Lactoferrin infant feeding trial_Canada (LIFT_Canada): protocol for a randomized trial of adding lactoferrin to feeds of very-low-birth-weight preterm infants

Elizabeth V Asztalos, Keith Barrington, Abhay Lodha, William Tarnow-Mordi, Andrew Martin, Elizabeth V Asztalos, Keith Barrington, Abhay Lodha, William Tarnow-Mordi, Andrew Martin

Abstract

Background: In Canada alone, almost 3000 VLBW infants are born and treated annually with almost 1200 going onto death or survival with severe brain injury, chronic lung disorders, aggressive retinopathy of prematurity, late-onset sepsis, or significant necrotizing enterocolitis. Lactoferrin is an antimicrobial, antioxidant, anti-inflammatory iron-carrying, bifidogenic glycoprotein found in all vertebrates and in mammalian milk, leukocytes and exocrine secretions. Lactoferrin aids in creating an environment for growth of beneficial bacteria in the gut, thus reducing colonization with pathogenic bacteria. It is hypothesized that oral bovine lactoferrin (bLF), through its antimicrobial, antioxidant and anti-inflammatory properties, will reduce the rate of mortality or major morbidity in very low birth weight preterm infants.

Method: Lactoferrin Infant Feeding Trial_Canada (LIFT_Canada) is a multi-centre, double-masked, randomized controlled trial with the aim to enroll 500 infants whose data will be combined with the data of the 1542 infants enrolled from Lactoferrin Infant Feeding Trial_Australia/New Zealand (LIFT_ANZ) in a pooled intention-to-treat analysis. Eligible infants will be randomized and allocated to one of two treatment groups: 1) a daily dose of 200 mg/kg bLF in breast/donor human milk or formula milk until 34 weeks corrected gestation or for a minimum of 2 weeks, whichever is longer, or until discharge home or transfer, if earlier; 2) no bLF with daily feeds. The primary outcome will be determined at 36 weeks corrected gestation for the presence of neonatal morbidity and at discharge for survival and treated retinopathy of prematurity. The duration of the trial is expected to be 36 months.

Discussion: Currently, there continues to be no clear answer related to the benefit of bLF in reducing mortality or any or all of the significant neonatal morbidities in very low birth weight infants. LIFT_Canada is designed with the hope that the pooled results from Australia, New Zealand, and Canada may help to clarify the situation.

Trial registration: Clinical Trials.Gov, Identifier: NCT03367013, Registered December 8, 2017.

Keywords: Lactoferrin; Neonatal mortality and morbidity; Very low birth weight infants.

Conflict of interest statement

Dr. Abhay Lodha is an associate editor and Dr. Elizabeth Asztalos is a section editor for BMC Pediatrics. All the remaining authors have nothing to disclose.

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STUDY FLOW CHART

References

    1. Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012;379(9832):2162–2172. doi: 10.1016/S0140-6736(12)60820-4.
    1. Canadian Neonatal Network, Available at: . Accessed Nov 30, 2019.
    1. Hamilton BE, Martin JA, Ventura SJ. Births: preliminary data for 2012. Natl Vital Stat Rep. 2013;62:1–20.
    1. Chow SSW, Le Marsney R, Creighton P, et al. Report of the Australian and New Zealand neonatal network 2015. ANZNN: Sydney; 2017.
    1. Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS. Whitfield MF; trial of indomethacin prophylaxis in Preterms (TIPP) investigators. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA. 2003;289(9):1124–1129. doi: 10.1001/jama.289.9.1124.
    1. Basler D, Stoll BJ, Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS. Trial of indomethacin prophylaxis in Preterms investigators. Using a count of neonatal morbidities to predict poor outcome in extremely low birth weight infants: added role of neonatal infection. Pediatrics. 2009;123(1):313–338. doi: 10.1542/peds.2008-0377.
    1. Schulzke SM, Deshpande GC, Patole SK. Neurodevelopmental outcomes of very low-birth-weight infants with necrotizing enterocolitis: a systematic review of observational studies. Arch Pediatr Adolesc Med. 2007;161(6):583–590. doi: 10.1001/archpedi.161.6.583.
    1. Lonnerdal B. Nutritional roles of lactoferrin. Curr Opin Clin Nutr Metab Care. 2009;12(3):293–297. doi: 10.1097/MCO.0b013e328328d13e.
    1. Albera E, Kankofer M. Antioxidants in colostrum and milk of sows and cows. Reprod Domest Anim. 2009;44(4):606–611. doi: 10.1111/j.1439-0531.2007.01027.x.
    1. Zagulski T, Lipinski P, Zagulska A, Broniek S, Jarzabek Z. Lactoferrin can protect mice against a lethal dose of Escherichia coli in experimental infection in vivo. Br J Exp Pathol. 1989;70(6):697–704.
    1. Edde L, Hipolito RB, Hwang FF, Headon DR, Shalwitz RA, Sherman MP. Lactoferrin protects neonatal rats from gut-related systemic infection. American journal of physiology. Gastrointest Liver Physiol. 2001;281(5):G1140–G1150. doi: 10.1152/ajpgi.2001.281.5.G1140.
    1. Buccigrossi V, de Marco G, Bruzzese E, Ombrato L, Bracale I, Polito G, Guarino A. Lactoferrin induces concentration dependent functional modulation of intestinal proliferation and differentiation. Pediatr Res. 2007;61(4):410–414. doi: 10.1203/pdr.0b013e3180332c8d.
    1. Bellamy W, Takase M, Wakabayashi H, Kawase K, Tomita M. Antibacterial spectrum of lactoferricin B, a potent bactericidal peptide derived from the N-terminal region of bovine lactoferrin. J Appl Bacteriol. 1992;73(6):472–479. doi: 10.1111/j.1365-2672.1992.tb05007.x.
    1. Tomita M, Wakabayashi H, Yamauchi K, Teraguchi S, Hayasawa H. Bovine lactoferrin and lactoferricin derived from milk: production and applications. Biochem Cell Biol. 2002;80(1):109–112. doi: 10.1139/o01-230.
    1. Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics. 2001;107(2):270–273. doi: 10.1542/peds.107.2.270.
    1. Metz-Boutigue MH, Jollès J, Mazurier J, Schoentgen F, Legrand D, Spik G, Montreuil J, Jollès P. Human lactotransferrin: amino acid sequence and structural comparisons with other transferrins. Eur J Biochem. 1984;145:659–676. doi: 10.1111/j.1432-1033.1984.tb08607.x.
    1. Pammi M, Suresh G. Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2017;6:CD007137.
    1. Schünemann HJ, Oxman AD, Brozek J, Glasziou P, Bossuyt P, Chang S, Muti P, Jaeschke R, Guyatt GH. GRADE: assessing the quality of evidence for diagnostic recommendations. ACP J Club. 2008;149(6):2.
    1. De Jesus LC, Pappas A, Shankaran S, Kendrick D, Das A, Higgins RD, Bell EF, Stoll BJ, Laptook AR, Walsh MC. Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Risk Factors for Post-Neonatal Intensive Care Unit Discharge Mortality among Extremely Low Birth Weight Infants. J Pediatr. 2012;161(1):70–74. doi: 10.1016/j.jpeds.2011.12.038.
    1. Swamy GK, Ostbye T, Skjaerven R. Association of preterm birth with long-term survival, reproduction, and next-generation preterm birth. JAMA. 2008;299(12):1429–1436. doi: 10.1001/jama.299.12.1429.
    1. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006;3:CD004454.
    1. Seger N, Soll R. Animal derived surfactant extract for treatment of respiratory distress syndrome. Cochrane Database Syst Rev. 2009;2:CD007836.
    1. Asztalos EV, Church PT, Riley P, Fajardo C. Shah PS; Canadian neonatal network and Canadian neonatal follow-up network investigators. Neonatal factors associated with a good neurodevelopmental outcome in very preterm infants. Am J Perinatol. 2017;34(4):388–396. doi: 10.1055/s-0036-1592129.
    1. Griffiths J, Jenkins P, Vargova M, Bowler U, Juszczak E, King A, Linsell L, Murray D, Partlett C, Patel M, Berrington J, Embleton N, Dorling J, Heath PT, McGuire W, Oddie S. Enteral lactoferrin to prevent infection for very preterm infants: the ELFIN RCT. Health Technol Assess. 2018;22(74):1–60. doi: 10.3310/hta22740.
    1. ELFIN trial investigators group Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial. Lancet. 2019;393(10170):423–433. doi: 10.1016/S0140-6736(18)32221-9.
    1. Martin A, Ghadge A, Manzoni P, Lui K, Brown R, Tarnow-Mordi W. LIFT Collaborative Study Group. Protocol for the Lactoferrin Infant Feeding Trial (LIFT): a randomised trial of adding lactoferrin to the feeds of very-low birthweight babies prior to hospital discharge. BMJ Open. 2018;8(10):e023044. doi: 10.1136/bmjopen-2018-023044.
    1. Manzoni P, Rinaldi M, Cattani S, Pugni L, Romeo MG, Messner H, Stolfi I, Decembrino L, Laforgia N, Vagnarelli F, Memo L, Bordignon L, Saia OS, Maule M, Gallo E, Mostert M, Magnani C, Quercia M, Bollani L, Pedicino R, Renzullo L, Betta P, Mosca F, Ferrari F, Magaldi R, Stronati M, Farina D. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA. 2009;302(13):1421–1428. doi: 10.1001/jama.2009.1403.
    1. Manzoni Paolo, Militello Maria Angela, Rizzollo Stefano, Tavella Elena, Messina Alessandro, Pieretto Marta, Boano Elena, Carlino Martina, Tognato Eleonora, Spola Roberta, Perona Anna, Maule Milena Maria, García Sánchez Ruben, Meyer Mike, Stolfi Ilaria, Pugni Lorenza, Messner Hubert, Cattani Silvia, Betta Pasqua Maria, Memo Luigi, Decembrino Lidia, Bollani Lina, Rinaldi Matteo, Fioretti Maria, Quercia Michele, Tzialla Chryssoula, Laforgia Nicola, Mosca Fabio, Magaldi Rosario, Mostert Michael, Farina Daniele, Tarnow-Mordi William. Is Lactoferrin More Effective in Reducing Late-Onset Sepsis in Preterm Neonates Fed Formula Than in Those Receiving Mother's Own Milk? Secondary Analyses of Two Multicenter Randomized Controlled Trials. American Journal of Perinatology. 2019;36(S 02):S120–S125. doi: 10.1055/s-0039-1691807.
    1. Sterne J. A. C., Sutton A. J., Ioannidis J. P. A., Terrin N., Jones D. R., Lau J., Carpenter J., Rucker G., Harbord R. M., Schmid C. H., Tetzlaff J., Deeks J. J., Peters J., Macaskill P., Schwarzer G., Duval S., Altman D. G., Moher D., Higgins J. P. T. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343(jul22 1):d4002–d4002. doi: 10.1136/bmj.d4002.
    1. Peto R, Pike MS, Armitage P, Breslow NE, Cox DR, Howard SV, Mentel N, McPherson K, Peto J, Smith PG. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. 1. Introduction and design. Br J Cancer. 1976;3:585–612. doi: 10.1038/bjc.1976.220.
    1. Huque MF. Validity of the Hochberg procedure revisited for clinical trial applications. Stat Med. 2016;35:5–20. doi: 10.1002/sim.6617.

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