The relationship between functional status and hematological parameters in children with spastic cerebral palsy: a retrospective cross-sectional study

Introduction

Cerebral palsy (CP) describes a group of permanent disorders of the development of movement and posture, causing activity limitation, which are caused by non-progressive damage that occurred in the brain of a developing fetus or infant (1,2). Each year, approximately 3.4 per 1,000 live births worldwide are born with CP, which has a tremendous socioeconomic impact on the families of the affected patients and the health care system (3,4).

Although CP results from a primary injury in the central nervous system (CNS), clinical symptoms are often observed in the motor system and osteoarticular muscular system in particular (5-7). The paradigm that CP often results in physical disabilities, motor and communication disorders, dysphagia, in turn, leads to mobility and social interaction limitations, undernutrition, as well as reduced quality of life, has been widely recognized (2,5). Therefore, early identification, proper support and tailored management of functional status are necessary for improving the prognosis and outcomes of children with CP. Distinctions between Gross Motor Function Classification System (GMFCS) levels represent differences in gross motor function (8). GMFCS describes mobility at the activity or participation level of the International Classification of Functioning, Disability and Health (ICF) framework. In contrast, the topographical pattern of CP (spastic CP subtypes) as described by the terms monoplegia, diplegia, hemiplegia, triplegia and quadriplegia is a classification at the body functions level of the ICF (9,10). It provides insight into the localization of the congenital or acquired lesion, the pathogenesis, and the etiology. These two most widely used classification schemes in CP are clearly complementary, capturing different functional status, especially the motor function in children with CP (11).

Since blood is easily sampled, hematological biomarkers can be evaluated and enable the prognosis of certain diseases (12). Body dysfunction in children with CP might be reflected in certain hematological parameters, although these indices are not specifically designed for CP. Generally, the severity of these clinical manifestations has been accompanied by abnormal levels of hematological parameters. The close monitoring of these laboratory results could help in predicting the functional status, recognizing the severe complications in the early phase, and guiding effective, timely management (13). Nevertheless, to date, few studies have investigated the characteristics of hematological parameters in children with CP. We previously identified that some children with quadriplegic CP had serum 25-hydroxyvitamin D (25[OH]D) deficiency, and the probability of this deficiency in the overnourished children was higher than that in healthy children (14). We conjectured that this deficiency, implying poor bone mineral status, may result from a lack of physical activity and weight-bearing, although the specific relationship and effects are still under research.

Hence, this study aims to describe the characteristics of hematological parameters in children with spastic CP, and to identify significant hematological parameters associated with the severity of motor dysfunction among those children. This study may provide valuable guidance for healthcare professionals in selecting appropriate hematological monitoring indicators for the effective management of children with CP throughout the course of the disease. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2024-564/rc).

Methods

Study design and participants

This retrospective study was one part of the project registered at the Chinese Clinical Trial Registry (www.chictr.org.cn) under ChiCTR2000033800. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Ethics Committee of Guangzhou Women and Children’s Medical Center (GWCMC) (approval No. 202023401). Informed consent was obtained from all participants’ legal guardians at the medical appointment or registration. Assent was also sought from children, depending on their age [≥8 years (y)] and capacity to understand the study.

Once diagnosed with CP (1), children recruited from GWCMC were registered on a purpose-built database [registered at the National Copyright Administration of The People’s Republic of China (http://www.ncac.gov.cn/), queried at the copyright protection center of China (https://register.ccopyright.com.cn/) under the register number of 2017SR409649] with information such as sex, age, type of CP, GMFCS level, etc. Children with spastic CP aged from 2 to 18 y were included between 2016 and 2023. Children were excluded if they met any of these criteria: (I) other neurological disorders not associated with CP or inherited metabolic disorders; (II) clinically unstable conditions such as infection, seizure, dialysis, shock, heart failure, liver failure, diabetic ketoacidosis, blood loss, or severe anemia; (III) received botulinum toxin (BTX) injection, anesthetic application, history of surgery or trauma in the past 3 months (Figure S1).

Functional status assessment

In our research, the functional status of children with CP was characterized by GMFCS levels and spastic CP subtypes. The GMFCS was used to evaluate the severity of motor impairment in the children. This well-established tool consists of a 5-point ordinal scale, ranging from GMFCS levels I (walks without limitations) to V (transported in a manual wheelchair) (8). Spastic CP subtypes as described by the terms monoplegia, diplegia, hemiplegia, triplegia and quadriplegia is a classification based on the pattern of limb involvement. Hemiplegia affects the upper and lower limbs on one side. Diplegia mainly impacts both lower limbs, with milder upper-limb involvement. Monoplegia affects only one limb (arm or leg). Triplegia involves three limbs, and quadriplegia affects all four limbs (9).

Hematological parameters collection

In addition to the basic clinical data and assessment results as described above, we also collected the hematological examination results of the included children with CP. Hematological examinations were carried out on the day of the visit, on admission or before medical intervention such as BTX injection or operative treatment. A trained phlebotomist performed all blood draws. The venipuncture site was typically the antecubital fossa of the dominant arm. After collection, the blood samples were sent to the laboratory for testing and analysis. Hematological parameters included in the analysis were white blood cell count (WBC, ×10⁹/L), red blood cell count (RBC, ×10¹²/L), hemoglobin (Hb, g/L), blood platelet count (PLT, ×10⁹/L), prothrombin time (PT, s), activated partial thromboplastin time (APTT, s), fibrinogen (g/L), calcium (mmol/L), potassium (mmol/L), sodium (mmol/L), chloride (mmol/L), magnesium (mmol/L), alanine aminotransferase (ALT, U/L), aspartate aminotransferase (AST, U/L), alkaline phosphatase (ALP, U/L), r-glutamyltransferase (U/L), total protein (TP, g/L), albumin (g/L), globulin (g/L), albumin-globulin ratio (A/G), total bilirubin (TB, µmol/L), direct bilirubin (DB, µmol/L), indirect bilirubin (IDB, µmol/L), total bile acid (TBA, µmol/L), glucose (mmol/L), creatine kinase (CK, U/L), lactate (mmol/L), uric acid (UA, µmol/L), creatinine (µmol/L), and urea (mmol/L). The results were collected through the electronic medical records system of GWCMC and analyzed according to the Clinical and Laboratory Standards Institute guideline document EP28-A3c (15).

Statistical analyses

The G*Power 3.1.9.7 (University of Dusseldorf, German) was used to calculate sample size. A previous study reported that birth prevalence for pre-/perinatal CP was as high as 3.4 per 1,000 live births (3). Hence, the proportion was set as 0.0034. With a 2-sided 95% confidence interval (95% CI) and an 80% statistical power, the minimum sample size required is 250. To maintain power for analysis on observed data, this estimate is increased by 20%. A final minimum number of participants was 300 in this study.

Statistical analyses were conducted using SPSS 27.0 (IBM Corp., Armonk, New York, USA) and data visualization was performed by GraphPad Prism 8.0 (GraphPad Software, Inc., Boston, Massachusetts, USA). Categorical data were presented as numbers and percentages. Quantitative data were presented as the mean and standard deviation (SD) with 95% CI. Unpaired t-test or one-way analysis of variance (ANOVA) with Bonferroni or Tamhane’s T2 post hoc comparisons were performed for probing the statistical differences of the hematological parameters among different GMFCS levels and spastic CP subtypes.

The relationships between blood lactate concentrations and GMFCS levels and spastic CP subtypes were also conducted using multiple linear regression models with defining dummy variables. Lactate serves as a sensitive marker of tissue hypoxia and metabolic disturbances, and any factor influencing oxygen delivery, glucose metabolism, or hepatic and renal function may have an impact on blood lactate concentrations (16). Since hematological parameters like glucose, CK, ALT, AST, r-glutamyltransferase, TB, creatinine, urea, WBC, RBC, Hb, potassium, magnesium, PT, APTT and fibrinogen can influence blood lactate concentration, the regression analyses were adjusted for these potential confounders as well as sex and age. ANOVA was used to test the statistical results of the regression model. The beta coefficients (b, mean blood lactate concentration difference) were used to interpret the outcomes. All statistical testing was 2-sided, and P<0.05 was considered statistically significant.

Results

Participants’ characteristics

A total of 770 children aged from 2 to 17 y [516 males, 254 females; mean age (SD): 4.55 (2.83) y] with spastic CP were enrolled. Most of the participants were 2–3 and 4–6 y (accounting for 53.12% and 29.22%, respectively). A higher proportion of participants presented with ambulatory CP (GMFCS levels I–III), compared to those who were severely mobility disabled (GMFCS levels IV and V), and the majority belonged to diplegia and hemiplegia, followed by quadriplegia (Figure 1A-1D).

Figure 1 Participants’ characteristics. (A-D) Demographic and clinical characteristics of included children with spastic CP (n=770). (E,F) The distribution of participants in different GMFCS levels (E) and spastic CP subtypes (F). The corresponding number of each GMFCS level and spastic CP subtype is shown above the bar charts. CP, cerebral palsy; GMFCS, Gross Motor Function Classification System; n, number; y, years.

Given the specific patterns of growth and development across different ages, children were categorized into the following age brackets for further analysis: 2–3, 4–6, 7–12, and 13–17 y. The distributions of participants in different GMFCS levels and spastic CP subtypes among the four age groups were consistent with the general distribution trend described above (Figure 1E,1F).

Comparisons of hematological parameters based on GMFCS level

Hematological parameters were calculated and compared among GMFCS levels for each age group. Due to sparsity of data in individual subgroups, some groups were merged according to the severity of CP (commonly, level I is defined as mild, level II and III are defined as moderate, and level IV and V are defined as severe) or the motion ability (level I–III are defined as ambulatory CP while level IV and V are defined as non-ambulatory CP).

In 2–3 y children (Table 1), no significant difference in the levels of blood routine tests and coagulation indicators was observed among different GMFCS groups (P>0.05). Children with GMFCS IV exhibited higher concentrations of potassium and magnesium compared to those with GMFCS I (P=0.03, P=0.01, respectively). The concentrations of blood lactate were significantly higher in children with GMFCS IV than in those with GMFCS I (P=0.006). Conversely, the levels of ALP were significantly lower in children with GMFCS IV (P=0.008). Besides, there exists a significant difference in the levels of ALP between GMFCS II and III (P=0.03), and between GMFCS II and IV (P<0.001). The levels of urea in children with GMFCS I were higher compared to children with GMFCS II (P=0.03).

In 4–6 y children (Table 2), there was no significant difference on the levels of blood routine tests, coagulation indicators and renal function indices among different GMFCS groups (P>0.05). Children with GMFCS IV–V exhibited higher concentrations of potassium than those with GMFCS I and III (P<0.001). The concentrations of chloride and lactate were significantly higher in children with GMFCS IV–V than those with GMFCS I (P=0.01). Rather, the levels of ALP were lower in children with GMFCS III and IV–V compared to children with GMFCS I (P=0.02, P<0.001, respectively).

In 7–12 y children (Table S1), there were significant differences in the levels of calcium, sodium and DB between GMFCS I and II (P=0.02, P=0.02, P=0.054, respectively). There were significant differences in the levels of magnesium and creatinine between GMFCS I and III–V (P=0.005, P<0.001, respectively) and between GMFCS II and III–V (P=0.03, P=0.01, respectively). Additionally, children with GMFCS III–V had lower UA levels compared to children with GMFCS II (P=0.04).

In 13–17 y children (Table S1), the levels of creatinine were much higher in children with GMFCS I–II than in those with GMFCS III–V (P=0.006). There was no significant difference in the levels of blood routine tests, coagulation indicators, electrolytes, liver function indices and myocardial and skeletal muscle indicators among different GMFCS groups (P>0.05).

Remarkably, despite comparison of hematological parameters such as potassium, sodium, ALP, DB, CK, and UA showed statistically significant differences among different GMFCS groups, those indices were within the normal reference range and carry no clinical significance. Overall, GMFCS-based comparisons of hematological parameters reveal remarkable variation in blood lactate concentrations among 2–3 and 4–6 y children with different GMFCS levels.

Comparisons of hematological parameters based on spastic CP subtype

Likewise, the hematological parameters were calculated and compared among different spastic CP subtypes in each age group. Some groups were also merged (unilateral CP includes monoplegia and hemiplegia, while bilateral CP includes diplegia, triplegia and quadriplegia).

In 2–3 y children (Table 3), no significant difference was observed in the levels of blood routine tests, coagulation indicators and renal function indices among different subtypes (P>0.05). Quadriplegic children had higher concentrations of potassium than monoplegic children and hemiplegic children (P=0.03, P=0.043, respectively). There were significant differences in the levels of DB among different subtypes (P=0.01). In addition, children with bilateral CP had higher concentrations of lactate compared to those with unilateral CP (P<0.001).

In 4–6 y children (Table 4), there was no significant difference in the levels of blood routine tests, coagulation indicators and renal function indices among different subtypes (P>0.05). Quadriplegic children had higher potassium and chloride concentrations than hemiplegic children (P=0.004, P=0.02, respectively), and the concentrations of chloride in quadriplegic children were higher than those in monoplegic children (P=0.04). There were significant differences in the levels of AST, ALP and albumin among different subtypes (P=0.008, P=0.01, P=0.03, respectively). Additionally, quadriplegic children had higher lactate concentrations than hemiplegic children (P=0.02).

As depicted in Table S2, there were significant differences in the levels of WBC, PT, sodium, DB and creatinine between unilateral CP and bilateral CP in 7–12 y children (P=0.009, P=0.006, P=0.03, P=0.007, P=0.03, respectively). All hematological parameters were not significantly different between unilateral CP and bilateral CP in 13–17 y children (P>0.05).

Similarly, only the lactate concentration was out of the normal reference range. Taken together, subtype-based comparisons of hematological parameters reveal significant differences in blood lactate concentrations among different subtypes in 2–3 and 4–6 y children.

Regression analysis for the relationship between blood lactate concentrations and GMFCS levels

Multiple linear regression models were estimated to investigate the relationship between blood lactate concentrations and GMFCS levels (Table 5). In 2–3 y children, the estimated mean difference in blood lactate concentrations between children with GMFCS I and IV from a linear regression model without adjustment was 0.847 (95% CI: 0.529, 1.164, P<0.001), revealing the association between blood lactate concentrations and GMFCS. The difference with adjustment for spastic CP subtype, age and sex was 0.614 (95% CI: 0.173, 1.055, P=0.006) and 0.428 (95% CI: 0.009, 0.846, P=0.045) with additional adjustment for hematological parameters that affect blood lactate. In 4–6 y children, there was no statistically significant difference between the estimated differences in blood lactate concentrations from children with different GMFCS (P>0.05).

Regression analysis for the relationship between blood lactate concentrations and spastic CP subtypes

Multiple linear regression models were also estimated to investigate the relationship between blood lactate concentrations and spastic CP subtypes (Table 6). In 2–3 y children, quadriplegic children had higher concentrations of blood lactate (b=0.394, 95% CI: 0.107, 0.682, P=0.007) compared with diplegic children from a linear regression model without adjustment. However, the estimated mean differences were small and statistically insignificant from 2–6 y children with different spastic CP subtypes (P>0.05) with any adjustment for the confounding factors, indicating spastic CP subtype has little influence on the blood lactate concentration.

Discussion

To our knowledge, this is the first cross-sectional study with a large sample size to demonstrate the characteristics of hematological parameters in children with spastic CP. The common hematological parameters with different GMFCS levels and spastic CP subtypes were investigated and compared across different ages, which has rarely been studied previously. Moreover, the current study reveals that the degree of blood lactate abnormality is statistically associated with the severity of motor dysfunction in 2–3 y children with spastic CP, with all regression models adjusted for participants’ characteristics and hematological parameters that affect blood lactate. Our study provides data support and research significance for analyzing the hematological parameters of children with CP.

CP is the most common motor disability of childhood, and is characterized by significant heterogeneity in terms of etiology, pathophysiology and clinical manifestations (2). Individuals with CP are prone to a series of secondary complications, including musculoskeletal problems, cardiovascular and respiratory diseases, liver and renal dysfunction and dysphagia, that may interfere with important aspects of quality of life, such as independence, mobility and participation. Hematological examination is conducive to assessing individual health status, assisting in monitoring the development trends of diseases, suggesting that various hematological parameters can be used to evaluate the progression of CP.

Disturbances in coagulation function are common in perinatal hypoxic-ischemic insult, which manifests as prolonged PT and APTT, decreased fibrinogen and PLT levels. These coagulation indices are strong predictors of outcomes such as abnormal neonatal encephalopathy grade, seizures, and mortality (17). However, PT and APTT have been found within the normal ranges in children with scoliosis secondary to CP, although they were significantly longer than those in the control group during the early phase of surgery (18). The homeostasis of electrolytes is important for neuroprotection and musculoskeletal function (19-21), and there are no abnormal electrolyte levels in the present study. No abnormal levels of liver function related indices was also observed in children with spastic CP in our study, which aligns with a recent cross-sectional study conducted in Denmark (22). In addition, renal function monitoring should also be considered in CP management. However, those renal function indices levels were within the normal reference range and carry no clinical significance.

We found increased blood lactate concentrations widely existed in children with spastic CP, suggesting that the lactate metabolism disorders need to be considered during CP management. Generally, when oxygen transport and tissue oxygenation are impaired, anaerobic metabolism occurs, leading to an increased lactate concentration (16). However, blood lactate would be elevated in conditions not associated with tissue hypoxia, such as organ dysfunction and metabolic factors that result in increased lactate production in oxygenated tissue (23). Spastic muscle fibers are unable to maintain oxidative function, causing hydrogen ions accumulation and muscular acidosis, as well as increased lactate concentrations (24). Prolonged hypertonia would also increase energy expenditure and reduce aerobic capacity, thereby elevating lactate concentration (14). Remarkably, attention should be given to the fact that struggling, crying and shouting in children during blood collection might increase the risk of bias in lactate measurement. Lactate is strongly produced in response to acute stress and struggling during blood collection in animal models (25), and glycolysis of contracting muscles during intense exercise, resulting in an increased rate of lactate entry into the plasma (26). It has been reported that the higher GMFCS levels seem to correlate with elevated resting concentrations of blood lactate (27). Children with severe CP (GMFCS IV–V) have low physical activity levels. Decreased activity or prolonged sitting in CP patients may result in decreased muscle content and muscle fibrosis (28). In inactive skeletal muscle, insufficient tissue perfusion and oxygenation may occur, resulting in elevated blood lactate concentration, while chronic lactate elevation signals metabolic stress and poor oxygen delivery, may indicate more profound systemic issues in the body (16,29,30). Existing studies have shown that dynamic standing training can reduce the blood lactate concentration in patients with non-ambulant CP (27), suggesting that exercise training, even only standing itself, is crucial for the rehabilitation management of children with CP (31,32). In line with previous studies, we reveal that elevated lactate concentrations were common in children with CP, and the lactate concentrations in 2–3 and 4–6 y children with spastic CP with severe levels (IV–V) were higher than those with mild and moderated levels (I–III). Thus, future studies are necessary to elucidate the mechanisms behind high levels of lactate and the long-term effects in children with non-ambulant CP. The interaction of high concentrations of lactate, poor nutritional status, secondary muscle pathology and physical inactivity also needs further investigations. Besides, the clinicians should screen for the comorbidities that accompany high concentrations of lactate and take timely treatments. Intramuscular BTX (33), short-acting drugs such as baclofen and diazepam (34) have been used to reduce spasticity. In addition, patients with severe spasticity should be referred to surgeons to aid in the selection of appropriate treatments, including nerve blocks (e.g., selective dorsal rhizotomy) (35).

Accumulating researches demonstrate that neurobiochemical markers, including neuron-specific enolase (NSE) and myelin basic protein (MBP), can be used to assess the severity of ongoing brain damage in infants with hypoxic-ischemic encephalopathy (36). The levels of serum NSE and MBP in children with CP have been found to be significantly higher than those in healthy children, and these levels increase with the severity of disease, as well as the corresponding gross motor function scores are lower (37). Accumulating evidence demonstrates the role of inflammation in the pathogenesis of brain injury and its detrimental role in neurodevelopment. The most commonly reported changes in inflammation in CP are noted for tumor necrosis factor (TNF), interleukin (IL)-6 and IL-10 (38,39). Previous research has stated that inflammation prevents endogenous brain repair and regeneration following injury (40,41). Early inflammatory biomarkers are associated with abnormal neurodevelopmental outcomes (42). However, the duration and extent of inflammation, as well as the implications in children and adults with CP, remain unclear. Future research is required to elucidate the role, extent and impact of inflammation in the population with CP.

Several limitations in the present study should be addressed. The small sample size in some groups limited our statistical power and the interpretation of findings to some extent, even though significant differences in individual hematological parameters among groups were observed in the recent study. We consider our results to be suggestive and should be treated with caution. Additionally, it is inadequate that only the GMFCS was adopted to analyze and reflect the functional status of children with CP in the study. Use of the Manual Ability Classification System (MACS), the Communication Function Classification System (CFCS), and the Eating and Drinking Ability Classification System (EDACS) would provide a more comprehensive understanding of the child’s function in daily life. Additionally, children with non-spastic CP were excluded in order to achieve homogeneity, so that the current results cannot be generalized to all children with CP.

Conclusions

In summary, we demonstrated that increased blood lactate concentrations widely existed in children with spastic CP. There were differences in blood lactate concentrations in 2–6 y children with different GMFCS levels and subtypes of spastic CP. Abnormality of blood lactate concentration is correlated with the functional status, particularly the severity of motor dysfunction (GMFCS) in 2–3 y children with spastic CP to a certain extent. Thus, the blood lactate concentration shall be given strengthened monitoring during the management of children with CP, as it facilitates prediction of functional outcomes, early detection of severe complications, and guidance for timely therapeutic interventions. Meanwhile, the mechanisms behind chronically high lactate concentrations and their long-term health effects on CP children need to be further explored. In addition, other hematological parameters such as blood routine tests, coagulation indicators, liver and renal function indices are within the normal reference range in children with spastic CP. Hematological parameters may not accurately reflect the functional status of children with spastic CP. The investigation of potential association between functional status and hematological parameters in children with CP requires further original studies.

Acknowledgments

We thank the study participants and their families for supporting the study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2024-564/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2024-564/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2024-564/prf

Funding: This study was supported by the Featured Clinical Technique of Guangzhou (grant No. 2023C-TS59); Guangzhou Municipal Science and Technology Project (grant Nos. 2023A03J0919 and 2024A03J01274); Natural Science Foundation of Guangdong Province (grant Nos. 2024A1515012920 and 2025A1515010379); Plan on enhancing scientific research in Guangzhou Medical University (grant No. GMUCR2024-02020); National Nature Science Foundation of China (grant No. 82472598); and Major Innovation Technology Construction Project of Synergistic Chinese Medicine and Western Medicine of Guangzhou (grant No. 2023-2318). The funders played no role in the design, conduct, or reporting of this study.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2024-564/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Guangzhou Women and Children’s Medical Center (GWCMC) (approval No. 202023401). Informed consent was obtained from all participants’ legal guardians at the medical appointment or registration. Assent was also sought from children, depending on their age (≥8 years) and capacity to understand the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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