The effect of iron supplementation on growth and development in children with thalassemia complicated with iron deficiency anemia
Bowen Feng1, Jing Wang1, Yuwei Shan1, Liqiong Zhu1, Dandan Hu*, Caiyun He2
1 Department of Children Healthcare，Guangzhou medical university affiliated women and children medical center，guangzhou, China.
2 Department of cardiology, the first affiliated hospital of guangzhou medical university
guangzhou, China.
* Children Healthcare，Guangzhou medical university affiliated women and children medical center，guangzhou,China.
*Corresponding author. Email: fengbowen880117@126.com
Dandan Hu and Caiyun He contributed equally to this work as corresponding authors and conceived the study.
Abstract: Objective: To investigate the impact of iron supplementation on the growth and development of children with thalassemia combined with iron deficiency anemia. Methods: A total of 38 children with thalassemia combined with iron deficiency anemia who visited the pediatric health care department of our hospital from August 2023 to December 2024 were selected as the observation group, and 38 children with simple iron deficiency anemia (IDA) treated during the same period were selected as the control group. Both groups were treated with iron dextran oral solution, vitamin C, and dietary supplementation. Blood routine, serum iron, and serum ferritin levels were monitored before treatment and at 1 month, 3 months, and 6 months after treatment, and changes in growth and development were observed. Results: There were no significant differences in blood routine indicators, serum iron, and serum ferritin levels, as well as growth and development status between the two groups before treatment (P>0.05). After treatment, blood routine indicators and growth and development in both groups were significantly improved (P<0.05). At 1 month, 3 months, and 6 months after treatment, there were significant differences in hemoglobin (HB) between the two groups (P<0.05). In addition, the serum iron and serum ferritin levels in the observation group were higher than those in the control group at 1 month, 3 months, and 6 months after treatment, with statistically significant differences (P<0.05). Conclusion: Both children with thalassemia combined with iron deficiency anemia and those with simple iron deficiency anemia showed significant improvements in blood indicators and growth and development after iron supplementation, but the former were more sensitive to iron supplementation, and the changes in growth and development were more significant.
Keywords: Mediterranean anemia; iron-deficiency anemia; Iron supplementation therapy; Growth and development
Thalassemia, also known as Mediterranean anemia, is primarily classified into two types: α-thalassemia and β-thalassemia. The etiology involves mutations or deletions in the α or β globin genes, leading to insufficient or absent synthesis of α or β globin chains, which in turn causes hemolytic anemia. This disease has a higher incidence in regions such as the Mediterranean, Southeast Asia, and India, and is also relatively common in southern China, including Guangxi, Guangdong, and Hainan [1]. Iron deficiency anemia (IDA) is caused by insufficient iron intake, absorption disorders, or excessive loss. Both thalassemia and IDA clinically manifest as microcytic hypochromic anemia [2].
The degree of iron deficiency varies among different types of thalassemia, with α+ thalassemia (70.59%) being the most prone to iron deficiency, followed by α0 thalassemia (39.62%). Research by CHANG-KINGLIN et al. [3] indicates that approximately 31% of patients with mild thalassemia have iron deficiency. Compared to thalassemia patients without iron deficiency, these patients have lower red blood cell counts, hemoglobin (HB) levels, and ferritin levels. For mild thalassemia patients with hemoglobin concentrations below 11.5 g/L, it is recommended to concurrently check iron metabolism indicators, with sensitivity and specificity of 79.8% and 82.6%, respectively. Therefore, the state of thalassemia combined with iron deficiency should be taken seriously. A cohort study in Sri Lanka showed that iron deficiency anemia (IDA) accounts for only half of the cases of microcytic anemia in children, with 25% having thalassemia traits and 9% having both IDA and thalassemia (α or β thalassemia) [4]. When thalassemia coexists with IDA, the incidence of anemia increases, and the severity of anemia worsens [5]. Iron plays a crucial role in cellular metabolism, participating in oxygen transport and utilization, ATP generation, DNA synthesis, catecholamine metabolism, and mitochondrial electron transport. If iron is not supplemented in time, IDA can affect the patient’s immune system, nervous system, and growth and development. Literature indicates [6] that mild thalassemia usually does not require blood transfusion and generally does not result in iron overload, while patients with pure IDA need active iron supplementation. Oral iron supplementation every other day can improve iron absorption, reduce serum hepcidin levels, thereby increasing hemoglobin levels and reducing gastrointestinal side effects [7].
Non-transfusion-dependent intermediate thalassemia is often accompanied by iron deficiency anemia (IDA), primarily due to the high iron demand during the patient’s growth and development period, coupled with low-iron diets and insufficient iron intake leading to iron deficiency. Additionally, chronic hemolysis causes compensatory bone marrow hyperplasia, increasing the demand for hematopoietic raw materials, further exacerbating iron deficiency and resulting in hemoglobin levels below normal. Therefore, for patients with thalassemia accompanied by IDA, it is recommended to monitor ferritin levels in real-time during iron supplementation treatment to prevent iron overload and improve treatment safety. Previous studies have shown that timely iron supplementation can promote the growth and development of patients with iron deficiency anemia, but the impact of thalassemia combined with iron deficiency anemia on growth and development still requires further research [4,8,9,13].
This study conducted iron supplementation treatment on 38 children with thalassemia accompanied by iron deficiency and children with pure iron deficiency anemia, while monitoring their blood routine and hemoglobin levels, as well as their growth and development indicators. The results are reported as follows.
1、Materials and Methods
1.1 Clinical Data
The study selected 38 children with IDA accompanied by non-transfusion-dependent thalassemia and 38 children with simple IDA treated during the same period in the pediatric health care department of our hospital from August 2023 to December 2024 as research subjects. The diagnostic criteria for anemia are as follows: the diagnosis of thalassemia refers to the diagnostic and efficacy standards for hematological diseases; the diagnosis of iron deficiency anemia refers to relevant domestic standards, specifically including: (1) hypochromic microcytic anemia, i.e., hemoglobin <110g/L, mean corpuscular volume (MCV) <80fL, mean corpuscular hemoglobin (MCH) <27pg, mean corpuscular hemoglobin concentration (MCHC) <320g/L; (2) clinical manifestations and etiology of iron deficiency; (3) serum ferritin <15μg/L. The screening conditions for the simple IDA control group were: no α or β thalassemia detected by genetic diagnosis, no hemoglobin variants detected by capillary electrophoresis screening, serum ferritin (SF) <15μg/L, and confirmed as IDA without iron supplementation treatment.
Exclusion criteria included: children with other hematological diseases with a history of transfusion therapy; children with hematological diseases caused by various infectious diseases; children with comorbid immune diseases; children with a history of drug allergies.
1.2 Methods
Both groups of children were diagnosed by pediatricians and guided for iron supplementation therapy. The treatment regimen was as follows: oral administration of iron dextran at a dose of 5 mg/kg/day, with the treatment duration adjusted according to the condition. During the treatment period, while ensuring a balanced diet, the children were supplemented with iron-rich foods and vitamin C to promote iron absorption. It was recommended that the families maintain a balanced diet for the children, and if possible, increase the intake of foods rich in iron and vitamin C (adding fruit puree as early as possible after 6 months of age). After 3 months of treatment, iron supplementation was enhanced by increasing the intake of iron-rich foods such as beef, egg yolk, lean meat, and pork liver.
1.3 Observation
Two groups of children were subjected to venous blood collection using vacuum blood collection tubes, with 2 ml of blood drawn and anticoagulated. The samples were immediately gently inverted and mixed for complete blood count testing. The remaining samples were centrifuged at 3000 r/min for 10 minutes to collect plasma for ferritin testing. Simultaneously, the following parameters were monitored: hemoglobin (HB), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), serum iron, serum ferritin (SF), height (cm), and weight (kg).
1.4 Statistical Methods
The data obtained in this study were statistically analyzed using the SPSS24.0 software package. Measurement data were expressed as (x±s), and intergroup comparisons were performed using t-tests. The test standard was α = 0.05, and P < α was considered statistically significant.
2、Results
The observation group (IDA with thalassemia) consisted of 20 male and 18 female children, aged from 6 months to 2 years, with a mean age of 1.19±0.45years, a mean height of 73.93±6.02 cm, and a mean weight of 9.06±1.73kg. The control group (simple IDA) included 21 male and 17 female children, aged from 6 months to 2 years, with a mean age of 1.18±0.44 years, a mean height of 74.08±6.08 cm, and a mean weight of 9.08±1.69 kg. There were no significant differences in the general clinical data between the two groups (P > 0.05), indicating balanced and comparable grouping.
There were significant differences in HB between the two groups of children at 1m, 2m, and 6m after treatment (P<0.05), as shown in Table 1.
Table 1 Comparison of blood routine indicators before and after treatment in the two groups of children (x ±s)
| observation indicators | observation group（n=38） | control group（n=38） | ||||||
| before treatment | after treatment 1m | after treatment 3m | after treatment 6m | before treatment | after treatment 1m | after treatment 3m | after treatment 6m | |
| Hb（g / L） | 96.16±4.18 | 101.92±4.15 ab | 110.58±3.61ab | 120.42±3.04 ab | 96.36±4.44 | 100.84±4.55 a | 108.32±3.60 a | 117.79±2.48 a |
Note: Compared with before treatment, a P<0.05; compared with the control group, b P<0.05.
Comparison of SF between the two groups of children before treatment showed that the serum iron and ferritin levels in the observation group were significantly higher than those in the control group at 1 month, 3 months, and 6 months after treatment, with statistical significance (P < 0.05), as shown in Table 2.
Table 2 Comparison of SF between the two groups of children before and after treatment (x ± s)
| observation indicators | observation group（n=38） | control group（n=38） | ||||||
| before treatment | aftcer treatment 1m | after treatment 3m | after treatment 6m | before treatment | after treatment 1m | after treatment 3m | after treatment 6m | |
| SF（ug / L） | 9.94±1.75 | 14.62±1.48 ab | 21.58±1.80 ab | 28.81±2.16ab | 9.89±1.78 | 13.91±1.37a | 18.91±1.61 a | 25.30±1.63 a |
Note: Compared with before treatment, a P<0.05; compared with the control group, b P<0.05.
The hematological indices and growth development changes of children in both groups at 1 month, 3 months, and 6 months after treatment were significantly improved compared to those before treatment (P<0.05), as shown in Table 3.
Table 3 Comparison of growth development indices before and after treatment in the two groups of children (x ±s)
| observation indicators | observation group（n=38） | control group（n=38） | ||||||
| before treatment | after treatment 3m | after treatment 6m | before treatment | after treatment 3m | after treatment 6m | |||
| height（cm） | 73.93±6.02 | 79.28±5.58ab | 84.72±5.24ab | 74.08±6.08 | 77.90±5.59a | 81.87±5.16a | ||
| weight（kg） | 9.08±1.69 | 9.90±1.171ab | 10.65±1.75ab | 9.06±1.73 | 9.75±1.64 a | 10.43±1.57a | ||
Note: Compared with before treatment, a P<0.05; compared with the control group, b P<0.05.
3 Discussion
Thalassemia is a hemolytic anemia caused by autosomal dominant inheritance, which is relatively common in China. According to statistics, the incidence of α and β types in thalassemia patients in China is approximately 3.5%-4.6%. Iron deficiency anemia, on the other hand, is caused by insufficient iron intake or inadequate iron storage in the body. Its causes include increased iron demand during growth and development, excessive iron loss, or reduced hemoglobin synthesis. The main contributing factors include congenital insufficient iron storage, inadequate iron intake, impaired iron absorption, increased iron demand, and excessive iron loss [10].
Long-term chronic hemolysis, impaired iron utilization, and repeated blood transfusions can lead to iron overload, damaging the functions of organs such as the heart, liver, and pancreas, ultimately leading to hemochromatosis. A study by Xia Weiyi et al. [11] on serum iron metabolism indicators in 218 thalassemia patients showed that the iron load status of patients is closely related to their genotype, but not all patients have iron overload. Among them, 16.97% of patients exhibited iron overload, 38.99% had concurrent iron deficiency, and the remaining patients had normal iron metabolism indicators. Patients with homozygous β-thalassemia and HBH disease are prone to iron overload due to severe red blood cell destruction, significant hemolysis, and frequent blood transfusions [12]. In contrast, patients with α+, α0 thalassemia, and β+ thalassemia have milder symptoms and fewer blood transfusions, making them more susceptible to iron deficiency under conditions of low iron diet, insufficient iron absorption, and increased iron demand. Iron deficiency anemia is mainly characterized by reduced hemoglobin production. Due to the presence of certain iron reserves in the body, the early clinical manifestation is a decrease in hemoglobin levels, while in the later stages, severe iron deficiency leads to inhibition of bone marrow hematopoiesis, resulting in a decrease in red blood cell count. Therefore, blood tests show a more significant decrease in hemoglobin than in red blood cells. Thalassemia patients have hyperactive bone marrow hematopoiesis, which can compensate for some anemia symptoms in the early stages, with no significant decrease in red blood cell count or hemoglobin levels. However, due to the short lifespan and variability of red blood cells produced in thalassemia, the mean corpuscular volume (MCV) and red cell distribution width (RDW) can sensitively reflect the variability in red blood cell volume. The results of this study indicate that the blood test indicators of children in the iron supplementation treatment group significantly improved compared to before treatment. Among them, children with thalassemia combined with iron deficiency anemia showed more significant changes in hemoglobin and serum ferritin levels and were more sensitive to treatment, a finding consistent with the results of Kong Xianling et al. [13].
Studies have shown that if iron deficiency in children is not corrected in time, it will adversely affect their growth, metabolism, and intellectual development. In severe cases, it can lead to attention deficits, significantly lower learning ability and cognitive function compared to peers, and severe impairment of growth and development [14]. Research has found that children with iron deficiency anemia experience increased plasma ghrelin levels and decreased leptin levels after iron treatment. This change may be the reason for increased appetite and improved growth and development after treatment [15]. Additionally, children with nutritional therapeutic iron deficiency anemia, after iron treatment, experience increased plasma ghrelin levels, decreased leptin levels, and accelerated growth due to enhanced appetite and increased daily calorie, carbohydrate, and protein intake. The reduction in leptin and increase in plasma ghrelin levels may be the reasons for increased appetite and accelerated growth in children with iron deficiency anemia. The most important finding of this study is the significant increase in plasma ghrelin levels after iron treatment, which may be related to improved appetite and catch-up growth [4].
To explore the impact of thalassemia combined with IDA on children’s growth and development, this study included 38 children with thalassemia combined with IDA, provided appropriate iron supplementation treatment, and compared them with children with simple IDA. During the study, blood tests and serum iron metabolism indicators of both groups were closely monitored to prevent iron overload in children with thalassemia combined with IDA during iron supplementation treatment. The results showed no significant difference in growth and development indicators between the two groups before treatment, but children with thalassemia combined with IDA showed more significant improvement in growth and development after treatment. This phenomenon may stem from the following reasons: First, thalassemia is mainly caused by genetic factors, and routine child health screenings often rely on blood tests. Both thalassemia and IDA present as microcytic hypochromic anemia, making it difficult to distinguish between the two through blood tests, leading to the neglect of IDA. Second, parents generally believe that thalassemia does not require iron supplementation treatment, which may lead to iron deficiency, while children with simple IDA usually receive timely iron supplementation treatment. Therefore, children with thalassemia combined with IDA are more sensitive to treatment and show more significant improvement in growth and development after iron supplementation treatment. Research [16] indicates that both thalassemia and IDA can clinically present as microcytic hypochromic anemia. Therefore, during routine thalassemia genetic testing or screening, attention should be paid to changes in body iron levels, and the measurement of iron metabolism indicators should be strengthened to improve the growth and development of thalassemia patients, avoiding adverse effects on height and weight, thereby achieving early detection, early diagnosis, early intervention, and early treatment.
This study has the following limitations: First, it is a single-center study with a relatively limited sample size. Second, the study did not standardize the monitoring of compliance with iron treatment, and poor compliance is a common factor leading to the ineffectiveness of oral iron treatment. Additionally, infections or inflammation may also cause a temporary decrease in hemoglobin levels or affect the efficacy of iron treatment.
The results of the study indicate that children with thalassemia combined with iron deficiency anemia and those with simple iron deficiency anemia both showed significant symptom improvement after iron supplementation treatment. However, children with thalassemia are more sensitive to iron supplementation treatment, so it is necessary to closely monitor blood tests and serum iron metabolism indicators, provide timely iron supplementation treatment, and combine it with a reasonable diet to promote the growth and development of the children.
Funding:
The Funding by Science and Technology Projects in Guangzhou，No. 2023A04J1505 No. 2023A03J0630
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