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American Journal of Clinical Nutrition, Vol. 71, No. 1, 245S-250S, January 2000
© 2000 American Society for Clinical Nutrition

Supplements

Essential fat requirements of preterm infants1,2,3

Ricardo Uauy and Dennis R Hoffman

1 From the Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, and the Retina Foundation of the Southwest, Dallas.

2 Supported by National Institute of Child Health and Human Development grant HD 22380.

3 Address reprint requests to DR Hoffman, Retina Foundation of the Southwest, 9900 North Central Expressway, #400, Dallas, TX 75231. E-mail: dhoffman{at}retinafoundation.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 BASIS FOR ESSENTIALITY
 EFFECTS OF ESSENTIAL FATS...
 PRETERM INFANT STUDIES
 CONCLUSIONS
 REFERENCES
 
The interest in factors that modify early infant development has led investigators to focus on n–3 and n–6 long-chain polyunsaturated fatty acids (LCPUFAs) in the past 2 decades. The presence of docosahexaenoic acid (DHA) and arachidonic acid (AA) in breast milk, compared with their absence from infant formulas available in the United States, has prompted clinical trials designed to examine whether LCPUFA enrichment of infant formula has beneficial effects on maturational events of the visual system. These trials have shown significant functional advantages of LCPUFA supplementation for preterm infants, whereas benefits for full-term infants remain controversial. The growth and safety of preterm infants was not compromised by LCPUFA enrichment, although these issues remain to be resolved in clinical trials with full-term infants.

Key Words: Essential fatty acids • docosahexaenoic acid • arachidonic acid • dietary fat • visual function • lipids • marine oil • preterm infants • human milk • breast milk • infant formula • long-chain polyunsaturated fatty acids


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
BASIS FOR ESSENTIALITY
 EFFECTS OF ESSENTIAL FATS...
 PRETERM INFANT STUDIES
 CONCLUSIONS
 REFERENCES
 
Lipids provide most of the dietary energy and constitute the major energy stores in the bodies of infants and young children. Traditionally, the main concern regarding dietary lipids was in their digestibility. Presently, there is growing interest in the quality of the dietary lipid supply during infancy as a major determinant of growth, visual and neural development, and long-term health (1). Thus, the selection of the dietary lipid supply during early life is considered to be of great importance. Lipids are structural components of all tissues and are indispensable for cell membrane synthesis. The brain, retina, and other neural tissues are particularly rich in long-chain polyunsaturated fatty acids (LCPUFAs; 2, 3). In addition to their structural roles, these fatty acids serve as specific precursors for production of eicosanoids (eg, prostaglandins, prostacyclins, thromboxanes, and leukotrienes). Eicosanoids are powerful autocrine and paracrine regulators of numerous cell and tissue functions, including thrombocyte aggregation, inflammatory reactions and leukocyte functions, vasoconstriction and vasodilatation, blood pressure, bronchial constriction, and uterine contraction (4). Dietary lipid intake also affects cholesterol metabolism at an early age and is associated with cardiovascular morbidity and mortality later in life (5). As reported herein, the dietary supply of lipids, especially the provision of LCPUFAs, has been shown to affect neural and retinal structural development and function.


   BASIS FOR ESSENTIALITY
TOP
 ABSTRACT
 INTRODUCTION
 BASIS FOR ESSENTIALITY
EFFECTS OF ESSENTIAL FATS...
 PRETERM INFANT STUDIES
 CONCLUSIONS
 REFERENCES
 
In 1929, George and Mildred Burr (6) introduced the concept that specific components of fat may be necessary for proper growth and development of animals and possibly humans. They proposed that the following 3 fatty acids be considered essential; linoleic acid (LA, 18:2n–6), arachidonic acid (AA, 20:4n–6), and {alpha}-linolenic acid (ALA, 18:3n–3). The essentiality of n–6 and n–3 fatty acids for humans is best explained by the inability of animal tissues to introduce double bonds in positions before carbon 9, counting from the methyl- or n-terminus. If the diet lacks n–3 and n–6 essential fatty acids, tissues accumulate eicosatrienoic acid (20:3n–9). The ratio of triene-containing to tetraene-containing fatty acids (20:3n–9 to 20:4n–6) may be used as an index of essential fatty acid deficiency, but is not valid as a marker of isolated n–3 deficiency (7). Typically, in n–3 fatty acid deficiency, the n–6 LCPUFA, docosapentaenoic acid (22:5n–6), tends to accumulate while the major n–3 LCPUFA, docosahexaenoic acid (DHA; 22:6n–3), decreases in tissue lipids (8). The biochemical and functional evidence indicates that in early life, ALA is not sufficiently converted to DHA (9, 10). Thus, not only LA and ALA but also DHA should be considered essential nutrients for normal human eye and brain development. DHA has a 22-carbon chain with 6 double bonds, making it one of the most highly unsaturated fatty acids in the human body. Metabolism of ALA involves a series of desaturases (which add double bonds to the molecule) and elongation reactions that add 2-carbon units. The final steps in DHA biosynthesis have been defined by Voss et al (11) as desaturation, elongation, and ß-oxidation reactions to convert the 22-carbon derivative (22:5n–3) to the end product, DHA. Although DHA represents a small percentage of the fatty acids in most human tissues, it reaches concentrations of 30–40% of total fatty acids in rod photoreceptor outer segments in the human retina (2). This high concentration of a highly unsaturated fatty acid can increase membrane fluidity (12, 13) and, in turn, modify the mobility of proteins and the activities of retinal enzymes critical to transduction of visual signals.

Essential fatty acids were considered to be of marginal nutritional importance for humans until the 1960s, when signs of clinical deficiency became apparent in infants fed skim milk–based formula and those given lipid-free parenteral nutrition (14, 15). These infants presented with growth faltering and dryness, desquamation, and thickening of the skin as frequent manifestations of LA deficiency. The epidermal pathology was primarily associated with deficiency of n–6 essential fatty acids, whereas more subtle clinical symptoms appear in n–3 essential fatty acid deficiency. The latter include effects on neurodevelopment, abnormal visual function, and peripheral neuropathy (16).


   EFFECTS OF ESSENTIAL FATS ON GROWTH AND NEURODEVELOPMENT
TOP
 ABSTRACT
 INTRODUCTION
 BASIS FOR ESSENTIALITY
 EFFECTS OF ESSENTIAL FATS...
PRETERM INFANT STUDIES
 CONCLUSIONS
 REFERENCES
 
Animal data accumulated over the past few decades strongly support the need for LCPUFAs in early life. Deficiency of n–3 fatty acids has resulted in abnormal electroretinographic (ERG) responses in rats (17, 18) and monkeys (8). Direct information from humans is limited because human investigation in this area began just one decade ago. Studies reported in the early 1990s provided evidence that dietary n–3 fatty acid deficiency affects eye and brain function of preterm infants as measured by ERG, cortical visual evoked potentials (VEPs), and behavioral testing of visual acuity (19–22). Changes in membrane chemical structure are likely to be responsible for the observed functional effects, and a molecular model for the role of DHA as a modulator of rhodopsin function has been proposed (23). Preliminary evidence suggests that term infants should also receive dietary DHA supplementation.

The unique relation between breast milk and essential fatty acid metabolism is based on the direct supply of LCPUFAs bypassing the regulatory step of the {Delta}6-desaturase. The effects of providing AA or DHA are not replicated by providing the equivalent amounts of LA or ALA because there appears to be inadequate conversion of ALA to DHA during infancy (9, 10, 24). Excess dietary LA associated with use of some vegetable oils, particularly safflower, sunflower, and corn oils, may reduce the formation of DHA from ALA because the {Delta}6-desaturase is inhibited by excess substrate (25). Therefore, provision of preformed DHA in infant formulas would bypass these biosynthetic inhibitory steps to achieve n–3 LCPUFA concentrations comparable to those in breast milk. Marine oils provide substantial amounts of preformed n–3 LCPUFAs such as DHA and eicosapentaenoic acid (EPA; 20:5n–3), however they provide minimal amounts of AA.

Clinical trials reported since 1992 have provided convincing evidence of the efficacy of modifying the LCPUFA composition of preterm infant formulas to reflect that of breast milk (26–30). Comprehensive clinical studies have shown that dietary supplementation with LCPUFAs results in increased blood concentrations of DHA and associated improvement in visual function to match that of breast-milk-fed preterm infants.


   PRETERM INFANT STUDIES
TOP
 ABSTRACT
 INTRODUCTION
 BASIS FOR ESSENTIALITY
 EFFECTS OF ESSENTIAL FATS...
 PRETERM INFANT STUDIES
CONCLUSIONS
 REFERENCES
 
In our studies (19–21, 31, 32), preterm infants received breast milk or were randomly assigned to receive 1 of the 3 following formulas: 1) corn-oil-based (CO) formula that provided 24% of total fat as LA and 0.5 % as ALA; 2) soy-oil-based (SO) formula that provided 21% of total fat as LA and 2.7% as ALA; and 3) soy- and marine-oil-based (SMO) formula that provided 20% of total fat as LA, 1.4 % as ALA, 0.65% as EPA, and 0.35% as DHA. The CO and SO provided no LCPUFA and the SMO provided no AA. The significant results of this research included a marked inability of the CO to support the necessary accumulation of LCPUFAs in plasma and red blood cell (RBC) lipids. Dietary supplementation of n–3 LCPUFAs was sufficient to elevate blood lipid DHA concentrations in the SMO group to concentrations that were 2- to 5-fold higher than those in the CO and SO groups (26). The functional impact of this fatty acid modification included significant maturation of ERG responses in infants fed SMO compared with infants fed CO or SO at 36 wk postconceptional age (PCA) (19, 21). ERG thresholds (the minimum amount of light required to elicit a given retinal response) were found to be equivalent in the groups of infants fed SMO and breast milk, but were significantly elevated (ie, less mature) in the SO group and even more so in the CO group.

In Table 1Go, the fatty acid composition of plasma phospholipids from infants in the 3 formula-fed groups and the breast-milk-fed group at 57 wk PCA (ie, after 26 wk on the respective diets) is shown. Infants who received DHA-containing diets (breast milk or SMO formula) had significantly higher concentrations of DHA in their plasma phospholipids than did the CO group, which was deficient in n–3 fatty acids, or the SO group, which received adequate amounts of ALA but no LCPUFAs. Supplementation of formula with n–3 LCPUFAs significantly reduced accumulation of long-chain n–6 fatty acids in infant plasma phospholipids and provided a better (ie, lower) ratio of n–6 to n–3 LCPUFAs than was found in the n–3 LCPUFA-deficient CO and SO groups.


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  		TABLE 1. Fatty acid composition, as percentage of total fatty acids, of plasma phospholipids in preterm infants at 57 wk postconceptional age1
 
By 57 wk PCA, when retinal development is nearly complete, the CO group reached normal levels in all indexes of retinal function except oscillatory potentials (21). The results of visual acuity tests that measure higher neural activity such as cortical function (ie, pattern-reversal VEP) or cortical plus motor function (ie, forced-choice preferential looking) showed less maturity in the CO and SO groups throughout the 6-mo study (20). The LCPUFA-supplemented SMO group had significantly better visual acuity as measured by VEP and preferential looking procedures than the n–3 deficient CO group, whereas visual acuity in the SO group was intermediate. The DHA concentration in each lipid fraction was found to be significantly correlated with both VEP and preferential looking acuities (32). The best correlations for VEP acuity and preferential looking acuity were found with the RBC phosphatidylserine-plus-phosphatidylinositol fraction (r = –0.71; P = 0.0001) and the RBC phosphatidylethanolamine fraction (r = –0.40; P = 0.0041), respectively. Highly significant correlations were also found between each of these measures of visual acuity and the ratio of n–6 to n–3 LCPUFA in multiple lipid fractions from study infants (Table 2Go). High ratios of n–6 to n–3 LCPUFAs were associated with poorer visual function (ie, high values of VEP and preferential-looking acuity; visual function units = log of the minimum angle of resolution).


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  		TABLE 2. Correlations between visual function and the ratio of n–6 to n–3 long-chain polyunsaturated fatty acids (LCPUFAs) in blood lipids of preterm infants at 57 wk postconceptional age1
 
The DHA concentrations in all lipid fractions were highly correlated with VEP measures. However, there was a slightly better correlation between preferential looking visual acuities and both the RBC phosphatidylcholine and RBC phosphatidylethanolamine fractions (32). No correlations between visual function and concentrations of the parent n–3 fatty acid, ALA, were found, but the n–6 LCPUFA, AA, was significantly correlated with visual outcomes such that higher AA concentrations in RBCs were associated with poorer VEP acuities (r = 0.43, P = 0.0015) at 57 wk PCA.

No significant differences among the 3 formula-fed groups in growth indexes were evident, despite reduced concentrations of AA in the SMO group; this was probably attributable to EPA accumulation (2–4-fold higher than in the other groups). These results were supported further by the standardized z scores for body weight, body length, and head circumference that were determined for all the infants who completed the 6-mo study (31). Absolute growth data were transformed to z scores with the use of National Center for Health Statistics norms (33). Body length and weight in the LCPUFA-supplemented group were not reduced; this is in contrast to the observations of Carlson et al (34). Differences in subject selection criteria and formula composition (higher LA and insufficient mineral and vitamin content), as well as the longer duration of LCPUFA provision (9 mo compared with 4 mo), may explain the differences between the 2 studies. The reduction in the n–6 LCPUFA, AA, when fish oil was provided as a source of n–3 fatty acids was a significant finding in this study. The reduction in AA was associated with reduced weight and length growth (r = 0.27–0.53, P < 0.05; 32). Similar correlations have been reported by others, yet no study has specifically tested this hypothesis prospectively (35–37).

In 1996, Leaf et al (38) reported the results of a small study (n = 16) with 2 groups of preterm infants fed breast milk; the infants were fed either limited (<50% of intake) or mostly (>50% of intake) breast milk for 24 wk. Both groups received early parenteral nutrition with Intralipid 20% (Pharmacia Ltd, London) containing preformed DHA. The authors reported no diet-related differences between the groups in RBC DHA concentrations or visual function measured by ERG at 38 wk PCA or VEP at 52 wk PCA. There was a positive correlation between blood DHA concentrations and ERG b-wave implicit times, suggesting that a retardation of the visual transduction signal was associated with elevated DHA concentrations. However, the lack of a control diet group (with no DHA) and the small group size limit the conclusions that can be drawn from this study.

In the randomized clinical study conducted by Carlson et al (22), preterm infants supplemented with 0.2% DHA and 0.3% EPA had better visual acuity (measured by the Teller Acuity Card Tests) at 2 and 4 mo of age. After this age, control infants reached the level of the supplemented infants in visual function measurements. These investigators also reported evidence of more rapid visual processing, as measured by the look-duration assessment of Fagan Test of Infant Intelligence (39), at 12 mo of age in LCPUFA-supplemented infants (40).

The question of whether enriching formula with DHA has direct benefits for visual and cognitive function was addressed in Carlson's (40) second preterm infant study; the infants were fed low-EPA marine-oil formula (containing 0.2% DHA and 0.06% EPA) up to 2 mo corrected age. This study found improved visual development at the 2-mo follow-up (28) and a 10-point difference in IQ favoring the DHA-supplemented group at 12 mo (40), showing that short-term provision of dietary DHA in infancy had long-term effects. Furthermore, the DHA-supplemented group had shorter look times in the novelty-preference test at 12 mo, suggesting better visual processing. No significant decrease in AA or deleterious effects on growth were observed at 2, 4, or 12 mo when low-EPA marine-oil formula (0.06% EPA) was used. However, this cohort of n–3 LCPUFA-supplemented infants weighed less at 6 and 9 mo and had smaller head circumferences at 9 mo of age compared with infants fed commercial formula. We are presently completing a study using formulas containing DHA and DHA plus AA to determine whether DHA supplementation by itself is sufficient or if DHA plus AA is needed to optimize efficacy, prevent deleterious effects, and maintain a balanced n–6 to n–3 fatty acid ratio. Additional preterm infant studies conducted in other laboratories (38, 41, 42) have confirmed the need for LCPUFA enrichment of formula to maintain blood concentrations of n–3 and n–6 LCPUFAs in these at-risk infants.

The highly unsaturated nature of DHA (with 6 double bonds) not only appears to contribute unique biophysical properties to the lipid membrane but also makes DHA particularly susceptible to lipid peroxidation. Because the generation of damaging free radicals is associated with extensive lipid peroxidation, there is concern regarding the safe use of LCPUFAs in infant formula. In conjunction with our preterm infant feeding studies, we followed several biological safety measures (31). We found that supplementation of formula with marine oil to provide 0.65% and 0.35% of total fat as EPA and DHA, respectively, did not result in clinically significant abnormalities. Bleeding time was measured in the preterm infants at 34 wk (after {approx}3 wk on the diets) and at 57 wk (after {approx}26 wk on the diets). When we used a pediatric lancet device, infants in the SMO group had significantly longer bleeding times than infants in the CO group at 34 wk (2.15 ± 0.69 compared with 1.67 ± 0.52 min, respectively; P < 0.05) but there were no differences among the groups at 57 wk. When we used an adult-type lancet device, there were no group differences at either 34 or 57 wk. None of the infants in any group had bleeding times outside the upper limit of normal (7 min).

RBC membrane function was not altered by dietary fat in this preterm infant study (31). Steady-state fluorescence of diphenylhexatriene was used to measure rotational membrane fluidity in RBCs from infants at study entry (31 wk), 36 wk, and 57 wk at both 25°C and 37°C. There were no significant differences among the groups of infants fed different formulas or breast milk. RBC membrane fragility was assessed after a hydrogen peroxide challenge and was not significantly different among the diet groups. Similarly, there were no differences in native concentrations of lipid peroxides (measured as thiobarbituric acid reactive substances) or in azide-challenged lipid peroxide concentrations (ie, blocking the activity of constituent antioxidant enzymes). In addition, the n–3 LCPUFAs had no effect on plasma concentrations of vitamins A or E (31). Both vitamin A and E concentrations in the LCPUFA-supplemented infants were within 10% of those in breast milk–fed infants and were marginally higher than those of the CO or SO groups. Overall, supplementation of formula with a fish-oil preparation of n–3 LCPUFAs (with both EPA and DHA) did not result in any growth or safety issues during this 6-mo feeding regime in a preterm infant population. New, second-generation infant formulas have refined concentrations of ALA, DHA, and AA with little or no added EPA.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 BASIS FOR ESSENTIALITY
 EFFECTS OF ESSENTIAL FATS...
 PRETERM INFANT STUDIES
 CONCLUSIONS
REFERENCES
 
Studies have shown that LCPUFAs have beneficial effects on infant development; the effects on visual and neural development are of particular interest. Breast milk has proven to be the best available source of dietary fat and essential fatty acids for infants. Recent technological advances on the basis of chemical and physical separation of the unsaturated fatty acids have permitted the elaboration of concentrated DHA and AA for clinical use. The development of single-cell oil sources has allowed for novel forms of LCPUFA delivery. Before the 1990s, low concentrations of ALA were found in most infant formulas, but by now virtually all infant formulas available in developed countries are supplemented with ALA and several manufacturers in Europe and Japan have added DHA, DHA plus AA, or 18:3n–6 to preterm and term infant formulas. Despite international recommendations, many developing countries continue to use formulas based on vegetable oil that are low in ALA. This is partly related to insufficient knowledge and the cost of modern commercial formulas.

The efficacy of LCPUFA supplementation for preterm infants seems fairly well established, but there is greater controversy about the results from term infant studies that assessed LCPUFA supplementation. Two randomized clinical studies showed benefits to visual function when formula DHA concentrations were >0.35% (43, 44). A third study showed transient benefits at a concentration of 0.23% (45), whereas a multicenter study in which 2 concentrations of DHA (0.23% and 0.12%) were fed showed no differences in visual function (46). Two factors that may help to explain the discrepancies among the results from these studies are the different methodologies used to measure visual acuity (some with greater variability than others) and the different concentrations of ALA in the study formulas.

We want to underscore the need for more comprehensive safety evaluation before the practice of LCPUFA supplementation can be advocated. Safety issues have been addressed in small- to medium-sized studies, but trials with larger sample sizes are required to identify potential side effects that have a low prevalence.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 BASIS FOR ESSENTIALITY
 EFFECTS OF ESSENTIAL FATS...
 PRETERM INFANT STUDIES
 CONCLUSIONS
 REFERENCES
 

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