Vol 94, No 7 (2023)
Review paper
Published online: 2023-03-07
Lactoferrin supplementation during pregnancy — a review of the literature and current recommendations
1
, 1
, 1
Abstract
Pregnancy is a period which requires special care and attention. Maintaining health during pregnancy helps to avoid birth related complications and is the best way of promoting a healthy birth. Besides a daily intake of folic acid, iron, iodine, vitamin D3 and A, calcium and polyunsaturated fatty-acids, as recommended by health agencies, supplementation of lactoferrin — a protein of multidirectional biological activity and proven safety of use — seems to be beneficial. A wide range of lactoferrin biological roles (including regulation of iron balance, modulation of immune responses, antimicrobial,
antiviral, antioxidant, and anti-inflammatory activity) may contribute to better pregnancy and birth related outcomes.
Keywords: lactoferrinsupplementationpregnancylactoferrin activity
References
- Hao L, Shan Q, Wei J, et al. Lactoferrin: major physiological functions and applications. Curr Protein Pept Sci. 2019; 20(2): 139–144.
- García-Montoya IA, Cendón TS, Arévalo-Gallegos S, et al. Lactoferrin a multiple bioactive protein: an overview. Biochim Biophys Acta. 2012; 1820(3): 226–236.
- Lönnerdal Bo. Infant formula and infant nutrition: bioactive proteins of human milk and implications for composition of infant formulas. Am J Clin Nutr. 2014; 99(3): 712S–7S.
- Marshall K. Therapeutic applications of whey protein. Altern Med Rev. 2004; 9(2): 136–156.
- Artym J, Zimecki M. Antimicrobial and prebiotic activity of lactoferrin in the female reproductive tract: a comprehensive review. Biomedicines. 2021; 9(12).
- Cignini P, Mangiafico L, Padula F, et al. Supplementation with a dietary multicomponent (Lafergin(®)) based on ferric sodium EDTA (Ferrazone(®)): results of an observational study. J Prenat Med. 2015; 9(1-2): 1–7.
- Paesano R, Torcia F, Berlutti F, et al. Oral administration of lactoferrin increases hemoglobin and total serum iron in pregnant women. Biochem Cell Biol. 2006; 84(3): 377–380.
- Lepanto MS, Rosa L, Cutone A, et al. Efficacy of Lactoferrin oral administration in the treatment of anemia and anemia of inflammation in pregnant and non-pregnant women: an interventional study. Front Immunol. 2018; 9: 2123.
- Miranda M, Saccone G, Ammendola A, et al. Vaginal lactoferrin in prevention of preterm birth in women with bacterial vaginosis. J Matern Fetal Neonatal Med. 2021; 34(22): 3704–3708.
- Locci M, Nazzaro G, Miranda M, et al. Vaginal lactoferrin in asymptomatic patients at low risk for pre-term labour for shortened cervix: cervical length and interleukin-6 changes. J Obstet Gynaecol. 2013; 33(2): 144–148.
- FDA 2011. Generally Recognized as Safe (GRAS) Notification 000423 for Cow’s Milk-Derived Lactoferrin as a Component of Cow’s Milk-Based Infant Formulas, Cow’s Milk Products, and Chewing Gum. https://www.fda.gov/downloads/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory (25.01.2023).
- EFSA Panel on Dietetic Products, Nutrition and Allergies: Scientific opinion on bovine lactoferrin. EFSA J. 2012;10,2701 2012.
- Chang R, Ng TB, Sun WZ. Lactoferrin as potential preventative and adjunct treatment for COVID-19. Int J Antimicrob Agents. 2020; 56(3): 106118.
- Artym J, Zimecki M. The role of lactoferrin in infections and inflammation. Forum Zakażeń. 2014; 4(6): 329–345.
- Sato AP, Fujimori E, Szarfarc SC, et al. Food consumption and iron intake of pregnant and reproductive aged women. Rev Lat Am Enfermagem. 2010; 18(2): 247–254.
- Black RE, Victora CG, Walker SP, et al. Maternal and Child Nutrition Study Group. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet. 2013; 382(9890): 427–451.
- World Health Organization. The Global Prevalence of Anaemia in 2011; WHO Library Cataloguing-in-Publication Data: Geneva, Switzerland, 2015.
- Georgieff MK, Krebs NF, Cusick SE. The benefits and risks of iron supplementation in pregnancy and childhood. Annu Rev Nutr. 2019; 39: 121–146.
- Georgieff MK. Iron deficiency in pregnancy. Am J Obstet Gynecol. 2020; 223(4): 516–524.
- Lozoff B, Beard J, Connor J, et al. Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr Rev. 2006; 64(5 Pt 2): S34–43; discussion S72.
- Lukowski AF, Koss M, Burden MJ, et al. Iron deficiency in infancy and neurocognitive functioning at 19 years: evidence of long-term deficits in executive function and recognition memory. Nutr Neurosci. 2010; 13(2): 54–70.
- Scholl TO, Reilly T. Anemia, iron and pregnancy outcome. J Nutr. 2000; 130(2S Suppl): 443S–447S.
- Baker HM, Baker EN. Lactoferrin and iron: structural and dynamic aspects of binding and release. Biometals. 2004; 17(3): 209–216.
- Paesano R, Pacifici E, Benedetti S, et al. Lactoferrin efficacy versus ferrous sulfate in curing iron deficiency and iron deficiency anemia in pregnant women. Biometals. 2010; 23(3): 411–417.
- Artym J, Zimecki M. Antimicrobial and prebiotic activity of Lactoferrin in the female reproductive tract: a comprehensive review. Biomedicines. 2021; 9(12).
- Chen PW, Ku YW, Chu FY. Influence of bovine lactoferrin on the growth of selected probiotic bacteria under aerobic conditions. Biometals. 2014; 27(5): 905–914.
- Tian H, Maddox IS, Ferguson LR, et al. Influence of bovine lactoferrin on selected probiotic bacteria and intestinal pathogens. Biometals. 2010; 23(3): 593–596.
- Meis PJ, Goldenberg RL, Mercer B, et al. The preterm prediction study: significance of vaginal infections. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol. 1995; 173(4): 1231–1235.
- Bretelle F, Rozenberg P, Pascal A, et al. Groupe de Recherche en Obstetrique Gynecologie. High Atopobium vaginae and Gardnerella vaginalis vaginal loads are associated with preterm birth. Clin Infect Dis. 2015; 60(6): 860–867.
- Andrews WW, Klebanoff MA, Thom EA, et al. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Midpregnancy genitourinary tract infection with Chlamydia trachomatis: association with subsequent preterm delivery in women with bacterial vaginosis and Trichomonas vaginalis. Am J Obstet Gynecol. 2006; 194(2): 493–500.
- Leitich H, Kiss H. Asymptomatic bacterial vaginosis and intermediate flora as risk factors for adverse pregnancy outcome. Best Pract Res Clin Obstet Gynaecol. 2007; 21(3): 375–390.
- Otsuki K, Imai N. Effects of lactoferrin in 6 patients with refractory bacterial vaginosis. Biochem Cell Biol. 2017; 95(1): 31–33.
- Otsuki K, Tokunaka M, Oba T, et al. Administration of oral and vaginal prebiotic lactoferrin for a woman with a refractory vaginitis recurring preterm delivery: appearance of lactobacillus in vaginal flora followed by term delivery. J Obstet Gynaecol Res. 2014; 40(2): 583–585.
- Mor G, Cardenas I, Abrahams V, et al. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci. 2011; 1221(1): 80–87.
- Kalagiri RR, Carder T, Choudhury S, et al. Inflammation in complicated pregnancy and its outcome. Am J Perinatol. 2016; 33(14): 1337–1356.
- Han VX, Patel S, Jones HF, et al. Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review. Transl Psychiatry. 2021; 11(1): 71.
- Gabay C. Interleukin-6 and chronic inflammation. Arthritis Res Ther. 2006; 8(Suppl 2): S3.
- Arcuri F, Toti P, Buchwalder L, et al. Mechanisms of leukocyte accumulation and activation in chorioamnionitis: interleukin 1 beta and tumor necrosis factor alpha enhance colony stimulating factor 2 expression in term decidua. Reprod Sci. 2009; 16(5): 453–461.
- Paesano R, Pietropaoli M, Berlutti F, et al. Bovine lactoferrin in preventing preterm delivery associated with sterile inflammation. Biochem Cell Biol. 2012; 90(3): 468–475.
- Maritati M, Comar M, Zanotta N, et al. Influence of vaginal lactoferrin administration on amniotic fluid cytokines and its role against inflammatory complications of pregnancy. J Inflamm (Lond). 2017; 14: 5.
- Legrand D, Elass E, Carpentier M, et al. Interactions of lactoferrin with cells involved in immune function. Biochem Cell Biol. 2006; 84(3): 282–290.
- Suzuki YA, Lopez V, Lönnerdal B. Mammalian lactoferrin receptors: structure and function. Cell Mol Life Sci. 2005; 62(22): 2560–2575.
- Actor JK, Hwang SA, Kruzel ML. Lactoferrin as a natural immune modulator. Curr Pharm Des. 2009; 15(17): 1956–1973.
- Shau H, Kim A, Golub SH. Modulation of natural killer and lymphokine-activated killer cell cytotoxicity by lactoferrin. J Leukoc Biol. 1992; 51(4): 343–349.
- Miyauchi H, Hashimoto S, Nakajima M, et al. Bovine lactoferrin stimulates the phagocytic activity of human neutrophils: identification of its active domain. Cell Immunol. 1998; 187(1): 34–37.
- Sorimachi K, Akimoto K, Hattori Y, et al. Activation of macrophages by lactoferrin: secretion of TNF-alpha, IL-8 and NO. Biochem Mol Biol Int. 1997; 43(1): 79–87.
- Håversen L, Ohlsson BG, Hahn-Zoric M, et al. Lactoferrin down-regulates the LPS-induced cytokine production in monocytic cells via NF-kappa B. Cell Immunol. 2002; 220(2): 83–95.
- Machnicki M, Zimecki M, Zagulski T. Lactoferrin regulates the release of tumour necrosis factor alpha and interleukin 6 in vivo. Int J Exp Pathol. 1993; 74(5): 433–439.
- Puddu P, Valenti P, Gessani S. Immunomodulatory effects of lactoferrin on antigen presenting cells. Biochimie. 2009; 91(1): 11–18.
- Zimecki M, Stepniak D, Szynol A, et al. Lactoferrin regulates proliferative response of human peripheral blood mononuclear cells to phytohemagglutinin and mixed lymphocyte reaction. Arch Immunol Ther Exp (Warsz). 2001; 49(2): 147–154.
- Zimecki M, Mazurier J, Spik G, et al. Human lactoferrin induces phenotypic and functional changes in murine splenic B cells. Immunology. 1995; 86(1): 122–127.
- van der Strate BW, Beljaars L, Molema G, et al. Antiviral activities of lactoferrin. Antiviral Res. 2001; 52(3): 225–239.
- Hashem NA. Immunomodulatory effect of lactoferrin on mucosal immunity of uterus in pregnant rat. Biomed J Sci Tech Res. 2021; 37(5).
- Zimecki M, Właszczyk A, Wojciechowski R, et al. Lactoferrin regulates the immune responses in post-surgical patients. Arch Immunol Ther Exp (Warsz). 2001; 49(4): 325–333.
- Jenssen H, Hancock REW. Antimicrobial properties of lactoferrin. Biochimie. 2009; 91(1): 19–29.
- González-Chávez SA, Arévalo-Gallegos S, Rascón-Cruz Q. Lactoferrin: structure, function and applications. Int J Antimicrob Agents. 2009; 33(4): 301.e1–301.e8.
- Artym J. Laktoferyna – Niezwykłe Białko. 1st ed. Wydawnictwo Borgis, Warszawa 2012.
- Arnold RR, Cole MF, McGhee JR. A bactericidal effect for human lactoferrin. Science. 1977; 197(4300): 263–265.
- Brandenburg K, Jürgens G, Müller M, et al. Biophysical characterization of lipopolysaccharide and lipid A inactivation by lactoferrin. Biol Chem. 2001; 382(8): 1215–1225.
- Ellison RT, Giehl TJ, LaForce FM. Damage of the outer membrane of enteric gram-negative bacteria by lactoferrin and transferrin. Infect Immun. 1988; 56(11): 2774–2781.
- Leitch EC, Willcox MD, Leitch EC, et al. Interactions between the constitutive host defences of tears and Staphylococcus epidermidis. Aust N Z J Ophthalmol. 1997; 25 Suppl 1(4): S20–S22.
- Qiu J, Hendrixson DR, Baker EN, et al. Human milk lactoferrin inactivates two putative colonization factors expressed by Haemophilus influenzae. Proc Natl Acad Sci U S A. 1998; 95(21): 12641–12646.
- Sessa R, Di Pietro M, Filardo S, et al. Lactobacilli-lactoferrin interplay in Chlamydia trachomatis infection. Pathog Dis. 2017; 75(5).
- Pino A, Giunta G, Randazzo CL, et al. Bacterial biota of women with bacterial vaginosis treated with lactoferrin: an open prospective randomized trial. Microb Ecol Health Dis. 2017; 28(1): 1357417.
- Verani JR, McGee L, Schrag SJ, et al. Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC). Prevention of perinatal group B streptococcal disease--revised guidelines from CDC, 2010. MMWR Recomm Rep. 2010; 59(RR-10): 1–36.
- Kothary V, Doster RS, Rogers LM, et al. Group b induces neutrophil recruitment to gestational tissues and elaboration of extracellular traps and nutritional immunity. Front Cell Infect Microbiol. 2017; 7: 19.
- Giunta G, Giuffrida L, Mangano K, et al. Influence of lactoferrin in preventing preterm delivery: a pilot study. Mol Med Rep. 2012; 5(1): 162–166.
- Fernandes KE, Carter DA. The antifungal activity of lactoferrin and its derived peptides: mechanisms of action and synergy with drugs against fungal pathogens. Front Microbiol. 2017; 8: 2.
- Wakabayashi H, Okutomi T, Abe S, et al. Cooperative anti-Candida effects of lactoferrin or its peptides in combination with azole antifungal agents. Microbiol Immunol. 1996; 40(11): 821–825.
- Zarember KA, Sugui JA, Chang YC, et al. Human polymorphonuclear leukocytes inhibit Aspergillus fumigatus conidial growth by lactoferrin-mediated iron depletion. J Immunol. 2007; 178(10): 6367–6373.
- Lupetti A, Paulusma-Annema A, Welling MM, et al. Synergistic activity of the N-terminal peptide of human lactoferrin and fluconazole against Candida species. Antimicrob Agents Chemother. 2003; 47(1): 262–267.
- Dzitko K, Dziadek B, Dziadek J, et al. Toxoplasma gondii: inhibition of the intracellular growth by human lactoferrin. Pol J Microbiol. 2007; 56(1): 25–32.
- Omata Y, Satake M, Maeda R, et al. Reduction of the infectivity of Toxoplasma gondii and Eimeria stiedai sporozoites by treatment with bovine lactoferricin. J Vet Med Sci. 2001; 63(2): 187–190.
- Fritsch G, Sawatzki G, Treumer J, et al. Plasmodium falciparum: inhibition in vitro with lactoferrin, desferriferrithiocin, and desferricrocin. Exp Parasitol. 1987; 63(1): 1–9.
- Gillin FD, Reiner DS, Wang CS. Killing of Giardia lamblia trophozoites by normal human milk. J Cell Biochem. 1983; 23(1-4): 47–56.
- Murray MJ, Murray A, Murray CJ. The salutary effect of milk on amoebiasis and its reversal by iron. Br Med J. 1980; 280(6228): 1351–1352.
- Tanaka T, Abe Y, Inoue N, et al. The detection of bovine lactoferrin binding protein on Trypanosoma brucei. J Vet Med Sci. 2004; 66(6): 619–625.
- Bukowska-Ośko I, Popiel M, Kowalczyk P. The immunological role of the placenta in SARS-CoV-2 infection-viral transmission, immune regulation, and lactoferrin activity. Int J Mol Sci. 2021; 22(11).
- Berlutti F, Pantanella F, Natalizi T, et al. Antiviral properties of lactoferrin--a natural immunity molecule. Molecules. 2011; 16(8): 6992–7018.
- Lang J, Yang N, Deng J, et al. Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans. PLoS One. 2011; 6(8): e23710.
- Chen Yu, Liu Q, Guo D, et al. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol. 2020; 92(4): 418–423.
- Fung SY, Yuen KS, Ye ZW, et al. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect. 2020; 9(1): 558–570.
- Serrano G, Kochergina I, Albors A, et al. Liposomal lactoferrin as potential preventative and cure for COVID-19. Int J Res Health Sci. 2020; 8(1): 08–15.
- Kamhi E, Joo EJi, Dordick JS, et al. Glycosaminoglycans in infectious disease. Biol Rev Camb Philos Soc. 2013; 88(4): 928–943.
- Miotto M, Di Rienzo L, Bò L, et al. Molecular mechanisms behind anti SARS-CoV-2 action of lactoferrin. Front Mol Biosci. 2021; 8: 607443.
- Mark EG, McAleese S, Golden WC, et al. Coronavirus disease 2019 in pregnancy and outcomes among pregnant women and neonates: a literature review. Pediatr Infect Dis J. 2021; 40(5): 473–478.
- Szczygiol P, Baranska K, Korczak I, et al. COVID-19 in pregnancy, management and outcomes among pregnant women and neonates — results from tertiary care center in Wroclaw. Ginekol Pol. 2022; 93(1): 47–53.
- Wenling Y, Junchao Q, Xiao Z, et al. Pregnancy and COVID-19: management and challenges. Rev Inst Med Trop Sao Paulo. 2020; 62: e62.
- Nappi C, Tommaselli GA, Morra I, et al. Efficacy and tolerability of oral bovine lactoferrin compared to ferrous sulfate in pregnant women with iron deficiency anemia: a prospective controlled randomized study. Acta Obstet Gynecol Scand. 2009; 88(9): 1031–1035.
- Paesano R, Pietropaoli M, Gessani S, et al. The influence of lactoferrin, orally administered, on systemic iron homeostasis in pregnant women suffering of iron deficiency and iron deficiency anaemia. Biochimie. 2009; 91(1): 44–51.
- Paesano R, Pacifici E, Benedetti S, et al. Safety and efficacy of lactoferrin versus ferrous sulphate in curing iron deficiency and iron deficiency anaemia in hereditary thrombophilia pregnant women: an interventional study. Biometals. 2014; 27(5): 999–1006.
- Vesce F, Giugliano E, Bignardi S, et al. Vaginal lactoferrin administration before genetic amniocentesis decreases amniotic interleukin-6 levels. Gynecol Obstet Invest. 2014; 77(4): 245–249.
- Mehedintu C, Ionescu OM, Ionescu S, et al. Iron deficiency and iron-deficiency anaemia in pregnant women corrected by oral bovine lactoferrin administration. Farmacia. 2015; 63: 922–926.
- Rezk M, Dawood R, Abo-Elnasr M, et al. Lactoferrin versus ferrous sulphate for the treatment of iron deficiency anemia during pregnancy: a randomized clinical trial. J Matern Fetal Neonatal Med. 2016; 29(9): 1387–1390.
- Trentini A, Maritati M, Cervellati C, et al. Vaginal Lactoferrin Modulates PGE, MMP-9, MMP-2, and TIMP-1 Amniotic Fluid Concentrations. Mediators Inflamm. 2016: 3648719.
- Darwish AM, Fouly HA, Saied WH, et al. Lactoferrin plus health education versus total dose infusion (TDI) of low-molecular weight (LMW) iron dextran for treating iron deficiency anemia (IDA) in pregnancy: a randomized controlled trial. J Matern Fetal Neonatal Med. 2019; 32(13): 2214–2220.
- Trentini A, Maritati M, Rosta V, et al. Vaginal lactoferrin administration decreases oxidative stress in the amniotic fluid of pregnant women: an open-label randomized pilot study. Front Med (Lausanne). 2020; 7: 555.
- Fathi M, Ali AS, Mohammed A. Efficacy of lactoferrin in prevention of premature rupture of membrane. Egypt J Hosp Med. 2021; 85(1): 2823–2827.
