ISSFAL Statement on Dietary Fats in Infant Nutrition (May 2008)

Panel members: Prof Robert Gibson; (Chair, to whom correspondence should be addressed, via the Society);  Assoc Prof Maria Makrides; Prof Berthold Koletzko; Prof Tom Brenna; Prof Margaret Craig-Schmidt.

Scope

Because infant formulas must supply the entire nutritional needs of growing infants, recommendations about dietary fats need to be made with extreme care and in light of the potential interactions between all macro and micro nutrients. The scope of the ISSFAL statement on the fats in infant formulas is limited to making comment on priority research areas in light of current recommendations and standards set by regulatory authorities.

General

Fat is an important energy source in infancy to support somatic growth and development.  There is consistency across scientific bodies and agencies regarding the total fat content of infant formulas with a range of 4.4–6.0 g/100 kcal that is equivalent to about 40–54% of energy content.  These values are consistent with those found in human milk, which is often used as a gold standard for infant feeds.

Saturates and monounsaturates.

There are no guidelines for the level of these two classes of fats in infant formulas. It is noted that the level of saturates in human milk is around 40-50% of total fatty acids and that monounsaturated fats are present at about 35-40% of total fatty acids.

 It should also be noted that fatty acids such as lauric acid (C12) varies from about 4.5-6% total fats while myristic acid varies from 3.5% to 6%. In countries where intake of energy is low and carbohydrate intake is high the level of myristic is up to 14% total fatty acids. Most agencies restrict the combined level of lauric and myristic to less than 20% of total fat because of their hypercholesterolemic effect (Table). In contrast, palmitic acid which is also cholesterol raising is a major constituent of human breast milk and its level is  not regulated in infant formulas. There is a need for further research in this area.

Trans fats

Trans fats are present in human breast milk in low levels (usually up to about 2-3% total fats) and this is generally the maximum level accepted in infant formulas. It should be noted that dairy fats that have been used in infant formulas contain a natural level of trans fats as a result of hydrogenation reactions carried out by ruminants.  It is noted that there is now debate about the comparable risk of trans fats from natural sources (dairy) compared with those from industrial sources (Chardigny et al, 2008). As many children graduate from breast milk and infant formulas to cow’s milk containing trans fats, the effect of this change of diet deserves further research.

Polyunsaturated fatty acids (PUFA): 18 carbon fatty acids

Linoleic acid (LA)

The level of LA in breast milk is dependent on dietary intake and varies with dietary habits and geographic region. For example it ranges from around 10-12% in Australia, Canada, Europe and the USA and can be as low as 8% in the Philippines and as high as 18% in Chile (Yuhas et al, 2006).

 The level accepted in formulas ranges  from around 6% to as much as  25 - 30% of total fatty acids. In general the minimum level of LA accepted is around 3% of total energy (Table).

 It has long been recognised that dietary LA has a suppressive effect on the incorporation of n-3 LCPUFA, and it might have effects on immunological and other endpoints. In this regard, research on high levels of LA in formulas is warranted.

 Alpha linolenic acid (ALA)

The level of ALA in human milk is very low – usually less than 0.2% of total fat. The need to provide an adequate source of n-3 fatty acids has prompted many agencies to legislate minimum levels of ALA in formulas. For example the level of ALA recommended in the EU is around 1% and in Australia the minimum level of ALA is also around 1% total fatty acids and the maximum level is 4 % total fats (Table).

 LA:ALA ratio

Since LA and ALA compete for the same desaturase and elongase enzymes involved in the synthesis of long chain PUFA (LCPUFA), regulatory authorities have made guidelines for the LA:ALA ratio in infant formulas – generally in the range 5-15:1 (Table). The balance may be most important when LCPUFA are not present in infant formulas. Studies have tested ratios ranging from 4:1 to 20:1 and in general there is modest improvement in some n-3 LCPUFA levels when the ratios are low. It should be noted that when the LA:ALA ratio is low and the total level of PUFA in formula fat  is also low, infant tissue levels of the n-3 LCPUFA, docosahexaenoic acid (DHA), are higher than when milks high in PUFA are consumed (Courage et al, 1998; Sanders & Naismith, 1979). There is scope for further research on this important topic.

 LCPUFA: PUFA with 20 and 22 carbons

Although LCPUFA are often discussed collectively in terms of infant health most discussion revolves around the requirement of the n-3 LCPUFA DHA and the n-6 compound arachidonic acid (AA). These two LCPUFA are major constituents of neuronal lipids and many other cell membranes and both are found in modest amounts in human milk (generally <1% total fatty acids) (Yuhas et al, 2006; Brenna et al, 2007).

 LCPUFA for preterm infants

The most extensive investigations regarding the role of LCPUFA supplementation of infant formula have revolved around the effect of n-3 LCPUFA (with or without AA) on the development of visual acuity (SanGiovanni et al, 2000; Gibson et al, 2001).  This work has generally shown that supplementation is associated with improved acuity in preterm infants who are denied the full in utero supply of LCPUFA. Studies assessing more global indices of development have demonstrated benefits when assessed using Bayley II (Smithers et al, 2008) but there are few data relating to other global developmental assessments.  Clearly more work is required to determine the effect of LCPUFA supplementation in preterm infants on specific developmental domains beyond vision, to determine the optimal dose of supplementation and whether there are specific sub-groups of preterm infants who benefit more than others. This is an important clinical issue as the preterm infant population is very heterogeneous covering infants with gestational ages from 24 to 36 weeks with very different clinical managements and often given mixed feeds of breast milk and formula.

 Growth outcomes in relation to LCPUFA supplementation have also been investigated and although some trials suggest no differences in growth parameters with supplementation others suggest negative or positive effects. As many preterm infants suffer from significant growth failure in early postnatal life, understanding the magnitude of any growth effect of LCPUFA, and of potential effects on body composition, is important. 

 LCPUFA may also modulate the immune and vascular systems and there have been very few investigations in these areas. Of importance is the recent systematic review and meta-analysis which aggregated the clinical outcomes of preterm infants with vascular and/or infective components (Smithers et al, 2008).  This review demonstrated no negative effects of infant formula supplementation on intra-ventricular haemorrhage, necrotising enterocolitis, sepsis and retinopathy of prematurity.

 Given the separate effects of n-6 and n-3 LCPUFA on immune function there is a need for further research to investigate the effects of altered n-6:n-3 balance on clinical outcomes with inflammatory components.

 LCPUFA for term infants

There have been many trials designed to evaluate the benefit of LCPUFA in term infants, some with n-3 LCPUFA alone and some with both n-6 and n-3 LCPUFA and this topic has been recently reviewed (Makrides et al, 2005; Simmer et al 2008). Although there have been some reports of benefits of n-3 LCPUFA (with and without AA) on visual development there have been few reports of benefits on more global measures of development using accepted validated tests. Further work in this important area is warranted.

 The effect of n-3 and n-6 LCPUFA on growth has been reviewed, and no clinically meaningful effects, either positive or negative, were determined (Makrides et al, 2005) but interventions were heterogeneous and potential effects of certain modes of supplementation cannot be excluded with certainty. There is a need to evaluate the effect of dietary LCPUFA on the quality of growth through sound body composition studies.

 A major clinical concern in term infants is the increasing incidence of allergy world wide. Given the suggested benefits of dietary n-3 LCPUFA in modulating the immune response in early life there is great interest in assessing the benefits of n-3 LCPUFA supplementation in reducing the incidence of childhood allergies. Particular attention needs to be paid to the relative effects of n-3 and n-6 LCPUFA since high n-6 fatty acid intakes have been associated with the manifestation of allergies in some studies. An area that requires research focus is in regard to partially hydrolysed formulas that are targeted to infants with high risk of allergy.

 Ratio of AA to DHA In summary, most regulatory authorities now permit the optional addition of n-3 LCPUFA and n-6 LCPUFA to infant formulas. In general maximal limits have been set so that the level of n-3 LCPUFA does not exceed the level of AA. There is great debate about the role of AA in infant diets and although there is no direct evidence for specific effects of dietary AA on measurable clinical endpoints it has nevertheless been included in most formulas primarily on the basis of the presence of AA in breast milk and its physiological roles in nervous and other tissues in animal models. There is a clear need to examine the specific role of AA and of the relation between AA and DHA in infant formulas in a systematic manner. A major priority is to better understand the balance of n-6 to n-3 LCPUFA on growth and development with particular emphasis on inflammatory conditions including allergies and vascular health.  Finally, as infant formulas become more complex there is also a need to understand the potential interactions between LCPUFA and other components and novel additives.

 Relevant publications

Brenna JT, Varamini B, Jensen RG, Diersen-Schade DA, Boettcher JA, Arterburn LM.  Docosahexaenoic and arachidonic acid concentrations in human breast milk worldwide. Am J Clin Nutr. 2007 Jun;85(6):1457-64.

Codex Alimentarius Commission. Standard for infant formul and formulas for special medical purposes intended for infants. CODEX STAN 72-1981, revision 2007

Chardigny JM, Destaillats F, Malpuech-Brugère C, Moulin J, Bauman DE, Lock AL, Barbano DM, Mensink RP, Bezelgues JB, Chaumont P, Combe N, Cristiani I, Joffre F, German JB, Dionisi F, Boirie Y, Sébédio JL.  Do trans fatty acids from industrially produced sources and from natural sources have the same effect on cardiovascular disease risk factors in healthy subjects?  Results of the trans Fatty Acids Collaboration (TRANSFACT) study. Am J Clin Nutr. 2008 Mar;87(3):558-66.

Courage ML, McCloy UR, Herzberg GR, Andrews WL, Simmons BS, McDonald AC, Mercer CN, Friel JK.  Visual acuity development and fatty acid composition of erythrocytes in full-term infants fed breast milk, commercial formula, or evaporated milk. J Dev Behav Pediatr. 1998;19:9-17.

Gibson RA, Chen W, Makrides M. Randomized trials with polyunsaturated fatty acid interventions in preterm and term infants: functional and clinical outcomes. Lipids. 2001 Sep;36(9):873-83.

Life Sciences Research Office (LSRO), American Societies for Nutritional Sciences. Assessment of Nutrient Requirements for Infant formulas. J Nutr 1988;128, Suppl: 2059S-2298S.Koletzko B, C Agostini, SE Carlson, T Clandinin, G Hornstra, M Neuringer, R Uauy, Y Yamashiro, P Willatts: Long chain polyunsaturated fatty acids (LC-PUFA) and perinatal development. Acta Paediatr 90 (2001) 460

Koletzko B, S Baker,  G Cleghorn, UF Neto, S Gopalan, O Hernell, QS Hock, P Jirapinyo, B Lonnerdal, P Pencharz, H Pzyrembel, J Ramirez-Mayans, R Shamir, D Turck, Y Yamashiro, D Zong-Yi: Global standard for the composition of infant formula: recommendations of an ESPGHAN coordinated international expert group. J Pediatr Gastroenterol Nutr 41 (2005) 584

Koletzko B, Lien E, Agostoni C, Böhles H, Campoy C, Cetin I, Decsi T, Dudenhausen JW, Dupont C, Forsyth S, Hoesli I, Holzgreve W, Lapillonne A, Putet G, Secher NJ, Symonds M, Szajewska H, Willatts P, Uauy R. The roles of long-chain polyunsaturated fatty acids in pregnancy, lactation and infancy: review of current knowledge and consensus recommendations. J Perinat Med. 2008;36(1):5-14.

Makrides M, Gibson RA, Udell T, Ried K and the International LCPUFA Investigators.  Supplementation of infant formula with LCPUFA does not influence the growth of term infants.  Am J Clin Nutr 2005;81:1094-1101.  IF = 6.562 [11]

Sanders TA, Naismith DJ.  A comparison of the influence of breast-feeding and bottle-feeding on the fatty acid composition of the erythrocytes. Br J Nutr. 1979 May;41(3):619-23.

SanGiovanni JP, Parra-Cabrera S, Colditz GA, Berkey CS, Dwyer JT.  Meta-analysis of dietary essential fatty acids and long-chain polyunsaturated fatty acids as they relate to visual resolutionacuity in healthy preterm infants. Pediatrics. 2000 Jun;105(6):1292-8.

Scientific Committee on Food. Report of the Scientific Committee on Food on the Revision of Essential Requirements of Infant Formulae and Follow-on Formulae. Brussels, European Commission 2003. SCF/CS/NUT/IF/65 Final. 2003.

Simmer K, Patole S, Rao S. Longchain polyunsaturated fatty acid supplementation in infants born at term. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD000376.

Smithers LG, Gibson RA, McPhee AJ, Makrides M. Effect of LCPUFA supplementation of preterm infants on disease risk and neurodevelopment: a systematic review of randomised controlled trials.  Am J Clin Nutr (in press).

The Commission of the European Communities. Commission Directive 2006/141/EC of 22 December 2006 on infant formulae and amending Directive 1999/21/EC.  Official Journal of the European Union 30.12.2006:L401/1401/33.

Yuhas R, Pramuk K, Lien EL.  Human milk fatty acid composition from nine countries varies most in DHA. Lipids. 2006 Sep;41(9):851-8.