October 2008 Issue

The Role of DHA and ARA in Infant Nutrition and Neurodevelopmental Outcomes
By Ana Abad-Jorge, MS, RD, CNSC
Today’s Dietitian
Vol. 10 No. 10 P. 66

Though still in its infancy, the research linking certain fatty acids to improved visual acuity and cognitive performance in babies is strong.

The importance of nutrition in relation to infants’ neurodevelopment during the first two years of life cannot be overstated. While breast milk is the optimal choice for infants during the first year, the role of long-chain polyunsaturated fatty acids, specifically docosahexaenoic acid (DHA), in children’s neurodevelopment has been an innovative and exciting area of research over the past 25 years.

DHA, the 22-carbon, long-chain fatty acid found in breast milk, plays a key role in the structure and function of neural tissues, most notably those of the retina and brain. The important role of DHA supplementation in the nutritional status of pregnant and lactating women and in infants’ and young children’s neurodevelopment is an important area of nutrition that has direct application to our practice as dietitians.

Infant brain growth and DHA neural tissue accumulation during the last trimester and first two years of life are significant. During the last trimester, the brain grows approximately 260%, with an average weight of approximately 400 grams at birth; the brain continues to grow 175% during the first year of life and another 18% during the second year.1 While significant changes occur in neural pathway adaptation and wiring during childhood, adolescence, and early adulthood, the brain grows only another 21% in size from the age of 2 until adulthood.

During the last trimester and during those first two critical years of brain development, DHA rapidly accumulates in the brain tissue and then reaches a plateau at the age of 2 and beyond. Other long-chain fatty acids, however, such as eicosapentaenoic acid, do not accumulate in the forebrain during infancy as seen with DHA.2

Moreover, the level of dietary DHA intake impacts the degree of brain DHA accumulation. In a study that looked at variable brain DHA levels in response to infant nutrition, the type of feeding was determined for infants who had died of sudden infant death syndrome. Those infants who were fed breast milk accumulated DHA in the brain cortex during the first year of life, while those who were fed formula that did not contain DHA did not demonstrate any appreciable change in brain cortex DHA content.3

DHA, an important structural and functional component of the developing brain, can be synthesized from the essential fatty acid alpha-linolenic acid through elongation and desaturation enzymes. Arachidonic acid (ARA), a 20-carbon fatty acid, which is also a key component of cell membranes and serves as a precursor to prostaglandin formation, is synthesized from the essential fatty acid linoleic acid. DHA serves as a key structural component of cell membranes and is found in high levels in the cells of the retina and the brain, comprising approximately 30% to 65% of the cell membrane fatty acids of the rods and cones in the retina.

While DHA can be synthesized from alpha-linolenic acid, this synthetic pathway is only a backup to direct dietary intake and the conversion process is low (estimated at only 0.2% to 4%). Intake of preformed DHA via either the placenta or diet is the preferred mode of DHA accumulation during infancy. Both DHA and ARA are preferentially transferred to the fetus across the placenta compared with other long-chain fatty acids.4 After birth, breast-fed infants take in both DHA and ARA directly from breast milk, while formula-fed infants can absorb DHA and ARA from supplemented formulas. Once older infants begin to take in solid foods, they can get DHA from foods such as fatty fish, meat, and eggs.

Breast Milk Levels of DHA and ARA and Current Intake Recommendations
The amount of DHA and ARA in breast milk is highly variable among different countries and dependent on a mother’s diet.5-7 Pregnant and lactating woman who live near coastal areas, such as those living in marine China and Japan, and rely on a diet high in fish and other seafood have the highest levels of DHA in their breast milk (2.76% and 1.00% fatty acids, respectively), whereas countries with diets high in vegetable protein and lacking in eggs or fresh seafood, such as in Sudan, have the lowest levels of breast milk DHA (0.07%).

Considerable variability is also found in DHA breast milk concentration among North American women. In general, Canadian women have higher breast milk DHA levels compared with American women. Furthermore, lactating women in the United States who consume a more varied diet, including eggs and fresh seafood, have higher levels of DHA in their breast milk compared with women who consume a highly processed diet lacking in fresh seafood.

A number of international expert groups have published recommendations for optimal levels of DHA and ARA supplementation in term infant formula.8-10 (See Table 1 for an overview of some of these recommendations.) The general recommendations of 0.2% to 0.4% fatty acids for DHA and between 0.35% and 0.7% fatty acids for ARA are based on the median worldwide range of DHA and ARA concentration in breast milk.

Since 2002, DHA and ARA have been supplemented into infant formulas in the United States, although formula supplementation began in European countries much earlier. Based on the available research over the past 15 years, Hoffman et al report, “Healthy, term formula-fed infants appear to require preformed DHA in amounts closer to the average worldwide human milk level to support blood phospholipid DHA levels as high as those of breast-fed infants.”11

Impact of Dietary DHA and ARA Intake on Infant Blood DHA Levels and Neurodevelopmental Outcomes
Numerous studies demonstrate a dose-response relationship between infant dietary intake of DHA from breast milk or formula and the level of DHA found in the red blood cells. Infants taking in unsupplemented formula had only approximately 4% DHA in their red blood cells, whereas infants taking in breast milk or formula with higher levels of DHA (0.29% to 0.36%) had the highest level of red blood cell DHA (10% to 12% fatty acids).5,11-13  The level of red blood cell DHA was directly related to the level of DHA in the breast milk or formula.

Moreover, a study directly comparing two different formulas with varying levels of DHA and ARA demonstrated that the formula with the higher DHA and ARA levels resulted in the higher level of red blood cell DHA.12

In another study by Hoffman et al, breast-fed infants were weaned from breast milk to either an unsupplemented control formula or a DHA- and ARA-supplemented formula at 4 to 6 months of age.14 At 12 months of age, the level of red blood cell DHA was significantly higher in the infants weaned to the DHA- and ARA-supplemented formula (24% higher than at the time of weaning) compared with those infants weaned to an unsupplemented formula (50% lower than at the time of weaning).

Visual Acuity Outcomes
Numerous studies have demonstrated a strong correlation between higher infant red blood cell DHA levels and improved visual outcomes.6,11,13,14 Most of these studies have evaluated infant visual acuity, a measure of the smallest detail recognized by the infant’s visual system. Visual acuity is measured using visual evoked potentials, which are electrophysiological responses generated by the brain in response to specific visual stimulation. Innis et al investigated the relationship between breast milk DHA levels, infant red blood cell DHA levels, and visual acuity.15 Infants were divided into three equal-sized groups based on their red blood cell DHA levels. Those infants with the highest DHA levels in their red blood cells also had intake of breast milk with the highest DHA levels and had the highest visual acuity scores at the ages of 2 and 12 months.

The level of DHA and ARA in the various formulas appears to have an impact on visual acuity during the first two years of life. Birch et al evaluated visual acuity in term infants during a four-month feeding study.6 Infants (n=79) were exclusively fed either unsupplemented term formula or two other formulas supplemented with DHA alone at a level of 0.35% of fatty acids or with both DHA and ARA (levels of 0.36% and 0.72% of total fatty acids, respectively) for a period of four months from birth. These formulas were also compared with a reference group of 29 breast-fed infants where the average breast milk level was 0.29% DHA. Infants fed the supplemented formula has similar red blood cell lipid profile and visual acuity as measured by visual evoked potential (VEP) to the reference breastfed group. Furthermore, visual acuity (VEP) was significantly higher at the ages of 11/2 , 4, 12, and 18 months in the supplemented formula groups as compared with the unsupplemented formula group. Visual acuity was significantly lower in the unsupplemented group as compared with the breast fed infants.

In a similarly designed study, Auestad et al conducted a 12-month feeding study of term infants who were fed either unsupplemented or DHA- and ARA-supplemented formula, but failed to demonstrate any significant improvements in visual acuity measures in the DHA- and ARA-supplemented groups with lower DHA levels in the formula (0.23% fatty acids or less).12 The improvements in visual acuity observed during the first two years of life appear to be related not only to DHA and ARA supplementation but also to supplementation at an appropriate level to promote a significant difference.

Cognitive Development Outcomes
The important role of optimal DHA and ARA nutrition in cognitive development has also been established through numerous studies during infancy and through preschool. The Bayley Scales of Infant Development are used as the gold standard for assessing infant mental and psychomotor developmental outcomes. Two scores are generated: the Mental Development Index (MDI), which measures perception, cognition, language, and social and sensorimotor skills, and the Psychomotor Development Index (PDI), which measures gross and fine motor skills. In the same study by Birch et al, term infants who were fed the DHA- and ARA-supplemented formulas at the higher levels of 0.36% DHA and 0.72% ARA had significantly higher MDI scores at the age of 18 months than the unsupplemented group, as well as higher PDI scores, although the difference did not reach statistical significance.6 However, higher MDI scores were not seen at the age of 12 months with the similarly designed Auestad et al study, which used lower DHA levels in the supplemented formula group.12

In a continuation of the Birch et al study in preschoolers, DHA supplementation at appropriate levels in formula resulted in improved developmental scores at the age of 4 years.16 In children older than the age of 2, the common measure for IQ is the Wechsler Preschool and Primary Scale of Intelligence-Revised, which uses two separate subscales, the performance and verbal IQs, to develop a full IQ scale.

Preschoolers who participated in the four-month feeding study as term infants were assessed for cognitive outcomes at the age of 4 years.16 The performance IQ scores of the children who were fed the DHA- and ARA-supplemented formulas (0.36% DHA and 0.72% ARA) during infancy were nearly identical to the reference breast-fed group and a full four points higher than the unsupplemented formula group; however, this difference was not statistically significant. When evaluating the verbal IQ scores, the children who had been fed the DHA- and ARA-supplemented formula had scores nearly six points higher than the unsupplemented formula group; again, the difference was not statistically significant.16

Dietary and Infant Formula Sources for DHA
The best dietary sources of DHA for pregnant and lactating women, as well as for infants and children, should be reviewed to promote optimal nutritional intake and improved neurodevelopmental outcomes in infants and children. The best sources of DHA are fatty fish, eggs, and some meats. Table 2 reviews the best dietary sources for DHA.17 A 3-ounce portion of salmon has 683 milligrams of DHA, while two large eggs have only 38 milligrams; furthermore, plant foods do not contain DHA. DHA-enriched eggs, with levels as high as 150 milligrams of DHA per egg, are available. Despite this, it is difficult for most pregnant women to consume 300 milligrams of DHA per day as recommended by the International Society for the Study of Fatty Acids and Lipids.10 Additionally, the 2001 FDA advisory recommended that pregnant women avoid consuming large fish such as swordfish, tile fish, shark, and King mackerel, as these fish have the highest concentration of methylmercury.18

The FDA and U.S. Environmental Protection Agency recommend that pregnant and lactating women limit their weekly fish intake to 12 ounces of low-mercury fish and shellfish such as salmon, pollock, trout, catfish, canned light tuna, shrimp, crab, and scallops.18 Albacore tuna should be limited to no more than 6 ounces per week. The safety and mercury levels of locally caught fish should be verified prior to consumption. Since the 2001 FDA advisory, dietary intake of all fish and canned tuna among pregnant women has decreased significantly.19

Term infants can receive appropriate DHA and ARA intake from breast milk (the optimal choice) or from DHA- and ARA-supplemented term formulas. Most of the formula companies in the United States now supplement infant formula with DHA and ARA.

Follow-up formulas for children between the ages of 9 months and 24 months are also available with DHA supplementation as toddlers are transitioning to solid foods. While they will receive some DHA from solid foods, such as eggs, chicken, and tuna, most toddler diets do not routinely include the fatty fish highest in DHA levels. While not yet widely recommended by pediatricians and other healthcare professionals, providing toddlers with a DHA-supplemented formula through the second year of life can provide them with the recommended levels of DHA that they do not take in from table foods.

Summary
DHA accumulates rapidly in the retina and cerebral cortex during the period of significant brain growth between the last trimester and the second year of life. During this time, infants and toddlers should receive optimal levels of DHA and ARA in their diet through either breast milk, DHA- and ARA-supplemented formula, and eventually solid foods. The level of DHA in breast milk varies significantly based on the mother’s diet. DHA levels in red blood cells and neural tissues and resulting neurodevelopmental outcomes—specifically, improved visual acuity and cognitive performance—in infants and young children have been linked to the levels of DHA and ARA in breast milk and formula. Different term and toddler formulas have different levels of DHA and ARA.

As such, the role of dietitians working in the area of pediatric nutrition should be to educate parents and healthcare providers of infants and young children on how to optimize the DHA status of children through their intake of breast milk, DHA-supplemented formulas, and DHA-containing foods.

— Ana Abad-Jorge, MS, RD, CNSC, is a dietetic internship program director and pediatric nutrition support specialist at the University of Virginia Health System and a speaker/consultant for Mead Johnson. She has authored more than 25 publications in the areas of pediatric and neonatal nutrition support.

 

References
1. Dobbing J, Sands J. Quantitative growth and development of human brain. Arch Dis Child. 1973;48(10):757-767.

2. Martinez M. Tissue levels of polyunsaturated fatty acids during early human development. J Pediatr. 1992;120(4 Pt 2):S129-S138.

3. Makrides M, Neumann MA, Byard RW, Simmer K, Gibson RA. Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infants. Am J Clin Nutr. 1994;60:(2)189-194.

4. Haggarty P, Page K, Abramovich DR, Ashton J, Brown D. Long-chain polyunsaturated fatty acid transport across the perfused human placenta. Placenta. 1997;18(8):635-642.

5. Auestad N, Halter R, Hall RT, 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(2):372-381.

6. Birch EE, Hoffman DR, Uauy R, Birch DG, Prestidge C. Visual acuity and the essentiality of docosahexaenoic acid and arachidonic acid in the diet of term infants. Pediatr Res. 1998;44(2):201-209.

7. Helland IB, Smith L, Saarem K, Saugstad OD, Drevon CA. Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children’s IQ at 4 years of age. Pediatrics. 2003;111(1):e39-e44.

8. The British Nutrition Foundation. Unsaturated fatty acids: Nutritional and physiological significance. London: Chapman & Hall; 1992;152-163.

9. Food and Agricultural Organization of the United Nations/World Health Organization Joint Expert Consultation. Lipids in early development. In: Fats and oils in human nutrition. FAO Food and Nutri Pap. 1994;57:49-55.

10. Simopoulos AP, Leaf A, and Salem N Jr. Workshop on the essentiality of and recommended dietary intakes for omega-6 and omega-3 fatty acids. J Am Coll Nutr. 1999;18(5):487-489.

11. Hoffman DR, Wheaton DKH, James KJ, et al. Docosahexaenoic acid in red blood cells of term infants receiving two levels of long-chain polyunsaturated fatty acids. J Pediatr Gastroenterol Nutr. 2006;42(3):287-292.

12. Auestad N, Montalto MB, Hall RT, 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):1-10.

13. Hoffman DR, Birch EE, CastanedaYS, et al. Dietary docosahexanoic acid (DHA) and visual maturation in the post-weaning term infant. Invest Opthamol Vis Sci. 2001;42:S122-128.

14. Hoffman DR, Birch EE, Castañeda YS, 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(6):669-677.

15. Innis SM, 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(4):532-538.

16. Birch EE, Garfield S, Castañeda Y, et al. Visual acuity and cognitive outcomes at 4 years of age in a double-blind, randomized trial of long-chain polyunsaturated fatty acid-supplemented infant formula. Early Human Dev. 2007;83(5):279-284.

17. U.S. Department of Agriculture. Agricultural Research Service. USDA national nutrient database for standard reference, release 18. Nutrient data laboratory. 2005. Available at: http://nal.usda.gov/fnic/foodcomp/Data/SR18/sr18.shtml

18. U.S. Food and Drug Administration. FDA/EPA Advisory on seafood consumption still current. June 6, 2006. Available at: http://www.fda.gov/bbs/topics/NEWS/2006/NEW01382.html

19. Oken E, Kleinman KP, Berland WE, et al. Decline in fish consumption among pregnant women after a national mercury advisory. Obstet Gynecol. 2003;102(2):346-351.

Table 1. Recommendations for DHA and ARA Supplementation in Term Infant Formulas8-10


Organization or Foundation

Percent Fatty Acids
DHA           ARA

British Nutrition Foundation

           0.4            0.4

Food and Agricultural Organization of the United Nations/World Health Organization expert panel

 

          0.35           0.7

Expert panel convened by the International Society for the Study of Fatty Acids and Lipids

 

          0.35           0.5

Table 2. Dietary Sources of DHA: Fatty Fish, Meat, and Eggs17

Food Item

DHA (mg)

Pink salmon filet, 3 oz, baked or broiled
Pink salmon, 3 oz, canned
White (albacore) tuna, 3 oz
Blue crab, 3 oz, steamed
Light tuna, 3 oz, canned in water
Enriched eggs, 1 large egg
Large shrimp, 12, steamed
Chicken (drumsticks), 2 pieces, fried in flour
Large eggs, 2, hard boiled

638
589
535
196
199
100 to 150
 95
 39
 38

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