Is there a role for long-chain polyunsaturated fatty acids in infant nutrition?

By Latha Chandran, MBBS, MPH

Does supplementing infant formula with long-chain polyunsaturated fatty acids have an effect on visual acuity, growth, and cognitive development? The author examines the evidence.

Since the late 1980s, nutritional researchers, health-care providers, and infant formula manufacturers have studied the influence of long-chain polyunsaturated fatty acids (LCPUFAs) on visual acuity, growth, and cognitive development of infants. In the United States, this focus has resulted in the recent marketing of at least two infant formulas fortified with the most often investigated LCPUFAs, docosahexaenoic acid (DHA) and arachidonic acid (ARA). What do we know about these compounds, and what evidence do we have regarding their role in promoting infant health?

The fetus receives LCPUFAs in utero by transplacental transfer; after birth, infants get LCPUFAs from breast milk. For older infants, fish, eggs, and meats in the diet are sources of LCPUFAs. Some endogenous synthesis of LCPUFAs using precursor essential fatty acids derived from the diet also occurs.

Early studies of LCPUFAs were conducted in rodents and primates. These studies and others in human subjects have demonstrated that formula-fed infants have lower plasma and tissue levels of DHA and ARA than breastfed infants.¹ Infant formulas generally contain essential fatty acids—

linoleic acid and a linolenic acid—but not LCPUFAs. Researchers assumed, therefore, that young infants and animals were not able to adequately convert the essential fatty acids to LCPUFAs endogenously. Because several subsequent studies in human subjects have shown that breastfed babies score higher than bottle-fed infants on standardized tests of neurodevelopment,^2,3 and because LCPUFAs are present in human milk but not infant formula, recent attention has focused on clarifying the role of LCPUFAs in the early neurodevelopment of young infants.⁴

What are LCPUFAs? Where are they found?

Long-chain polyunsaturated fatty acids are more than 18 carbon atoms in length and have more than one double bond. Names of fatty acids designate the number of carbon atoms, the number of double bonds, and the position of the first double bond from the non-carboxyl (methyl, omega) end of the fatty acid chain. For example, the essential fatty acid linoleic acid (18:2 omega 6) is a polyunsaturated fatty acid, but is not long-chain. DHA (22:6 omega 3) and ARA (20:4 omega 6) are LCPUFAs.

DHA is the major omega-3 fatty acid of neural tissue in the eye, comprising 40% of the total fatty acid content of the photoreceptor membranes of the retina. ARA is the major omega-6 fatty acid in other neural tissues. LCPUFAs are found primarily in phospholipid membranes and synaptic terminals. They increase membrane fluidity and thus influence the functional characteristics of membranes.⁴

How does the body synthesize LCPUFAs?

Many studies have demonstrated higher LCPUFA levels in plasma lipids of breastfed infants compared to formula-fed infants.^5,6 Autopsies show that at 4 months of age, brain levels of DHA are lower in formula-fed infants.⁷ The LCPUFA content of plasma lipids reflects dietary intake.^5,8

Linoleic and a linolenic acid are the parent fatty acids of omega-6 and omega-3 fatty acids. These relatively short-chain, sparsely desaturated compounds are converted into longer-chain, more unsaturated fatty acids by a series of desaturases and elongases (see the figure). Although these enzymes have a clear preference for the omega-3 series of fatty acids, the omega-6 and omega-3 series compete for them. The liver enzyme,

-6 desaturase, is considered the rate-limiting factor in the endogenous synthesis of LCPUFAs. Dietary

linoleic acid is preferentially converted to ARA, and dietary a linolenic acid to DHA.

Endogenous synthesis may be inadequate to maintain plasma levels of DHA and ARA in formula-fed infants similar to those in breastfed infants. Hence the recent interest in supplementing infant formulas with these LCPUFAs.

Where do LCPUFAs for supplementation come from?

Three sources of LCPUFAs for supplementing infant formula are generally recognized: fish oils, egg yolks, and algae or fungal oils. Marine (fish) oils contain large amounts of omega-3 and small amounts of omega-6 fatty acids, but they also contain large amounts of eicosapentanoic acid (EPA), which has been associated with growth retardation in some human studies. Some fish oils have less EPA than others, but even these may inhibit growth. In addition, heavy metal contamination is a theoretical concern.

The second source of LCPUFAs is egg-yolk lipids (lipid and triglyceride or phospholipid). Because egg-yolk lipids have a high cholesterol content, they are not considered desirable for formula supplementation. Other concerns include the ratio of ARA to DHA, the presence of allergens, intestinal digestion and absorption of phospholipid vs. triglycerides, and the presence of other fatty acids.

The third source of LCPUFAs is oils obtained from single-cell algae and fungi by controlled fermentation, extraction, and purification. The algae and fungi are neither pathogenic nor toxic. These oils are classified by the Food and Drug Administration as GRAS (generally recognized as safe).

What do the studies show?

A number of studies have assessed the effect of LCPUFAs from various sources in different concentrations and proportions (ARA:DHA) on visual function and cognitive development in term and preterm infants. Because retinal and neural tissue have high concentrations of LCPUFAs, research has focused on measures of visual acuity and neurodevelopmental testing. Table 1 compares some studies done in term infants, looking at the study groups, number of infants included, outcome measures, duration of follow-up, and results. Table 2 compares studies in preterm infants in similar fashion.

TABLE 1
Comparison of studies in term infants using LCPUFA–supplemented formulas

TABLE 2
Comparison of studies in preterm infants using LCPUFA–supplemented formulas

Visual function studies. Visual acuity can be tested in young infants by monitoring electrophysiologic responses of the visual cortex or by behavioral measures. Electrophysiologic response tests include the electroretinogram and visual evoked potential (VEP) test. The electroretinogram quantifies retinal response in infants under 6 months of age by means of a contact lens electrode placed on the cornea to measure the electrical activity of the retina in response to light.

Visual evoked potential (VEP) measures retinal response as well as transmission to the visual cortex. Black-and-white stripe patterns are presented to the infant on a video screen, and the amplitude of the retinal response (monitored by occipital electroencephalogram scalp electrodes) is measured and correlated with the size of the stripe patterns. A modified form of this is the sweep VEP.

Behavioral measures to test visual acuity include preferential looking, which involves observing which side of a series of cards the infant looks at preferentially; grating acuity, a test based on the infant's inherent tendency to look at a pattern rather than a blank field; and the Teller acuity card procedure, a modified, more rapid version of the preferential looking method. VEP is considered more sensitive than behavioral measures. Stereoacuity, which estimates binocular vision, is measured using the random dot stereoacuity test, which measures the smallest detectable difference between images of an object presented independently to two eyes.

In term infants, data on visual acuity outcomes in infancy are conflicting. Several studies, involving fewer than 100 participants, have found a beneficial effect on visual acuity among infants fed human milk or LCPUFA supplemented formulas,^9–11 whereas others found no significant differences.^12,13 The reasons advanced for this contradiction are that the methods of assessing visual acuity, level of DHA in human milk, and level of a linolenic acid in supplemented formula differed among the studies. It is noteworthy that none of the larger studies involving several hundred children found any significant sustained differences between the supplemented and unsupplemented groups.

Two systematic reviews of the data on term infants have been published.^14,15 One review of both randomized and nonrandomized studies on dietary LCPUFAs indicates significantly higher visual acuity at 2 months and possibly 4 months of age among infants receiving human milk or supplemented milk compared with those on unsupplemented formulas.¹⁴ A Cochrane systematic review, however, found no significant differences in growth, visual acuity, or neurodevelopmental outcomes between term infants fed supplemented formula and control groups.¹⁵

Several smaller studies of visual function in preterm infants have shown that human milk or LCPUFA– supplemented formulas had some benefit.^16–18 Although the duration of supplementation and the study outcomes varied, these data suggest that supplemented infants or infants fed human milk had better early visual development. The effects were not long term, however, and the differences in visual acuity did not persist after 4 months of age.

One recent large randomized, controlled trial enrolled 470 preterm infants and evaluated visual acuity and growth as well as measures of infant intelligence and neurodevelopment.¹⁹ Growth parameters and measures of visual acuity in the group receiving supplemented formula did not differ significantly from the control group.

Two meta-analyses of the data on preterm infants have been published.^20,21 The first, which examined four randomized clinical trials, concluded, based on behavioral and electrophysiologic testing of visual acuity, that human milk and supplemented formula have an advantage over unsupplemented formula.²⁰ The second meta-analysis, a Cochrane systematic review of five randomized trials, found no long-term benefit in LCPUFA supplementation for premature infants but noted that the early rate of visual maturation was better in the LCPUFA–supplemented group.²¹

Cognitive and behavioral development studies. Cognitive function is arguably more difficult to measure than visual function. Attention, habituation, novelty preference (the Fagan test of infant intelligence), and imitation and problem solving in older infants all have been used to assess cognitive function. Global developmental tests, such as the Bayley Scales of Infant Development (BSID Revised), and the Brunet-Lezine Test are usually used.

BSID has subsections for assessing mental function and psychomotor development of children. The Bayley Mental Development Index (MDI) at 12 months of age assesses perception, memory, learning, problem solving, vocalization, early verbal communication, and abstract thinking. The Psychomotor Development Index (PDI) evaluates gross visual motor abilities and hand-finger manipulation. Data regarding effects on cognitive development of dietary LCPUFA supplementation beyond 1 year of age, using any of these tools, are scant.

Among term infants, smaller studies have inconsistently shown a statistically significant difference in Bayley MDI scores between infants fed supplemented and unsupplemented formula.²² Two large randomized, controlled trials, however, failed to demonstrate any significant cognitive benefit to infants fed LCPUFA–supplemented formula.^12,23 Two systematic reviews of all eligible prior studies found no conclusive evidence to indicate a beneficial effect of supplemented formula on the cognitive development of term infants.^14,15

In preterm, low birth-weight infants, at least two large randomized studies showed no difference in the Bayley MDI between LCPUFA– supplemented and unsupplemented groups.^19,24 The first study tested 470 preterm infants using the Fagan test of infant intelligence and the Bayley MDI as measures of neurodevelopment. On the Fagan test, supplemented infants scored better at 6 months of age, but the difference did not persist past 9 months of age. Although, overall, the Bayley MDI scores showed no difference between the supplemented and control groups, a statistically significant difference in scores occurred between supplemented and nonsupplemeted infants who weighed less than 1,250 g at birth.¹⁹ In the second study, of 240 premature infants, no differences were noted in Bayley MDI and Bayley PDI scores at 18 months of age.²⁴

Two studies have investigated the effect of maternal prenatal supplementation with DHA on infant outcomes.^25,26 Neither one showed a sustained difference between the supplemented groups and the control groups in visual acuity or Bayley developmental scores.

What are the potential adverse effects of LCPUFAs?

Additives to infant formulas must be carefully evaluated for safety as well as potential beneficial effects. As discussed previously, omega-3 and omega-6 fatty acids use the same enzymes for conversion to LCPUFAs, and they compete for those enzymes. Studies using formulas containing high-EPA fish oil without ARA supplementation have raised concerns about impaired growth in infants fed such formulas.^27,28 The higher the level of ARA in the plasma, the higher the weight of the infant. The higher the ratio of

linoleic acid to a linolenic acid, the better the weight gain of the infant.

EPA and ARA compete for incorporation into membranes as well as conversion to eicosanoids. The greater the unsaturated fatty acid composition of membranes, the higher the concern that it may increase the risk of peroxidation, and thus oxidant damage (bronchopulmonary dysplasia, necrotizing enterocolitis, retrolental fibroplasia), at the site of the double bonds.

The fatty acid composition of cell membranes also is important in determining insulin sensitivity and possibly gene transcription. Unbalanced supplementation of omega-3 and omega-6 fatty acids may alter eicosanoid metabolism. One study looked at data regarding the occurrence of bronchopulmonary dysplasia, necrotizing enterocolitis, and sepsis in infants receiving LCPUFA–supplemented and unsupplemented formula.²⁸ The individual prevalences of necrotizing enterocolitis and sepsis were higher, but not significantly so, in the supplemented group. When the prevalence rates were combined, however, the difference between the supplemented and unsupplemented groups was statistically significant.²

This finding was not substantiated in subsequent studies, which found no differences in the rates of complications between the supplemented groups and the unsupplemented control groups.^29,30 However, the inclusion criteria excluded the sickest infants, in whom such complications are more likely to occur. In at least one of the studies, preterm infants with BPD had a poorer outcome on visual acuity in the supplemented group.²⁸

Breast is still best

Twenty-eight countries, most recently the US, have infant formulas supplemented with LCPUFAs on the market, and over half a million infants have been fed on these formulas with no clinically significant adverse effects. Studies of LCPUFA supplementation are generally small in size, however, and have yielded conflicting results on its efficacy, particularly for the term infant. Moreover, long-term data on beneficial or adverse effects of routine LCPUFA supplementation are not available.

Larger studies have consistently failed to demonstrate a significant benefit from supplementation. Systematic reviews using stricter criteria for inclusion in the meta-analysis, such as the Cochrane systematic review, have yielded a paucity of evidence to indicate significant, sustained benefits in either visual function or cognitive development of term and preterm infants receiving LCPUFA– supplemented formula. It is unclear what other factors in association with the LCPUFAs in human milk facilitate neurodevelopment in infants. LCPUFAs exist at different positions in the triglyceride molecules of single-cell oil and human milk. The relevance of their positioning is unclear.

In light of the available information, pediatricians should continue to strongly recommend breastfeeding of both full-term and preterm infants (see the Guide for Parents). Larger studies with longer follow-up are needed to determine conclusively the cost-effectiveness and safety of routine LCPUFA supplementation of infant formulas.

DR. CHANDRAN is associate professor of clinical pediatrics and director, division of general pediatrics, Health Sciences Center, State University of New York at Stony Brook. She has nothing to disclose in regard to affiliations with, or financial interests in, any organization that may have an interest in any part of this article.

REFERENCES

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3. Lucas A, Morley R, Cole TJ, et al: Early diet in preterm babies and developmental status at 18 months. Lancet 1990;335(8704):1477

4. Heird WC: The role of polyunsaturated fatty acids in term and preterm infants and breastfeeding mothers. Pediatr Clin North Am 2001;48(1):173

5. Innis SM, Akrabawi SS, Diersen-Schade DA, et al: Visual acuity and blood lipids in term infants fed human milk or formulae. Lipids 1997;32(1):63

6. Makrides M, Neumann MA, Simmer K, et al: Erythrocyte fatty acids of term infants fed either breast milk, standard formula, or formula supplemented with long-chain polyunsaturates. Lipids 1995;30(10):941

7. Makrides M, Neumann MA, Byard RW, et al: Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infants. Am J Clin Nutr 1994; 60(2):189

8. 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

9. Birch EE, Hoffman DR, Uauy R, et al: Visual acuity and the essentiality of docosahexaenoic acid and arachidonic acid in the diet of term infants. Pediatr Res 1998;44(2):201

10. Jorgensen MH, Hernell O, Lund P, et al: Visual acuity and erythrocyte docosahexaenoic acid status in breast-fed and formula-fed term infants during the first four months of life. Lipids 1996;31(1):99

11. Birch EE, Hoffman DR, Castaneda YS, et al: 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(3):570

12. 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

13. Carlson SE, Ford AJ, Werkman SH, et al: 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(5):882

14. SanGiovanni JP, Berkey CS, Dwyer JT, et al: Dietary essential fatty acids, long-chain polyunsaturated fatty acids, and visual resolution acuity in healthy full-term infants: A systematic review. Early Hum Dev 2000; 57(3):165

15. Simmer K: Long-chain polyunsaturated fatty acid supplementation in infants born at term. Cochrane Database Syst Rev 2000(2):CD000376.

16. Hoffman DR, Birch EE, Birch DG, et al: Effects of supplementation with omega-3 long-chain polyunsaturated fatty acids on retinal and cortical development in premature infants. Am J Clin Nutr 1993;57(5 Suppl):807S

17. Faldella G, Govoni M, Alessandroni R, et al: Visual evoked potentials and dietary long-chain polyunsaturated fatty acids in preterm infants. Arch Dis Child Fetal Neonatal Ed 1996;75(2):F108

18. Carlson SE, Werkman SH, Rhodes PG, et al: Visual acuity development in healthy preterm infants: Effect of marine oil supplementation. Am J Clin Nutr 1993; 58(1):35

19. O'Connor DL, Hall R, Adamkin D, et al: Growth and development in preterm infants fed long-chain polyunsaturated fatty acids: A prospective, randomized, controlled trial. Pediatrics 2001;108(2):359

20. SanGiovanni JP, Parra-Cabrera S, Colditz GA, et al: 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(6):1292

21. Simmer K: Long-chain polyunsaturated fatty acid supplementation in preterm infants. Cochrane Database Syst Rev 2000(2):CD000375.

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23. Carlson S, Mehra S, Kagey W: Growth and development of term infants fed formulas with docosahexaenoic acid (DHA) from algal or fish oil and arachidonic acid (AA) from fungal oil. Pediatr Res 1999;45:278

24. Fewtrell MS, Morley R, Abbott RA, et al: Double-blind, randomized trial of long-chain polyunsaturated fatty acid supplementation in formula fed to preterm infants. Pediatrics 2002;110(1 Pt 1):73

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The parent guide on choosing a formula with LCPUFA may be photocopied and distributed to families in your practice without permission of the publisher.

GUIDE FOR PARENTS

Does your infant need a formula supplemented with long-chain polyunsaturated fatty acids?

LCPUFAs are chemical compounds known as long-chain polyunsaturated fatty acids. Two of them have been found in human milk, and they are present in high concentrations in the nerve tissue and retina of the eye. Because babies fed on human milk score higher on cognitive and neurodevelopmental tests than babies fed infant formula, interest in adding LCPUFAs to formula has increased. Recently, two infant formulas supplemented with LCPUFAs in oils derived from single-cell organisms (algae or fungi) have been put on sale in the United States for use in full-term infants.

Doctors and other scientists have studied infant formulas with different concentrations of LCPUFAs. They have tested visual function and neurologic (nervous system) development among infants receiving human milk, unsupplemented formula, and formula supplemented with LCPUFAs. Because the tests are performed on young infants, some of them are difficult to do and may not be very reliable. Most studies have involved only small numbers of infants and have not followed the babies for longer than a year. So the long-term impact of supplemented formulas on infants is really still unknown. Moreover, these studies have produced conflicting results. When strictly reviewed, they do not provide strong evidence of significant benefit from using formula supplemented with LCPUFAs.

Are supplemented formulas safe?

Although some concerns have been raised about infant growth and other issues, none of them have been proved. LCPUFAs in oils extracted from single-celled organisms are generally considered safe. For this reason the Food and Drug Administration (FDA) has recently approved their use as an additive to infant formula for full-term babies. LCPUFA-supplemented formulas are not approved by the FDA for use in premature infants.

How much do these formulas cost?

The wholesale prices of LCPUFA– supplemented formulas are about 15% higher than the prices of unsupplemented formulas currently on the market. Their cost is not covered by the special supplemental nutrition program for Women, Infants and Children (WIC).

What should you do?

Breastfeeding is the best option for your baby. If you choose not to breastfeed, discuss with your pediatrician whether to use LCPUFA-supplemented infant formula. If you have a full-term infant and can afford the price, consider using supplemented formula with the understanding that such formulas are generally considered safe and may or may not offer a real benefit for your child.

Reproduction for any other purpose requires express permission of the publisher.