Jacquelyn M. Powers

Diagnosis and Management of Iron Deficiency Anemia

Iron deficiency anemia (IDA) is a common hematologic condition, affecting a substantial proportion of the worlds women and young children. Optimal management of IDA requires an accurate diagnosis, identification and correction of the underlying cause, provision of medicinal iron therapy, and confirmation of treatment success. There are limited data to support current treatment approaches regarding oral iron preparation, dosing, monitoring, and duration of therapy. New intravenous iron agents have improved safety profiles, which may foster their increased utilization in the treatment of patients with IDA. Clinical trials focused on improving current treatment standards for IDA are sorely needed.

Intravenous Ferric Carboxymaltose in Children with Iron Deficiency Anemia Who Respond Poorly to Oral Iron

Objective To assess the benefits and risks of intravenous (IV) ferric carboxymaltose (FCM) in children with iron deficiency anemia (IDA). Study design In a retrospective cohort study of patients seen at our center, we identified all FCM infusions in children with IDA over a 12‐month period through a query of pharmacy records. Clinical data, including hematologic response and adverse effects, were extracted from the electronic medical record. Results A total of 116 IV FCM infusions were administered to 72 patients with IDA refractory to oral iron treatment (median age, 13.7 years; range, 9 months to 18 years). Median preinfusion and postinfusion hemoglobin values were 9.1 g/dL and 12.3 g/dL, respectively (at 4‐12 weeks after the initial infusion; n = 53). Sixty‐five patients (84%) experienced no adverse effects. Minor transient complications were encountered during or immediately after 7 infusions. Conclusion FCM administered as a short IV infusion without a test dose proved to be safe and highly effective in a small yet diverse population of infants, children, and adolescents with IDA refractory to oral iron therapy.

Deficiencies in the Management of Iron Deficiency Anemia During Childhood

Limited high‐quality evidence supports the management of iron deficiency anemia (IDA). To assess our institutional performance in this area, we retrospectively reviewed IDA treatment practices in 195 consecutive children referred to our center from 2006 to mid‐2010. The majority of children were ≤4 years old (64%) and had nutritional IDA (74%). In 11‐ to 18‐year‐old patients (31%), the primary etiology was menorrhagia (42%). Many were referred directly to the emergency department and/or prescribed iron doses outside the recommended range. Poor medication adherence and being lost‐to‐follow‐up were common. Substantial improvements are required in the management of IDA.

Management of iron deficiency anemia: A survey of pediatric hematology/oncology specialists

Iron deficiency anemia (IDA) is the most common hematologic condition in children and adolescents in the United States (US). No prior reports have described the management of IDA by a large cohort of pediatric hematology/oncology specialists.

Effect of Low-Dose Ferrous Sulfate vs Iron Polysaccharide Complex on Hemoglobin Concentration in Young Children With Nutritional Iron-Deficiency Anemia: A Randomized Clinical Trial.

Importance Iron-deficiency anemia (IDA) affects millions of persons worldwide, and is associated with impaired neurodevelopment in infants and children. Ferrous sulfate is the most commonly prescribed oral iron despite iron polysaccharide complex possibly being better tolerated. Objective To compare the effect of ferrous sulfate with iron polysaccharide complex on hemoglobin concentration in infants and children with nutritional IDA. Design, Setting, and Participants Double-blind, superiority randomized clinical trial of infants and children aged 9 to 48 months with nutritional IDA (assessed by history and laboratory criteria) that was conducted in an outpatient hematology clinic at a US tertiary care hospital from September 2013 through November 2015; 12-week follow-up ended in January 2016. Interventions Three mg/kg of elemental iron once daily as either ferrous sulfate drops or iron polysaccharide complex drops for 12 weeks. Main Outcomes and Measures Primary outcome was change in hemoglobin over 12 weeks. Secondary outcomes included complete resolution of IDA (defined as hemoglobin concentration >11 g/dL, mean corpuscular volume >70 fL, reticulocyte hemoglobin equivalent >25 pg, serum ferritin level >15 ng/mL, and total iron-binding capacity <425 &mgr;g/dL at the 12-week visit), changes in serum ferritin level and total iron-binding capacity, adverse effects. Results Of 80 randomized infants and children (median age, 22 months; 55% male; 61% Hispanic white; 40 per group), 59 completed the trial (28 [70%] in ferrous sulfate group; 31 [78%] in iron polysaccharide complex group). From baseline to 12 weeks, mean hemoglobin increased from 7.9 to 11.9 g/dL (ferrous sulfate group) vs 7.7 to 11.1 g/dL (iron complex group), a greater difference of 1.0 g/dL (95% CI, 0.4 to 1.6 g/dL; P < .001) with ferrous sulfate (based on a linear mixed model). Proportion with a complete resolution of IDA was higher in the ferrous sulfate group (29% vs 6%; P = .04). Median serum ferritin level increased from 3.0 to 15.6 ng/mL (ferrous sulfate) vs 2.0 to 7.5 ng/mL (iron complex) over 12 weeks, a greater difference of 10.2 ng/mL (95% CI, 6.2 to 14.1 ng/mL; P < .001) with ferrous sulfate. Mean total iron-binding capacity decreased from 501 to 389 &mgr;g/dL (ferrous sulfate) vs 506 to 417 &mgr;g/dL (iron complex) (a greater difference of −50 &mgr;g/dL [95% CI, −86 to −14 &mgr;g/dL] with ferrous sulfate; P < .001). There were more reports of diarrhea in the iron complex group than in the ferrous sulfate group (58% vs 35%, respectively; P = .04). Conclusions and Relevance Among infants and children aged 9 to 48 months with nutritional iron-deficiency anemia, ferrous sulfate compared with iron polysaccharide complex resulted in a greater increase in hemoglobin concentration at 12 weeks. Once daily, low-dose ferrous sulfate should be considered for children with nutritional iron-deficiency anemia. Trial Registration clinicaltrials.gov Identifier: NCT01904864

Potential for Improved Screening, Diagnosis, and Treatment for Iron Deficiency and Iron Deficiency Anemia in Young Children

I ron deficiency is the most common cause of anemia worldwide. In developed countries, children aged 12-36 months are at risk for iron deficiency (ID) and progression to frank iron deficiency anemia (IDA), primarily as a result of prolonged breast feeding without iron supplementation and/or excessive cow’s milk intake. So-called “cow’s milk anemia” became highly prevalent in the 1950s owing to a decline in breastfeeding, in concert with widespread promotion of the benefits of milk. From the 1960s through the 1990s, advances in laboratory testing fostered more precise measurement of hemoglobin (Hgb) concentration, red blood cell indices, and iron measurements, thereby facilitating the diagnosis of ID and IDA and the assessment of interventions aimed at treatment. Although ferritin was discovered in the 1930s, it was not until the 1970s that an immunoassay for serum ferritin was developed as a reliable measure of total iron body stores. Shortly thereafter, a Hgb concentration of 110 g/L and a serum ferritin level of 10-12 μg/L became the widely accepted threshold values for diagnosis of IDA in young children. The introduction of iron-fortified formulas and implementation of the Women, Infants, and Children program during this time frame were additional steps taken to reduce the burden of nutritional ID and IDA in young children. Finally, Lozoff and other investigators conducted landmark studies that defined important nonhematologic effects of ID, including long-lasting neurocognitive impairment. These advances during the final decades of the twentieth century helped foster the advocacy of universal screening for ID and IDA in infants and young children by the Committee on Nutrition of the American Academy of Pediatrics. It was assumed that the implementation of such screening efforts, using primarily Hgb concentration, would lead to a substantial decline in the prevalence of ID and IDA. Yet despite these advances emphasizing prevention and early diagnosis, ID and IDA continue to be extremely common between age 12 and 36 months. Furthermore, relying on Hgb concentration alone for screening results in nonanemic children being overlooked and thus at risk of experiencing the myriad negative consequences of ID. Such ongoing limitations in our capacity to accurately screen for ID in infants and young children result in the tragedy of ID and IDA being as common today as they were several decades ago. In this volume of The Journal, Abdullah et al report an insightful study that sheds new light on serum ferritin values in a population of healthy 12to 36-month-old Canadian children. The authors’ efforts were prompted by careful reassessment of serum ferritin studies performed decades ago showing that the commonly referenced “normal ranges” still in wide use today had been determined in small sample sizes not representative of the general population of children. Accordingly, the Toronto group sought to establish more clinically relevant thresholds for serum ferritin by studying their large, well-established, contemporary patient cohort. Using restricted cubic spline modeling, an analytic approach that accounts for the previously underappreciated nonlinear relationship between Hgb and serum ferritin, they demonstrated a “plateau” effect of serum ferritin on Hgb concentration. By doing so, they defined more meaningful and physiologically relevant values than existing norms. Using this analysis, they identified “Hgb plateau points” of 121.2 g/L and 121.0 g/L, corresponding to serum ferritin values of 23.7 μg/L and 17.9 μg/L. In comparison, a Hgb concentration of 110 g/L, currently considered the cutoff value for defining ID and IDA, was associated with extremely low serum ferritin values of 2.4-4.6 μg/L, clearly indicative of ID. These findings raise the extremely important question of whether the longstanding “threshold” Hgb value of 110 g/L should continue to be the accepted lower limit of normal used to initiate an evaluation for clinically significant ID in young children. Abdullah et al have been engaged in a critically important area of clinical research that has long been underappreciated. Their present work demonstrates the importance of revisiting long-held concepts and controversies in pediatrics. Until we understand whether a Hgb of 110 g/L, 120 g/L, or some other value is the best threshold for a considering a diagnosis of IDA, it is imperative to remember that IDA is the final stage of ID, not an early marker of iron deprivation. In any child at high risk based on age, dietary history, ethnicity, or family income, the care provider should assess serum ferritin level irrespective of whether the patient’s Hgb concentration is at or even somewhat above 110 g/L. Several important steps seem to be indicated to fully validate the importance of the present research. First, a prospective therapeutic cohort study could support the authors’ observation that 120 g/L, not 110 g/L, is a better cutoff Hgb concentration to ensure that a corresponding normal serum ferritin measurement (eg, >15-20 μg/L) is associated with it. Second, and equally important, is the need for improved management of all patients with IDA. Few high-quality published clinical trials inform how best to treat young children with ID and IDA. Textbooks, review articles, and opinion pieces

Background and Pathophysiology of Autoimmune Neutropenia

Autoimmune neutropenia is estimated to occur in at least 1 in 100,000 children. The majority of patients are affected during the first 2 years of life, with resolution by age 5. Primary autoimmune neutropenia of infancy may present at the time of an acute infection or incidentally when a complete blood count is obtained for another reason. The neutropenia is a result of peripheral destruction due to autoantibody production against antigens on the neutrophil surface, most commonly human neutrophil antigen 1 on the neutrophil immunoglobulin receptor FcγRIIIb. Antibodies often remit within 18–24 months from the time of diagnosis. Most children experience a benign course with limited increased risk of infections. In contrast, secondary autoimmune neutropenia may present at any age with a more variable clinical course. Patients with the latter may have pan-FcγRIIIb autoantibodies and should undergo investigation for other autoimmune or primary immune system disorders.

Effect of Different Iron Preparations for Young Children With Iron-Deficiency Anemia—Reply

Effect of Different Iron Preparations for Young Children With Iron-Deficiency Anemia To the Editor In a randomized clinical trial comparing the efficacy of different iron drops containing the same amounts of essential iron for infants and young children (aged 9-48 months) with nutritional iron-deficiency anemia (IDA), ferrous sulfate drops increased mean hemoglobin concentration by 4.0 g/dL during the study period of 12 weeks compared with 3.4 g/dL with iron polysaccharide complex drops (difference, 1.0 g/dL; 95% CI, 0.4-1.6 g/dL).1 Consequently, Dr Powers and colleagues1 recommended ferrous sulfate as the first-line treatment for IDA among infants and young children. Given that the bioavailability of ferric iron preparations such as iron polysaccharide complex is 3 to 4 times less than that of ferrous iron formulations,2 the study design may have favored ferrous sulfate. Nevertheless, the study may suggest that both ferrous sulfate and iron polysaccharide complex would be useful, particularly in the treatment of mild IDA. Generally, infants and young children (aged 6-24 months) are diagnosed as having IDA when their hemoglobin levels are less than 11.0 g/dL and serum ferritin levels are less than 12.0 ng/mL.3 In the study by Powers and colleagues, mean baseline levels of hemoglobin were less than 8.0 g/dL and ferritin levels were less than 3.1 ng/mL in both groups, meaning that the study cohort was composed of participants with high-grade IDA. In Figure 2 in the article, the advantages of ferrous sulfate over iron polysaccharide complex were almost achieved at 4 weeks with hemoglobin levels greater than 10.0 g/dL in the ferrous sulfate group and greater than 9.0 g/dL in the iron polysaccharide complex group; thereafter, the bioavailability of both iron preparations appears similar. These findings might indicate that iron polysaccharide complex would be as effective as ferrous sulfate when used for infants and young children with hemoglobin levels of 9.0 g/dL to 10.0 g/dL. Powers and colleagues suggested that the difference of 1.0 g/dL in mean hemoglobin level is clinically relevant, referring to the 2004 report from the World Health Organization that the relative risk associated with a 1.0 g/dL increase in mean hemoglobin level in the population was 0.78 (95% CI, 0.70-0.86) for “mental retardation.”4 However, a more recent study based on the same database failed to show the association of iron supplementation with mental and psychomotor development despite significant hemoglobin responses to oral iron in infants and young children.5 Replenishment of iron storage is slower with the use of iron polysaccharide complex for infants and young children compared with ferrous sulfate, but the effect of this difference on child health is unclear. Tetsuji Fujita, MD