Term infant studies of DHA and ARA supplementation on neurodevelopment: results of randomized controlled trials

      Abstract

      Healthy term infants who are not breast-fed may need long-chain polyunsaturated fatty acids (LCPUFA) in their feeding, based on the changes in plasma and tissue fatty composition. However, consistent functional effects across different studies conducted over the past two decades has been more difficult to document. The interpretation of these data has scientific and public interest with the introduction of LCPUFA supplemented formula. There are 14 controlled trials in term infants that have included formula feeding with or without LCPUFA and functional assessment of visual and other measures of neural development; in addition, 7 have evaluated specific measures related to cognitive development. We chose to examine the effect of DHA dose provided daily on the development of visual acuity to explain the differences in visual acuity responses across randomized studies. A “meta-regression” was performed with the use of a DHA effective dose as the independent variable and visual acuity at 4 months as the dependent variable. Since the two main dietary determinants of DHA status are the LNA provided and the preformed DHA consumed, we defined DHA equivalent dose across studies by assuming a 1%, 5%, and 10% conversion of LNA to DHA. Results indicate a strong and significant effect of DHA equivalent dose on magnitude of the visual acuity response at all conversions tested; greatest significance was found when using a 10% bioequivalency ( r 2 = 0.68, and P = .001). We conclude that there is a significant relation between the total DHA equivalents provided and effectiveness as defined by visual acuity measurements at 4 months of age.

      Abbreviations:

      ARA ( Arachidonic acid (20:4 n-6)), CGMP ( Cyclic guanosine monophosphate), CNS ( Central nervous system), DHA ( Docosahexaenoic acid (22:6 n-3)), EFA ( Essential fatty acid), EPA ( Eicosapentaenoic acid (20:5 n-3)), FA ( Fatty acid), FPL ( Forced-choice preferential looking), GLA ( γ-Linolenic acid (18:3 n-6)), HM ( Human milk), LA ( Linoleic acid (18:2 n-6)), LCPUFA ( Long-chain polyunsaturated fatty acids), LNA ( α-Linolenic acid (18:3 n-3)), MAR ( Minimum angle of resolution), MDI ( Mental development index), PUFA ( Polyunsaturated fatty acid), RBC ( Red blood cell), VEP ( Visual evoked potential), VLBW ( Very low birth weight)
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      References

        • Makrides M.
        • Neumann M.A.
        • Gibson R.A.
        Is dietary docosahexaenoic acid essential for term infants?.
        Lipids. 1996; 31: 115-119
        • Carlson S.E.
        • Ford A.J.
        • Werkman S.H.
        • Peeples J.M.
        • Koo W.W.
        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. 1996; 39: 882-888
        • Horby J.M.
        • Holmer G.
        • Lund P.
        • Hernell O.
        • Michaelsen K.F.
        Effect of formula supplemented with docosahexaenoic acid and gamma-linolenic acid on fatty acid status and visual acuity in term infants.
        J Pediatr Gastroenterol Nutr. 1998; 26: 412-421
        • Auestad N.
        • Montalto M.B.
        • Hall R.T.
        • Fitzgerald K.M.
        • Wheeler R.E.
        • Connor W.E.
        • et al.
        Visual acuity, erythrocyte fatty acid composition, and growth in term infants fed formulas with long chain polyunsaturated fatty acids for one year: Ross Pediatric Lipid Study.
        Pediatr Res. 1997; 41: 1-10
        • Scott D.T.
        • Janowsky J.S.
        • Carroll R.E.
        • Taylor J.A.
        • Auestad N.
        • Montalto M.B.
        Formula supplementation with long-chain polyunsaturated fatty acids: are there developmental benefits?.
        Pediatrics. 1998; 102: E59
        • 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
        • Agostoni C.
        • Trojan S.
        • Bellu R.
        • Riva E.
        • Bruzzese M.G.
        • Giovannini M.
        Developmental quotient at 24 months and fatty acid composition of diet in early infancy: a follow up study.
        Arch Dis Child. 1997; 76: 421-424
        • Birch E.E.
        • Hoffman D.R.
        • Uauy R.
        • Birch D.G.
        • Prestidge C.
        Visual acuity and the essentiality of docosahexaenoic acid and arachidonic acid in the diet of term infants.
        Pediatr Res. 1998; 44: 201-209
        • Birch E.E.
        • Garfield S.
        • Hoffman D.R.
        • Uauy R.
        • Birch D.G.
        A randomized controlled trial of early dietary supply of long-chain polyunsaturated fatty acids and mental development in term infants.
        Dev Med Child Neurol. 2000; 42: 174-181
        • Forsyth J.S.
        • Willatts P.
        • DiModogno M.K.
        • Varma S.
        • Colvin M.
        Do long-chain polyunsaturated fatty acids influence infant cognitive behaviour?.
        Biochem Soc Trans. 1998; 26: 252-257
        • Willatts P.
        • Forsyth J.S.
        • DiModugno M.K.
        • Varma S.
        • Colvin M.
        Effect of long-chain polyunsaturated fatty acids in infant formula on problem solving at 10 months of age.
        Lancet. 1998; 352: 688-691
        • Slater A.
        Individual differences in infancy and later IQ.
        J Child Psychol Psychiatry. 1995; 36: 69-112
        • Gibson R.A.
        Long-chain polyunsaturated fatty acids and infant development.
        Lancet. 1999; 354: 1919-1920
        • Makrides M.
        • Neumann M.A.
        • Simmer K.
        • Gibson R.A.
        A critical appraisal of the role of dietary long-chain polyunsaturated fatty acids on neural indices of term infants: a randomized, controlled trial.
        Pediatrics. 2000; 105: 32-38
        • Lucas A.
        • Stafford M.
        • Morley R.
        • Abbott R.
        • Stephenson T.
        • MacFadyen U.
        • et al.
        Efficacy and safety of long-chain polyunsaturated fatty acid supplementation of infant-formula milk: a randomised trial.
        Lancet. 1999; 354: 1948-1954
        • Auestad N.
        • Halter R.
        • Hall R.T.
        • Blatter M.
        • Bogle M.L.
        • Burks W.
        • et al.
        Growth and development in term infants fed long-chain polyunsaturated fatty acids: a double-masked, randomized, parallel, prospective, multivariate study.
        Pediatrics. 2001; 108: 372-381
        • SanGiovanni J.P.
        • Berkey C.S.
        • Dwyer J.T.
        • Colditz G.A.
        Dietary essential fatty acids, long-chain polyunsaturated fatty acids, and visual resolution acuity in healthy fullterm infants: a systematic review.
        Early Hum Dev. 2000; 57: 165-188
        • SanGiovanni J.P.
        • Parra-Cabrera S.
        • Colditz G.A.
        • Berkey C.S.
        • Dwyer J.T.
        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. 2000; 105: 1292-1298
        • Gibson R.A.
        • Neumann M.A.
        • Makrides M.
        Effect of increasing breast milk docosahexaenoic acid on plasma and erythrocyte phospholipid fatty acids and neural indices of exclusively breast fed infants.
        Eur J Clin Nutr. 1997; 51: 578-584
        • Innis S.M.
        • Gilley J.
        • Werker J.
        Are human milk long-chain polyunsaturated fatty acids related to visual and neural development in breast-fed term infants?.
        J Pediatr. 2001; 139: 532-538
        • Jorgensen M.H.
        • Hernell O.
        • Hughes E.
        • Michaelsen K.F.
        Is there a relation between docosahexaenoic acid concentration in mothers' milk and visual development in term infants?.
        J Pediatr Gastroenterol Nutr. 2001; 32: 293-296
        • Lauritzen L.
        • Hansen H.S.
        • Jorgensen M.H.
        • Michaelsen K.F.
        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
        • Uauy R.
        • Mena P.
        • Wegher B.
        • Nieto S.
        • Salem N.J.
        Long chain polyunsaturated fatty acid formation in neonates: effect of gestational age and intrauterine growth.
        Pediatr Res. 2000; 47: 127-135
        • Birch E.E.
        • Hoffman D.R.
        • Castaneda Y.S.
        • Fawcett S.L.
        • Birch D.G.
        • Uauy R.D.
        A randomized controlled trial of long-chain polyunsaturated fatty acid supplementation of formula in term infants after weaning at 6 wk of age.
        Am J Clin Nutr. 2002; 75: 570-580
        • Hoffman D.R.
        • Birch E.E.
        • Castañeda Y.S.
        • Fawcett S.L.
        • Wheaton D.H.
        • Birch D.G.
        • et al.
        Visual function in breast-fed term infants weaned to formula with or without long-chain polyunsaturates at 4 to 6 months: a randomized clinical trial.
        J Pediatr. 2003; 142: 669-677
        • Anonymous
        Breastfeeding and the use of human milk: American Academy of Pediatrics: Working Group on Breastfeeding.
        Pediatrics. 1997; 100: 1035-1039
        • Birch E.
        • Birch D.
        • Hoffman D.
        • Hale L.
        • Everett M.
        • Uauy R.
        Breast-feeding and optimal visual development.
        J Pediatr Ophthalmol Strabismus. 1993; 30: 33-38
        • Koletzko B.
        • Agostoni C.
        • Carlson S.E.
        • Clandinin T.
        • Hornstra G.
        • Neuringer M.
        • et al.
        Long chain polyunsaturated fatty acids (LC-PUFA) and perinatal development.
        Acta Paediatr. 2001; 90: 460-464
        • Makrides M.
        • Neumann M.
        • Simmer K.
        • Pater J.
        • Gibson R.
        Are long-chain polyunsaturated fatty acids essential nutrients in infancy?.
        Lancet. 1995; 345: 1463-1468