Lactoferrin and prematurity: a promising milk protein?

Despite considerable progress in neonatal medicine and an improved survival rate of children born prematurely, the incidence of preterm births has increased in most countries ( Harrison and Goldenberg 2015 ). These infants are at risk of infections, inflammation, oxidative stress that can lead to serious disease such as sepsis, bronchopulmonary dysplasia, necrotising enterocolitis, and preterm encephalopathy or periventricular leukomalacia ( Frey and Klebanoff 2016 ) all risk factors for later neurodevelopmental disabilities. Infection/inflammation in the mother and/or foetus is not only a risk factor for preterm birth but also one of the main cause of cerebral white and grey matter injuries in the preterm infant as well as aggravating factor for other perinatal cerebral insults such as hypoxia/ischemia ( Volpe 2009 ). These later becoming a leading cause of long term neurodevelopmental disabilities including cerebral palsy, learning impairment, visual and hearing disorders, language difficulties and also psychiatric illnesses at adult age ( Back and Miller 2014 ; Salmaso et al. 2014 ). In Europe and other developed countries, the incidences of premature birth range from 6 to 12% with an increasing trend over the last decade. High-risk pregnancies with prematurity are a large burden to the society due to the high morbidity, social and economic costs associated, both for the mother and the child ( Bhutta et al. 2014 ; Hoyert et al. 2006 ; Walker et al. 2007 ). On the other hand, breast milk has recognised beneficial effects in term and preterm infants, including decreased rates of infection and NEC and improved cognitive and behaviour skills ( Lucas and Cole 1990 ; Meinzen-Derr et al. 2009 ; Quigley et al. 2007 ; Sullivan et al. 2010 ; Vohr et al. 2007 ; Vohr et al. 2006 ). The protective effects of human milk are due to the multiple factors transmitted through milk, including secretory antibodies, oligosaccharides, glycoconjugates, lactoferrin (Lf), lysozyme, leukocytes, cytokines and other factors produced by the mother’s acquired and innate immune systems ( Ballard and Morrow 2013 ; Walker 2010 ). Lf is the second most abundant protein in human milk. Lactoferrin (Lf) is a physiological compound produced by exocrine glands and released at a high level in colostrum and maternal milk ( Ronayne de Ferrer et al. 2000 ). It plays numerous biological and beneficial functions such as iron absorption, anti-inflammatory action, immunomodulator, antioxidant, host defence mechanism and anti-cancer agent ( Sandomirsky et al. 2003 ; Satue-Gracia et al. 2000 ; Wong et al. 1998 ). High levels are found in human milk ( Ronayne de Ferrer et al. 2000 ) but not in most of formula milk resulting in a higher level of iron-induced oxidation products in preterms formula fed ( Raghuveer et al. 2002 ). Free radical injury plays a significant role in several prematurity related diseases: brain injury, necrotising enterocolitis, retinopathy, bronchopulmonary dysplasia. ( Kelly 1993 ). The role of Lf as a potential protectant in preterm infants and its effects in prematurity related translational research are reviewed here.

Infection and NEC are major burden for immediate and long terms outcome in preterm infants that often require heavy antimicrobial treatments, surgery and prolonged hospital stay. They also contribute to brain injury and altered development through activation of inflammatory processes that are also major determinants of neurodevelopmental disabilities later in life. To date there is no protective strategies in the preterm infant to reduce brain injury and dysfunction despite increased survival at low gestational age. In addition to the effects of Lf on preterm infection, NEC and on brain injury in preclinical studies, Lf might have a potential therapeutic effect in pulmonary bronchodysplasia and retinopathy of prematurity of the preterm that are also mediated by oxidative stress and inflammation. Lactoferrin research is these fields is needed and could be also of interest to reduce morbidity of the preterm infants. Lactoferrin through its multiple properties and actions appears to have some potential to reduce several major morbidities in preterm infants. Importantly no secondary effects to date have been reported in preclinical and clinical studies. It is now clear that from the clinical studies on preterm infection and NEC and the preclinical data that the effects of Lf need to be further investigated and established in this vulnerable population.

Lactoferrin has some potential to prevent infection and help for recovery of brain damage in preterm infants but few preclinical and clinical studies appear to show that by reducing inflammation in pregnant animal/women it might also be prevent preterm birth as infection/inflammation are a well-known risks for preterm delivery and brain injury ( Edwards and Tan 2006 ; Hagberg et al. 2005 ). In a rabbit model of intrauterine infection with E. coli ( Hasegawa et al. 2005 ), recombinant human Lf as local treatment increased survival rate of foetus and extended length of pregnancy compared to infected controls. Lf treated animals showed no inflammatory exudates or necrosis in the endometrium, decidua, or placenta that were present in the infected only animals. These also had significantly higher levels of TNFα compared to the animals receiving Lf. In a similar manner intraperitoneal injection of Lf after LPS challenge in pregnant mice prolonged the duration of gestation by reducing IL6 plasma levels in the treated group. Interestingly human recombinant Lf had greater effects compared to bovine Lf ( Mitsuhashi et al. 2000 ; Sasaki et al. 2004 ). In mice, markers of LPS induced endometriosis such as histological inflammatory changes, myeloperoxydase activity, NFκB, TNFα and IL1ß were reduced in Lf treated animals ( Otsuki et al. 2005 ) and in a dose dependent manner ( Li et al. 2015 ). In pregnant women, administration of oral and intravaginal Lf to the women with risk of preterm delivery decreased IL-6 in both serum and cervicovaginal fluids, cervicovaginal prostaglandin F2a, and suppressed uterine contractility. Lf administration blocked further shortening of cervical length and the increase of fetal fibronectin thus prolonging the length of pregnancy ( Paesano et al. 2012 ). Similarly, on a selection of women at risk of preterm delivery based on borderline cervical length and elevated cervico-vaginal IL6 that received vaginal tablets of Lf (300mg/day), IL6 levels were reduced whereas cervical length increased compared to the non-treated women. Further a greater number of women in the control group had regular uterine contraction and reduced cervical consistency before 37 weeks of pregnancy ( Locci et al. 2013 ). These initial data are supportive for reduced inflammation induced by Lf that could prevent preterm delivery.