EVIDENCE-BASED ANSWER
Healthy infants who test positive for anemia on routine screening at 1 year of age are most likely iron-deficient and may be treated empirically with a trial of iron therapy (3–6 mg of elemental iron/kg/d). Documentation of response to iron confirms the diagnosis of iron-deficiency (strength of recommendation [SOR]: B; evidence from randomized controlled trials with some conflicting results; lack of evidence for long-term benefits/harms of screening strategies).
In these cases, further testing with a complete blood count, mean corpuscular volume, red cell distribution width (RDW), serum ferritin concentration, as well as hemoglobinopathy screening when appropriate, may be effective in determining the cause of anemia (SOR: C, expert opinion).
Evidence summary
A prospective study of 1128 children identified as anemic with a screening hemoglobin level showed that subsequent testing—which included mean corpuscular volume, protoporphyrin, transferrin, and ferritin measurements—did not reliably distinguish potential responders from nonresponders to a 3-month trial of empiric iron therapy.1 In fact, more than half of the responders would have been missed if treatment had been restricted to infants with abnormal mean corpuscular volume or iron studies.
Because of the simplicity, low cost, and relative safety of iron therapy for infants, this trial suggests that a therapeutic trial of iron be given first, reserving further work-up for the small number of infants that still have unexplained hemoglobin concentrations of <11.0 g/dL after a therapeutic trial. Similar results were found in a prospective controlled treatment trial among Alaskan Native children2 as well as a trial of empiric iron therapy among infants with anemia.3
Another prospective study of 970 healthy infants identified 62 infants with a heel-stick capillary hematocrit of <33%. Of these, 31 had repeat hematocrit values of <33% as confirmed by subsequent heel-stick complete blood count measurement. Twenty of these anemic infants (65%) completed the study protocol, which included a 1-month trial of iron, a follow-up complete blood count, and hemoglobin electrophoresis for those infants with persistent microcytosis or positive sickle preparation (performed at initial screening for all African American infants). Six infants (30%) had an increase in hemoglobin concentration of 1.0 g/dL or more and were presumed to be iron-deficient; they went on to receive an additional 2 months of iron therapy. Two of these were found to have co-existing alpha-thalassemia. Of the remainder, 11 (55%) were determined to have a low-normal hematocrit (mean=31.5 ± 0.9), 1 had alpha thalassemia alone, 1 had coexisting alpha-thalassemia and hemoglobin AS, and 1 had hemoglobin SC. Review of data showed that abnormal diagnoses (iron deficiency, thalassemia, and sickle cell trait or disease) were found in 9 of 11 infants with high RDW and in none of the 9 with normal RDW. The authors concluded that RDW alone appears to be predictive of identifiable causes of anemia when used to screen healthy 12-month-old babies.4
A recent Cochrane review suggests there is a clinically significant benefit for the treatment of iron-deficiency anemia; however, there is a need for further randomized controlled trials with long-term follow-up.5 A randomized controlled trial of iron supplementation vs placebo in 278 infants testing positive for iron-deficiency anemia demonstrated that once daily, moderate-dose ferrous sulfate (FeSO4) therapy (3 mg/kg/d of elemental iron) given to fasting 1-year-old infants results in no more gastrointestinal side effects than placebo therapy.6 Another study demonstrated that iron sulfate drops (40 mg elemental iron divided 3 times a day) or a single daily dose of microencapsulated ferrous fumarate sprinkles (80 mg elemental iron) plus ascorbic acid resulted in a similar rate of successful treatment of anemia without side effects.7
In a retrospective cohort study8 of 1358 innercity children aged 9 to 36 months who underwent screening, 343 (25%) had anemia (Hgb <11 g/dL); of these, 239 (72%) were prescribed iron and 95 (28%) were not. Responders were defined as those with a hemoglobin value of greater than 11 g/dL or an increase of 1 g/dL documented within 6 months of the initial screening visit. Follow-up rates for both groups were low (~50%), but of those prescribed iron, 107 of 150 (71%) responded to treatment compared with 27 of 48 (68%) of those who did not receive iron. Since similar response rates were seen among infants who did and infants who did not receive iron therapy, proving the benefit of routine screening followed by a trial of iron may be problematic in populations with higher rates of anemia, low follow-up rates, and high spontaneous resolution rates.