The basics of prescribing infant formulas

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CPD: The basics of prescribing infant formulas 25 Vol 54 No 1 S Afr Fam Pract 2012 Introduction Regulatory bodies around the world agree that breastfeeding provides the best nutrition for infants 1 Exclusive breastfeeding is recommended by the World Health Organization (WHO) for the first six months, and supplemental breastfeeding for up to two years, or more. Although breastfeeding provides more benefits than formula feeding, many parents still choose infant formula as an alternative to the former 3,4 Human milk contains antibodies, hormones, enzymes, and many other components, which cannot be added to formula. However, additives with proven benefits, are added to modern day infant formulas 5 This article looks at the basics of prescribing infant formula. Serious medical cases, such as short bowl syndrome and malabsorption, are beyond the scope of this article Components of standard infant formulas The nutritional composition of all infant formulas must meet the global standards as recommended by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition’s (ESPGHAN) international expert group that was commissioned by The Codex Alimentarius Commission in November 2004. All infant formulas must contain sufficient amounts of basic nutrients, and are thus nutritionally interchangeable (Table I). No evidence exists to recommend one brand over another 1,2 Prescribing the correct infant formula Infant formulas developed as unmodified cows’ milk are not recommended for infants younger than 12 months of age, as they pose serious health risks 6,7 A wide variety of infant formulas are available, which makes choosing a suitable one difficult for parents and healthcare professionals. The majority of infants who are not being breastfed can use a standard infant formula, but a select few will require a more specialised formula. This will depend on gestational age and the presence of an illness 1 Table II provides a guide of available infant formulas, and indication of use. Formulas that are marketed for infants who are older than one year of age are not included, as no evidence exists to promote the use of such milk, or to demonstrate their superiority in terms of growth or development, when compared to whole milk 6 Caseinvs. whey-predominant infant formulas Manufacturing companies market caseinor curdpredominant formulas to “hungry” babies. However, there is no conclusive evidence that babies sleep longer, or have better quality sleep, if given such milk. These formulas form relatively indigestible curds in the stomach, and are not recommended for young babies 6 By comparison, whey-predominant infant formulas are more easily digested. Its composition of whey:casein (60:40) is similar to that found in human milk. For this reason, wheypredominant infant formulas are usually prescribed for newborn infants 6 Additional components added to infant formulas As more human milk components are discovered, modifications to existing infant formula and new infant formulas are made 5 The European Society for Paediatric Gastroenterology, Hepatology and Nutrition’s (ESPGHAN) The basics of prescribing infant formulas Owens CJW , BScDietetics; Labuschagne IL, BScDietetics; Lombard MJ , PhD Nutrition Information Centre, Stellenbosch University Correspondence to : C Owens, e-mail: nicus@sun.ac.za Keywords: infant formula, milk, whey protein, infant nutrition, feeding Abstract All infant formulas must support the normal growth and development of infants, and this needs to be scientifically demonstrated. Formulas have to contain sufficient amounts of basic nutrients, and so are nutritionally interchangeable, with no evidence indicating that one brand is superior to another 1,2 © Medpharm S Afr Fam Pract 2012;54(1):25-30

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CPD: The basics of prescribing infant formulas 26 Vol 54 No 1 S Afr Fam Pract 2012 international expert group, commissioned by The Codex Alimentarius Commission in November 2004, reported that the mere fact that a component is found in human milk, does not justify its addition to formula. Formula milk additives have to demonstrate that they provide a scientifically proven benefit 2 Long-chain polyunsaturated fatty acid supplementation Alpha-linolenic acid (ALA) is the precursor for docosahexaenoic acid (DHA), more commonly referred to as omega-3 fatty acids. Linoleic acid (LA) is the precursor of arachidonic acid (AA), also known as omega-6 fatty acids. Omega-3 and omega-6 fatty acids are long-chain polyunsaturated fatty acids, important for neurological, cognitive, and visual development in the rapidly growing newborn 8 DHA and AA are present in human milk, in variable amounts. However, until recently, infant formulas only contained their precursors, LA and ALA. The addition of LA and ALA to formulas is standard, and they have to be added to all infant formulas on ESPGHAN’s recommendation 1,2,9 In a recent Cochrane review, it was reported that the supplementation of DHA and AA in formula milk has not shown any beneficial effect with regard to the visual, physical, and neurodevelopment of term infants 2 Further research is needed before routine supplementation of DHA and AA in infant formulas can be recommended 2 Preand probiotics Prebiotics, mostly in the form of indigestible oligosaccharides, are frequently added to infant formulas. Evidence that prebiotics reduce allergic disease is insufficient. Adding them is optional, providing they do not exceed 0.8 g/ 100 ml 10,11 The motivation for adding probiotics to infant formula is that they might have a positive effect on digestion, with regard to the frequency and duration of gastrointestinal infections, including acute rotavirus gastroenteritis. They might reduce the risk of antibiotic-associated diarrhoea developing, as well as improve immunity. When added to infant formulas, Bifidobacterium lactis and Lactobacillus reuteri showed a significant decrease in the incidence and duration of diarrhoea caused by rotavirus 12 A systematic review conducted by ESPGHAN indicated that there is not enough evidence to recommend the addition of probiotics to infant formula 1 Nucleotides A randomised control trial by Singhal et al found that healthy term infants fed nucleotide supplemented formulas experienced a greater weight increase and greater head circumference measurement compared to nonsupplemented formulas 13 ESPGHAN supports the addition of nucleotides to infant formula, provided that they do not exceed the maximum allowed amount of 5 mg/100 kcal 2,13,14 Table I: The European Society for Paediatric Gastroenterology, Hepatology and Nutrition’s recommended standards for the macroand micronutrient composition of infant formula 1 Component Minimum Maximum Energy : kcal/100 ml 60 70 Protein : g/100 kcal Cows’ milk Soy Hydrolysed 1.8 2.25 1.8 a 3 3 3 Lipids : g/100 kcal Total fat Linoleic acid α -linoleic acid 4.4 0.3 50 6.0 1.2 Not specified Carbohydrates : g/100 kcal 9.0 14.0 Fat-soluble vitamin s: µg/100 kcal (unless otherwise specified) Vitamin A: µg RE/100 kcal (retinol equivalent) Vitamin D 3 Vitamin E: mg α -TE/100 kcal ( α -tocopherol equivalent ) Vitamin K 60 1 0.5 4 180 2.5 5 25 Water-soluble vitamins : µg/100 kcal (unless otherwise specified) Thiamine Riboflavin Niacin Vitamin B 6 Vitamin B 12 Pantothenic acid Folic acid Vitamin C: mg/100 kcal Biotin 60 80 300 35 0.1 400 10 8 1.5 300 400 1 500 175 0.5 2 000 50 30 7.5 Minerals and trace elements: mg/100 kcal Iron (cows’ milk and hydrolysate protein) Iron (soy-based protein) Calcium Phosphorus (cows’ milk and hydrolysate protein) Phosphorus (soy-based protein) Magnesium Sodium Chloride Potassium Minerals and trace elements: µg/100 kcal Manganese Fluoride Iodine Selenium Copper Zinc 0.3 b 0.45 50 25 30 5 20 50 60 1 Not specified 10 1 35 0.5 1.3 20 140 90 100 15 60 160 160 50 60 50 9 80 1.5 Other substances : mg/100 kcal Choline Myo-inositol L-carnitine 7 4 1.2 50 40 Not specified a = If an infant formula is based on hydrolysed protein, and it contains less than 2.25 g/100 kcal protein, it should be clinically tested. b = In areas where iron deficiency is proven, a higher iron content can be approved at national level.

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CPD: The basics of prescribing infant formulas 27 Vol 54 No 1 S Afr Fam Pract 2012 Table II: Infant formula available in South Africa, and indication of use Class Indication of use Brand name Kcal/ 100 ml Protein source and g/100 ml Carbohydrates and g/100 ml Additives Standard term infant formula 0-6 months of age, but can be used up to 12 months of age Healthy term infants, of normal birth weight Nestlé, Nan 1 ® 67 Demineralised whey, 30:70 whey-dominant, 1.23 Lactose, 7.47 DHA a , AA b , and nucleotides Nestlé, Lactogen 1 ® 67 Demineralised whey, 55:45 casein-dominant, 1.51 Lactose, maltodextrin, 7.46 - Pfizer, S 26 1 ® 67 Skimmed milk 40:60 whey-dominant, 1.5 Lactose, 7.2 - Pfizer, S 26 Gold 1 ® 67 Skimmed milk, 40:60 whey-dominant, 1.5 Lactose, 7.2 DHA, AA, and nucleotides Pfizer, SMA 1 ® 67 Skimmed milk, 1.6 80:20 casein-dominant Lactose, 7.0 - Aspen, Infacare 1 ® 67 Whey protein, 40:60 whey-dominant, 1.5 Glucose, lactose, 7.5 - Aspen, Infacare Gold 1 ® 68 Whey protein, 40:60 whey-dominant, 1.4 Lactose, 7.5 DHA, AA, and nucleotides Aspen, Infacare Nurture 1 ® 67 Whey protein, 40:60 whey-dominant, 1.5 Lactose, 7.5 DHA and AA. Prebiotics and nucleotides Pharmac, Novolac 1 ® 66.1 Demineralised whey, 50:50 whey:casein, 1.5 Lactose, maltodextrin, 7.5 - Abbott, Similac Advance with Iron ® 68 Whey protein, 1.4 Lactose, 7.3 DHA, AA, and nucleotides Standard term infant formula 6-12 months of age (not to be used for infants < 6 months of age) Healthy term infants older than 6 months of age Nestlé, Nan 2 ® 67 Demineralised whey, 60:40 casein-dominant, 2.02 Lactose, 7.67 DHA probiotics: Lactobacillus GG and Bifidobacteriumlongum Nestlé, Lactogen 2 ® 67 Skim milk, 64:35 casein-dominant, 2.03 Lactose, maltodextrin, sucrose, 8.05 Probiotics: Lactobacillus reuteri Pfizer, S 26 Promil 2 ® 67 Whey protein, 60:40 casein-dominant, 2.2 Lactose and sucrose, 8.2 Nucleotides Pfizer, S 26 Gold Promil 2 ® 67 Whey protein, 60:40 casein-dominant, 2.2 Lactose and sucrose DHA, AA, and nucleotides Aspen, Infacare 2 ® 66 Whey protein, 65:35 casein-dominant, 2.4 Sucrose and glucose syrup, 8.6 - Aspen, Infacare Gold 2 ® 69 Whey protein, 50:50 casein:whey Lactose and sucrose DHA, AA, and nucleotides Aspen, Infacare Nuture 2 ® 67.3 Skim milk, 40:60 casein-dominant Lactose and sucrose, 8.1 DHA, AA, and nucleotides. Pre-and probiotics Pharmaco, Novolac 2 ® 66 Skimmed milk, 80:20 casein-dominant,1.6 Lactose and maltodextrin, 7.7 - Preterm formula Premature infants < 37 weeks gestation. Birth weight < 2.5 kg Nestlé, Pre nan powder ® 80 30:70 whey, 2.3 Lactose, maltodextrin, 8.57 DHA, AA and nucleotides Nestlé, Pre nan ready to drink ® 80 100% partially hydrolysed whey protein, 2.9 8.4 DHA, AA and nucleotides Abbott, Similac Special Care 24 Cal ® 81 Skimmed milk, whey protein concentrate, 2.4 Lactose and corn syrup solids 8.4 DHA and AA Abbott, Similac Special Care 20 Cal ® 68 Skimmed milk, whey protein, 2.0 Lactose and corn syrup solids, 7 DHA and AA Soya formula 0-6 months of age Primary lactase deficiency. Galactosaemia. Vegetarian diet Abbott, Similac Isomil Advance ® 68 Soy protein isolate, 1.66 Corn syrup and sucrose, 7.0 DHA and AA Abbott, Isomil 1 ® 68 Soy protein isolate, 1.8 Corn syrup, sucrose, maltose, 6.9 - Pfizer, Infasoy 1 ® 67 Soy protein isolate, 1.8 Corn syrup and sucrose - Aspen, Infacare soya 1 ® 65 Soy protein isolate, 1.8 Corn syrup solids, 6.6 - Aspen, Infacare Gold Soya 1 ® 67 Soy protein isolate Corn syrup solids DHA, AA, and nucleotides

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CPD: The basics of prescribing infant formulas 28 Vol 54 No 1 S Afr Fam Pract 2012 Class Indication of use Brand name Kcal/ 100 ml Protein source and g/100 ml Carbohydrates and g/100 ml Additives Soya formula 6-12 months of age Primary lactase deficiency. Galactosaemia. Vegetarian diet Abbott, Isomil 2 ® 69 Soy protein isolate,2.3 Corn syrup, sucrose and maltose, 8.0 - Aspen, Infacare soya 2 ® 72 Soy protein isolate, 2.2 Corn syrup solids, 7.7 - Aspen, Infacare Gold Soya 2 ® - Soy protein isolate Corn syrup solids DHA, AA, and nucleotides Pfizer, Infasoy 2 ® 66 Soy protein isolate, 2.5 Corn syrup and sucrose, 6.9 Nucleotides Anti-reflux formula Reflux associated with failure to thrive, respiratory symptoms and esophagitis Nestlé, Nan AR ® 67 Demineralised whey 30:70 casein-dominant, 1.24 Lactose, potato and corn starch, 7.7 - Pharmaco, Novolac AR 1 (Also AR 2) ® 66 Skim milk, 80:20 casein-dominant 1.7 Lactose and corn starch, 7.4 Long-chain polyunsaturated fatty acids Aspen, Infacare AR ® 67 Skim milk, 80:20 casein-dominant, 1.6 Corn syrup solids, carob bean gum - Aspen, Infacare Nurture AR ® 67 Skim milk, 80:20 casein-dominant, 1.6 Corn syrup solids, 7.0 DHA, AA, and nucleotides Acidified formula Infants with an increased risk of developing gastroenteritis Nestlé, Nan Pelargon ® 67 Demineralised whey, 50:50. 1.49 Lactose, maltodextrin, 7.57 Chemically acidified with lactic acid Aspen, Melegi ® 67 Whey protein, 40:60 whey-dominant, 1.5 Corn syrup solids, lactose, 7.5 Chemically acidified with citric acid Low-lactose or lactose-free Galactosaemia. (However, not all of the formulas in this category are suitable for patients with galactosaemia). Acute diarrhoea. Lactose intolerance Nestle, Nan Lactose free ® 67 Potassium caseinate, whey protein 40:60, whey-dominant, 1.4 Corn syrup (maltodextrin), 7.8 DHA, AA, and nucleotides Aspen, Infacare ® Nurture LF ® Not for galactosaemia 67 Calcium caseinate, 1.5 Corn syrup solids, 7.2 DHA and AA Prebiotics Hydrolysed cows’ milk formula Limited research on the prevention of cows’ milk and other allergies (infants 0-6 months of age) Nestlé, Nan HA ® 1 (new) 67 100% partially hydrolysed whey protein, 1.51 Lactose, maltodextrin, 7.56 DHA and AA Limited research on the prevention of cows’ milk and other allergies (infants 6-12 months of age) Nestlé, Nan HA 2 ® 67 100% partially hydrolysed whey protein, 2.01 Lactose, maltodextrin, 8 DHA and AA Probiotics: Lactobacillus GG and Bifidobacteriumlongum Limited research on the prevention of cows’ milk and other allergies (infants 0-12 months of age) Abbott, Similac Advanced HA ® 71 26% degree of hydrolysis, 1.9 Maltodextrin, 7.9 Nucleotides Pharmaco, Novolac HA ® 65 16-22% degree of hydrolysis, 1.6 Lactose, starch, glucose syrup, 7.6 - Aspen, Infacare Nurture HA Comfort ® 67 Hydrolysed whey, 1.5 Corn syrup, lactose, 7.2 DHA and AA Probiotics Extensively hydrolysed formula Diagnosed cows’ milk allergy, and other medical conditions Nestlé, Alfaré ® 70 100% whey protein extensively hydrolysed (80% small peptides, 20% free amino acids Maltodextrin and potato starch DHA and nucleotides Abbott, Similac Alimentum ® 66.7 Extensively hydrolysed casein, supplemented with 60% free amino acids,1.8 Sucrose, modified tapioca, 6.8 DHA and AA Cow’s milk protein allergy 0-6 months Pharmaco, Novolac Allernova ® 61.7 39 % degree of hydrolysis, 1.4 Glucose syrup. 6.7 - Cow’s milk protein allergy Nutricia, Pepticate ® 66 Extensively hydrolysed whey, 1.6 Maltodextrin, 7.1 DHA, AA, and nucleotides

CPD: The basics of prescribing infant formulas 29 Vol 54 No 1 S Afr Fam Pract 2012 Specialised formulas In a small percentage of cases, due to feeding intolerances, infants require specialised formulas. This should only be given on the recommendation of a dietitian or physician 1 Protein-modified formula Preventing cows’ milk allergies, as well as others There is no evidence to support giving hydrolysed cows’ milk over exclusive breast milk in an attempt to prevent allergies in infants. Limited evidence exists to support giving hypoallergenic (partially hydrolysed or extensively hydrolysed) formula vs. cows’ milk formula to infants at high risk of developing allergies 15 Evidence indicates that giving soy-based formula, rather than cow’s milk formula, does not reduce the risk of the development of allergies such as asthma, eczema, rhinitis, and cow’s milk allergy, in later infancy and childhood 16,17 Treatment of cows’ milk allergies Where exclusive breastfeeding is not possible, extensively hydrolysed cows’ milk protein formulas and amino acidbased formulas should be given to treat infants with diagnosed cows’ milk protein allergies. Amino acid-based formulas should be given to infants who are highly allergic 18 Treatment of colic The authors of a recent Cochrane review concluded that there is some evidence to promote offering hydrosylate cow’s milk formula to bottle-fed infants suffering from colic 19 However, the recommendation is based on a small randomised control trial, and further research is required. Soy infant formulas should not be given to prevent or treat colic 17 Soy-based infant formula Cows’ milk protein allergy (CMPA) is a major financially driven indication for soy formulas to be given, but giving hydrolysed cow’s milk protein formula and amino acid-based formula has proven to be more effective, and should be the first option in treating CMPA. ESPAGHAN recommends that there should be a transition from hydrolysed cow’s milk protein formula to soy-based formula after six months of age, as it is better tolerated by older infants. The viewpoint of the American Academy of Paediatrics (AAP) is as follows: “… for infants with documented CMPA, extensively hydrolysed protein formula should be considered, because 10-14% of these infants will also have a soy protein allergy.” 17 The only medical indication for giving soy infant formulas is galactosaemia and primary lactase deficiency. ESPGHAN and the AAP recommend a lactose-containing formula for realimentation, but a lactose-free formula is better tolerated in infants with secondary lactose intolerance after acute gastroenteritis. This has encouraged the consumption of isolated soy-based infant formula, but research has shown that the use of lactose-free formula is also well tolerated 17 Carbohydrate-modified formula The major carbohydrate in breast milk and standard cows’ milk formula is lactose. Strong evidence suggests that a lactose-free infant formula is effective in the dietary management of acute diarrhoea 17 Galactose and glucose make up lactose, and therefore, infants with galactosaemia require a lactose-free infant formula, and cannot be breastfed 20 Acidified formula Infant formula can be chemically acidified through the addition of L (+) lactic acid, or biologically through fermentation, which transforms lactose into lactic acid. The method of acidification does not have an effect on the growth of infants. The growth of pathogenic bacteria is inhibited through the use of an acidified formula, leading to a decreased incidence of diarrhoea in infants 20 Preterm milk Human milk is the best source of nutrition for all infants, including infants who are born prematurely 21,22 An Class Indication of use Brand name Kcal/ 100 ml Protein source and g/100 ml Carbohydrates and g/100 ml Additives Free amino acid-based formula Highly allergic infant. Other conditions where an elemental diet may be indicated Nutricia, Neocate ® 71 Free amino acids, 1.95 Glucose, syrup, 8.1 - Highly allergic infant. Other conditions where an elemental diet may be indicated. Children > 1 year of age Nutricia, Neocate advanced ® 100 Free amino acids, 2.5 Glucose syrup, 14.6 - a = docosahexaenoic acid, b = arachidonic acid

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CPD: The basics of prescribing infant formulas 30 Vol 54 No 1 S Afr Fam Pract 2012 appropriate preterm formula should be prescribed by a neonatologist on an individualised basis, to premature infants who cannot be breastfed. It should be given in the early months, after birth 23 Continuous nutritional intervention post-discharge must be encouraged, and is of vital importance 24 Anti-reflux formula Almost half of all infants are affected by symptomatic gastroesophageal reflux (GER). Uncomplicated GER usually resolves spontaneously, and needs no treatment. Infants with GER presenting with failure to thrive, and esophagitis and respiratory complications, typically need pharmacological, or other treatment. Non pharmacological treatment includes giving an infant formula that is pre-thickened with precooked corn starch or locust bean gum, which has been proven to decrease episodes of regurgitation and emesis. Pre-thickened formula is nutritionally safe, and contains adequate amounts of the necessary nutrients 1,14,25,26 Follow-on milk for infants aged six to 12 months Giving follow-on milk was deemed “not necessary” by the World Health Assembly. The United Nations Children’s Fund’s (UNICEF) position is that parents can continue to give first milk until an infant reaches 12 months of age. First milk, together with complimentary foods, will provide enough nutrients to satisfy a healthy infant’s nutritional needs 6 Conclusion Breastfeeding is the best source of nutrition for most infants, and should be promoted, supported, and protected at all times. In rare cases, for example, infants with galactosaemia or primary lactase deficiency, or for any other medical reasons where the mother is unable, or unwilling, to breastfeed, it is important to select a suitable infant formula based on the infant’s individual needs, and medical condition Conflict of interest I declare that I have no financial or personal relationship(s) which may have inappropriately influenced me in writing this paper References 1. O’Connor NR. Infant formula. Am Fam Physician. 2009;79(7):565-570. 2. Koletzko B, Baker S, Cleghorn G, et al. Global standard for the composition of infant formula: recommendations of an ESPGHAN coordinated international expert group. J Pediatr Gastroenterol Nutr. 2005;41(5):584-599. 3. Hudara S, Mimouni F, Rachman Y, et al. Retrospective cohort study of a new infant formula during the first 6 months of life: reflections on growth curves, human milk and formula feeding. Isr Med Assoc J. 2010;12(11):676-680. 4. Le Huerou-Luron I, Blat S, Boudry G. Breastv. formula-feeding: impacts on the digestive tract and immediate and long-term health effects. Nutr Res Rev. 2010;23(1):23-36 5. Carver JD. Advances in nutritional modifications of infant formulas. Am J Clin Nutr. 2003;77(6):1550 S-1554 S. 6. The United Nations Children’s Fund.The health professional’s guide to: “A guide to infant formula for parents who are bottle feeding”. 2010 [homepage on the Internet]. c 2011. Available from: http://www.unicef.org.uk/Documents/Baby_ Friendly/Leaflets/health_professionals_guide_infant_formula.pdf 7. Wijndaele K, Lakshman R, Landsbaugh JR, et al. Determinants of early weaning and use of unmodified cow’s milk in infants: a systematic review. J Am Diet Assoc. 2009;109(12):2017-2028. 8. Wright K, Coverston C, Tiedeman M, Abegglen JA. Formula supplemented with docosahexaenoic acid (DHA) and arachidonic acid (ARA): a critical review of the research. J Spec Pediatr Nurs. 2006;11(2):100-112 9. Simmer K, Patole SK, Rao SC. Longchain polyunsaturated fatty acid supplementation in infants born at term [Cochrane review] In: The Cochrane Library, Issue 1, 2008. Oxford: Update Software 10. Osborn DA, Sinn J. Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants. [Cochrane review] In: The Cochrane Library, Issue 4, 2006. Oxford: Update Software 11. Braegger C, Chmielewska A, Decsi T, et al. Supplementation of infant formula with probiotics and/or prebiotics: a systematic review and comment by the ESPGHAN committee on nutrition. J Pediatr Gastroenterol Nutr. 2011;52(2):238-250. 12. Thomas DW, Greer FR. American Academy of Pediatrics Committee on Nutrition, American Academy of Pediatrics Section on Gastroenterology, Hepatology, and Nutrition. Probiotics and prebiotics in pediatrics. Pediatrics. 2010;126(6):1217-1231. 13. Singhal A, Kennedy K, Lanigan J, et al. Dietary nucleotides and early growth in formula-fed infants: a randomized controlled trial. Pediatrics. 2010;126(4):e 946-e 953. 14. Joeckel RJ, Phillips SK. Overview of infant and pediatric formulas. Nutr Clin Pract. 2009;24(3):356-362. 15. Osborn DA, Sinn J. Soy formula for prevention of allergy and food intolerance in infants [Cochrane review] In: The Cochrane Library, Issue 4, 2006. Oxford: Update Software 16. Osborn DA, Sinn JK. Probiotics in infants for prevention of allergic disease and food hypersensitivity [Cochrane review] In: The Cochrane Library, Issue 4, 2007. Oxford: Update Software 17. Vandenplas Y, De Greef E, Devreker T, Hauser B. Soy infant formula: is it that bad? Acta Paediatr. 2011;100(2):162-166. 18. Dupont C, de Boissieu D. Treatment of severe cow’s milk protein allergy using Neocate. Allerg Immunol (Paris). 2002;34(3):85-90. 19. Swadling C, Griffiths P. Is modified cow’s milk formula effective in reducing the symptoms of infant colic? [Cochrane review] In: The Cochrane Library, Issue 4, 2011. Oxford: Update Software 20. Velaphi SC, Cooper PA, Bolton KD, et al. Growth and metabolism of infants born to women infected with human immunodeficiency virus and fed acidified wheyadapted starter formulas. Nutrition. 2008;24(3):203-211. 21. Charpak N, Ruiz JG, KMC Team. Breast milk composition in a cohort of preterm infants’ mothers followed in an ambulatory programme in Colombia. Acta Paediatr. 2007;96(12):1755-1759. 22. Hay WW, Thureen P. Protein for preterm infants: how much is needed? How much is enough? How much is too much? Pediatr Neonatol. 2010;51(4):198-207. 23. Fanaro S, Ballardini E, Vigi V. Different pre-term formulas for different pre-term infants. Early Hum Dev. 2010;86 Suppl 1:27-31. 24. 24. Henderson G, Fahey T, McGuire W. Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge [Cochrane review] In: The Cochrane Library, Issue 4, 2007. Oxford: Update Software 25. 25. Vanderhoof JA, Moran JR, Harris CL, et al. Efficacy of a pre-thickened infant formula: a multicenter, double-blind, randomized, placebo-controlled parallel group trial in 104 infants with symptomatic gastroesophageal reflux. Clin Pediatr (Phila). 2003;42(6):483-495. 26. 26. Moukarzel AA, Abdelnour H, Akatcherian C. Effects of a prethickened formula on esophageal pH and gastric emptying of infants with GER. J Clin Gastroenterol. 2007;41(9):823-829.

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