Which is the ideal target for preterm growth?

In the last two decades the improved survival of very low birth weight (VLBW) and extremely low birth weight (ELBW) infants has underscored the problem of postnatal growth failure of these subjects. Notwithstanding the evident improvements in the general management of these infants during the hospital stay, most of them acquire a significant extrauterine growth restriction (EUGR). Frequent illnesses, medical and surgical therapies, feeding intolerance and, most of all, inadequacy of nutrient deliveries are responsible for the great part of this growth failure. However other factors, such as genetics, prenatal environment, hormones and metabolic pathways may contribute to growth impairment, that my persist until adulthood. Most of VLBW infants exhibit some catch-up growth, especially in late childhood and adolescence, but they generally remain smaller than their term peers. However, the most worrying aspect is related to the detrimental effect of growth impairment, especially if involving head circumference, on neurodevelopment outcomes of these infants. The endocrine, metabolic and cardiovascular long term consequences of under- and/or hypernutrition of VLBW infants are still to be elucidated. In the meantime, the efforts of the neonatotolgists should be focused on improving, how much as possible, the early nutrient management of these infants, allowing them to reach an adequate growth rate (at least 18-20 g/kg/d), then avoiding the need of a late unphysiological catch-up growth.

[Infant formulas supplemented with prebiotics: intestinal microbiota and immune responses]. / I prebiotici nei latti per lattanti: ruolo nello sviluppo dell'ecosistema microbico intestinale e nella modulazione del sistema immunitario.

It is well known that the type of feeding influences the composition of the gut microflora after birth. Human milk favours the growth of a ''bifidus flora'' which, according to several evidences, may activate the immune system and defend from pathogens. Breast milk oligosaccharides, which are involved in many functional effects both at local and systemic level, are thought to stimulate the growth of health promoting microbes, such as bifidobacteria, and may ultimately influence the immune system. In accordance with this current working hypothesis, dietary modulation of the gut microbiota to obtain a ''bifidus flora'' also in bottle-fed infants may be a useful way to stimulate immunological functions and to harbour a biological barrier against pathogens. In several clinical trials prebiotic oligosaccharides have been used to mimic the beneficial effects of breast milk oligosaccharides. A mixture of oligosaccharides has shown its efficacy in stimulating the establishment of a ''bifidus flora'', with stools closer to those found in breast-fed infants. Several experimental data also indicate that oligosaccharides might modulate the immune system and contribute to the improvement of the protective properties of infant formulas.

Acidic oligosaccharides from pectin hydrolysate as new component for infant formulae: effect on intestinal flora, stool characteristics, and pH.

OBJECTIVES: To come even closer to the functional composition of human milk, acidic oligosaccharides (AOS) from pectin were added to well known neutral prebiotics (galacto-oligosaccharides (GOS) and long-chain fructo-oligosaccharides (FOS)). The effect of AOS and GOS/FOS/AOS on intestinal flora, stool characteristics as well as acceptance and tolerance was investigated. METHODS: Human milk contains 75% to 85% neutral and 15% to 25% acidic oligosaccharides. In this prospective, randomized, double blind study, a mixture of 80% neutral oligosaccharides (from long-chain galacto- and long-chain fructo-oligosaccharides) with 20% acidic oligosaccharides derived from pectin hydrolysis was investigated. Forty-six term infants were fed a standard formula supplemented with either maltodextrin as control (n=15), or with 0.2 g acidic oligosaccharides (n=16), or with the latter plus 0.6 g neutral oligosaccharides (mixture of galacto- and fructo-oligosaccharides; n=15). Fecal flora using plating technique and pH were measured. Stool characteristics and possible side effects (crying, vomiting, and regurgitation) were recorded. RESULTS: There was no difference in the bifidobacteria counts between the control and the group supplemented with acidic oligosaccharides alone (8.75+/-0.50 vs. 8.58+/-0.94 log colony forming units [CFU]/g stool). In infants fed the combination of acidic and neutral oligosaccharides, bifidobacteria were increased (9.61+/-0.70 log CFU/g stool; P<0.01). The same pattern was observed with lactobacilli. Stool consistency was softest in infants fed the complete oligosaccharide mixture, but also in those fed formula supplemented with acidic oligosaccharides alone, the stool consistency was significantly softer compared with the control group. Fecal pH increased in the controls, remained constant in acidic oligosaccharides alone, and decreased in the complete mixture of oligosaccharides group. CONCLUSION: There was no difference in growth, crying, vomiting, and regurgitation patterns between the groups. In summary, acidic oligosaccharides from pectin hydrolysate are well tolerated as ingredient in infant formulae but do not affect intestinal microecology.

Prebiotics in infant formulas.

BACKGROUND: The intestinal flora of breast-fed infants is an important physiologic factor in the function of the gut and in the development of the immune system. The current research is part of a group of studies performed to answer the question whether a bovine milk formula supplemented with a prebiotic mixture from galactooligosaccharides and fructooligosaccharides can stimulate an intestinal flora similar to that of breast-fed infants. METHODS: The prebiotic effect of the oligosaccharide mixture was tested in preterm and term infants by measuring fecal flora using plating as well as fluorescent in situ hybridization techniques. The effect of the oligosaccharides on the bacterial metabolism was studied by measuring short-chain fatty acid production in vitro and the short-chain fatty acid pattern in the stools of a group of term infants. RESULTS: The oligosaccharide mixture increases significantly the number of bifidobacteria and reduces the number of pathogens in term as well as in preterm infants when compared with a group of infants fed an unsupplemented formula. Using a concentration of 0.8 g oligosacchrides/100 mL formula, the amount of bifidobacteria is similar to that typical of breast-fed infants. In vitro, the short-chain fatty acids produced by the mixture of oligosaccharides under study were similar to those produced by the human milk oligosaccharides fraction. In clinical trials the pattern of fecal short-chain fatty acids in infants fed the oligosaccharide mixture was similar to that of breast-fed infants but was significantly different from that of a group of infants fed with an unsupplemented formula. Additionally, the fecal pH was significantly higher in the group fed an unsupplemented formula than in the groups fed either breast milk or a supplemented formula. CONCLUSION: The data obtained indicate that the prebiotic mixture under study is able to stimulate the development of a microbial flora similar to that of breast-fed infants. Several biota, whose growth is enhanced by this prebiotic mixture, represent important factors in the postnatal development of the immune system. On this evidence it can be suggested that prebiotics may play a role as modulators of the postnatal development of the immune system.

Intestinal microflora in early infancy: composition and development.

The neonatal intestinal microbiota is a complex ecosystem composed of numerous genera, species and strains of bacteria. This enormous cell mass performs a variety of unique activities that affect both the colonic and systemic physiology. Its primary activities include nutritive, metabolic, immunological and protective functions. Most studies of infants have been based on faecal samples using the classical plating techniques with culturing on specific media. The limitations of these methods must be taken into account when evaluating the varying results of the different studies. The establishment of the gut microbial population is not strictly a succession in the ecological sense; it is rather a complex process influenced by microbial and host interactions and by external and internal factors. The climax intestinal flora is attained in successive stages. The foetal intestine is sterile and bathed in swallowed amniotic fluid. Following delivery, multiple different antigens challenge the intestine of the newborn. The maternal intestinal flora is a source of bacteria for the neonatal gut. The bacterial flora is usually heterogeneous during the first few days of life, independently of feeding habits. After the first week of life, a stable bacterial flora is usually established. In full-term infants a diet of breast milk induces the development of a flora rich in Bifidobacterium spp. Other obligate anaerobes, such as Clostridium spp. and Bacteroides spp., are more rarely isolated and also enterobacteria and enterococci are relatively few. During the corresponding period, formula-fed babies are often colonized by other anaerobes in addition to bifidobacteria and by facultatively anaerobic bacteria; the development of a "bifidus flora" is unusual. In other studies the presence of a consistent number of bifidobacteria in infants delivered in large urban hospitals has not been demonstrated, whether the babies were bottle fed or exclusively breastfed. The predominant faecal bacteria were coliforms and bacteroides. According to these studies, environmental factors may be more important than breastfeeding in gut colonization after delivery. Environmental factors are indeed extremely important for the intestinal colonization of infants born by caesarean section. In these infants, the establishment of a stable flora characterized by a low incidence of Bacteroides spp. and by the isolation of few other bacteria is consistently delayed. In extremely low-birthweight infants, hospitalization in neonatal intensive care units, characterized by prolonged antibiotic therapy, parenteral nutrition, delayed oral feedings and intubation seems to affect the composition of the intestinal microbiota. The gut is colonized by a small number of bacterial species; Lactobacillus and Bifidobacteria spp. are seldom, if ever, identified. According to the few studies so far performed, the predominant species are Enterococcus faecalis, E. coli, Enterobacter cloacae, Klebsiella pneumoniae, Staphylococcus epidermidis and Staphylococcus haemolyticus. Hygienic conditions and antimicrobial procedures strongly influence the intestinal colonization pattern.

Advances in the modulation of the microbial ecology of the gut in early infancy.

It is now generally accepted that the microbiota of the human gut may influence health and well-being. Lactic acid bacteria are the most important microorganisms associated with these beneficial effects and the elevated bifidobacterial count may be one of the greatest advantages that breastfed infants have over infants fed with milk formulas. Several studies relative to the selective growth stimulation of bifidobacteria, both in vitro and in vivo, are reported in this review. Over the years, diverse human milk components have been identified as the specific factors able to modulate the growth of bifidobacteria. Even if there is a certain agreement that the bifidogenic activity of human milk may be based not on single growth substances, but on a complex set of interacting factors, the present state of knowledge indicates that the use of non-digestible but fermentable carbohydrates may be an easy and reliable method to influence the growth of lactic acid bacteria. In this context, some of the characteristics of the major physiological effects of inulin-type fructans, of galacto-oligosaccharides, but also of lactoferrin, a milk whey protein fraction with purported bifidogenic activity, are briefly examined.

Prebiotic concept for infant nutrition.

In the neonatal period, the intestine is colonised in a stepwise process that depends on mode of delivery, environmental factors, bacterial interactions, and the host itself resulting in a colonisation with a complex heterogeneous bacterial flora. Oligosaccharides have been identified as an important prebiotic factor of human milk As long as analogues of human milk oligosaccharides are not available now and in the near future it is aimed to resemble the prebiotic effect of human milk by oligosaccharides from available sources. In the present study in preterm infants, a mixture of 90% galacto-oligosaccharides and 10% fructo-oligosaccharides has been tested. The mixture of GOS/FOS was composed to mimic the molecule size distribution of human milk oligosaccharides. Microbiological analysis of the faces was performed before and 7, 14, and 28 days after start of supplementation and stool characteristics have been recorded. Maltodextrin was used as placebo and infants fed human milk have been used as reference. After a 28 days feeding period, the number of bifidobacteria of the group fed the oligosaccharide supplemented formula was in the upper range of the reference group whereas the numbers of the group fed the formula supplemented with the placebo were in the lower range of the reference group (placebo: 7.9 +/- 0.83 and GOS/FOS mixture: 10,0 +/- 2.05 log 10 CFU/g wet stool; reference (M +/- SD): 7.14-10.7 log 10 CFU/g wet stool). Stool characteristics in the group fed the supplemented formula were close to those found in the human milk fed infants. In summary, supplementation of a preterm formula with a mixture of galacto- and fructo-oligosaccharides has a stimulating effect on the growth of bifidobacteria in the intestine and results in more frequent produced and softer stools. Thus, prebiotic mixtures such like the studied oligosaccharide mixture might help in improving intestinal tolerance to enteral feeding in preterm infants.

Effects of a new mixture of prebiotics on faecal flora and stools in term infants.

A double-blind, randomized, controlled study was performed in 90 full term infants to evaluate dose-related bifidogenic effects of a new synergistic mixture of galacto-oligosaccharides (GOS) and fructo-oligosacharides (FOS). The GOS/FOS mixture showed a dose-dependent stimulatory effect on the intestinal growth of bifidobacteria. Also stool consistency and faecal pH were positively affected.

"Minor" feeding problems during the first months of life: effect of a partially hydrolysed milk formula containing fructo- and galacto-oligosaccharides.

BACKGROUND: Colic, regurgitation and constipation are common feeding problems in formula-fed infants that might benefit from dietary treatment. A formula containing fructo- and galacto-oligosaccharides, partially hydrolysed proteins, low levels of lactose and palmitic acid in the beta position and higher density has been tested to reduce the occurrence of these symptoms. The aim of this prospective study was to describe the effects of such a formula in infants with minor gastrointestinal disorders. METHODS: An observational prospective trial involving practising Italian paediatricians was performed. Formula fed-infants up to 90 d of age with minor gastrointestinal problems such as infantile colics and/or regurgitation and/or constipation were enrolled in the study from January 2001 to May 2001. The study was completed within 14 d of treatment. On days 1, 7 and 14 the infants were visited by the paediatricians. Parents were given a structured diary to record daily episodes of colic, regurgitation and type and number of stools. RESULTS: Of the 932 infants enrolled, 604 completed the study. Of the 214 infants with colic, 169 (79%) demonstrated a reduction in frequency of colic from 4.1 +/- 2.0 per day at the beginning of the study to 2.0 +/- 1.8 at the end of the study (I.C. 95%: 1.72-2.39; p < 0.005). A reduction in the number of episodes of colic of 1.8 per day at the beginning of the study (I.C. 95%: 1.49-2.11; p < 0.05) was recorded between day 1 and day 7, and of 0.26 (I.C. 95%: 0.15-0.37; p < 0.05) between day 7 and day 14. Of the 201 infants with regurgitation problems, 141 (70%) demonstrated a reduction of frequency of the symptoms from 4.2 +/- 2.0 per day at the beginningof the study to 2.1 +/- 2.2 at the end of the study (I.C. 95%: 1.75-2.35; p < 0.005). A reduction of 1.87 in the number of regurgitation episodes was reported between day 1 and day 7 (I.C. 95%: 1.57-2.16; p < 0.05) and of 0.18 (I.C. 95%: 0.06-0.31; p < 0.05) between day 7 and day 14. Of the 232 infants with constipation, 147 (63%) demonstrated an increase in the daily number of stools of 0.42 (I.C. 95%: 0.5-0.3; p < 0.005). An increase in stool frequency of 0.41 (I.C. 95%: 0.51-0.23; p < 0.05) was reported between day 1 and day 7, and of 0.04 (I.C. 95%: 0.22-0.14; p = ns) between day 7 and day 14. Parents' evaluation of the formula was 7.9 +/- 1.8 (score 0-10); 550 parents (91%) gave a positive judgement (score > 6). The evaluation by the paediatricians of the improvement in symptoms after the treatment was 8.2 +/- 1.5; 574 (95%) a positive effect (score > 6). CONCLUSION: This study shows that the majority of infants followed by paediatricians for minor gastrointestinal symptoms improve within 2 wk of feeding with this new formula. Further double-blind, controlled studies are needed to confirm whether the amelioration of symptoms observed in this trial is in fact due to the new formula.

[Protein quality and quantity in infant formulas. A critical look]. / Le proteine nei latti per lattanti. Quali e in che misura?

The ideal quantity and quality of dietary proteins in milk formulas employed for infant nutrition is still a matter of controversy and debate. During the last years, there has been a tendency to lower the protein content in response to new estimations of protein requirements based on protein intakes and growth rates of breastfed infants. In most infant formulas the protein content is in the range of 1.4-1.8 g/100 ml. The lower limit of this range appears to be adequate for the growth and metabolic needs of the healthy infant. The safety of a further reduction of this limit to 1.2 g/100 ml (~1.8 g/100 kcal), which has been recently proposed, needs additional scrutiny and observation. In addition, the real benefits of this choice have still to be proven. Adjustments for protein digestibility and quality have recently been introduced. The removal from the whey protein fraction of the glycomacropeptide (GMP), with a consequent reduction of excessive threonine intakes, is a novel approach and a further step in the development of infant formulas closer to the model of hu-man milk.

[The biological specificity and superiority of human milk. Scientific basis, guarantees and safety controls]. / Unicità e superiorità biologica del latte di donna. Basi razionali, garanzie e controlli.

Scientific knowledge has demonstrated that breastfeeding is the ideal method of feeding and nurturing infants and has recognised breastfeeding as primary in achieving optimal infant health, growth and development. Human milk is species-specific and offers a superior method of feeding. All other options differ markedly from it. Milk formulas are designed to mimic human milk as much as possible, but important compositional differences between human milk and formulas remain, and it is unlikely that this situation will change very soon, if ever. Thus, the breastfed infant remains the reference model against which all alternative feeding methods are measured, with regard to health, growth and development. Human milk has a dynamic nature and varies with time postpartum, but the variations of its composition with time of lactation match the changing needs of the growing infant. The role of the pediatrician is essential in promoting, protecting and supporting breastfeeding in the hospital, medical schools, individual practices and in the community. The purpose of this review is to describe and provide insight into the nutritional benefits, the contributions to host defence and the social and psychological benefits of maternal-infant bonding obtained by breastfeeding. This paper also summarises other substantial advantages obtained when infants are fed at the breast and describes the rare situations and medical reasons when human milk is not recommended, when alternative options should be considered, or when breastfeeding must be closely monitored. Early identification of those infants fed at the breast who have inadequate intakes is important, also to preserve breastfeeding.

Dosage-related bifidogenic effects of galacto- and fructooligosaccharides in formula-fed term infants.

BACKGROUND: Human milk oligosaccharides have been shown to stimulate selectively the growth of Bifidobacteria and Lactobacilli in the intestine. In this study, the bifidogenic effect of an experimental prebiotic oligosaccharide mixture consisting of low-molecular-weight galactooligosaccharides and high-molecular-weight fructooligosaccharides was analyzed in 90 term infants. METHODS: Two test formulas were supplemented with either 0.4 g/dL or with 0.8 g/dL oligosaccharides. In the control formula, maltodextrin was used as placebo. At study day 1 and study day 28, the fecal species, colony forming units (cfu) and pH were measured and stool characteristics, growth, and side effects were recorded. RESULTS: At study day 1, the median number of Bifidobacteria did not differ among the groups (0.4 g/dL group, mean [interquartile range] 8.5 [1.9] cfu/g; 0.8 g/dL group, 7.7 [6.1] cfu/g; and the placebo group, 8.8 [6.1] cfu/g) (figures in square brackets are interquartile range). At the end of the 28-day feeding period, the number of Bifidobacteria was significantly increased for both groups receiving supplemented formulas (the 0.4 g/dL group, 9.3 [4.9] cfu/g; the 0.8 g/dL group, 9.7 [0.8] cfu/g) versus the placebo group (7.2 [4.9] cfu/g, P < 0.001). This effect was dose dependent (0.4 g/dL versus 0.8 g/dL, P < 0.01). The number of Lactobacilli also increased significantly in both groups fed the supplemented formulas (versus placebo, P < 0.001), but there was no statistically significant difference between the group fed formula with 0.4 g/dL oligosaccharides and the group fed formula with 0.8 g/dL oligosaccharides. The dosage of supplement significantly influenced the change in fecal pH (P < 0.05) (placebo, pH 5.5-6.1; 0.4 g/dL formula, pH 5.48-5.44; 0.8 g/dL formula, pH 5.54-5.19). Slight changes in the stool frequency resulted in a significant difference between the placebo group and the group fed the 0.8 g/dL formula at day 28 (P < 0.01). Supplementation had a significant dose-dependent influence on stool consistency (0.8 g/dL versus placebo, P < 0.0001; 0.8 g/dL versus 0.4 g/dL, P < 0.01). Supplementation had no influence on the incidence of side effects (crying, regurgitation, vomiting) or growth. CONCLUSIONS: These data indicate that supplementation of a term infant's formula with a mixture of galacto- and fructooligosaccharides has a dose-dependent stimulating effect on the growth of Bifidobacteria and Lactobacilli in the intestine and results in softer stool with increasing dosage of supplementation.

[Food allergies in early childhood. 2. Food choices]. / Le allergie alimentari nella prima infanzia. 2. Le scelte nutrizionali.

The incidence of allergic diseases appears to be on the increase in industrialized societies. In infants at high risk for atopic diseases prevention in early life seems to be a high priority at this time. However, many questions remain to be answered because, in the absence of breast feeding which should be encouraged in all infants, substitute formula employed for prevention should guarantee the following requisites: optimal nutrition, reduced allergenicity or better hypoallergenicity, good palatability and low cost. Current concepts in the field of prophylaxis and diet therapy of food allergy are reviewed. Special emphasis is given to the biochemical, nutritional and antigenic properties of the different formulas employed in the management of these conditions.

[Food allergies in early childhood. 1. General concepts, etiopathogenesis, and main clinical features]. / Le allergie alimentari nella prima infanzia. 1. Concetti generali, eziopatogenesi e principali quadri clinici.

Abnormal immune reactions to food antigens are a rather common event during infancy. Adverse reactions to milk proteins occur in 2.5% of suckling infants. Both IgE and non IgE-mediated allergic mechanisms may be involved in the pathogenesis of food allergy. IgE mediated allergic responses are the most dramatic and the most often diagnosed types. Non IgE mediated food allergy is usually more difficult to diagnose and its clinical course is more chronic. Food induced allergic reactions mediate a variety of symptoms, involving the gastrointestinal and respiratory tract and the skin. A limited number of foods are responsible for the vast majority of allergic reactions: cow milk proteins, egg, fish and peanuts are the main causes. The vast majority of infants with formula-protein intolerance will outgrow their symptoms by the third year of age. Eliminating the food allergens is the only means of dealing with the problem. In part I of this series, immunopathogenic mechanisms and clinical disorders are described.