Fatty Acids in Infant Nutrition: Two series of polyunsaturated fatty acids, the n-6 (or omega-6) and the n-3 fatty acids are essential dietary nutrients. There is considerable controversy, however, over how much, and in particular which n-6 and n-3 fatty acids are needed in the diet of young infants. Indeed, the literature contains many studies to suggest that as a group, infants who are breast-fed have a developmental advantage and subsequently a higher intelligence quotient (IQ) than infants who are bottle-fed. This has fostered interest in the possible role of human nutrients in infant development. The presence of high concentrations of the n-6 fatty acid arachidonic acid (AA, 20:4n-6) and of the n-3 fatty acid docosahexaenoic acid (DHA, 22:6n-3) in the brain and retina, and of small amounts of these same fatty acids in human milk has raised questions on the potential need for a source of AA and DHA during development. This paper will review current recommendations, and studies from Canada and other countries on n-6 and n-3 fatty acids in infant nutrition. In discussing studies on diet and neurodevelopment, it is important first to touch on the complexities (and limitations) of studies with young infants. One of the major hurdles for studies on the role of human milk nutrients is that breast feeding and formula feeding mothers are non-randomized. Because of this, a bias in socio-economic class or mother’s education is often an inherent confounding variable which is difficult, if not impossible to control. In addition to AA and DHA, human milk has many other factors, for example, other nutrients, hormones and growth factors, which could also explain any beneficial effects of human milk. Other equally important considerations centre around the physiological and psychological effects of breast-feeding, for example, the effects of maternal-infant interaction, as distinct from the nutritional characteristics of breast-milk. Some of these obstacles can be overcome by comparing infants fed formulae which differ only in the fatty acids in question. In this case, it is vitally important that the composition of formula in other countries is adequate and well-defined. Of note, the composition of formulae in other countries can differ quite widely from those in North America; making international comparisons difficult. It must also be remembered that infant feeding practices have undergone substantial changes in the past several decades. For example, prior to the 1980’s, many infants were fed cow’s milk, either unmodified or with the addition of sugars. These feedings had high protein, exceedingly low levels of linoleic acid (18:2n-6), as well as inappropriate levels of many other nutrients. Information on the development of children fed these formulations cannot be extrapolated to infer problems with today’s infant formulae. Several studies on infant essential fatty acid requirements have been done with premature infants of birthweight less than 1500 grams. Very premature infants are often more vulnerable to nutritional deficiencies, including essential fatty acid deficiency, than healthy term infants. Their needs for higher intakes of protein and minerals than in term infants is also well known. 1Several reasons suggest premature infants may also have higher or different n-6 and n-3 fatty acid needs than term infants. These reasons include the much earlier stage of brain maturation, minimal stores of essential fatty acids in adipose tissue (which represents only 1-2% bodyweight in a 1,000g premature infant but closer to 20% bodyweight in a 3,500g term infant), and possible immaturity of lipid metabolism. Because of this, information on the fatty acid needs of premature infants clearly cannot be extrapolated to the needs of term gestation infants. Dietary Essential Fatty Acids:The dietary essential fatty are linoleic acid (18:2n-6) of the n-6 series and alpha (a) linolenic acid (18:3n-3) of the n-3 series 2. These fatty acids are found predominately in polyunsaturated vegetable oils. Once consumed, linoleic and linolenic acid can be converted to longer chain, more unsaturated fatty acids of the same series; AA from linoleic acid and DHA from a-linolenic acid. Adequate tissue levels of AA and DHA are crucially important to many different functions; for example, AA is a precursor of eicosanoids and DHA is needed for normal visual function. 2AA and DHA acid are formed only in animal cells. Small amounts are present in meat and fish, and in human milk. Vegetarian and vegan diets, however, lack AA and DHA. No adverse effects during pregnancy or lactation, or in the subsequent growth or adult life of vegetarians due to the lack of dietary AA and DHA have been noted. Studies with rodents and monkeys have shown that diets virtually devoid (less than 0.1% dietary energy) of a-linolenic acid result in reduced visual function and altered learning when compared to diets with a-linolenic acid 2. The functional changes are accompanied by reduced brain and retina DHA. It is important not to confuse these studies identifying some of the roles of DHA in the central nervous system (CNS) with a demonstration of a dietary DHA essentiality (i.e. the diets were deficient in a-linolenic acid). Indeed, in these and other studies, intakes of about 0.7% energy from a-linolenic acid result in high levels of DHA in the developing CNS. 2 Recent studies have shown newborn infants can convert linoleic acid to AA and a-linolenic acid to DHA. However, the information is not quantitative so it is possible AA and DHA synthesis in the human, unlike other species, is too slow to meet tissue needs. This has been addressed recently through studies on CNS development and growth of breast-fed and formula-fed infants. Human milk and Infant Formulae:In the ideal situation, the lipid composition of infant formula should match human milk. Human milk, however is exceedingly sophisticated with a complex milk fat globule structure, specifically arranged fatty acid patterns and lipase enzymes, and well over 150 identified fatty acids. The fatty acids usually contain 8 to 30% linoleic acid and 0.5-2.0% a-linolenic acid, with about 0.5-0.8% AA and 0.1 - 0.4% DHA 3. The variability in fatty acids is largely explained by variations in the fat composition of the mother’s diet. Linoleic acid is increased by diets high in polyunsaturated fats rather than saturated or monounsaturated fats. Levels of DHA also vary widely, from about 1.4% fatty acids in the breast-milk of vegetarians. This dependence of milk fatty acids on maternal diet makes it very difficult to use human milk as a guide for determining fatty acid requirements of young infants, or as a model on which to base infant formulae compositions (i.e. which milk should be used). Infant formula fats are generally a blend of different saturated and unsaturated oils, providing about 10-20 different fatty acids, held in suspension by plant lecithins. The selection of oils has traditionally been based on providing fats which are well absorbed, contain adequate essential fatty acids and are free of any potential harmful agent. Theoretically, many different fatty acid combinations are possible. Infant formulae in Canada and the United States contain linoleic acid and a-linolenic acid, but not AA or DHA. The Nutritional Recommendations from Health and Welfare Canada (1990) recommend n-6 fatty acids should be at least 3% dietary energy and n-3 fatty acids should be at least 0.5% dietary energy. For infants who are not breast-fed, it is recommended that a-linolenic acid should be at least 1% dietary energy if no other n-3 fatty acids are in the diet. Infant formulae available in Canada meet these recommendations. Some formulae in other countries however, have lower levels of a-linolenic acid than required in Canada. This must be considered when examining results of studies on the growth and neurodevelopment of infants outside North America. Several potential sources of AA and DHA are available to infant formula manufacturers. These include fish and other marine oils, egg lipids, and oils derived from micro-algal and fungal sources (single cell triglycerides). These oils provide AA or DHA, all the other fatty acids, and any unusual triglyceride configurations in the oil in question. Unfortunately, matching the levels of particular fatty acids in human milk does not give assurance that individual fatty acids are absorbed or assimilated from formula in the same way as for human milk. For example, DHA from fish oil seems to be preferentially transported in lymph triglycerides, rather than in lymph phospholipids as when fed as human milk DHA. Term Gestation Infants:Information from several studies with breast-fed and formula-fed infants in Canada and the United States became available last year. A prospective study at the University of British Columbia found no differences in visual, mental or motor-skill development from birth to 18 months of age between breast-fed infants and infants fed formula with about 8% energy (18% fatty acids) linoleic acid and 1% energy (2% fatty acids) a-linolenic acid and no AA or DHA. 4Similarly, a large study of over 430 term infants in Vancouver found no differences in growth, visual function or developmental tests at 9 months of age which could be related to duration of breast or bottle feeding 5. As expected, other well documented factors, such as the parent’s level of education, were related to the infant’s test scores. Similar data have come from a multi centre study with 197 infants in the United States. In these studies, no differences in visual acuity, measured with acuity cards and visual evoked potential (VEP), or in a variety of mental and motor developmental test were found between breast-fed infants and infants fed formula with 10% energy linoleic acid and 1% energy a-linolenic and no AA or DHA. 6Infants fed a formula with 0.2% DHA from fish oil, however, had significantly lower scores on vocabulary production at 14 months of age than the breast-fed infants. 7 In contrast to these studies, lower indicies of neurodevelopment, which appear to be responsive to DHA, have been found in other studies with formula-fed infants. Full-term infants in Australia who were fed a placebo formula with 0.77% energy (1.6% fatty acids) a-linolenic acid, but not infants fed an experimental formula with eicosapentaenoic acid (20:5n-3) and DHA from fish oil and dihommo g-linolenic acid (18:3n-6) from evening primrose oil, had lower VEP acuities at 16 and 30 weeks of age than breast-fed infants. 8A study in Milan found scores on a psychomotor development test were lower in 4 month old infants fed formula with about 0.33% energy (0.7% fatty acids) a-linolenic acid than in breast-fed infants, or infants fed formula with about 0.14% energy dihommo g-linolenic acid, 0.21% energy AA and 0.14% energy DHA. 9The formulae in these studies in Australia and Spain had less than the 1% dietary energy from a-linolenic acid recommended in Canada. It is not yet clear if the low amount of a-linolenic acid in the formulae explain the visual or developmental problems found in the infants. Premature Infants:Studies from the University of Tennessee have reported higher visual acuity at 2 and 4 months of age in premature infants fed formula with DHA than in infants fed formula without DHA. 10The differences in visual acuity between the groups disappeared at later ages. It is not known if short term, apparently transient differences in visual acuity have any later effect on the ability to see. In the same study, infants fed the formula with DHA had slower growth (linear, head circumference and weight), lower scores on the Bayley psychomotor developmental index and in a novelty preference test than infants fed a formula without DHA. 11, 12In a second study from the same group, scores on the Bayley mental developmental index (MDI) were higher, but the percent novelty preference was again lower for infants fed a formula with, rather than without DHA. 13Low novelty preference scores are usually considered a risk for poorer later neurodevelopmental outcome. These studies clearly show that whereas maturation of visual acuity may be increased, dietary supplementation with DHA can also have significant adverse effects on the development of premature infants. Recommendations:Recommendations on infant fatty acid requirements differ for different countries and expert groups. These differences are probably best explained by different principles used to set recommendations, and the limited data on the fatty acid requirements. Breast-fed infants receive AA and DHA in milk, and the foetus probably receives AA and DHA by placental transfer. It is reasonable to then recommend a dietary source of AA and DHA for infants who are fed artificially. This has been done by the Committee on Nutrition of the European Society of Paediatric Gastroenterology and Nutrition (ESPGAN) and The British Nutrition foundation. Such recommendations, however, may be viewed as endorsement for addition of AA and/ or DHA to infant formula. Premature infant formulae with fish oils, blackcurrant seed oil, egg lipid, evening primrose oil, or single cell oils, and term infant formulae with fish oils, blackcurrant seed oil, evening primrose oil, and egg lipid are available in countries other than Canada and the United States. Information on the growth and neurodevelopment of infants fed these formulae have not been published. On the other hand, studies in Canada and the United States have not shown problems with growth and development among healthy infants fed formulae with at least 5% energy linolenic acid and 1% energy a-linolenic acid, but growth and developmental problems have been found with modified formulae containing DHA. Recommendations to include AA and DHA in infant formulae were not made in the recently released Nutrient Needs of Premature Infants from the Nutrition Committee of the Canadian Pediatric Society because of risks of adverse effects of untested oil sources of these fatty acids. 14However, support of breast-feeding, or for premature infants, feeding with expressed mother’s milk, can be unequivocally supported as the best way to ensure the lipid requirements of young infants are met. References 1. Tsang, RC, Lucas A, Uauy R, Zlotkin SH, (Eds.) Nutritional needs of the preterm infant: Scientific basis and practical guidelines. Caudicus Medical Pub. 1993, 65-86. 2. Innis, S.M. Essential fatty acids in growth and development. Prog Lipid Res 1991; 30:39-103. 3. Innis, S.M. Human Milk and formula fatty acids. J.Pediatrics 1992; 120:S56-61. 4. Nelson, C.M., Innis, S.M., Waslen P., Whitfield, M. Prospective measures of visual and cognitive development in term gestation breast-fed and formula-fed infants to 18 months of age. Pediatr Res 1995; 37:1873A. 5. Innis, S.M. Nelson, C.M., Rioux, F.M., Waslen,P.,Lwanga,D. Visual acuity, cognitive development and nutrition in term infants. Pediatr Res 1995;37:1844A. 6. Auestad, N., Montalto, M.B., Wheeler, R.E., Fitzgerald, K.R., Hall, R.T., Neuringer, M., Connor, W.E., Hartmann, E.E., Taylor, J.A. Visual acuity, RBC fatty acids and growth in term infants fed formulas with and without long chain polyunsaturated fatty acids (LCP). Pediatric res 1995; 37:1794A. 7. Janowsky, J.S., Scott, D.T., Wheeler, R.E., Auestad, N. Fatty acids affect early language development. Pediatr Res 1995; 37:1847A. 8. Makrides, M., Neumann, M., Simmer, K., Pater, J., Gibson, R. Are long-chain polyunsaturated fatty acids essential nutrients in infancy? Lancet 1995; 345: 1463-68. 9. Agostoni, C., Trojan, S., Bellu, R., Riva, E., Giovannini, M. Neurodevelopmental quotient of healthy term infants at 4 months and feeding practice: the role of long chain polyunsaturated fatty acids. Pediatr Res 1995; 38:262-266. 10 Carlson, S.E., Werkman, S.H. Rhodes, P.G., Tolley, E.A. Visual acuity development in healthy preterm infants: effect of marine-oil supplementation. Am J Clin Nutr 1993; 58:35-42. 11. Carlson, S.E., Cooke, R.J., Werkman, S.H., Tolley, E.A. First year growth of preterm infants fed standard compared to marine oil n-3 supplemented formula. Lipids 1992; 27:901-7. 12 Carlson, S.E., Werkman, S.H. Peeples, J.M., Cooke, R.J., Tolley, E.A., Wilson, W.M. Growth and development of very low-birthweight infants in relation to n-3 and n-6 essential fatty acid status. In: Essential fatty acids and eicosanoids. Sinclair, A., Gibson, R. (eds). Am Oil Chem Soc. Champaign, Illinois. 1993; 192-196. 13. Carlson, S.E., werkman, S.H., Peeples, J.M., wilson, W.M. Growth and development of very low-birthweight infants in relation to w-6 and w-3 fatty acid status. In: Fatty acids and lipids: Biological aspects. Galli C, Simopoulos AP, Tremoli E (eds). World Rev Diet., Basel, Karger, 1994; 63-69. 14. Canadian Paediatric society, Nutrition Committee. Nutrient needs and feeding of premature infants. Can Med Assoc J 1995; 152:1765-1785.
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