Deficiencies in the Management of Iron Deficiency Anemia during Childhood

Abstract

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 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.

Introduction

Despite declining prevalence, iron deficiency anemia (IDA) during childhood remains a common and serious problem(1, 2) being especially prevalent in toddlers aged 12–36 months and girls with menorrhagia.(3) Sequelae from IDA include long-term neurocognitive deficits, fatigue, pica, and in severe cases high output heart failure or stroke.(4) Much attention has focused on prevention and early diagnosis of IDA,(5–7), yet little research has assessed treatment and follow-up of those children in whom IDA is diagnosed in spite of preventive strategies.(8)

A recently published survey indicates wide variation in pediatric hematology-oncology specialists’ self-reported management of patients with IDA(9), resulting in part from the lack of contemporary scientific literature regarding evidence-based treatment of IDA.(8, 10, 11) Few studies have been published in either young children with nutritional IDA or adolescents with heavy menstrual bleeding—the two patient populations at greatest risk—to determine which formulations and dosage schedules are most tolerable and effective.(8)

In 2011, our center initiated a formal IDA Program, which included the establishment of standard practices for IDA management and a subsequent clinical trial for young patients with nutritional IDA.(12) To characterize how IDA had previously been managed locally, we examined records of children with IDA referred to our center during the 4 ½ year period prior to this initiative.

Results

Methods

After obtaining a waiver of informed consent from the Institutional Review Board, a retrospective study of children with IDA referred to the hematology program at the University of Texas Southwestern Medical Center and Children’s Health in Dallas, Texas from January 1, 2006 to June 30, 2010 was performed. Eligible subjects were identified by query of the hematology program’s clinical database. Inclusion criteria were age ≤18 years and a diagnosis of IDA confirmed in the clinical notes of the consultant hematologist at the initial visit. Patients were excluded if their medical records were incomplete. Using the center’s electronic medical record (EMR), data elements were abstracted into Microsoft Excel 2007™ for each subject (Table I). Patients were considered lost-to-follow-up if the last encounter in the EMR was a missed or cancelled hematology appointment. Analyses with Microsoft Excel were descriptive and included proportions, mean with standard deviation, median with range, and cross-tabulations.

Table I.

Data elements collected for each patient with IDA

Demographic Information	Age Race/Ethnicity
Referral Information	Pre-referral laboratory values Referring provider IDA management
Hematology Information	Initial presentation & management (ED versus clinic) Presumptive etiology Hematologist treatment recommendations Adverse effects of iron therapy Response to therapy (hematologic measurements) Treatment outcome
Adherence measures	Medication adherence (per clinic notes) Clinic visit attendance

Patient Characteristics

One hundred ninety five new patients had confirmed IDA during the study frame (Table II). In young children, the etiology was primarily nutritional, while in adolescents it was heavy menstrual bleeding (42%). Some children had multiple causes of IDA, and an etiology was not recorded in 17 patients.

Table II.

Characteristics of Young Children and Adolescents with IDA

Characteristic	Young children Age ≤4 years (N=128)	Adolescents Age 11 to 18 years (N=60)
Sex
Male	63%	17%
Female	37%	83%
Race/Ethnicity
Caucasian	12%	15%
Latino	60%	37%
African American	9%	35%
Asian	8%	3%
Other/Unknown	11%	10%
Etiology
Nutritional, exclusive etiology	74%	17%
(Excessive cow milk)	(66%)	–
(Breastfeeding without supplementation)	(8%)	–
Prematurity	1.5%	–
Malabsorption/molecular defect	2.5%	5%
Menorrhagia	–	42%
GI or other blood loss	4%	17%
Multiple etiologies	11%	6%
Not documented	7%	13%
Initial hemoglobin concentration upon referral
ED (N=49)	6.0 g/dL (3.4 to 8.2)	6.4 g/dL (2.6 to 9.6)
Hematology clinic (N=146)	8.7 g/dL (4.1 to 12.4)	9.0 g/dL (2.4 to 13.2)
Last completed hematology visit*
Hemoglobin concentration	11.7 g/dL (5.3 to 14.7)	11.7 g/dL (6.7 to 16.8)

^*For patients with more than 1 visit (n=146), the median time frame between first and last visit was 12 weeks (range: 1 to 156 weeks).

Treatment of Iron Deficiency Prior to Initial Hematology Consultation

IDA treatment had been initiated by the primary care provider in 83 of the 195 patients (43%) prior to referral. Among young children for whom the elemental iron dosing could be determined (n=59), 35 (59%) were prescribed doses outside the recommended range of 3–6 mg/kg/day. Twenty-nine (83%) were prescribed <3 mg/kg/day, including 5 children prescribed a daily multivitamin with iron (10 mg of elemental iron per dose). In 24 adolescent patients for whom the elemental iron dose was recorded, the median prescribed dose was 65 mg (range 6 mg to 540 mg) daily.

Most of the patients were directly referred to the hematology clinic, but 49 (25%) initially presented to the emergency department (ED). Twenty eight (57%) of them were subsequently hospitalized, and 25 received a transfusion for a median Hgb of 4.9 g/dL (range 2.3 to 8.5 g/dL). While 9 of the 25 transfused patients had acute blood loss at time of presentation, the precise indication for transfusion (i.e. symptomatic anemia) was not clearly documented for the majority of patients. All hemoglobin concentrations (Hgb) at initial presentation are detailed in Table II.

Treatment by the Hematology Clinic Staff

At the initial hematology clinic evaluation, 167 patients (86%) were prescribed ferrous sulfate. Among 104 children ≤4 years of age for whom the prescribed elemental iron dose was recorded, 28 (27%) received a dose outside of the standard recommended range of 3–6 mg/kg/day: 11 were prescribed <3 mg/kg/day (median of 2 mg/kg/day) and 17 >6 mg/kg/day (median of 7 mg/kg/day). Moreover, 40 (67%) of the adolescents 11–18 years of age were prescribed doses below the usual recommended range of 150–300 mg/day elemental iron.(13) Nineteen children received intravenous (IV) iron sucrose (the center’s preferred IV iron preparation during the study period), 2 initially due to concern about impaired iron absorption and an additional 17 after failing multiple trials of oral iron.(14)

Patient Adherence, Follow-up, and Outcome

Sixty-four patients (33%) exhibited poor adherence to oral iron as manifested by: taking less than prescribed (38%), medication intolerance and/or gastrointestinal upset (30%), never obtaining the prescribed medication (14%), and/or misunderstanding of the prescribed dose (7%). Overall, 77 of the 195 children (39%) were considered lost-to-follow-up, 61 of whom failed to return despite still being anemic at the time of their last visit. Nine such patients had worsening anemia between the first and last visit due to either ongoing blood loss and/or non-adherence to iron therapy. Despite the poor medication adherence and high number of patients who were lost-to-follow-up, the median increment in Hgb from first to last visit (n=146) was 2.7 g/dL (range: −2.7 to 9.4 g/dL), with a final median Hgb of 11.7 g/dL (Table II).

Discussion

This study was designed to assess management of children with IDA by their primary physician and our institutional hematology specialists during a 4 ½ year period ending in 2010, prior to the establishment of a more structured approach to IDA management. Our predominantly Latino patient population reflects the diverse setting of our center as well as the disproportionate prevalence of IDA in this group, which has been previously well described.(6) Treatment practices then employed by the referring provider were widely variable, as were the management decisions of our center’s hematology specialists, consistent with the recent survey of pediatric hematology/oncology physicians who regularly treat IDA.(9) Many patients received less than recommended iron doses and/or initially presented to the ED rather than being referred for an elective outpatient hematology consultation. After an initial hematology assessment some children improved, but inappropriate dosing and poor adherence to oral iron therapy were common, with many patients being lost to follow-up, likely with persistent IDA.

A 2010 statement by the American Academy of Pediatrics Committee on Nutrition outlined strategies for prevention and early diagnosis of IDA in infants and young children.(5) These recommendations, however, fail to address the major problem illustrated by the data presented here, i.e., how to effectively treat IDA after the diagnosis is made. Review articles and textbooks typically recommend 3–6 mg/kg per day of elemental iron for young children (15–18) and 150–300 mg of elemental iron daily for adolescents and adults (13), but supporting data are lacking. The scarcity of evidence for adolescents with menorrhagia is especially striking (19), being limited to hormonal control of menstrual bleeding without details regarding therapy for the accompanying anemia.

Retrospective studies such as this have many limitations including incomplete data collection and reliance on the EMR for clinical information. Only patients referred to a hematology specialist were assessed, likely reflecting more severe or resistant IDA. Nonetheless, these results provide further insight into the need for prospective research involving IDA management.

In response to the poor outcomes of patients with IDA treated at our center, an IDA Program was initiated to both improve overall clinical care and facilitate research to inform the management of these patients. These efforts included: (1) an ongoing investigator initiated clinical trial comparing two oral iron medications in the treatment of young children with nutritional IDA (Clinicaltrials.gov NCT01904864), (2) practice guidelines for oral iron therapy in patients not enrolled on a research study, and (3) a clinical protocol for consideration and administration of intravenous iron therapy in patients with oral iron treatment failure.

The therapeutic approach of both primary care providers and hematology specialists to children and adolescents with IDA is widely variable and often suboptimal. We believe this is in great part due to lack of scientific evidence derived from carefully performed clinical trials.(8, 10, 11, 15, 19, 20) This field is especially ripe for the execution of novel comparative effectiveness studies that assess patient-centered outcomes such as fatigue, cognitive impairment, and quality of life in addition to hematologic response. Such research has the potential to substantially advance the treatment of this most common of all hematologic disorders affecting children.