In a Peruvian DBRCT, 550 healthy, primarily breastfed 6- to 11-month-old infants consumed 40 g/day of an instant complementary food fortified with 1 recommended dietary allowance of multiple micronutrients and a protein source for 6 months. They were randomized to the protein source being either an MFGM-enriched protein fraction (Lacprodan® MFGM-10; Arla Foods Ingredients, Viby, Denmark) or skim milk powder (control group) [20]. There was no difference between the groups in the incidence of diarrhea, but longitudinal prevalence of diarrhea was significantly lower in the MFGM group compared to the control group (3.84 vs. 4.37%, p < 0.05). In a multivariate model adjusted for initial anemia and potable water facilities, the incidence of bloody diarrhea was lower in the MFGM group, with an adjusted OR of 0.59 (95% CI 0.34–1.02, p = 0.025).

In a DBRCT performed in Indonesia, 70 term infants were randomized to a control formula or an infant formula enriched with bovine milk gangliosides, provided as a complex bovine milk lipid fraction (AnmumInfacare; Fonterra Cooperative Group, Auckland, New Zealand) [21]. A breastfed reference group (BFR) (n = 40) was also recruited. The intervention started between 2 and 8 weeks and continued until 24 weeks of age. After adjustment for socioeconomic background variables, the hand-eye coordination IQ (129.5 vs. 122.0, p = 0.006), performance IQ (131.1 vs. 123.2, p < 0.001), and general IQ (125.4 vs. 120.6, p = 0.041) measured with the Griffiths Mental Developmental Scale were higher in the ganglioside-supplemented group than in the control group, and the ganglioside-supplemented group did not differ from the BFR group.

In a Belgian DBRCT, 253 preschool children aged 2.5–6 years received 200 mL of a chocolate formula milk daily for 4 months [22]. They were randomized to a formula without phospholipids (placebo group) or enriched with 500 mg of phospholipids with the addition of 2.5% of a phospholipid-rich MFGM concentrate (Inpulse; Büllinger SA, Büllingen, Belgium) (intervention group). The intervention group had fewer days with fever (mean ± SD: 1.71 ± 2.47 vs. 2.60 ± 3.06, p = 0.028), and lower parental scoring of internal (p < 0.003), external (p < 0.005), and total (p < 0.002) behavioral problems measured by the Achenbach System of Empirically Based Assessment (ASEBA). However, ASEBA scoring was only performed after the intervention but not at baseline, and differences were not confirmed when the children’s teachers made the scoring.

In an Indian DBRCT, 450 infants between 8 and 24 months of age were randomized to a daily dose of milk powder supplemented with 2 g of a spray-dried ganglioside concentrate (Fonterra Cooperative Ltd,) or milk powder only (control group) for 12 weeks [23]. There was no difference between the groups, nor in the primary outcome rotavirus diarrhea, or in secondary outcomes including all-cause diarrhea. However, the authors noted that the incidence of rotavirus diarrhea during the study period was lower than expected, making the study under-powered as compared to the intention of the design.

In a Swedish DBRCT, 160 formula-fed healthy term infants were randomized to receive an experimental formula (EF) supplemented with a protein-rich MFGM fraction (Lacprodan® MFGM-10; Arla Foods Ingredients) or standard formula (SF) from <2 to 6 months of age. The EF had lower energy (60 vs. 66 kcal/100 mL) and protein (1.20 vs. 1.27 g/100 mL) densities, and MFGM-proteins made up 4% (wt/wt) of the total protein content in the formula. In addition, a BFR group including 80 infants was also studied. The formula-fed infants regulated their ingested volumes by increasing meal size, resulting in no differences in energy intake, protein intake, blood urea nitrogen (BUN), serum insulin level, or growth, including body fat percentage, up to 12 months of age [24]. The surprisingly high level of self-regulation for the bottle-fed infants might be explained by a low level of parental control in the study population [25].

At 12 months of age, the EF group achieved higher scores (mean ± SD) in the cognitive domain of Bayley III (105.8 ± 9.2) than the SF group (101.8 ± 8.0, p = 0.008) and did not differ from the BFR group (106.4 ± 9.5, p = 0.73) [24]. During the intervention, the EF group had a lower incidence of acute otitis media than the SF group (1 vs. 9%, p = 0.034), a lower incidence and longitudinal prevalence of antipyretic use, lower concentrations of serum IgG against pneumococci after vaccination and a lower prevalence of Moraxella catarrhalis in the oral microbiota, all suggesting an infection-protective effect of EF [26, 27]. During the intervention, the EF group gradually reached higher serum cholesterol concentrations than the SF group, and there was no significant difference between the EF and BFR group at 6 months of age [28].

In a multicenter noninferiority DBRCT, 199 healthy term infants were randomized to 3 different formulas from 14 days to 4 months of age; a SF (control), a formula enriched with lipids (MFGM-L; Fonterra Cooperative Group Ltd), and a formula with a protein-rich (MFGM-P, Lacprodan® MFGM-10, Arla Foods Ingredients) bovine MFGM fraction, respectively [29]. Weight gain was noninferior in the MFGM-L and MFGM-P groups compared with the control group. Adverse events and morbidity rates were similar across groups except for a higher rate of eczema in the MFGM-P group (13.9 vs. 1.4% in the MFGM-L group and 3.5% in the control group, p = 0001). It is, however, not clear how and when eczema was diagnosed, and the number of infants diagnosed were few in the MFGM-L and control groups (1 and 2, respectively). The authors also concluded that care must be taken in interpreting the exploratory endpoints. A higher risk of skin rash was not confirmed in a Swedish study [30] which studied the same MFGM-P fraction.

      Conclusions

      Studies on the supplementation of bovine MFGM to the diet of infants and children have shown promising results regarding both neurodevelopment and defense against infections. These findings are supported by known effects of individual components of MFGM mostly based on in vitro and/or animal studies. However, the scientific base of knowledge for MFGM supplementation to infants and children is still limited. The number of published studies on MFGM supplementation to infants and children is small, and the interventions are heterogeneous: different MFGM concentrates have been given for different durations at different ages and with different main outcomes. However, MFGM supplementation seems safe down to the age of the first week of life in term infants, as no serious adverse effects have been reported.

      Infant formulas supplemented with bovine MFGM concentrates have already been launched on many markets, but before any general recommendations or guidelines of MFGM use in infants and children can be given, more high-quality DBRCTs are needed.

      Disclosure Statement

      O.H. has participated as a clinical investigator and/or scientific advisory board member, speaker, and consultant for Semper, Hero, Mead Johnson Nutrition, Arla Foods, Arla Foods Ingredients, Nestlé Nutrition Institute, and Hipp. M.D. has participated as clinical investigator and/or speaker for Hero, Semper,