A More Comprehensive Approach to the Neuroprotective Potential of Long-Chain Polyunsaturated Fatty Acids in Preterm Infants Is Needed-Should We Consider Maternal Diet and the n-6:n-3 Fatty Acid Ratio?

Abstract

There is growing evidence that long-chain polyunsaturated fatty acids (LCPUFAs) are of importance for normal brain development. Adequate supply of LCPUFAs may be particularly important for preterm infants, because the third trimester is an important period of brain growth and accumulation of arachidonic acid (n-6 LCPUFA) and docosahexaenoic acid (n-3 LCPUFA). Fatty acids from the n-6 and n-3 series, particularly, have important functions in the brain as well as in the immune system, and their absolute and relative intakes may alter both the risk of impaired neurodevelopment and response to injury. This narrative review focuses on the potential importance of the n-6:n-3 fatty acid ratio in preterm brain development. Randomized trials of post-natal LCPUFA supplementation in preterm infants are presented. Pre-clinical evidence, results from observational studies in preterm infants as well as studies in term infants and evidence related to maternal diet during pregnancy, focusing on the n-6:n-3 fatty acid ratio, are also summarized. Two randomized trials in preterm infants have compared different ratios of arachidonic acid and docosahexaenoic acid intakes. Most of the other studies in preterm infants have compared formula supplemented with arachidonic acid and docosahexaenoic acid to un-supplemented formula. No trial has had a comprehensive approach to differences in total intake of both n-6 and n-3 fatty acids during a longer period of neurodevelopment. The results from preclinical and clinical studies indicate that intake of LCPUFAs during pregnancy and post-natal development is of importance for neurodevelopment and neuroprotection in preterm infants, but the interplay between fatty acids and their metabolites is complex. The best clinical approach to LCPUFA supplementation and n-6 to n-3 fatty acid ratio is still far from evident, and requires in-depth future studies that investigate specific fatty acid supplementation in the context of other fatty acids in the diet.

Keywords: arachidonic acid; docosahexaenoic acid; neurodevelopment; polyunsaturated fatty acids; preterm infant.

Figure 1

Metabolism and major food sources of important n-6 and n-3 fatty acids. Linoleic acid (LA, 18:2 n-6) is primarily obtained from vegetable oils (soy, corn, and sunflower oils). α-linolenic acid (ALA, 18:3 n-3) is also derived from plant-based oils, such as canola (rapeseed) and flaxseed. Arachidonic acid (AA, 20:4 n-6) derives from animal fats, particularly poultry. Eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3) are largely obtained from fish, shellfish, and algae.

Figure 2

Total n-3 (A) and n-6 (B) fatty acid forebrain (FB) content, and relative content of docosahexenoic acid (DHA) and arachidonic acid (AA) (C). Fatty acid content measured in post-mortem samples from infants who died soon after birth due to causes not related to the central nervous system. Relative percentages of DHA (22:6 n-3, black circles) and AA (20:4 n-6) in the brain over the final 20 weeks of gestation shows a relative increase in DHA such that the two exist in a ratio of roughly 1:1 at 40 weeks. Reproduced with permission from Martinez (14).

Figure 3

Pathways of lipid mediator production. In peripheral or systemic injuries or infections, phospholipases act on membrane phospholipids to release these PUFAs, whereupon they are metabolized by lipoxygenases (LO) LO-5, LO-12, and LO-15, as well as cyclo-oxygenase-2 (COX-2) into the various lipid mediators. Initially, release of pro-inflammatory mediators, such as prostaglandins (PGs) and leukotrienes (LTs) derived from AA promote the recruitment of neutrophils and initiate the inflammatory process. These pathways are tightly-linked to the process of preterm birth and neonatal inflammatory or hypoxic-ischemic brain injury. Hours to days after an initial inflammatory insult, resolution and healing occurs. Specialized pro-resolving mediators signal this switch, which includes lipoxins (LXs), resolvins (Rvs), (neuro)protectins (NPD/PDs), and maresins (MaRs). Lipoxins, such as LXA4 are derived from AA, but the majority of specialized pro-resolving mediators are produced using EPA and DHA as precursors. Conversely, LA is able to compete with AA, EPA, and DHA for certain COX-2, 12-LO, and 15-LO, resulting in oxidized linoleic acid metabolites (OxLAMs), such as 9- and 13-hydroxy-octadecadienoic acid (9- and 13-HODE) and 9- and 13-oxo-octadecadienoic acid (9- and 13-oxoODE). Adapted from Serhan and Petasis (31).