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Towards improving outcomes: Protein, body composition, and brain development in preterm infants

Pediatric Research (2025)Cite this article

Nutritional supplementation is a modifiable component of clinical care for extremely preterm (EPT) infants (born before 28 weeks’ gestation) with the potential to improve long-term neurodevelopmental outcomes. Early human milk feeding in this population promotes brain development with long-lasting neurocognitive benefits.1,2,3,4,5 Human milk alone, however, does not provide the necessary macronutrients and energy to support the rapid extrauterine somatic and brain growth required of these infants, warranting additional nutrient fortification.6,7 Many unanswered questions remain regarding the ideal type and timing of nutritional interventions to support optimal brain development in EPT infants, as clinicians must overcome the increased metabolic demands of a vastly different extrauterine milieu to the in utero developing fetus.8,9 EPT infants can rapidly accrue deficits in vital nutrients for brain development, particularly proteins that are crucial for neuronal growth and differentiation, synaptogenesis, and cell signaling.7,10

In this issue of Pediatric Research, authors Jeffcoat and Salas report on the “Long-term growth and neurodevelopment of extremely preterm infants randomized to fortified human milk diets enriched with a protein supplement.”11 In this randomized-controlled trial of EPT infants born between 25 and 28 weeks’ gestation, they primarily assessed the effect of providing “standard” versus “high” enteral protein supplementation on evolving body composition utilizing serial air displacement plethysmography (ADP).12 All infants received milk fortified with a multicomponent bovine human milk fortifier beginning on postnatal day 14, with those in the high protein group supplemented with a fixed dose of enteral liquid protein ( ~ 0.75 g/100 mL) through 32 weeks postmenstrual age (PMA).12 Additional supplementation in the high protein group translated to 0.6–1 g/kg/day greater protein intake, resulting in higher fat-free mass (FFM) z-scores at 36 weeks PMA. This novel study methodology highlights technological advances that provide real-time insight into the influence of specific nutritional interventions on somatic growth. Measures of body composition obtained from ADP allow investigators to go beyond traditional anthropometric markers of neonatal growth towards promoting lean mass accretion, represented by FFM, as increased adiposity may lead to adverse long-term cardiometabolic consequences.13

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Authors and Affiliations

  1. Developing Brain Institute, Children’s National Hospital, Washington, DC, USA

    Katherine M. Ottolini & Nickie Andescavage

  2. Division of Neonatology, Children’s National Hospital, Washington, DC, USA

    Katherine M. Ottolini & Nickie Andescavage

Authors
  1. Katherine M. Ottolini
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  2. Nickie Andescavage
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Drs. Ottolini and Andescavage both conceptualized, wrote, and critically reviewed this manuscript.

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Correspondence to Katherine M. Ottolini.

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Ottolini, K.M., Andescavage, N. Towards improving outcomes: Protein, body composition, and brain development in preterm infants. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04704-8

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