expert opinion

Evidence for infant formulas providing both docosahexaenoic acid and arachidonic acid

Stewart Forsyth

June 19, 2019

Although the importance of fatty acids for human health and wellbeing was initially recognized almost 90 years ago 1,2, it is during the last three decades that there has been considerable interest in the roles of long chain polyunsaturated fatty acids (LCPUFAs) in infant growth and development 3-6. However, despite there now being a wealth of information on the functional roles of docosahexaenoic acid (DHA) and arachidonic acid (ARA) from cellular, animal and human studies, policies relating to dietary intakes of DHA and ARA in early life continue to lack a consensus across key policymakers 7,8 and a pivotal issue relates to whether infant formulas should contain both DHA and ARA.

Relevant biological factors

In early life there is biological evidence that human development recognizes the importance of DHA and ARA as necessary structural and functional nutritional metabolites for optimal growth and development. For example, DHA and ARA are always available in breast milk whereas in cow’s milk, goat milk, soya- and rice-based beverages DHA and ARA are either not detected or only present in trace amounts 9. The need for an adequate supply of these fatty acids during pregnancy is evidenced by an active transport mechanism for the transfer of these fatty acids across the placenta from the mother to the fetus 10,11. In the postnatal period, DHA and ARA are released from maternal lipid stores to increase the DHA and ARA content of breast milk during lactation, and this process is dependent upon maternal dietary intake of DHA and ARA 12,13.

Seminal work by Manuela Martinez demonstrated that, during the latter part of pregnancy and during the first 2 years of life, there is a rapid accumulation of both DHA and ARA in the developing brain 14. Subsequent publications have shown that the DHA content of the infant brain is higher in breastfed infants compared with infants who receive infant formulas that are devoid of both DHA and ARA 15,16. In addition, infants receiving a formula supplemented with added DHA and ARA have higher blood levels of DHA and ARA during the first year of life compared with infants who receive a formula that was not supplemented 17.

Human milk

In 2007, Brenna et al. published data from 65 studies and confirmed that DHA and ARA are consistently present in breast milk with the mean concentration of DHA being 0·32 percent fatty acids (range 0·06–1·4 percent) and the mean concentration of ARA was 0·47 percent (range 0·24–1·0  percent) 18.  In 2016, Fu et al. provided updated data from 78 studies conducted in 41 countries and included 4,163 breast milk samples and they reported that the worldwide mean levels of DHA and ARA in breast milk were 0·37 (SD 0·11) percent and 0·55 (SD 0·14) percent 19. Both studies showed that the ARA content of breast milk is more consistent compared with DHA, the latter being particularly influenced by maternal diet. The levels of DHA were remarkably low in populations with the greatest poverty with levels of 0·06 percent DHA in Pakistan, and Northern Sudan, and 0·10 percent DHA in Southern Sudan.

Based on the WHO recommendation on exclusive breastfeeding for 6 months and the assumption that the mother is receiving an adequate intake of DHA, infants will receive approximately 190 mg/d ARA and 130 mg/d DHA at 6 months. This is based on a breast milk intake of 850 ml/d and the reported mean concentrations of DHA and ARA in human milk. Breastfed infants should continue to receive a supply of DHA and ARA throughout the recommended breastfeeding period of 2 years or beyond. An infant exclusively receiving a formula without DHA and ARA will clearly have zero consumption from milk feeds during this time.

Complementary foods

From 6 months of age, breast milk or infant formula need to be complemented by higher energy food products that will meet the increasing energy and nutrient requirements of the rapidly growing infant.  There is clear evidence that in both developed and developing countries, the DHA and ARA content of complementary food intake is low 20-23. In a global study, the contribution of DHA and ARA intake from complementary foods was directly related to the gross national income (GNI) of the country; the intakes of DHA and ARA from complementary foods during the period of 6-36 months for 76 medium- and low-income countries were 14.6 and 17.9 mg/day, respectively, and in the lowest income countries, intakes fell to 9.6 and 8.9 mg/day, respectively 24. The DHA and ARA intake from complementary foods was exceptionally low in Nepal (DHA 0.7 mg/day; ARA 1.1 mg/day), Ethiopia (DHA 1.1 mg/day; ARA 3.8 mg/day), and Rwanda DHA 1.8 mg/day; ARA 1.7 mg/day). It is therefore evident that both breast milk and supplemented milk products, including infant formula, can provide a safety net for those infants at greatest risk of DHA and ARA deficiency during the first 3 years of life.

Endogenous synthesis

The importance of dietary intake of preformed DHA and ARA is highlighted by the evidence of low endogenous synthesis of these fatty acids during early life 25. Endogenous synthesis of DHA and ARA is directed through a metabolic pathway where the n-3 and n-6 fatty acids compete for a shared desaturation and elongation enzyme system. As a consequence, the balance in intake of the essential 18-carbon n-3 and n-6 precursors can influence the levels of DHA and ARA derived from endogenous synthesis. The competition between n-3 and n-6 fatty acids is particularly evident at the rate-limiting Δ5- and Δ6-desaturase steps in the metabolic pathway.

It is now recognized that, in addition to substrate competition, the efficiency of the Δ-5 and Δ-6-desaturase steps are also dependent on the genotype of fatty acid desaturase 1 (FADS1) and desaturase 2 (FADS2), both located on chromosome 11, and which encode Δ-5 and Δ-6 desaturase enzymes, respectively 26. Several studies have reported associations between single nucleotide polymorphisms (SNPs) in the FADS genes and LCPUFA status, with carriers of the minor alleles of FADS SNPs being associated with lower red blood cell content (RBC) of LCPUFAs, most notably of ARA, and it has been concluded that infant FADS genotype could contribute to differences in AA and DHA concentrations between breastfed and formula fed infants 27.  Moreover, there is emerging data that there is regional and intra-regional variation in the prevalence of the minor alleles of FADS SNPs and this may contribute to population differences in LCPUFA status and subsequent health outcomes 28,29. These data provide further evidence of the need to ensure that dietary intakes are sufficient to achieve optimum DHA and ARA status during early life.   

Because of the shared metabolic pathway, there is also a biochemical interdependence between DHA and ARA that needs to be considered when supplementing DHA and ARA. There is clear evidence from animal and human studies that alteration of the intake of either DHA or ARA can influence the endogenous synthesis of the other interdependent fatty acid and this can impact on brain composition. Non-human primate data revealed that DHA >ARA intake resulted in reductions in ARA concentrations in multiple areas of the brain 30,31. More recently differences in human brain structure and function were reported in infants supplemented for the first 12 months of life with formula containing 0.64 percent of ARA and a range of DHA levels of 0.32 percent, 0.64 percent and 0.96 percent 32. Using magnetic resonance imaging (MRI) at age 9 years, differences in brain structure were found when the ratio of DHA to ARA significantly deviated from that present in breast milk, with the changes most evident in the anterior cingulate cortex, which controls attention and inhibition. This imaging data supported previous cognitive function data from this research cohort that showed attention control was diminished in infants who received a formula that had a higher DHA to ARA ratio compared to the mean ratio reported in breast milk 33.

It is therefore evident that with low conversion rates from 18-carbon to 20- and 22-carbon fatty acids in early life, and DHA status being influenced by genetic variation in fatty acid metabolism, and an imbalance in dietary DHA and ARA intake altering DHA and ARA function 25, a pragmatic way forward is to be guided by the composition of breast milk and supplement milk products in early life with levels of DHA and ARA that are equivalent to that reported in breast milk.  It has been recommended that at least 100 mg DHA per day, should be recognized as dietary reference values for infants 0-12 months of age 7,34 and a scientific review concluded that an adequate daily intake of ARA during infancy is 140 mg per day.

Risk assessment

It is important that policymakers turn to risk assessors to discuss and consider the totality of the available evidence. Experimental data have demonstrated that n-3 LCPUFAs influence cellular membrane structure and function 3,4,5,6, and DHA is especially important in the development of the brain and retina. DHA is also the precursor of potent lipid mediators called resolvins and protectins, that play crucial roles in the prevention or treatment of common chronic diseases that can cause significant morbidity and mortality. The n-6 LCPUFAs, particularly ARA, are widely distributed throughout human cells and tissues 6. In addition to the central nervous system where ARA plays an essential structural and functional role 35, ARA is also a metabolic requirement for all cells as a precursor for eicosanoids which modulate a variety of biological processes, particularly those relating to cerebral, cardiovascular and immune function 6.

Translating the experimental evidence into clinical benefit has been challenging. This predominantly relates to difficulties with conducting intervention randomized controlled trials (RCTs) in infants and young children and the published RCTs show considerable variation in design, sample size and methodology; and they have mostly been undertaken in high-income countries 36,37. The interventions have been limited to relatively short intervention periods, for example, the last 4-5 months of pregnancy or the initial months of the postnatal period. In the vast majority of studies, the intervention has included both DHA and ARA; there are only a handful of DHA alone studies and no published studies of ARA as the sole intervention. The majority of studies have used developmental assessments that provide an overall score for a wide range of cognitive functions. Based on this heterogeneous dataset some systematic reviewers have tended to conclude that the overall RCT data does not conclusively support or refute benefits from postnatal supplementation of DHA and ARA in preterm and term infants 38, However, it is evident that many of the assessments adopted may not be sufficiently sensitive to specific areas of cerebral function and there are studies where a primary outcome has been specifically targeted, such as  visual function, problems solving, information processing and attention control, and the results from these studies are more consistent with positive effects in visual function and high-level cognitive functions 39-43.

Conclusions

Relating early life nutritional interventions to later life health outcomes is always going to be challenging and all research methods will have their limitations. There is a real concern that null RCT studies of LCPUFA supplementations that have methodological weaknesses could outweigh the considerable evidence provided by experimental, animal and more specific visual and cognitive function studies. Population based evidence indicates that a high proportion of the global childhood population may be at risk of LCPUFA deficiency, especially in early life 24 and it is important that the body of research available to policymakers reflects the diversity of need across communities and countries.

Infant formulas and follow-on formulas with both DHA and ARA have been consumed by more than 230 million infants worldwide over the last two decades and no national or international regulatory body has raised concerns regarding safety. The principal objective of recommendations on dietary DHA and ARA in early life should be to provide a safety net for the most vulnerable infants worldwide. Based on the well documented levels of DHA and ARA present in breast milk, and the WHO recommendation that breastfeeding should continue for 2 years or beyond, it is recommended that infants who are not breastfed should receive infant formulas and follow-on formulas that are supplemented with both DHA and ARA and in concentrations that are similar to breast milk (44,45). For countries that can clearly evidence that infants and young children consume adequate intakes of DHA and ARA during early life, an optional recommendation for these countries may be considered.

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