Grasas 17 RonaldEKleinman-2020-Contents-PediatricNutrition 3 PDF

Chapter 17
Fats and Fatty Acids
General Considerations
The absolute fat requirement of the human species is the amount of
essential fatty acids needed to maintain optimal fatty acid composition
of all tissues and normal eicosanoid and docosanoid synthesis. At most,
this requirement is no more than approximately 5% of an adequate energy
intake. However, fat accounts for approximately 50% of the nonprotein
energy content of both human milk and currently available infant formulas.
This fat content is believed to be necessary to ensure that total energy intake
is adequate to support growth and optimal utilization of dietary protein. In
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theory, the energy supplied by fat could be supplied by carbohydrate, from

which all fatty acids except the essential ones can be synthesized. In prac-
tice, however, it is difficult to ensure an adequate energy intake without a fat IV
intake considerably in excess of the requirement for essential fatty acids. In
part, this is difficult because the osmolality of such a diet containing simple
carbohydrates (eg, monosaccharides and disaccharides) will be sufficiently
high to result in diarrhea and because such a diet containing more complex
carbohydrates may not be fully digestible, particularly during early infancy.
Moreover, because approximately 25% of the energy content of carbohydrate
that is converted to fatty acids is consumed in the process of lipogenesis,
metabolic efficiency is greater if nonprotein energy is provided as a mixture
of fat and carbohydrate rather than predominately carbohydrate. Fat also
facilitates the absorption, transport, and delivery of fat-soluble vitamins
and is an important satiety factor.
Dietary Fats
Triglycerides account for the largest proportion of dietary fat. Structurally,
these have 3 fatty acid molecules esterified to a single molecule of glycerol.
They usually contain at least 2, often 3, different fatty acids. Other dietary
fats include phospholipids, free fatty acids, monoglycerides and diglycer-
ides, and small amounts of sterols and other nonsaponifiable compounds.
Naturally occurring fatty acids contain 4 to 26 carbon atoms. Some of
these are saturated (ie, no double bonds in the carbon chain), some are
Copyright 2020. American Academy of Pediatrics.
monounsaturated (ie, 1 double bond), and some are polyunsaturated (ie,

2 or more double bonds). All have common names but, by convention, are
identified by their number of carbon atoms, their number of double bonds,
and the site of the first double bond from the terminal methyl group of the
Section IV: Micronutrients and Macronutrients 509

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510 Chapter 17
Table 17.1.
Common Names and Numerical Nomenclature of Selected Fatty Acids
Common Name Numerical Nomenclature

Caprylic acid 8:0
Capric acid 10:0
Lauric acid 12:0
Myristic acid 14:0
Palmitic acid 16:0
Stearic acid 18:0
Oleic acid 18:1ω-9a
Linoleic acid 18:2ω-6a
Arachidonic acid 20:4ω-6a
Linolenic acidb 18:3ω-3a
Eicosapentaenoic acid 20:5ω-3a
Docosahexaenoic acid 22:6ω-3a
a
ω-9, ω-6, and ω-3 are used interchangeably with n-9, n-6, and n-3.
b
Usually designated α-linolenic acid to distinguish it from 18:3ω-6 or γ-linolenic acid.
molecule. For example, palmitic acid, a saturated, 16-carbon fatty acid, is

designated 16:0, and oleic acid, an 18-carbon, monounsaturated fatty acid
with the single double bond located between the ninth and tenth carbon
from the methyl terminal, is designated 18:1ω-9. Linoleic acid, 18:2ω-6, is
an 18-carbon fatty acid with 2 double bonds, the first between the sixth and
seventh carbon from the methyl terminal. The common names as well as the
shorthand numerical designations of a number of common fatty acids are
shown in Table 17.1.
Unsaturated fatty acids are folded at the site of each double bond; in this
configuration, they are said to be in the cis form. During processing, the
molecules may become unfolded, transforming them to trans fatty acids,
which have been implicated in development of atherosclerosis. In general,
the amount of trans fatty acids in infant formulas and foods is low; however,
some processed fats (eg, margarines) may have a higher content. The trans
fatty acid content of human milk also is reasonably low unless the mother’s
diet is high in trans fatty acids.
Pediatric Nutrition, 8th Edition
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Fats and Fatty Acids 511
Fat Digestion, Absorption, Transport, and Metabolism

At birth, the infant must adjust from using carbohydrate as the major
energy source to using a mixture of carbohydrate and fat. Hence, some
aspects of fat digestion and metabolism are not fully developed, even at
term. However, most term infants have sufficient fat digestive capacity to
adjust satisfactorily. The limitations of fat digestion are somewhat more
serious in the preterm infant, but there is little evidence that these infants
have significant limitations beyond the first few weeks of life.
Fat digestion begins in the stomach, where lingual lipase hydrolyzes
short- and medium-chain fatty acids from triglycerides and gastric lipase
hydrolyzes long- as well as medium- and short-chain fatty acids.1 The
intragastric release of fatty acids with formation of monoglycerides delays
gastric emptying and facilitates emulsification of fat in the intestine.
Further, some of the released short- and medium-chain fatty acids can be IV
absorbed directly from the stomach.2 When they enter into the duodenum,
the monoglycerides and free fatty acids stimulate release of a number of
enteric hormones; among these is cholecystokinin, which stimulates con-
traction of the gall bladder and secretion of pancreatic enzymes.3 Lingual
and gastric lipases are largely inactivated in the duodenum, and fat diges-
tion continues through the action of pancreatic lipase and colipase, which
may be somewhat limited during the first few weeks of life. Like lingual and
gastric lipase, pancreatic lipase hydrolyzes triglycerides into free fatty acids
and a monoglyceride.
Human milk contains 2 additional lipases, lipoprotein lipase and bile
salt-stimulated lipase. The former is essential for formation of milk lipid in
the mammary gland but plays little role in intestinal fat digestion. The latter
is present in much larger amounts. It is stable at a pH as low as 3.5 if bile
salts are present and it is not affected by intestinal proteolytic enzymes.4
However, it is heat labile and, hence, is inactivated by pasteurization, which
is believed to be a major factor in the poor fat absorption of infants fed
pasteurized human milk.5
Bile salt-stimulated lipase hydrolyzes triglyceride molecules into free
fatty acids and glycerol rather than into free fatty acids and a monoglycer-
ide. In theory, the bile salt-stimulated lipase of human milk can substitute
for limited pancreatic lipase4; however, this does not appear to be of great
importance for fat digestion of most infants. On the other hand, because
bile salt-stimulated lipase is much more effective than pancreatic lipase in
hydrolyzing esters of vitamin A, the primary form of this vitamin in human
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512 Chapter 17
milk and many other foods, it may be important for optimal vitamin A
absorption.
The bile acids released by contraction of the gall bladder help emulsify
the intestinal contents, thereby facilitating triglyceride hydrolysis and fat
absorption. They are released primarily as salts of taurine or glycine and,
hence, have both a water-soluble and a lipid soluble portion. Alone, bile salts
are poor emulsifiers, but in combination with monoglycerides, fatty acids,
and phospholipids, they are quite effective. Thus, the fat hydrolysis that
occurs in the stomach is an important adjunct to intestinal fat digestion.
The rate of synthesis of bile salts by newborn infants is less than that of
adults, and the bile salt pool of newborn infants is only about one quarter
that of adults.6 However, an intraduodenal concentration of bile salts below
2 to 5 mM, the critical concentration required for the formation of micelles,
is unusual.6 Bile salts are actively reabsorbed in the distal ilium, transported
back to the liver, and eventually reappear in bile.7 This enterohepatic circula-
tion occurs approximately 6 times daily, with loss of only approximately 5%
of the bile salts with each circulation, although the enterohepatic circulation
of bile salts is likely to be less mature in preterm infants.8
The monoglycerides and diglycerides and long-chain fatty acids resulting
from lipolysis as well as phospholipids, cholesterol, and fat-soluble vitamins
are insoluble in water but are solubilized by physicochemical combination
with bile salts to form micelles.8 Because of their amphiphilic nature, bile
salts aggregate with their hydrophobic region to the interior, or core, of
the micelle and their hydrophilic region to the exterior. The components of
the micelle are transferred into the enteric mucosal cell, where long-chain
fatty acids and monoglycerides are re-esterified into triglycerides and
subsequently combined with protein, phospholipid, and cholesterol to form
chylomicrons or very low-density lipoproteins. In this form, they enter the
intestinal lymphatics, then the thoracic duct, and finally, the peripheral
circulation.
Medium-chain triglycerides can be absorbed into the enteric cells
without being hydrolyzed.8 However, they also are rapidly hydrolyzed in
the duodenum, and because the released medium-chain fatty acids are
relatively soluble in the aqueous phase of the intestinal lumen, they can be
absorbed without being incorporated into micelles, making them particu-
larly useful in treatment of infants and children with a variety of pancreatic,
hepatic, biliary, and/or intestinal disorders, as well as with preterm infants.
In general, long-chain unsaturated fatty acids are absorbed more
readily than long-chain saturated fatty acids. Apart from the degree of
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unsaturation, to position of the fatty acid on the triglyceride molecule also

influences absorption.9 For the most common dietary saturated fatty acids,
palmitic acid (16:0), the 2-monoglyceride of palmitic acid, is well absorbed,
but free palmitic acid released from the terminal positions of the triglycer-
ide molecule is not. The palmitic acid content of human milk is esterified
primarily to the 2-position of glycerol, and this is believed to account for the
better absorption of palmitic acid from human milk than from formulas
containing butterfat. Synthetic fats that contain palmitic acid, primarily
in the 2 position, are available10,11 and are increasingly being used in infant
formula.
In the circulation, chylomicrons acquire a specialized apoprotein from
high-density lipoproteins.8 This enables the triglycerides of the chylomicron
to be hydrolyzed by lipoprotein lipase, the major enzyme responsible for
intravascular hydrolysis of chylomicrons and very low-density lipopro- IV
teins.12 Lipoprotein lipase is synthesized in most tissues, and the flow of
fatty acids to tissues reflects its activity in the tissue’s capillary bed. Levels of
lipoprotein lipase are somewhat low in preterm and small-for-gestational-
age infants, but this does not appear to impose major difficulties except,
perhaps, in tolerance of intravenously administered lipid emulsions.13
The phospholipid and most of the apoproteins remaining after hydrolysis
of chylomicron triglyceride are transferred to high-density lipoprotein,
and the remainder of the apoproteins is transferred to other lipoprotein
particles. This reduces the chylomicron to a fraction of its original mass,
resulting in a chylomicron remnant that is removed from the circulation by
specialized hepatic receptors.
Essential Fatty Acids

Fatty acids with double bonds in the ω-6 and ω-3 positions cannot be
synthesized endogenously by the human species.14 Therefore, specific
ω-6 and ω-3 fatty acids or their precursors with double bonds at these
positions—that is, linoleic acid (LA [18:2ω-6]) and α-linolenic acid (ALA
[18:3ω-3])—must be provided in the diet. The precursor fatty acids are
metabolized by the same series of desaturases and elongases to longer-
chain, more unsaturated fatty acids,14 referred to collectively as long-chain
polyunsaturated fatty acids (LC-PUFAs). This pathway is outlined in Fig 17.1.
Important metabolites of 18:2ω-6 and 18:3ω-3 include 18:3ω-6 (gamma
linolenic acid [GLA]), 20:3ω-6 (dihomogamma linolenic acid [DHLA]),
20:4ω-6 (arachidonic acid [ARA]), 20:5ω-3 (eicosapentaenoic acid [EPA]),
and 22:6ω-3 (docosahexaenoic acid [DHA]).
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514 Chapter 17
Figure 17.1.
Metabolism of omega-6 and omega-3 fatty acids
Metabolism of 6 and 3 Fatty Acids
6 polyunsaturated 3 polyunsaturated
fatty acids fatty acids
18:2 n-6 18:3 n-3

6 desaturase
18:3 n-6 18:4 n-3
elongation
20:3 n-6 20:4 n-3
5 desaturase
20:4 n-6 20:5 n-3
elongation
22:4 n-6 22:5 n-3
elongation
24:4 n-6 24:5 n-3
6 desatrase
24:5 n-6 24:6 n-3
– “ - oxidation
22:5 n-6 22:6 n-3
LA (18:2ω-6) and ALA (18:3ω-3) are present in many vegetable oils (see
Table 17.2). In vivo, they are found in storage lipids, cell membrane phos-
pholipids, intracellular cholesterol esters, and plasma lipids. The longer-
chain, more unsaturated fatty acids synthesized from these precursors,
in contrast, are found primarily in specific cell membrane phospholipids.
DHLA, ARA, and EPA are immediate precursors of eicosanoids,14,15 and DHA
is the precursor of the docosanoids,16 each being converted to a different
series with different biological activities and/or functions.
The same series of desaturases and elongases that catalyze desaturation
and elongation of ω-6 and ω-3 fatty acids also catalyze desaturation and
elongation of ω-9 fatty acids. The substrate preference of these enzymes is
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Table 17.2.
Fatty Acid Composition of Common Vegetable Oilsa
High-Oleic
Fatty Acid Canola Corn Coconut Palm Olein Safflowerb Soy Sunflower
6:0–12:0 — 0.1 62.1 0.2 — — —
14.0 — 0.1 18.1 1.0 0.1 0.1 —
16:0 4.0 12.1 8.9 39.8 6.8 11.2 3.7
18:0 2.0 2.4 2.7 4.4 2.4 0.4 5.4
18:1ω-9 55.0 32.1 6.4 42.5 76.8 22.0 81.3
18:2ω-6 26.0 50.9 1.6 11.2 12.5 53.8 9.0
Fats and Fatty Acids

18:3ω-3 10.0 0.9 — 0.2 0.1 7.5 —
Other 2.0 1.0 — <1.6 <1.0 <1.0 <1.0
a
Percent of total fatty acids (g/100 g).
b
High-oleic safflower oil: approximately 77% 18:1ω-9 and 12.5% 18:2ω-6.
515
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IV
516 Chapter 17
ω-3, ω-6, and finally, ω-9.14 Thus, competition between the ω-9 fatty acids
and either the ω-6 or ω-3 fatty acids is not an issue unless LA and/or ALA
concentrations are very low, as occurs in deficiency states. In this case, oleic
acid (18:1ω-9) is readily desaturated and elongated to eicosatrienoic acid
(20:3ω-9). The ratio of this fatty acid to 20:4ω-6, called the triene-to-tetraene
ratio, has been used as a diagnostic index of ω-6 fatty acid deficiency. This
ratio usually is <0.1. A ratio of >0.4 is usually cited as indicative of defi-
ciency,17 but most believe that an even lower value (eg, >0.2) might be more
reasonable. In the few documented cases of isolated 18:3ω-3 deficiency in
which the triene-to-tetraene ratio was measured (see later discussion), it
was not elevated.
LA (18:2ω-6) has been recognized as an essential nutrient for the human
species for more than 85 years.18,19 The most common symptoms of defi-
ciency are poor growth and scaly skin lesions. These symptoms are usually
preceded by an increase in the triene-to-tetraene ratio of plasma lipids. It is
now clear that ALA (18:3ω-3) also is an essential nutrient. In animals, defi-
ciency of this fatty acid results in visual and neurologic abnormalities.20–23
Neurologic abnormalities also were observed in a human infant who had
been maintained for several weeks on a parenteral nutrition regimen
lacking ALA24 and in elderly nursing home residents who were receiving
intragastric feedings of an elemental formula with no ALA.25
Although symptoms related to deficiency of the 2 series of fatty acids
seem to differ, many studies on which the description of ω-6 fatty acid
deficiency are based used a fat-free or very low-fat diet rather than a diet
deficient in only 18:2ω-6. Thus, there may be some overlap in the symptoms
of LA and ALA deficiency. The clinical symptoms of ω-6 fatty acid deficiency
can be corrected by LA or ARA; those related to ALA deficiency can be cor-
rected by ALA, EPA, or DHA. Thus, it is not clear whether LA and ALA serve
specific functions other than as precursors of LC-PUFAs.
LA usually represents between 8% and 20% of the total fatty acid content
of human milk, and ALA usually represents between 0.5% and 1%.26 Human
milk also contains small amounts of a number of longer-chain, more
unsaturated metabolites of both fatty acids, primarily AA (20:4ω-6) and
DHA (22:6ω-3). Maternal diet has a marked effect on the concentration of
most fatty acids in human milk. The concentration of DHA in the milk of
women consuming a typical North American diet is generally in the range
of 0.1% to 0.3% of total fatty acids, and the level of ARA ranges from 0.4%
to 0.6%.26 The milk of vegetarian women contains less DHA,27 and that of
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women whose dietary fish consumption is high or who take DHA supple-
ments is higher.28,29 The ARA content of human milk is less variable and
appears to be less dependent on maternal ARA intake, perhaps reflecting
the relatively high LA intake of most populations.
Corn, coconut, safflower, and soy oils as well as high-oleic safflower and
sunflower oils and palm olein oil are commonly used in the manufacture
of infant formulas (see Table 18.2). All except coconut oil contain adequate
amounts of LA, but only soybean oil contains an appreciable amount of ALA
(6% to 9% of total fatty acids). Canola oil, a component of many formulas
available outside the United States, contains somewhat less LA and more
ALA. Until the 1990s, little emphasis was placed on the ALA content of infant
formulas, and many with virtually no ALA were available (see also Chapter
4: Formula Feeding, and Appendix B). Current recommendations specify
minimal intakes of LA ranging from 2.7% to 8% of total fat and maximum IV
intakes ranging from 21% to 35% of total fatty acids.30,31 The most recent
recommendations for the minimum and maximum contents of ALA in term
infant formulas are 1.75% and 4% of total fatty acids, respectively.30,31 Some
recommendations aim to maintain a reasonable balance between LA and
ALA and recommend that the LA-to-ALA ratio be between 5 and 15,30 and
others suggest that a ratio is unnecessary.31 Term and preterm infant formu-
las currently available in the United States contain approximately 20% of
total fatty acids as LA and approximately 2% as ALA; hence, their LA-to-ALA
ratios are approximately 10.
Long-Chain Polyunsaturated Fatty Acids

LC-PUFAs are fatty acids with a chain length of more than 18 carbons and
2 or more double bonds. Those of primary interest for infant nutrition are
ARA (20:4ω-6) and DHA (22:6ω-3), the plasma and erythrocyte lipid con-
tents of which are higher in breastfed than formula-fed infants.32,33 Because
human milk contains these fatty acids but, until 2002, formulas did not, the
lower content of these fatty acids in plasma lipids of formula-fed infants
were interpreted as indicating that the infant cannot synthesize enough
of these fatty acids to meet ongoing needs. Prior and concurrent observa-
tions of better cognitive function of breastfed versus formula-fed infants34–37
focused attention on the possibility that the lower cognitive function of
formula-fed infants might be related, in part, to inadequate LC-PUFA intake.
The possibility that cognitive function is related to LC-PUFA intake is
supported by the facts that ARA and DHA are the major ω-6 and ω-3 fatty
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518 Chapter 17
acids of neural tissues38–40 and that DHA is a major component of retinal

photoreceptor membranes.40 Further, the major supply of these fatty acids
to the fetus during development is from maternal plasma.41 Thus, the need
for these fatty acids by the infant born before or during the third trimester
of pregnancy and, hence, receiving a limited supply of LC-PUFA prior to
birth is thought to be greater than that of the term infant. However, the
daily rates of accumulation of these fatty acids in the developing central
nervous system change minimally between mid-gestation and 1 year of
age.40
On the basis of postmortem studies,42,43 the cerebral content of DHA, but
not ARA, is minimally but significantly lower in formula-fed term infants.
However, the DHA content of the retina does not differ between breastfed
and formula-fed infants,43 perhaps because the content of this fatty acid in
retina reaches adult levels at approximately term, whereas adult levels in
the cerebrum are not reached until much later. In piglets, the cerebral DHA
content of formula-fed infants reflected the ALA content of the formula
received before death.44 In this study, ALA intakes less than 0.7% of total
energy resulted in low brain levels of DHA.44 Further, studies in infants
have shown a positive relationship between ALA intake and rates of DHA
synthesis.45
Both term and preterm infants can convert LA to ARA and ALA to
DHA.46–50 This has been established by studies in which the precursor fatty
acids labeled with stable isotopes of either carbon (13C) or hydrogen (2H)
were administered to the infant and blood concentrations of the labeled
fatty acids as well as labeled metabolites of each were measured by gas chro-
matography/mass spectroscopy (see Fig 17.1). The studies of Sauerwald et
al45,49 and Uauy et al50 suggested that the overall ability of preterm infants to
convert LA and ALA to LC-PUFAs is at least as good as that of term infants.
On the other hand, there is considerable variability in conversion among
both preterm and term infants fed the same formula. Moreover, because
measurements of enrichment have been limited to plasma, which repre-
sents only a small fraction of the body pool of precursor as well as product
fatty acids and may not be representative of fatty acid pools of other tissues,
including the central nervous system, the amount of LC-PUFAs that either
preterm or term infants can synthesize is not known.
The higher DHA content of plasma and erythrocyte lipids of breastfed
infants and infants fed formulas supplemented with LC-PUFAs versus
infants fed unsupplemented formulas, including those with a relatively high
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ALA content,51–53 suggests that the amounts of LC-PUFAs formed endoge-

nously are less than the amounts provided by human milk or supplemented
formulas. However, the extent to which the concentration of individual
LC-PUFAs in plasma reflects the content of these fatty acids in tissues,
particularly the brain, is not known.
In this regard, animal studies have demonstrated that the content of
LC-PUFAs in plasma is much less highly correlated with the content of these
fatty acids in brain than with the content in erythrocytes and liver.54 In con-
trast, postmortem studies in human infants have demonstrated a weak but
statistically significant, correlation between erythrocyte and brain contents
of DHA.43 Correlation between the content of this fatty acid in erythrocyte
membranes and the contents of other tissues was not reported. Studies in
isolated cell systems suggest that precursors of DHA are transferred from
plasma to astrocytes where they are converted to DHA, which is subse- IV
quently transferred to neurons.55 This pathway for direct synthesis of DHA
within the central nervous system appears to occur in vivo in some animal
species,56 but the extent to which it occurs in humans is not known.
Importance of LC-PUFAs in Development
The findings discussed previously, although far from definitive, are
compatible with the possibility that failure to provide preformed LC-PUFAs
during early infancy, perhaps longer, may compromise development of
tissues/organs with a high content of these fatty acids, particularly
22:6ω-3. However, the specific roles of LC-PUFAs in normal development
are not clear.57 These fatty acids affect gene transcription and may produce
post-translational modifications. Moreover, many are precursors of eico-
sanoids and docosanoids that, in turn, modify several processes. These fatty
acids also have effects on signal transduction, and the amount of these fatty
acids in cell membranes can modify membrane fluidity, membrane thick-
ness, and the microenvironment of the membrane as well as interactions
between the fatty acid and membrane proteins. Such changes, in turn, can
affect receptor function, and the fatty acids also may exert direct effects on
receptor function. Although the degree of unsaturation of membrane fatty
acids affects fluidity, this effect is most marked by substituting a monoun-
saturated or polyunsaturated fatty acid for a saturated fatty acid. In 22:6ω-3
deficiency, 22:5ω-6 replaces 22:6ω-3 with little effect on fluidity.
Despite the lack of a clear mechanism of the role of LC-PUFAs in devel-
opment, numerous studies over the past 2 decades have focused on differ-
ences in visual acuity and neurodevelopmental indices between breastfed
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520 Chapter 17
and formula-fed infants. Because human milk contains several factors other
than LC-PUFAs that might affect visual acuity and/or neurodevelopmental
indices, studies comparing breastfed versus formula-fed infants cannot
help resolve the specific role of LC-PUFAs in infant development. Rather,
intervention studies comparing infants fed LC-PUFA-supplemented and
unsupplemented formulas and studies comparing different LC-PUFA
intakes of breastfed infants secondary to maternal supplementation can
provide important insights into cause-and-effect relationships between
LC-PUFA intake and early childhood outcomes.
LC-PUFA Intake and Visual Function
Early studies in rodents established the importance of ω-3 fatty acids for
normal retinal function,20,23 and subsequent studies established this in
primates.21,22 These studies showed that abnormal retinal/visual function of
ω-3 fatty acid-deficient animals clearly resulted from an inadequate intake
of 18:3ω-3 and were partially reversed by adding this fatty acid or DHA. It
is with this rationale that many human studies of assessed the effects of
DHA (22:6ω-3) intake on retinal and/or visual function in babies. The early
randomized controlled trials of LC-PUFA interventions were designed to
assess whether infant formulas required supplementation with ω-3 (and
often ω-6 LCPUFA) as formulas were devoid of all LCPUFA and contained
only the precursor essential fatty acid ALA (18:3ω-3) in small amounts and
much larger quantities of the ω-6 EFA and LA (18:2 ω-6).
Because infants in these studies were preverbal, visual acuity was most
often assessed behaviorally or electrophysiologically. The most common
behavioral assessment of visual acuity is the Teller Acuity Card procedure
and is based on the innate tendency to look toward a discernible pattern
rather than a blank field.58 The infant is shown a series of cards with stripes
(gratings) of different widths on one side and a blank field on the other, and
his or her looking behavior is observed through a peephole in the center of
the card.59 Cards with wider stripes are shown initially followed by cards
with progressively decreasing stripe widths. The infant’s visual acuity is the
finest grating toward which he or she clearly looks preferentially (ie, the
finest grating that he or she is able to resolve).
The electrophysiologically based tests use visual evoked potentials
(VEPs) that measure the activation of the visual cortex in response to
visual information that is processed by the retina and transmitted to the
visual cortex.60,61 The presence of a reliable evoked response indicates that
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the stimulus information was resolved up to the visual cortex, where the
response is processed. Use of VEPs to assess visual acuity requires measur-
ing the electrical potentials of the visual cortex in response to patterns of
contrast reversal with vertical square wave gratings or checkerboards. The
frequency of the gratings or checkerboards is decreased from low (large) to
high (small), and the visual acuity threshold is estimated by linear regres-
sion of the VEP amplitudes versus the frequency, or size, of the grating
or checkerboard stimulus.60,61 A rapid VEP method (sweep VEP) has been
developed for use in infant populations.62
Electroretinography, unlike the aforementioned procedures that
measure the response of the entire visual system, measures only the
activity of the retina.63–65 However, this methodology is somewhat more
invasive and time consuming than the other methods and has been used to
assess effects of LC-PUFAs in only a few studies. The primary components IV
of the electroretinogram generated in response to a flash of light are the
a-wave, which is produced by hyperpolarization of the photoreceptor, and
the b-wave, which reflects the subsequent activation of retinal neurons.
Performance is quantified by parameters such as the threshold (the minimal
intensity of light necessary to elicit a small amplitude), the implicit time or
peak latency (the time from the presentation of a brief flash of light to the
response peak), the maximal amplitude, and the sensitivity (the intensity of
light that elicits a response of half the maximal amplitude).
To date, there have been 9 trials assessing the effect of LC-PUFA supple-
mentation of infant formulas for term infants that have included a measure
of visual acuity. VEP acuity was assessed in 6 trials, the behavioral method
of Teller Acuity Cards was used in 2 studies, and another trial used both
electrophysiological and behavioral methods. These have recently been sum-
marized in a Cochrane systematic review.66 Four of the 9 included studies
reported a beneficial effect of supplementation on visual acuity, and the 5
remaining studies reported no effect of supplementation. All of the included
studies have compared a low to modest dose of DHA supplementation (up
to approximately 0.3% of total fatty acids) with no supplementation. The
results of the meta-analyses were inconsistent, although all meta-analyses
assessing visual acuity using Teller Acuity Cards at different ages consis-
tently showed no effect of supplementation. Because the electrophysiologi-
cal protocols for assessing visual acuity were different between trials, it is
not possible to ascertain whether the inconsistent results are attributable to
methodologic differences, random error, or some other factor.
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522 Chapter 17
Some have suggested that dietary DHA dose may be an important factor
and that at least 0.3% of total fatty acids as DHA is required in the infant
diet to document a beneficial effect of supplementation on visual acuity.52,53
This view has recently been supported in a dose-response trial involv-
ing 4 different doses of DHA. This was a 2-site trial in which formula-fed
infants were randomly allocated to equivalent formulas containing either
0%, 0.32%, 0.64%, or 0.96% DHA as total fatty acids.67 All formulas also
contained 0.64% total fatty acids as AA. Infants fed the control formula
(0% DHA) had poorer visual evoked potential acuity compared with DHA-
supplemented infants. There were no differences in the visual acuity
between the groups fed the 3 different doses of DHA at any time point.67
Although the overall data from this trial are suggestive that a dose of at
least 0.3% DHA may be needed to maximize visual acuity development,
a significant study site by formula group interaction suggested that the
visual acuity response to the formulas varied by enrolling site, with differ-
ences between control and DHA-supplementation being most marked in
only one of the study sites. Interestingly, a dose-response trial conducted
in breastfed infants some 13 years earlier reported that supplementation of
lactating women to increase the average DHA concentration of their human
milk from a mean of approximately 0.2% total fatty acids as DHA to either
0.35%, 0.46%, 0.86%, or 1.13% DHA as total fatty acids resulted in no differ-
ences in infant visual evoked potential acuity or latency between groups.68
Unfortunately, the visual acuity estimates from the 2 trials do not appear to
be directly comparable because of methodologic differences.
Maternal supplementation with DHA during pregnancy has been inves-
tigated in 4 randomized controlled trials, including 467 infants, with visual
outcomes in term infants.69–72 Three of the 4 studies reported no differ-
ences in VEP latency71,72 and no difference in visual acuity measured either
using VEPs72 or the card procedure.69 Only 1 study with a small sample size
suggested improvement with Teller acuity card acuity at 4 but not 6 months
of age.70
Infants born preterm are at greatest risk of dietary LC-PUFA insuf-
ficiency, because they miss the large and active accumulation of LC-PUFAs
that occurs during the last trimester of pregnancy, they are born with few
fat reserves, and their feeding regimens often contain minimal LC-PUFA.
Therefore, it follows that any beneficial effects of LC-PUFAs will be more
obvious in preterm infants rather than their counterparts who are born
at term. However, this hypothesis has not been consistently supported by
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studies investigating the effects on LC-PUFA supplementation of preterm

infant formulas and visual outcomes. The relevant trials have been sum-
marized in a recent Cochrane systematic review.73 Eight randomized trials
were included; 3 tested the addition of only ω-3 LC-PUFAs to infant for-
mulas, 4 tested the addition of ω-3 LC-PUFAs and AA, and another had 2
intervention groups – 1 with ω-3 LC-PUFAs only and 1 with ω-3 LC-PUFAs
and AA. Seven trials have visual acuity outcomes, and 4 of these studies
reported beneficial effects of supplementation during early infancy,63,74–76
although in 2 cases this was confined to specific subgroups.75,76 It is impor-
tant to note that the methodologies of assessing acuity differed, the sample
sizes were generally small, and some of the randomization processes were
not adequately reported. Similar issues were apparent in the 2 trials that
assessed electroretinographic responses, with 1 study reporting a positive
effect of supplementation and the other reporting no effect.53,77 IV
Most recently, the dose of DHA in milks fed to preterm infants has
been assessed in a randomized trial based on realistic feeding practices in
which infants are fed a combination of expressed human milk and infant
formula.78 This trial tested a high dose of DHA (1% total fatty acid) against
a standard dose of DHA (0.3% total fatty acids), with the ARA concentra-
tion being held constant in both groups at about 0.4% of total fatty acids,
and found that infants fed the high-DHA diet had better visual acuity at
4 months’ corrected age compared with control infants. No differences were
noted at 2 months’ corrected age.78
LC-PUFAs and Cognitive, Behavioral, and Other
Neurodevelopmental Outcomes
Most studies addressing the cognitive or behavioral development of infants
fed LC-PUFA-supplemented versus unsupplemented formulas have used
the Bayley Scales of Infant and Toddler Development, which are considered
the “gold standard” for assessing global abilities of infants from birth to
about 42 months of age. They provide standardized indices of both mental/
cognitive and motor development. However, they are intended to distin-
guish between “normal” and “abnormal,” not degrees of either. Thus, unless
cognitive and/or psychomotor function as assessed by the Bayley Scales
early in life is abnormal, the relationship between these early scores and
later function is relatively poor.79
Other nonstandardized or more experimental approaches have also been
used to assess specific developmental domains. Tests have included novelty
preference, auditory evoked potentials, problem-solving ability, measures of
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524 Chapter 17
attention, measures of general movements, and most recently, assessment

of brain structure using magnetic resonance imaging. Although it has been
argued that the standardized tests assessing global developmental mea-
sures (such as the Bayley Scales) are less sensitive than some of the more
targeted experimental approaches, the data gained from both standardized
and experimental approaches in studies of LC-PUFA supplementation have
been variable. Some of the studies utilizing these tests have shown advan-
tages of LC-PUFA supplementation with both approaches, some with one
but not the other, and still others with neither approach. Available studies
in term infants were initially critically reviewed in 1998 by an expert panel
appointed by the Life Sciences Research Organization to assess the nutrient
requirements for term infant formulas.30 These studies were criticized by
consultants to the panel for including too few infants, failing to control ade-
quately for confounding factors, failing to assess function at more than one
age, failing to examine individual differences in development, and failing to
follow the infants for a sufficiently long period (eg, none of the studies avail-
able at that time included data beyond 1 year of age). Partially on the basis
of these criticisms, the panel did not recommend addition of LC-PUFAs to
term infant formulas but suggested that the issue be reevaluated.
The randomized trials involving term infants published since 199830,80–84
have not resolved many of these criticisms, although infant formula with
LC-PUFAs became widely available since the early 2000s. The trials have dif-
fered with respect to the source of LC-PUFA supplementation, the duration
of supplementation, the amounts of 22:6ω-3 and 20:4ω-6 supplementa-
tion, and the ratio of 22:6ω-3 to 20:4ω-6. There also were differences in the
18:2ω-6 and 18:3ω-3 contents of the control and experimental formulas.
The variance in Bayley mental and motor scores also varied among studies,
being smallest in the one study that showed an advantage of 22:6ω-3 and
20:4ω-6 supplementation for the first 4 months of life on the Bayley mental
development score at 18 months of age.81
Relevant data from LC-PUFA intervention trials involving term formula-
fed infants have most recently in a Cochrane systematic review,66 including
11 trials with neurodevelopmental outcomes. This systematic review66 as well
as an earlier review85 both reported no effect of LC-PUFA supplementation
of infant formula for term infants on Bayley mental or motor scores.
Two recent systematic reviews and meta-analyses are also available
summarizing the randomized controlled trials assessing LC-PUFA–
supplemented versus –unsupplemented formulas for preterm infants.73,86
Both reviews included the same 7 trials with Bayley outcomes, and both
ch17-509-540-9781610023603.indd 524 7/3/19 10:12 AM

reported no overall effect of LC-PUFA supplementation on Bayley mental or

psychomotor scores, although these trials are subject to many of the same
criticisms levied against the studies in term infants.73,86 Indeed, some sen-
sitivity analyses have suggested that the heterogeneity between trials may
be related to the administration of different versions of the Bayley Scales,
the sample population studied, the way the intervention was applied, or
trial methodology.86 Interestingly, the subgroup of 5 of the 7 studies using
the second version of the Bayley Scales and including the majority of infants
tested (n=879) demonstrated that supplementation of preterm formula
with LC-PUFAs resulted in an increase in mental development scores by
3.4 points (95% confidence interval [CI], 0.6–6.3) compared with controls.86
Further high-quality trials are clearly needed to substantiate these findings
but are probably unlikely to occur, because most infant formulas for preterm
infants are now supplemented with LC-PUFAs. IV
Of more current clinical relevance are 2 recent trials in which DHA doses
reflective of the estimated in utero accretion rate were used.87–89 These trials
also included infants fed human milk. Both trials reported no differences
in mental development scores at 18 to 20 months of age.88,89 However, the
larger and more robust of the 2 trials demonstrated that girls had a 4.5
point (approximately 0.3 standard deviations [SDs]) improvement in mental
development scores (95% CI, 0.5–8.5), and significant mental delay (mental
development scores <70) was reduced from 10.5% in the control group
to 5% in the higher DHA group (relative risk, 0.50; 95% CI, 0.26–0.93).88
Although there was some suggestion of benefit with DHA supplementation
at 18 months of age, there was no benefit of DHA supplementation at 7 years
of age.90
The effects of maternal supplementation with ω-3 LC-PUFAs, either in
pregnancy or during lactation, on childhood developmental outcomes has
also been investigated in randomized controlled trials, and some of these
trial have been large and rigorous and followed children until 7 years of age.
These studies91–93 as well as the available systematic reviews94,95 indicate no
consistent benefit of ω-3 LC-PUFA supplementation on childhood develop-
mental outcomes.
Effects of LC-PUFAs on Pregnancy Outcomes and Childhood
Allergies
Outside the sphere of neurologic development, interest has focused on
the anti-inflammatory and immune-modulating effects of ω-3 LC-PUFAs.
Increased ω-3 LC-PUFAs, particularly EPA, antagonize the actions of ARA
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526 Chapter 17
and can lead to a range of biochemical and immunologic changes that limit
inflammatory responses, which has been an important aspect of the ratio-
nale to explain the effects of dietary LC-PUFAs on childhood allergies and
pregnancy duration.
With regard to childhood allergic disease, some postnatal dietary inter-
vention studies designed to increase ω-3 LC-PUFA status through a com-
bination of DHA-rich tuna oil supplementation and a reduction in dietary
LA intake have suggested that dietary intervention lowers the prevalence of
early asthma symptoms, such as cough and wheeze, but follow-up studies
have generally failed to detect an effect.96,97
Randomized trials that have commenced intervention with ω-3
LC-PUFA, mainly as fish oil, during pregnancy have produced some inter-
esting results and are summarized in a Cochrane systematic review.98
There is some supportive evidence from the Cochrane systematic review
that suggests that at least 1 g of ω-3 LC-PUFA supplementation during
pregnancy results in a reduction in atopic eczema in the first 3 years of life
and a reduction in sensitization during the first year of life in children who
have a higher-than-normal risk of allergic disease.98 The review showed no
clear effects on asthma or wheeze outcomes.98 However, the 2 largest and
highest-quality trials show contrasting results, with the most recent trial
being published after the Cochrane review. The newest trial by Bisgaard et
al99 showed a 25% reduction in persistent wheeze/asthma at 3 to 5 years with
no effects on eczema or sensitization, whereas Palmer et al100 demonstrated
reductions in sensitization and atopic eczema at 1 year that were no longer
evident at 3 or 6 years.101,102 There were no effects of ω-3 LC-PUFA supple-
mentation during on wheeze or asthma at 3 and 6 years.101,102 This inconsis-
tency is perplexing and may relate to the different interventions (about 1 g
of ω-3 LC-PUFA, largely as DHA, vs 3 g of ω-3 LC-PUFA, largely as EPA), the
different populations studied, or the definitions used to diagnose asthma.
Asthma can be difficult to accurately diagnose in early childhood, and not all
persistent wheeze is asthma.103 Further work is needed, using standardized
assessments, to understand the responsiveness of fetus and child based on
maternal and family allergic history and if dose or class of ω-3 LC-PUFA are
important in determining outcome.
Supplementation studies with ω-3 LC-PUFA during pregnancy, regard-
less of the longer-term infant or childhood outcome, have generally all
collected basic information relating to birth outcomes and this has provided
the most solid evidence base for the effects of ω-3 LC-PUFA on pregnancy
ch17-509-540-9781610023603.indd 526 7/3/19 10:12 AM

outcomes. More than 50 trials with data from more than 15 000 women have
been included in the most recent systematic review.104 This review shows
that ω-3 LC-PUFA supplementation during pregnancy is clearly associated
with an increase in the mean length of gestation, resulting in a 39% reduc-
tion in early preterm birth at <34 weeks’ gestation and an 8% reduction in
preterm births at <37 weeks’ gestation.104 However, the results also indicate
that ω-3 LC-PUFA supplementation also results in a 57% increase in the risk
of prolonged gestation (>42 weeks’ gestation).104 Modern obstetric practice
generally will not allow women to progress their pregnancies beyond the
middle of their 41st week of gestation, and indeed, the largest and one of the
most recent trials also demonstrates that ω-3 LC-PUFA supplementation
during pregnancy also resulted in need for obstetric intervention (induc-
tion or elective caesarian section) because of post-term gestations.91 The
reductions observed in the rate of early preterm birth also had the expected IV
consequences of reducing the number of low birth weight infants and the
frequency of admission to the neonatal intensive care unit.91 However,
these promising data have not resulted in widespread implementation into
clinical practice, because it is not yet fully understood how to identify the
group of pregnant women who are most likely to benefit from ω-3 LC-PUFA
supplementation and avoid supplementation of women who may not
benefit or may even be exposed to increased risks.
Effects of LC-PUFAs on Postnatal Growth
The observation in the early 1990s that preterm infants assigned to a
formula supplemented with fish oil (0.3% of total fatty acids as 20:5ω-3 and
0.2% as 22:6ω-3) versus an unsupplemented formula had lower normalized
weight and lower normalized length at various times during the first year
of life105 generated considerable concern. In this study, weight at 12 months’
corrected age was correlated with plasma phospholipid 20:4ω-6 content at
various times during the first year of life.106 This led to the assumption that
the lower rate of weight gain was related in some way to the 20:5ω-3 content
of the fish oil. Two additional studies in preterm infants75,107 demonstrated
an adverse effect of ω-3 LC-PUFAs on growth, whereas another trial sug-
gested a positive effect,108 and yet others demonstrated no effects.52 These
confusing data may be the result of random error and/or the small sample
sizes in most trials. It is difficult to think of a biologic mechanism by which
ω-3 fatty acids may inhibit growth. Possibilities that have been suggested
include inhibition of desaturation and elongation of 18:2ω-6 to 20:4ω-6 by
the ω-3 fatty acids, inhibition of eicosanoid synthesis from 20:4ω-6 by the
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528 Chapter 17
intake of preformed 20:5ω-3 or endogenous synthesis of 20:5ω-3 from a

moderately high intake of 18:3ω-3, and effects of ω-3 and ω-6 fatty acids on
transcription of genes controlling lipolysis and lipogenesis.109
Trials of infant formula feeding for preterm infants including a com-
bination of ω-3 LC-PUFAs with ARA have generally been of higher quality
than the earlier trials of formula feeding that have included only ω-3
LC-PUFAs, and these trials most consistently have demonstrated no effect
of LC-PUFA supplementation on the growth of preterm infants, as sum-
marized in the most recent Cochrane systematic review.73 Interestingly, the
only growth effects noted are higher weights and higher lengths in infants
at 2 months post-term, and the meta-analysis included a combination of
trials that supplemented infants with ω-3 LC-PUFAs alone or in combina-
tion with ARA.73
The single largest trial of LC-PUFA supplementation to assess growth,
involving more than 650 infants born at <33 weeks’ gestation, compared
supplementation with DHA of approximately 1% total fatty acids and
supplementation with DHA of approximately 0.3% total fatty acids, sup-
plied through human milk, infant formula, or a combination of both to
mimic typical feeding practices in neonatal intensive care units.110 All milks
contained approximately 0.5% total fatty acids. There was no effect of higher
dietary DHA on weight or head circumference at any age, but infants given
more DHA were 0.7 cm (95% CI, 0.1–1.4 cm; P =.02) longer at 18 months’
corrected age. There was an interaction effect between treatment and birth
weight strata for weight and length. Higher DHA supplementation resulted
in increased length in infants born weighing ≥1250 g at 4 months’ corrected
age and in both weight and length at 12 and 18 months’ corrected age.110
Although complex, these data indicate that DHA up to 1% total dietary fatty
acids does not adversely affect growth.
The data regarding LC-PUFA supplementation and growth of term
infants are more straightforward. A meta-analysis of growth data from 14
(from a total of 21 known trials) generally high-quality trials that involved
LC-PUFA supplementation of infant formula fed to term infants found no
evidence that such supplementation influences the growth of term infants
in either a negative or a positive way.111 Subgroup analyses showed that
neither supplementation with only ω-3 LC-PUFAs nor source of LC-PUFA
supplementation affected infant growth. This analysis of data from 1846
infants has put to rest the question of growth inhibition by ω-3 LC-PUFAs.
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Possible Adverse Effects of LC-PUFAs

In addition to the original concerns about adverse effects of ω-3 fatty acids
on growth, a number of theoretical concerns related to the known biologic
effects of ω-6 and ω-3 LC-PUFAs should be considered. Among these is the
possibility that supplementation with highly unsaturated oils will increase
the likelihood of oxidant damage. This is because peroxidation occurs at
the site of double bonds, making membranes with unsaturated fatty acids
more vulnerable to oxidant damage. Thus, it is possible that LC-PUFA
supplementation will increase the incidence of conditions thought to be
related to oxidant damage (eg, necrotizing enterocolitis, bronchopulmonary
dysplasia, retrolental fibroplasia). There has also been concern that unbal-
anced supplementation with ω-3 and/or ω-6 LC-PUFAs will result in altered
eicosanoid and docosanoid metabolism with potential effects on a variety of
physiological mechanisms (eg, blood clotting, infection). There are few data IV
to support these theoretical concerns with respect to the small amounts of
LC-PUFAs that are added to infant formulas.
Many of the randomized controlled trials comparing the outcomes of
preterm infants receiving supplemented formulas with either DHA or both
DHA and ARA from a variety of sources (single-cell oils, fish oil, egg yolk
triglyceride, egg yolk phospholipids) with infants receiving unsupplemented
formula have reported a range of clinical outcomes, including necrotizing
enterocolitis, sepsis, retinopathy of prematurity, intraventricular hemor-
rhage, and bronchopulmonary dysplasia (BPD). The relevant trials have
been summarized in a systematic review and meta-analysis specifically
designed to consider the effects of LC-PUFA supplementation of infant
formula on the typical diseases of prematurity.86 The clinical signs and
symptoms used to diagnose a disease may differ between neonatal units
and may change with improvements in clinical practice over time. Thus, the
reported meta-analyses included all outcomes according to any definition
as well as sensitivity analyses including trials only using internationally
accepted definitions or trials with a low risk of bias on the basis of report-
ing adequate concealment of randomization and analysis according to the
intention-to-treat principle. In meta-analyses of data from approximately
1500 preterm infants, the risk of necrotizing enterocolitis and sepsis did
not differ between infants fed LC-PUFA–supplemented or control formula
when all available data were included, when necrotizing enterocolitis
or sepsis were confirmed, or in sensitivity analysis.86 There were also no
ch17-509-540-9781610023603.indd 529 7/3/19 10:12 AM

530 Chapter 17
clear differences in rates of retinopathy of prematurity, intraventricular

hemorrhage, or bronchopulmonary dysplasia between preterm infants fed
LC-PUFA–supplemented or control formula in overall analyses or when
trials reported diseases according to the prespecified definitions or in sensi-
tivity analysis.86 However, in many cases, the small numbers of infants and
low disease rates limited these analyses. Collectively, these data together
with those from LC-PUFA supplementation of infant formulas have not
resulted in a greater incidence of adverse conditions and suggest that
the amounts and the sources of LC-PUFAs used in these studies are safe.
Furthermore, supplementation with DHA at higher doses (up to 1% of total
fatty acids) has had no effect on the incidence of sepsis, necrotizing entero-
colitis, or intraventricular hemorrhage.88,112 However, a trial published in
2017 with 1273 infants born at <29 weeks’ gestation showed that a high-dose
enteral DHA emulsion (providing a total of 60 mg DHA/kg/day, about 1%
total dietary fatty acids) compared with a soy oil emulsion (without DHA)
may increase the risk of BPD.112 In this study,112 all infants in the control
group received DHA according to standard feeding practice, which provided
about 20 mg/kg/day. Further work is needed to understand the relation-
ship of DHA dose with BPD and whether there is any interplay with oxidant
damage or the balance of bioactive lipid mediators, such as the eicosanoids
and docosanoids.
Sources for LC-PUFA Supplementation
Available sources for LC-PUFA supplementation include egg yolk lipid,
phospholipid, and triglyceride, all of which contain ω-6 as well as ω-3
LC-PUFAs; fish oils; and oils produced by single-cell organisms (ie, micro-
algal and fungal oils). Few untoward effects of the available supplements
have been noted at the relatively modest doses that are commonly used for
infants. In vitro and animal studies of toxicity also have revealed little toxic-
ity of any of these sources. In fact, the US Food and Drug Administration
has accepted the conclusion of a manufacturer of a combination of algal and
fungal oils as well as that of a manufacturer of a combination of low-EPA
tuna and a fungal oil that their products are generally regarded as safe
sources of DHA and ARA for addition to formulas intended for normal
infants.
Supplementation of Infant Formulas With LC-PUFAs
The American Academy of Pediatrics has no official position on supplemen-
tation of term or preterm infant formulas with LC-PUFAs. The Life Sciences
Research Organization Expert Panel on Nutrient Composition of Term
ch17-509-540-9781610023603.indd 530 7/3/19 10:12 AM

Infant Formulas recommended neither a minimum nor maximum content

of either AA or DHA.30 The Life Sciences Research Organization Expert
Panel on Nutrient Composition of Preterm Formulas specified a maximum
amount of ARA and DHA for preterm infant formulas but did not specify a
minimum amount of either fatty acid.113 In contrast, regulatory and advi-
sory groups from other countries recommend that infant formulas, particu-
larly those intended for preterm infants, be supplemented with these 2 fatty
acids,31 although a more recent option has suggested that term infants only
require additional DHA. 31 Formulas with both DHA and ARA are available
in most countries, including the United States. It has been estimated that
approximately 75% of the term formulas and 100% of the preterm formulas
sold in the United States are supplemented with DHA and ARA.
The evidence for efficacy of supplementing term infant formulas with
these fatty acids is only modestly different from that available to the Life IV
Sciences Research Organization term formula panel in 1998, but the evi-
dence for efficacy of modest supplementation of preterm formulas is more
convincing, with a few studies suggesting that there may be advantages
to early childhood development. Moreover, most of the safety concerns
expressed earlier have been resolved.
Finally, considering the marked variability among infants of apparent
conversion of ALA to DHA and LA to ARA, it is conceivable that some infants
will benefit from supplementation, whereas others will not. Such a scenario
certainly would help explain the marked variability in outcomes docu-
mented by virtually every study. It also is likely that any beneficial effects of
LC-PUFA supplementation will be subtle and possibly not detectable with all
methodologies.
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Chapter 17

Fats and Fatty Acids

theory, the energy supplied by fat could be supplied by carbohydrate, from

monounsaturated (ie, 1 double bond), and some are polyunsaturated (ie,

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Common Name Numerical Nomenclature

molecule. For example, palmitic acid, a saturated, 16-carbon fatty acid, is

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Fat Digestion, Absorption, Transport, and Metabolism

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unsaturation, to position of the fatty acid on the triglyceride molecule also

Essential Fatty Acids

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18:2 n-6 18:3 n-3

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18:2ω-6 26.0 50.9 1.6 11.2 12.5 53.8 9.0

Fats and Fatty Acids

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Long-Chain Polyunsaturated Fatty Acids

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acids of neural tissues38–40 and that DHA is a major component of retinal

Pediatric Nutrition, 8th Edition

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ALA content,51–53 suggests that the amounts of LC-PUFAs formed endoge-

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studies investigating the effects on LC-PUFA supplementation of preterm

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attention, measures of general movements, and most recently, assessment

Pediatric Nutrition, 8th Edition

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reported no overall effect of LC-PUFA supplementation on Bayley mental or

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intake of preformed 20:5ω-3 or endogenous synthesis of 20:5ω-3 from a

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Possible Adverse Effects of LC-PUFAs

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clear differences in rates of retinopathy of prematurity, intraventricular

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