Breast milk is the gold standard of infant nutrition, delivering nutrients and bioactive molecules as needed to support optimal infant growth and cognitive development. Increasing evidence links human milk oligosaccharides (HMOs) to these early childhood development milestones.
Aims:
To summarize and synthesize the evidence relating to HMOs and infant brain development, physical growth, and cognitive development. In addition, HMO concentrations in secretor and nonsecretor mothers were compared via a meta-analysis.
Study Design:
A systematic review and meta-analysis were carried out in accordance with the PRISMA statement. This review used three databases (PubMed, Scopus, and Web of Science) and was limited to English-language articles published between 2000 and June 30, 2023.
Results:
The initial searches yielded 245 articles, 27 of which were included in the systematic review and 12 in the meta-analysis. The meta-analysis revealed a substantial between-study heterogeneity, I2 = 97.3%. The pooled effect was 0.21 (95% CI: −0.41 to 0.83; p = 0.484), indicating that secretors had higher HMO concentrations, although this difference was not statistically significant. At one month of age, 2′FL, 3FL, and 3′SL play an important role in brain maturation and thus play a critical role in cognitive development. Secretors produce higher concentrations of 2′FL and 3′SL, explaining the benefits to infants of secretor mothers. Growth velocity was correlated to fucosylated and sialylated HMO concentrations, with lower concentrations linked to stunting.
Conclusions:
According to evidence from the systematically reviewed articles, HMOs are essential for a child’s early development, but the extent to which they have an impact depends on maternal secretor status.
Get full access to this article
View all access options for this article.
References
1.
VictoraCG, BahlR, BarrosAJD, et al.Breastfeeding in the 21st century: Epidemiology, mechanisms, and lifelong effect. Lancet, 2016; 387(10017):475–490; doi: 10.1016/S0140-6736(15)01024-7
2.
DinleyiciM, BarbieurJ, DinleyiciEC, et al.Functional effects of human milk oligosaccharides (HMOs). Gut Microbes, 2023; 15(1):2186115; doi: 10.1080/19490976.2023.2186115
3.
AndersonJW, JohnstoneBM, RemleyDT. Breast feeding and cognitive development: A meta-analysis. Am J Clin Nutr, 1999; 70(4):525–535.
BallardO, MorrowAL. Human milk composition. nutrients and bioactive factors. Pediatr Clin North Am, 2013; 60(1):49–74; doi: 10.1016/j.pcl.2012.10.002
6.
BodeL. Human milk oligosaccharides: Every baby needs a sugar mama. Glycobiology, 2012; 22(9):1147–1162; doi: 10.1093/glycob/cws074
7.
ChenX. Human milk oligosaccharides (HMOs): Structure, function, and enzyme-catalyzed synthesis. 1st ed. Elsevier Inc.; 2015; doi: 10.1016/bs.accb.2015.08.002
8.
KunzC, RudloffS, BaierW, et al.Oligosaccharides in human milk: Structural, functional, and metabolic aspects. Annu Rev Nutr, 2000; 20:699–722; doi: 10.1146/annurev.nutr.20.1.699
9.
KunzC, RudloffS, HintelmannA, et al.High-pH anion-exchange chromatography with pulsed amperometric detection and molar response factors of human milk oligosaccharides. J Chromatogr B Biomed Appl, 1996; 685(2):211–221; doi: 10.1016/S0378-4347(96)00181-8
10.
WilliamsJE, McGuireMK, MeehanCL, et al.Key genetic variants associated with variation of milk oligosaccharides from diverse human populations. Genomics, 2021; 113(4):1867–1875; doi: 10.1016/j.ygeno.2021.04.004
11.
TottenSM, ZivkovicAM, WuS, et al.Comprehensive profiles of human milk oligosaccharides yield highly sensitive and specific markers for determining secretor status in lactating mothers. J Proteome Res, 2012; 11(12):6124–6133; doi: 10.1021/pr300769g
12.
ThurlS, MunzertM, HenkerJ, et al.Variation of human milk oligosaccharides in relation to milk groups and lactational periods. Br J Nutr, 2010; 104(9):1261–1271; doi: 10.1017/S0007114510002072
13.
BodeL. The functional biology of human milk oligosaccharides. Early Hum Dev, 2015; 91(11):619–622; doi: 10.1016/j.earlhumdev.2015.09.001
14.
HamoshM. Bioactive factors human milk. Pediatr Clin North Am, 2001; 48(1):69–86; doi: 10.1016/s0031-3955(05)70286-8
15.
NewburgDS. Neonatal protection by an innate immune system of human milk consisting of oligosaccharides and glycans. J Anim Sci, 2009; 87(13 Suppl):26–34; doi: 10.2527/jas.2008-1347
16.
TriantisV, BodeL, van NeervenJRJ. Immunological effects of human milk oligosaccharides. Front Pediatr, 2018; 6(July):190; doi: 10.3389/fped.2018.00190
17.
AldereteTL, AutranC, BrekkeBE, et al.Associations between human milk oligosaccharides and infant body composition in the first 6 mo of life. Am J Clin Nutr, 2015; 102(6):1381–1388; doi: 10.3945/ajcn.115.115451
18.
DavisJCC, LewisZT, KrishnanS, et al.Growth and morbidity of Gambian infants are influenced by maternal milk oligosaccharides and infant gut microbiota. Sci Rep, 2017; 7:40466; doi: 10.1038/srep40466
19.
YuZT, ChenC, NewburgDS. Utilization of major fucosylated and sialylated human milk oligosaccharides by isolated human gut microbes. Glycobiology, 2013; 23(11):1281–1292; doi: 10.1093/glycob/cwt065
20.
TarrAJ, GalleyJD, FisherSE, et al.The prebiotics 3’sialyllactose and 6’sialyllactose diminish stressor-induced anxiety-like behavior and colonic microbiota alterations: Evidence for effects on the gut-brain axis. Brain Behav Immun, 2015; 50:166–177; doi: 10.1016/j.bbi.2015.06.025
21.
JacobiSK, YatsunenkoT, LiD, et al.Dietary isomers of sialyllactose increase ganglioside sialic acid concentrations in the corpus callosum and cerebellum and modulate the colonic microbiota of formula-fed piglets. J Nutr, 2016; 146(2):200–208; doi: 10.3945/jn.115.220152
22.
GaleC, LoganKM, SanthakumaranS, et al.Effect of breastfeeding compared with formula feeding on infant body composition: A systematic review and meta-analysis. Am J Clin Nutr, 2012; 95(3):656–669; doi: 10.3945/ajcn.111.027284
23.
NorrishI, SindiA, SakalidisVS, et al.Relationships between the Intakes of Human Milk Components and Body Composition of Breastfed Infants: A systematic review. Nutrients, 2023; 15(10); doi: 10.3390/nu15102370
24.
HouL, LiX, YanP, et al.Impact of the duration of breastfeeding on the intelligence of children: A systematic review with network meta-analysis. Breastfeed Med, 2021; 16(9):687–696; doi: 10.1089/bfm.2020.0364
25.
LechnerBE, VohrBR. Neurodevelopmental outcomes of preterm infants fed human milk: A systematic review. Clin Perinatol, 2017; 44(1):69–83; doi: 10.1016/j.clp.2016.11.004
26.
LockyerF, McCannS, MooreSE. Breast milk micronutrients and infant neurodevelopmental outcomes: A systematic review. Nutrients, 2021; 13(11):1–16; doi: 10.3390/nu13113848
27.
PageMJ, McKenzieJE, BossuytPM, et al.The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Bmj, 2021; 372:n71; doi: 10.1136/bmj.n71
28.
OuzzaniM, HammadyH, FedorowiczZ, et al.Rayyan-a web and mobile app for systematic reviews. Syst Rev, 2016; 5(1):210–210; doi: 10.1186/s13643-016-0384-4
29.
WellsG, SheaB, O’ConnellD, et al.The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses. 2017. Available from: https://www.ohri.ca//programs/clinical_epidemiology/oxford.asp [Last accessed: September29, 2022].
30.
LagströmH, RautavaS, OllilaH, et al.Associations between human milk oligosaccharides and growth in infancy and early childhood. Am J Clin Nutr, 2020; 111(4):769–778; doi: 10.1093/ajcn/nqaa010
31.
MansellT, FurstA, O’HelyM, et al.Age-dependent associations of human milk oligosaccharides with body size and composition up to 4 years of age. Am J Clin Nutr, 2023; 117(5):930–945; doi: 10.1016/j.ajcnut.2023.02.016
32.
DouY, LuoY, XingY, et al.Human milk oligosaccharides variation in gestational diabetes mellitus mothers. Nutrients, 2023; 15(6):1441; doi: 10.3390/nu15061441
33.
SprengerN, LeeLY, De CastroCA, et al.Longitudinal change of selected human milk oligosaccharides and association to infants’ growth, an observatory, single center, longitudinal cohort study. PLoS One, 2017; 12(2):e0171814–15; doi: 10.1371/journal.pone.0171814
34.
BergerPK, PlowsJF, JonesRB, et al.Human milk oligosaccharide 2′-fucosyllactose links feedings at 1 month to cognitive development at 24 months in infants of normal and overweight mothers. PLoS One, 2020; 15(2):e0228323–12; doi: 10.1371/journal.pone.0228323
35.
BergerPK, PlowsJF, JonesRB, et al.Human milk oligosaccharides and Hispanic infant weight gain in the first 6 months. Obesity (Silver Spring), 2020; 28(8):1519–1525; doi: 10.1002/oby.22884
36.
TononKM, de MoraisMB, AbrãoACFV, et al.Maternal and infant factors associated with human milk oligosaccharides concentrations according to secretor and Lewis phenotypes. Nutrients, 2019; 11(6):1–23; doi: 10.3390/nu11061358
37.
BergerPK, BansalR, SawardekarS, et al.Associations of human milk oligosaccharides with infant brain tissue organization and regional blood flow at 1 month of age. Nutrients, 2022; 14(18):1–14; doi: 10.3390/nu14183820
38.
SabenJL, SimsCR, AbrahamA, et al.Human milk oligosaccharide concentrations and infant intakes are associated with maternal overweight and obesity and predict infant growth. Nutrients, 2021; 13(2):1–16; doi: 10.3390/nu13020446
39.
MenzelP, VogelM, AustinS, et al.Concentrations of oligosaccharides in human milk and child growth. BMC Pediatr, 2021; 21(1):481–411; doi: 10.1186/s12887-021-02953-0
40.
OliverosE, MartínMJ, Torres-EspínolaFJ, et al.Human milk levels of 2′-fucosyllactose and 6’-sialyllactose are positively associated with infant neurodevelopment and are not impacted by maternal BMI or diabetic status. J Nutr Food Sci, 2021; 4(1):100024.
41.
WangM, ZhaoZ, ZhaoA, et al.Neutral human milk oligosaccharides are associated with multiple fixed and modifiable maternal and infant characteristics. Nutrients, 2020; 12(3):10–3390; doi: 10.3390/nu12030826
42.
PaganiniD, UyogaMA, KortmanGAM, et al.Maternal human milk oligosaccharide profile modulates the impact of an intervention with iron and galacto-oligosaccharides in Kenyan infants. Nutrients, 2019; 11(11); doi: 10.3390/nu11112596
43.
CheemaAS, GridnevaZ, FurstAJ, et al.Human milk oligosaccharides and bacterial profile modulate infant body composition during exclusive breastfeeding. Int J Mol Sci, 2022; 23(5):1–28; doi: 10.3390/ijms23052865
44.
WillemsenY, BeijersR, GuF, et al.Fucosylated human milk oligosaccharides during the first 12 postnatal weeks are associated with better executive functions in toddlers. Nutrients, 2023; 15(6); doi: 10.3390/nu15061463
45.
ChoS, ZhuZ, LiT, et al.Human milk 3′-Sialyllactose is positively associated with language development during infancy. Am J Clin Nutr, 2021; 114(2):588–597; doi: 10.1093/ajcn/nqab103
46.
BiniaA, LavalleL, ChenC, et al.Human milk oligosaccharides, infant growth, and adiposity over the first 4 months of lactation. Pediatr Res, 2021; 90(3):684–693; doi: 10.1038/s41390-020-01328-y
47.
CharbonneauMR, O’DonnellD, BlantonLV, et al.Sialylated milk oligosaccharides promote microbiota-dependent growth in models of infant undernutrition. Cell, 2016; 164(5):859–871; doi: 10.1016/j.cell.2016.01.024
48.
RozéJC, HartwegM, SimonL, et al.Human milk oligosaccharides in breast milk and 2-year outcome in preterm infants: An exploratory analysis. Clin Nutr, 2022; 41(9):1896–1905; doi: 10.1016/j.clnu.2022.07.024
49.
WejrydE, MartíM, MarchiniG, et al.Low diversity of human milk oligosaccharides is associated with necrotising enterocolitis in extremely low birth weight infants. Nutrients, 2018; 10(10); doi: 10.3390/nu10101556
50.
FerreiraALL, Alves-SantosNH, Freitas-CostaNC, et al.Associations between human milk oligosaccharides at 1 month and infant development throughout the first Year of Life in a Brazilian Cohort. J Nutr, 2021; 151(11):3543–3554; doi: 10.1093/jn/nxab271
51.
JorgensenJM, YoungR, AshornP, et al.Associations of human milk oligosaccharides and bioactive proteins with infant growth and development among Malawian mother-infant dyads. Am J Clin Nutr, 2021; 113(1):209–220; doi: 10.1093/ajcn/nqaa272
52.
SamuelTM, HartwegM, LebumfacilJD, et al.Dynamics of human milk oligosaccharides in early lactation and relation with growth and appetitive traits of Filipino breastfed infants. Sci Rep, 2022; 12(1):17304–17313; doi: 10.1038/s41598-022-22244-7
53.
NuzhatS, PalitP, MahfuzM, et al.Association of human milk oligosaccharides and nutritional status of young infants among Bangladeshi mother–infant dyads. Sci Rep, 2022; 12(1):9456–9459; doi: 10.1038/s41598-022-13296-w
54.
LarssonMW, LindMV, LaursenRP, et al.Human milk oligosaccharide composition is associated with excessive weight gain during exclusive breastfeeding—an explorative study. Front Pediatr, 2019; 7(July):297–214; doi: 10.3389/fped.2019.00297
55.
RobertsonRC, MangesAR, FinlayBB, et al.The human microbiome and child growth – first 1000 days and beyond. Trends Microbiol, 2019; 27(2):131–147; doi: 10.1016/j.tim.2018.09.008
56.
MarriageBJ, BuckRH, GoehringKC, et al.Infants fed a lower calorie formula with 2′FL show growth and 2′FL uptake like breast-fed infants. J Pediatr Gastroenterol Nutr, 2015; 61(6):649–658; doi: 10.1097/MPG.0000000000000889
57.
PuccioG, AllietP, CajozzoC, et al.Effects of infant formula with human milk oligosaccharides on growth and morbidity: A randomized multicenter trial. J Pediatr Gastroenterol Nutr, 2017; 64(4):624–631; doi: 10.1097/MPG.0000000000001520
58.
DurhamSD, WeiZ, LemayDG, et al.Creation of a milk oligosaccharide database, MilkOligoDB, reveals common structural motifs and extensive diversity across mammals. Sci Rep, 2023; 13(1):10345–10326; doi: 10.1038/s41598-023-36866-y
59.
HigginsJPT, ThompsonSG. Quantifying heterogeneity in a meta-analysis. Stat Med, 2002; 21(11):1539–1558; doi: 10.1002/sim.1186
60.
KunzC, RudloffS. Compositional analysis and metabolism of human milk oligosaccharides in infants. Nestle Nutr Inst Workshop Ser, 2017; 88:137–147; doi: 10.1159/000455398
61.
NewburgDS. Human milk oligosaccharides vary among populations. Am J Clin Nutr, 2017; 105(5):1027–1028; doi: 10.3945/ajcn.117.155721
62.
ThurlS, MunzertM, BoehmG, et al.Systematic review of the concentrations of oligosaccharides in human milk. Nutr Rev, 2017; 75(11):920–933; doi: 10.1093/nutrit/nux044
63.
SabenJL, AbrahamA, BodeL, et al.Third-trimester glucose homeostasis in healthy women is differentially associated with human milk oligosaccharide composition at 2 months postpartum by secretor phenotype. Nutrients, 2020; 12(8):1–15; doi: 10.3390/nu12082209
64.
SamuelTM, BiniaA, de CastroCA, et al.Impact of maternal characteristics on human milk oligosaccharide composition over the first 4 months of lactation in a cohort of healthy European mothers. Sci Rep, 2019; 9(1):11767–11710; doi: 10.1038/s41598-019-48337-4
65.
PaceRM, WilliamsJE, RobertsonB, et al.Variation in human milk composition is related to differences in milk and infant fecal microbial communities. Microorganisms, 2021; 9(6):1–17; doi: 10.3390/microorganisms9061153
66.
McGuireMK, MeehanCL, McGuireMA, et al.What’s normal? Oligosaccharide concentrations and profiles in milk produced by healthy women vary geographically. Am J Clin Nutr, 2017; 105(5):1086–1100; doi: 10.3945/ajcn.116.139980.Am
67.
VinjamuriA, DavisJCCC, TottenSM, et al.Human milk oligosaccharide compositions illustrate global variations in early nutrition. J Nutr, 2022; 152(5):1239–1253; doi: 10.1093/jn/nxac027
68.
AsherAT, MangelL, AriJB, et al.Human milk oligosaccharide profile across lactation stages in Israeli women—A prospective observational study. Nutrients, 2023; 15(11):1–16; doi: 10.3390/nu15112548
69.
PellLG, OhumaEO, YonemitsuC, et al.The human-milk oligosaccharide profile of lactating women in Dhaka, Bangladesh. Curr Dev Nutr, 2022; 5(12):nzab137; doi: 10.1201/9780429293016
70.
MoossaviS, AtakoraF, MilikuK, et al.Integrated analysis of human milk microbiota with oligosaccharides and fatty acids in the child cohort. Front Nutr, 2019; 6(May):58–16; doi: 10.3389/fnut.2019.00058
71.
Lemay-NedjelskiL, YonemitsuC, AsburyMR, et al.Oligosaccharides and microbiota in human milk are interrelated at 3 months postpartum in a cohort of women with a high prevalence of gestational impaired glucose tolerance. J Nutr, 2021; 151(11):3431–3441; doi: 10.1093/jn/nxab270
72.
DangatK, JoshiS. Breast Milk and Cognitive Performance in Children. Elsevier Inc.; 2023.; doi: 10.1016/b978-0-323-89834-8.00014-3
73.
HauserJ, PisaE, Arias VásquezA, et al.Sialylated human milk oligosaccharides program cognitive development through a non-genomic transmission mode. Mol Psychiatry, 2021; 26(7):2854–2871; doi: 10.1038/s41380-021-01054-9
74.
WangB. Sialic acid is an essential nutrient for brain development and cognition. Annu Rev Nutr, 2009; 29:177–222; doi: 10.1146/annurev.nutr.28.061807.155515
75.
Khodayar-PardoP, Mira-PascualL, ColladoMC, et al.Impact of lactation stage, gestational age and mode of delivery on breast milk microbiota. J Perinatol, 2014; 34(8):599–605; doi: 10.1038/jp.2014.47
76.
MulingeMM, MwanzaSS, KabahwezaHM, et al.The impact of neonatal intensive care unit antibiotics on gut bacterial microbiota of preterm infants;: A systematic review. Front Microbiomes, 2023; 2:1180565; doi: 10.3389/frmbi.2023.1180565
77.
DrorDK, AllenLH. Overview of nutrients in human milk. Adv Nutr, 2018; 9(suppl_1):278S–294S; doi: 10.1093/advances/nmy022
78.
CapucoAV, AkersRM. The origin and evolution of lactation. J Biol, 2009; 8(4):37–11; doi: 10.1186/jbiol139
79.
UNICEF/WHO/World Bank. Levels and trends in child malnutrition. 2020.
80.
LyonsKE, RyanCA, DempseyEM, et al.Breast milk, a source of beneficial microbes and associated benefits for infant health. Nutrients, 2020; 12(4); doi: 10.3390/nu12041039
81.
NgKM, FerreyraJA, HigginbottomSK, et al.Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature, 2013; 502(7469):96–99; doi: 10.1038/nature12503
82.
RautavaS. Early-Life Antibiotic Exposure, the Gut Microbiome, and Disease in Later Life. INC; 2021; doi: 10.1016/b978-0-12-818097-6.00006-7
83.
YuZT, ChenC, KlingDE, et al.The principal fucosylated oligosaccharides of human milk exhibit prebiotic properties on cultured infant microbiota. Glycobiology, 2013; 23(2):169–177; doi: 10.1093/glycob/cws138
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
