{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:14:12Z","timestamp":1792088052737,"version":"4.4.0"},"reference-count":50,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Sickle cell disease (SCD) is the most common monogenic disorder worldwide and remains a major cause of morbidity and mortality. Sickle cell anemia (SCA), the homozygous HbSS genotype, represents the most severe and frequent form within the spectrum of SCD. Hydroxyurea (HU), a ribonucleotide reductase inhibitor, represents the first and most widely used disease-modifying therapy for SCA. This review summarizes current evidence on the mechanisms of action, clinical efficacy, systemic effects, and long-term safety of chronic HU therapy in patients with SCA. A comprehensive literature search was conducted in PubMed up to 2025 using the terms \u201csickle cell disease,\u201d \u201csickle cell anemia\u201d, \u201chydroxyurea,\u201d and \u201cchildren\u201d or \u201cpaediatric.\u201d Eligible studies included randomized controlled trials, cohort studies, and systematic reviews evaluating HU therapy in SCA. Literature analysis showed that HU exerts pleiotropic effects by inducing fetal hemoglobin (HbF) synthesis, improving red blood cell deformability, reducing leukocyte and platelet counts, and enhancing nitric oxide bioavailability. These mechanisms lead to decreased vaso-occlusive crises, acute chest syndrome, transfusion requirements, and overall mortality. Beyond hematologic improvement, HU confers neuroprotective benefits, modulates inflammatory and immune pathways, and supports normal growth and endocrine development in children. Adverse events, primarily mild bone marrow suppression, are dose-dependent and reversible with appropriate monitoring. No evidence supports an increased risk of malignancy with long-term use. In conclusion, chronic HU therapy is a safe, effective, and multifaceted treatment that substantially improves survival and quality of life in patients with SCA. Early initiation and individualized dosing maximize its therapeutic benefits and help prevent irreversible organ damage.<\/jats:p>","DOI":"10.3390\/jcm14238599","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T16:20:29Z","timestamp":1765210829000},"page":"8599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Chronic Hydroxyurea Therapy in Children with Sickle Cell Anemia: Mechanisms of Action, Systemic Effects, and Long-Term Safety"],"prefix":"10.3390","volume":"14","author":[{"given":"Federica","family":"Fogliazza","sequence":"first","affiliation":[{"name":"Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Berzieri","sequence":"additional","affiliation":[{"name":"Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Carbone","sequence":"additional","affiliation":[{"name":"Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Ciriaco","sequence":"additional","affiliation":[{"name":"Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4103-2837","authenticated-orcid":false,"given":"Susanna","family":"Esposito","sequence":"additional","affiliation":[{"name":"Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e633","DOI":"10.1016\/S2352-3026(23)00096-0","article-title":"Defining global strategies to improve outcomes in sickle cell disease: A Lancet Haematology Commission","volume":"10","author":"Piel","year":"2023","journal-title":"Lancet Haematol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"18011","DOI":"10.1038\/nrdp.2018.10","article-title":"Sickle cell disease","volume":"4","author":"Kato","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1016\/S0140-6736(10)61029-X","article-title":"Sickle-cell disease","volume":"376","author":"Rees","year":"2010","journal-title":"Lancet"},{"key":"ref_4","unstructured":"GBD 2021 Sickle Cell Disease Collaborators (2023). Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000\u20132021: A systematic analysis from the Global Burden of Disease Study 2021. Lancet Haematol., 10, e585\u2013e599."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1186\/1750-1172-8-169","article-title":"Organizing national responses for rare blood disorders: The Italian experience with sickle cell disease in childhood","volume":"8","author":"Colombatti","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1001\/jama.2022.10233","article-title":"Sickle cell disease: A review","volume":"328","author":"Kavanagh","year":"2022","journal-title":"JAMA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/S0140-6736(17)30193-9","article-title":"Sickle cell disease","volume":"390","author":"Ware","year":"2017","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13045-022-01237-z","article-title":"Advances in the diagnosis and treatment of sickle cell disease","volume":"15","author":"Brandow","year":"2022","journal-title":"J. Hematol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1172\/JCI89741","article-title":"Intravascular hemolysis and the pathophysiology of sickle cell disease","volume":"127","author":"Kato","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3188","DOI":"10.1182\/blood.V106.11.3188.3188","article-title":"Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension and death in patients with sickle cell disease","volume":"106","author":"Kato","year":"2005","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"464","DOI":"10.3324\/haematol.2012.068965","article-title":"The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe","volume":"98","author":"Nouraie","year":"2013","journal-title":"Haematologica"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1146\/annurev-pathmechdis-012418-012838","article-title":"Pathophysiology of sickle cell disease","volume":"14","author":"Sundd","year":"2019","journal-title":"Annu. Rev. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1002\/ajh.23232","article-title":"Genetic modifiers of sickle cell disease","volume":"87","author":"Steinberg","year":"2012","journal-title":"Am. J. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/ng1533","article-title":"Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia","volume":"37","author":"Sebastiani","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.ajpath.2018.12.012","article-title":"Ischemia-reperfusion injury in sickle cell disease: From basics to therapeutics","volume":"189","author":"Ansari","year":"2019","journal-title":"Am. J. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/ejh.13430","article-title":"The vaso-occlusive pain crisis in sickle cell disease: Definition, pathophysiology, and management","volume":"105","author":"Darbari","year":"2020","journal-title":"Eur. J. Haematol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1073\/pnas.052522799","article-title":"Primary role for adherent leukocytes in sickle cell vascular occlusion: A new paradigm","volume":"99","author":"Turhan","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","first-page":"532","article-title":"Hemoglobinopathies: Clinical manifestations, diagnosis, and treatment","volume":"108","author":"Kohne","year":"2011","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3885979","DOI":"10.1155\/2022\/3885979","article-title":"Sickle cell disease in children and adolescents: A review of the historical, clinical, and public health perspective of sub-Saharan Africa and beyond","volume":"2022","author":"Egesa","year":"2022","journal-title":"Int. J. Pediatr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1542\/pir.33.5.195","article-title":"Sickle cell disease","volume":"33","author":"McCavit","year":"2012","journal-title":"Pediatr. Rev."},{"key":"ref_21","unstructured":"Casale, M., Casciana, M.L., Ciliberti, A., Colombatti, R., Del Vecchio, G.C., Fasoli, S., Scacco, C.F., Giordano, P., Kiren, V., and Ladogana, S. (2023). Linee-Guida per la Gestione della Malattia Drepanocitica in eta\u2019 Pediatrica in Italia, Associazione Italiana Ematologia Oncologia Pediatrica."},{"key":"ref_22","first-page":"1061","article-title":"The modern use of hydroxyurea for children with sickle cell anemia","volume":"110","author":"Quinn","year":"2025","journal-title":"Haematologica"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Wang, W., Zou, P., Hwang, S., Kang, G., Ding, J., Heitzer, A., Schreiber, J.E., Helton, K., and Hankins, J.S. (2021). Effects of Hydroxyurea on Brain Function in Children with Sickle Cell Anemia, Authorea, Inc.","DOI":"10.22541\/au.161446690.09460099\/v1"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1111\/bjh.14235","article-title":"Hydroxycarbamide treatment and brain MRI\/MRA findings in children with sickle cell anaemia","volume":"175","author":"Nottage","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1182\/blood-2018-09-876318","article-title":"Hydroxyurea reduces cerebral metabolic stress in patients with sickle cell anemia","volume":"133","author":"Fields","year":"2019","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lai, J., Zou, P., da Rocha, J.L.D., Heitzer, A.M., Patni, T., Li, Y., Scoggins, M.A., Sharma, A., Wang, W.C., and Helton, K.J. (2024). Hydroxyurea maintains working memory function in pediatric sickle cell disease. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0296196"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e26","DOI":"10.1016\/S2352-3026(21)00368-9","article-title":"Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): A double-blind, multicentre, randomised, phase 3 trial","volume":"9","author":"Abdullahi","year":"2022","journal-title":"Lancet Haematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1207\/S15326942DN2401_01","article-title":"Patterns of verbal long-term and working memory performance reveal deficits in strategic processing in children with frontal infarcts related to sickle cell disease","volume":"24","author":"White","year":"2003","journal-title":"Dev. Neuropsychol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1002\/ajh.23604","article-title":"Parent education and biologic factors influence on cognition in sickle cell anemia","volume":"89","author":"King","year":"2014","journal-title":"Am. J. Hematol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1182\/blood-2015-10-675231","article-title":"Long-term treatment follow-up of children with sickle cell disease monitored with abnormal transcranial Doppler velocities","volume":"127","author":"Bernaudin","year":"2016","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1111\/bjh.17687","article-title":"Hydroxyurea treatment and neurocognitive functioning in sickle cell disease from school age to young adulthood","volume":"195","author":"Heitzer","year":"2021","journal-title":"Br. J. Haematol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1111\/bjh.16519","article-title":"Association between hydroxycarbamide exposure and neurocognitive function in adolescents with sickle cell disease","volume":"189","author":"Partanen","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/S0140-6736(15)01041-7","article-title":"Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia\u2014TCD With Transfusions Changing to Hydroxyurea (TWiTCH): A multicentre, open-label, phase 3, non-inferiority trial","volume":"387","author":"Ware","year":"2016","journal-title":"Lancet"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Emokpae, M.A., Aruomaren, A., and Osime, E. (2016). Relationship between neutrophil-to-lymphocyte ratio and inflammatory markers in sickle cell anaemia patients with proteinuria. Med. Sci., 4.","DOI":"10.3390\/medsci4030011"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1182\/blood-2013-03-490623","article-title":"High prevalence of red blood cell alloimmunization in sickle cell disease despite transfusion from Rh-matched minority donors","volume":"122","author":"Chou","year":"2013","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1076029619828839","DOI":"10.1177\/1076029619828839","article-title":"Circulating microparticles in children with sickle cell anemia in a tertiary center in upper Egypt","volume":"25","author":"Zahran","year":"2019","journal-title":"Clin. Appl. Thromb. Hemost."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1038\/s41390-021-01627-y","article-title":"Regulatory T-cell phenotypes in children with sickle cell disease","volume":"91","author":"Zahran","year":"2022","journal-title":"Pediatr. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.cyto.2015.07.016","article-title":"Evaluation of CD4+CD25+FoxP3+ T cell populations, IL-10 production, and their correlation with clinical and biochemical parameters in sickle cell anemia patients with leg ulcers","volume":"75","author":"Pereira","year":"2015","journal-title":"Cytokine"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1076029619895111","DOI":"10.1177\/1076029619895111","article-title":"Effect of hydroxyurea treatment on the inflammatory markers among children with sickle cell disease","volume":"26","author":"Zahran","year":"2020","journal-title":"Clin. Appl. Thromb. Hemost."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1002\/pbc.22137","article-title":"Growth patterns in children with sickle cell anemia during puberty","volume":"53","author":"Rhodes","year":"2009","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_41","first-page":"101","article-title":"Growth and growth hormon-insulin like growth factor-I (GH-IGF-I) axis in chronic anemias","volume":"88","author":"Soliman","year":"2017","journal-title":"Acta Biomed."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1067\/mpd.2002.121383","article-title":"Effect of hydroxyurea on growth in children with sickle cell anemia: Results of the HUG-KIDS Study","volume":"140","author":"Wang","year":"2002","journal-title":"J. Pediatr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1097\/MPH.0000000000001477","article-title":"Effect of sickle cell anemia therapies on the natural history of growth and puberty patterns","volume":"41","author":"Nagalapuram","year":"2019","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e26774","DOI":"10.1002\/pbc.26774","article-title":"Hydroxyurea prescription, availability and use for children with sickle cell disease in Italy: Results of a National Multicenter survey","volume":"65","author":"Colombatti","year":"2018","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1182\/blood.2023021575","article-title":"Hydroxyurea reduces infections in children with sickle cell anemia in Uganda","volume":"143","author":"Namazzi","year":"2024","journal-title":"Blood"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1016\/S0140-6736(11)60355-3","article-title":"Hydroxycarbamide in very young children with sickle-cell anaemia: A multicentre, randomised, controlled trial (BABY HUG)","volume":"377","author":"Wang","year":"2011","journal-title":"Lancet"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/S0248-8663(00)87226-4","article-title":"Secondary cutaneous effects of hydroxyurea: Prospective study of 26 patients from a dermatologic consultation","volume":"21","author":"Leborgne","year":"2000","journal-title":"Rev. Med. Interne"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1046\/j.1365-2141.2003.03849.x","article-title":"The role of hydroxyurea in sickle cell disease","volume":"120","author":"Halsey","year":"2003","journal-title":"Br. J. Haematol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"988","DOI":"10.3324\/haematol.11515","article-title":"Influence of sickle cell disease and treatment with hydroxyurea on sperm parameters and fertility of human males","volume":"93","author":"Berthaut","year":"2008","journal-title":"Haematologica"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"102924","DOI":"10.1016\/j.jogc.2025.102924","article-title":"Safety of Hydroxyurea in Pregnancy: A Systematic Review of the Literature","volume":"47","author":"Zitoun","year":"2025","journal-title":"J. Obstet. Gynaecol. Can."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/23\/8599\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T16:42:40Z","timestamp":1765212160000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/23\/8599"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,4]]},"references-count":50,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["jcm14238599"],"URL":"https:\/\/doi.org\/10.3390\/jcm14238599","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,4]]}}}