Human Breast Milk for Very Preterm Neonates: Comparison
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Prematurity is the leading cause of death in children younger than 5 years old and a main reason for morbidity in the pediatric population. Annually, almost 15 million neonates are born prematurely (before 37 week of gestation), and the prevalence is increasing every year. According to World Health Organization (WHO), among 184 countries, the percentage of preterm birth ranges between 5% and 18%. In Greece, 4.7% of total births were premature between the years 1980 and 2008, with the percentage of prematurity reaching 9.6% in 2008. Very preterm neonates (<32 weeks of gestation) and extremely preterm neonates (<28 weeks of gestation) account for about 10% and 5%, respectively, of all premature neonates, with their morbidity and mortality being inversely related with gestation age.

  • breast milk
  • immune system
  • gastrointestinal system
  • central nervous system

1. Immunology of Human Breast Milk (HBM)

HBM is essential for very VPIs apreterm infants (VPIs, <32 weeks of gestation) as it provides various factors, such as immunoglobulins, lactoferrin, lysozyme, G-CSF, oligosaccharides, lipids, cytokines and growth factors. These nutrients directly protect newborns (passive immunity), and additionally, they modulate the immune response inducing the maturation of their immune system and moderate inflammation responses (anti-inflammatory function) [84][1]. In a relative study, Patel AL et al. found that increasing the average daily dose of HM from day 1 to 28 in VLBW infants (mean gestation age 28.1 ± 2.4 weeks) was associated with lower odds of sepsis (OR 0.981, 95% CI 0.967–0.995, p = 0.008) [129][2].
Immunoglobulins are abundant in human breast milk. The major isotype is secretory IgA (80–90%), followed by IgM (8%) and IgG (2%) [130][3]. Secretory IgA is a dimeric of two IgAs linked together with a joining chain and a secretory component [131][4]. This domain remains stable in the preterm stomach even 3 h after feeding, is attached to the neonatal intestinal mucus, binds to local microorganisms and toxins, and blocks their penetration into the epithelium [85,86,132][5][6][7]. Secretory IgA is higher in colostrum [87[8][9],88], and titers are even higher in very preterm HBM (p < 0.05–0.0001) [89][10].
Lactoferrin is an iron-binding glycoprotein, directly protecting newborns against enteric pathogens. Through iron binding, lactoferrin blocks its use by pathogens that need iron for their survival and multiplication. A recent multicenter clinical trial in Peru showed that lactoferrin supplementation decreased the risk of infections in low-birth-weight infants (LBW < 2500 g) and especially in those with very low birth weight (VLBW < 1500 g) (LBW: lactoferrin groups vs. placebo, 12.6 vs. 22.1%; VLBW: lactoferrin group vs. placebo, 20 vs. 37.5%) [90][11]. Another Cochrane meta-analysis found that lactoferrin supplementation reduces relative risk for late-onset sepsis and NEC in VPIs (RR = 0.59, 95% CI 0.40–0.87 and RR = 0.4, 95% CI 0.18–0.86, respectively) [91][12]. These data implicate a further protective action of natural lactoferrin for VPIs [92][13].
Lysozyme is an active enzyme found in extremely high concentrations in HBM. It lyses Gram-positive bacteria by deconstruction of proteoglycans at the cell surface and seems to have a synergistic function with lactoferrin against Gram-negative bacteria. After lactoferrin binding through LPSlipopolysaccharides (LPS) to Gram-negative bacteria, it creates pores through which lysozyme can insert into inner membrane and digest the proteoglycans [93][14]. The HBM of mothers of VPIs contains lysozyme in higher concentrations (p < 0.05–0.0001) [89][10].
Lactadherin is an HBM protein that binds to all human rotavirus strains, thus preventing infection by it [133][15]. This virus is quite common in VPIs. This could be explained by the lower concentrations of lactadherin in the milk of their mothers in contrast to that of mothers of full-term infants (p < 0.05–0.0001) [89][10].
HBM lipids are known for their nutritional value and for their protective role against infectious diseases. Salivary and gastric lipases break down lipids to free fatty acids and monoglycerides [94][16]. Long-chain polyunsaturated fatty acids (LCPUFAs) have significant antibacterial and antiviral action by acting directly against microorganisms or indirectly by producing bioactive molecules that enhance the phagocytic action of immune cells [134][17]. Finally, components that are found in the HBM lipid globule membrane possibly block the binding of pathogens to GI mucosa [95][18].
Colostrum and mature HBM are abundant in oligosaccharides. HBM oligosaccharides (HMOs) are produced by the mammary gland and have great immunomodulatory action [96][19]. They are resistant to digestion and are not absorbed in great amounts. They alter the immune response, degrading inflammation by interacting with intestinal lymphoid tissues or by interacting systemically with selectins, dendritic cells (DCs), integrins, and Toll-like receptors (TLRs) [97][20]. HMOs also improve the immune system response. Azagra-Boronat et al., in an animal study, reported that daily supplementation of 2′ Fucosyllactose during the first 2 weeks of life in suckling rats increased serum release of IgG (control vs. 2′FL group 3693.28 ± 180.15 vs. 5732.33 ± 284.11, p < 0.05) and IgA (control vs. 2′FL group 63.32 ± 1.4990.15 ± 3.37, p < 0.05) and increased T cell production in the lymph nodes of the mesentery (controls vs. 2′FL group 62.01 ± 2.12 vs. 74.97 ± 2.03, p < 0.05) [135][21].
Although the main role of HBM immunoglobulins is to provide passive immunity to newborns, they also modulate the adaptive immune response of breastfed infants. Maternal antibodies interact with host B and T cells and influence their programming [136][22]. In animal studies, lactoferrin was reported to affect immune response. Specifically, almost two-fold titers of IgG, IL-10 and TNF-a (p < 0.05) and increased numbers of natural killer cells (p < 0.01) were detected in piglets fed with formula milk supplemented with lactoferrin than in the control group [98,137][23][24]. Lysozyme also has anti-inflammatory action [84][1].
Cytokines and growth factors affect immune response by binding to intracellular receptors in target cells. Interleukin-10 (IL-10), transformation growth factor beta (TGF-β) and tumor necrosis factor receptor I and II (TNFR I, II) are some of the molecules that act against inflammation [132][7].
Breast milk cytokines, such as IL-7, also seem to induce the growth of the thymic gland; therefore, they enhance the immunity of neonates [99,100][25][26]. Thymic development and activity are better in breastfed infants than in formula-fed ones, and T cells are found in higher titers in their serum [101][27].
MicroRNAs (miRNAs) are tiny RNA fragments found in great amounts in HBM and can modulate genetic expression. Lately, there has been an increased interest in their possible protective effects for neonates. It seems that miRNAs interfere with the maturation and modulation of the immune system. MicroRNAs affect B and T cell differentiation and induce monocyte development and granulocyte reproduction [102,103][28][29].
Soluble TLRs and CD14 are present in HBM. They seem to interact with the TLRs of intestinal mucosa and prevent inflammatory response in VPIs’ gut [138][30].
Breast milk lipids, such as omega-3 polyunsaturated fatty acids (PUFAs), interfere with gene expression and immune cell migration and alter gut microbes, protecting neonates against inflammation. PUFAs affect Th1 and Th2 cell responses and alter the cellular membrane domain, increasing arachidonic acid [139][31].

2. HBM and Gastrointestinal System

The gastrointestinal tract of VPIs is predisposed to inflammatory damage and NECNecrotizing Enterocolitis (NEC). Feeding with HBM decreases the risk for NEC, in contrast to formula, probably due to the anti-inflammatory agents that it contains, some of which have already been described. Interestingly, in a relative study with 797 very low-birth-weight neonates (VLBW < 1500 g) with mean gestation age 28.4 ± 2.6 weeks, those with HBM feeding for ≥90% of their hospitalization had a significantly lower risk for death or NEC in contrast with neonates that did not receive human milk (mortality rate 7.9% vs. 0.0%, p = 0.016; NEC rate 10.5% vs. 0.0%, p = 0.005) [140][32]. In another observational study, neonates born before 33 weeks of gestation and fed exclusively with HM had a significantly lower risk for NEC onset after day 7 than controls (1% vs. 3.4%, respectively, p = 0.009) [141][33].
HBM also promotes GI barrier maturation and alters microbial colonization. Human milk oligosaccharides contribute significantly to it [104][34]. The most abundant oligosaccharide in HBM is HMO-2′-fucosyllactose (2′FL) [142][35]. Oligosaccharides are selectively consumed by Bifidobacterium species, which are the dominant microorganisms in full-term neonates’ gut flora. The GI microbiota of VPIs, however, differs, and Bifidobacteria are present in significantly lower levels, something that is reasonable as VPIs are usually hospitalized and are treated with antibiotics for long periods [143][36]. On the other hand, the preterm GI tract is mainly colonized by potentially pathogenic bacteria, such as Gram-negative Enterobacteriaceae of the Proteobacteria phylum [143,144][36][37]. Through breastfeeding, VPIs are nourished with HBM oligosaccharides and other nutrients, which promote the development of Bifidobacteria against enteric pathogenicity [142,145][35][38]. Lactoferrin also promotes the growth of protective bacteria against pathogens [105][39].
HBM growth factors also contribute significantly to the protection of VPIs’ gastrointestinal systems. They induce the maturation of the GI barrier and the production of mucus by goblet cells, making VPIs less vulnerable to GI damage and infection [106][40]. More specifically, epidermal growth factor (EGF), which is found in greater amounts in colostrum and in preterm HBM, enables the recovery of intestinal mucosa from damage. It is resistant to digestion, stimulates enterocyte proliferation and blocks programmed cell death, thus healing injured tissues [107][41]. Heparin-binding EGF-like growth factor (HB-EGF) is found in HBM in lower amounts and is the main growth factor contributing to the remediation of intestinal tissue. Radulescu A et. al., in an animal study, reported that HB-EGF increases collagen deposition and enhances angiogenesis [108][42]. HB-EGF induces the maturation of the enteric nervous system and protects it from damage by NEC [109][43]. Hepatocyte growth factor (HGR) mainly induces organogenesis and maturation of the gastrointestinal system. It also interacts with vascular endothelial growth factor (VEGF) to promote angiogenesis [110][44]. Brain-derived neurotrophic factor (BDNF) and glial cell-line derived neurotrophic factor (GDNF) promote the maturation of the enteric nervous system and are contained in HBM [111][45].
Platelet-activating factor acetylhydrolase (PAF-AH) is detected in HBM and seems to have a protective role. It is an enzyme secreted by milk macrophages, and its biological action is to degrade platelet-activating factor (PAF), which can damage intestinal mucosa [112][46]. Another factor that possibly has a protective action against tissue damage and NEC is IL-8, a cytokine detectable in significant titers in HBM and which is stable in digestion. Its receptors CXCR1 and CXCR2 are expressed in the fetal GI tract early in gestation. Maheshwari A et al. reported that human fetal and adult intestinal cells, after in vitro administration of rhIL-8, presented augmented migration, proliferation and differentiation (p < 0.04) [113][47].
On the other hand, human formula contains nutrients that could induce tissue damage in VPIs. In a relative animal study by Singh P. et al., maltodextrin, a polysaccharide contained in human formulas, was correlated with increased injury scores [146][48].
Furthermore, progressively increased feeding of VPIs with HBM leads to sooner disengagement from parenteral nutrition, which indirectly decreases the risk of correlated complications, such as liver disease and central line-associated bloodstream infections (CLASBIs) [147,148][49][50].

3. Significance of HBM for Cerebral Tissue

HBM has a great role in the development of the neonatal brain. Vohr et al. reported that HBM is beneficial for extremely low-birth-weight neonates (ELBW < 1000 g) when it comes to neurodevelopmental outcome at 18 and 30 months corrected age [149,150][51][52]. A recent study showed that dominant ingestion of HBM (≥50% of total enteric intake) during the first 28 days of VPI life was correlated with better cognitive development at the age of 7 (IQ, mathematics and working memory test were 0.5 points higher for each additional day of dominant ingestion of HM (95% CI 0.1–0.2, 0.8–0.9)) [151][53].
VPIs require greater energy for physical growth and brain development compared to fetuses because they depend on the extra-uterus environment [38][54]. This means that it is essential for VPIs to receive all necessary macro- and micronutrients and energy via their nutrition. Formula and donor milk are alternative choices; however, enteral feeding with HBM is preferred, as it has been associated with better long-term neurodevelopmental outcomes [152][55].
Lipids account for more than 50% of cerebral tissue’s dry weight and are the nutrients that have mostly been related to brain development. Docosahexaenoic acid (DHA) and arachidonic acid (AA) are two LCPUFAs that are involved in many functions of neural cells, such as neurogenesis, neuronal migration and synaptogenesis [114,115][56][57]. Their role is also crucial for physiological retinal development [116][58]. Girls fed with HBM rich in DHA had better school performance that non-breastfed ones (β = 2.96 points, 95% CI 0.24; 5.69) [117][59], whereas such a correlation was not found in boys. The possible benefit of supplementation with PUFAs in VPIs and in breastfeeding mothers is a controversial topic. However, two recent Cochrane systematical reviews reported that there is no beneficial effect on neurodevelopment [118,119][60][61].
Sphingomyelin is a phosphosphingolipid that constitutes an essential molecule of the myelin sheath and has higher levels in HBM than in formulas. Infants fed with products abundant in sphingomyelin during the first 3 months postnatally had better verbal development at 2 years of life and greater myelination of the brain. Increased proliferation, maturation and differentiation of oligodendrocyte predecessor cells and increased production of myelin after in vitro sphingomyelin supplementation were observed [120][62].
Gangliosides are glycosphingolipids that are present in HBM in higher levels than in formulas [121][63]. They are essential in synaptogenesis, in neurotransmission, in neurogenesis, in neuronal maturation and in memory formation [122,123][64][65].
Human milk oligosaccharides are the third most abundant nutrient in HBM after lipids and lactose and possibly stimulate neurodevelopment [153][66]. Berger PK et al. showed in an animal study that chronic oral administration of the oligosaccharide 2′-fucosyllactose (2-FL) to mice and rats led to better performance in behavior tests and to increased expression of molecules that are involved in memory function. Yet, in human neonates, the correlation between 2-FL and cognitive development was found only in the first month of life but not at six months of life [124][67].
HBM contains various micronutrients, such as vitamin B6 (pyridoxal) and carotenoids. These nutrients seem to be of great significance for developing cerebral tissue. Pyridoxal is a water-soluble vitamin that is involved in the synthesis of GABA, dopamine and serotonin. Boylan LM et al. observed a positive correlation between the levels of B6 in breast milk and infant scores on habituation (r = 0.94, p < 0.05) and autonomic stability scales (r.34, p < 0.05) of NBAS at 8–10 days after birth [125][68]. Carotenoids are natural pigments that are normally contained in fruits and vegetables. According to a relative study, infants fed with milk that contained greater carotenoid levels (b-carotene and lycopene) presented greater psychomotor development at the first and third month postnatally (β = 0.359, p ≤ 0.05) [126][69].
Lactoferrin’s role in neurodevelopment has not yet been clarified; however, it seems that it could have a beneficial function in the neonatal brain. In some animal studies, supplementation of lactoferrin to subjects led to greater neurodevelopment results [127,128][70][71].
Although HBM contains many components that could lead to better neurodevelopmental outcomes, their supplementation to formula milk has not yet been proven beneficial. According to a hypothesis, the better results in neurodevelopment of breastfeeding VPIs could be attributed, not to the nutrients of HBM, but to the maternal–infant interaction. Mothers that feed their infants with their HBM seem to allow more hours interacting with their infant, which could lead to a better-developing brain. This hypothesis is supported by data that do not find donor milk beneficial for neurodevelopment [154][72].
Finally, HBM leads to a decreased risk for neonatal sepsis, NEC and neonatal inflammation. By protecting VPIs from these clinical conditions, HBM seems to have an additional, indirect neuroprotective effect.

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