{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T02:54:36Z","timestamp":1785207276540,"version":"3.55.0"},"reference-count":37,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"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>Background: Preterm birth (PTB) remains a leading cause of neonatal morbidity and mortality worldwide. Inflammatory cytokines, particularly IL-6, are central to PTB pathogenesis. Lactoferrin (LF), an iron-binding glycoprotein with antimicrobial and immunomodulatory properties, has been proposed as a potential protective factor against PTB. This narrative review aimed to synthesize current evidence on LF supplementation and its effects on inflammation, cytokine modulation, biochemical markers, and obstetric outcomes related to PTB. Methods: Eight clinical studies involving pregnant women at risk of PTB were included. LF was administered orally, vaginally, or through combined regimens, with variations in dosage and duration. Reported outcomes encompassed inflammatory markers, cervical and uterine parameters, oxidative stress biomarkers, and obstetric or neonatal endpoints. Results: Across the studies, LF supplementation was consistently associated with reduced pro-inflammatory cytokines, improvements in cervical length and uterine activity, and favorable changes in oxidative stress markers. Clinically, supplementation was linked with prolonged gestation, fewer preterm births, and reduced neonatal intensive care admissions. Immunological analyses further suggested a positive modulation of cytokine profiles in amniotic fluid. Conclusions: LF appears to exert multifaceted immunomodulatory effects that mitigate inflammation and support pregnancy maintenance. Although findings point to its potential role in PTB prevention, they should be interpreted with caution given the limited and heterogeneous evidence. Further large-scale, multicenter randomized trials are needed to confirm efficacy and to establish optimal dosage, route, and timing of administration.<\/jats:p>","DOI":"10.3390\/nu17193164","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T10:48:07Z","timestamp":1759834087000},"page":"3164","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Role of Lactoferrin in Modulating Inflammation and Preventing Preterm Birth: A Narrative Review"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6868-036X","authenticated-orcid":false,"given":"Alessandro","family":"Messina","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, University Hospital \u201cDegli Infermi\u201d, 13875 Ponderano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0925-0542","authenticated-orcid":false,"given":"Safae","family":"El Motarajji","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University Hospital \u201cDegli Infermi\u201d, 13875 Ponderano, Italy"},{"name":"Department of Public Health and Pediatrics, University of Torino, via Santena 5bis, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5243-0940","authenticated-orcid":false,"given":"Bianca","family":"Masturzo","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University Hospital \u201cDegli Infermi\u201d, 13875 Ponderano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1340-3493","authenticated-orcid":false,"given":"Paolo","family":"Manzoni","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Torino School of Medicine, 10121 Turin, Italy"},{"name":"Division of Paediatrics and Neonatology, Degli Infermi Hospital, 10126 Ponderano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"key":"ref_1","unstructured":"WHO (2022). Recommendations for Care of the Preterm or Low Birth Weight Infant, World Health Organization. [1st ed.]."},{"key":"ref_2","unstructured":"World Health Organization (2025, May 15). \u201cPreterm Birth,\u201d WHO, Geneva, 2023. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/preterm-birth."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.clp.2024.02.015","article-title":"Overview of the Global and US Burden of Preterm Birth","volume":"51","author":"Ward","year":"2024","journal-title":"Clin. Perinatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.bpobgyn.2018.04.003","article-title":"The global epidemiology of preterm birth","volume":"52","author":"Vogel","year":"2018","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Karampitsakos, T., Mavrogianni, D., Machairiotis, N., Potiris, A., Panagopoulos, P., Stavros, S., Antsaklis, P., and Drakakis, P. (2025). The Impact of Amniotic Fluid Interleukin-6, Interleukin-8, and Metalloproteinase-9 on Preterm Labor: A Narrative Review. Biomedicines, 13.","DOI":"10.3390\/biomedicines13010118"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1055\/s-2006-956773","article-title":"The role of inflammation and infection in preterm birth","volume":"25","author":"Romero","year":"2007","journal-title":"Semin. Reprod. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2475065","DOI":"10.1080\/01443615.2025.2475065","article-title":"Relationship between gastrointestinal disturbances, blood lipid levels, inflammatory markers, and preterm birth","volume":"45","author":"Hu","year":"2025","journal-title":"J. Obstet. Gynaecol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Vajrychova, M., Stranik, J., Kupcik, R., Sadibolova, M., Kukla, R., Bolehovska, R., and Kacerovsky, M. (2025). Quantification of intra-amniotic inflammation in late preterm prelabour rupture of membranes. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-99969-8"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Jin, S., and Kang, P.M. (2024). A Systematic Review on Advances in Management of Oxidative Stress-Associated Cardiovascular Diseases. Antioxidants, 13.","DOI":"10.3390\/antiox13080923"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.2174\/138161209788453202","article-title":"Lactoferrin as a Natural Immune Modulator","volume":"15","author":"Actor","year":"2009","journal-title":"Curr. Pharm. Des."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1016\/j.jpeds.2016.02.071","article-title":"Overview of Lactoferrin as a Natural Immune Modulator","volume":"173","author":"Legrand","year":"2016","journal-title":"J. Pediatr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1093\/advances\/nmac047","article-title":"Effect of Lactoferrin Supplementation on Inflammation, Immune Function, and Prevention of Respiratory Tract Infections in Humans: A Systematic Review and Meta-analysis","volume":"13","author":"Berthon","year":"2022","journal-title":"Adv. Nutr. Int. Rev. J."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Talbert, J.A., Lu, J., Spicer, S.K., Moore, R.E., Townsend, S.D., and Gaddy, J.A. (2022). Ameliorating adverse perinatal outcomes with Lactoferrin: An intriguing chemotherapeutic intervention. Bioorganic Med. Chem., 74.","DOI":"10.1016\/j.bmc.2022.117037"},{"key":"ref_14","first-page":"273","article-title":"Role of lactoferrin in preventing preterm birth and pregnancy complications: A systematic review and meta-analysis","volume":"75","author":"Buca","year":"2023","journal-title":"Minerva Obstet. Gynecol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s41073-019-0064-8","article-title":"SANRA\u2014A scale for the quality assessment of narrative review articles","volume":"26","author":"Baethge","year":"2019","journal-title":"Res. Integr. Peer Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.3346\/jkms.2013.28.8.1226","article-title":"Intra-Amniotic Infection\/Inflammation as a Risk Factor for Subsequent Ruptured Membranes after Clinically Indicated Amniocentesis in Preterm Labor","volume":"28","author":"Lee","year":"2013","journal-title":"J. Korean Med Sci."},{"key":"ref_17","unstructured":"National Cancer Institute (2020, March 19). Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Bethesda (MD): U.S. Department of Health and Human Services, National Institutes of Health, Available online: https:\/\/ctep.cancer.gov\/protocoldevelopment\/electronic_applications\/docs\/CTCAE_v5_Quick_Reference_5x7.pdf."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"144","DOI":"10.3109\/01443615.2012.740527","article-title":"Vaginal lactoferrin in asymptomatic patients at low risk for pre-term labour for shortened cervix: Cervical length and interleukin-6 changes","volume":"33","author":"Locci","year":"2013","journal-title":"J. Obstet. Gynaecol. J. Inst. Obstet. Gynaecol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3704","DOI":"10.1080\/14767058.2019.1690445","article-title":"Vaginal lactoferrin in prevention of preterm birth in women with bacterial vaginosis","volume":"34","author":"Miranda","year":"2021","journal-title":"J. Matern.-Fetal Neonatal Med."},{"key":"ref_20","first-page":"162","article-title":"Influence of lactoferrin in preventing preterm delivery: A pilot study","volume":"5","author":"Cianci","year":"2012","journal-title":"Mol. Med. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1139\/o11-060","article-title":"Bovine lactoferrin in preventing preterm delivery associated with sterile inflammation","volume":"90","author":"Paesano","year":"2012","journal-title":"Biochem. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1159\/000358877","article-title":"Vaginal lactoferrin administration before genetic amniocentesis decreases amniotic interleukin-6 levels","volume":"77","author":"Vesce","year":"2014","journal-title":"Gynecol. Obstet. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Trentini, A., Maritati, M., Rosta, V., Cervellati, C., Manfrinato, M.C., Hanau, S., Greco, P., Bonaccorsi, G., Bellini, T., and Contini, C. (2020). Vaginal Lactoferrin Administration Decreases Oxidative Stress in the Amniotic Fluid of Pregnant Women: An Open-Label Randomized Pilot Study. Front. Med., 7.","DOI":"10.3389\/fmed.2020.00555"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3648719","DOI":"10.1155\/2016\/3648719","article-title":"Vaginal Lactoferrin Modulates PGE2, MMP-9, MMP-2, and TIMP-1 Amniotic Fluid Concentrations","volume":"2016","author":"Trentini","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s12950-017-0152-9","article-title":"Influence of vaginal lactoferrin administration on amniotic fluid cytokines and its role against inflammatory complications of pregnancy","volume":"14","author":"Maritati","year":"2017","journal-title":"J. Inflamm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1095\/biolreprod.105.045328","article-title":"Proinflammatory cytokines found in amniotic fluid induce collagen remodeling, apoptosis, and biophysical weakening of cultured human fetal membranes","volume":"74","author":"Kumar","year":"2006","journal-title":"Biol. Reprod."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.bpobgyn.2007.01.008","article-title":"Infection and the role of inflammation in preterm premature rupture of the membranes","volume":"21","author":"Menon","year":"2007","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1016\/j.ajog.2004.06.085","article-title":"Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes","volume":"191","author":"Shim","year":"2004","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/j.1471-0528.2005.00579.x","article-title":"Role of matrix metalloproteinases in preterm labour","volume":"112","year":"2005","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/S0002-9378(98)70271-6","article-title":"A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition","volume":"179","author":"Romero","year":"1998","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Tency, I., Verstraelen, H., Kroes, I., Holtappels, G., Verhasselt, B., Vaneechoutte, M., Verhelst, R., and Temmerman, M. (2012). Imbalances between Matrix Metalloproteinases (MMPs) and Tissue Inhibitor of Metalloproteinases (TIMPs) in Maternal Serum during Preterm Labor. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049042"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1002\/iub.1687","article-title":"Investigating the expression of MMPs and TIMPs in preterm placenta and role of CpG methylation in regulating MMP-9 expression","volume":"69","author":"Sundrani","year":"2017","journal-title":"IUBMB Life"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Rasc\u00f3n-Cruz, Q., Siqueiros-Cend\u00f3n, T.S., Sia\u00f1ez-Estrada, L.I., Villase\u00f1or-Rivera, C.M., \u00c1ngel-Lerma, L.E., Olivas-Espino, J.A., Le\u00f3n-Flores, D.B., Espinoza-S\u00e1nchez, E.A., Ar\u00e9valo-Gallegos, S., and Iglesias-Figueroa, B.F. (2024). Antioxidant Potential of Lactoferrin and Its Protective Effect on Health: An Overview. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26010125"},{"key":"ref_34","first-page":"1357417","article-title":"Bacterial biota of women with bacterial vaginosis treated with lactoferrin: An open prospective randomized trial","volume":"28","author":"Pino","year":"2017","journal-title":"Microb. Ecol. Health Dis."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Artym, J., Zimecki, M., and Kruzel, M.L. (2021). Lactoferrin for Prevention and Treatment of Anemia and Inflammation in Pregnant Women: A Comprehensive Review. Biomedicines, 9.","DOI":"10.3390\/biomedicines9080898"},{"key":"ref_36","first-page":"521","article-title":"Review, role of lactoferrin in preventing preterm delivery","volume":"36","author":"Otsuki","year":"2022","journal-title":"Biometals Int. J. Role Met. Ions Biol. Biochem. Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Rosa, L., Cutone, A., Lepanto, M.S., Paesano, R., and Valenti, P. (2017). Lactoferrin: A Natural Glycoprotein Involved in Iron and Inflammatory Homeostasis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18091985"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/19\/3164\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:49:58Z","timestamp":1760035798000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/19\/3164"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,7]]},"references-count":37,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["nu17193164"],"URL":"https:\/\/doi.org\/10.3390\/nu17193164","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,7]]}}}