Abstract
Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is highly concentrated in CNS tissues. Although breast milk contains the fatty acids DHA and arachidonic acid, infant formulas marketed in North America do not contain these nutrients. The potential deleterious effects of rearing infants with formulas devoid of these nutrients was assessed by comparing nursery-reared rhesus macaque infants (Macaca mulatta) fed standard formula with infants fed standard formula supplemented with physiologically relevant concentrations of DHA (1.0%) and arachidonic acid (1.0%). Neurobehavioral assessments were conducted on d 7, 14, 21, and 30 of life using blinded raters. The 30-min assessment consisted of 45 test items measuring orienting, temperament, reflex capabilities, and motor skills. Plasma concentrations of DHA in standard formula-fed infants were significantly lower than those fed supplemented formula or mother-raised (breast-fed) infants; however, infants fed the supplemented formula exhibited higher arachidonic acid levels than either mother-reared infants or infants fed standard formula. Infant monkeys fed the supplemented formula exhibited stronger orienting and motor skills than infants fed the standard formula, with the differences most pronounced during d 7 and 14. This pattern suggests an earlier maturation of specific visual and motor abilities in the supplemented infants. Supplementation did not affect measures of activity or state control, indicating no effect on temperament. These data support the assertion that preformed DHA and arachidonic acid in infant formulas are required for optimal development.
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Abbreviations
- DHA:
-
docosahexaenoic acid
- AA:
-
arachidonic acid
- BHT:
-
butylated hydroxytoluene
- LC-PUFA:
-
long-chain polyunsaturated fatty acid
- NBAS:
-
Neonatal Behavioral Assessment Scale
- NICHD:
-
National Institute of Child Health and Human Development
- NIAAA:
-
National Institute on Alcohol Abuse and Alcoholism
References
Farquharson J, Cockburn F, Patrick WA, Jamieson EC, Logan RW 1992 Infant cerebral cortex phospholipid fatty-acid composition and diet. Lancet 340: 810–813
Farquharson J, Jamieson EC, Abbasi KA, Patrick WJA, Logan RW, Cockburn F 1995 Effect of diet on the fatty acid composition of the major phospholipids of infant cerebral cortex. Arch Dis Child 72: 198–203
Jamieson EC, Farquharson J, Logan RW, Howatson AG, Patrick WJA, Weaver LT, Cockburn F 1999 Infant cerebellar gray and white matter fatty acids in relation to age and diet. Lipids 34: 1065–1071
Makrides M, Neumann MA, Byard RW, Simmer K, Gibson RA 1994 Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infants. Am J Clin Nutr 60: 1889–1894
Salem N Jr, Kim HY, Yergey JA 1986 Docosahexaenoic acid: membrane function and metabolism. In: Simopoulos AP, Kifer RR, Martin R (eds) The Health Effects of Polyunsaturated Fatty Acids in Seafoods. Academic Press, New York, 263–317
Carnielli VP, Wattimena DJL, Luijendijk IHT, Boerlage A, Degenhart HJ, Sauer PJJ 1996 The very low birth weight premature infant is capable of synthesizing arachidonic and docosahexaenoic acids from linoleic and linolenic acids. Pediatr Res 40: 169–174
Salem N Jr, Wegher B, Mena P, Uauy R 1996 Arachidonic and docosahexaenoic acids are biosynthesized from their 18-carbon precursors in human infants. Proc Natl Acad Sci USA 93: 49–54
Sauerwald TU, Hachey DL, Jensen CL, Chen HM, Anderson RE, Heird WC 1996 Effect of dietary alpha-linolenic acid intake on incorporation of docosahexaenoic and arachidonic acids into plasma phospholipids of term infants. Lipids 31( suppl): S131–S135
Su H-M, Bernardo L, Mirmiran M, Ma XH, Corso TN, Nathanielsz PW, Brenna JT 1999 Bioequivalence of dietary α-linolenic and docosahexaenoic acids as sources of docosahexaenoate accretion in brain and associated organs of neonatal baboons. Pediatr Res 45: 87–93
Jensen RG 1996 The lipids in human milk. Prog Lipid Res 35: 53–92
Cunnane SC, Francescutti V, Brenna JT, Crawford MJ 2000 Breast fed infants achieve a higher rate of brain and whole body docosahexaenoate accumulation than formula fed infants not consuming dietary docosahexaenoate. Lipids 35: 105–111
Makrides M, Simmer K, Goggin M, Gibson RA 1993 Erythrocyte docosahexaenoic acid correlates with the visual response of healthy, term infants. Pediatr Res 33: 425–427
Decsi T, Thiel I, Koletzko B 1995 Essential fatty acids in full term infants fed breast milk or formula. Arch Dis Child 72: F23–F28
Birch E, Birch D, Hoffman D, Hale L, Everett M, Uauy R 1993 Breast-feeding and optimal visual development. J Pediatr Opthalmol Strabismus 30: 33–38
Lucas A, Morley R, Cole TJ, Gore SM 1994 A randomised multicentre study of human milk versus formula and later development in preterm infants. Arch Dis Child 70: F141–F146
Johnson DL, Swank PR, Howie VM, Baldwin CD, Owen M 1996 Breast feeding and children's intelligence. Psychol Rep 79: 1179–1185
Horwood LJ, Fergusson DM 1998 Breastfeeding and later cognitive and academic outcomes. Pediatrics 101: 9–20
Lucas A, Morley R, Cole TJ, Lister G, Leeson-Payne C 1992 Breast milk and subsequent intelligence quotient in children born preterm. Lancet 339: 261–264
Lawrence PB 1994 Breast milk: best source of nutrition for term and preterm infants. Pediatr Clin North Am 41: 925–941
Silva PA, Buckfield P, Spears GF 1978 Some maternal and child developmental characteristics associated with breast feeding: a report from the Dunedin Multidisciplinary Child Development Study. Aust Paediatr J 14: 265–268
Jacobson SW, Jacobson JL 1992 Breastfeeding and intelligence. [letter]. Lancet 339: 745
Boehm G, Borte M, Böhles HJ, Müller H, Kohn G, Moro G 1996 Docosahexaenoic and arachidonic acid content of serum and red blood cell membrane phospholipids of preterm infants fed breast milk, standard formula or formula supplemented with n-3 and n-6 long-chain polyunsaturated fatty acids. Eur J Pediatr 155: 410–416
Carlson SE, Ford AJ, Werkman SH, Peeples JM, Koo WWK 1996 Visual acuity and fatty acid status of term infants fed human milk and formulas with and without docosahexaenoate and arachidonate from egg yolk lecithin. Pediatr Res 39: 882–888
Carlson SE 1996 Arachidonic acid status of human infants: influence of gestational age at birth and diets with very long chain n-3 and n-6 fatty acids. J Nutr 126: 1092S–1098S
Birch EE, Garfield S, Hoffman DR, Uauy R, Birch DG 2000 A randomized controlled trial of early dietary supply of long-chain polyunsaturated fatty acids and mental development in term infants. Dev Med Child Neurol 42: 174–181
Lucas A, Stafford M, Morley R, Abbott R, Stephenson T, MacFadyen U, Elias-Jones A, Clements H 1999 Efficacy and safety of long-chain polyunsaturated fatty acid supplementation of infant-formula milk: a randomised trial. Lancet 354: 1948–1954
Agostoni C, Trojan S, Bellù R, Riva E, Giovanni M 1995 Neurodevelopmental quotient of healthy term infants at 4 months and feeding practice: the role of long-chain polyunsaturated fatty acids. Pediatr Res 38: 262–266
Willatts P, Forsyth JS, DiModugno MK, Varma S, Colvin M 1998 Effect of long-chain polyunsaturated fatty acids in infant formula on problem solving at 10 months of age. Lancet 352: 688–691
Werkman SH, Carlson SE 1996 A randomized trial of visual attention of preterm infants fed docosahexaenoic acid until nine months. Lipids 31: 91–97
Carlson SE, Werkman SH 1996 A randomized trial of visual attention of preterm infants fed docosahexaenoic acid until two months. Lipids 31: 85–90
Agostoni C, Trojan S, Bellù R, Riva E, Bruzzese MG, Giovanni M 1997 Developmental quotient at 24 months and fatty acid composition of diet in early infancy: a follow up study. Arch Dis Child 76: 421–424
Carlson SE, Werkman SH, Rhodes PG, Tolley EA 1993 Visual-acuity development in healthy preterm infants: effect of marine-oil supplementation. Am J Clin Nutr 58: 35–42
Birch DG, Birch EE, Hoffman DR, Uauy RD 1992 Retinal development in very low birth weight infants fed diets differing in omega-3 fatty acids. Invest Ophthalmol Vis Sci 33: 2365–2376
SanGiovanni JP, Berkey CS, Dwyer JT, Colditz GA 2000 Dietary essential fatty acids, long-chain polyunsaturated fatty acids, and visual resolution acuity in healthy fullterm infants: a systematic review. Early Human Dev 57: 165–188
SanGiovanni JP, Parra-Cabrera S, Colditz GA, Berkey CS, Dwyer JT 2000 Meta-analysis of dietary essential fatty acids and long-chain polyunsaturated fatty acids as they relate to visual resolution acuity in healthy preterm infants. Pediatrics 105: 1292–1298
Carlson SE, Neuringer M 1999 Polyunsaturated fatty acid status and neurodevelopment: a summary and critical analysis of the literature. Lipids 34: 171–178
Carlson SE 2000 Behavioral methods used in the study of long-chain polyunsaturated fatty acid nutrition in primate infants. Am J Clin Nutr 71: 268S–274S
Auestad N, Montalto MB, Hall RT, Fitzgerald KM, Wheeler RE, Connor WE, Neuringer M, Connor SL, Taylor JA, Hartmann EE 1997 Visual acuity, erythrocyte fatty acid composition, and growth in term infants fed formulas with long chain polyunsaturated fatty acids for one year. Pediatr Res 41: 1–10
Scott DT, Janowsky JS, Carroll RE, Taylor JA, Auestad N, Montalto MB 1998 Formula supplementation with long-chain polyunsaturated fatty acids: are there developmental benefits?. Pediatrics 102: 1203–1204( abstr)
Gibson RA, Makrides M 1999 Polyunsaturated fatty acids and infant visual development: a critical appraisal of randomized clinical trials. Lipids 34: 179–184
Neuringer M, Connor WE, Lin DS, Barstad L, Luck S 1986 Biochemical and functional effects of prenatal and postnatal omega-3 fatty acid deficiency on retina and brain in rhesus monkeys. Proc Natl Acad Sci USA 83: 4021–4025
Reisbick S, Neuringer M, Gohl E, Wald R, Anderson GJ 1997 Visual attention in infant monkeys: effects of dietary fatty acids and age. Dev Psychol 33: 387–395
Reisbick S, Neuringer M, Hasnain R, Connor WE 1990 Polydipsia in rhesus monkeys deficient in omega-3 fatty acids. Physiol Behav 47: 315–323
Reisbick S, Neuringer M, Hasnain R, Connor WE 1994 Home cage behavior of rhesus monkeys with long-term deficiency of omega-3 fatty acids. Physiol Behav 55: 231–239
Young C, Hikita T, Kaneko S, Shimizu Y, Hanaka S, Abe T, Shimasaki H, Ikeda R, Miyazawa Y, Nakajima A 1997 Fatty acid compositions of colostrum, cord blood, maternal blood and major infant formulas in Japan. Acta Paediatr Jpn 39: 299–304
Kanazawa A, Miyazawa T, Hirono H, Hayashi M, Fujimoto K 1991 Possible essentiality of docosahexaenoic acid in Japanese monkey neonates: occurrence in colostrum and low biosynthetic capacity in neonate brains. Lipids 26: 53–57
Schneider ML, Suomi SJ 1992 Neurobehavioral assessment in rhesus monkey neonates (Macaca mulatta): developmental changes, behavioral stability, and early experience. Infant Behav Dev 15: 155–177
Brazelton TB 1973 Neonatal Behavioral Assessment Scale (Clinics in Developmental Medicine, No. 50). William Heinemann Medical Books, London
Schneider ML, Moore CF, Suomi SJ, Champoux M 1991 Laboratory assessment of temperament and environmental enrichment in rhesus monkey infants (Macaca mulatta). Am J Primatol 25: 137–155
Schneider ML 1992 The effect of mild stress during pregnancy on birthweight and motor maturation in rhesus monkey infants (Macaca mulatta). Infant Behav Dev 15: 389–403
Schneider ML, Coe CL, Lubach GR 1992 Endocrine activation mimics the adverse effects of prenatal stress on the neuromotor development of the infant primate. Dev Psychobiol 25: 427–439
Champoux M, Suomi SJ, Schneider ML 1994 Temperament differences between captive Indian and Chinese-Indian hybrid rhesus macaque neonates. Lab Anim Sci 44: 351–357
Champoux M, Kriete MF, Eckhaus MA, Suomi SJ 1997 Behavioral and physical concomitants of congenital hydrocephalus in a rhesus macaque (Macaca mulatta) neonate. Contemp Top Lab Anim Sci 36: 56–61
Ruppenthal GC 1979 Survey of protocols for nursery rearing infant macaques. In: Ruppenthal GC (ed) Nursery Care of Nonhuman Primates. Plenum Press, New York, 165–185
Schneider ML 1987 A rhesus monkey model of human infant individual differences. Unpublished doctoral dissertation, University of Wisconsin-Madison
Folch J, Lees M, Sloane-Stanley GH 1957 A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226: 497–509
Morrison WR, Smith LM 1959 Preparation of fatty acid methyl esters and dimethylacetals from lipids with boron-fluoride-methanol. J Lipid Res 5: 600–608
Moriguchi T, Sheaf Greiner R, Salem N 2000 Behavioral deficits associated with dietary induction of decreased brain docosahexaenoic acid concentration. J Neurochem 75: 2563–2573
LePage G, Roy CC 1986 Direct transesterification of all classes of lipids in a one-step reaction. J Lipid Res 27: 114–120
Brunet O, Lézine I 1966 Le Développement Psychologique de la Première Enfance, 2nd Ed. Presses Universitaires de France, Paris
Golub MS, Gershwin ME 1984 Standardized neonatal assessment in the rhesus monkey. In: Nathanielz PW, Parer JT (eds) Research in Perinatal Medicine. Perinatology Press, Ithaca NY, 55–86
Chan GM, Borschel MW, Jacobs JR 1994 Effects of human milk or formula feeding on the growth, behavior, and protein status of preterm infants discharged from the newborn intensive care unit. Am J Clin Nutr 60: 710–716
DiPietro JA, Larson SK, Porges SW 1987 Behavioral and heart rate pattern differences between breast-fed and bottle-fed neonates. Dev Psychol 23: 467–474
Mineka S, Suomi SJ 1978 Social separation in monkeys. Psychol Bull 85: 1376–1400
Mineka S, Gunnar M, Champoux M 1986 Control and early socioemotional development: infant rhesus monkeys reared in controllable versus uncontrollable environments. Child Dev 57: 1241–1256
Champoux M, Boyce WT, Suomi SJ 1995 Biobehavioral comparisons between adopted and nonadopted rhesus monkey infants. J Dev Behav Pediatr 16: 6–13
Bell RQ 1966 Level of arousal in breast-fed and bottle-fed human newborns. Psychosom Med 28: 177–180
Bernal J, Richards MPM 1970 The effects of bottle and breast feeding on infant development. J Psychosom Res 14: 247–252
Champoux M, Jaquish CE, Higley SB, Suomi SJ 1999 Heritability of standardized biobehavioral assessment scores in rhesus monkey infants. Am J Primatol 49: 42( abstr)
Lands WEM, Libelt B, Morris A, Kramer NC, Prewitt TE, Bowen P, Schmeisser D, Davidson MH, Burns JH 1992 Maintenance of lower proportions of (n-6) eicosanoid precursors in phospholipids of human plasma in response to added dietary (n-3) fatty acids. Biochim Biophys Acta 1180: 147–162
Schneider ML 1992 Delayed object permanence development in prenatally stressed rhesus monkey infants (Macaca mulatta). Occup Ther J Res 12: 96–110
Burbacher TM, Gunderson VM, Grant-Webster KS, Mottet NK 1990 Methods for assessing neurobehavioral development during infancy in primates. In: Johnson BL (ed) Advances in Neurobehavioral Toxicology: Applications in Environmental and Occupational Health. Lewis Publishers, Chelsea, MI, 449–454
Ruppenthal GC, Sackett GP 1992 Research Protocol and Technician's Manual: A Guide to the Care, Feeding, and Evaluation of Infant Monkeys, 2nd Ed. IPRL, University of Washington, Seattle WA
Acknowledgements
The authors thank Wendy Airoso, Gwen Dube, and Margro Purple for their assistance in infant care and testing. Dr. Mary Schneider, University of Wisconsin, developed the neonatal assessment and trained Maribeth Champoux in its use. We also thank Jacqueline Fragard and Linda Siegel for obtaining the Brunet-Lézine manual for Maribeth Champoux; the National Institutes of Health Translating Service translated the manual from French to English (National Institutes of Health 98–348). Martek Biosciences Corporation (Columbia, MD, U.S.A.) supplied the formula supplement and provided financial support. The authors are grateful to three anonymous reviewers for their insightful comments.
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Martek Biosciences Corporation (Columbia, MD, U.S.A.) provided partial financial support for this study. This research was supported by the Intramural Research Programs of the National Institute of Child Health and Human Development and the National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health.
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Champoux, M., Hibbeln, J., Shannon, C. et al. Fatty Acid Formula Supplementation and Neuromotor Development in Rhesus Monkey Neonates. Pediatr Res 51, 273–281 (2002). https://doi.org/10.1203/00006450-200203000-00003
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DOI: https://doi.org/10.1203/00006450-200203000-00003
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