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Department of Pediatrics, Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030-2600
* To whom correspondence should be addressed. E-mail: wheird{at}bcm.tmc.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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The Code applies to the marketing (and related practices) of breast-milk substitutes: infant formula and other milk products as well as foods and beverages that are marketed as suitable substitutes for breast-feeding. It also applies to the marketing of feeding bottles and nipples and to the availability and quality of information concerning their use.
To date, all or some provisions of the Code have been enacted into law by many countries; several others have drafted measures to do so. In still others some or all of the Code's provisions have been implemented voluntarily, and yet other countries are studying whether to adopt provisions of the Code. A few countries including the United States have taken no official action on the Code, but even in these countries, the marketing practices of companies that manufacture or distribute breast-milk substitutes, feeding bottles, and nipples tend to comply with the provisions of the Code.
Progress in promoting breast-feeding
Today, the rates of initiation of breast-feeding (>90% of women in developing countries and 50% to 90% of women in industrialized countries) are substantially higher than 25 y ago (2). The duration of breast-feeding is longer, but exclusive breast-feeding has not increased dramatically; currently, fewer than 50% of mothers in developing countries are breast-feeding exclusively at 3 mo postpartum, and fewer than 35% of mothers worldwide are breast-feeding exclusively at 4 mo postpartum (3).
To further increase breast-feeding, it is important to address the many determinants of a mother's decision to breast-feed or not (4). Underlying determinants include familial, medical, and cultural attitudes and norms; demographic and economic conditions; commercial pressures; and national as well as international policies and norms. The Code has helped to reduce some of the commercial pressures that are unfavorable to breast-feeding (e.g., advertising to parents). Intermediate determinants of a mother's decision to breast-feed include the information that she receives as well as the physical and social support provided during pregnancy, childbirth, and postpartum, all of which have been favorably influenced by the Code. Finally, once the mother makes a choice, she must be able to act on that choice. For example, the necessity of returning to work may interfere with her choice to initiate breast-feeding as well as how long she will breast-feed exclusively or partially.
Progress in combating infant malnutrition
Parallel to the greater prevalence of breast-feeding, considerable progress has been made in combating malnutrition among infants. In 1980, 49% of preschool children (younger than 5 y) in developing countries were stunted (low length/height for age). The prevalence of stunting was 30% in 2000 and 27% in 2005 (5). The prevalence of underweight (low weight for age) preschool children also has decreased, from 38% in 1995 to 23% in 2005. An exception is Africa, where the prevalence of both stunting and underweight among preschool children in all regions except Northern Africa has not changed appreciably or has even increased since 1980 (5). Because the population has increased, the absolute number of stunted and underweight children in the continent as a whole has increased by 
50 and 75%, respectively.
The prevalence of wasting (low weight-for-height/length) remained the same (8.3% of preschool children) in developing countries from 1995 to 2005. Yet, overall, the prevalence of malnutrition among infants and children is less today than 25 y ago. The Code undoubtedly has played a role in supporting beneficial changes throughout the world and in at least maintaining the status quo in many African countries that have enacted some or all of the provisions of the Code into law.
Advances in infant formula composition and use
Quantitatively, the macronutrient composition of infant formulas resembles that of human milk and has changed little over the past 25 y. However, several qualitative changes have been made in an attempt to mimic more closely the nutrient and nonnutrient composition of human milk and/or the performance of the breast-fed infant. There have also been changes in feeding practices over the past 25 y.
Trends in feeding practices. One main trend over the last 25 y has been to delay introduction of cow's milk into the infant's diet (6). A report of a nationwide telephone survey of 2515 U.S. mothers of infants and toddlers ages 4–24 mo, the "Feeding Infants and Toddlers Study," indicated that the intake of whole cow's milk during the first 6 mo of life was virtually nil and, compared with past practices, was still quite low at 12 mo of age (7). Of the survey respondents whose child was 12 mo or older, fewer than 25% had introduced cow's milk during the first year of life.
Another trend over the past 25 y has been the more widespread use of whey-predominant rather than casein-predominant formulas (6). Twenty-five years ago, only 1 infant formula containing whey-predominant protein was available, whereas today, at least 50% of the protein content of most available formulas is comprised of whey proteins. Although the nutritional quality of bovine caseins and whey proteins differ minimally (8), whey-predominant formulas more closely approximate the proteins in human milk. However, it is important to note that the casein and whey fractions of human milk and bovine milk differ considerably (9). Further, despite the widespread use of whey-predominant formulas, there is no clear evidence that this confers a major benefit to the recipient infant.
The use of iron-fortified formulas has increased over the past 25 y, from 32% of all formulas consumed in 1971 to 76% in 1991 (6), with further increases likely since 1991. The widespread use of iron-fortified formulas has been credited with reducing the incidence of iron deficiency anemia in infancy.
Changes in the types of fats used in infant formulas more closely mimic the fatty acid pattern of human milk and have enhanced fat absorption. The combination of vegetable oils that is used today results in fat absorption within the same range as observed in breast-fed infants and, with the recent addition of long-chain PUFA (see below), the fatty acid pattern of modern formulas resembles that of human milk more closely than ever before.
Follow-on formulas (containing somewhat more protein but otherwise similar to standard infant formulas) are intended for use following cessation of breast-feeding or after 6 mo of age. They are quite popular in many countries but have never been used widely in the United States. Moreover, the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition concluded recently that regular term formulas meet nutritional requirements of infants over 6 mo old and that transitional or follow-on formulas are not needed (10).
Premature/Low-birth-weight infant nutrition. There have been marked advances in nutritional care of premature/low-birth-weight (LBW) infants over the past 25 y. At the beginning of this period, survival of very LBW infants (BW <1500 g) was just beginning to improve; this trend has continued. Today, survival of very LBW infants approaches 100%, and that of extremely LBW infants (BW <1000 g) approaches 90% (11). Survival of even smaller and less mature infants also has improved dramatically. These surviving infants have poorly coordinated suck and swallow abilities, and this, along with a number of other medical and developmental problems, makes feeding them, particularly the smallest ones, a major challenge. The goals to be achieved in feeding these surviving infants, who until recently would have died, are still debated, but most agree that their rates of growth and nutrient accretion should mimic as closely as possible the rates that would have occurred in utero.
As more infants survived, it became clear that breast milk and formulas intended for term infants did not provide sufficient protein, calcium, or phosphorus for accumulation of these nutrients at rates comparable to what would have been achieved in utero (12). Thus, formulas tailored to the perceived needs of premature/LBW infants were introduced for use during hospitalization. Although the protein, calcium, and phosphorus contents of these formulas are higher than the contents of term formulas, they lacked the immunological and other benefits of human milk. Hence, breast-milk fortifiers were introduced, allowing delivery of roughly the same nutrients as premature/LBW formulas without severely compromising the many benefits of human milk (13).
Despite fortified human milk and formulas designed specifically for premature/LBW infants, a study of infants born from 1994 to 1995 indicates that at least 90% of such infants weighed less than the 10th percentile of intrauterine weight standards at hospital discharge (14). Further, because premature/LBW formulas and fortified human milk are not intended for use after discharge, intake of most nutrients decreases after hospital discharge. To address this problem, "postdischarge" formulas were recently introduced. These contain somewhat more protein, calcium, and phosphorus than standard term formulas but less than premature/LBW formulas. The postdischarge formulas are now being used widely, often in combination with breast-feeding, and most available data indicate that they result in more rapid growth over the first few months after discharge than do term formulas and that this growth advantage persists through 12–18 mo postnatal age (15,16). The most recent such study, however, showed no difference in growth between infants fed enriched vs. term formula (17).
Modifications of infant formulas.
Taurine, usually thought to be an end product of sulfur amino acid metabolism, was added to most infant formulas 25 y ago. This was precipitated by clinical studies showing that plasma and urine taurine concentrations of formula-fed infants were lower than those of breast-fed infants, presumably reflecting the presence of taurine in human milk but not formulas (18). Although the physiological consequences of lower taurine concentrations are not clear, long-term use of taurine-free parenteral nutrition regimens has been associated with retinal abnormalities (19). Neither recent U.S. (20) nor European (10) recommendations for the nutrient contents of infant formulas specify a minimal amount of taurine, indicating that data supporting efficacy are insufficient. Both, however, specify a maximum content of taurine, indicating that intakes less than this are safe.
Carnitine also has been added to some infant formulas. This micronutrient is present in both human milk and cow's milk but, until 20 y ago, was not present in soy-derived infant formulas. Because of its crucial role in fat oxidation (21), carnitine is now contained in soy-based formulas. Current recommendations specify a minimum amount for all infant formulas.
Other recent additions to infant formulas reflect additional efforts to more closely reproduce the nutrient and nonnutrient contents of human milk. Nucleotides have been added to infant formulas for several years because there is some evidence that they may help strengthen responses to immunizations and lower the number of diarrheal episodes (22). Current recommendations do not specify a minimum nucleotide content but do indicate a maximum.
The long-chain PUFAs docosahexaenoic acid and arachidonic acid have been added to infant formulas in some areas of the world for as long as 15 y, but for only 5 y in U.S. formulas. Most of the early clinical studies of these fatty acids showed a small beneficial effect on cognitive and/or visual development, but a few also showed an adverse effect on growth. More recent studies have shown no effect on growth and mixed effects on cognitive and/or visual development (23). The latest meta-analyses suggest that the benefit of adding these fatty acids to term infant formulas, if any, is small (24). Supplementing premature/LBW infant formulas with these fatty acids also appears to confer few benefits for cognitive and/or visual development (25). The role of docosahexaenoic and arachidonic acids in infant nutrition remains a focus of considerable research.
Current considerations regarding formula composition. Although hydrolyzed protein formulas have been available for decades, they have been used primarily in infants with gastrointestinal problems. More recently, these formulas have been used to ameliorate or prevent the allergic response of many infants to whole proteins. Some studies show an advantage of these formulas, but others do not (26). A factor that has generated considerable discussion concerns the degree of hydrolysis, with more extensively hydrolyzed proteins generally showing more benefit (27).
There also is considerable interest in adding specific proteins to infant formulas either to enhance the nutritional quality (e.g., 
-lactalbumin) or to confer other benefits (28,29). There also is concern that the proteins commonly used in infant formulas may be too limited in some amino acids. Those of concern include glycine, leucine, arginine, cyst(e)ine, and tryptophan (30).
The role of prebiotics (i.e., factors that support growth of beneficial organisms in the gastrointestinal tract) and/or probiotics (beneficial organisms such as Lactobacilli) in infant nutrition is another area of interest (31,32). Despite several reports of encouraging experimental results, few products containing either or both of these agents will be available until evidence of their safety and benefit accumulates from carefully controlled clinical studies.
Structured triglycerides are triglycerides that have been rearranged to change the position of fatty acids on the glycerol "backbone." One of particular interest in pediatric nutrition has the bulk of palmitic acid in the sn-2 rather than the sn-1 or -3 position, which enhances fat absorption. Experimental formulas containing structured lipids have been evaluated clinically and found to be efficacious with respect to fat absorption (33), but such formulas are not yet commercially available.
Formula development over the past 25 y has expanded from focusing only on the short-term health and growth of recipients to recognizing that intakes during infancy may affect subsequent development, including development of adult diseases. Initial epidemiological data indicated that small size at birth (34) or at 1 y of age (35) was associated with hypertension, coronary artery disease, and diabetes in adulthood, suggesting that the goal of infant nutrition should be to improve birth weight and size at 1 y of age. More recent data suggest that "too rapid" a rate of growth during some periods of early life may be equally detrimental with respect to obesity in childhood and to adult health (36,37). There is thus considerable interest in identifying these periods. The concern that rapid rates of weight gain during infancy and early childhood may have detrimental long-term effects as well as concerns about the cause(s) of the present epidemic of obesity and overweight among children have generated considerable discussion concerning the possibility that some infants may need a formula with a lower energy and/or protein density.
Current research and development efforts. Research concerning almost all aspects of infant feeding and formula composition remains substantial. About 5000 publications describing this research can be identified through PubMed using the simple search strategy of "infant nutrition" plus a specific nutrient and the time limits of 1975 to 2005 (38). These research and developmental efforts to improve early infant nutrition are supported by infant formula manufacturers as well as by national and international funding agencies. Unfortunately, the costs of the research required to document both safety and efficacy are increasing, which is likely to inhibit development of new formulas. It has been estimated that the studies required to support the safety of introducing a new component into an infant formula cost approximately $2 million, a relatively substantial impediment to new formula development.
Overall, there have been a number of changes in the types and composition of infant formulas over the past 25 y. Additional changes are being studied. Most of the additions and alterations were made to mimic the composition of human milk and/or the beneficial response of the breast-fed infant. Although research and developmental efforts to achieve this aim have been and remain active, many of the advantages of breast-feeding (as discussed in the following article) have not been achieved with formula feeding. Thus, efforts to promote breast-feeding and to prolong the duration of exclusive breast-feeding remain essential.
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FOOTNOTES |
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2 Author disclosure: no relationships to disclose.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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1. World Health Organization. International code of marketing of breast-milk substitutes. World Health Organization 1981 [cited 2006 Apr 10];Available from: URL: http://www.who.int/nutrition/publications/code_english.pdf
2. March of Dimes Task Force on Nutrition and Optimal Human Development. Nutrition today matters tomorrow. Wilkes-Barre (PA): Education Services, March of Dimes; 2002.
3. United Nations System Standing Committee on Nutrition. 5th Report on the world nutrition situation: nutrition for improved development outcomes [March, 2004]. Available from: www.unsystem.org/scn/Publications/html/RWNS.html.
4. Administrative UN Committee on Coordination, Sub-Committee on Nutrition. 4th report on the world nutrition situation: nutrition throughout the life cycle. 2000. ACC/SCN Nutrition Policy Papers.
5. UNICEF. Progress for children: a report card on nutrition. 2006. Report No. 4, May 2006.
6. Fomon SJ. Nutrition of normal infants, ed. 3. St. Louis: Mosby-Year Book; 1993.
7. Devaney B, Ziegler P, Pac S, Karwe V, Barr SI. Nutrient intakes of infants and toddlers. J Am Diet Assoc. 2004;104:s14–21.[Medline]
8. Mueller AJ, Cox WM. Comparative nutritive value of casein and lactalbumin for man. J Nutr. 1947;34:285–94.
9. Hambraeus L. Proprietary milk versus human breast milk in infant feeding. A critical appraisal from the nutritional point of view. Pediatr Clin North Am. 1977;24:17–36.[Medline]
10. Koletzko B, Baker S, Cleghorn G, Neto UF, Gopalan S, Hernell O, Hock QS, Jirapinyo P, Lonnerdal B, et al. Global standard for the composition of infant formula: recommendations of an ESPGHAN coordinated international expert group. J Pediatr Gastroenterol Nutr. 2005;41:584–99.[Medline]
11. Lemons JA, Bauer CR, Oh W, Korones SB, Papile LA, Stoll BJ, Verter J, Temprosa M, Wright LL, et al. Very low birth weight outcomes of the National Institute of Child health and human development neonatal research network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics. 2001;107:E1.
12. Schanler RJ. The use of human milk for premature infants. Pediatr Clin North Am. 2001;48:207–19.[Medline]
13. Kashyap S, Schulze KF, Forsyth M, Dell RB, Ramakrishnan R, Heird WC. Growth, nutrient retention, and metabolic response of low-birth-weight infants fed supplemented and unsupplemented preterm human milk. Am J Clin Nutr. 1990;52:254–62.
14. Ehrenkranz RA, Younes N, Lemons JA, Fanaroff AA, Donovan EF, Wright LL, Katsikiotis V, Tyson JE, Oh W, et al. Longitudinal growth of hospitalized very low birth weight infants. Pediatrics. 1999;104:280–9.
15. Carver JD, Wu PY, Hall R, Ziegler EE, Sosa R, Jacobs J, Baggs G, Auestad N, Lloyd B. Growth of preterm infants fed nutrient-enriched or term formula after hospital discharge. Pediatrics. 2001;107:683–9.
16. Lucas A, Fewtrell M, Morley R, Lucas PJ, Baker BA, Lister G, Bishop NJ. Randomized outcome trial of human milk fortification and developmental outcome in preterm infants. Am J Clin Nutr. 1996;64:142–51.
17. Koo WW, Hockman EM. Posthospital discharge feeding for preterm infants: effects of standard compared with enriched milk formula on growth, bone mass, and body composition. Am J Clin Nutr. 2006;84:1357–64.
18. Jarvenpaa AL, Raiha NC, Rassin DK, Gaull GE. Feeding the low-birth-weight infant: I. Taurine and cholesterol supplementation of formula does not affect growth and metabolism. Pediatrics. 1983;71:171–8.
19. Sturman JA, Wen GY, Wisniewski HM, Neuringer MD. Retinal degeneration in primates raised on a synthetic human infant formula. Int J Dev Neurosci. 1984;2:121–9.
20. Raiten DJ, Talbot JM, Waters JH. LSRO report: assessment of nutrient requirements for infant formulas. J Nutr. 1998;128:2059S–2294S.
21. Rebouche CJ. Carnitine function and requirements during the life cycle. FASEB J. 1992;6:3379–86.[Abstract]
22. Pickering LK, Granoff DM, Erickson JR, Masor ML, Cordle CT, Schaller JP, Winship TR, Paule CL, Hilty MD. Modulation of the immune system by human milk and infant formula containing nucleotides. Pediatrics. 1998;101:242–9.
23. Heird WC, Lapillonne A. The role of essential fatty acids in development. Annu Rev Nutr. 2005;25:549–71.[Medline]
24. Simmer K. Longchain polyunsaturated fatty acid supplementation in infants born at term. Cochrane Database Syst Rev. 2001;(4)CD000376.
25. Simmer K, Patole S. Longchain polyunsaturated fatty acid supplementation in preterm infants. Cochrane Database Syst Rev. 2004;(1)CD000375.
26. Hernell O, Lonnerdal B. Nutritional evaluation of protein hydrolysate formulas in healthy term infants: plasma amino acids, hematology, and trace elements. Am J Clin Nutr. 2003;78:296–301.
27. Marini A, Agosti M, Motta G, Mosca F. Effects of a dietary and environmental prevention programme on the incidence of allergic symptoms in high atopic risk infants: three years' follow-up. Acta Paediatr Suppl. 1996;414:1–21.[Medline]
28. Conneely OM, Ward PP, Zhou X, Wagner S. The role of lactoferrin in the gastrointestinal tract. In: Bindels JG, Goedhart AC, Visser HKA, editors. Recent developments in infant nutrition. Boston, MA: Kluwer Academic Publishers; 1996. p. 377–86.
29. Heine WE, Klein PD, Reeds PJ. The importance of alpha-lactalbumin in infant nutrition. J Nutr. 1991;121:277–83.
30. Klein CJ. Nutrient requirements for preterm infant formulas. J Nutr. 2002;132:1395S–577S.
31. Boehm G, Jelinek J, Stahl B, van Laere K, Knol J, Fanaro S, Moro G, Vigi V. Prebiotics in infant formulas. J Clin Gastroenterol. 2004;38:S76–9.[Medline]
32. Vanderhoof JA. Probiotics: future directions. Am J Clin Nutr. 2001;73:1152S–5S.
33. Carnielli VP, Luijendijk IH, Van Goudoever JB, Sulkers EJ, Boerlage AA, Degenhart HJ, Sauer PJ. Structural position and amount of palmitic acid in infant formulas: effects on fat, fatty acid, and mineral balance. J Pediatr Gastroenterol Nutr. 1996;23:553–60.[Medline]
34. Barker DJP, Osmond C, Winter PD, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet. 1989;2:577–80.[Medline]
35. Eriksson JG, Forsen T, Tuomilehto J, Osmond C, Barker DJ. Early growth and coronary heart disease in later life: longitudinal study. BMJ. 2001;322:949–53.
36. Stettler N, Zemel BS, Kumanyika S, Stallings VA. Infant weight gain and childhood overweight status in a multicenter, cohort study. Pediatrics. 2002;109:194–9.
37. Toschke AM, Grote V, Koletzko BvonKR. Identifying children at high risk for overweight at school entry by weight gain during the first 2 years. Arch Pediatr Adolesc Med. 2004;158:449–52.
38. Agostoni C, Domellof M. Infant formulae: from ESPGAN recommendations towards ESPGHAN-coordinated global standards. J Pediatr Gastroenterol Nutr. 2005;41:580–3.[Medline]
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