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their synthesis is regulated by the iron dependent tyrosine and tryptophan hy- droxylase, respectively. ARA is found in membranes through- out the body, ful?lls the role of n-6 fatty acids in growth, and is the precursor for eicosanoids and other signal molecules. N-6 and n-3 fatty acids also regulate carbohydrate and lipid metabolism through effects on gene expression involving ste- roid regulatory element binding proteins and peroxisomal pro- liferator activated receptors (3,5,6). The desaturases required for synthesis of ARA and DHA, and delta

9 desaturase re- quired for synthesis of oleic acid (18) (which is the major monoenoic fatty acid in brain white and grey matter), are iron dependent enzymes. Essential fatty acids in the fetus and preterm infant. The higher ARA and DHA and lower LA in fetal, (rather than maternal or infant) plasma (7,8) maybe explained in part by Received December 15, 2004;

accepted February 1, 2005. Correspondence: Michael K. Georgieff, M.D., Professor of Pediatrics, University of Minnesota School of Medicine, Minneapolis, MN 55455;

E-mail: [email protected] 0031-3998/05/5705-0099R PEDIATRIC RESEARCH Vol. 57, No. 5, Pt 2,

2005 Copyright ?

2005 International Pediatric Research Foundation, Inc. Printed in U.S.A. 99R placental fatty acid binding and transport proteins that favor transfer of ARA and DHA (8,9). Other differences in plasma lipids before and after birth include the high ARA in fetal cholesterol esters, presence of high-density lipoprotein (HDL) as a major lipoprotein, low chylomicrons and very low-density lipoprotein (VLDL), and transport of ARA and DHA by ?-fetoprotein (8). Whether the low LA relative to ARA and DHA is fetal plasma is important in facilitating optimal tissue delivery of these fatty acids is unclear. However, the possibility that high LA may inhibit tissue DHA accumulation has been raised (8,10). LA and LNA are the major n-6 and n-3 fatty acids in human milk fat (mean 12% LA, 1.4% LNA, 0.4% ARA, 0.2% DHA), formula (16C20% LA, 1,5C2.3% LNA, 0.4C0.6% ARA, 0.2C 0.3% DHA) and IV lipids (53% LA, 7% LNA, 0.2% ARA, 0.2% DHA in

20 g/dL soybean triglyceride emulsions contain- ing egg phospholipid) (11,12). The desaturation of LNA to DHA in humans, including infants, is low with ?1% to 9% of a dose of isotopically labeled LNA converted to DHA (13). However, LNA conversion appears to be at least as high in preterm as term infants (14). Increasing the LNA content of formula has little effect in increasing blood lipid DHA, but feeding with ARA or DHA is ef?cacious in increasing blood and tissue ARA and DHA, respectively (10,15,16). Thus, DHA is clearly more ef?cacious for tissue DHA accretion than the LNA precursor (17,18). There is no evidence that infants are unable to form adequate ARA, except possibly following eicosapentaenoic acid (EPA, 20:5n-3) and DHA supplementa- tion which could antagonize ARA synthesis or acylation. Studies with preterm infants supplemented with ARA and DHA. Several sources of DHA (?sh oils, egg lipids and single cell (algal) oil), and ARA (egg lipids and single cell (fungal) oil), have been considered for addition to infant formula. Early studies found evidence of reduced growth and lower peripheral nerve conduction velocities in preterm infants fed formula with DHA without ARA (19C22). The lower growth was presumed to be due to suppression of ARA by EPA and/or DHA. Subsequent studies have not found lower growth in infants fed formulas with both DHA and ARA (16,23,24). Rather, higher growth in preterm infants fed formula with ARA and DHA from single cell oils and a positive relation between plasma ARA and preterm infant growth has been shown (16,25). A recent study has noted lower growth at