Review| Volume 44, ISSUE 4, P612-621, April 2022

Human Milk and Preterm Infant Brain Development: A Narrative Review



      To review and synthesize the literature on human milk and structural brain development and injury in preterm infants, focusing on the application of quantitative brain magnetic resonance imaging (MRI) in this field.


      For this narrative review, we searched PubMed for articles published from 1990 to 2021 that reported observational or interventional studies of maternal milk or donor milk in relation to brain development and/or injury in preterm infants assessed with quantitative MRI at term equivalent age. Studies were characterized with respect to key aspects of study design, milk exposure definition, and MRI outcomes.


      We identified 7 relevant studies, all of which were observational in design and published between 2013 and 2021. Included preterm infants were born at or below 33 weeks’ gestation. Sample sizes ranged from 22 to 377 infants. Exposure to human milk included both maternal and donor milk. No study included a full-term comparison group. Main MRI outcome domains were white matter integrity (assessed with diffusion tensor imaging, resting state functional connectivity, or semiautomated segmentation of white matter abnormality) and total and regional brain volumes. Studies revealed that greater exposure to human milk versus formula was associated with favorable outcomes, including more mature and connected cerebral white matter with less injury and larger regional brain volumes, notably in the deep nuclear gray matter, amygdala-hippocampus, and cerebellum. No consistent signature effect of human milk exposure was found; instead, the beneficial associations were regional and tissue-specific neuroprotective effects on the areas of known vulnerability in the preterm infant.


      Evidence to date suggests that human milk may protect the preterm infant from the white matter injury and dysmaturation to which this population is vulnerable. Brain MRI at term equivalent age is emerging as a useful tool to investigate the effects of human milk on the preterm brain. When grounded in neurobiological knowledge about preterm brain injury and development, this approach holds promise for allowing further insight into the mechanisms and pathways underlying beneficial associations of human milk with neurodevelopmental outcomes in this population and in the investigation of specific milk bioactive components with neuroprotective or neurorestorative potential.


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        • Doyle LW
        • Spittle A
        • Anderson PJ
        • Cheong JLY.
        School-aged neurodevelopmental outcomes for children born extremely preterm.
        Arch Dis Child. 2021; 106: 834-838
        • Belfort MB.
        Human milk and preterm infant brain development.
        Breastfeed Med. 2018; 13: S23-S25
        • Ramel SE
        • Belfort MB.
        Preterm nutrition and the brain.
        World Rev Nutr Diet. 2021; 122: 46-59
        • Lechner BE
        • Vohr BR.
        Neurodevelopmental outcomes of preterm infants fed human milk: a systematic review.
        Clin Perinatol. 2017; 44: 69-83
        • Miller J
        • Tonkin E
        • Damarell RA
        • et al.
        A systematic review and meta-analysis of human milk feeding and morbidity in very low birth weight infants.
        Nutrients. 2018; 10: 707
        • Belfort MB
        • Anderson PJ
        • Nowak VA
        • et al.
        Breast milk feeding, brain development, and neurocognitive outcomes: a 7-year longitudinal study in infants born at less than 30 weeks’ gestation.
        J Pediatr. 2016; 177 (e1): 133-139
        • Parker MG
        • Stellwagen LM
        • Noble L
        • et al.
        Promoting human milk and breastfeeding for the very low birth weight infant.
        Pediatrics. October 11, 2021; (Published online)e2021054272
        • Makrides M
        • Uauy R.
        LCPUFAs as conditionally essential nutrients for very low birth weight and low birth weight infants: metabolic, functional, and clinical outcomes-how much is enough?.
        Clin Perinatol. 2014; 41: 451-461
        • Maas C
        • Franz AR
        • Shunova A
        • et al.
        Choline and polyunsaturated fatty acids in preterm infants’ maternal milk.
        Eur J Nutr. 2017; 56: 1733-1742
        • Shunova A
        • Böckmann KA
        • Minarski M
        • et al.
        Choline content of term and preterm infant formulae compared to expressed breast milk-how do we justify the discrepancies?.
        Nutrients. 2020; 12: E3815
        • Brink LR
        • Lönnerdal B.
        Milk fat globule membrane: the role of its various components in infant health and development.
        J Nutr Biochem. 2020; 85108465
        • Ochoa TJ
        • Sizonenko SV.
        Lactoferrin and prematurity: a promising milk protein?.
        Biochem Cell Biol. 2017; 95: 22-30
        • Lis-Kuberka J
        • Orczyk-Pawiłowicz M.
        Sialylated oligosaccharides and glycoconjugates of human milk: the impact on infant and newborn protection, development and well-being.
        Nutrients. 2019; 11: E306
        • Christian P
        • Smith ER
        • Lee SE
        • Vargas AJ
        • Bremer AA
        • Raiten DJ.
        The need to study human milk as a biological system.
        Am J Clin Nutr. 2021; 113: 1063-1072
        • Fleming SA
        • Mudd AT
        • Hauser J
        • et al.
        Human and bovine milk oligosaccharides elicit improved recognition memory concurrent with alterations in regional brain volumes and hippocampal mRNA expression.
        Front Neurosci. 2020; 14: 770
        • Joung S
        • Fil JE
        • Heckmann AB
        • Kvistgaard AS
        • Dilger RN.
        Early-life supplementation of bovine milk osteopontin supports neurodevelopment and influences exploratory behavior.
        Nutrients. 2020; 12: E2206
        • Manca S
        • Upadhyaya B
        • Mutai E
        • et al.
        Milk exosomes are bioavailable and distinct microRNA cargos have unique tissue distribution patterns.
        Sci Rep. 2018; 8: 11321
        • Buffet-Bataillon S
        • Bellanger A
        • Boudry G
        • et al.
        New insights into microbiota modulation-based nutritional interventions for neurodevelopmental outcomes in preterm infants.
        Front Microbiol. 2021; 12: 676622
        • Cheong JLY
        • Burnett AC
        • Treyvaud K
        • Spittle AJ.
        Early environment and long-term outcomes of preterm infants.
        J Neural Transm (Vienna). 2020; 127: 1-8
        • Klawetter S
        • Greenfield JC
        • Speer SR
        • Brown K
        • Hwang SS.
        An integrative review: maternal engagement in the neonatal intensive care unit and health outcomes for U.S.-born preterm infants and their parents.
        AIMS Public Health. 2019; 6: 160-183
        • Inder TE
        • de Vries LS
        • Ferriero DM
        • et al.
        Neuroimaging of the preterm brain: review and recommendations.
        J Pediatr. 2021; 237 (e4): 276-287
        • Ottolini KM
        • Andescavage N
        • Keller S
        • Limperopoulos C.
        Nutrition and the developing brain: the road to optimizing early neurodevelopment: a systematic review.
        Pediatr Res. 2020; 87: 194-201
        • Belfort MB
        • Woodward LJ
        • Cherkerzian S
        • et al.
        Targeting human milk fortification to improve very preterm infant growth and brain development: study protocol for Nourish, a single-center randomized, controlled clinical trial.
        BMC Pediatr. 2021; 21: 167
        • Pogribna U
        • Yu X
        • Burson K
        • et al.
        Perinatal clinical antecedents of white matter microstructural abnormalities on diffusion tensor imaging in extremely preterm infants.
        PLoS One. 2013; 8: e72974
        • Blesa M
        • Sullivan G
        • Anblagan D
        • et al.
        Early breast milk exposure modifies brain connectivity in preterm infants.
        Neuroimage. 2019; 184: 431-439
        • Niu W
        • Xu X
        • Zhang H
        • et al.
        Breastfeeding improves dynamic reorganization of functional connectivity in preterm infants: a temporal brain network study.
        Med Biol Eng Comput. 2020; 58: 2805-2819
        • Parikh NA
        • Sharma P
        • He L
        • et al.
        Perinatal risk and protective factors in the development of diffuse white matter abnormality on term-equivalent age magnetic resonance imaging in infants born very preterm.
        J Pediatr. 2021; 233 (e3): 58-65
        • Ottolini KM
        • Andescavage N
        • Kapse K
        • Jacobs M
        • Limperopoulos C.
        Improved brain growth and microstructural development in breast milk-fed very low birth weight premature infants.
        Acta Paediatr. January 10, 2020; (Published online)
        • Vasu V
        • Durighel G
        • Thomas EL
        • et al.
        Preterm nutritional intake and MRI phenotype at term age: a prospective observational study.
        BMJ Open. 2014; 4e005390
        • Volpe JJ.
        Dysmaturation of premature brain: importance, cellular mechanisms, and potential interventions.
        Pediatr Neurol. 2019; 95: 42-66
        • Volpe JJ.
        Primary neuronal dysmaturation in preterm brain: Important and likely modifiable.
        NPM. 2021; 14: 1-6
        • O'Brien K
        • Robson K
        • Bracht M
        • et al.
        Effectiveness of family integrated care in neonatal intensive care units on infant and parent outcomes: a multicentre, multinational, cluster-randomised controlled trial.
        Lancet Child Adolesc Health. 2018; 2: 245-254
        • Paviotti G
        • De Cunto A
        • Zennaro F
        • et al.
        Higher growth, fat and fat-free masses correlate with larger cerebellar volumes in preterm infants at term.
        Acta Paediatr. 2017; 106: 918-925
        • Coviello C
        • Keunen K
        • Kersbergen KJ
        • et al.
        Effects of early nutrition and growth on brain volumes, white matter microstructure, and neurodevelopmental outcome in preterm newborns.
        Pediatr Res. 2018; 83: 102-110
        • O'Connor DL
        • Gibbins S
        • Kiss A
        • et al.
        Effect of supplemental donor human milk compared with preterm formula on neurodevelopment of very low-birth-weight infants at 18 months: a randomized clinical trial.
        JAMA. 2016; 316: 1897-1905
        • Xia Y
        • Jiang B
        • Zhou L
        • et al.
        Neurodevelopmental outcomes of healthy Chinese term infants fed infant formula enriched in bovine milk fat globule membrane for 12 months: a randomized controlled trial.
        Asia Pac J Clin Nutr. 2021; 30: 401-414
        • Nieto-Ruiz A
        • Diéguez E
        • Sepúlveda-Valbuena N
        • et al.
        The effects of an infant formula enriched with milk fat globule membrane, long-chain polyunsaturated fatty acids and synbiotics on child behavior up to 2.5 years old: the COGNIS study.
        Nutrients. 2020; 12: E3825
        • Nieto-Ruiz A
        • Diéguez E
        • Sepúlveda-Valbuena N
        • et al.
        Influence of a functional nutrients-enriched infant formula on language development in healthy children at four years old.
        Nutrients. 2020; 12: E535
        • Li F
        • Wu SS
        • Berseth CL
        • et al.
        Improved neurodevelopmental outcomes associated with bovine milk fat globule membrane and lactoferrin in infant formula: a randomized, controlled trial.
        J Pediatr. 2019; 215 (e8): 24-31
        • Colaizy TT.
        Effects of milk banking procedures on nutritional and bioactive components of donor human milk.
        Semin Perinatol. 2021; 45151382
        • Mudd AT
        • Dilger RN.
        Early-life nutrition and neurodevelopment: use of the piglet as a translational model.
        Adv Nutr. 2017; 8: 92-104