Source: Parkin PC, Borkhoff CM, Macarthur C, et al. Randomized trial of oral iron and diet advice versus diet advice alone in young children with non-anemic iron deficiency [published online ahead of print February 3, 2021]. J Pediatr. 2021. doi:10.1016/j.jpeds.2021.01.073Investigators from multiple Canadian institutions conducted a randomized trial to compare the effect of oral iron supplementation versus diet advice alone on neurodevelopmental outcomes in children. Parents of children with health supervision visits at 1 of 8 primary care practices in Toronto, Canada, during the study period were eligible. Children were included if they were 12-40 months of age and met criteria for non-anemic iron deficiency (NAID), defined as a hemoglobin ≥110 g/L and serum ferritin <14 μg/L. Children were excluded if they had a developmental condition, were born at a gestational age of <35 weeks or birth-weight of <2,500 grams, had acute illness, had previous anemia or iron deficiency, were receiving iron, or had a c-reactive protein ≥10 mg/L. Child demographics were collected at baseline.Participants were randomized to receive either liquid ferrous sulfate (6 mg elemental iron/kg/day) or liquid placebo in 2 divided doses daily by mouth for 4 months. All parents received diet advice on improving iron status via a written guide. Parents and researchers were blinded to treatment arm. Participants received a developmental assessment of gross motor and cognitive at baseline as well as 4 and 12 months after baseline using the Mullen Scales of Early Learning (MSEL).The primary outcome was MSEL scores 4 and 12 months after baseline. Secondary outcomes included serum ferritin values at 4 and 12 months. The investigators used an intention-to-treat analysis to assess the effect of intervention arm on outcomes, adjusting for baseline score, baseline ferritin, and unbalanced demographic characteristics across treatment arms.There were 60 participants randomized. Participants had a mean age of 24.2 months. Serum ferritin and mean MSEL scores were similar across treatment groups at baseline. The mean between-group difference in MSEL scores at 4 months was 1.1 points (95% CI, -4.2, 6.5) and at 12 months was 4.1 points (95% CI, -1.9, 10.1). The mean between-group difference in serum ferritin at 4 months was 16.9 μg/L (95% CI, 6.5, 27.2) and at 12 months was 3.9 μg/L (95% CI, -7.3, 15.1).The investigators conclude that there is no important between-group difference in neurodevelopmental outcomes in young children NAID treated with ferrous sulfate plus diet advice versus diet advice alone, though serum ferritin values are higher among those who received ferrous sulfate 4 months later.Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.NAID is found in an estimated 11% of US children ages 6 months to 5 years.1 Approximately 25% to 42% of NAID eventually contributes to anemia in this age group.1 Duration, severity, and age onset of NAID may impact neurocognitive skills, breath-holding spells, restless leg syndrome, attention-deficit, pagophagia (ice craving), and athletic performance.2The definitive diagnostic study for NAID is absent iron staining on bone marrow biopsy, an invasive study.3 Although serum ferritin is specific and usually aligned with total body iron stores, normal thresholds vary with age and assay types. Serum ferritin levels rise during and for days to weeks after acute or chronic infection, injury, exercise, and inflammatory conditions.1-3 Consensus among health organizations as to definitions of NAID based on serum ferritin and other biomarkers vary.1-3Strengths of the current study include randomization and longitudinal data. Limitations include a small, homogeneous, well-educated cohort with self-reported medication compliance, adverse effects, and dietary intake. Even though iron supplementation was prescribed for 4 months, both groups had similarly improved ferritin levels after 12 months and equivalent hemoglobin levels throughout. CRP levels were not obtained at 4 and 12 months’ time points to determine the accuracy of the ferritin levels.1-3 Red blood cell indices, transferrin saturation, reticulocyte hemoglobin content, soluble transferrin receptor, and hepcidin—which are available serum biomarkers to help differentiate low iron stores from NAID—were not assessed.1Non-anemic iron deficiency due to inadequate iron intake in children ages 6 months to 5 years seems resolvable with written nutrition education within 12 months. More research is needed to determine whether low serum ferritin levels are associated with neurodevelopmental outcomes. (See AAP Grand Rounds. 2021;45[3]:27.)4The AAP recommends universal screening for anemia with measurement of hemoglobin concentration at approximately 12 months of age.3 Although the association of iron deficiency anemia in infancy and later cognitive deficits is supported by a number of prior studies, the same cannot be said of NAID.3 Unfortunately, the results of the current study are also inconclusive. Perhaps if low-dose ferrous sulfates (3 mg/kg elemental iron/day) had been used, compliance would have improved, potentially leading to differences in neurodevelopmental outcomes. (See AAP Grand Rounds. 2017;38[4]39.)5
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