See “Infections in Infants Fed Formula Supplemented With Bovine Milk Fat Globule Membranes” by Domellöf et al on page 384.
For many years, the goal in the design of infant formulas has been to narrow the gap in performance and outcomes between breast-fed infants and those fed infant formulas. This has involved modifications to the macro- and micronutrient content of formulas, but also the addition of various specific components hypothesised to be causally related to observed differences in outcome, such as long-chain polyunsaturated fatty acids, nucleotides, and pre- and probiotics. Randomised trials testing these interventions have often failed to consistently demonstrate the anticipated outcome effects, even when differences are sometimes observed at a biochemical level. The failure of “single-component” supplementation to produce hypothesised effects on outcome may reflect a number of issues, including the manner in which components are added (eg, free as opposed to bound), difficulty in establishing the optimal amounts given variability in the composition of human milk between mothers and populations and within mothers depending on stage of lactation or diet, unphysiological formulations, and the possibility that outcome effects may result from complex interactions between components, which cannot easily be mimicked in a formula.
In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Domellöf et al (1) report data from a randomised trial in healthy term Swedish infants using infant formula supplemented with a bovine milk fat globule membrane (MFGM)–enriched whey protein concentrate. The intervention resulted in a significantly reduced risk of acute otitis media (AOM) and decreased use of antipyretics compared with a standard term formula. These findings are secondary outcomes from this trial that has already reported significant beneficial effects of the intervention on cognitive function at 12 months (2) and on serum cholesterol concentrations (3); for all of these outcomes, the results of the MFGM-supplemented infants were closer to those of a breast-fed reference group. Although this is the only trial testing infant formula supplemented with MFGM, and further trials are required together with longer term follow-up, the apparent effects of this intervention on several important outcomes are remarkable in the context of existing research aiming to optimise infant formulas.
The MFGM, which has historically been discarded with the milk fat during the production of infant formulas, is a triple membrane resulting from the mammary secretory cell that surrounds the triglyceride core of the milk fat globule, enabling fat to be conveyed in an aqueous environment. Interestingly, the genes associated with the production of the milk fat globule and MFGM are the most greatly conserved lactation genes throughout evolution (4), supporting the likely functional importance of this structure. The MFGM contains numerous lipids such as sphingomyelin, gangliosides, sialic acid, and cholesterol, but also a small (1%–2%) proportion of the total milk protein, which includes a large number of bioactive components such as mucin (MUC1), lactadherin, and lactoferrin. Both lipid and protein fractions of the MFGM have been shown to exert a range of antimicrobial effects, and previous clinical trials have shown preventive effects of MFGM-enriched complementary foods against diarrhoea in 6- to 12-month-old Peruvian infants (5) and a reduction in febrile episodes in 2.5- to 6-year-old Belgian children who received MFGM-enriched milk (6).
A higher incidence of infection, notably gastroenteritis and AOM, is the most consistent and accepted outcome difference for infants fed formula instead of human milk, even amongst those living in high-income countries (7–9). In the study by Domellöf et al, the intervention resulted in a lower cumulative incidence of AOM, which was already uncommon in this healthy population, most of whom were vaccinated against pneumococcal disease (1 case [1%] vs 7 cases [9%] in control infants, P = 0.03). There was no effect on other bacterial infections treated with antibiotics or on hospitalisation for viral infections including gastroenteritis, perhaps because of the even lower incidence of these infections (1 in the intervention group vs 4 in the control group and 1 in the breast-fed reference group). Although symptoms were self-reported by parents, cases of AOM were verified from the medical notes and diagnosed by otoscopy.
As discussed in the article, there are a number of potential mechanisms for these findings, including effects on the humeral immune system, or alterations in the composition or function of the microbiota in the oral cavity or gut resulting from antimicrobial factors in MFGM. It also seems plausible, as previously highlighted by the group, that the observed effects of supplementation with MFGM on different outcomes could be the result of single or multiple factors, with the possibility that different factors are limiting in individual infants.
In combination with data previously published from this trial, the results of Domellöf et al suggest that, although further research is clearly required, supplementation of infant formulas with MFGM has potential in achieving the goal of narrowing the gap in performance between breast-fed and formula-fed infants. Although this intervention is perhaps scientifically less satisfactory than using single-component interventions, in that it does not enable determination of the precise component(s) responsible for a given outcome, it is arguably a more pragmatic and physiological approach.
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3. Timby N, Lonnerdal B, Hernell O, et al. Cardiovascular risk markers until 12 mo of age in infants fed a formula supplemented with bovine milk fat globule membranes. Pediatr Res
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