{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T07:01:14Z","timestamp":1780124474819,"version":"3.54.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007950","name":"Tanta University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007950","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Pediatr"],"abstract":"Abstract<\/jats:title>\n The aim of this study is to investigate the effects of melatonin on the left ventricular (LV) function in persistent pulmonary hypertension of the newborn (PPHN) and to assess its potential role in enhancing cardiac performance and reducing oxidative stress. This randomized controlled trial was conducted on 80 neonates (\u2265\u200936\u00a0weeks\u2019 gestational age) with PPHN confirmed by echocardiography (Echo). Participants were assigned to receive standard therapy alone or in combination with oral melatonin. LV function was evaluated using echocardiographic parameters, and levels of serum biomarkers of oxidative stress and inflammation were also measured. Unlike the placebo group, the melatonin group exhibited significantly better LV function, regarding the conventional and advanced echocardiographic parameters. Additionally, melatonin administration was associated with earlier weaning from mechanical ventilation (MV) and respiratory support, shorter hospital stays, lower levels of serum high-mobility group box-1 (HMGB1) protein, and N-terminal pro-B-type natriuretic peptide (NT-proBNP).<\/jats:p>\n \n Conclusion<\/jats:italic>\n : Melatonin can enhance LV function in PPHN, likely through its cardioprotective and antioxidative mechanisms. These findings support melatonin as a promising adjunctive therapy in neonatal pulmonary hypertension, warranting further investigation in larger clinical trials.\n <\/jats:p>\n \n Trial registration<\/jats:italic>\n : registered on ClinicalTrials.gov (ID: NCT07090720), URL:\n https:\/\/clinicaltrials.gov\/study\/NCT07090720?cond=NCT07090720&rank=1<\/jats:ext-link>\n , Date: (29\/7\/2025).\n \n \n \n \n \n What is Known:<\/jats:bold>\n \u2022\n PPHN induces hypoxic respiratory failure, jeopardizing multiorgan function, including LV performance<\/jats:italic>\n .\u2022\n Oxidative stress is crucial in pulmonary arterial hypertension development<\/jats:italic>\n .\n <\/jats:td>\n <\/jats:tr>\n \n \n What is New:<\/jats:bold>\n \u2022\n Melatonin\u2019s antioxidant and vasodilatory properties may serve as an adjunctive therapy in PPHN and enhance myocardial protection from the hypoxic effect of PPHN<\/jats:italic>\n .\n <\/jats:td>\n <\/jats:tr>\n <\/jats:tbody>\n <\/jats:table>\n <\/jats:table-wrap>\n <\/jats:p>","DOI":"10.1007\/s00431-026-06864-z","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T12:44:18Z","timestamp":1775738658000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Melatonin effects on the left ventricular function in neonates with persistent pulmonary hypertension"],"prefix":"10.1007","volume":"185","author":[{"given":"Sarah M.","family":"Nofal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdel-Rahman M.","family":"El-Mashad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5474-1424","authenticated-orcid":false,"given":"Asmaa M.","family":"Elmesiry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amany M.","family":"Abouelenain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa M.","family":"Awny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"6864_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ppedcard.2024.101777","volume":"76","author":"JP Priya Cooper","year":"2025","unstructured":"Priya Cooper JP, Budhwani A, Kunneth LS, Patel IA, Omohundro A, Sholola OB et al (2025) Persistent pulmonary hypertension of the newborn. Prog Pediatr Cardiol 76:101777. https:\/\/doi.org\/10.1016\/j.ppedcard.2024.101777","journal-title":"Prog Pediatr Cardiol"},{"key":"6864_CR2","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2025.1502385","author":"Y Huang","year":"2025","unstructured":"Huang Y, Yang T, Liang X, Chen Y, Zhou P, Yu Z et al (2025) Global, regional and national trends in the burden of persistent pulmonary hypertension of the newborn and essentials of its management from 1993 to 2023: a scoping review. Front Pediatr. https:\/\/doi.org\/10.3389\/fped.2025.1502385","journal-title":"Front Pediatr"},{"key":"6864_CR3","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1136\/archdischild-2020-319705","volume":"106","author":"HM Siefkes","year":"2021","unstructured":"Siefkes HM, Lakshminrusimha S (2021) Management of systemic hypotension in term infants with persistent pulmonary hypertension of the newborn: an illustrated review. Arch Dis Child Fetal Neonatal Ed 106:446\u2013455. https:\/\/doi.org\/10.1136\/archdischild-2020-319705","journal-title":"Arch Dis Child Fetal Neonatal Ed"},{"key":"6864_CR4","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1007\/s00431-025-06364-6","volume":"184","author":"E Mosca","year":"2025","unstructured":"Mosca E, Moulis L, Ouhab I, Gaudaire A, Mesnage R, Gautheyrou L et al (2025) Early echocardiographic predictors of death or early severe morbidity in extremely low gestational age neonates: a prospective study. Eur J Pediatr 184:508. https:\/\/doi.org\/10.1007\/s00431-025-06364-6","journal-title":"Eur J Pediatr"},{"key":"6864_CR5","doi-asserted-by":"publisher","first-page":"690","DOI":"10.21608\/zumj.2019.11098.1147","volume":"26","author":"HO Mosbah","year":"2020","unstructured":"Mosbah HO, shedeed sE, Tolba sAR (2020) Speckle tracking echocardiographic ventricular functions in infants with pulmonary hypertension with shunt disease. Zagazig Univ Med J 26:690\u2013699. https:\/\/doi.org\/10.21608\/zumj.2019.11098.1147","journal-title":"Zagazig Univ Med J"},{"key":"6864_CR6","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2021.106853","volume":"138","author":"EG Figueroa","year":"2021","unstructured":"Figueroa EG, Gonzal\u00e9z-Candia A, Villanueva CA, Ebensperger G, Reyes RV, Llanos AJ et al (2021) Beneficial effects of melatonin on prostanoids pathways in pulmonary hypertensive neonates. Vasc Pharmacol 138:106853. https:\/\/doi.org\/10.1016\/j.vph.2021.106853","journal-title":"Vasc Pharmacol"},{"key":"6864_CR7","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222212098","volume":"22","author":"J Hudson","year":"2021","unstructured":"Hudson J, Farkas L (2021) Epigenetic regulation of endothelial dysfunction and inflammation in pulmonary arterial hypertension. Int J Mol Sci 22:1209810. https:\/\/doi.org\/10.3390\/ijms222212098","journal-title":"Int J Mol Sci"},{"issue":"1","key":"6864_CR8","doi-asserted-by":"publisher","DOI":"10.1186\/s43054-021-00058-y","volume":"69","author":"TA Abdel Hamid","year":"2021","unstructured":"Abdel Hamid TA, Eldin ZME, Hegazy RA, Esmail RI, El-sholkamy LMA (2021) B-natriuretic peptide serum levels in neonates with persistent pulmonary hypertension. Egypt Pediatr Assoc Gaz 69(1):1310. https:\/\/doi.org\/10.1186\/s43054-021-00058-y","journal-title":"Egypt Pediatr Assoc Gaz"},{"key":"6864_CR9","doi-asserted-by":"publisher","DOI":"10.3390\/children4080063","volume":"4","author":"B Mathew","year":"2017","unstructured":"Mathew B, Lakshminrusimha S (2017) Persistent pulmonary hypertension in the newborn. Children 4:6310. https:\/\/doi.org\/10.3390\/children4080063","journal-title":"Children"},{"issue":"10","key":"6864_CR10","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1016\/S2213-2600(21)00072-2","volume":"9","author":"M Jankowich","year":"2021","unstructured":"Jankowich M, Maron BA, Choudhary G (2021) Mildly elevated pulmonary artery systolic pressure on echocardiography: bridging the gap in current guidelines. Lancet Respir Med 9(10):1185\u2013119110. https:\/\/doi.org\/10.1016\/S2213-2600(21)00072-2","journal-title":"Lancet Respir Med"},{"key":"6864_CR11","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1038\/jp.2014.186","volume":"35","author":"H Aly","year":"2015","unstructured":"Aly H, Elmahdy H, El-Dib M, Rowisha M, Awny M, El-Gohary T et al (2015) Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. J Perinatol 35:186\u2013191. https:\/\/doi.org\/10.1038\/jp.2014.186","journal-title":"J Perinatol"},{"key":"6864_CR12","doi-asserted-by":"publisher","DOI":"10.32794\/MR11250025","author":"DP Cardinali","year":"2019","unstructured":"Cardinali DP (2019) Are melatonin doses employed clinically adequate for melatonin-induced cytoprotection? Melatonin Res. https:\/\/doi.org\/10.32794\/MR11250025","journal-title":"Melatonin Res"},{"key":"6864_CR13","doi-asserted-by":"publisher","unstructured":"Elmesiry A (2020) Three-dimensional speckle tracking echocardiography for the assessment of cardiac function in newborns with extra-cardiac diseases. J Cardiol Res Rev Reports SRC\/JCRRR-115:3 https:\/\/doi.org\/10.47363\/JCRRR\/2020(1)113","DOI":"10.47363\/JCRRR\/2020(1)113"},{"key":"6864_CR14","doi-asserted-by":"publisher","unstructured":"Rodriguez MJ, Martinez-Orgado J, Corredera A, Serrano I, Arruza L (2022) Diastolic dysfunction in neonates with hypoxic-ischemic encephalopathy during therapeutic hypothermia: a tissue doppler study. Front Pediatrics 10 https:\/\/doi.org\/10.3389\/fped.2022.880786.","DOI":"10.3389\/fped.2022.880786"},{"key":"6864_CR15","doi-asserted-by":"publisher","first-page":"1516","DOI":"10.1016\/j.jcmg.2023.08.011","volume":"16","author":"J Nyberg","year":"2023","unstructured":"Nyberg J, Jakobsen EO, \u00d8stvik A, Holte E, St\u00f8len S, Lovstakken L et al (2023) Echocardiographic reference ranges of global longitudinal strain for all cardiac chambers using guideline-directed dedicated views. JACC Cardiovasc Imaging 16:1516\u20131531. https:\/\/doi.org\/10.1016\/j.jcmg.2023.08.011","journal-title":"JACC Cardiovasc Imaging"},{"key":"6864_CR16","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/s41390-018-0077-x","volume":"84","author":"D van Laere","year":"2018","unstructured":"van Laere D, van Overmeire B, Gupta S, El-Khuffash A, Savoia M, McNamara PJ et al (2018) Application of NPE in the assessment of a patent ductus arteriosus. Pediatr Res 84:46\u20135610. https:\/\/doi.org\/10.1038\/s41390-018-0077-x","journal-title":"Pediatr Res"},{"key":"6864_CR17","doi-asserted-by":"publisher","first-page":"e145","DOI":"10.1097\/pcc.0000000000002579","volume":"22","author":"A Jain","year":"2021","unstructured":"Jain A, El-Khuffash AF, van Herpen CH, Resende MHF, Giesinger RE, Weisz D et al (2021) Cardiac function and ventricular interactions in persistent pulmonary hypertension of the newborn. Pediatr Crit Care Med 22:e145\u2013e157. https:\/\/doi.org\/10.1097\/pcc.0000000000002579","journal-title":"Pediatr Crit Care Med"},{"key":"6864_CR18","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1038\/s41372-023-01762-w","volume":"43","author":"S Timberline","year":"2023","unstructured":"Timberline S, Bhatt A, Sunderji S, Tancredi DJ, Lakshminrusimha S, Siefkes H (2023) Novel scoring tool of hypoxemic respiratory failure and pulmonary hypertension for defining severity of persistent pulmonary hypertension of newborn. J Perinatol 43:1281\u20131287. https:\/\/doi.org\/10.1038\/s41372-023-01762-w","journal-title":"J Perinatol"},{"key":"6864_CR19","doi-asserted-by":"publisher","DOI":"10.1016\/j.siny.2022.101366","author":"K More","year":"2022","unstructured":"More K, Soni R, Gupta S (2022) The role of bedside functional echocardiography in the assessment and management of pulmonary hypertension. Semin Fetal Neonatal Med. https:\/\/doi.org\/10.1016\/j.siny.2022.101366","journal-title":"Semin Fetal Neonatal Med"},{"key":"6864_CR20","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.3390\/nu15061406","volume":"15","author":"A-Y Xia","year":"2023","unstructured":"Xia A-Y, Zhu H, Zhao Z-J, Liu H-Y, Wang P-H, Ji L-D et al (2023) Molecular mechanisms of the melatonin receptor pathway linking circadian rhythm to type 2 diabetes mellitus. Nutrients 15:1406. https:\/\/doi.org\/10.3390\/nu15061406","journal-title":"Nutrients"},{"key":"6864_CR21","first-page":"1233","volume":"68","author":"QM Ahmad","year":"2018","unstructured":"Ahmad QM, Chishti AL, Waseem N (2018) Role of melatonin in management of hypoxic ischaemic encephalopathy in newborns: a randomized control trial. J Pak Med Assoc 68:1233\u20131237","journal-title":"J Pak Med Assoc"},{"key":"6864_CR22","doi-asserted-by":"publisher","unstructured":"Cardinali DP (2019) An assessment of melatonin\u2019s therapeutic value in the hypoxic-ischemic encephalopathy of the newborn. Front Synaptic Neurosci 11 https:\/\/doi.org\/10.3389\/fnsyn.2019.00034.","DOI":"10.3389\/fnsyn.2019.00034"},{"key":"6864_CR23","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.767173","volume":"9","author":"H Xie","year":"2021","unstructured":"Xie H, Huo Y, Chen Q, Hou X (2021) Application of B-type natriuretic peptide in neonatal diseases. Front Pediatr 9:767173. https:\/\/doi.org\/10.3389\/fped.2021.767173","journal-title":"Front Pediatr"},{"key":"6864_CR24","doi-asserted-by":"publisher","first-page":"228","DOI":"10.26650\/IUITFD.957968","volume":"85","author":"S T\u00fcfekci","year":"2022","unstructured":"T\u00fcfekci S, K\u0131z\u0131lca O, Ayg\u00fcn E (2022) N-terminal prohormone of brain natriuretic peptide in the diagnosis and management of persistent pulmonary hypertension in newborns. J Istanbul Faculty Med \/ \u0130stanbul T\u0131p Fak\u00fcltesi Dergisi 85:228\u2013235. https:\/\/doi.org\/10.26650\/IUITFD.957968","journal-title":"J Istanbul Faculty Med \/ \u0130stanbul T\u0131p Fak\u00fcltesi Dergisi"},{"key":"6864_CR25","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.7150\/ijms.34344","volume":"16","author":"Z Tang","year":"2019","unstructured":"Tang Z, Jiang M, Ou-Yang Z, Wu H, Dong S, Hei M (2019) High mobility group box 1 protein (HMGB1) as biomarker in hypoxia-induced persistent pulmonary hypertension of the newborn: a clinical and in vivo pilot study. Int J Med Sci 16:1123\u20131131. https:\/\/doi.org\/10.7150\/ijms.34344","journal-title":"Int J Med Sci"},{"key":"6864_CR26","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1080\/14767058.2019.1598363","volume":"34","author":"AF AbdelMassih","year":"2021","unstructured":"AbdelMassih AF, Al. Zahraa Hassan F, El-Gammal A, Tawfik M, Nabil D (2021) The overlooked left ventricle in persistent pulmonary hypertension of the newborn. J Matern Fetal Neonatal Med 34:72\u20137610. https:\/\/doi.org\/10.1080\/14767058.2019.1598363","journal-title":"J Matern Fetal Neonatal Med"},{"key":"6864_CR27","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2023.1175178","author":"K Le Duc","year":"2023","unstructured":"Le Duc K, Rakza T, Baudelet JB, Boukhris MR, Mur S, Houeijeh A et al (2023) Diastolic ventricular function in persistent pulmonary hypertension of the newborn. Front Pediatr. https:\/\/doi.org\/10.3389\/fped.2023.1175178","journal-title":"Front Pediatr"},{"key":"6864_CR28","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1007\/s10554-024-03120-z","volume":"40","author":"SL Sumbaraju","year":"2024","unstructured":"Sumbaraju SL, Nayak K, Prabhu S, Nayak V, Prabhu KP, Lewis LE (2024) Myocardial performance imaging for the early identification of cardiac dysfunction in neonates with sepsis. Int J Cardiovasc Imaging 40:1435\u20131444. https:\/\/doi.org\/10.1007\/s10554-024-03120-z","journal-title":"Int J Cardiovasc Imaging"},{"key":"6864_CR29","doi-asserted-by":"publisher","DOI":"10.1186\/s43054-024-00326-7","volume":"72","author":"AMK Baz","year":"2024","unstructured":"Baz AMK, El-Agamy OAE-F, Eldegwi M, Agha HM (2024) Speckle tracking of left ventricle in pediatric patients with hemodynamically significant patent ductus arteriosus (PDA): case\u2013control study. Egypt Pediatr Assoc Gaz 72:86. https:\/\/doi.org\/10.1186\/s43054-024-00326-7","journal-title":"Egypt Pediatr Assoc Gaz"},{"key":"6864_CR30","doi-asserted-by":"publisher","first-page":"2310","DOI":"10.3889\/oamjms.2018.270","volume":"6","author":"NM Habeeb","year":"2018","unstructured":"Habeeb NM, Youssef OI, Elguindy WM, Ibrahim AS, Hussein WH (2018) Three dimensional (3D) echocardiography as a tool of left ventricular assessment in children with dilated cardiomyopathy: comparison to cardiac MRI. Open Access Maced J Med Sci 6:2310\u20132315. https:\/\/doi.org\/10.3889\/oamjms.2018.270","journal-title":"Open Access Maced J Med Sci"}],"container-title":["European Journal of Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00431-026-06864-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00431-026-06864-z","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00431-026-06864-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T06:02:32Z","timestamp":1780120952000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00431-026-06864-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,9]]},"references-count":30,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["6864"],"URL":"https:\/\/doi.org\/10.1007\/s00431-026-06864-z","relation":{},"ISSN":["1432-1076"],"issn-type":[{"value":"1432-1076","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,9]]},"assertion":[{"value":"20 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 March 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 March 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 April 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This research was carried out at the Neonatal Intensive Care unit (NICU), Tanta University Hospitals, Egypt, between January 2023 and January 2025 and was authorized by the local Ethical Committee of Faculty of Medicine, Tanta University (36173\/12\/22).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Patients\u2019 parents gave their signed, informed consent.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"247"}}