Iron deficiency is the most common nutrient deficiency in the world.(24
) Although ample evidence exists from animal studies regarding the role of iron for fetal and neonatal brain development, little human data exists regarding in utero
iron status and its concomitant effect on brain development.(3
) Our findings suggest that CF concentration, an index measurement for in utero
iron status, is associated with auditory neural maturation when evaluated by ABR soon after birth in premature infants.
Progressive development is seen in the fetal auditory nervous system during the last trimester of pregnancy and iron is an essential nutrient for this critical development of the nervous system.(4
) ABR has been used as a non-invasive tool to assess auditory neural maturation in premature infants as a function of enteral feedings, taurine supplementation, hypothyroxinemia, and antenatal steroid exposure.(18
) By evaluating the wave latencies, which are influenced by the degree of myelination, axonal growth, dendritic growth, and synaptic function, inferences can be made about the possible effects of iron status on auditory neural maturation, a surrogate outcome for brain maturation.
Several previous observational studies in infants and older children have used ABR to evaluate the effect of iron deficiency anemia on brain development.(23
) Although these studies demonstrated an association between ABR changes and iron status, they involved older infants with iron deficiency anemia which is a late manifestation of iron deficiency. Therefore, these studies also failed to answer the question whether iron deficiency without anemia causes neurological impairment. The ABR changes were irreversible despite correction of iron status and anemia with iron therapy.(28
) Several studies have demonstrated that brain and other tissues are depleted long before red blood cells are depleted and, therefore, early identification and treatment of iron deficiency before anemia develops may be essential.(9
Compared with studies in older children which evaluated specific neurodevelopmental process such as myelination using interpeak latencies, our study was aimed to evaluate auditory neural maturation. Most premature infants < 33 weeks GA do not have a complete ABR waveform with all three absolute wave latencies necessary for measuring interpeak latencies, a surrogate marker of myelination. In our study group, more infants with latent iron deficiency had immature ABR waveform compared with infants with normal iron status. Our findings strongly suggest that iron status in the absence of anemia influences auditory neural maturation at both auditory nerve (wave I latency) and brainstem level (wave III and V) and infants with latent iron deficiency have abnormal auditory neural maturation compared with infants with normal iron status.
Some of the perinatal factors such as preeclampsia may be associated with accelerated auditory neural maturation, and hyperbilirubinemia may be associated with transient ABR changes including prolongation of wave latencies.(33
) Most studies have reported no significant changes in auditory neural maturation among small for GA infants compared with appropriate for GA infants.(35
) Despite the fact that more infants with latent iron deficiency were born to mothers with pre-eclampsia and had lesser degree of hyperbilirubinemia, we found that absolute latencies were prolonged in infants with latent iron deficiency compared with infants with normal iron status.
There is growing evidence from observational studies that latent iron deficiency during the fetal and neonatal period may be associated with acute and long-lasting detrimental effects on neurodevelopment.(15
) Tamura et al reported that late preterm and term infants born with CF < 76 ng/ml had poorer performance in fine motor skills and language development at 5 years of age than those with CF ≥ 76 ng/ml, (17
) In another study involving term infants of diabetic mothers, infants with CF ≤ 34 ng/ml had poorer auditory recognition memory as newborns and lower psychomotor developmental scores at 1 year of age than term infants of diabetic mothers with CF > 34 ng/ml.(16
) In the only study involving premature infants < 34 weeks GA, serum ferritin concentration < 75 ng/ml was associated with abnormal neurobehavioral status at 37 weeks post-menstrual age.(15
) Our findings that in utero
iron status strongly influences auditory neural maturation are consistent with the findings of Tamura et al and Sidappa et al.(16
) Our study differs from previous studies in two ways. Our study population was different and involved more premature infants. Secondly, we measured concomitant effects of latent iron deficiency on brain maturation using ABR. Further meaningful analysis of our ABR data using a CF < 35 ng/ml as reported by Sidappa et al was not possible as there were only 3 subjects with CF < 35 ng/ml and measurable absolute latencies in our study group.
The major strength of our study is the objective assessment of an ABR outcome after confirming absence of middle ear disease and outer hair cell dysfunction. Moreover, Response Type assignments were done by audiologists without knowledge of the infants’ CF concentrations. Because our study was limited to 27 to 33 weeks GA infants, our findings may not be generalizable to premature infants > 33 weeks GA. Our findings suggest that ABRs may be a surrogate outcome marker that can be used to assess the potential effect of iron status on brain maturation during the critical period of brain development.
In summary, our findings suggest that iron status influences auditory neural maturation in premature infants. The little evidence currently available suggests that the effect of iron deficiency on neurodevelopment may be long-lasting.(16
) Latent iron deficiency is very common among premature infants, and if the subtle neurodevelopmental changes secondary to latent iron deficiency in the neonatal period lay the foundation for abnormal long-term cognitive, motor, language, and behavioral functioning, then a large unrecognized population of premature infants could be at risk as a consequence of an easily treatable nutritional deficiency.(16
) Therefore, there is an urgent need to determine if there is a causal relationship between latent iron deficiency and abnormal brain development. To establish a causal relationship, a well designed randomized clinical trial is warranted in high- risk premature infants using an objective test such as the ABR. A similar trial during pregnancy, although feasible, will be technically difficult to conduct without knowledge of at-risk fetuses.