Growth is a major challenge for premature and low birth weight infants (born < 37 weeks gestation or with a birth weight of < 2500 g). They have several factors that put them at risk for nutritional deficiencies resulting in poor growth. Decreased nutrient stores result in low body stores of glycogen, fat, protein, fat soluble vitamins, calcium, phosphorus, magnesium and trace minerals. Preterm infants require increased energy and nutrients for rapid growth and may need a 10 fold increase in weight gain in order to achieve optimum catch up growth [1, 2]. To achieve optimum growth for the preterm infant, the goals are to continue the process of intra-uterine growth in an extra-uterine environment until 40 weeks post conception, foster catch-up growth and nutrient accumulation in the post discharge period [3–6]. A weight gain of 15 to 20 g/ kg/day, length of 0.75 to 1.0 cm/week and head circumference 0.75 cm/week is required. This is difficult to achieve and requires between 130 – 135 kcal / kg /day to maintain this growth rate . Furthermore, infants lose weight after birth (up to 6% to 8% for extreme low birth weight infants) and they often do not regain the weight for up to 1 to 2 weeks . Daily growth monitoring (weight gain, linear and head circumference) then becomes vital.
Preterm infants have immature physiological systems due to an underdeveloped gastrointestinal barrier function as reflected by increased intestinal permeability. As a result, potentially pathogenic bacteria translocate from the intestinal lumen and cause systemic infections . Reducing intestinal permeability is associated with gut maturation which promotes growth and avoids severe infections . In addition, digestive and absorptive capabilities are decreased due to low concentration of lactase, pancreatic lipase and bile salts. Gastrointestinal motility and stomach capacity are decreased which limits feeding volume and gastric emptying. A coordinated suck and swallow is not developed until 32 to 34 weeks gestation. Introduction of enteral feeding maybe delayed due to increased risk of aspiration [1, 2, 8, 9]. Preterm infants in neonatal intensive care units (NICUs) develop a different intestinal microbiota compared to healthy breast fed infants. This is due to decreased exposure to the maternal microbiota, increased exposure to organisms that colonize NICUs, multiple courses of antibiotics and delays in feeding [8, 9].
Humans have consumed probiotics in the form of fermented food, dairy products and more recently infant and toddler formula. Probiotics are defined as “live microorganisms” which when administered in adequate amounts confer a health benefit to the host . The main probiotic organisms used worldwide belong to the genera Lactobacillus and Bifidobacteria and are found in the gastrointestinal micro flora [10, 11]. Prebiotics are found in fruit and vegetable components, they are non- digestible food ingredients that benefit the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon and improving the host’s health [12, 13]. The most widely studied prebiotics are inulin, fructo-oligosaccharide (FOS) and galacto-oligosaccharide (GOS) which are plant storage carbohydrates in vegetables, cereals and fruit. FOS and inulin are added to different foods as fat and sugar replacements to improve texture or for their functional benefits [12, 14–16]. Probiotics and prebiotics are added to infant formula to promote an intestinal microbiota resembling that of breastfed infants which have a greater concentration of bifidobacteria and less pathogenic bacteria than formula fed infants [10, 17].
There are a number of ways in which probiotics improve health. Health benefits conferred by probiotic bacteria are strain specific and not species or genus specific . Probiotic bacteria improve health by affecting the immune system in different ways. They increase cytokine production such as Interleukin-6 (IL-6), Interferon- gamma (IFN-γ), Tissue Necrosis Factor – alpha (TNF-α), Interleukin-1beta (IL-1β) and Interleukin-10 (IL-10) . Some strains increase phagocytic activity of peripheral blood leukocytes (monocytes, polymorphonuclear cells). Other strains strengthen the mucosal barrier function by promoting the production of mucosal antibodies and reducing the trans mucosal transfer of antigens. This reduces the intestinal permeability which in turn promotes growth [19–22]. Probiotics bacteria also enhance production of low molecular weight antibacterial substances produced by epithelial cells and production of short chain fatty acids, the main energy source for colonocytes. This maintains the integrity of colon mucosa [19, 23–26].
Prebiotics are resistant to digestive enzymes and pH extremes found in the human gastrointestinal tract. They transit through the upper gastrointestinal tract and reach the colon intact where they are selectively fermented by indigenous bacteria, especially bifidobacteria and lactobacilli [12, 15, 26, 27]. Beneficial bacteria (including bifidobacteria and lactobacilli) possess enzymes needed to metabolize prebiotics, while other bacteria (such as E coli, clostridia and salmonella) do not [15, 27]. Consumption of prebiotics by preterm formula fed infants results in an increase of beneficial microorganisms in the colon, decreasing harmful bacteria to the levels found in breastfed infants. This improves the gastrointestinal mucosal barrier (decreasing intestinal permeability) which prevents infections and eventually results in improved growth [27, 28]. In general the aim of adding probiotics and prebiotics to preterm infant formula is to improve growth, development and decrease infections by promoting an intestinal microbiota resembling that of breastfed infants [9, 29, 30].
The effects of probiotics on the intestinal microbiota of premature infants have been varied due to differences on gestational age and products administered. Effects of probiotics on weight gain have also been varied. Administration of Bifidobacteria breve led to improved weight gain while Saccharomyces bourladii did not . With premature infants optimal strains and dose regimens are yet to be examined closely . The effects of prebiotics on the growth of premature infants are not clear. If prebiotic supplementation reduces the risk of Necrotizing Enterocolitis (NEC) or improves feed tolerance in very low birth weight infants is yet to be established [8, 9]. Recent systematic reviews (published from 2005 to 2009) on the use of probiotics or prebiotics in preterm infants have focused on prevention of NEC and / or sepsis, impact on diarrhea [31–34]. These reviews focused on studies that used breast milk and mixed feeds (formula combined with breast milk). This review included infants given only infant formula and focused on growth with clinical outcomes that were not adequately addressed by previous reviews.
The Human Research Ethics Committee at the University of Stellenbosch, South Africa reviewed the review protocol (unpublished), ruled that all data to be collected for this review was from the public domain and was therefore exempt from ethical approval.