Iron plays an important role in neurodevelopmental functions in the brain. Serum ferritin levels are different in children with attention deficit hyperactivity disorder and tic disorder than in healthy children.

To explore the current status of iron deficiency in children with neurodevelopmental disorders and its sex and age effects.

A total of 1565 children with attention deficit hyperactivity disorder (ADHD), 1694 children with tic disorder (TD), 93 children with ASD and 1997 healthy control children were included between January 1, 2020, and December 31, 2021 at Beijing Children's Hospital. We describe the differences in age levels and ferritin levels between different disease groups and their sex differences. The differences between the sexes in each disease were analyzed using the t test. The incidence rate of low serum ferritin was used to describe the differences between different diseases and different age groups. A chi-square test was used to analyze the difference in the incidence of low serum ferritin between the disease group and the control group. Analysis of variance was used for comparisons between subgroups, and regression analysis was used for confounding factor control.

A total of 1565 ADHD patients aged 5-12 years were included in this study, and the average serum ferritin levels of male and female children were 36.82 ± 20.64 μg/L and 35.64 ± 18.56 μg/L, respectively. A total of 1694 TD patients aged 5-12 years were included in this study, and the average serum ferritin levels of male and female children were 35.72 ± 20.15 μg/L and 34.54 ± 22.12 μg/L, respectively. As age increased, the incidence of low serum ferritin in ADHD and TD first decreased and then increased, and 10 years old was the turning point of rising levels. The incidence of ADHD with low serum ferritin was 8.37%, the incidence of TD with low serum ferritin was 11.04%, and the incidence of the healthy control group with low serum ferritin was 8.61%, among which male children with TD accounted for 9.25% and female children with TD accounted for 11.62%. There was a significant difference among the three groups (P < 0.05). In addition, there were 93 children with ASD with an average serum ferritin level of 30.99 ± 18.11 μg/L and a serum ferritin incidence of 15.05%.

In conclusion, low serum ferritin is not a risk factor for ADHD or TD. The incidence of low serum ferritin levels in children with ADHD and TD between 5 and 12 years old decreases first and then increases with age.

Iron deficiency in early childhood can lead to developmental abnormalities in gene expression, neurotransmitter function, neurometabolism and other aspects related to brain development, which in turn affects children’s sensorimotor functions, growth and development, cognitive language, social emotions, the development of learning and memory, and so on[1]. Iron deficiency can also lead to a decrease in iron content in the brain, which can cause central nervous system dysfunction and ultimately lead to neuropsychiatric symptoms[2]. Iron participates in several basic biochemical functions in the brain, is a cofactor for many metabolic processes and material synthesis and has important effects on neurodevelopmental functions such as myelination, transmitter transmission, and gene expression[3].

Notably, it has been reported that iron deficiency in children is associated with neurodevelopmental diseases, leading to abnormalities in growth and development, learning behavior, motor function, social emotion, intellectual development, cognitive ability, language function, sleep cycle, etc.[4-6]. Ferritin is an objective and sensitive indicator for the investigation and study of iron deficiency because serum ferritin is an important iron storage protein that is crucial for iron homeostasis and participates in a variety of physiological and pathological processes. Serum ferritin is one of the most reliable and widely used markers of iron storage status in the body[7]. The variability of serum ferritin levels is lower than that of serum iron levels, and when iron reserves are depleted, the decline of serum ferritin precedes the decline of serum iron[8].

Neurodevelopmental outcomes include attention deficit disorder hyperactivity (ADHD), tic disorders (TD) and autism spectrum disorders (ASD). The incidence of neurodevelopmental disorders in children is also increasing year by year[8]. The following will introduce iron deficiency-related research on these three diseases. First, a study of ADHD confirmed that the serum ferritin level of children with ADHD was significantly lower than that of the control group[9]. Mahmoud et al studied 58 untreated children with ADHD and found that the serum ferritin level of children with ADHD was significantly lower than that of the control group[10]. There are also studies on the serum ferritin level and the Conners Parental Rating Scale (CPRS) total score. There is a significant negative correlation between serum ferritin levels and scores on the Conners Teacher Rating Scale (CTRS)[11,12]. This suggests that iron deficiency may indicate more severe ADHD symptoms. It should be emphasized that iron supplementation can also improve ADHD symptoms[13,14]. Studies have also found that iron supplementation is related to the increase in serum ferritin levels and the parallel reduction in the severity of ADHD symptoms assessed by the parents' Conners score[15]. Second, studies on TD have shown that children and adults with mature Tourette syndrome have reduced serum ferritin[3]. A large-scale epidemiological study showed that children with iron deficiency anemia are at increased risk of tic disorder, iron storage status may be related to children’s tics, and low ferritin levels may be the result of pediatric tic risk factors for the development of the disease or predictors of the severity of tics in children[16]. A study of 107 children and adults found that ferritin levels were significantly reduced. Compared with the control group, the caudate nucleus and putamen nucleus of TS patients were larger[17]. Lower iron reserves may help to reduce the size of the caudate and putamen nuclei, thereby increasing the susceptibility to tics[18]. Third, research on ASD has shown that anemia diagnosed earlier in pregnancy was associated with an increased risk of the development of ASD, ADHD, and particularly ID in offspring[19]. In a study that investigated iron levels in ASD patients aged 19 mo to 13 years, 52% of ASD children developed ID[20]. Another study showed that 8.3% of autistic children aged 1 to 2 years, 14.2% of autistic children aged 3 to 5 years, and 20% of autistic children aged 6 to 10 years had below-normal serum ferritin levels[21]. Other studies have shown that children with ASD have significantly lower serum hemoglobin, hematocrit, iron, and mean corpuscular volume levels than healthy children, but these are not enough to cause anemia[22]. However, meta-analyses have shown that the available evidence is inconsistent with regard to whether iron levels are lower in children with ASD[23].

There is a lack of cohort studies on the status of iron deficiency and iron supplementation in children with ADHD, TD and ASD among Chinese children and adolescents. The sex and age effects of iron deficiency and the critical period of iron supplementation are unclear. In conclusion, the level of iron deficiency in neurodevelopmental disorders of ADHD, TD and ASD and the status of sex-age effects are still unclear, and data from Chinese samples are lacking. This study will adopt the thinking of retrospective research and investigation by enrolling ADHD, TD and ASD children in the psychiatric department of Beijing Children's Hospital as the sample. The sample size is large, and more attention can be paid to the comparison of the difference in serum ferritin levels of ADHD, TD and ASD children with respect to gender and age than previous studies. This study will explore the current status of iron deficiency in children with neurodevelopmental disorders and its influence on sex and age, providing an important reference for the correlation between neurodevelopmental disorders and ferritin and necessary iron supplementation.

This study mainly explores the level of ferritin in children with ADHD and TD and its effects on sex and age. This study is currently the largest sample size study in China to explore ADHD and TD iron deficiency. This study shows that serum ferritin levels are significantly correlated with sex, age and disease type, which is inconsistent with most previous research results on ADHD and TD ferritin levels at home and abroad[9,12,24]. This may be due to the further research results obtained on the basis of fully controlling confounding factors by using more scientific statistical methods. The results showed that the incidence of ADHD with low serum ferritin was 8.37%, and the incidence of TD with low serum ferritin was 11.04%. The incidence of low serum ferritin in ASD was 15.05%, but low serum ferritin was not a risk factor for ADHD or TD. The results are consistent with previous studies[25-27]. At the same time, we reported ferritin levels of children of different ages and sexes, which can provide an important reference for follow-up studies of iron deficiency in children with ADHD and TD.

The results of this study show that the incidence of low serum ferritin deficiency in children 5-12 years old with ADHD is 8.37%, and the incidence of low serum ferritin deficiency in children 5-12 years old with TD is 11.04%, which is related to the normal control group. This is lower than the results of similar studies at home and abroad[12,28]. Low serum ferritin was not a risk factor for ADHD or TD. The possible reason is that the reference value ranges used in different studies are different. This study uses the World Health Organization guidelines and expert consensus on the diagnosis and treatment of iron deficiency in China. The reference value limit is 15 μg/L[29], and the reference value range used in domestic studies on ADHD serum ferritin is 24 μg/L or 30 μg/L[25,27]. In related foreign studies, the limit of ADHD serum ferritin is set higher[12]. Thus, when the cutoff value of serum ferritin levels in children with ADHD is different, the incidence of low serum ferritin deficiency is also different. This highlights the lack of ferritin norms in children with ADHD. Therefore, in future studies, it is necessary to establish serum ferritin standards based on Chinese ADHD samples to provide a more detailed and substantial basis and recommendations for the supplementation of ferritin in children with ADHD.

The results of this study showed that ferritin levels were different at different ages of ADHD and TD, and the incidence of low serum ferritin levels in children with ADHD and TD between 5 and 12 years old decreases first and then increases with age. Ten years old is the turning point. Generally, the age range of 5-10 years old is a period of high incidence for ADHD and TD visits, as well as a period of high incidence of iron deficiency. This suggests that the relationship between iron deficiency and ADHD and TD still needs to be further explored. Although there are many qualitative studies on the relationship between the two[12], there are few studies on the levels of serum ferritin in different age groups. Therefore, based on this research, this study recommends that at the age of 5-10 years, special attention should be given to the assessment of serum ferritin levels in children with ADHD and TD. It is necessary to pay attention to differences in different age groups and determine whether it is possible to establish reference intervals for different age groups of ADHD and TD based on different serum ferritin levels to facilitate more sensitive detection of these levels and timely supplementation. Achieving the greatest improvement in ADHD and TD symptoms will be an important research direction for future ADHD and TD ferritin deficiency investigations and follow-up interventions.

The etiological and physiological mechanisms of ADHD and TD caused by iron deficiency are as follows: First, this metal plays an active role in the anabolism of neurotransmitters, the activity of dopamine D2 receptors, and the concentration of basal ganglia (especially the Globus pallidus). Iron is a cofactor of enzymes necessary for the synthesis and catabolism of monoaminergic neurotransmitters[12,30]. Monoamine neurotransmitters mainly include epinephrine and norepinephrine, 5-hydroxytryptamine, and dopamine. Dopamine neurotransmitters act on the prefrontal lobe and striatum, and dysfunction of the prefrontal striatum plays an important role in the pathogenesis of ADHD. Iron deficiency is related to a decrease in dopamine transporter expression[18], the gene of dopamine transporter is related to the genetic susceptibility of ADHD[31]. Second, iron is a part of neuron development, myelination, DNA synthesis/repair and phospholipid metabolism[1], which is the basis for the neurodevelopmental disease ADHD in children. Third, iron deficiency leads to residual structural defects and the neurological function-related gene imbalance hypothesis[6]. Early nutrient intake (such as malnutrition) during the critical period of life will lead to abnormal structural development, ranging from overall structural abnormalities to fine ultrastructural changes. Therefore, in future research, we need to further explore the inner link between iron deficiency and the occurrence of ADHD symptoms and provide a new perspective for the exploration of the pathophysiological mechanism of ADHD and TD[32].

Future research directions of ADHD and TD iron deficiency are discussed in the following. After combining ADHD and TD ferritin research, ADHD and TD iron deficiency research can be carried out from the following three aspects in the future. First, the sensitivity index and cutoff value of ADHD and TD iron deficiency, or the establishment of a cutoff value of serum ferritin levels in different age groups, can be used to formulate specific guidelines for screening and appropriate iron supplementation. Second, most studies evaluating iron status in ADHD and TD are based on measurements of serum ferritin levels, but there is no strong evidence that serum ferritin is a highly reliable marker of brain iron. Brain iron affects nerve function and white matter myelination. The degree of correlation between serum ferritin and brain iron levels is unclear[29,33]. Therefore, in addition to evaluating the surrounding iron markers, the evaluation of brain iron levels is essential to determine the possible role of iron deficiency in the pathophysiology of ADHD and TD. Third, regarding whether iron supplementation can alleviate the symptoms of ADHD, related research results are inconsistent, and some studies have shown that iron supplementation can improve ADHD and TD[13]. Studies have also found that iron supplementation is related to the increase in serum ferritin levels and the parallel reduction in the severity of ADHD and TD symptoms as assessed by the parents' Conner’s score[15]. These aspects need to be validated further. Therefore, future investigations should include iron-supplemented ADHD and TD cohort studies to provide a new perspective for ADHD and TD intervention research. In terms of iron supplementation, the course, safety and compliance of iron supplementation are also very important references[32,33].

The advantage of our research lies in the extraction of large samples of data. At the same time, the average serum ferritin levels of children with ADHD and TD at 5-12 years of age were analyzed, which is a measure of the serum ferritin levels of children with ADHD and TD at different ages. These measurements can provide a reference for iron supplementation. Some limitations of our study need to be pointed out. First, neurodevelopmental disorders were studied in outpatient cases, and only individuals who used medical resources to seek psychiatric care were identified. Our sampling method involves convenience sampling. There may be some selection bias in the sample; however, the patients included in our study were diagnosed by professional psychiatrists, and the diagnoses were more reliable than self-reported diagnoses. Second, serum ferritin concentrations may be related to inappropriate dietary habits, and the link between neurodevelopmental disorders and altered dietary patterns remains unclear. Third, we did not have personal information that would help us understand patients' risk of mental disorders, such as environmental factors (long-term life stress, traumatic experiences) and a family history of mental disorders. Fourth, our study cannot prove a causal relationship between low serum ferritin and neurodevelopmental disease, although our results suggest a significant association between neurodevelopmental disease and serum ferritin.

Neurodevelopmental disorders (ADHD, TD and ASD) are heterogeneous diseases. The relationship between ADHD and TD and serum ferritin needs further exploration. We found that the incidence of low serum ferritin levels in children with ADHD and TD between 5-12 years old was 8.37% and 11.04%, respectively. The incidence of ASD with low serum ferritin was 15.05%. It is recommended to routinely check the serum ferritin levels and related hematological indicators of children with ADHD, TD and ASD and to perform necessary iron supplementation. In particular, children with ADHD and TD aged 5-10 years were diagnosed. In the future, we need to conduct cohort studies to further consolidate the evidence of iron deficiency in children with ADHD, TD and ASD and carry out necessary iron intervention studies to explore the underlying mechanisms.