Long-Chain Polyunsaturated Fatty Acid Supplementation Of Infant Formula

Executive Summary

• Experts disagree about whether it is necessary to include the long-chain polyunsaturated fatty acids docosahexaenoic acid (DHA) and arachidonic acid (ARA) in infant formulas to promote optimal brain and visual development.
• It has been widely reported in the news media that breastfed children have higher IQs than formula-fed children, and that the presence of DHA and ARA in human milk is responsible for this difference. However, the scientific evidence does not conclusively support either of these statements. In actuality, it is uncertain whether there is any difference in IQ between breastfed and formula-fed children that cannot be accounted for by differences in parental education, family income, and related factors. If a true difference in IQ does exist, components of human milk other than DHA and ARA and/or aspects of breastfeeding other than milk composition may be responsible.
• Several research studies have compared the visual or neurological development of infants receiving formulas supplemented with DHA/ARA with that of infants receiving conventional formulas. The results of these studies have also been inconsistent. Because few of the studies have followed the children beyond the age of two years, the long-term effects of DHA/ARA supplementation on development continue to be unknown.

Some concerns have been raised about the safety of adding DHA/ARA to infant formulas. Actually, the safety issues in question appear to be relatively minor. But because infant formula is the sole source of nutrients for many infants, making changes in formula composition must always be approached with extreme caution. Based on extensive clinical testing, the U.S. Food and Drug Administration has approved supplementation of formulas intended for full-term infants with DHA and ARA.

The American Council on Science and Health has examined the issue, and has also concluded that such supplementation is safe. While currently available scientific evidence does not clearly establish the advantages of including DHA and ARA in infant formulas, such supplemented formulas have been used safely in many countries.

• Although breastfeeding is the preferred form of infant feeding, formula-feeding is an acceptable alternative that provides adequate nutrition. The infant formulas currently sold in the U.S. are designed to provide complete nutrition for young infants and to serve as a major source of nutrients for older infants. DHA- and ARA-supplemented formulas are now being offered in the United States. Their composition and production, like those of all infant formulas, are strictly controlled by federal law. Parents can be confident that the formulas that they feed to their infants are safe and nutritious, as long as they are prepared and handled correctly.
• Sigma Economic issues may also help determine the choice of infant formula. DHA/ARA-supplemented formulas may be expected to be somewhat more expensive than similar ones that do not contain these fatty acids.
• Currently, long-term studies that demonstrate a clear developmental advantage for infants fed DHA- and ARA-supplemented formulas are lacking. Thus, ACSH cannot urge all parents who elect to use formulas to choose the DHA- and ARA-supplemented varieties. Such decisions must be made on an individual basis with input from an infant's healthcare provider.

Introduction

The question of whether it is beneficial to add certain fatty acids to infant formula remains controversial. These fatty acids, docosahexaenoic acid (DHA) and arachidonic acid (ARA), are present in human milk and are believed by some experts to play an important role in early visual and neurological development. Thus, some researchers think that any formula without DHA and ARA is a deficient product providing less-than-optimal nutrition. Others argue, however, that the addition of these fatty acids to infant formula has not been shown conclusively to be useful. The controversy has spilled over into the popular press as well as the scientific literature; even some formula manufacturers seem reluctant to urge universal use of the supplemented formulas (1).

This special report by the American Council on Science and Health (ACSH) reviews the current scientific evidence on the role of DHA and ARA in infant nutrition. The report focuses primarily on the nutritional needs of healthy, full-term infants. Premature infants and those with special health problems may have different nutritional needs.

Background: Basic Facts About Fats

The fats in our diet and in our bodies contain a variety of different types of fatty acids. Fatty acid molecules consist primarily of long hydrocarbon chains (chains of carbon atoms with hydrogen atoms bound to them) (2). Many of the common fatty acids contain 18 carbons. However, some fatty acids have longer chains, and others have shorter ones.

The links in the carbon chain of a fatty acid may consist of either single bonds or double bonds, as shown in Figure 1. The number and position of double bonds in fatty acids are very important in terms of their effects in the human body and their health implications.

In a saturated fatty acid, all of the links between carbon atoms are single bonds. In an unsaturated fatty acid, at least one link is a double bond. An unsaturated fatty acid that has only one double bond is called monounsaturated. An unsaturated fatty acid with two or more double bonds is called polyunsaturated. Figure 2 shows examples of saturated, monounsaturated, and polyunsaturated fatty acids. In numbering, the left-most carbon atom is number 1.

There are two different families of polyunsaturated fatty acids: the n-3 series and the n-6 series (2). The numbers refer to the location of the first double bond in the carbon chain either at the third or the sixth carbon atom. Figure 3 shows the locations of these double bonds. One n-3 and one n-6 polyunsaturated fatty acid are essential nutrients, meaning that they must be supplied by the diet. The human body can perform the biochemical reactions necessary to convert some of the fatty acids to others within a series, but it cannot convert an n-6 fatty acid into an n-3 fatty acid or vice versa. Table 1 lists some major food sources of n-3 and n-6 fatty acids. The n-6 fatty acid called linoleic acid and the n-3 fatty acid called alpha-linolenic acid are considered essential fatty acids.

Table 1: Food Sources of Polyunsaturated Fatty Acids

Both n-3 and n-6 fatty acids play important roles in the human body. In many of these roles, the two families of fatty acids have either complementary or contrary effects. It is possible, therefore, that the ratio of n-3 to n-6 fatty acids may be as important to health and nutrition as the absolute amounts present in the diet or in body tissues. Current Western diets tend to be relatively high in n-6 fatty acids and relatively low in n-3 fatty acids. This is due to our high intake of vegetable oils, which are rich in n-6 fatty acids, and our low intake of oils and foods rich in n-3 fatty acids, such as fatty fish.

Infant Formula: A Very Special Type of Food

Infant formula is a very special food product because it is intended to be used as the sole source of nourishment during the first four to six months of life (3). It must meet all of an infant's nutritional needs over this prolonged critical period, without any harmful inadequacies or excesses. Its composition is crucial to the infant's health.

Because human milk is considered to be the ideal food for full-term infants, it has served as the model for the composition of formulas. However, formulas need not exactly duplicate the composition of human milk. Formulas differ from human milk in several ways. For example, the levels of some nutrients in infant formula are deliberately made higher than those in human milk in order to compensate for differences in bioavailability (how well the body can absorb the nutrients).

Formulas intended for premature infants are a special case. After all, in the ideal situation, these infants wouldn't be eating at all. They would still be in the uterus, where they would receive nutrients through the placenta. The feeding of tiny infants who are not developmentally ready to eat is a particular challenge. Even human milk cannot fully meet certain of their nutritional needs (especially in the case of very low birth weight infants) and should be fortified with additional protein, certain vitamins, and minerals (3). Similarly, conventional formulas used in the feeding of full-term infants are not well suited for premature infants; for them, special fortified preterm formulas should be used (3).

Fats in Breast Milk and Infant Formula

Almost 50% of the calories in human milk and infant formula come from fat (3,4). To people who are accustomed to thinking in terms of adults' nutritional needs, this may seem astonishingly high. However, infants need this high level of fat in their diets in order to grow properly. The reduced-fat diets that are healthful for adults are not appropriate during the first two years of life (3).

Both human milk and infant formula contain a variety of different fatty acids. The exact mixture of fatty acids in commercial formulas, however, differs from that of human milk (3).

The fats in human milk are absorbed very easily from the digestive tract into the bloodstream. The fats in cows' milk are not so easily absorbed by human babies, however. To provide infants with a more absorbable fat source, manufacturers remove the butterfat from the cows' milk used in the preparation of infant formulas and replace it with a blend of vegetable oils that provides appropriate proportions of saturated and unsaturated fatty acids (3). Infant formulas are required to contain sufficient amounts of the two fatty acids that are known to be essential in human nutrition linoleic acid and alpha-linolenic acid (4).

Fatty Acids and Neurological Development

Docosahexaenoic acid (DHA) is an n-3 fatty acid with 22 carbon atoms. Arachidonic acid (ARA) is an n-6 fatty acid with 20 carbon atoms. During the last trimester of pregnancy, large amounts of these fatty acids, especially DHA, are deposited in the brain and in the retina of the eyes of the fetus. The relative amounts of these fatty acids in the brain and eyes continue to increase in the months after birth, and thus they are believed to be important in normal neurological and visual development in the fetus and infant.

Fatty Acids in Human Milk and Formula

Human milk naturally contains DHA and ARA, with levels varying depending on the mother's diet (4). Women consuming typical North American diets usually have relatively low milk DHA levels (0.2-0.4% of total fatty acids) (4). In contrast, DHA levels as high as 1.4% of fatty acids have been found in the milk of women who eat large amounts of fish (4). ARA levels in human milk have also been found to vary in women from different parts of the world who eat different types of diets (5,6). Human milk content of these fatty acids can also be increased if a lactating mother's diet is supplemented with them (7).

Currently, most standard infant formulas sold in the United States contain no DHA or ARA, but they do contain other fatty acids (alpha-linolenic acid and linoleic acid) that the infant can convert into DHA and ARA. Both full-term and premature infants can synthesize DHA and ARA from these precursors (8-10). It is uncertain, however, whether infants can produce enough DHA and ARA in this way to completely meet their needs (11). It is this uncertainty that has prompted the controversy about whether or not DHA and ARA should be added directly to infant formulas.

Cognitive Development in Breastfed and Formula-fed Infants

More than 20 scientific studies have compared the mental development of breastfed infants with that of formula-fed infants (12). In most of these studies, the test scores of children who had been breastfed tended to be higher than those of children who had been formula-fed. However, it has been difficult for scientists to determine whether this difference was due to the type of milk per se. The mothers of the infants in these studies chose for themselves whether to breastfeed or formula-feed; they were not assigned randomly to one condition or the other. Surveys have shown that, at least in the United States, women who choose to breastfeed tend to be older and more highly educated than those who do not (3,13). They also have higher family incomes. These factors, rather than breastfeeding itself, might be responsible for differences in the infants' test scores.

To attempt to resolve this issue, a group of researchers conducted a combined analysis of 11 similar studies of infant feeding and cognitive development that considered other factors as well. (12). These included socioeconomic status and the mothers' levels of education (which are markers of the mothers' IQ and parenting skills). They found that the average IQ scores of the breastfed children in these studies were 5 points higher than those of the formula-fed children before the other factors were taken into account. After the other factors were considered, the difference narrowed to 3 points. In both instances, the differences between the breastfed and formula-fed groups were statistically significant.

This doesn't necessarily mean, however, that the DHA and ARA in human milk are responsible for even this small difference in IQ. Other components of human milk may also be involved (14). The experience of breastfeeding, rather than the composition of the milk, might also be a relevant factor (14). In addition, characteristics of the mothers that were not controlled in the combined analysis may play a role. For example, in a study that was completed too recently to be included in the combined analysis, no difference was found between the IQs of breastfed and formula-fed children when the mothers' IQs and their scores on a test of parenting skills were taken into account (15). None of the earlier studies of infant feeding and intelligence directly measured these two factors.

Thus, it is unclear whether the IQs of breastfed children are truly higher than those of formula-fed children, and if a difference does exist, it is uncertain whether the DHA or ARA content of human milk is even partially responsible.

Effects of Diet on Blood Levels of Fatty Acids

The amounts and proportions of fatty acids in the diet do influence the fatty acid composition of blood and body tissues. This is true in both infants and adults. Nursing mothers who consume large amounts of fatty fish have higher levels of DHA in their milk than do mothers whose diets do not include such foods (16,17).

The blood DHA and ARA levels of infants fed standard formulas are lower than those of breastfed infants (18-21). And in breastfed babies, one study found that blood levels of DHA were associated with somewhat improved visual and neural development (22). The feeding of formulas supplemented with DHA or ARA can increase blood levels of these fatty acids so that they more closely resemble those found in breastfed infants (20,21,23-26). It is unclear, however, whether these biochemical differences translate into meaningful effects on development and function. The mere fact that blood levels of fatty acids vary in infants receiving different diets does not mean that the levels of these fatty acids cause a specific functional outcome. To determine this, it is necessary to examine the relationship between dietary intake, blood or tissue levels of specific fatty acids, and measures of actual functioning such as visual acuity tests or cognitive tests.

Studies of Visual Acuity and Neurological Development in Full-Term Infants

Only a small number of studies have sought to evaluate the effects of formula supplementation with DHA (or DHA and ARA) on measures of visual function or neurological development in full-term infants, and their results have been inconsistent. Table 2 lists the results of these studies. Most of the studies listed in the table included only small numbers of infants and assessed their visual function or neurological development at only one or a few time points. None of the studies completed to date followed the children beyond the age of two years. Thus, nothing is really known about the effects of formula supplementation on long-term development into later childhood, adolescence, or adulthood. Clearly, further research, including longer-term studies, is needed. There have been a few recent review reports that combine results of smaller studies (see Table 2). One found benefit from supplementation on cognitive development at 18 months of age (27). Similarly, one review of visual acuity studies found a benefit from DHA supplementation for two month-old babies (28), but another did not (29).

Table 2: Results of Studies of Formula Supplementation in Full-Term Infants

^* LCPUFA stands for long chain polyunsaturated fatty acids. This category includes both DHA and ARA, and may include other fatty acids as well.

Sources of Supplemental DHA and ARA

DHA and ARA for use in infant formula can come from egg yolk lipids (a source of both DHA and ARA), fish oil (a source of DHA only), or oils derived from special strains of single-celled algae and fungi (the algae synthesize DHA and the fungi synthesize ARA). The DHA- and ARA-supplemented infant formulas currently on the U.S. market derive their fatty acids from algal, fungal, and tuna oil sources, not from egg yolk lipids (42,43).

The principal concern about oils derived from algae and fungi (also called single-cell oil) has been that they are new food ingredients without a history of safe use in infant feeding in this country. All new food ingredients must undergo formal safety testing before they can be allowed in the food supply. Extensive toxicological studies have been conducted on oils from algae and fungi, with generally favorable results (4), and authorities in several countries have approved their use in infant formula. The U.S. Food and Drug Administration (FDA), after being petitioned by one manufacturer of single-cell oil (as is the normal procedure), declared them to be Generally Recognized as Safe (GRAS), thereby permitting their use in infant formulas (44).

One important safety issue that may pertain to all sources of DHA is the possible adverse developmental effect reported in one study of infants receiving supplemented formula (41). In that study, infants who had received formula supplemented with DHA from fish oil had lower scores on one vocabulary measure at age 14 months than breastfed infants did. On another vocabulary measure, the scores of fish oil-supplemented infants were lower than those of infants fed conventional formula. In the same study, infants receiving a formula supplemented with both DHA and ARA (from egg yolk lipids) did not show any evidence of adverse effects. It is unclear from this single study whether the lower scores in the DHA-only group were due to a specific effect of DHA, to the lack of ARA in the fish oil-supplemented formula, to other factors, or simply to random chance.

Concerns have also been raised about the possibility that formulas supplemented with DHA might lead to slower growth in infants. Slower growth was observed in two studies of preterm infants who received formulas supplemented with fish oil (45,46). The lack of ARA in these formulas may have been responsible for the effect. No adverse effects on growth have been observed in any studies in which formulas were supplemented with both DHA and ARA or in any studies of full-term infants. In fact, four studies of full-term infants that specifically addressed the growth issue (all of which involved both DHA and ARA) found no evidence of any adverse effect (24,26,40,47).

It is important to emphasize that there is no substantial, replicated body of evidence that feeding infants formulas supplemented with any of the available sources of DHA or ARA causes any harm or developmental delay.

Divergent Views on the Addition of DHA and ARA to Infant Formula

Scientists, health professionals, and officials in various countries differ in their views on whether DHA and ARA should be added to infant formula. Although some people have claimed that these divergent views are attributable to ulterior economic motives, it seems more likely that they reflect honest disagreements on how best to interpret an incomplete body of scientific evidence.

On the basis of the currently available evidence, authorities in some Asian and European countries have decided to allow but not require the inclusion of DHA and ARA in infant formulas. Various international organizations including the European Society for Pediatric Gastroenterology and Nutrition, the British Nutrition Foundation, the WHO/FAO Expert Committee on Fats and Oils in Human Nutrition, and the International Society for the Study of Fatty Acids and Lipids, have also approved their use (48).

An expert panel that was commissioned by the FDA to assess nutrient requirements for formulas issued a report in 1998 that recommended against the addition of DHA and ARA to full-term infant formulas at that time (4). The panel members concluded that the evidence of benefits to visual acuity or neurodevelopment was still inconclusive. The panel recommended that the question of including DHA and ARA in infant formulas should be reassessed within five years, after additional research has been completed. While the agency usually follows the advice of its expert panels, in this case, when additional studies showed no evidence of harm, and some showed benefits, the FDA is allowing sales of ARA and DHA-supplemented formulas, as noted above.

ACSH's View: Parents' Decision

After reviewing the scientific evidence, ACSH believes that the evidence for benefits of DHA and ARA-supplemented infant formulas is still equivocal at this time. The studies that have been completed to date have not consistently shown that supplementation of formulas with DHA and ARA has a lasting beneficial effect on infant development. It must be noted, however, that not all studies used the same methodologies supplementation levels, identity of fatty acid(s) added, ratio of n-3 to n-6 fatty acids, outcome measures, and ages differed and this fact may have influenced the lack of consistency in results. It does seem clear that such supplementation does not retard developmental progress. The Nutrition Committee of the American Academy of Pediatrics has noted the lack of a clear beneficial effect of DHA and ARA on infant development. The committee has suggested that the Academy not take an official stand on formula supplementation until more data on its effects has been collected (49).

At present, both supplemented and unsupplemented versions of the same formulas are available to American parents, and thus they will be able to choose which one they use. The supplemented versions will likely be more expensive than the unsupplemented ones (49). ACSH urges parents who choose to feed formula to discuss their choices with their infant's healthcare provider before opting for one type over the other.

The Special Situation of Premature Infants

The balance of risks, costs, and benefits of DHA/ARA supplementation for premature infants may prove to be different from that for full-term infants. Some experts believe that premature infants may have a greater need for dietary sources of DHA because they miss out on the DHA transfer from their mothers that ordinarily occurs near the end of pregnancy. On the other hand, because premature infants are fragile, they may be especially vulnerable to any adverse effects that might result from changes in formula composition.

Several studies have shown that premature infants who received formulas supplemented with DHA alone or DHA plus ARA had better scores on measures of visual function than those receiving unsupplemented formulas (34,39-43). In some of these studies, however, the effects were transient, disappearing as the infants grew older (34,39). Overall, the evidence for a potential benefit of DHA and ARA is stronger for premature infants than for full-term infants. Nevertheless, uncertainties remain because most of the studies have involved only small numbers of infants, who were followed for relatively short periods of time.

There is an urgent need for additional, longer-term studies of DHA and ARA supplementation in premature infants. Unlike full-term infants, many premature infants (especially those born very early or at very low birth weights) do not thrive. Providing them with the best possible nutrition may help to increase their chances of survival and decrease the risk of long-term health problems.

Putting the Fatty Acid Controversy into Perspective

Modern infant formulas are safe and nutritious. They contain all of the nutrients known to be essential to infants' health, including essential fatty acids. Practically all formula-fed full-term infants thrive, just as practically all breastfed full-term infants thrive.

It may be helpful to parents to know that enhanced cognitive development is not advocated as a major reason why breastfeeding is considered superior to formula feeding. The number one argument in favor of breastfeeding is that it substantially reduces the risk of infectious diseases, such as ear infections, lower respiratory tract infections, and gastrointestinal illnesses (3,37,44).

Although breastfeeding is the preferred method of infant feeding, formula-feeding is certainly an acceptable alternative. Parents who feed their infants any of the commercial iron-fortified infant formulas currently available in the United States and that now includes ARA- and DHA-supplemented versions can be confident that they are providing their infants with appropriate and adequate nutrition.

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