Liposomal iron matches conventional iron in anemic children with heart defects, with fewer side effects

Children with certain congenital heart defects who also have mild-to-moderate iron deficiency anemia gained similar hemoglobin improvements from four weeks of liposomal iron as from a conventional iron preparation, according to a randomized, double-blind clinical trial conducted at Cairo University Children’s Hospital in Egypt. The trial, published in the Egyptian Pediatric Association Gazette, also found that the liposomal formulation caused fewer adverse effects, with less constipation and metallic taste reported by the children receiving it.

The study enrolled children aged 6 months to 12 years who were clinically stable and had hemodynamically insignificant acyanotic congenital heart disease — structural heart defects that do not cause cyanosis and do not require anti-failure medication — together with mild-to-moderate iron deficiency anemia. Anemia was defined according to World Health Organization hemoglobin thresholds for age, and iron deficiency was defined as a ferritin level below 30 micrograms per liter and/or transferrin iron saturation below 20 percent. Children with severe anemia, clinical heart failure, prior corrective cardiac surgery, chronic kidney disease, chronic hemolytic anemia, disorders interfering with iron absorption, ongoing blood loss, or a recent blood transfusion were excluded.

A total of 100 eligible patients were recruited during regular follow-up visits at the hospital’s Pediatric Cardiology Outpatient Clinic between January 2025 and April 2025. Sixty-seven participants who met the inclusion criteria were initially included, and after seven patients were excluded because they discontinued supplementation following surgical correction of their cardiac anomalies or were lost to follow-up, the final analysis included 60 children: 34 females (56.7 percent) and 26 males (43.3 percent), with a median age of 12 months. Participants were randomly assigned in a 1:1 ratio using permuted block randomization with sealed envelopes to one of two parallel treatment regimens. One group received oral iron hydroxide polymaltose complex, a conventional iron preparation, at 3 milligrams per kilogram per day; the other received oral liposomal iron at 1 milligram per kilogram per day, a lower dose chosen because of the formulation’s reportedly better bioavailability. Both treatments lasted four weeks, and the study preparations were matched for color and odor and dispensed in identical bottles. Healthcare providers, patients, and the study statistician were blinded to treatment allocation, although the outcome assessor knew which arm each child had been assigned to.

The trial was registered with the Pan African Clinical Trial Registry under number PACTR202501496307274 on January 23, 2025. The primary outcome was the change in hemoglobin level from baseline to the end of the study, with changes in other hematological parameters and iron indices, and the tolerability of the two iron forms, assessed as secondary objectives. At baseline and again after four weeks, the researchers measured a complete blood count — including hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, and red cell distribution width — as well as serum iron, serum ferritin, and total iron-binding capacity. Nutritional and clinical assessments, including appetite and activity observations reported by parents, were also performed.

After four weeks of supplementation, both groups showed statistically significant improvements in hemoglobin, hematocrit, serum iron, serum ferritin, and transferrin saturation compared with their baseline values. However, when the researchers compared the two groups directly, the percentage change in hemoglobin did not differ between them (p = 0.959), and neither did the other hematological and iron indices. To account for the fact that the conventional iron group had started with significantly lower hemoglobin, hematocrit, serum iron, and transferrin saturation, the investigators used analysis of covariance. After adjusting for baseline differences, the covariate-adjusted mean hemoglobin was 10.8 grams per deciliter (95 percent confidence interval 10.5 to 11.1) in one group versus 10.7 grams per deciliter (95 percent confidence interval 10.4 to 11.04) in the other, a difference that was not statistically significant (p = 0.137). The conventional iron group showed significant within-group improvements in mean corpuscular volume and mean corpuscular hemoglobin that were not observed in the liposomal group.

One hematological result ran counter to expectations: both groups exhibited a statistically significant increase in red cell distribution width after treatment, whereas a decrease might have been anticipated as anemia resolved. The authors note that previous research has shown red cell distribution width may rise within days of starting iron therapy because of reticulocytosis, remain elevated for up to four weeks, and only subsequently decline, and that normalization may require a longer duration than the trial’s four-week follow-up. By the end of the study, the liposomal iron group showed greater improvement in anemia severity grading (p = 0.05), although the researchers reported no clear superiority of either iron form on this measure, and compliance was comparable between the two groups.

The clearest differences between the formulations lay in tolerability and certain clinical observations. A lower incidence of constipation (p = 0.015) and metallic taste (p = 0.007) was reported in the liposomal iron group, and neither group reported nausea, flatulence, diarrhea, dyspepsia, or black or tarry stools. The liposomal group also showed a statistically significant greater improvement in appetite (p = 0.012) and activity level (p < 0.001) compared with the conventional iron group. Improvements in respiratory rate, heart rate, weight, height, and body mass index favored the liposomal group but did not reach statistical significance between groups. The authors caution that the absence of a significant difference in hematological outcomes cannot be interpreted as evidence of equivalence or non-inferiority between the two treatments.

The trial also documented the nutritional context of anemia in this population. Predisposing factors for anemia in the cohort included lack of iron supplementation in all patients, poor intake of iron-rich foods in 93.3 percent, a history of hospital admissions in 58.3 percent, prior surgeries in 21.7 percent, food allergy and parasitic infestations in 13.3 percent each, and recurrent blood loss such as recurrent epistaxis in 5 percent. Nutritional assessment revealed that 33.3 percent of the children had been exclusively breastfed, 20 percent formula-fed, and 46.7 percent mixed-fed; only 3.3 percent followed optimal weaning practices that included all essential dietary components. The authors suggest that suboptimal weaning practices and malnutrition may represent important predisposing factors for anemia in this group. In a multiple regression model of post-treatment hemoglobin levels, older age was associated with higher hemoglobin (p = 0.033), while lesion type, body mass index, and iron intake did not contribute significantly.

The findings arrive against a broader clinical backdrop in which iron deficiency anemia is common among children with congenital heart disease and has been linked to increased morbidity and mortality, with anemia capable of causing and exacerbating heart failure in patients with acyanotic congenital heart disease. Congenital heart disease is the most common major congenital malformation, with a global prevalence of 27.8 per 10,000 births, and a higher prevalence of iron deficiency anemia has been observed among children with congenital heart disease than in the general pediatric population. Liposomal iron, typically ferric pyrophosphate enclosed within a phospholipid bilayer, is thought to be absorbed partly through uptake of the intact liposome, which can improve bioavailability and reduce gastrointestinal irritation because very little free iron is exposed to the intestinal lumen. Iron hydroxide polymaltose, by contrast, mimics the structure of ferritin and releases iron gradually, tending to cause less oxidative stress and fewer gastrointestinal adverse effects than ferrous salts but with slower and somewhat less efficient absorption.

The authors outline several limitations. The inclusion mainly of children with hemodynamically insignificant cardiac lesions means the findings cannot be generalized to patients with significant congenital heart disease, cyanotic heart disease, or heart failure. The relatively small number of patients and the short four-week follow-up period, along with the absence of investigations such as reticulocyte count, serum transferrin receptor, and inflammatory markers, constrained the interpretation of the hematological data, so the study primarily evaluated short-term effects and tolerability rather than long-term outcomes. The researchers also note that liposomal iron does not yet have a universally accepted pediatric guideline dose from major bodies such as the World Health Organization, the American Academy of Pediatrics, ESPGHAN, or the American Society of Hematology, so the potential influence of the dose difference between the two arms cannot be excluded. Incomplete blinding — because the outcome assessor knew the allocations — and the subjective nature of some patient-reported outcomes, such as appetite, activity, and compliance, may have introduced bias. The authors conclude that larger randomized trials are needed to confirm the efficacy of liposomal iron in pediatric iron deficiency anemia, and that fewer adverse effects with liposomal iron may contribute to possibly better long-term compliance in this vulnerable group.

Subject of Research: A randomized controlled trial comparing liposomal iron with iron hydroxide polymaltose for treating iron deficiency anemia in children with acyanotic congenital heart disease

Article Title: Is liposomal iron superior in treating anemic children with congenital acyanotic heart diseases? A randomized controlled clinical trial

Article References: Aboudeif, M. O., Mostafa, F. A., El Koofy, N., Al Komy, M., Sakr, S. K. A. S., & Sedkey, M. A. (2026). Is liposomal iron superior in treating anemic children with congenital acyanotic heart diseases? A randomized controlled clinical trial. Egyptian Pediatric Association Gazette, 74(1), Article 131. https://doi.org/10.1186/s43054-026-00633-1

Image Credits: AI Generated

DOI: 10.1186/s43054-026-00633-1

Keywords: liposomal iron, iron deficiency anemia, congenital heart disease, pediatrics, randomized controlled trial, hemoglobin, iron hydroxide polymaltose, drug tolerability, Cairo University, acyanotic heart disease, iron supplementation, adverse effects