Table of Contents

HK J Paediatr (New Series)
Vol 4. No. 2, 1999

HK J Paediatr (New Series) 1999;4:82-88

Feature Article

The Role of Long Chain Polyunsaturated Fatty Acids in Infant Nutrition

WJ Goldman


Introduction

Long chain polyunsaturated fatty acids (PUFAs) are important to all living organisms because they are essential components of cell membranes. The necessity for the presence of these essential components of fats has been known at least since 1929.1 Studies have been conducted which have demonstrated that the essential components of the human diet are linoleic acid 2 and linolenic acid. 3 Recent evidence has shown the importance of the PUFAs arachidonic acid (AA) and docosahexanoic acid (DHA) in infant cognitive and visual development.4,5 The PUFAs AA and DHA are synthetic products derived from linoleic and linolenic acid metabolism.

Classification

Structurally, fatty acids are a linear chain of carbon atoms with a carbon tail at one end and an acid moiety at the other end. Double bonds may or may not be present.

Figure 1

Further classifications are made into families depending upon the locations of the double bond closest to the carbon tail. An omega-6 fatty acid has a double bond in the 6th position from the carbon tail and an omega 3 fatty acid is in the 3rd position from the carbon tail. Figure 2 contains some examples of fatty acids classified according to the relative position of the first double bond from the carbon tail.

Figure 2

Table 1 contains a listing of some important PUFAs with their usual abbreviation and chemical shorthand. Thus Linoleic acid is abbreviated LA and the shorthand nomenclature 18:2v-6 represents an 18-carbon chain with two double bonds, the first double bond occurring after the 6th carbon. 18:3v-3 represents an 18 carbon chain with three double bonds, the first double bond occurring after the 3rd carbon.

Table 1
Name Abbreviation Shorthand
Linoleic Acid LA 18:2 ω-6
γ-Linolenic Acid GLA 18:3 ω-6
α-Linolenic Acid LNA 18:3 ω-3
Arachidonic Acid AA or ARA 20:4 ω-6
Eicosapentaenoic Acid EPA 20:5 ω-3
Docosahexaenoic Acid DHA 22:6 ω-3

Synthesis

The two main long chain polyunsaturated fatty acids which are relied upon for brain cell structure are DHA, an omega-3 fatty acid and AA, an omega-6 fatty acid. The parent compounds, which synthesize these two fatty acids in the body, are a-linolenic acid and linoleic acid. Infants are likely to need DHA and AA in their diets, as they may be unable to synthesize sufficient amounts from a-linolenic and linoleic acid until 4 to 6 months postpartum.6 Figure 3 represents a diagram of the LCPUFA synthetic pathway.

The omega-3 fatty acid series including linolenic acid, eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) are present as a major component of tissues Docosahexanoic acid is present as a major component of membrane phospholipids in retinal photoreceptors, cerebral gray matter and sperm. Linoleic acid an omega 6 fatty acid is a minor component of most membrane phospholipids while arachidonic acid is present in much higher concentrations. Oleic acid and eicosatrienoic acid, omega 9 fatty acids are components of many tissues including white matter and myelin (Table 2).

Biosynthesis of LCPs
Figure 3

Deficiency Patterns

Characteristics of omega 3 and omega 6 deficiencies have been determined. The clinical features of an omega 3 deficiency include reduced learning and an abnormal ERG (retinal response to light) as well as impaired vision in the face of normal skin integrity but with fluid retention and normal growth. On the other hand, an omega 6 fatty acid deficiency results in growth retardation, skin lesions, reproduction failure, the occurrence of a fatty liver and fluid retention.7 For infants, deficiencies in the amounts of DHA and AA and their metabolites in the diet during infancy may affect the maturation of the central nervous system, including visual development and intelligence.8

The relationship between DHA and AA in terms of their effects upon growth has been well established. Carlson9 found that preterm infants fed with EPA and DHA as the sole LCPUFA component of the diet exhibited growth retardation, which corresponded to a progressive deficiency of AA. It was soon discovered that supplementation with AA in addition to DHA is essential for proper growth and development. Several investigators10,11 have shown that only a balanced addition of DHA and AA supports optimal tissue accretion of both of these important fatty acids.

A growth study conducted by Vanderhoff12 and colleagues in preterm infants showed that there were no significant differences in weight, length and head circumference as a result of receiving a formula containing

Table 2 Metabolic Pathways for the Synthesis of Various Essential Fatty Acids and Their Tissue Distribution
Fatty Acid Series Major Members Tissue Distribution
n3 Linolenic Acid (18:3n3)
Eicosapentaenoic Acid (20:5n3)
Docosahexaenoic Acid (22:6n3)
Minor Component of Tissues
Minor Component of Tissues
Major Component of Membrane Phospholipids in Retinal Photoreceptors, Cerebral Gray Matter, and Sperm
n6 Linoleic Acid (18:2n6)
Arachidonic Acid (20:4n6)
Docosapentaenoic Acid (22:5n6)
Minor Component of Most Tissues
Major Component of Most Membrane Phospholipids
Very Low in Normal Tissues but Replaces 22: 6n3 in n3 Fatty Acid Deficiency
n9 Oleic Acid (18:1n9)
Eicosatrienoic Acid (20:3n9)
Major Component of Many Tissues, Including White Matter and Myelin
Accumulates in Total Essential Fatty Acid
Deficency
From Neuringer M. Connor WE: n-3 Fatty Acids in the Brain and Retina: Evidence for Their Essentiality Nutr Rev 1986; 44: 285-294

LCPUFAs as compared to preterm infants receiving human milk or a formula without supplementation from birth to 40 weeks postconceptional age (Table 3). The finding further suggests that feeding a diet balanced in both DHA and AA is equivalent in terms of growth, safety and tolerance to preterm infants receiving the two formulas or human milk.

Table 3 Growth Study at 40 Wks Postconceptional Age (Mean ±)
  Human Milk (n = 65) Controla (n = 66) LCPsb (n = 60)
Weight (g) 2892.9
±492.38
3270.7
±569.83
3376.2
±436.53
Length (cm) 48.55
±2.65
49.01
±2.61
49.95
±2.77
Head Circumference (cm) 34.79
±1.49
35.33
±1.47
35.62
±1.3
a 24 Kcal/oz Preterm Formula; b Preterm Formula Supplemented with ARA (0.6%) and DHA (0.4%). Vanderhoff et al., 1997

Tissue Distribution

Breast Milk

Koletzko et al 13 have reviewed a number of studies of the PUFA content of breast milk. In their report they have reviewed 14 European studies and 10 African studies which have measured the fatty acid content in addition to the PUFA content of breast milk. While individual levels of fatty acids may vary from community to community in accordance with the mother's diet as can be seen in Table 4, the DHA to AA ratio remains at a relatively constant value of 1.6 to 2.2.

Table 4 Medians and Ranges Calculated from Average Fatty Acid Values Reported in the Reviewed Studies on Mature Human Milk in Europe and Africa
    Europe (14 Studies) Africa (10 Studies)
Fatty Acid Totals (% wt/wt)
  Saturated 45.2 (39.0 - 51.3) 53.5 (35.5 - 62.3)
  Monosaturated 38.8 (34.2 - 44.9) 28.2 (22.8 - 49.0)
  n-6 + n-3 PUFA 13.6 (8.5 - 19.6) 16.6 (6.3 -24.7)
n-6 PUFA (% wt/wt)
  C18:2n-6 (Linoleic Acid) 11.0 (6.9 - 16.4) 12.0 (5.7 - 17.2)
  C 20:2n-6 0.3 (0.2 - 0.5) 0.3 (0.3 - 0.8)
  C 20:3n-6 0.3 (0.2 - 0.7) 0.4 (0.2 - 0.5)
  C 20:4n-6 (Arachidonic Acid) 0.5 (0.2 - 1.2) 0.6 (0.3 - 1.0)
  C 22:4n-6 0.1 (0.1 - 0.2) 0.1 (0.0 - 0.1)
  C 22:5n-6 (Docosapentaenoic Acid ) 0.1 (0.0 - 0.2) 0.1 (0.1 - 0.3)
  Total n-6 LCP 1.2 (0.4 - 2.2) 1.5 (0.9 - 2.0)
n-3 PUFA (% wt/wt)
  C 18:3n-3 (Linolenic Acid) 0.9 (0.7 - 1.3) 0.8 (0.1 - 1.44)
  C 20:5n-3 (Eicosapentaenoic Acid) 0.2 (0.0 - 0.6) 0.1 (0.1 - 0.5)
  C 22:5n-3 0.2 (0.1 - 0.5) 0.2 (0.1 - 0.4)
  C 22:6n-3 (Docosahexaenoic Acid) 0.3 (0.1 - 0.6) 0.3 (0.1 - 0.9)
  Total n-3 LCP 0.6 (0.3 - 1.8) 0.6 (0.3 - 2.9)
Ratios
  18:2n-6/18:3n-3 12.1 (8.6 - 16.9) 14.2 (8.8 - 157)
  20:4n-6/22:6n-3 1.8 (0.7 - 5.0) 2.2 (0.7 - 10)
  n-6 LCP/n-3 LCP 2.7 (0.3 - 3.7) 2.4 (0.8 - 6)
  Polyunsaturated/Saturated 0.3 (0.2 - 0.5) 0.3 (0.1 - 0.5)
  Monounsaturated/Saturated 0.9 (0.7 - 1.1) 0.5 (0.4 - 1.4)
Koletzko B. et al. The Fatty Acid Composition of Human Milk in Europe and Africa. The Journal of Pediatrics 120:562-70 April 1992

Serum Levels

Serum levels of the long chain polyunsaturated fatty acids DHA and AA in term infants have been determined by Gibson et al. 14 He and his colleagues studied the effects of varying the dietary intake of DHA and AA in term infants upon serum levels of LCPUFAs (Table 5). In their study five different levels of intake were assessed. One group received a standard diet with low levels of LCPUFAs; a second group received human breast milk; another group received a diet containing 0.2% AA and 0.2% DHA; a fourth group received 0.32% AA and 0.2% DHA; the fifth group received 0.4% AA and 0.25% DHA. An analysis of the plasma phospholipids was conducted both at 0 and 6 weeks of study. At 6 weeks, the plasma phospholipids which resulted from feeding the blend containing 0.32% AA with 0.2% DHA and the blend containing 0.4% AA with 0.25% DHA were noted to approach plasma phospholipid levels which resulted from feeding human milk.

Similar results have been reported to occur in preterm infants 15,16 and in term infants. 17,18 In fact, in the preterm infant study by Gross et al.,15 it was demonstrated that the addition of AA (0.6%) and DHA (0.4%) to a preterm formula maintained a phospholipid profile in preterm infants that was closer to the serum phospholipid level of preterm infants fed human milk.

Brain Levels

It is generally agreed that the majority of brain growth occurs in-utero. However, a term infant's brain development is still not complete at the time of birth. A substantial and very high rate of brain growth occurs during the first three months of life. Figure 4 demonstrates that an additional finite level of brain growth will occur during this time and the availability of appropriate nutrients is critical for neutral development.19

Clandinin, et al., 20 have evaluated the fatty acid accretion rates in infant brains. These investigators found that postpartum deposition of fatty acids lagged for the first four weeks of life but increased more dramatically during the latter stages of infancy. The greatest deposition of fatty acids was noted by these investigators in previous studies to occur in the third trimester of pregnancy. It has been previously noted that infants may be unable to synthesize fatty acids with higher degrees of unsaturation or elongation until four to six months postpartum. 6 There is a suggestion that during this period of time the preformed DHA and AA necessary for CNS accretion are similarly not available if the infant receives a formula which is not supplemented with PUFAs. Farquharson21 and his colleagues have stated that as the phospholipids are known to perform an important role in membrane function and are possibly integral to neurotransmission, it is recommended that breast milk substitute infant formulas should contain n-3 and n-6 series polyunsaturated fatty acids in proportions similar to those of human milk.

Brain Growth

Adapted from: Dobbing J., (1974). In: Scientific Foundation of Pediatrics, p.565 Eds: J.A. Davies and J. Dobbing. Heinemann, London

Figure 4

 

Table 5 Plasma Phospholipids ARA & DHA Levels [mg/ml; x (S.D.)]

 

 

Control

Blend 1 Blend 2 Blend 3 HM

ARA

Week 0 156 (26)a 153 (32)a 143 (33)a 146 (37)a 183 (30)b
  6 95 (16)a 119 (17)a,b 134 (47)b 139 (23)b 148 (27)c
DHA
Week 0 50 (11)a,b 47 (12)a,b 45 (15)a 45 (13)a 57 (16)b
  6 28 (6)a 50 (6)b 52 (16)b 54 (10)b 55 (13)b
Different Superscripts Above Indicate P<0.05. Plasma Triglyceride, Plasma Cholesterol Ester and Erythrocyte Phospholipid ARA and DHA Levels Showed Similar Results. Gibson et al., 1997

Visual Acuity

Since brain and retinal tissue long chain fatty acid content and accretion is exceptionally high in the infant, it is suggested that visual acuity might be expected to be influenced by the fatty acid content of the diet. A study conducted by Uauy and his colleagues22 evaluated electroretinographic responses in a group of infants fed formulas containing various levels of omega-3 and omega-6 fatty acids starting at 36 weeks postconceptual age. One group received an unsupplemented formula sufficient in linoleic acid but relatively deficient in α-linolenic acid, another was fed breast milk, a third group received a-linolenic acid supplementation while a fourth group received a combination of a-linolenis acid and marine oil which contained eicosapentaenoic acid and docosahexaenoic acid. As is demonstrated by Table 6, the EPA/DHA supplemented formula resulted in an electroretinographic response that was similar to the response of infants receiving breast milk. An additional supply of long-chain omega-3 fatty acid is necessary to enhance and sustain rod electroretinographic function.

In a confirmatory study conducted by Birch, et al., 23 visual acuity and the essentiality of docosahexaenoic acid and arachidonic acid in the diet of term infants was established. These investigators divided four groups of infants into those receiving a control formula, one receiving a formula supplemented with DHA, another receiving a formula supplemented with both DHA and AA and the fourth group receiving breast feedings. Outcomes measured included sweep VEP and FPL acuities expressed as the Log of the Minimum Angle of Resolution (LogMAR) at enrollment, 6,17, 26 and 52 weeks. 20/20 vision corresponds to a minimum angle of resolution of 1 min arc and a LogMAR of 0.0. 20/200 vision corresponds to a minimum angle of resolution of 10 min arc a LogMAR of 1.0. Figure 5 demonstrates that sweep VEP is a function of diet during the first year of life. One can see that DHA/AA or DHA supplementation in terms of sweep VEP results in visual acuity which is very similar to the results found to occur in breast-fed infants. Visual acuity in the control formula group was significantly poorer than in the other groups. It was noted by these authors that FPL acuity (Figure 6) is less sensitive to subtle differences in visual acuity than the sweep VEP.

Sweep VEP Acuity

Sweep VEP Acuity as a Function of Diet Group During the First Year of Life: Control Formula (), DHA-Supplemented Formula (), DHA + AA Supplemented Formula (), Human Milk (). The Control Formula Group Had Significantly Poorer Acuity than the Other Groups at 6, 17, and 52 Wk (See Table 7 for Details). () Indicate the Standard Deviations.

Figure 5

 

FPL Acuity

FPL Acuity as a Function of Diet Group During the First Year of Life: Control Formula (), DHA-Supplemented Formula (), DHA + AA Supplemented Formula (), Human Milk (). () Indicate the Standard Deviations. No Significant Differences Were Found Among Diet Groups.

Figure 6

 

Table 6 Electroretinographic Responses At 36 WK Postconceptual Age (MEAN ?/b> SD)*

 

Human Milk (n = 10) Unsupplemental Formula (n = 10)

LNA Supplemental Formula (n = 10)

EPA/DHA Supplemental Formula (n = 10) ANOVA
F P

Rod Function

Log Threshold (scot td-s) 0.414 ± 0.59a 1.105 ± 0.37b 0.739 ± 0.64a,b 0.410 ± 0.63a 3.309 <0.028
Log Vmax (mV) 1.20 ± 0.14a 1.02 ± 0.05b 1.07 ± 0.13a,b 1.20 ± 0.17a 4.99 <0.005
Log K (scot td-s) 1.25 ± 0.54 1.72 ± 0.31 1.43 ± 0.6 1.25 ± 0.55 1.94 <0.14
Cone Function
Log Threshold (phot td-s) -0.11 ± 0.24 0.09 ± 0.15 -0.04 ± 0.03 -0.04 ± 0.24 NS NS
CFF (Hz) 51.5 ± 6.6 48.5 ± 5.6 48.9 ± 6.3 47.4 ± 6.9 NS NS

*Groups with Different Superscripts are Significantly Different (p<0.05) Using Newman-Keuls Multiple Comparison Test. Scot td-s, Scotopic Troland-Seconds; Phot td-s, Photopis Troland-Seconds
Uauy et al. Ped Res 1990; 28: 485-492

Cognitive Function

In 1992 Lucas and his colleagues24 reported in the Lancet the results of a study that they undertook wherein they had examined the IQ of 7 1/2 to 8 year old children who were either formula fed or breast fed as infants. Even after accounting for multiple variables, such as mother's education and social class, there was an 8.3 advantage for the breast fed group (Table 7). It was suggested that the presence of long chain polyunsaturated fatty acids in breast milk which was not present in formula milks accounted for the relative advantage of breast feeding in terms of IQ.

A further demonstration of the beneficial effects on cognitive function as a consequence of feeding LCPUFAs to infants can be provided by the study reported by Willets et al.25 Willets and colleagues undertook this study to determine whether feeding LCPUFAs in infancy made any difference in cognitive function in later life. Ninety-three infants were recruited into the study. Seventy-two infants were randomized to receive either a formula supplemented with LCPUFAs (n = 34) or and unsupplemented formula (n = 38) from birth to age 4 months. Problem solving was assessed at 10 months of age. Twenty-one of the supplemented group and twenty-three of the unsupplemented group completed the problem solving assessment. Infants were required to solve a three step problem which included a barrier, cloth or cover removal to retrieve a toy (Table 8).

Table 9 lists the result obtained by the 10 month old infants separated according to diet. The study showed that infants with LCPUFA supplementation had significantly improved results than the infants who received a diet without LCPUFAs. These authors suggested that formula fed term infants may benefit from LCPUFA supplementation and the effects persist beyond the period of supplementation. They further suggest that LCPUFAs may be important for the development of childhood intelligence.

Table 7 IQ At 7 1/2-8 Years
       Mean (SEM) Scores Advantage for Breast Fed Babies (95%CI)
Formula Fed Breast Fed
Abbreviated WISC-R
  Verbal Scale 92-0 (2-0) 102-1 (1-3) 10-1 (4-7, 15-5)*
  Performance Scale 93-2 (1-7) 103-3 (1-2) 10-2 (6-0, 14-2)*
  Overall IQ 92-8 (1-6) 103-0 (1-2) 10-2 (6-3, 14-1)*
* p<0.001, Group I vs. Group II; CI= Confidence Interval. Lucas Lancet 339: 264-269, 1992 et al

 

Table 8 Criteria for Scoring Intention on Steps of Three-Step Problem
Step No Intention (0) Possible Intention (1) Clear Intention (2)
Barrier
Barrier Behaviour Play: Barrier Not Removed Hesitant Removal Remove Barrier
Fixation Fixate Away from Cloth Fixate Briefly Away from Cloth Fixate Cloth Continuously
Cloth Retrieval Ignore Cloth Attempt to Grasp Cloth Pick Up Cloth
Cloth
Cloth Behaviour Play: Cover Not within Reach Heistant Pulling Pull Cloth
Fixation Fixate Away from Cover Fixate Briefly Away from Cover Fixate Cover Continuously
Cover Retrieval Ignore Coveer Attempt to Grasp Cover Pick Up Cover
Cover
Cover Behaviour Play: Cover Not Removed Hesitant Removal Remove Cover
Fixation Fixate Away from Toy Fixate Briefly Away from Toy Fixate Toy Continuously
Toy Retrieval Ignore Toy Attempt to Grasp Toy Pick Up Cover
Source: The Lancet, Vol. 352, August 29, 1998

 

Table 9 Median (Quartiles) Problem-Solving Scores on Entire Problem and Each Individual Step
Step LCPUFA (n = 21) No-LCPUFA (n = 23) p
Intention Score
Entire Problem 14.0 (11.8, 17.1) 11.5 (10.0, 13.3) 0.035
Barrier Step 5.5 (4.3, 6.0) 4.8 (3.5, 5.8) 0.221
Cloth Step 5.0 (4.5, 6.0) 4.5 (3.5, 5.8) 0.147
Cover Step 4.3 (2.6, 5.3) 2.5 (1.0, 3.5) 0.032
Intentional Solutions
Entire Problem 2.0 (0.5, 3.0) 0.0 (0.0, 0.2) 0.021
Barrier Step 4.0 (2.0, 4.0) 3.0 (2.0, 4.0) 0.337
Cloth Step 3.0 (2.0, 4.0) 3.0 (1.0, 4.0) 0.234
Cover Step 3.0 (1.5, 3.5) 1.0 (0.0, 2.0) 0.005
Source: The Lancet, Vol. 352, August 29, 1998

Conclusion

The long chain polyunsaturated fatty acids DHA and AA are found in infants brains, eyes and serum. Long chain polyunsaturated fatty acids are also found in breast milk. Infants have a limited capacity to synthesize long chain polyunsaturated fatty acids which are necessary for proper neurological development and visual acuity. Infants who are not breast fed must be given a formula that contains long chain polyunsaturated fatty acids.


References

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