CP has attracted lots of attention from doctors and parents of patients due to its harms to neurological and motor systems in China. Identification of the potential risk factors for CP susceptibility is helpful for the prevention and treatment of CP. Our meta-analysis showed that CP cases demonstrated significantly lower levels of Cu, Zn, iron and Ca than those in controls, which indicated that the deficiency of Cu/Zn/iron/ Ca may be involved in the risk of CP. Early monitoring and intervention may be helpful for CP prevention and therapy.
Several facts may account for our findings. CP is a neurological disorder usually induced by preterm birth and infection. Metal ions are closely associated with the normal functioning of human body [24]. Trace elements deficiency is likely to cause the immune dysfunction, resulting in the increased risk of infection. Cu is a key cofactor for various enzymes, such as Cu/Zn superoxide dismutase, which plays an important role for neurological development [25]. Cu is also involved in the redox reactions [26]. Cu deficiency affects the role of other cellular constituents involved in antioxidant activities, such as iron, selenium, and also play an important role in diseases in which oxidative stress is elevated. Oxidative stress was involved in the brain injury. Hence, the disorder of Cu may cause severe brain dysfunction. For example, higher level of Cu was associated with decreased risk of Parkinson’s disease, which is the second most common neurodegenerative disease [27].
Zn is necessary for the survival of various cell types. Lots of enzymes exert the effects by creating bonds with Zn ions [28]. Zn plays a role in cell proliferation as an element of transcription factors and enzymes of DNA replication, Zn deficiency leads to a decline of Th1 immunity and promotes inflammatory reactions. Zn is also present throughout the central nervous system, playing a role in synaptic transmission, neuroregulation and neuroprotection [29]. Zn also promotes spinal cord injury recovery through upregulating Zn transporter-1 and brain-derived neurotrophic factors [30]. Zn inhibits free radical by promoting metallothionein production. Meanwhile, Zn is crucial for retinol-binding protein synthesis and vitamin A mobilization. Zn plays a role in removing the heavy metals from the body, such as Pb, As and Hg, which are implicated in the pathophysiology of Parkinson’s disease [31]. Based on the comprehensive role of Zn, Zn disorder may result in the unpredictable injury including neurological lesions.
Iron is an important constituent of hemoglobin, which transfers oxygen. Iron deficiency leads to anemia. Thus, iron regulates and influences the activity of various organs, as well as the whole organism. Iron also exerts effects in the catalysis of enzymatic reactions [32]. Th cells maturation was impaired in children with iron-deficiency anemia and was regenerated by the supplementation of iron.Iron participates in the neurodevelopment [33]. Iron deficiency lowers the chances of recovery of the central nervous system and influences the children’s adaptation ability.
Ca, an important constituent of bones, plays a vital role in the muscle contraction and relaxation, and regulates the electrical conduction system of the heart [34]. Ca also regulates the function of enzymes and is associated with the metabolism of other trace elements [35]. Mg, another important constituent of bones, is an antagonist of Ca, prevents excessive acetylcholine release and stimulation at the neuromuscular junction. Notably, we observed null difference of Mg between CP and controls, which may be due to that Mg was not directly related to the neurodevelopment. Further larger number of studies are needed to validate our findings.
Our findings supported the idea that nutritional status influences the neurodevelopment, neurocognitive performances, and later life health outcomes. Appropriate nutritional diet is important for lowering the adverse health consequences. Also, compared with included previously published single studies, our study was a pooled investigation with robust significances. Although the positive association between Cu/Zn/iron/Ca and CP provided novel insight for CP prevention and therapy, several limitations should be considered. First, the between-study heterogeneity may distort the final result, the random-effects model decreased the influence of the heterogeneity. On the other hand, sensitivity analysis did not change the overall results, which indicated that our conclusion was comparatively robust. Second, the publication bias was noted for the association between Cu/Zn and CP, the exclusion of certain studies also removed the bias, strengthening our conclusions, indicating the outlier studies did not change the overall results. Finally, despite the significant differences of Cu/Zn/iron/Ca between CP and controls, the cause-effect relationship between trace elements levels and CP risk remains inconclusive. The enrolled participants were all children with a lower age, we speculated that trace elements deficiency may precede the CP onset. Due to the lack of specific age in our investigation, further larger number studies should be performed to address this issue.
In terms of our findings, the following issues should be addressed: 1) time-series analysis of the alteration of trace elements in CP, 2) longitudinal observation of the association between trace elements levels and CP progress, 3) clarification of the cause-effect relationship between trace elements status and CP risk in prospective studies.
In conclusion, our investigation indicates that CP cases demonstrated significantly lower levels of Cu/Zn/iron/Ca than those in healthy controls. Monitoring and intervention may be helpful for CP prevention and therapy.