Meta-Analysis of Enteral Lactoferrin Supplementation for Reducing the Risk of Preterm Infants Sepsis

Yehuda Tri Nugroho Supranoto, Dini Cynthia Dewi Tanuwijaya


Introduction: Severe COVID-19 in pregnancy is strongly associated with preterm infant late-onset sepsis (LOS), which is a major cause of morbidity and mortality in infants. Recently, Lactoferrin, an iron-binding protein significantly discovered in human colostrum, shows potential effect on reducing the risk of preterm infant LOS and mortality by its immunomodulatory properties. Therefore, this study aimed to evaluate the effect of Lactoferrin on reducing the risk of preterm LOS, necrotizing enterocolitis (NEC), and mortality in preterm infants.
Methods: This study followed the guidelines provided by PRISMA. A literature search was conducted with PubMed, Cochrane Library, Google Scholar, and ScienceDirect. The combined effect of LOS, NEC and mortality incidence were presented as risk ratios (RR) with a 95% confidence interval (CI) using a random-effects model (REM) or fixed-effects model (FEM) forest plot. Furthermore, the heterogeneity level was checked by I2 and the p-value of the chi2 test.
Results: The incidence of LOS was significantly higher in the control than lactoferrin supplementation group [RR=0.65, 95% CI (0.56,0.77), p<0.00001, I2=56%]. However, there were no significant differences in NEC [RR=0.80, 95% CI (0.63,1.02), p=0.10, I2=39%] and mortality [RR=0.94, 95% CI (0.77,1.13), p=0.49, I2=39%], despite the trends are higher in the control group.
Conclusion: This meta-analysis showed that enteral lactoferrin supplementation in preterm infants was associated with a significant reduction in LOS, but not NEC stage II or III and all-cause mortality.
Registered Protocol: The protocol of this review was already registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42021279189.


lactoferrin; premature birth; neonatal sepsis; systematic review; meta-analysis

Full Text:



Walani SR. Global burden of preterm birth. Int J Gynecol Obstet. 2020;150(1):31–3.

Sukma HAD and Tiwari S. Risk factors of premature birth in Indonesia. Jurnal Biometrika dan Kependudukan. 2021;10(1):61–7.

Wei SQ, Bilodeau-Bertrand M, Liu S, Auger N. The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis. Canadian Medical Association Journal. 2021;193(16):540-8.

Villar J, Ariff S, Gunier RB, Thiruvengadam R, Rauch S, Kholin A, et al. Maternal and Neonatal Morbidity and Mortality Among Pregnant Women With and Without COVID-19 Infection: The INTERCOVID Multinational Cohort Study. JAMA Pediatrics. 2021;175(8):817-26.

Simonsen KA, Anderson-Berry AL, Delair SF, Davies HD. Early-Onset Neonatal Sepsis. Clinical Microbiology Reviews. 2014;27(1):21-47.

Hassani SM, Berkhout DJC, Niemarkt HJ, Mann S, Boode WP, Cossey V, Hulzebos CV, Kaam AH, Kramer BW, Lingen RA, Goudoever JB, Vijlbrief DC, Weissenbruch MM, Benninga MA, Boer NKH, Meij TGJ. Risk Factors for Late-Onset Sepsis in Preterm Infants: A Multicenter Case-Control Study. Neonatology. 2019;116(1):42–51.

Jiang S, Yang C, Yang C, Yan W, Shah V, Shah PS, Lee SK, Yang Y, Cao Y. Epidemiology and microbiology of late-onset sepsis among preterm infants in China, 2015–2018: A cohort study. International Journal of Infectious Diseases. 2020;96(1):1-9.

Berardi A, Sforza F, Baroni L, Spada C, Ambretti S, Biasucci G, Bolognesi S, Capretti M, Caretto E, Ciccia M, Lanari M, Pedna MF, Rizzo V, Venturelli C, Tzialla C, Lucaccioni L, Reggiani MLB. Epidemiology and complications of late-onset sepsis: an Italian area-based study. PLOS ONE. 2019;14(11):1-15.

Gao Y, Hou L, Lu C, Wang Q, Pan B, Wang Q, Tian J, Ge L. Enteral Lactoferrin Supplementation for Preventing Sepsis and Necrotizing Enterocolitis in Preterm Infants: A Meta‑Analysis With Trial Sequential Analysis of Randomized Controlled Trials. Frontiers in Pharmacology. 2020;11(1):1-11.

Razak A and Hussain A. Lactoferrin Supplementation to Prevent Late-Onset Sepsis in Preterm Infants: A Meta-Analysis. American Journal of Perinatology. 2019;38(03):283-90.

Akin IM unga., Atasay B, Dogu F, Okulu E, Arsan S, Karatas HD, et al. Oral lactoferrin to prevent nosocomial sepsis and necrotizing enterocolitis of premature neonates and effect on T-regulatory cells. Am J Perinatol. 2014;31(12):1111–20.

Barrington KJ, Assaad MA, Janvier A. The Lacuna Trial: A double-blind randomized controlled pilot trial of lactoferrin supplementation in the very preterm infant. J Perinatol [Internet]. 2016;36(8):666–9. Available from:

Dai, J., and Xie, C. (2015). Effect of lactoferrin combined with Lactobacillus rhamnosus on prevention of sepsis in premature infants and low birth weight infants. China Pract. Med. 10, 98–10. doi: 10.14163/j.cnki.11-5547/r.2015.17.060

Griffiths J, Jenkins P, Vargova M, Bowler U, Juszczak E, King A, et al. Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial. Lancet. 2019;393(10170):423–33.

Farag M, Eldin OK., Attia M, Morsi N., El haddad RA. Effect of lactoferrin in the prevention of late-onset sepsis in preterm neonates: a randomized-controlled trial. Alexandria J Pediatr. 2021;34(1):1.

Kaur G, Gathwala G. Efficacy of bovine lactoferrin supplementation in preventing late-onset sepsis in low birth weight neonates: A randomized placebo-Controlled clinical trial. J Trop Pediatr. 2015;61(5):370–6.

Liu YH, Guan HS, Liang GJ, et al. The effect of lactoferrin on low birth weight neonates during hospitalization. MCH Care China 2016;31:4464–4465

Manzoni P, Rinaldi M, Cattani S, Pugni L, Romeo MG, Messner H. for Prevention of Late-Onset Sepsis in Very Low-Birth-Weight Neonates. J Am Med Assoc. 2009;302(13):1421–8.

Manzoni P, Stolfi I, Messner H, Cattani S, Laforgia N, Romeo MG, et al. Bovine lactoferrin prevents invasive fungal infections in very low birth weight infants: A randomized controlled trial. Pediatrics. 2012;129(1):116–23.

Manzoni P, Meyer M, Stolfi I, Rinaldi M, Cattani S, Pugni L, et al. Bovine lactoferrin supplementation for prevention of necrotizing enterocolitis in very-low-birth-weight neonates: A randomized clinical trial. Early Hum Dev [Internet]. 2014;90(SUPPL.1):S60–5. Available from:

Ochoa TJ, Zegarra J, Cam L, Llanos R, Pezo A, Cruz K, et al. Randomized Controlled Trial of Lactoferrin for Prevention of Sepsis in Peruvian Neonates Less than 2500 g. Pediatr Infect Dis J. 2015;34(6):571–6.

Ochoa TJ, Zegarra J, Bellomo S, Carcamo C, Cam L, Castaneda A, Villavicencio A, Gonzales J, Rueda MS, Turin CG, Zea-Vera A, Guillen D, Campos M, Ewing-Cobbs L.Randomized Controlled Trial of Bovine Lactoferrin for Prevention of Sepsis and Neurodevelopment Impairment in Infants <2000 G. J Pediatr. 2020; 219:118-125.e5.

Sherman,M. P., Adamkin, D. H.,Niklas,V.,Radmacher, P., Sherman, J.,Wertheimer, F., et al. (2016). Randomized Controlled Trial of Talactoferrin Oral Solution in Preterm Infants. J. Pediatr. 175, 68–73.e63. doi: 10.1016/j.jpeds.2016.04.084

Tang, J., Sun, H., Zheng, Y., and Lu, G. (2017). A randomized controlled trial of bovine lactoferrin for prevention of late onset sepsis in preterm infants]. Maternal Child Health Care China 32, 1223–1225. doi: 10.7620/zgfybj.j.issn

Tarnow-Mordi WO, Abdel-Latif ME, Martin A, Pammi M, Robledo K, Manzoni P, et al. The effect of lactoferrin supplementation on death or major morbidity in very low birthweight infants (LIFT): a multicentre, double-blind, randomised controlled trial. Lancet Child Adolesc Heal. 2020;4(6):444–54.

Siqueiros-Cendón T, Arévalo-Gallegos S, Iglesias-Figueroa BF, García-Montoya IA, Salazar-Martínez J, Rascón-Cruz Q. Immunomodulatory effects of lactoferrin. Acta Pharmacol Sin. 2014;35(5):557–66.

Kruzel ML, Zimecki M, Actor JK. Lactoferrin in a context of inflammation-induced pathology. Front Immunol. 2017;8(NOV).

Sagheb S, Lamsehchi A, Jafary M, Atef-Yekta R, Sadeghi K. Two seriously ill neonates born to mothers with COVID-19 pneumonia- a case report. Ital J Pediatr. 2020;46(1):1–6.

Easterlin MC, De Beritto T, Yeh AM, Wertheimer FB, Ramanathan R. Extremely Preterm Infant Born to a Mother With Severe COVID-19 Pneumonia. J Investig Med High Impact Case Reports. 2020;8:0–4.

Naidu S, Clemens R, Pressman P, Zaigham M, Davies K, Naidu A. COVID-19 during Pregnancy and Postpartum:. Journal of Dietary Supplements. 2020;:1-37.


  • There are currently no refbacks.