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Department of Pediatrics, Division of Neonatology, VU University Medical Center, 1081 HV, Amsterdam, The Netherlands
* To whom correspondence should be addressed. E-mail: hn.lafeber{at}vumc.nl.
| ABSTRACT |
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| Introduction |
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Infections in preterm infants may originate in utero (6). In particular, intraamniotic bacterial infections in relation to premature rupture of membranes may cause preterm birth followed by a severe threat of immediate postnatal sepsis and/or meningitis. Another cause of infections of which the origin can be found in severe IUGR caused by poor placental function during the second and last trimester of fetal development may be traced to intrauterine infections. In the Western world, this is often caused by severe preeclampsia, leading to a poor perfusion via the placenta and resulting in a relative sparing of the brain but a very poor development of the splanchnic organs including the gut. The underdeveloped gut, often suffering from relative hypoxia, is very sensitive to poor motility, leading to stasis in the lumen and rapid overgrowth of (potentially) pathogenic bacteria (7). This may lead to the typical disease seen in high-risk preterm infants: necrotizing enterocolitis (NEC) (7). That these risk factors causing infections in preterm infants often originate before birth should always be considered in investigating the effects of pre- and/or probiotics added to the nutrition of these infants. The hostile environment in the lumen of the gut of preterm infants may be caused by pathogenic factors before birth, and the growth of pathogenic bacteria during the early postnatal period may be enhanced by relative hypoxia from poor ventilation.
Origin of infections related to the NICU environment
Recently, we reviewed the literature on the development of the intestinal microflora of preterm infants and the factors influencing its environment (8). Most studies show that the intestinal bacterial colonization with beneficial bacteria is delayed in preterm infants (8).
The number of potentially pathogenic bacteria is high. The widespread use of antibiotics at the NICU has a negative effect on the development of the intestinal microflora. Many preterm infants receive prophylactic antibiotics at birth. Over the period 1998–2000, a surveillance study on nosocomial infections was performed at our NICU (9,10). During 50% of the admission time, at least 1 antibiotic was administered to the preterm infants (9). The risk of sepsis was negatively related to birth weight: <1000 g birth weight, 31% risk of sepsis; 1000–1500 g birth weight, 28% risk of sepsis; and 1550–2500 g birth weight, 4% risk of sepsis. Apart from low birth weight, another high-risk factor for sepsis in preterm infants is the use of total parenteral nutrition mixtures (9,10).
Origin of infections related to the gastrointestinal tract
Severe infections in preterm infants often originate from the gastrointestinal (GI) tract because of the developmental immaturity of the gut. Often the gut wall is not yet fully mature, and the ultimately tight junctions between the mucosal cell layers are still open, permitting bacteria from the intestinal lumen to penetrate into the interstitium or vascular system causing sepsis (11). The process of gut maturation is influenced not only by the gestational age but also by the effect of administrating enteral feeding late or early by so-called gavage feeding using an indwelling plastic probe. Over the last 10–15 y, the concept of minimal enteral trophic feeding has been introduced into clinical practice: the early start of enteral feeding in small quantities (maximal 12–24 mL · kg–1 · d–1) in ventilated preterm infants during the period of parenteral feeding to enhance the gut function and with the intention to enable full enteral feeding sooner after birth (12). Preferably breast milk is given by nasal drip into the stomach to enhance mucosal development because mucosal growth factors in human milk facilitate mucosal growth (13). Pulsed minimal enteral feeding with breast milk may stimulate gastric emptying and may cause less reflux than bolus feeding. There may also be several nonmucosal effects of minimal enteral feeding such as stimulation of the motor activity of the muscular layer of the gut and enhancement of the postprandial response: lowering of the vascular resistance of the gut wall and increased oxygen consumption (14). Breast milk consumption may also result in the release of endocrine and metabolic factors such as gastrin, enteroglucagon, motilin, neurotensin, gastroinhibiting peptide, and pancreatic polypeptide (15). Enhancement of Lactobacillus and Bifidus flora by breast milk, known to diminish the risk of overgrowth of (potentially) pathogenic bacteria has already been discussed above. All these factors may lower the risk of NEC, a clinical entity in preterm infants leading to extremely high morbidity and/or mortality (7,16,17).
It remains very difficult, however, to collect sufficient clinical evidence for the validity of the concept of minimal enteral feeding (18). Most relevant clinical studies have been reviewed in a Cochrane meta-analysis (12,16). We concluded that minimal enteral feeding diminishes the number of days to reach full enteral feeding without increasing the risk of NEC. A study by Mihatsch et al. (19) showed that, even in IUGR preterm infants, the first postnatal day that full enteral feeding can be administered is reached earlier by increasing the amount of nutrition by 16 mL · kg–1 · d–1 up to 160–176 mL · kg–1 · d–1 until enteral nutrition is reached. Following this protocol, no increase in the incidence of NEC was observed, and the infants left the NICU sooner. In contrast, Berseth et al. (20) in 2003 claimed that increasing the amount of enteral nutrition with 20 mL · kg–1 · d–1 in preterm infants could be responsible for the fact that the team observed more cases of NEC.
Effects on infections by components of the nutrition
Quantitative aspects of important metabolic nutritional substrates: proteins. Proteins/amino acids are important anabolic substrates for the developing fetus and newborn. From numerous kinetic metabolic studies in preterm infants using amino acids labeled with stable isotopes, we know that the daily protein gain in preterm infants may be as high as 2 g · kg–1 · d–1 of protein during preterm life (21). This can be reached only by feeding fortified human milk or special protein-enriched preterm formula.
As demonstrated by Embleton et al. (22), preterm infants, particularly those born below 30 wk gestational age, may suffer from an increasing cumulative energy/protein deficit despite all efforts to feed them properly. The catabolic situation that develops in such infants has a negative effect on their infection risk during their time of stay in the NICU.
Qualitative aspects of important metabolic substrates: essential amino acids. Apart from protein quantity, the protein quality of the enteral feeding may influence metabolic conditions in the luminal part of the developing gut. Essential amino acids such as glutamine and glutamate are important energy sources for the intestinal intraepithelial lymphocytes, which require these amino acids for their proliferation (23). Indirectly, these amino acids may contribute to important functions including production of secretory immunoglobulin preservation of the gut-associated lymphoid tissue system and intestinal integrity (maturation of the crypt cells), prevention of bacterial translocation, and decrease of transcellular permeability (23–26). In a randomized controlled trial, Van den Berg et al. (27,28) investigated the effects of glutamine supplementation on the enteral feeding of 102 very low-birth-weight newborn infants. As clinical outcomes, feeding tolerance, serious infectious morbidity, and short-term outcome were investigated together with the postnatal adaptation of the gut and possible modulation of the immune response. No direct effects of enteral glutamine supplementation were seen studying the development of the intestinal microflora at postnatal day 30 (Table 2).
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Breast milk contains numerous factors with direct trophic effects on the intestinal wall cell layer protecting the infant to infections, resulting in better absorption and motility (13). In this manner it may help to protect a preterm infant to the pathophysiological process of NEC (13). This protection may be caused by an inhibiting effect on the development of a potentially pathogenic intestinal microflora that results from stimulating the growth of Bifidobacteriae and Lactobacillus strains (29,30).
Effects of nucleotides
Nucleotides are components of human milk that have been identified as affecting the immune function. In animal models, nucleotides have been shown to stimulate growth and maturation of the GI tract (31). Over the past 10 y, several clinical studies have shown effects of infant formula containing nucleotides on the immune status of infants (5,32). Most studies describe stimulated humoral responses after vaccination (5) and effects on the immune cell development (33). It is interesting to note that in both term and preterm infants, dietary nucleotides stimulate the intestinal circulation directly as observed by measuring the blood flow in the superior mesenteric artery (34,35). However, the clinical implications of these findings remain to be determined.
Effects of probiotics
Feeding with breast milk leads to the development of a healthy intestinal microflora of Lactobacillus and Bifidobacteriae instead of the potentially pathogenic Enterobacteriae. In an attempt to create a similar effect, clinical studies have been conducted to investigate the addition of Lactobacillus and/or Bifidus bacteria directly to the formula of infants (2,36,37). In term infants, positive effects have been described on the development of Lactobacillus and Bifidus in the gut microflora (36,37). In particular, infants with diarrhea may restore their gut function more rapidly and dramatically after addition of probiotics to the formula (36). For preterm infants, it is feared that probiotics may contribute to the onset of bacterial resistance against antibiotics, whereas most Bifidus and Lactobacillus strains may be killed by the use of broad-spectrum intravenously administered antibiotics (38). Only Lin et al. (39) in Taiwan investigated the effects of the addition of probiotics in preterm infants. This study reported no side effects and showed beneficial effects on survival, infection rate, and incidence of NEC in preterm infants. However, it was surprising to see that the incidence of NEC was much higher in Taiwan than in either North America or Europe (39).
Effects of prebiotics
The immunomodulatory effects of oligosaccharides in infant nutrition have been described frequently (40–43). Most studies describe a bifidogenic effect on the gut microflora and a positive effect on the incidence of infections at short term and possibly also at long term. The bifidogenic effect may also lead to less atopy (4). Characteristically, softer stools are also observed after introduction of galacto-oligosaccharides or mixtures of galacto- and fructo-oligosaccharides (1,2). Similar clinical beneficial effects have been described in a limited number of studies in preterm infants (3,44). One of the problems in preterm infants is the widespread use of broad-spectrum antibiotics, negatively influencing the bifidogenic development of the gut microflora (3). To study the long-term effects of adding prebiotics to infant formulas, more clinical studies are needed (45). At present, we are investigating the (possibly) beneficial effects of adding so-called acidic (46) and neutral oligosaccharides to the formula in preterm infants.
In summary, we conclude that studying the immunomodulatory effects of breast milk and dietary components such as pre- and probiotics and nucleotides added to the preterm formula in preterm infants is complex because of the multicausal risk of infections in these infants. A multitude of immunoregulatory factors, then, must be considered in clinical studies investigating the effects of immune components in the nutrition of preterm infants.
Other articles in this supplement include references (48–57).
| FOOTNOTES |
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2 Author disclosures: H. N. Lafeber, E. A. M. Westerbeek, A. van den Berg, W. P. F. Fetter, and R. M. van Elburg, no conflicts of interest. ![]()
3 Abbreviations used: GI, gastrointestinal; IUGR, intrauterine growth retardation; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit. ![]()
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