Iron and Neurodevelopment in Preterm Infants

Synaptogenesis, myelination, energy metabolism, and neurotransmitter production depend on iron for brain development. NICU infants are at distinct risk for iron deficiency due to high iron needs, preterm birth, maternal or placental health disruptions, and phlebotomy. A deficiency during critical phases of brain development can result in permanent alterations to brain structure and function, despite subsequent supplementation. 

Children with perinatal iron deficiency can suffer delayed nerve conduction speeds, disrupted sleep patterns, impaired recognition memory, motor deficits, and lower global developmental scores that may present as early as in the neonatal period and persist into adulthood. Thus, it is crucial to ensure brain iron sufficiency during the neonatal period to optimize neurodevelopmental outcomes and to target iron supplementation to correlate with improved outcomes.

Research indicates the importance of iron status and its impacts on brain development, yet the optimal iron supplementation dose, monitoring regimen, and target markers are still unclear. However, we may prevent it by minimizing maternal iron deficiency, optimizing maternal health during pregnancy, and preventing neonatal phlebotomy.

Considering the value <76 microgram/L, given by Tamura et al., to be associated with worse neurodevelopmental outcomes, German KR and Juul SE. in their recent work, proposed that ferritin values above this range are likely needed to ensure that adequate iron is available for brain development. However, optimal cutoffs for ferritin and other iron markers that maximize outcomes are yet unclear.

Phlebotomy in critically ill neonates primarily contributes to iron deficiency. Measuring iron status through serum measures may enhance these losses. Thus, emerging studies suggest using non-hematologic measures of iron status, such as urine ferritin or hepcidin. Additionally, measures such as reticulocyte hemoglobin equivalent may also benefit.

Lastly, although the exact mechanism of microbiome affecting neurodevelopment remains unclear, dysbiosis may correlate with neurodevelopmental effects. High levels of unabsorbed iron in the gut lumen may significantly impact microbial populations and gut inflammation. Specifically, potentially pathogenic species, such as Clostridia, E. coli, and Pseudomonas, may expand in increased luminal iron, suggesting the risk of excessive enteral iron supplementation, particularly in preterm infants who are already at risk for dysbiosis and intestinal inflammation. 

Thus, optimizing iron balance is crucial for neurodevelopmentally-focused neonatal critical care as it represents a common yet potentially modifiable intervention. Besides avoiding iron excess, we should give iron supplementation in infants with iron deficiency to prevent anemia and ensure uninterrupted brain development. 

Further, there is a lack of universal supplementation doses appropriate for all neonates since infants have variable risk factors both pre and post-natally. However, we need an individualized supplementation strategy based on iron measures in at-risk infants. Future national and other expert guidelines would benefit from recognizing the need for individualized dosing guidelines in preterm neonates and ideally individualized strategies based on iron measure targets based on neurodevelopmental outcomes. 

Source: Nutrients. 2021 Oct 23;13(11):3737. doi: 10.3390/nu13113737. PMID: 34835993; PMCID: PMC8624708.