<p> Possible Adverse Effects of Added Long-chain Polyunsaturated Fatty Acids in Infant Formula Marsha Walker, RN, IBCLC</p><p>Fish Oil  n-3 LCPUFA but  n-6 LCPUFA  some fish oil contains up to 1.5-fold as much EPA as DHA   EPA has been associated with adverse effects on growth (Carlson 1992, Carlson 1993)  can be contaminated with heavy metals</p><p>Egg-yolk lipid, egg-yolk triglyceride or phospholipid  egg-yolk lipid contains excessive amounts of cholesterol  egg-yolk triglyceride and phospholipid contain ARA and DHA but not in the same proportions as human milk; the proportions are changed by altering the diet of the hens  could contain allergens  differences in intestinal digestion, absorption, and metabolism between phospholipid versus triglyceride sources  contain other unusual fatty acids in addition to DHA and ARA o these, in turn, could contain toxins, pigments, or contaminants</p><p>Algae, soil fungus, and other single-cell organisms  fermented microalgae and soil fungus could contain contaminants from the fermentation and oil extraction process, such as hexane residue  positional distributions of LCPUFA are different from those of human milk triglycerides o ARA and DHA in human milk are present in the sn-1 and sn-2 positions, but are present in all three positions in the single cell oils (Myher 1996) o Human milk triglycerides usually contain no more than one molecule of DHA or ARA, while some single-cell triglycerides contain two or even three o DHA and ARA added to infant formula may act differently in the body than human DHA/ARA, depending on where and in what proportion they are found on the triglyceride  Animal tests showed signs of toxicity that included oily, soft stool (steatorrhea); fat loss through the stool; higher liver weights; elevated mean serum alkaline phosphatase levels  Fungal sources of ARA pose the risk of mycotoxins that could act as an opportunistic pathogen in an immunocompromised host  Fungal and microalgal oil supplements have been shown to cause a dose dependent increase in excess gas and belching in adults (Innis 1996)  The National Alliance for Breastfeeding Advocacy has received numerous complaints of babies experiencing watery explosive diarrhea, diaper rash, excessive foul smelling gas, and abdominal cramping from ingesting infant formula with the highest levels of LCPUFA supplementation. Also reported was obesity in 6 month old babies who initially breastfed but had DHA/ARA supplemented formula added to their diet as a supplement, followed by infant cereal at 4 months of age General Concerns (Heird 1999)</p><p> o Supplementation with highly unsaturated oils increases the susceptibility of membranes to oxidant damage and disrupts the antioxidant system. Damage from oxygen radicals can provoke diseases thought to be related to oxidant damage such as, necrotizing enterocolitis (NEC), bronchopulmonary dysplasia, and retrolental fibroplasia (Song 2000, Song 2001); LCPUFA administration has effects on retinol and alpha-tocopherol metabolism (Decsi 1995) o More PUFAs in muscle cell membranes has been related to increased insulin sensitivity (Pan 1994) o There is a possible effect on gene transcription (Clarke 1996) o Large fat supplementation of formula and baby foods has raised the question that this may contribute to the obesity epidemic (Massiera 2003) o Increasing DHA fortification of commercial baby food adds the concerns of excessive intake and/or imbalanced ratios of n-6 and n-3 fatty acids o Many studies have insufficient sample size to determine any functional benefit or safety profile; comparison of research is confounded by the use of differing sources of DHA and ARA, different amounts and ratios, different composition of the base formula, and differing length of time the study formulas were consumed (Koo 2003) o Most studies compare supplemented versus unsupplemented formulas to each other with no control group of exclusively breastfed infants; many have high attrition rates o The accuracy and reliability of tests to determine visual and cognitive effects of LCPUFA during the first two years are controversial o Enrollment criteria for most studies typically excluded sick infants, twins and higher order multiples, and most infants with any type of problem. This may leave doubts about the suitability of fatty acid supplemented formula for these babies, regardless of the source of the LCPUFAs o Meta-analysis of randomized trials suggests that any functional benefit in visual or neurodevelopment from LCPUFA supplementation of infant formula is likely to be of minor clinical significance, at least for the term infant (Koo) o Although there is little evidence that LCPUFA containing infant formula provides clinically significant improved vision and intelligence in health term infants, the 25% increase in cost can be a significant burden to a family’s budget and to public nutrition programs o Human milk also contains LCPUFAs other than DHA and ARA that can be converted to DHA and ARA and effect the conversion of ALA and LA to DHA and ARA. Their presence may partially explain the apparent need for greater amounts of DHA and ARA in formula to result in the same plasma lipid content of these fatty acids observed in human milk-fed babies (Clandinin 1997) o Breast milk contains lipases that enhance fat digestion in breastfed infants; breast milk is a complex matrix, containing numerous bioactive components, hormones, and live cells not found in infant formula; important physiologic considerations relative to the matrix are not accounted for by the simple addition of LCPUFAs to infant formula (Office of Food Additive Safety 2001) References</p><p>Carlson SE, Cooke RJ, Werkman SH, et al. First year growth of preterm infants fed standard compared to marine oil n-3 supplemented formula. Lipids 1992; 27:901-907</p><p>Carlson SE, Werkman SH, Peeples JM, et al. Arachidonic acid status correlates with first year growth in preterm infants. Proc Natl Acad Sci USA 1993; 90:1073-1077</p><p>Clandinin MT, van Aerde JE, Parrot A, et al. Assessment of the efficacious dose of arachidonic and docosahexaenoic acids in preterm infant formulas: fatty acid composition of erythrocyte membrane lipids. Pediatr Res 1997; 42:819-825</p><p>Clarke SD, Jump DB. Polyunsaturated fatty acid regulationof hepatic gene transcription. J Nutr 1996; 126(Suppl):1105-1109</p><p>Decsi T, Koletzko B. Growth, fatty acid composition of plasma lipid classes, and plasma retinol and alpha-tocopherol concentrations in full-term infants fed formula enriched with n-6 and n-3 long-chain polyunsaturated fatty acids. Acta Paediatr Scand 1995; 84:725-732</p><p>Heird WC. Biological effects and safety issues related to long-chain polyunsaturated fatty acids in infants. Lipids 1999; 34:103-224</p><p>Innis SM, Hansen JW. Plasma fatty acid responses, metabolic effects, and safety of microalgal and fungal oils rich in arachidonic and docosahexaenoic acids in healthy adults. Am J Clin Nutr 1996; 64:159-167</p><p>Koo WWK. Efficacy and safety of docosahexaenoic acid and arachidonic acid addition to infant formulas: can one buy better vision and intelligence? J Am Coll Nutr 2003; 22:101-107</p><p>Massiera F, et al. Arachidonic acid and prostacyclin signaling promote adipose tissue development: a human health concern? J Lipid Research 2003; 44:271-279</p><p>Myher JJ, Kuksis A, Geher K, et al. Stereospecific analysis of triacylglycerols rich in long-chain polyunsaturated fatty acids. Lipids 1996; 31:207-215</p><p>Office of Food Additive Safety: “GRAS Notice No. GRN 000041.” Washington, DC: US Food and Drug Administration, May 17, 2001</p><p>Pan DA, Hylbert AJ, Storlien LH. Dietary fats, membrane phospholipids and obesity. J Nutr 1994; 124:1555-1565</p><p>Song JH, et al. Polyunsaturated (n-3) fatty acids susceptible to peroxidation are increased in plasma and tissue lipids of rats fed docosahexaenoic acid-containing oils. J Nutrition 2000; 130:3028-3033)</p><p>Song JH, Miyazawa T. Enhanced level of n-3 fatty acid in membrane phospholipids induces lipid peroxidation in rats fed dietary docosahexaenoic acid oil. Atherosclerosis 2001 Mar; 155(1):9-18 Marsha Walker 2003</p>