Alpha-linolenic Acid in Infant Formulas: Is There an Optimum Level

The specific formulation of some infant formulas may not meet the new level of ALA recommended by the Scientific Committee on Food (SCF) on the Revision of Essential Requirements of Infant Formulae and Follow-on Formulae (1) for formulas without 0.2% of fatty acids as DHA. 

Several infant formulas available elsewhere have the higher recommended content of a-linolenic acid, or more, and they are tolerated quite well by the recipient infants. If manufacturers currently produce a formula with less than the newly recommended minimum ALA content, their fat blends should  be re-formulated. Primarily, this means they will have to add either soy or canola oil, the only oils with an appreciable content of ALA, both of which are acceptable for use in the European Union (EU.) Further, both are well tolerated and well absorbed, so this is not likely to be an insurmountable problem. The SCF should issue clear statements about the type of clinical testing envisioned if the fat blend is changed and whether such a change constitutes a change in the matrix of the formula, which may necessitate more extensive clinical testing of a formula with the new fat blend. 

The SCF refers to a paper from Lauritzen et al (2) in suggesting the new indications. In this paper, the Authors refer to four reports, three on term babies (3-5) and one on preterms (6), of clinical trials with varying amounts of ALA. None of the mentioned trials showed any relevant improvement in visual acuity for the groups fed the higher a-linolenic acid amounts. In the preterm study, three groups were included. The group that received the formula with the higher ALA content had intermediate omega-3 levels in erythrocyte membranes but significantly poorer visually evoked potential (VEP) acuity at 57 weeks compared with the group with the higher ALA plus fish oil content. Only the higher ALA/fish oil group had visual acuities comparable to the "gold standards" of very low birth weight (VLBW) infants fed human milk.

There are many reasons to include a reasonable amount of a-linolenic acid in infant formulas aside from any expected effect on visual acuity (7, 8). Further, based on Lauritzen et al. review, the evidence warranting the conclusion that there is no specific amount of ALA, or a ratio of linolenic acid (LA) to ALA that will support better visual acuity in recipient infants is insufficient. A recent paper by Blank et al. (9) suggests that this may not be true. In this study, and a few others, a LA/ALA ratio less than 3 or 4 actually decreases rather than increases plasma and tissue levels of docosahexaenoic acid (DHA.) A review of all studies on the effect of long chain polyunsaturated fatty acid (LC-PUFA) intake on visual function of term infants reveals that many of the studies showing no advantage of breastfeeding or supplemented formula on visual acuity utilized a control formula containing 1.5-2.0% of total fatty acids as ALA whereas those studies that showed an advantage of breastfeeding for LC-PFUA supplementation utilized a control formula with a lower ALA content (2). There are exceptions to this general pattern but, as pointed out by Lauritzen et al., this interpretation cannot be completely refuted (or entirely supported) by the available data. 

It should also be emphasized that all of the studies cited were small and had insufficient data to reach a definitive conclusion. In the Jensen et al. study (4), for example, the group that was fed the formula with the highest ALA content had a shorter VEP latency than the group fed the lowest ALA content, and the difference in latency between these two groups was of sufficient magnitude to be biologically significant. However, the study lacked sufficient size to detect this difference at a statistically significant level. Further, this was the only study that included more than two ALA intakes at the same LA intake. Some of the other studies cited suffer from having different LA contents and/or similar LA:ALA ratios despite different ALA contents.

The issue of whether ALA can substitute for DHA is a complex one and one for which definitive data are lacking. At any rate, the recommendation of the SCF concerning the minimum content of ALA in infant formulas is supported by the limited amount of data available from studies on infants. The Life Sciences Research Office's (LSRO) minimum recommendation (10) is somewhat lower but this choice was based largely on data from animal studies (See Table below for comparisons). Either is reasonable and preferable to the current minimal recommendation for ALA content of infant formulas, not necessarily to improve visual acuity but rather to assure more balanced metabolism of LA and ALA.

There is enough experience with formulas containing ALA within the range recommended that clinical evaluation, at least in terms of full-scale growth studies, probably is not necessary. On the other hand, formula with a high content of ALA (3-4% of total fatty acids) should not be marketed without clinical evaluation as there is some evidence that it may inhibit growth. For example, Jensen et al. (4), observed a statistically significant (760 g) difference in weight at 4 months of age between groups that received a formula with 3.2% vs. 0.4% of fatty acids as ALA. There was no statistically significant differences in weight at any age between groups that received 3.2% vs. ~1% or ~ 2% as observed also by Makrides et al (5).

Conclusions and suggestions

Based the above points, we can identify the following grey areas for discussion:

1. What type of clinical testing is envisioned for a formula that, as currently marketed, has less than the minimal recommended ALA content but is reformulated to meet the new recommendation (for example, the substitution of canola or soy oil for, say, corn oil)?
   
2. The better visual performance of the breastfed vs. those who had been formula-fed has been explained by the lower ALA content (0.5% energy, 1% fatty acids) of the conventional formulas used, but this explanation ignores the other qualities of breast milk. There have not been “functional” advantages for infants receiving  formulas providing 1% of energy as ALA vs those receiving 0.5% energy as ALA, but just biochemical effects in raising the amount of DHA incorporated. Until such functional evidence is available, it seems reasonable to allow the current minimum 50mg/100kcal. The LSRO lower limit of 77mg/100kcal should also be considered.
   
3. From 6 months of age on, a formula will not be the only source of  the parent essential fatty acids (linoleic and linolenic). It is unnecessary, therefore, to apply the same stringent guidelines for a follow on formula as for an infant formula that may be the only source of these fatty acids in the diet of a young infant. However, a minimum of 50 mg/100 kcal should be included to provide for the potential risk that, in case of restricted diets, no sources of n-3 are provided.

1. Report of the Scientific Committee on Food on the Revision of Essential Requirements of Infant Formulae and Follow-on Formulae. SCF/CS/NUT/IF/65 Final 18 May 2003.
2. Lauritzen L, Hansen HS, Jorgensen MH, et al. The essentiality of long chain n-3 fatty acids in relation to development and function of the brain and retina. Prog Lipid Res 2001; 40:1-94.
3. Innis SM, Akrabawi SS, Diersen-Schade DA et al. Visual acuity and blood lipids in term infants fed human milk or formulae. Lipids 1997;32:63-72.
4. Jensen CL, Prager TC,Fraley JK, et al. Effect of dietary linoleic/alpha-linolenic acid ratio on growth and visual function of term infants. J Pediatr 1997;131:200-9.
5. Makrides M, Neumann MA, Jeffrey B, et al. A randomized trial of different ratios of linoleic to alpha-linolenic acid in the diet of term infants: effects on visual function and growth. Am J Clin Nutr 2000;71:120-9.
6. Birch EE, Birch DG, Hoffman DR, et al. Dietary essential fatty acid supply and visual acuity development. Invest Ophthalmol Vis Sci 1992; 33:3242-53.
7. Innis S. Fat. In Tsang RC, Lucas A, Uauy R, Zlotkin S, eds. Nutritional needs of the preterm  infants,William and Wilkins, 1993: 65-86.
8. Koletzko B, Agostoni C, Carlson SE, et al. Long-chain polyunsaturated fatty acids (LCPUFA) and perinatal development. Acta Paediatr 2001; 90:460-4.
9. Blank C, Neumann MA, Makrides M, Gibson RA. Optimizing DHA levels in piglets by lowering the linoleic acid to alpha-linolenic acid ratio. J Lipid Res 2002;43:1537-43.
10. LSRO (Life Sciences Research Office) (1998). LSRO Report: Assessment of Nutrient Requirements for Infant formulas. Center for Food Safety and Applied Nutrition Food and Drug Administration Department of Health and Human Services, Washington.

This material has been prepared by a member of the IFM's Advisory Committee on Child Health and Nutrition, December 2004.