Human Milk and Preterm Infant Brain Development: A Narrative Review

Clin Ther. 2022 Apr;44(4):612-621. doi: 10.1016/j.clinthera.2022.02.011. Epub 2022 Mar 17.


Purpose: 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.

Methods: 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.

Findings: 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.

Implications: 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.

Keywords: brain development; dysmaturation; human milk; preterm infants; white matter injury.

Publication types

  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Brain / diagnostic imaging
  • Diffusion Tensor Imaging*
  • Humans
  • Infant
  • Infant, Newborn
  • Infant, Premature*
  • Magnetic Resonance Imaging
  • Milk, Human