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What is the Right Level of DHA in the Infant Diet?: Commentary on article by Hsieh et al. on page 537

Docosahexaenoic acid (DHA, 22:6n-3) is a most extraordinary molecule, containing six double bonds, about the most that you can fit onto a 22-carbon fatty acid in the methylene-interrupted structure commonly used in the biologic motif. What is even more extraordinary is that the brain and retina concentrate this fatty acid against a concentration gradient and incorporate it at high levels into their membrane phospholipids (1). Although these observations were made several decades ago, the curiosity of lipid biochemists has only recently begun to be assuaged with some appreciation of what the functions of this unusual fatty acid might be. It is now apparent that DHA-phospholipid species subserve a regulatory role for G protein coupled receptors (2) due to their ability to impart unique physical properties to biologic membranes or microenvironments thereof (3). Also of direct relevance to the issue of neurodevelopment is the demonstration that DHA can protect against apoptosis (4,5) and increase neuronal process outgrowth. DHA is also known to be a ligand for the RXR receptor and influence protein expression. It can be made into potent bioactive eicosanoid-like compounds termed neuroprotectins that may play a role in Alzheimer's disease (5). A wealth of animal work has indicated that when the nervous system is deficient in DHA, there are many adverse consequences for brain and retinal function as indicated by behavioral or physiologic endpoints (1,6).

It should be no surprise then that leaving DHA out of infant formulas, as was done in the United States and much of the world in the 20th century, could result in suboptimal neurodevelopment. There have now been many randomized, controlled trials of infant formula with or without DHA, or with DHA and arachidonic acid (ARA) as the key variable. Many of these studies, although not all, have shown a benefit for DHA in the range of from 0.12–0.36 wt% for nervous system function or development (7).

These studies then lead to the question as to the level of DHA in human milk and the infant diet. A recent sampling of human milk DHA content in nine countries indicates a range of from a low of 0.17 wt% in both the United States and Canada to a high of 0.99 wt% in Japan (8). It was of interest that milk ARA content was more consistent with a value of around 0.4 wt% across these countries with their varied diets. The considerable variation in milk DHA content is a direct result of the varying levels of DHA intake in these populations and the milk content can be readily manipulated by increasing DHA intake (9). The low level of DHA observed in women in the Northern Hemisphere is due to their very low intake of preformed DHA.

In the featured work in this issue of Pediatric Research, Hsieh and colleagues, working in Tom Brenna's laboratory, demonstrated that when DHA is added to formula fed to newborn baboons in a range similar to that found in some human infant formulas (0.33 wt% theoretical and 0.42 wt% actual), that brain DHA content was significantly increased in the plasma, erythrocyte, heart, cerebral cortex (both precentral gyrus and frontal lobe), globus pallidus, caudate, and superior and inferior colliculi (10). This is consistent with previous work from this laboratory showing that DHA supplementation could largely prevent the losses in brain DHA associated with unsupplemented formulas and restore them to the breast-fed control level (11). This study extends our knowledge considerably farther by then examining the brain response with respect to DHA and ARA content when the formula contains about a 3-fold higher DHA content (1.0 wt% theoretical and 1.13 wt% actual). Hsieh et al. found an additional increment in DHA content over that of the 0.42 wt% supplemented animals in the liver, plasma, heart and the brain precentral gyrus (10). There was not a widespread effect of the higher DHA supplementation on tissue ARA content as it was lowered only in the plasma (by 22%), globus pallidus (by 11%) and superior colliculus (by 5%) relative to the animals fed the 0.42 wt% DHA formula. There is a well known antagonism between the n-3 and n-6 fatty acids in general, and for ARA and DHA in the brain, in particular. This study gains relevance to the human situation in that it was done in our fellow primates, baboons, and so it is very likely that the human brain will respond in a similar fashion to these ARA and DHA feeding regimens.

With this new data in hand, the question should now be asked, “What is the right level of DHA in the infant diet?”. This study showed that frontal cortex DHA increased by about 15% with the higher DHA feeding relative to the lower DHA feeding. This is a significant change and may well result in more optimal brain development and function. Moriguchi et al. has shown that spatial task performance is directly related to rat brain DHA content (12). Nevertheless, there is at present no data that clearly demonstrates that a 15% increase in the human brain DHA has functional/developmental consequences. While the increased brain DHA content may not by itself be a sufficient criteria for increasing formula DHA content, it certainly indicates that the higher level may be preferable and needs to be tested from both functional and safety perspectives. There are statistically significant decreases in ARA in a couple of brain structures, albeit an only 5–11% effect, due to the higher level of DHA supplementation and possible adverse effects of this change must also be better understood. Perhaps some concomitant increase in ARA formula content would be optimal such that it would prevent this loss. It should also be kept in mind that this ARA decrease may disappear in older animals and the transitory decline may not have physiologic consequences. One study of infant rhesus monkeys found a benefit for orienting and motor skill development over the first month of life when fed a 1 wt% DHA plus 1 wt% ARA formula compared with an unsupplemented formula, but a lower DHA formula was not tested (13). Randomized, controlled trials have begun with human infants where safety and efficacy of higher DHA content in formulas will be assessed (14).

If the outcome of these studies suggest that the higher DHA content in the infant diet is preferable, then the question arises as to how much dietary DHA intake by the breast-feeding mother would that require? In Australian women, Makrides et al. showed that it took about 1.1 g of DHA supplement per day to reach a breast milk DHA level of 1 wt%, or stated in other terms, about a 50 mg dose of DHA per BMI unit per day (9). This is not an unusually high level for many Asian women but it is far greater than typical intakes for Western women. If taken as fish rather than supplements, this amount of DHA intake would be obtained from about 5 oz/d of broiled salmon or mackerel (15).

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Correspondence to Norman Salem Jr..

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This work was supported by the Intramural Research Program of the National Institutes of Health, NIAAA.

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Salem, N. What is the Right Level of DHA in the Infant Diet?: Commentary on article by Hsieh et al. on page 537. Pediatr Res 61, 518–519 (2007). https://doi.org/10.1203/pdr.0b013e318057fa93

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