Abstract
Arachidonic acid (AA) is supplied together with docosahexaenoic acid (DHA) in infant formulas, but we have limited knowledge about the effects of supplementation with either of these long-chain polyunsaturated fatty acids (LCPUFA) on growth and developmental outcomes. AA is present in similar levels in breast milk throughout the world, whereas the level of DHA is highly diet dependent. Autopsy studies show similar diet-dependent variation in brain DHA, whereas AA is little affected by intake. Early intake of DHA has been shown to affect visual development, but the effect of LCPUFA on neurodevelopment remains to be established. Few studies have found any functional difference between infants supplemented with DHA alone compared to DHA+AA, but some studies show neurodevelopmental advantages in breast-fed infants of mothers supplemented with n-3 LCPUFA alone. It also remains to be established whether the AA/DHA balance could affect allergic and inflammatory outcomes later in life. Disentangling effects of genetic variability and dietary intake on AA and DHA-status and on functional outcomes may be an important step in the process of determining whether AA-intake is of any physiological or clinical importance. However, based on the current evidence we hypothesize that dietary AA plays a minor role on growth and development relative to the impact of dietary DHA.
Main
Lipids play varied and critical roles in metabolism, and their function is modulated by the individual fatty acid moieties. Membrane function has been shown to be modulated by the fatty acid composition of the phospholipids. Saturated and monounsaturated fatty acids represent the richest energy sources, whereas the essential n-6 and n-3 polyunsaturated fatty acids (PUFA) are the most biologically active fatty acids. The long-chain PUFAs (LCPUFA), arachidonic (AA), eicosapentaenoic (EPA), and docosahexaenoic acid (DHA), are incorporated into membrane phospholipids, precursors of signaling molecules (e.g., eicosanoids and docosanoids), and potent activators of a number of gene transcription factors (e.g., peroxisome proliferator activated receptors). Perinatal intake and maternal transfer of LCPUFA may therefore have an impact on growth, development, and susceptibility to diseases.
A distinctive feature of the intrauterine and neonatal period is that DHA is incorporated in high levels in the membranes of the central nervous system and this is in part dependent on maternal and infant diet. AA is incorporated into the membranes of all tissues in almost equal amounts and is less dependent on diet. AA has been shown to be readily taken up and incorporated into brain phospholipids and subsequently released upon activation of phospholipase A2 with a possible role in brain signaling (1). However, the role of dietary AA-intake relative to infant development is still not well defined. In this commentary, we will discuss indirect as well as direct evidence of the role of AA in growth and development. As AA is often supplied together with DHA, we also discuss the effect of DHA in order to try to disentangle the effect of these LCPUFAs.
Maternal–Fetal Transfer of Arachidonic Acid
In the last weeks of pregnancy, LCPUFAs accumulate in the fetus and tend to reach higher concentrations in fetal/neonatal plasma than in the mother (2). So far, synthesis of LCPUFA has not been shown to occur in the placenta and most of the n-3 and n-6 LCPUFA acquired by the fetus is thought to come from the maternal circulation across the placenta through a facilitated diffusion process (3). Transfer of DHA across the placenta involves specific binding and transfer proteins facilitating the higher concentration of DHA in fetal compared with maternal plasma (4). AA-concentrations are also higher in the fetus, whereas concentrations of linoleic acid (LA) and α-linolenic acid (ALA) in maternal and infant blood differ much less (5,6). The phenomenon of increasing LCPUFA in the fetal department has been described as “biomagnification” (7), but could also be interpreted as a natural consequence of a dual liver system (i.e., the combined PUFA-metabolism of the mother and the fetus/infant).
In the third trimester, fetal growth is accompanied by deposition of fat tissue, which contains AA and DHA, although in more limited amounts than previously believed (8,9). On the other hand, LCPUFAs are also deposited in large amounts relative to the accretion rates of other fatty acids in the fetal brain during the period of maximum brain growth, which lasts through the first years of postnatal life (8,10). It has been estimated that fetal PUFA-accumulation is supported by a supply of ~50 mg/(kg × day) of n-3 PUFA and 400 mg/(kg × day) of n-6 PUFA (11). In both growth-retarded fetuses (IUGR) and infants born preterm, the progressive accumulation of n-6 and n-3 PUFA in fetal tissues is truncated at the end of pregnancy. The differences observed in the relative fetal–maternal relationships for AA and DHA associated with IUGR-pregnancies could also be related to a lack of LCPUFA-generating enzyme systems in the fetus, or impairments in the placental transfer of LCPUFA, and could potentially contribute to the neural and vascular complications that are associated with IUGR (12).
A few case–control studies have been conducted to evaluate whether maternal and fetal n-3 and n-6 PUFA-status might play a role in the pathogenesis of preterm birth. Women who deliver preterm have been demonstrated to have higher levels of AA and other n-6 LCPUFA in their blood and trophoblast tissue compared to women who deliver at term (13). Furthermore, maternal dietary supplementation with marine n-3 LCPUFA has been shown in randomized controlled trials (RCT) to reduce the risk of early preterm delivery (<34 wk) (relative risk = 0.74; (95% confidence interval = 0.58, 0.94)) and result in a modest increase in birth weight (14). Due to the role of AA-derived eicosanoids in the initiation of delivery it is biologically plausible that a slight dampening of this effect by competition with n-3 LCPUFA could explain a protective effect of n-3 LCPUFA against the risk of early labor (15). It could even be speculated that the relatively lower fetal accumulation of AA relative to DHA is due to the need for the placenta to retain AA to initiate prostaglandin production and delivery. However, overall the mechanisms involved in placental transfer of LCPUFA remain unclear, and the extent to which the liver in the developing fetus contributes to the overall accumulation of LCPUFA in fetal membranes through endogenous synthesis from the precursors also requires clarification.
Breast Milk Arachidonic Acid Content
Infant blood PUFA-levels remain higher than maternal levels for some time postnatally especially in the breast-fed infant (16,17). Whereas the erythrocyte (RBC) DHA-status of breast-fed infants has been found to be associated with maternal RBC DHA-status during lactation, no such association was observed for AA (18). Breast milk LCPUFA-levels, i.e., the absolute quantities of DHA and AA, seem to be quite stable throughout 12 mo of lactation (19). Considering DHA and AA-concentrations in breast milk worldwide, Brenna et al. (20) showed that the mean concentration of DHA was 0.3 ± 0.2% and that of AA was 0.5 ± 0.1%. The correlation between breast milk content of DHA and AA was surprisingly low with a high degree of variability in the ratio of DHA to AA in individual breast milk samples. It is noteworthy that the SD of breast milk DHA is >50% of the mean value, whereas that for AA is around 30%. The higher variability of DHA is consistent with the conclusions of another review (21), which reported that although mean breast milk levels of AA were very similar in all countries, ranging from 0.36% to 0.49%, mean DHA-levels ranged from 0.17 to 0.99%, with the highest levels in Japan and the lowest in samples from Canada and the USA. Typically, breast milk has 1.5- to 2-fold more AA than DHA, but in countries with a high fish consumption the DHA-content may be higher than that of AA. The AA/DHA-ratio in breast milk is therefore high in mothers who consume little fish and low in mothers with high n-3 LCPUFA-consumption. It has been shown that the DHA-level in breast milk is directly related to the DHA-content of the maternal diet (22), but it is not known if the lower variability in breast milk AA is explained by metabolic or dietary mechanisms. Breast milk AA was not affected in lactating mothers who were allocated to consume increasing doses of DHA (22) or 3 g/d DHA-rich tuna oil (23) to achieve a breast milk DHA-concentration of around 1% of the fatty acids. Two recent studies confirm the different regulation of AA and DHA in breast milk, indicating that AA is affected by the genetic pattern in the FADS-gene cluster (24) and less sensitive than DHA to dietary supplementation (25).
Brain Composition in Infancy—Influence of Diet
On the whole, membrane PUFA-composition (the principal components of which are LA, AA and DHA) seem to be more responsive to LA and DHA in the diet than to intake of AA. Animal studies have demonstrated that an increase in dietary n-3 PUFA as ALA is almost completely reflected in the membrane n-3/n-6 PUFA-ratio in tissues at LA/ALA intakes of <10, whereas the dietary balance between ALA and LA has little influence at higher ALA intakes and a similar biphasic response is also seen in diets that contain LCPUFA (26). These results show a high sensitivity of brain membranes to dietary variations in the PUFA-supply within the normal range, strongly favoring incorporation of n-3 LCPUFA over LA and AA. In neonate baboons, dietary DHA consistently supported greater brain DHA-incorporation and maintenance of cortex DHA-concentration with feeding duration, while brain AA was not related to the dietary supply and decreased with age in all tissues (27). In the case of a dietary deficiency of n-3 PUFA, there is a trend for DHA to be replaced with the nearest n-6 PUFA equivalents, whereas few changes are seen for the reciprocal lack of dietary of n-6 PUFA (28,29). Thus, n-3 PUFA seems to be the main determinant of the membrane PUFA-composition and the data are consistent with the hypothesis that brain membranes are regulated towards a high level of unsaturation.
Cerebral structures accumulate n-6 and n-3 PUFA during the perinatal period and early infancy. Although the brain, in common with most tissues, accumulates considerable amounts of AA, DHA appears to accumulate preferentially in neural structures. High deposition rates of DHA in the third trimester have been calculated and derived from postmortem studies and the average whole-body DHA-accretion during this period amounts to around 50 mg/d. The accretion of AA is approximately double (100 mg/d), but the relative measure (i.e., % of fatty acids) indicates a preferential accumulation of DHA in brain compared to AA (8). In the mid-1990’s, two research groups investigated PUFA-accumulation in brain autopsies from human infants who had died of Sudden Infant Death Syndrome in the first months of life. The UK group (30) found that the mean cortical phospholipid weight % of DHA was around 25% greater in five breast-fed infants (9.7%) compared to five age-comparable formula-fed infants (7.6%). However, the overall percentage of LCPUFA was maintained in term formula-fed infants and the reduction in DHA was compensated for by a significantly increased incorporation of all the dominant n-6 PUFA. However, in formula-fed preterm infants with the lowest concentration of cortical DHA, this compensatory effect in n-6 PUFA was only partial and an increase in the n-9 series PUFA was also detected. The second autopsy study of brain tissue from Australia (31) found a greater proportion of DHA in both RBC and brain cortex in term breast-fed infants relative to those who were formula-fed. Furthermore, cortex DHA increased with age in breast-fed but not in formula-fed infants. In contrast to DHA, the percentage of AA in the brain increased with age to a similar extent in all infants, irrespective of diet. Observations in human infants are thus consistent with experimental data in infant baboons, showing that brain DHA-levels are responsive to diet, while AA-levels are not. The question therefore arises whether lack of preformed dietary AA would result in lower brain AA or if it might be obtained from body stores or by synthesis from LA as suggested by the autopsy data (32).
Dietary Arachidonic Acid, Postnatal Growth and Development
Support for the concept of the essentiality of AA in infant nutrition came from the observation of potentially adverse effects in preterm infants of a marine-oil containing formula (0.5% n-3 LCPUFA of which 0.3% was EPA, which thus dominated over DHA) (33). In this study, plasma phosphatidylcholine AA-concentration was found to correlate with measures of normalized growth, which led the authors to hypothesize that AA deficiency may contribute to decreased growth in preterm infants over the first year of life (33). Earlier observational data had also shown a positive correlation between body weight and postnatal plasma triglyceride AA (and total n-6 PUFA) and an inverse correlation with ALA (34). These data do not, however, prove an essential role of dietary AA and furthermore have not been replicated in subsequent larger RCTs in preterm or term infants. In fact, formula LCPUFA-supplementation of preterm infants (who are potentially more sensitive to dietary changes, particularly in LCPUFA, than term infants) have not shown significant effects of supplementation on weight, length or head circumference ≥12 mo, as reported in a meta-analysis (35). The largest preterm DHA-supplementation RCT to date, which included both formula-fed and breast-fed infants and kept infant AA-intake constant, suggests that infants in the high-DHA group were slightly longer than infants in the standard-DHA group at 18 mo corrected age (23).
Overall, data from RCTs indicate no benefit on growth of maintaining a higher intake of AA relative to DHA as currently recommended for infant formulae (36). For term infants, few of the RCTs on formula LCPUFA-enrichment have investigated the effects of addition of DHA alone and, although this has been shown to decrease RBC-AA-status (37,38,39,40), the functional consequences of the decrease are not clear. The majority of the RCTs investigating the effect of dietary LCPUFA-supplementation in term infants have added both AA and DHA, although some have varied DHA-intake at a constant intake of AA. Overall, meta-analyses of these trials have shown no effect of LCPUFA-supplementation on physical growth throughout the first 3 y of life irrespective of the type of LCPUFA-supplementation, duration of supplementation and method of outcome assessment (41,42). However, the heterogeneous study designs with respect to doses, supplementation strategies, group size and methodologies for primary outcome assessment complicate attempts to combine data in meta-analyses to achieve conclusions with respect to the functional consequences of the addition of LCPUFA, or the specific effects of AA addition. A meta-analysis of RCTs that supplemented lactating mothers with n-3 LCPUFA showed that infants of supplemented mothers were around 1 cm shorter at 2 y, but had larger heads at 1–2 y of age (43). Thus, although these studies do not allow for definitive conclusions about potential effects of dietary AA (44), they do not indicate that dietary AA is important for growth.
With respect to neural function, the most accepted developmental effect of LCPUFA-supplementation in infants is an increased rate of visual acuity development (45), which seems to be explained solely by DHA. Some of the RCTs in this field compared formulae with DHA and DHA+AA with a control formula without LCPUFA and found that the visual acuity of all supplemented infants was similar to that of human milk–fed infants, whereas that of the unsupplemented infants was significantly lower (37,46). A metaregression analysis also found that variability in the effects on visual acuity between studies was explained by the dose of DHA (47).
One RCT found that addition of AA to formula in a highly bioavailable form (egg phospholipids) resulted in RBC AA-concentrations that exceeded that in breast-fed infants (48) and observed a positive association between the AA/LA-ratio in RBC phosphatidylcholine and developmental test scores (Brunet-Lezine) at 24 mo. The effect was, however, independent of group allocation and could therefore be confounded (49). Another RCT in term infants that also varied formula DHA-concentrations (from 0.32 to 0.96%) at constant AA (0.6%) found that cognitive outcomes differed between all LCPUFA-groups and the control group, but not between groups given formula with different levels of DHA relative to AA (50,51). This might be interpreted as an effect of AA, but this conclusion is limited by the fact that no group received a formula with only AA. The largest available RCT in preterm infants, which as previously mentioned included both breast-fed and formula-fed infants that differed only in DHA-intake (0.35 vs. 1.0% at a constant intake of 0.6% AA), found a higher Bayley scale mental development index (MDI) and fewer girls with delayed mental development at 18 mo of age in the high-DHA group (23).
Since there are insufficient data to consider the effects of individual LCPUFAs, meta-analyses have considered the effects of AA and DHA together. Meta-analyses of all RCTs with neurodevelopmental outcomes at different ages throughout the first 2 y of life have not shown any statistically significant benefit of LCPUFA-supplementation of infant formula on the Bayley scales of development in term or preterm infants (41,44,52). However, a trend for an effect on Bayley MDI at around 12 mo of age (p = 0.06) was shown in a meta-analysis that combined all LCPUFA formula supplementation trials in both term and preterm infants (52). This meta-analysis did not find any effect of prematurity on the efficacy of LCPUFA-supplementation nor did it find an effect of LCPUFA dose, although there was a trend towards an effect of DHA dose (β = 9(−6; 23)), without any such trend for AA (β = −0.3(−7.9;7.3)) (52). Meta-analyses looking at the developmental effects of maternal n-3 LCPUFA-supplementation in pregnancy and lactation have suggested some effects on neurodevelopment, but this was based on very few studies (43,53). It should be noted that the age at which the effects were examined in the different RCTs, both those with direct addition of LCPUFA to formula and maternal n-3 LCPUFA trials varied a lot, and that the effects in the first few years of life may not be representative of effects in the long term. These and other methodological aspects (e.g., the questionable use of the Bayley scales to detect differences within normally developing children) should be considered. It is at present not possible to draw any firm conclusions regarding the effects of either DHA or AA on mental performance.
A few RCTs have investigated the effect of LCPUFA-supplemented formulas on the development of allergy, with positive effects in some, but not all studies (54). It is, however, unlikely that these effects are explained by the addition of AA as other studies seem to indicate such effects in RCTs with maternal n-3 LCPUFA-supplementation, in agreement with the previously mentioned meta-analysis of all RCT of n-3 LCPUFA-supplemented lactating mothers (43) and other systematic reviews of the effect of perinatal n-3 LCPUFA-supplementation of mothers (45,46). Long-term follow-up studies of RCTs have found a possible role of maternal fish oil or fish intake on the offspring’s risk of allergy, but the role of early dietary AA-supply in this context is not known (47,48).
Role of Genetic Variability in LCPUFA Levels and Functional Responses
Applying current knowledge about the genetic control of LCPUFA-synthesis is a further way to derive indications for the dietary requirement for preformed LCPUFA in the perinatal period. Single nucleotide polymorphisms (SNPs) in the fatty acid desaturase (FADS) gene cluster have been shown to explain as much as 29% of the variation in serum AA-contents in adults, while serum DHA-concentrations were found to be primarily determined by the dietary supply of preformed DHA. Minor allele homozygotes of various FADS SNPs have also been found to have lower blood (RBC and plasma) levels of AA during pregnancy and consistently higher levels of LA and ALA (55,56). This is in line with findings in plasma from both mothers and neonates showing strong inverse associations between the minor allele for two FADS SNPs and concentrations of AA, EPA and DHA and furthermore suggesting that new-born infants had a greater capacity to synthesize AA than n-3 LCPUFA, although some synthesis of DHA was occurring as well (57). Curiously, a study of 2,000 cord blood samples found that minor allele FADS SNPs in the mother gave rise to increased levels of n-6 PUFA before the delta-5 desaturation step (LA and di-homo γ-linolenic acid), whereas minor allele SNPs in the child resulted in decreased levels of AA and other n-6 LCPUFA beyond this point in the metabolic pathway (58). Colostrum AA (and DHA)-levels have also been found to be decreased in minor allele carriers of a number of FADS SNPs (59), but studies in mature breast milk have shown that the concentration of AA is influenced to a larger extent by FADS polymorphism than that of DHA (20,50,57).
Overall, the data suggest that the n-6 PUFAs in breast milk, plasma and blood cell membranes across all ages are more affected by FADS polymorphisms than n-3 PUFAs, typically with an increase in LA and a decrease in AA-levels in minor allele carriers (55,56,60,61,62,63). However, we have recently found that FADS polymorphisms contributed substantially to DHA-status in late infancy, and some SNP minor alleles were even found to up-regulate DHA-status (60), whereas minor alleles of all the investigated SNPs lowered AA in a consistent way (64). Furthermore, a longitudinal study of serum phospholipid fatty acid composition at 2 and 6 y in 331 children found lower tracking of n-6 LCPUFA in children who were homozygous for the major allele of various FADS SNPs compared to the tracking that was seen in carriers of at least one minor allele, whereas the tracking in n-3 LCPUFA-levels was highest in major allele carriers (65).
Several studies have found associations between FADS haplotype patterns and neurodevelopmental outcomes in breast-fed vs. formula-fed infants although the observed effects currently appear to be somewhat inconsistent (59,65,66,67). The differences in the observations may be explained by the observed variable associations between different FADS SNPs and blood levels, especially for DHA (60) as indicated by the most recent studies (64,68). The importance of FADS genotypes has also been investigated in relation to plasma lipid profile in childhood (69,70) and atopic development, specifically of asthma (71,72,73). Furthermore, daily margarine intake (amongst the major sources of n-6 PUFA) has been found to be associated with increased asthma in children who were major allele homozygotes, indicating that FADS gene variants may modulate risk of allergic diseases possibly via a reduction in AA (72). Current knowledge about the functional effects of FADS polymorphism is still limited (74) and although most clearly associated with AA-status, functional associations with FADS genotype cannot be taken as proof of the role of AA. The influence of FADS polymorphisms on status—and specifically the observed variations between specific fatty acids and SNPs over time—introduces a new variable to be considered in the evaluation of the effects of LCPUFA-supplementations on the growth, development and health of young children.
Conclusion
The role of dietary AA in the perinatal period needs to be clarified and disentangled from the effects of DHA. To date, few studies have examined and/or found any difference between the effects of DHA-supplementation alone to mothers or infants and the more customary DHA+AA-supplementation. AA in breast milk is less associated with maternal dietary habits and very stable throughout the world. Autopsy studies show a similar low variability in brain AA in breast-fed infants and dependence of DHA-levels on dietary intakes. It has been hypothesized that there may be synergistic as well as antagonistic effects between n-6 and n-3 LCPUFA and that it is important to aim at a balance to maintain tissue level homeostasis. While synergism might be a feature at low n-3 PUFA-status, AA becomes suppressed by antagonism at high levels of EPA+DHA (≥8% in RBC) (75). This level matches exactly the limit suggested as optimal in relation to prevention of cardiovascular diseases (76). However, it remains to be established if this is indicative of optimal function and health in infants. It also remains to be established if the potential effects of DHA are antagonized by n-6 PUFA and whether single addition of n-3 LCPUFA can positively affect neurodevelopment or decrease allergic and pro-inflammatory reactions later in life. Thus, the question about whether intake of preformed AA is of any importance (good or bad) is still unanswered and we hypothesize that it will have a minor role relative to the impact of dietary DHA on growth and development.
Disclosure
The authors declare no conflict of interest.
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Lauritzen, L., Fewtrell, M. & Agostoni, C. Dietary arachidonic acid in perinatal nutrition: a commentary. Pediatr Res 77, 263–269 (2015). https://doi.org/10.1038/pr.2014.166
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DOI: https://doi.org/10.1038/pr.2014.166
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