Early Childhood Chronic Iron Deficiency and Later Cognitive Function: The Conundrum Continues

Though iron deficiency anemia (IDA) remains a common cause of anemia in young children, even more common is the prevalence of nonanemic iron deficiency (NAID). For decades, there has been concern for irreversible adverse effects of chronic iron deficiency with or without anemia on cognitive function in children. In a landmark observational study begun in the early 1980s, Lozoff and colleagues studied 185 Costa Rican infants from a low-resource setting and followed them into adulthood. They reported both initial and long-term cognitive inferiority in the subjects with chronic iron deficiency with or without anemia.^1–4  The report by Gingoyon et al in this issue of Pediatrics readdresses these concerns in a high-resource setting, using a select group of infants from a multisite, longitudinal cohort study, TARGet Kids!, based in Toronto, Canada.⁵  Healthy children were recruited at primary care visits between 12 and 40 months of age and screened for iron deficiency with or without anemia using serum hemoglobin (Hgb), serum ferritin and C-reactive-protein. Infants with elevated C-reactive-protein were excluded from further study. In a previous report from TARGet Kids!, the prevalence of IDA and NAID in this cohort was reported as 2% and 12%, respectively.⁶ 

Gingoyon et al⁵  modeled this new observational study of chronic iron deficiency after that of Lozoff and colleagues.¹  They identified 41 infants (mean age 22 months) with chronic iron deficiency, which included 32 infants with IDA (Hgb <11.0 g/L, serum ferritin <14 µg/L) and 9 infants with NAID (Hgb ≥11.0 g/L, serum ferritin ≤14 µg/L) whose NAID did not correct after 4 months of treatment. The comparative iron sufficient group included 75 infants (mean age 25 months), 29 infants without IDA or NAID, and 46 infants whose NAID had previously respondent to treatment.⁶  The primary endpoints were cognitive outcome as measured by the Early Learning Composite assessment scores at 4 and 12 months after the baseline screening. The Early Learning Composite results are presented in Table 2 of the current report.⁵  The authors report cognitive superiority for the iron sufficient status group over the iron deficiency group at both 4 and 12 months. Visual reception scores also significantly favored iron sufficiency at 4 and 12 months. Receptive language scores differed significantly at 4 months, but not at 12 months.

There are several important limitations of this study. For example, the sample size number is small, especially in the chronic iron deficiency group; there was a 30% loss to follow-up; and the duration of chronic iron deficiency is unknown. It remains unknown whether cognitive scores of infants with chronic iron deficiency will improve over the long term in a setting with mothers with a high level of education and presumably a higher social economic status.

Both the study by Gingoyon et al⁵  and Lozoff and colleagues incur the pitfalls of a small observational study. The study by Gingoyon et al⁵  only follows subjects for 12 months versus the Lozoff et al study, which followed subjects for 19 years.

Gingoyon et al⁵  point out the legitimate concerns for cognitive outcomes in infants with chronic iron deficiency that may be associated with IDA or NAID. They note that the American Academy of Pediatrics recommends universal screening for anemia with a serum Hgb at 12 months of age and has acknowledged that it is not possible to define IDA or NAID without at least 1 additional screening test for iron status.⁷  Despite this, it is still questionable whether screening for NAID is warranted in the absence of anemia. The current level of evidence does not unequivocally demonstrate that treating NAID with iron therapy improves long-term cognitive outcomes. This is a critical gap in knowledge given the many known risk factors for chronic IDA in young children, including exclusive breastfeeding beyond 4 to 6 months of age, decreasing use of iron fortified cereals, and poor utilization of iron-rich complementary foods.^7–9  Strong, evidence-based recommendations for the screening and treatment of chronic iron deficiency remain elusive. Clinicians, even with the findings shared in this study by Gingoyon et al,⁵  continue to face a conundrum about whether to screen for both IDA and NAID with a test that measures iron status,⁷  and whether this should lead to treatment. Hopefully, future studies will iron out this conundrum. In the interim, using mostly expert opinion and our clinical judgement, we would recommend screening all infants at ∼12 months of age with at least an Hgb and a measure of iron status such as serum ferritin. Either IDA or NAID should be treated with iron therapy, with appropriate follow-up to include a repeat screen.

Hgb

hemoglobin

IDA

iron deficiency anemia

NAID

nonanemic iron deficiency