The Preterm Brain Is Also What It Eats: A Systematic Review of Nutrition and Neuroimaging Outcomes in Preterm Infants

Background: Nutrition is one of the most modifiable determinants of brain development in preterm infants. Although increasing evidence supports associations between early nutritional exposures and neurodevelopment, studies remain heterogeneous regarding nutritional interventions, imaging biomarkers, and long-term outcomes. This systematic review aimed to summarize contemporary evidence on the relationship between nutrition and brain development in preterm infants using neuroimaging as the primary assessment tool while proposing an integrated translational framework to guide future research. Methods: Following a PECO framework, a systematic literature search was conducted in PubMed, Scopus, and CINAHL: population, infants born before 37 completed weeks of gestation; exposure, any enteral or parenteral nutritional exposure, supplementation strategy, fortification approach, or individualized nutritional intervention; comparator, an alternative nutritional strategy, lower or absent exposure, standard care or, when relevant, a term-born reference group; outcomes, MRI- or CUS-based measures of brain growth, maturation, connectivity, or injury. Studies reporting volumetric, morphometric, diffusion, connectivity, spectroscopy, or quantitative ultrasound outcomes were eligible. The methodology was adapted from the PROSPERO-registered review by Ottolini et al. Original studies published between 2020 and 2026 (1 January 2020–4 September 2026) evaluating nutritional exposures or interventions in preterm infants with magnetic resonance imaging (MRI) and/or cranial ultrasound (CUS) outcomes were included. Risk of bias was assessed using the Newcastle–Ottawa Scale (NOS), ROBINS-I and RoB 2 according to study design. Quantitative imaging studies were screened for eligibility for ATLAS assessment. Given the substantial heterogeneity in nutritional exposures, imaging protocols, timing of assessments, and neurodevelopmental outcomes, meta-analysis was not performed. Certainty of evidence was assessed at the level of each causal question and neuroimaging outcome domain using the GRADE framework. Randomized intervention evidence and observational exposure evidence were evaluated according to the design and target contrast contributing to each body of evidence. Judgments considered risk of bias, inconsistency, indirectness, imprecision, publication bias, and, where applicable, factors that could increase certainty. Statistical significance was not used to determine certainty, and studies arising from shared or partially overlapping parent populations were not counted as independent replication. Results: We found 33 reports that met the inclusion criteria: 4 evaluated randomized treatment contrasts, 5 non-randomized intervention comparisons, and 24 observational nutritional exposure analyses. Greater exposure to human milk and selected strategies involving early protein and lipid provision, docosahexaenoic acid, omega-3 fatty acids, and individualized nutritional support were associated in several studies with favorable MRI measurements, including larger total or regional brain volumes, more advanced white-matter maturation, and differences in structural or functional connectivity. Some studies also reported associations with later neurodevelopment. However, findings were not uniform, and GRADE certainty across outcome-specific nutrition–neuroimaging questions ranged from very low to low, principally because of risk of bias, imprecision, heterogeneous exposure and imaging definitions, and limited independent replication. Although causal inference cannot be directly drawn, neuroimaging may provide quantitative measures of brain development that can be investigated alongside long-term neurodevelopmental outcomes. We propose the Roadmap for Imaging-Guided Enhancement of Neurodevelopment (RIGEL), an integrative research framework combining imaging, molecular biomarkers, standardized neurodevelopmental assessment, and epidemiological evidence across developmental stages. RIGEL should be regarded as a hypothesis-generating research framework that requires prospective validation before any clinical implementation.