Essential Fatty Acid Requirements for Term and Preterm Infants

Lipids in Modern Nutrition, edited byM. Horisberger and U. Bracco. Nestld Nutrition,Vevey/Raven Press, New York © 1987.

Essential Fatty Acid Requirements for Termand Preterm Infants

Zvi Friedman

Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030

The essential fatty acids (EFAs) are a group of naturally occurring unsaturatedfatty acids with a chain length of 18, 20, or 22 carbon atoms and containing be-tween two and six methylene-interrupted double bonds in cis-configuration. Thesefatty acids are essential to the diet of humans and all higher animals, as they can-not be synthesized de novo from other lipids or from carbohydrates and aminoacids. There are two fundamental EFAs, linoleic and a-linolenic acid, from whichall others are derived metabolically (1-3). The essentiality of the polyunsaturatedfatty acids (PUFAs) is related to their capability to incorporate into lipids and toact as a precursor in the formation of prostaglandins.

PLACENTAL TRANSFER AND CORD BLOOD POLYUNSATURATEDFATTY ACIDS

Normal growth of infants is dependent upon an adequate supply of EFAs (4).The human fetus, like the adult, is unable to synthesize the EFAs, which musttherefore be derived from the maternal circulation and pass through the placenta.We confirmed the observations that maternal plasma lipids are elevated duringpregnancy and that these levels are significantly higher than in the neonate (5).However, we showed no change in cord plasma phospholipids, cholesterol esters,triglycerides, and free fatty acid concentration throughout gestation.

No differences in the fatty acid composition of the phospholipids, cholesterolesters, triglycerides, and free fatty acids were found in cord venous and arterialplasma obtained from 32 Caucasian infants at birth. The fatty acid composition ofcord plasma phospholipids at different gestational ages is shown in Fig. 1. Gesta-tional age varied from 24 to 44 weeks; all were normally grown infants. The con-centration of linoleic acid in cord plasma phospholipids was less than 40% that ofthe maternal value. The lowest levels of this fatty acid were noted before 34 weeksgestation. However, venous and arterial cord plasma contained higher concentra-tions of the more unsaturated fatty acid—arachidonate—than did maternal plasma(5,6). The concentration of docosahexaenoic acid, which is a homologue of the a-linolenic acid series, was noted to be higher in cord blood plasma at term as com-

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80 FATTY ACID REQUIREMENT FOR INFANTS

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FIG. 1. Percent fatty acid composition of plasma phospholipids in mothers and their infantsof 24-33, 34-37, 38-42, and 43-44 weeks of gestational age. Note that the relative percentof linoleic acid is lower in cord plasma phospholipids than in maternal plasma; however, thelevels of arachidonate, docosahexaenoic acid, and A-5,8,11-eicosatrienoic acid are higher incord plasma than maternal plasma. The relative percent of the latter acids increased with ad-vanced gestational age.

pared with maternal levels (5,6). The combined percentages of fatty acid concen-trations of the linoleic and linolenic acid series in cord plasma phospholipidshowed a steady rise in values from 25.5 at 24 to 33 weeks to 33.7 at 34 to 37weeks and 36.0 at term as compared with maternal levels of 39.9. The increasedcombined total of the linoleic acid series in plasma phospholipid correlated wellwith the tissue levels of these fatty acids (5). Bruce et al. (7) reported a continuousrise in the relative concentration of fatty acids of the linoleic series in skeletal mus-cle phosphoglycerides, from 10% at the beginning of the second trimester of gesta-tion to almost 50% at the age of 1 year. Factors that may be responsible for thesefindings are (a) the increased concentration of the polyenoic fatty acids—deriva-tives of linoleic acid—may result from increased activity of the fetomaternal unitby preferential transfer of these fatty acids in later gestation, or (b) enzymatic ac-tivity in the placenta or the fetus may be responsible for the desaturation and elon-gation of these essential fatty acids (8).

Fatty acid composition of adipose tissue triglycerides in the newborn infant alsodiffers from that of the mother (9) in the same manner as that of plasma lipids.These data are consistent with the presence of a placental transfer mechanism forcertain fatty acids, including the EFAs. Because of the low concentration of lino-leic acid in fetal adipose tissue, its contribution to fetal plasma free fatty acid com-position during lipolysis is small.

FATTY ACID REQUIREMENT FOR INFANTS 81

The concentration of the fatty acid A5,8,l 1-eicosatrienoic acid was found to behigher in cord plasma of all infants than in maternal plasma, and the level appearsto increase with advanced gestation (Fig. 1). Although this abnormal fatty acid iselevated in EFA deficiency, such a diagnosis is not certain at the time of birthsince the polyenoic acids of the linoleic acid series may be higher in the newborninfant than in the mother, yet the possibility is not eliminated that the infant mayhave a relative lack of EFAs. Furthermore, increased A-5,8,11-eicosatrienoic acidlevel may reflect a generalized increase in desaturation and/or elongation of fattyacid chains in the developing fetus.

TISSUE POLYUNSATURATED FATTY ACID COMPOSITION

Body stores of EFAs are low in low birth weight infants (10). The concentrationof linoleic acid in fetal tissue is less than that seen in adults, and the proportionof linoleic acid in muscle phospholipids is found to increase with advancing gesta-tional age (7).

We have analyzed various tissue samples from 25 human fetuses and newbornsfor the relative concentration of the fatty acids in phospholipids, cholesterol esters,triglycerides, and free fatty acids. Their gestational ages ranged from 16 to 44weeks. Representative tissue from kidney medulla and cortex is shown in Fig. 2.No differences are observed between the levels of the individual EFAs, linoleateand arachidonate, in the different tissues beyond 16 weeks of gestation. However,the level of arachidonate in the various tissue phospholipids is markedly elevatedas compared with the level of linoleic acid. These studies demonstrate that fetaltissues are rich in the EFA arachidonate, the prostaglandin precursor. Linoleateand arachidonate cord plasma values are a reflection of their tissue levels (9). Bothshow a reduced linoleate level compared with the maternal level; however, thelevel of higher homolog, arachidonate, is higher than the maternal value. The lowplasma concentration of linoleate reflects the reduced tissue level of this fatty acid.This situation increases the maternal-fetal gradient for linoleic acid, which mayfacilitate its transfer across the placenta. The relatively high concentration of thehigher PUFA arachidonate in fetal tissue could result from increased activity ofthe fetoplacental unit by preferential transfer of these fatty acids or by enzymaticactivity in the placenta or the fetus that is responsible for desaturation and elonga-tion of these EFAs. Tissue enrichment in arachidonic acid may play an importantrole by maintaining the normal function of biological membranes and serving as asubstrate for prostaglandin biosynthesis. These functions may influence fetal phys-iology during intrauterine development.

Following birth, the diet affects the fatty acid composition of adipose tissue. Inthe period of rapid weight gain, during early infancy, changes in adipose tissuecomposition can occur in a relatively short time (11,12). Widdowson et al. (13)demonstrated a profound difference in the fatty acid composition of adipose tissuebetween British and Dutch infants between birth and 1 year. The differences wereinfluenced directly by the nature of the fat in the diet.


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FIG. 2. Percent fatty acid composition of renal phospholipids in neonates at various gesta-tional ages. No changes are seen between the levels of linoleate and arachidonate in the renaltissue beyond 16 weeks of gestation. Closed circles, arachidonic acid medulla; open circles,arachidonic acid cortex; closed squares, linoleic acid medulla; open squares, linoleic acidcortex.

ESSENTIAL FATTY ACID DEFICIENCY SYNDROME

Associated with Oral Diets

Work with experimental animals showed that the very young are more suscepti-ble to develop EFA deficiency due to lack of fat in the diet than are adults (14).Similarly, body stores of EFAs are low in low birth weight infants, which resultsin the deficiency state becoming evident more rapidly and the administration of thedeficient nutrient inducing a more rapid response than in an adult. Most of theearlier studies that have been performed on humans included infants. These stud-ies, which started as early as 1919 by Von Groer (15), show the effects of dietslow in fat on growth or weight loss, susceptibility to infection (15,16), and skineruption (16). The observation that skin lesions in rats fed low-fat diet were curedby the addition of fats rich in PUFAs stimulated clinical studies in infants and chil-dren with chronic eczema (17). Moreover, these results were encouraging enoughto warrant further studies in order to evaluate the role of unsaturated fatty acids inhuman nutrition.

Combes et al. (18) did not observe skin changes uniformly in premature infants


who were fed milk mixtures low in linoleic acid for periods of 18 to 37 days.However, histologic features of the skin showed evidences of linoleic acid defi-ciency and serum di-, tri-, and tetra-anoic acid levels were significantly differentfrom infants fed 4% of the calories as linoleate. Hansen et al. (4) fed 42% healthyinfants one of five proprietary milk mixtures adequate in protein, minerals, andvitamins but varying in linoleic acid content from less than 0.1% to 7.3% of thecalories. Two of the milk mixtures were found to contain inadequate amounts oflinoleic acid for the infant's requirement. One was low in fat (1.0% of calories),and one contained fat low in linoleic acid. A high proportion of babies who werefed the latter two milk mixtures before 6 weeks of age and who remained on thediets for 3 months developed dry, thick desquamated skin and retarded growth.The clinical manifestations disappeared after the administration of diets that pro-vided 1% or more of calories as linoleic acid.

Further studies (19) demonstrated that infants do not usually show overt signsof fat deficiency until they have been on cow's milk formula for about 2 months.The clinical syndrome of linoleic acid deficiency appears as inefficient somaticgrowth with poor weight gain in spite of adequate caloric intake and skin lesions.These manifestations showed a dramatic response to a diet containing linoleicacid.

In infants fed diets low in linoleic acid, increased caloric consumption was re-ported by Adam (20). In spite of the differences of 20% to 40% in caloric intakebetween infants fed diets low in linoleic acids and infants fed linoleic acid supple-mented diets, weight curves were similar for the majority of infants. Hansen et al.(4) found no significant difference in caloric efficiency for infants between milkmixtures containing 2.8% or 7.3% of calories as linoleic acid.

Associated with Parenteral Nutrition

The provision of optimal nutrition for low birth weight infants and for infantswith congenital anomalies of the gastrointestinal tract and with inflammatorybowel disease remains a significant problem. Recently, total parenteral nutrition(TPN) has been established as a form of therapy for these conditions (21,22).Studies on infants who were maintained on long-term fat-free parenteral nutritiondemonstrated the development of clinical signs together with biochemical evidenceof EFA deficiency (23,24). The administration of diets containing linoleic acidconverted these clinical and biochemical manifestations to normal.

We studied (21) five sick newborns who were maintained on fat-free intrave-nous alimentation and developed very rapid biochemical changes in the plasmathat were compatible with the diagnosis of EFA deficiency during the first weekof life and were reversible with oral feedings containing EFAs. The youngest andsmallest infants exhibited these changes as early as the second and third days oflife.

The body of a premature infant of 1,000 g contains approximately 0.5% glyco-gen, 1% fat, and 8.5% protein (10). In such an infant, the total caloric reserve is


450 kcal/kg and the nonprotein calorie reserve is only 110 kcal/kg. The minimalmetabolic requirement of an infant this size is about 30 to 40 kcal/kg/24 hr on thefirst day of life and rises to 45 to 50 kcal/kg/24 hr thereafter. With increments foractivity, stress of hypo- or hyperthermia, asphyxia, infection etc, the total caloricexpenditure is probably in the order of 50 to 75 kcal/kg/24 hr. Because of thelimited nonprotein caloric reserve, these infants must mobilize fatty acids early forcaloric needs when faced with deficient dietary intake. Thus, the borderline storesof EFAs characteristic of the premature and the high caloric expenditure in theseinfants may contribute to the early onset of EFA deficiency, which we observedamong prematures on fat-free parenteral feedings. Furthermore, during parenteralhyperalimentation the outflow of linoleic acid from adipose tissue is blocked, atleast in part, by the high insulin levels accompanying glucose administration.During prolonged fat-free intravenous hyperalimentation, there is a correlationbetween low EFA levels in plasma and in tissues (24). Similar correlation hasbeen demonstrated by us (unpublished data) in cases with rapid onset of EFAdeficiency.

Effect on Red Blood Cells

Fatty acid composition of red blood cells changes in relation to dietary linoleateas it does in plasma, but the changes become evident more slowly (25). Nochanges in red blood cell osmotic fragility in neonates with rapid onset of EFAdeficiency were demonstrated in our study.

Effect on Platelets

The importance of arachidonic acid biotransformation in platelets has been elu-cidated (26). In addition, hemorrhagic problems of unknown etiology are commonin sick low birth weight infants (27). Many premature infants are being treatedwith TPN, and EFA deficiency is a frequent occurrence. Hence, we examined therapid onset of EFA deficiency in premature infants and its possible effect on plate-let function and found that the deficient infants had impaired platelet aggregationwhen compared with controls (28). In addition, the platelets from EFA-deficientinfants demonstrated clearly evidence of disaggregation. On recovery from then-deficient state, the low birth weight infants had platelet functions similar to thoseof apparently healthy premature infants. The relationship between the platelet dys-function and EFA deficiency is speculated on the possible connection between ara-chidonic acid depletion (i.e., EFA deficiency) and decreased thromboxane, a keymediator of human platelet aggregation. Decreased arachidonic acid content inplatelet phospholipids was documented in our laboratory in a newborn infant whorapidly developed EFA deficiency in the neonatal period (29).


Effect on Prostaglandins

We measured the excretion of the major urinary metabolite of prostaglandins E,and E2, 7a-hydroxy-5, 11-diketotetranor-prostane-l, 16-dioic acid (PGE-M) inthree infants during EFA deficiency, upon recovery from the deficiency state andin nine thriving control neonates (30). A significant difference between the PGE-M excretion in the group of infants with EFA deficiency before and after treatmentwas found (p < 0.05) (Fig. 3). Significant differences in PGE-M excretion werealso found between the control group and the EFA-deficient infants. The biochem-ical evidences of EFA deficiency and the decreased levels of PGE-M excretion arerapidly corrected when patients resume a diet containing EFA.

Effect on Pulmonary Surfactant

We studied a low birth weight infant who developed biochemical evidence ofEFA deficiency in the plasma after suffering from chronic bronchopulmonary dys-

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INTRALIPID

FIG. 3. Comparison of the urinary excretion of PGE-M expressed as nanograms/mg urinarycreatinine (CR) between three groups of infants: (a) Infants pre- and posttreatment with Intrali-pid; (b) thriving neonates (controls); and (c) infants with EFA deficiency and upon recovery.Note that PGE-M excretion following the administration of Intralipid is similar to the levels ob-tained from infants with essential fatty acid deficiency. (From ret. 30.)


plasia and recurrent episodes of necrotizing enterocolitis (31). A lower than nor-mal level of palmitic acid and an increased level of palmitoleic and oleic acidswere seen in pulmonary surfactant phospholipid components. Upon treatment andrecovery from EFA deficiency, the fatty acid pattern both in plasma and surfactantphospholipids returned to normal along with clinical improvements in the respira-tory illness. The impairment of surfactant phospholipids may diminish lung func-tion and so contribute to the pathophysiology of hyaline membrane disease,chronic bronchopulmonary dysplasia, cystic fibrosis (32), and other respiratorydiseases associated with inadequate nutrition inviting an EFA deficiency.

Effect on the Central Nervous System

The availability of long-chain PUFAs seems to be related to the degree of brainand central nervous system development. Linoleic and a-linolenic acids representa small proportion of the fatty acyl components of the phosphoglycerides of fetalbrain (8). In contrast, arachidonic and docosahexaenoic acids, more unsaturatedEFAs, are readily incorporated into the structural lipids of the developing brain(8,33). In humans, the brain undergoes an accelerated growth phase during the lasttrimester of pregnancy and the first 18 months of postnatal life. During this vulner-able period, EFAs are required for structural expansion of the brain.

Since brain phospholipids contain high levels of PUFAs of both the linoleic anda-linolenic acid series, it has been shown that changes in their ratio in the dietmodify the relative proportion of PUFAs derived from these essential precursors,in tissues including brain and brain subcellular structures (34).

White et al. (35) studied the brain lipids of three premature infants who weremaintained on fat-free parenteral nutrition and succumbed. They demonstratedfatty acid alterations indicative of essential fatty acid deficiency in the two majorcomponent phospholipids of brain, ethanolamine and choline phosphoglycerides,in the cerebrum and less so in the cerebellum. There was also a tendency towardreduction of brain phospholipid concentrations in these infants.

Crawford et al. (33) demonstrated in the human a stepwise progression in thedegree of polyunsaturation and chain length from maternal diet to maternal liver,placenta, fetal liver, and fetal brain. Thus, it is attractive to postulate that pro-longed intra- and extrauterine malnutrition may produce a low birth weight infantand that this individual may suffer significant, perhaps irreparable, developmentaldamage to the central nervous system.

REQUIREMENTS FOR POLYUNSATURATED FATTY ACIDS

Estimates of quantitative requirements of linoleic acid were based upon the rateof growth or the development of dermatitis, phenomena to which many factorscontribute, some of which are unrecognized and uncontrolled.

The earliest estimate of the infant's requirements for linoleic acid as approxi-


mately 1% of the calories was based on clinical observations, caloric intake andserum levels of the di-, tri-, and tetraenoic acids (20). When the means of assess-ing linoleate requirement from a curve relating triene-tetraene ratio to intake oflinoleate was developed (1), it became apparent that the requirements of infantscould be deduced from this biochemical parameter as well. Extensive data relatingPUFAs of human serum to intake of linoleate are presented in the classical studyof Hansen et al. (4). From that study it appears that 1% of calories is a minimumrequirement and that 4% of calories is an optimal intake. The plot of triene-tetraene ratio of serum fatty acids versus linoleate intake in infants reveals that thelow ratio indicative of normal EFA metabolism was reached by about 1 % of calo-ries as linoleic acid (36). The effect of dose responsive dietary intake of linoleicacid upon the total dienes, trienes, and tetraenes of serum revealed that 1% to 2%of calories as linoleate satisfies the requirements for all the biochemical conver-sions of PUFA, as well as permitting normal growth and preventing dermatitis(37).

The potency of arachidonic acid as EFA has been shown to be greater than thatof linoleic or a-linolenic acids, but all are effective in the treatment of EFA defi-ciency and promote normal growth. Although the a-linolenic (w3) series has beenconsidered to be essential, it cannot fulfill all the functions of the 6 series and sohas been questioned as possessing true essentiality (38). Although tissues, the cen-tral nervous system in particular, contain relatively high proportion of the meta-bolic products of 7-linolenic acids, we must await demonstration of their particularfunction.

SUPPLEMENTATION OF POLYUNSATURATED FATTY ACIDS

Traditionally, linoleic acid is considered the dietary essential fatty acid for it isthe commonest fatty acid that will provide sufficiently all the requirements knownfor PUFAs in human and animals and can function alone in the diet to meet theEFA requirements.

Diet

Human Breast Milk

The fatty acid composition of human milk has been studied in detail. The pat-terns of fatty acids from the two breasts were found to be similar after the samenursing, but fasting and time of day both influenced total fat and fatty acid compo-sition of the milk (39). Fatty acid composition of breast milk changes with thenature of the dietary fat (40). With the trend in the fatty acid content of the UnitedStates diet toward a higher proportion of unsaturated fatty acids including linole-ate, there is an increase in breast milk content that can vary from 1.0% to 43.0%fat, but an average content range from 8% to 10%. Since fat provides about 50%


of the calories in human milk, it contains more than an adequate amount of theEFA linoleate.

Infant Formulas

The American Academy of Pediatrics has recommended (41) that infant formu-las should contain a minimum of 3.3 g of fat/100 kcal (30% of calories) and 300mg of linoleic acid/100 kcal (approximately 1.7% of total calories) to provide afat to carbohydrate ratio within a range that is customary in infant diets. The acad-emy was concerned that excess linoleic acid would produce peroxidation and in-crease the vitamin E requirements but did not set an upper limit on the linoleatecontent of the diet, noting that in some human milks the linoleic acid content is8% to 10% of the fat.

Several of the most widely used formulas are based on cow's milk protein withlactose. All contain vegetable oils of one type or another. All the formulas containconsiderably more linoleic acid than human milk lipids (42). The long-term effectsof these dietary regimens are unknown.

Parenteral Fat Emulsion

In order to achieve complete parenteral nutrition in infants, it is necessary toadminister adequate amounts of calories and nutrients in a restricted volume. Inthe newborn infant, it is difficult to provide an optimal caloric intake in the formof amino acids and carbohydrates, because excessive fluid volumes are neededwhen isotonic solutions are used and the glucose load of hypertonic solutions isfrequently not tolerated. Therefore, fat emulsions, which have a high density andlow osmolality, have been used increasingly to provide additional calories and es-sential fatty acids (43,44). These emulsions, like most vegetable oils, are rich inthe essential fatty acid linoleate. Studies (30,44) documented the efficacy of theadministration of fat emulsions in alleviating clinical and biochemical manifesta-tions of EFA deficiency and that its administration would result in an increase ofthe linoleic acid level in the plasma and tissue lipids.

Inunction of Oil

Inunction of sunflower seed oil to forearms of patients with EFA deficiency low-ered the rate of water loss, cured scaly lesions and corrected abnormal skin lipids(45), and restored their abnormal plasma fatty acids, indicating that penetration ofthe linoleic acid through the skin had occurred (46). We studied two sick newborninfants who received fat-free parenteral nutrition and developed biochemical andclinical evidence of EFA deficiency (25). Following the inunction of sunflowerseed oil these manifestations disappeared. However, it seems impossible from ourstudies to predict the exact amount of linoleic acid absorbed following inunction.


Even the cutaneous application of relatively large quantities used in our patientsfailed to replenish tissues deficient in EFA. We demonstrated the ability to correctplatelet dysfunction and to increase prostaglandin E biosynthesis and turnover bythe inunction of sunflower seed oil in newborn infants with EFA deficiency (47).

EXCESSIVE INTAKE OF POLYUNSATURATED FATTY ACIDS

Since Burr and Burr demonstrated the importance of certain fats necessary fornormal growth (48), research on EFAs has been mainly concerned with the symp-toms of EFA deficiency and the administration of the minimal EFA requirementto prevent or treat the deficiency state. However, little is known about the toxicityor adverse effects of high levels of these substances in the diet.

Toxic Effect of Polyunsaturated Fatty Acids

The release by the United States Food and Drug Administration of artificial fatemulsions has made available for parenteral feeding a preparation of high caloricdensity that is rich in essential fatty acids, especially linoleic. However, severalhazardous effects have been reported in the newborn infant: a reduced clearancerate in small-for-date infants, as well as among premature infants born before 32weeks of gestation and during an acute illness (49), displacement of bilirubin fromalbumin binding sites and an increased risk of kernicterus in jaundiced newborns(50), the deposition of lipid material in macrophages that may alter immunity(44,51), immunosuppressive effect (52), altered pulmonary gas exchange (53),and the potential risk for substitution of phytosterols for cholesterol in the develop-ing central nervous system, which could lead to changes in myelin configurationand function (49).

Effect on Tissue Fatty Acid Composition and Prostaglandin Biosynthesis

We have measured tissue lipid composition and the excretion of the major uri-nary metabolite of prostaglandins E] and E2, PGE-M, in three infants who receivedtotal parenteral nutrition including Intralipid for several weeks and compared thesevalues with control infants (30). Linoleic acid is incorporated into the major lipidclasses of the plasma, red blood cells, and tissues in infants receiving Intralipid.Concomitantly with the increase in the relative concentration of linoleate, a de-crease in the higher PUFA homolog, arachidonate, is apparent (Fig. 4). This mayindicate a competition between these EFAs for esterification and storage in tissuelipids, a balanced content of the intake of the linoleic and linolenic acids, a rapidturnover of the long chain PUFAs, or a combination of these factors. However,the sum of the two EFAs, linoleate and arachidonate, is similar in red blood celland tissue phospholipids of control infants and in infants who received Intralipid.

A significant difference between the PGE-M excretion in the group of infants


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before and after the administration of Intralipid was found in this study (Fig. 3).Differences in the urinary excretion were seen between the control group and theinfants receiving Intralipid. PGE-M excretion following the administration of In-tralipid was similar to that obtained from infants with EFA deficiency. The de-crease in PGE-M excretion in patients receiving high amounts of linoleic acid ismost likely related to a decrease in the precursor EFA, arachidonate, although aninhibiting effect of linoleic acid on prostaglandin synthesis is possible (54).

Effect on Platelet Function

Chronic administration of a diet rich in linoleate reduced platelet aggregation inhumans (55). Prolonged administration of Intralipid to sick newborn infants re-sulted in changes of the fatty acid composition of their platelets' phospholipids andthose platelets showed reduced aggregation in response to different agents knownto induce platelet aggregation (Z. Friedman, unpublished data).

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3. Alfin-Slater RB, Aftergood L. Essential fatty acids reinvestigated. Physiol Rev 1968;48:758-84.4. Hansen AE, Wiese HF, Boelsche AB, et al. Role of linoleic acid in infant nutrition: Clinical and

chemical study of 428 infants fed on milk mixtures varying in kind and amount of fat. Pediatrics1963;31:171-92.

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6. Olegerd R, Svennerholm L. Fatty acid composition of plasma and red cell phosphoglycerides infull term infants and their mothers. Acta Paediatr Scand 1970;59:637-47.

7. Bruce A, Svennerholm L. Skeletal muscle lipids. I. Changes in fatty acid composition of lecithinin man during growth. Biochim Biophys Acta 1971;239:393^KX).

8. Crawford MA, Hassam AG, Williams G. Essential fatty acids and fetal brain growth. Lancet1976; 1:452-3.

9. King KC, Arlam PAJ, Laskowski DE, et al. Sources of fatty acids in the newborn. Pediatrics1971;47:192-8.

10. Widdowson EM. Growth and composition of the fetus and newborn. In: Assali NS, ed. Biologyof gestation. U. The fetus and neonate. New York: Academic Press, 1968:1-49.

11. Sweeney MJ, Etteldorf JN, Throop LJ, et al. Diet and fatty acid distribution in subcutaneous fatand in the cholesterol-triglyceride fraction of serum of young infants. J Clin Invest 1963;42:l-9.

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17. Hansen AE, Knott EM, Wiese HF, et al. Eczema and essential fatty acids. Am J Dis Child1947;73:1-18.

18. Combes M, Pratt EL, Weise HF. Essential fatty acids in premature infant feeding. Pediatrics1962;30:136-^4.

19. Hepner R. Balances of fatty acids in infant nutrition. Curr Ther Res 1977;9(suppl): 140-8.20. Adam DJD, Hansen AE, Wiese HF. Essential fatty acids in infant nutrition. J Nutr 1958;66:555-

64.21. Friedman Z, Danon A, Stahlman MT, et al. Rapid onset of essential fatty acid deficiency in the

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Essential Fatty Acid Requirements for Term and Preterm Infants

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