This article was first published in the March 2020 edition of The World of Food Ingredients.
As scientific understanding of early life nutrition and its effect on the human body evolves, discussion remains as to how best to mimic the composition of breast milk as closely as possible, and which components merit recommended inclusion and specific guidelines.
Breastfeeding is universally considered to be the ideal choice of infant nourishment, providing all the necessary nutrients to support an infant’s development. However, when breastfeeding is not possible for whatever reason, infant and follow-on formulas are widely considered and regulated as a safe and appropriate alternative. These products must, therefore, provide the right nutrients at the right levels.
Active discussion remains about the recommendations surrounding, for example, specific nutritional lipids in infant and follow-on formulas, including long-chain polyunsaturated fatty acids (LCPUFAs), in particular docosahexaenoic acid (DHA; 22:6n-3) and arachidonic acid (ARA, sometimes noted as AA; 20:4n-6).
Notably, in a position paper published in October 2019 in The American Journal of Clinical Nutrition, experts in the field of infant nutrition, have emphasized their view that, based on the available information, infants should not be fed formula products with high DHA contents without ARA until this approach has been thoroughly evaluated.
Their efforts come in response to new EU regulatory standards stipulating that from February 2020, all infant and follow-on formulas marketed in the EU must contain DHA at higher amounts than in many recently marketed infant formulas (approximately 0.5–1 percent of total FAs). The addition of ARA, however, was not deemed necessary, and it thus remains optional for producers of infant formula products.
A widely cited argument for the inclusion of both DHA and ARA in infant formula is that human breast milk of adequately nourished mothers contains both these LCPUFAs at varying levels. In fact, global studies have found that the ARA content in human breast milk is much less variable and usually even higher than that of DHA.
Both DHA and ARA play a role in a variety of physical processes, including membrane structure and function, cell signaling, lipid mediator production and gene expression. DHA is mainly present in neural cell membranes, where it concentrates in phospholipids in the brain and retina. Similarly present in the brain, ARA is also the primary unsaturated fatty acid in the heart, muscles, vascular endothelium, T-lymphocytes, adrenal glands, kidneys, liver and the placenta.
ARA has also been noted to fulfill specific functions in the vasculature and aspects of immunity. Moreover, ARA is also the precursor of signaling molecules called eicosanoids, which are linked to the release of somatostatin, the principal hormone thatregulates cell proliferation and growth.
Optionality vs. essentiality
Listed in the Commission Delegated Regulation (EU) 2016/127, which defines the latest compositional criteria for infant and follow-on formulas, the recent EU regulatory standards follow a Scientific Opinion issued by the European Food Safety Authority (EFSA) in 2014 on the essential composition of infant and follow-on formulas.
This 2014 opinion suggested that such products should contain the aforementioned level of 20-50 mg DHA/100 kcal, while ARA remains optional. EFSA explains this optionality by noting that while infant formulas containing DHA but no ARA do lead to lower concentrations of ARA in erythrocytes (red blood cells) compared with the consumption of control formula without DHA, “no direct functional consequences have been observed in relation to growth and neurodevelopment.” This lower concentration of ARA in erythrocytes seems not to be linked to a decrease in concentrations of ARA in the brain, EFSA adds.
Following the adoption of these new regulatory standards, the authors of the recent position paper note that the first commercial formula products with relatively high contents of DHA – but without ARA – have already been introduced in the European market. They add, however, that this “novel concept of infant formula composition has given rise to concern and controversy because there is no accountable evidence on its suitability and safety in healthy infants.”
DHA levels, they say, should equal at least the mean content in human milk globally (0.3 percent of FAs) but preferably reach 0.5 percent of FAs. While optimal ARA intake amounts remain to be defined, the experts “strongly recommend” that ARA should be provided along with DHA.
“We also concluded that a novel composition of infant formula polyunsaturated fatty acids, with two to three times the DHA levels than previously established and without ARA, should not be used unless suitability and safety have been convincingly established by well-designed and adequately powered clinical trials,” notes lead author, Professor Berthold Koletzko.
These clinical trials are particularly crucial since adverse effects of modifying polyunsaturated fatty acid supply to infants on their development have been previously reported, adds Koletzko, who is a Professor of Pediatrics at LMU – University of Munich, Germany, and Head, Div. Metabolic & Nutritional Medicine, Hauner Children’s Hospital, University of Munich.
In the case of DHA and ARA, he notes, well-designed clinical studies should evaluate the optimal intakes of DHA and ARA in infants at different ages based on relevant outcomes, such as safety, growth, neurodevelopment and immune development.
In response to questions regarding the 2019 position paper, an EFSA spokesperson reiterated the basis for the scientific conclusions of the 2014 EFSA opinion.
“First, we would like to emphasize that scientific discussion is limited to the question of whether ARA becomes an essential fatty acid in infant formula when DHA is added to formulas,” the spokesperson says. “ARA alone has never been considered essential in a formula, and products without this fatty acid and without DHA had been on the market for several years,” the spokesperson notes.
“Directive 2006/141/EC on infant formulae and follow-on formulae” specified that the DHA content (if DHA is added) should not exceed the content of n-6 long-chain polyunsaturated fatty acids (n-6 LCP), which may have a maximum content of 2 percent with a maximum of 1 percent ARA. In practice, according to the EFSA opinion, this meant that ARA was added to the formula when also DHA was added, it but could have been absent if DHA was not present.
“This concept of essentiality of ARA in formulas in the presence of DHA was originally derived from two studies in preterm infants available at the time of EFSA’s assessment in which blood concentration of ARA positively correlated with measures of normalized growth,” the spokesperson notes.
However, in the six randomized controlled trials in term infants that were available at the time of EFSA’s assessment, the consumption of formula with DHA alone reportedly did not lead to significant differences in growth, although ARA concentrations were observed to be lower in the groups consuming infant formula with DHA alone than in the groups consuming the control formula.
EFSA further cites studies that observed no effects in term infants that would have allowed independent effects of ARA to be established and that investigated cognitive outcomes or visual development.
“In this context, it is important to note that the target population of the formula for which scientific advice was given is term infants (and not preterm infants). Studies in term infants available at the time of assessment consistently did not reveal a dietary need for ARA in the presence of DHA,” the spokesperson puts forward.
While the EU regulation does not advise against the addition of ARA to infant and follow-on formulas, the fact that the health authority does not require it along with the addition of DHA contrasts with jurisdictions in other parts of the world. It also differs from the global infant formula standards of the Codex Alimentarius Commission of WHO and FAO, Koletzko states.
Some experts have also argued that in compiling its report on infant formulas, EFSA virtually overlooked critical earlier research on the importance of ARA. For example, in an article published in the journal Prostaglandins, Leukotrienes and Essential Fatty Acids, Crawford, Wang, Forsyth, and Brenna (2015) note that the 2014 EFSA Scientific Opinion, concluding that ARA was not required for substitutes for human milk, only reviewed the literature from roughly 2000 onwards. The authors of that EFSA report have thus not considered potentially key research underscoring the significance of ARA.
The position paper published in October, which resulted from discussions organized by the Child Health Foundation and the European Academy of Paediatrics at a May 2019 workshop, is just one of myriad publications showing substantial differences in opinion between EFSA’s assertions and expert opinions on the composition of infant formulas regarding the addition of DHA without ARA.
Speaking about EFSA’s decision on the optionality of ARA, J. Thomas Brenna, Professor of Pediatrics at Dell Medical School, notes that some experts think it may even be a case of “a simple misunderstanding.”
“The many random controlled trials with DHA and AA were always designed as studies of DHA-specific outcomes, with the AA added to avoid concern over potential growth issues, always a concern in infants,” Brenna says.
In adult nutrition, concerns also exist about the overconsumption of omega-6, which could explain a certain reluctance towards the addition of ARA, which is itself an omega-6 fatty acid, to formulas.
“The fact remains, however, that a DHA-only ARA-absent diet is untested,” Brenna notes, adding that essentially, the EU regulatory standards are “overruling human breast milk without evidence on ARA-specific outcomes.”
“That is, they are endorsing an unprecedented composition with respect to breast milk of healthy women,” he states.
Scrutiny is vital
Considering the well-established importance of nutrition during the first 1,000 days of a child’s life and its effect on long-term health, scientific and regulatory scrutiny is vital when it comes to the recommendations and standards set with regard to infant nutrition products.
“In the past, major adverse effects occurred from the use of formula with modified nutrient concentration but without the addition of novel components, e.g., formula with low amounts of chloride or lesser amounts of thiamine, which caused neurodevelopmental damage and even infant deaths,” Koletzko explains, speaking about previous major modifications to the composition of infant or follow-on formulas.
“The composition of human breast milk is a good starting point for designing infant formula, and one would need to justify any significant deviation from the human breast milk with good scientific data. However, the similarity of composition by itself does not guarantee the suitability and safety of an infant formula composition,” Koletzko notes.
These factors combined serve to underline the ongoing need for adequate research into the suitability and safety of food products for infants by comparing effects in infants to those of populations of breastfed infants, with respect to growth, metabolism, health endpoints such as infections or allergy, neurodevelopment, and immune function, Koletzko concludes.
A clear role exists here for investment in public research funding to “enable the execution of adequately designed and powered clinical studies,” as well as clear communication between health bodies and the scientific community at large.
By Lucy Gunn
 “Should formula for infants provide arachidonic acid along with DHA? A position paper of the European Academy of Paediatrics and the Child Health Foundation,” Berthold Koletzko, Karin Bergmann, J Thomas Brenna, Philip C Calder, Cristina Campoy, M Tom Clandinin, John Colombo, Mandy Daly, Tamás Decsi, Hans Demmelmair, Magnus Domellöf, Nataša FidlerMis, Ines Gonzalez-Casanova, Johannes B van Goudoever, Adamos Hadjipanayis, Olle Hernell, Alexandre Lapillonne, Silke Mader, Camilia R Martin, Valerie Matthäus, Usha Ramakrishan, Cornelius M Smuts, Sean J J Strain, Conny Tanjung, Patrick Tounian, Susan E Carlson, on behalf of the European Academy of Paediatrics and the Child Health Foundation (2019), The American Journal of Clinical Nutrition, nq z252, https://doi.org/10.1093/ajcn/nqz252.
 “EFSA NDA Panel (EFSA Panel on Dietetic Products), Scientific opinion on the essential composition of infant and follow-on formulae,” EFSA J. 12 (2014), 3760.
 “The European Food Safety Authority recommendation for polyunsaturated fatty acid composition of infant formula overrules breast milk, puts infants at risk, and should be revised,” Crawford, Michael A. et al. (2015), Prostaglandins, Leukotrienes and Essential Fatty Acids, Volume 102, 1-3.