Pediatric Intravenous Iron Therapy: Evaluating the Safety and Efficacy of Iron Isomaltoside and Low Molecular Weight Dextran

[1]¿p1 [1]¿m1 BACKGROUND: Iron deficiency (ID) and iron deficiency anemia (IDA) are prevalent among children and adolescents, significantly impacting growth and development. While oral iron is the first-line treatment, intravenous iron is required in cases of poor tolerance or inadequate response. However, no published data on the safety and efficacy of iron isomaltoside (IIM) in the pediatric population exist, while data on low molecular weight dextran (LMWD) remain limited. PROCEDURE: A retrospective cohort study (2021–2023) at Vilnius University Hospital Santaros Klinikos, a tertiary center in Lithuania, included pediatric patients (<18 years) with ID/IDA receiving IIM or LMWD. Assessment of hematological response was based on hemoglobin levels (HGB), reticulocyte hemoglobin equivalent (Ret-He), mean corpuscular volume (MCV), serum ferritin, and transferrin saturation (TSAT) at early (3–7 days) and late (4–6 weeks) time points. Adverse events were systematically monitored. RESULTS: Seventy-two patients (IIM: 50, LMWD: 22; 135 infusions), 68.1% female, with a median age of 13.5 years, were included in the study. Mean HGB increase was 32.4 g/L (IIM) vs. 33.1 g/L (LMWD) (p = 0.912). Median ferritin increase was 71.4 µg/L (IIM) vs. 117.8 µg/L (LMWD) (p = 0.316). Ret-He improved significantly (p < 0.05). Mild AEs occurred in 5.6%, with similar AE rates in both groups (IIM: 6.0%, LMWD: 4.5%). CONCLUSION: Our findings suggest that IIM and LMWD are effective and safe IV iron therapies for pediatric ID/IDA. Given the lack of data on the safety and efficacy of IIM in the pediatric population, our findings provide valuable preliminary evidence. [1]¿p1 [1]¿m1 Pediatric Intravenous Iron Therapy: Evaluating the Safety and Efficacy of Iron Isomaltoside and Low Molecular Weight Dextran Authors: Dragūnė Ernesta 1, Agnė Morkūnaitė 1, Trakymas Gaudas Benediktas 1, Vaišnorė Ramunė 2, Šaulytė Trakymienė Sonata 3 1 Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania 2 Institute of Data Science and Digital Technologies, Faculty of Mathematics and Informatics, Vilnius University, 08412 Vilnius, Lithuania 3 Clinic of Children’s Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius University Hospital Santaros Klinikos, 08661 Vilnius, Lithuania Correspondence Sonata Šaulytė Trakymienė, Santariškių g. 4, 08661 Vilnius. Email: [email protected] Word Count:

246 words Main Text: 2734 words Number of tables: 6 Running title: Safety and Efficacy of Pediatric IV Iron Therapy

iron isomaltoside, low molecular weight dextran, intravenous iron Abbreviations: | ID | Iron deficiency | | IDA | Iron deficiency anemia | | IV | Intravenous | | IIM | Iron isomaltoside | | LMWD | Low molecular weight dextran | | AE | Adverse event | | HGB | Hemoglobin | | RBC | Red blood cell(s) | | MCV | Mean corpuscular volume | | Ret-He | Reticulocyte hemoglobin equivalent | | TSAT | Transferrin saturation | | FCM | Ferric carboxymaltose | | IS | Iron sucrose | | IQR | Interquartile range | | SD | Standard deviation |

BACKGROUND: Iron deficiency (ID) and iron deficiency anemia (IDA) are prevalent among children and adolescents, significantly impacting growth and development. While oral iron is the first-line treatment, intravenous iron is required in cases of poor tolerance or inadequate response. However, no published data on the safety and efficacy of iron isomaltoside (IIM) in the pediatric population exist, while data on low molecular weight dextran (LMWD) remain limited. PROCEDURE: A retrospective cohort study (2021–2023) at Vilnius University Hospital Santaros Klinikos, a tertiary center in Lithuania, included pediatric patients (<18 years) with ID/IDA receiving IIM or LMWD. Assessment of hematological response was based on hemoglobin levels (HGB), reticulocyte hemoglobin equivalent (Ret-He), mean corpuscular volume (MCV), serum ferritin, and transferrin saturation (TSAT) at early (3–7 days) and late (4–6 weeks) time points. Adverse events were systematically monitored. RESULTS: Seventy-two patients (IIM: 50, LMWD: 22; 135 infusions), 68.1% female, with a median age of 13.5 years, were included in the study. Mean HGB increase was 32.4 g/L (IIM) vs. 33.1 g/L (LMWD) (p = 0.912). Median ferritin increase was 71.4 µg/L (IIM) vs. 117.8 µg/L (LMWD) (p = 0.316). Ret-He improved significantly (p < 0.05). Mild AEs occurred in 5.6%, with similar AE rates in both groups (IIM: 6.0%, LMWD: 4.5%). CONCLUSION: Our findings suggest that IIM and LMWD are effective and safe IV iron therapies for pediatric ID/IDA. Given the lack of data on the safety and efficacy of IIM in the pediatric population, our findings provide valuable preliminary evidence. 1 INTRODUCTION Iron deficiency anemia (IDA) is the most common type of anemia, particularly prevalent among children under the age of 5 years and adolescent females.[1–3] Globally, it is estimated that up to 40% of preschool-aged children and 30% of adolescent females are affected by iron deficiency (ID), with IDA being the most severe form.[4–6] Historically, iron deficiency was only addressed when it progressed to IDA. However, it is now clear that ID without anemia is a clinically relevant condition that warrants correction, especially when symptomatic. Symptoms are non-specific and may vary from mild fatigue to neurodevelopmental and behavioral disorders.[7] Iron deficiency can be treated with either oral or intravenous (IV) iron formulations. Oral iron remains the first-line treatment due to its safety and low cost. However, it requires prolonged daily use in order to be effective and is frequently associated with gastrointestinal side effects, leading to poor adherence, particularly in children.[8,9] IV iron formulations offer an excellent alternative when oral options are poorly tolerated or ineffective. IV iron offers several benefits over oral iron, including a faster hematological response and a lower rate of side effects, especially gastrointestinal.[8,10] Despite its well-established role in treating ID and IDA in adults, the use of IV iron in pediatrics, particularly third-generation products, remains limited. IV iron is seldom used in children due to safety concerns and because not all formulations are officially approved for pediatric use.[11] Existing data on pediatric IV iron use are primarily derived from retrospective studies, small cohorts, or extrapolated from adult populations, resulting in uncertainty regarding optimal dosing, long-term safety, and comparative efficacy across different formulations.[8,10,12] Nevertheless, in clinical practice, IV iron is frequently used off-label when oral iron is ineffective or poorly tolerated, particularly in children with chronic inflammatory conditions, gastrointestinal malabsorption, or severe IDA requiring rapid iron repletion. Despite well-established safety and efficacy profiles in adults, currently, no published data exist on the safety and efficacy of iron isomaltoside (IIM) in the pediatric population, while data for low molecular weight dextran (LMWD) remain limited. Before formal approval of IIM for pediatric use, any available data on its safety and efficacy would be valuable in guiding clinical practice. The aim of our study was to evaluate the safety and efficacy of IV iron isomaltoside and low molecular weight dextran in children under 18 years of age. 2 METHODS 2.1 Study design and data collection This retrospective cohort study included patients diagnosed with ID or IDA who were treated with IV iron isomaltoside (IIM) or low molecular weight dextran (LMWD) at the Pediatric Hematology/Oncology Unit of Vilnius University Hospital Santaros Klinikos, a tertiary center in Lithuania, between January 1, 2021, and December 31, 2023. Approval from the Lithuanian Bioethics Committee (No. 2022/5-1436-908, amendment No. 2) was obtained for the study. In Lithuania, LMWD is approved for use in children aged 14 years and older, whereas IIM lacks approval for pediatric use worldwide. In this study, demographic and clinical characteristics of the patients, along with hematological response parameters, and the occurrence of adverse events (AE) were collected. 2.2 Methodology for assessing efficacy and safety This study employed a retrospective cohort design to evaluate the efficacy and safety of IV iron formulations in pediatric patients diagnosed with ID or IDA. Patients were treated with either IIM or LMWD (n = 72) . IV iron doses were calculated using either the Ganzoni formula or a simplified formula. Efficacy was assessed only in anemic patients who had not received red blood cell (RBC) transfusions to eliminate potential bias. Based on this criterion, 22 patients were excluded from the efficacy analysis, resulting in a final efficacy evaluation cohort of n = 50. Hematological response was analyzed in the total study sample (n = 50) and stratified into treatment groups: IIM group (n = 30) and in LMWD group (n = 20). Early response to IV iron was assessed by measuring reticulocyte hemoglobin equivalent (Ret-He) and reticulocyte count (%) before and 3–7 days after IV iron infusion. Late response was assessed by analyzing changes in RBC count, hemoglobin (HGB), mean corpuscular volume (MCV), serum ferritin, and transferrin saturation (TSAT) at 4–6 weeks post-infusion. The safety of IIM and LMWD was evaluated in the entire cohort (n = 72) and separately in each treatment group: LMWD group (n = 22) and IIM group (n = 50). Safety assessment was based on the incidence and frequency of AEs reported during and after IV iron administration. Anemia was diagnosed based on Vilnius University Hospital Santaros Klinikos laboratory reference values (Table 1). [1]¿p1 [1]¿m1 TABLE 1 Hemoglobin reference values by age group at Vilnius University Hospital Santaros Klinikos | Age groups | Hemoglobin reference values (g/L) | | 12–18 years | 120–145 | | 6–12 years | 120–124 | | 2–6 years | 110–135 | | 6 months–2 years | 110–130 | IDA was defined as microcytic anemia (based on patient’s age), a serum ferritin level <15 µg/L, and/or transferrin saturation 2.3 Data analysis and statistical methods Statistical analysis was performed using Microsoft Excel and the R statistical programming language R (version 4.3.2). The Shapiro-Wilk test was applied to assess the normality of data distribution. For non-normally distributed data, the median and interquartile range (IQR) were calculated. For normally distributed data, the mean and standard deviation (SD) were calculated. For categorical variables, frequencies and percentages were calculated and presented. Pearson’s Chi-square test with Yates’ continuity correction was used to assess the differences between categorical variables. The t-test was used to compare normally distributed data, while the Wilcoxon test was applied to compare non-normally distributed data. Statistical significance was defined as a p-value of <0.05. 3 RESULTS 3.1 Patient population A total of 135 IV infusions were administered to 72 patients. Low molecular weight dextran was administered to 22 patients (30.5%), while iron isomaltoside was administered to 50 patients (69.5%). The study cohort was 68.1% females and 31.9% males. The median age of the study population was 13.5 years [IQR 6-15] including two patients younger than 1 year. The median age in the IIM group was 11 years [IQR 5-15], whereas in the LMWD group, it was 15 years [IQR 14-16]. Most patients (48.6%) received a single infusion, with a median dose of 500 mg [IQR 300-725] in the IIM group and 1000 mg [IQR 800-1000] in the LMWD group. IDA due to gastrointestinal disorders was the most common indication for IIM or LMWD therapy, accounting for 34.7% of cases, followed by heavy menstrual bleeding in 22.2%, nutritional IDA (13.9%) and other etiologies (29.2%) . A total of 74 IIM infusions were administered to 50 patients, of whom 14 (28%) had ID without anemia, and 36 (72%) had IDA. In the LMWD group, 61 infusions were administered to 22 patients, all of whom had IDA. Patient characteristics are summarized in Table 2. [1]¿p1 [1]¿m1 TABLE 2 Patients’ characteristics | All patients (n = 72) | LMWD group (n = 22) | IIM group (n = 50) | | | Age, years (median) [IQR] | ||| | 13.5 [6-15] | 15.0 [14-16] | 11.0 [5-15] | | | Gender, n (%) | ||| | Male | 23 (31.9) | 4 (18.2) | 19 (38.0) | | Female | 49 (68.1) | 18 (81.8) | 31 (62.0) | | IV iron doses received, n (%) | ||| | 1 dose | 35 (48.6) | 10 (45.5) | 25 (50.0) | | 2 doses | 19 (26.4) | 5 (22.7) | 14 (28.0) | | 3 doses | 15 (20.8) | 5 (22.7) | 10 (20.0) | | 4 doses | 1 (1.4) | 0 | 1 (2.0) | | 5 doses | 1 (1.4) | 1 (4.5) | 0 | | 8 doses | 1 (1.4) | 1 (4.5) | 0 | | Distribution by anemia severity, n (%) | ||| | Iron deficiency without anemia | 14 (19.4) | 0 | 14 (28.0) | | Mild anemia | 28 (38.9) | 12 (54.5) | 16 (32.0) | | Moderate anemia | 15 (20.8) | 4 (18.2) | 11 (22.0) | | Severe anemia | 15 (20.8) | 6 (27.3) | 9 (18.0) | LMWD -- low molecular weight dextran IIM -- iron isomaltoside IV -- intravenous IQR -- interquartile range 3.2. Hematological response to IIM Early response, assessed by hemoglobin content of reticulocytes (Ret-He), showed a mean pre-infusion value of 17.6 ± 4.8 pg, increasing to 28.0 ± 2.8 pg post-infusion. Mean pre-infusion and post-infusion hemoglobin values were 86.8 ± 19.4 g/L and 120.0 ± 15.1 g/L, respectively, at 4-6 weeks after the initial infusion. Median serum ferritin and TSAT increase were 72 µg/L and 27.3% post-infusion, respectively (Table 3). [1]¿p1 [1]¿m1 TABLE 3 Patients’ hematological response to iron isomaltoside (IIM) | Parameter | Value (pre-infusion), mean ± SD | Value (post-infusion), mean ± SD | Increase, mean ± SD | | RBC, ×10 12 | 4.3 ± 0.9 | 4.7 ± 0.7 | 0.5 ± 0.4 | | HGB, g/l | 86.8 ± 19.4 | 120.0 ± 15.1 | 32.4 ± 8.6* | | MCV, fl | 69.6 ± 9.4 | 78.9 ± 6.9 | 9.1 ± 3.1* | | Ret-He, pg | 17.6 ± 4.9 | 28.0 ± 2.8 | 10.5 ± 2.1* | | Parameter | Value (pre-infusion), median [IQR] | Value (post-infusion), median [IQR] | Increase, mean | | Reticulocyte count (%) | 1.1 [0.8–1.3] | 2.7 [1.9–5.1] | 0.6* | | Ferritin, µg/L | 6.4 [3.7–13.7] | 72.0 [49.5–152.2] | 111.7* | | TSAT, % | 7.2 [5.5–10.1] | 27.3 [25.4–41.5] | 15.5* | *p-value<0.05 RBC – red blood cells HGB – hemoglobin MCV – mean corpuscular volume Ret-He – reticulocyte hemoglobin equivalent TSAT – transferrin saturation level IQR – interquartile range SD – standard deviation 3.3. Hematological response to LMWD Low molecular weight dextran was administered to 40% of patients treated with IV iron (n = 20). The median dose was 1000 mg [IQR 800-1000]. 3–7 days post-infusion, Ret-He and reticulocyte count (%) were evaluated. The mean Ret-He ± SD change was 9.475 ± 2.69 pg and the median reticulocyte change was 0.87%. A statistically significant increase in all late hematological response (4–6 weeks post-infusion) values was observed, as shown in Table 4. TABLE 4 Patients’ hematological response to low molecular weight dextran (LMWD) | Parameter | Value (pre-infusion), mean ± SD | Value (post-infusion), mean ± SD | Increase, mean ± SD | | RBC, ×10 12 | 4.1 ± 0.8 | 4.9 ± 0.4 | 0.7 ± 0.4* | | HGB, g/l | 93.6 ± 20.6 | 127.6 ± 10.8 | 33.1 ± 11.1* | | MCV, fl | 73.4 ± 8.6 | 81.4 ± 7.6 | 6.8 ± 1.9* | | Ret-He, pg | 18.8 ± 4.5 | 29.8 ± 2.3 | 9.48 ± 2.7* | | Parameter | Value (pre-infusion), median [IQR] | Value (post-infusion), median [IQR] | Increase | | Reticulocyte count (%) | 0.8 [0.7–0.9] | 2.0 [1.3–3.0] | 0.9* | | Ferritin, µg/L | 5.5 [4.4–6.9] | 123.7 [80.1–180.0] | 117.8* | | TSAT, % | 4.9 [3.8–8.5] | 39.5 [34.7–44.2] | 22.4* | *p-value: <0.05 RBC – red blood cells HGB – hemoglobin MCV – mean corpuscular volume Ret-He – reticulocyte hemoglobin equivalent TSAT – transferrin saturation level IQR – interquartile range SD – standard deviation 3.4. Safety of intravenous iron Safety of IIM and LMWD was assessed for the entire sample size (n = 72) and separately in each group. The majority of patients (94.4%) experienced no AEs, while 4 patients (5.6%) in the overall cohort reported mild transient AEs. In the IIM group (n = 50), 3 patients (6.0%) experienced AEs. One patient experienced heart palpitations, another developed subfebrile temperature, and the third reported chest discomfort and cough. IV iron infusions were temporarily stopped for all three patients, however, none of the patients in this study required permanent discontinuation of the infusion, as all reported AEs resolved within the 15–20 minutes observation period, allowing the total dose to be successfully re-administered. In the LMWD group (n=22), only one patient (4.5%) experienced a mild AE – urticaria on the arm. The infusion was temporarily stopped, and treatment with dexamethasone, clemastine, and crystalloids was administered. After treatment, the total cumulative iron dose was re-administered successfully. All AEs were mild, and no severe hypersensitivity reactions were observed. [1]¿p1 [1]¿m1 3.5. Safety and efficacy comparison of iron isomaltoside (IIM) and low molecular weight dextran (LWMD) The early hematological response, including Ret-He and reticulocyte count (%), showed significant improvements in both groups, with no notable difference between IIM and LMWD. The late hematological response, assessed 4–6 weeks post-infusion, demonstrated statistically significant increase in hemoglobin, serum ferritin, MCV, and TSAT in both groups, again with no significant differences between the two. All comparisons of changes in hematological parameters between the two formulations are shown in Table 5. When monitoring AEs associated with IV formulations, no statistically significant difference in frequency was found between the two groups (p = 1.00). No serious AEs were observed in any participants. TABLE 5 Comparison of hematological parameter increases between IV iron formulations (IIM vs. LMWD) | Parameter | Increase (IIM group), mean ± SD | Increase (LMWD group), mean ± SD | p-value | | RBC, ×10 12 | 0.5 ± 0.4 | 0.7 ± 0.4 | 0.495 | | HGB, g/l | 32.4 ± 8.6 | 33.1 ± 11.1 | 0.912 | | MCV, fl | 9.1 ± 3.1 | 6.8 ± 1.9 | 0.673 | | Ret-He, pg | 10.5 ± 2.1 | 9.5 ± 2.7 | 0.833 | | Parameter | Increase (IIM group), median | Increase (LMWD group), median | p-value | | Reticulocyte count (%) | 1.5 | 0.9 | 0.407 | | Ferritin, µg/L | 71.4 | 117.8 | 0.316 | | TSAT, % | 18.0 | 22.4 | 0.106 | [1]¿p1 [1]¿m1 IIM – iron isomaltoside LMWD – low molecular weight dextran RBC – red blood cells HGB – hemoglobin MCV – mean corpuscular volume; Ret-He – reticulocyte hemoglobin equivalent TSAT – transferrin saturation level SD – standard deviation 3.6. Focus on heavy menstrual bleeding Data from paediatric females with menorrhagia treated with IV iron were analyzed separately. A total of 23 IV infusions with LMWD (36%) and IIM (64%) were administered to 14 patients with iron deficiency of menorrhagic origin with or without anemia. Thirty six percent (36%) of patients, with a mean age of 14.4 ± 1.9 years, had moderate to severe anemia. The median dose was 800 mg [IQR 500-1000]. Fifty seven percent of patients (57%) received one dose, while 43% received two to three doses. Hematological responses to the two IV iron formulations were comparable. Compared with baseline mean pre-infusion hemoglobin content of reticulocytes of 21.4 ± 7.3 pg, a significant increase was observed at 3–7 days post-infusion (29.8 ± 1.9 pg, p<0.05). Furthermore, a significant increase in HGB and serum ferritin was observed at 4–6 weeks post-infusion 99.2 ± 26.8 vs. 128.9 ± 19.4 g/L, p<0.05 and 7.6 [IQR 3.3-16.0] vs. 135.6 µg/L [IQR 75.0-157.1], p<0.05 respectively (Table 6). Thirteen patients (93%) did not experience any AEs, while one patient (7%) reported a mild AE. No severe hypersensitivity reactions were recorded. TABLE 6 Hematological response to IV iron (LMWD and IIM) in patients with iron deficiency of menorrhagic origin, with or without anemia (n = 14) | Parameter | Value (pre-infusion), mean ± SD | Value (post-infusion), mean ± SD | Increase, mean ± SD | | RBC, ×10 12 | 4.3 ± 1.0 | 4.5 ± 0.5 | 0.4 ± 0.8 | | HGB, g/l | 99.2 ± 26.8 | 128.9 ± 19.4 | 29.3 ± 19.6* | | MCV, fl | 78.4 ± 11.7 | 86.8 ± 4.3 | 6.8 ± 6.1* | | Ret-He, pg | 21.4 ± 7.3 | 29.8 ± 2.0 | 7.9 ± 5.9* | | Parameter | Value (pre-infusion), median [IQR] | Value (post-infusion), median [IQR] | Increase | | Reticulocyte count (%) | 0.9 [0.7–1.2] | 4.7 [2.7–5.4] | 3.9 | | Ferritin, µg/L | 7.6 [3.3–16.1] | 135.6 [75.0–157.1] | 124.6* | *p-value: <0.05 RBC – red blood cells HGB – hemoglobin MCV – mean corpuscular volume Ret-He – reticulocyte hemoglobin equivalent SD – standard deviation IQR – interquartile range 4 DISCUSSION Our study provides a comprehensive evaluation of the efficacy and safety of two IV iron formulations—iron isomaltoside (IIM) and low molecular weight dextran (LMWD)—in a pediatric population with ID and IDA. The results highlight comparable hematological responses between the two formulations, with no significant differences in efficacy or safety outcomes. Our findings align with and expand upon previously published data on pediatric IV iron use. A substantial body of evidence supports the use of IV iron in adults, however data on safety and efficacy of IV iron in the pediatric population remain limited. Due to these concerns, IV iron therapy has been underutilized in children. First-generation IV iron formulations, such as high molecular weight iron dextran, were associated with severe hypersensitivity reactions. However, newer IV iron formulations, including low molecular weight dextran (LMWD), iron sucrose, ferric carboxymaltose (FCM), and iron isomaltoside (IIM), offer improved safety profiles and are increasingly being considered for pediatric patients. [13,14] A 2011 study by Crary et al. analyzed 38 pediatric patients (median age: 5 years, range: 3 months–18 years) treated with iron sucrose (IS). The median total dose was 100 mg, administered over a median of three doses, with a hemoglobin increase of 19–31 g/L. AEs were rare (1.2%), with only one serious AE reported.[14] This study, along with others, supports the safety of IS in children. A recent study from Boucher et al. (2021) evaluated 191 pediatric patients (mean age: 11.5 years, range: 7 months–21 years) treated with LMWD. The mean total dose was 657 mg (maximum 1000 mg), and 78% of patients received a single dose. The mean hemoglobin increase was 20 g/L, AEs occurred in 4.7% of cases, with 67% of these were observed during test dosing.[8] Based on the U. S. Food and Drug Administration (FDA) recommendations, LMWD is approved for children older than 4 months.[8] In comparison to our study, the mean hemoglobin increase in the LMWD group was 33.1 g/L, exceeding the 20.0 g/L increase reported by Boucher et al. Meanwhile, median ferritin levels increased similarly in both studies (117.8 µg/L in our study vs. 114.0 µg/L in Boucher et al.). A retrospective study by Hassan et al. (2017) examined 72 pediatric patients (median age: 13.7 years, range: 9 months–18 years) treated with FCM. The median dose was 750 mg, with 46% of patients receiving a single dose and 50% receiving two doses. Mean pre-infusion hemoglobin levels were 91 g/L, increasing to 123 g/L post-infusion. The AE rate was 9.7% (7 cases).[15] In 2022, the U. S. Food and Drug Administration (FDA) approved FCM for use in children older than 1 year, while the European Medicines Agency (EMA) recommends use in patients aged ≥14 years.[10] Additionally, a 2017 study by Powers et al. analyzed 54 pediatric patients receiving FCM. The mean age was 141 ± 70 months (range: 1 month–19 years), and the mean dose was 10 mg/kg. Pre-infusion hemoglobin levels averaged 92 g/L, rising to 118 g/L post-infusion. The AE rate was 9.2% (5 cases).[16] A case series study published in 2013 by Plummer et al. examined the efficacy of LMWD in 31 pediatric patients.[17] Among them, 24 patients (24/31) were eligible for efficacy evaluation. The median hemoglobin increase was 35 g/l in the nutritional IDA group, 19 g/l in the chronic blood loss IDA group, and 18 g/l in mixed etiology IDA group. In the same study 9 patients (29%) experienced mild AEs. Efficacy rates were comparable to those in our study, with a slightly lower hemoglobin increase observed in iron deficiency due to menorrhagia, 33 g/l and 29 g/l, respectively. However, safety outcomes differed, as our study reported a lower AE rate (4.5%; n = 3) compared to 29% in Plummer et al. In our study, we evaluated the efficacy and safety of off-label IIM in children younger than 18 years. Unlike LMWD, iron isomaltoside (IIM) has no prior published pediatric data, making this study the first to evaluate its efficacy and safety in children. IIM is widely used in adults for treating IDA, particularly in cases where rapid iron repletion is necessary. While no direct pediatric comparisons exist, our study demonstrated that IIM resulted in a mean hemoglobin increase of 32.4 g/L, a ferritin increase of 71.39 µg/L, and a TSAT increase of 18.0%, values that are comparable to adult findings.[18–20] The ongoing phase III pediatric clinical trial for IIM will provide additional data to validate its safety and efficacy in children.[21] Based on our findings, IIM appears to be a promising IV iron formulation for pediatric patients, particularly those requiring rapid iron repletion.[21] All patients in our study achieved complete hematological response after IIM administration. Notably, a highly satisfactory response was also observed in adolescent females with ID/IDA associated with heavy menstrual bleeding. In terms of efficacy and safety, there was no statistically significant difference between the two IV agents, indicating that both IV iron formulations were equally safe and effective. This finding suggests that IV iron therapy for pediatric IDA could be expanded to include IIM, especially given its high response rate and favorable safety profile. Despite providing valuable data on IV iron administration in children, this study has limitations. As a single-center, retrospective analysis, patient data were heterogeneous, which limits generalizability. Addiotionally, the small sample size also restricts the ability to draw definitive conclusions regarding the safety and efficacy of IIM. Furthermore, it cannot be confirmed that changes in hematological parameters were solely due to IV iron infusions, as other factors, including underlying etiology and dietary modifications, could have influenced the response. Efficacy was assessed based on variables that may fluctuate due to other conditions, such as serum ferritin levels, which can be affected by inflammation. Nevertheless, our analysis provides evidence for the efficacy and safety of both IIM and LMWD for treating pediatric IDA. The lack of pediatric data on IIM underscores the importance of ongoing phase III trials to establish its safety and efficacy in this population. IIM, when administered in a diverse group of infants, children, and adolescents with ID/IDA, resulted in satisfactory hematological responses and infrequent AE, further supporting its potential role in pediatric iron deficiency management. CONFLICT OF INTEREST STATEMENT The authors declare they have no conflicts of interest related to this work. ACKNOWLEDGMENTS We sincerely thank the parents for agreeing to contribute to medical research by allowing the publication of generalized data on their children. ETHICS STATEMENT This study received an approval from Lithuania’s Bioethics Committee No. 2022/5-1436-908 prior to any research activities.

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Authors Metrics & Citations Metrics Article Usage 484views 435downloads Citations Download citation Dragūnė Ernesta, Agnė Morkūnaitė, Trakymas Gaudas Benediktas, et al. Pediatric Intravenous Iron Therapy: Evaluating the Safety and Efficacy of Iron Isomaltoside and Low Molecular Weight Dextran. Authorea. 25 March 2025. DOI: https://doi.org/10.22541/au.174291334.48681620/v1 DOI: https://doi.org/10.22541/au.174291334.48681620/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.