, Bollampalli V, Bell T, Hussain N, Liss J. Serum caffeine concentrations and short-term outcomes in premature infants of \u2a7d29 weeks of gestation. J Perinatol. 2015;35(6):434\u20138.","journal-title":"J Perinatol"},{"issue":"4","key":"2344_CR32","first-page":"212","volume":"12","author":"P Gal","year":"2007","unstructured":"Gal P. Caffeine therapeutic drug monitoring is necessary and cost-effective. J Pediatr Pharmacol Ther. 2007;12(4):212\u20135.","journal-title":"J Pediatr Pharmacol Ther"},{"issue":"1","key":"2344_CR33","first-page":"45","volume":"18","author":"SJ Francart","year":"2013","unstructured":"Francart SJ, Allen MK, Stegall-Zanation J. Apnea of prematurity: caffeine dose optimization. J Pediatr Pharmacol Ther. 2013;18(1):45\u201352.","journal-title":"J Pediatr Pharmacol Ther"},{"key":"2344_CR34","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.jpeds.2017.08.064","volume":"191","author":"G Koch","year":"2017","unstructured":"Koch G, Datta AN, Jost K, Schulzke SM, van den Anker J. Caffeine citrate dosing adjustments to assure stable caffeine concentrations in preterm neonates. J Pediatr. 2017;191:50\u20136.","journal-title":"J Pediatr"},{"issue":"1","key":"2344_CR35","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1159\/000528914","volume":"120","author":"DG Sweet","year":"2023","unstructured":"Sweet DG, Carnielli VP, Greisen G, Hallman M, Klebermass-Schrehof K, Ozek E, et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome: 2022 Update. Neonatology. 2023;120(1):3\u201323.","journal-title":"Neonatology"},{"key":"2344_CR36","unstructured":"NICE. Recommendations | Specialist neonatal respiratory care for babies born preterm | Guidance | NICE [Internet]. 2019 Apr [cited 2025 Apr 26]. Available from: https:\/\/www.nice.org.uk\/guidance\/ng124\/chapter\/recommendations."}],"container-title":["Italian Journal of Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13052-026-02344-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13052-026-02344-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13052-026-02344-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:07:14Z","timestamp":1790255234000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13052-026-02344-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,21]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2344"],"URL":"https:\/\/doi.org\/10.1186\/s13052-026-02344-0","relation":{},"ISSN":["1824-7288"],"issn-type":[{"value":"1824-7288","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,21]]},"assertion":[{"value":"23 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 September 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"143"}}