Asthma and overt stroke in children with sickle cell disease: a multicenter pediatric cohort study in French Guiana

Abstract

Background

Stroke remains one of the most severe complications of sickle cell disease (SCD) in children. Although asthma is increasingly recognized as a clinical marker of SCD severity, its association with cerebrovascular complications remains insufficiently characterized. We aimed to evaluate the association between physician-documented asthma and overt stroke in children with SCD and to explore the associations of ferritin levels and continuity of care with overt stroke.

Methods

We conducted a multicenter observational cohort study including 175 children with confirmed SCD followed in three public hospitals in French Guiana between January 2012 and December 2022. Overt stroke was defined as a clinically documented neurological deficit lasting > 24 h and confirmed by brain MRI. Asthma status, ferritin levels, and continuity of care, defined as attendance at ≥ 75% of scheduled routine visits during a 12-month period, were assessed.

Multivariable penalized logistic regression was used to estimate adjusted associations with overt stroke.

Results

Twenty-four children (13.7%) had a history of overt stroke. Asthma was significantly more frequent among children with stroke than among those without stroke (41.7% vs. 16.6%; unadjusted OR 3.60; 95% CI 1.44–9.02). All 175 children had complete data for the covariates included in the adjusted multivariable analysis.

In multivariable analysis, asthma remained associated with higher odds of overt stroke (adjusted OR 3.05; 95% CI 1.12–8.31). Ferritin showed a non-significant trend toward higher odds of stroke (adjusted OR 1.58 per SD increase; 95% CI 0.99–2.63). Irregular continuity of care also showed a non-significant increase in the odds of stroke (adjusted OR 2.10; 95% CI 0.88–5.02). All 175 children were included in the adjusted multivariable analysis.

Conclusions

Physician-documented asthma remained associated with higher odds of overt stroke after adjustment in this multicenter pediatric SCD cohort. Ferritin levels and irregular continuity of care showed non-significant exploratory trends. These findings suggest that asthma may identify a subgroup of children with SCD requiring closer clinical assessment. Prospective studies are needed to confirm this association and clarify its clinical significance.

Introduction

Sickle cell disease (SCD) remains one of the most prevalent inherited hemoglobin disorders worldwide and continues to impose a substantial burden of morbidity in children. Among its complications, cerebrovascular disease represents one of the most severe manifestations, with overt ischemic stroke occurring in up to 10% of children in historical cohorts and silent cerebral infarctions affecting an even larger proportion. Pediatric stroke in SCD is associated with long-term neurocognitive impairment, reduced academic achievement, and diminished quality of life [1–5]. Clinical assessment of stroke vulnerability has traditionally relied on transcranial Doppler (TCD) velocity measurements and genotype severity, particularly in homozygous SS or Sβ⁰ disease. However, growing evidence suggests that cerebrovascular complications are influenced by multiple interacting biological and contextual factors, highlighting the need to identify additional clinical and healthcare-related markers [1–3, 5].

Asthma is one of the most common chronic comorbidities in children with SCD, with reported prevalence rates ranging from 15% to 30% across different cohorts [6, 7]. Beyond its respiratory manifestations, asthma has been described as a potential marker of disease severity, with studies reporting increased incidence of acute chest syndrome (ACS), higher rates of vaso-occlusive crises (VOC), and greater healthcare utilization among affected children [6–8]. While the relationship between asthma and pulmonary complications in SCD is well described, its association with cerebrovascular complications remains less clearly defined. Asthma was selected as the main clinical exposure because it represents a frequent chronic respiratory comorbidity in children with SCD and has been associated with acute chest syndrome, hypoxemia, vaso-occlusive complications, systemic inflammation, and increased healthcare utilization [6–8]. These pathways may potentially contribute to cerebrovascular vulnerability, although causal mechanisms remain uncertain [9–11]. However, asthma may also reflect a more severe underlying SCD phenotype rather than acting as an independent causal determinant. Therefore, in this study, asthma was considered primarily as a clinically identifiable marker potentially associated with overt stroke rather than as a proven mechanistic risk factor.

In addition to clinical comorbidities, both biological and healthcare-related factors may provide contextual information about cerebrovascular vulnerability. Biomarkers reflecting systemic disease activity, such as ferritin, have been proposed as indicators of combined inflammatory and iron-related processes in SCD [12–14]. Nevertheless, ferritin is influenced by multiple factors and should be interpreted as an exploratory marker rather than a specific predictor of stroke. Furthermore, healthcare organization factors, including frequency of follow-up and geographic residence, may influence access to preventive strategies and continuity of care [15–17]. French Guiana represents a distinctive epidemiological context characterized by a high prevalence of SCD within a geographically dispersed healthcare network, providing an opportunity to investigate clinical, biological, and healthcare-system variables within the same pediatric cohort.

The present study aimed to evaluate whether asthma is associated with overt stroke in children with SCD and to explore whether ferritin levels and continuity of care provide additional contextual information regarding cerebrovascular vulnerability. Although previous studies have reported associations between asthma and adverse outcomes in SCD, including acute chest syndrome and cerebrovascular events [6–8, 18], the biological and healthcare-related context of this association remains insufficiently characterized. In particular, few studies have simultaneously examined respiratory comorbidity, exploratory biological markers such as ferritin, and healthcare continuity within a multicenter pediatric cohort [12, 15–17]. The knowledge gap addressed by this study is therefore whether asthma identifies a subgroup of children with SCD who have higher odds of overt stroke after accounting for selected clinical, biological, and healthcare-related variables.

Materials and methods

Study design and setting

We conducted a multicenter observational study using a consolidated clinical and biological dataset derived from pediatric patients with confirmed sickle cell disease (SCD) followed in French Guiana. The dataset combined standardized clinical, laboratory, and follow-up variables collected across three public hospitals located in Cayenne, Saint-Laurent-du-Maroni, and Kourou. These centers provide comprehensive pediatric hematology care within a geographically dispersed healthcare network serving both urban and semi-remote populations. Transcranial Doppler (TCD) screening was not systematically available during the study period due to logistical and resource-related constraints.

Data were collected retrospectively from medical records covering the period from January 2012 to December 2022.

The present analysis specifically focuses on cerebrovascular outcomes and frequency of follow-up and does not reproduce descriptive analyses previously published from this cohort.

Study population

Children were eligible if they:

• Were aged 6 months to 17 years;

• Had laboratory-confirmed SCD (SS, Sβ⁰, SC, or Sβ⁺ genotype);

• Were actively followed in one of the participating hospitals;

• Had documented data regarding stroke status and asthma diagnosis.

Children with HbSC and Sβ + genotypes were included to reflect the full spectrum of sickle cell disease followed in routine clinical practice across participating centers. Patients were excluded if stroke status could not be determined or if key exposure or covariate data were unavailable.

The final analytic sample included 175 children.

Definitions and study variables

Stroke

The primary outcome was overt stroke, defined as a clinically documented acute neurological deficit lasting more than 24 h, in accordance with standard clinical definitions used in SCD cerebrovascular studies [1, 5, 19]. For the present analysis, all stroke cases included in the final dataset were confirmed by brain MRI. Stroke history was retrieved from hospital medical records and coded as a binary variable (yes/no). Silent cerebral infarctions without overt clinical neurological deficit were not considered as outcome events in this analysis.

Asthma

Asthma was defined as a physician-documented diagnosis recorded in hospital medical records during routine clinical care, consistent with previous pediatric SCD studies evaluating asthma as a clinical comorbidity [6–8, 18]. Children followed in pediatric hematology clinics were systematically questioned about respiratory symptoms during routine visits, and those with symptoms suggestive of asthma were clinically evaluated and referred for respiratory assessment when indicated. Because this was a retrospective study, standardized asthma-control scores, asthma severity classification, spirometric confirmation, and treatment data were not consistently available for all children. Therefore, asthma was analyzed as a binary clinical variable. Some degree of misclassification cannot be excluded, and this limitation is acknowledged in the Discussion.

Ferritin

Ferritin levels were measured during steady-state conditions. Ferritin values were extracted from routine steady-state assessments; however, the available retrospective data did not consistently allow confirmation that ferritin measurement preceded the stroke event. Ferritin was therefore analyzed as a cross-sectional exploratory correlate rather than as a prospective predictor.

Ferritin is routinely assessed as part of annual baseline laboratory evaluation in children with SCD. In addition to reflecting iron metabolism, ferritin is recognized as an acute-phase reactant and may reflect combined inflammatory and iron-related processes [12–14, 20]. Because ferritin can be influenced by transfusion exposure, infection, inflammation, iron overload, and disease severity, it was analyzed as an exploratory biological variable rather than as a specific marker of stroke risk.

Frequency of follow-up

Frequency of follow-up was assessed using adherence to scheduled routine hematology visits documented in hospital medical records. Regular follow-up referred to sickle cell disease follow-up in pediatric hematology and not to asthma-specific follow-up and was defined as attendance at ≥ 75% of scheduled routine visits during a standardized 12-month observation period. The 75% threshold was chosen a priori as a pragmatic indicator of regular attendance at scheduled routine hematology visits, reflecting whether children attended most planned follow-up visits during the observation period. This variable was intended to capture continuity of sickle cell disease care rather than asthma-specific follow-up or emergency healthcare use, in line with previous work emphasizing the importance of care continuity and barriers to healthcare access in sickle cell disease [15–17].

Irregular follow-up was defined as attendance at < 75% of scheduled routine visits during the same period. This definition included only routine scheduled visits and did not include unscheduled or post-hospitalization visits. The definition was applied uniformly across genotypes. The variable was analyzed as a dichotomous variable (regular vs. irregular follow-up).

Place of residence was categorized as Cayenne, Saint-Laurent-du-Maroni, or Kourou.

Covariates

Candidate covariates included age, sex, genotype category, hydroxyurea treatment, baseline hemoglobin, fetal hemoglobin percentage, ferritin level, follow-up regularity, and place of residence. Because of the limited absolute number of overt stroke events, model parsimony was prioritized. Hydroxyurea exposure was defined as a documented active prescription of hydroxyurea in the medical record during the study observation period. Information on treatment duration, dose intensity, and adherence was not consistently available.

Data management

There were no missing data for the variables included in the primary multivariable model, including stroke status, asthma status, ferritin level, follow-up regularity, genotype, age, and hydroxyurea exposure. Consequently, all 175 participants were included in the adjusted analysis, and no multiple imputation was performed. Data harmonization across centers was performed before analysis. Variables were defined using a common data dictionary, and clinical, laboratory, and follow-up variables were reviewed for consistency across the three participating hospitals. Discrepant or ambiguous entries were checked against the original medical records whenever possible. The same definitions for stroke, asthma, genotype category, ferritin measurement, hydroxyurea exposure, and follow-up regularity were applied uniformly across centers. This approach was used to improve comparability across sites and to reduce information bias in this retrospective multicenter dataset [15–17].

Statistical analysis

Continuous variables were described using means ± standard deviations or medians with interquartile ranges, as appropriate. Categorical variables were summarized as counts and percentages.

Comparisons between children with and without stroke were performed using Student’s t-test or Mann–Whitney U test for continuous variables and chi-square or Fisher’s exact test for categorical variables.

Continuous variables were visually inspected using histograms and boxplots to assess distributional properties and identify extreme values.

Given the limited absolute number of stroke events available for multivariable modeling (n = 24) and the risk of small-sample bias or sparse-data bias in conventional logistic regression, multivariable analyses were conducted using penalized logistic regression with Firth correction. This approach was selected a priori to obtain more stable estimates in the presence of a rare outcome and a limited number of events, while maintaining model parsimony.

Covariates included in multivariable models were selected a priori based on clinical relevance and evidence from previous literature on predictors of stroke in sickle cell disease. Given the limited number of stroke events, the number of variables included in the model was restricted to maintain an appropriate events-per-variable ratio.

Multicollinearity among covariates was assessed using variance inflation factors (VIF), and no significant collinearity was detected.

The primary multivariable model assessed the association between asthma and overt stroke, adjusting for age, genotype category, hydroxyurea treatment, standardized ferritin, and follow-up regularity. Because of the limited number of stroke events, sex, baseline hemoglobin, fetal hemoglobin percentage, and place of residence were examined descriptively but were not retained in the final multivariable model to preserve model parsimony and avoid overfitting. Sensitivity analyses excluding hydroxyurea from the multivariable model were performed to evaluate the stability of the association between asthma and overt stroke.

Adjusted odds ratios (OR) with 95% confidence intervals were reported.

All analyses were performed using R statistical software (version 4.3.1). A two-sided p-value < 0.05 was considered statistically significant in frequentist analyses.

Results

Among the 175 children included in the study (Fig. 1), 24 (13.7%) had a history of overt stroke.

Fig. 1.

Flowchart of patient selection. Among 390 children with confirmed major sickle cell disease (SCD), patients with incomplete stroke data, missing asthma status, or missing key covariates were excluded. The final analytic cohort included 175 children, among whom 24 experienced stroke and 151 had no stroke

Stroke diagnosis was confirmed by brain MRI in all cases. Of these, 19 (79.2%) were ischemic strokes and 5 (20.8%) were hemorrhagic strokes. Most stroke cases occurred in children with HbSS/Sβ⁰ genotypes (19/24, 79.2%), whereas a smaller proportion occurred in children with HbSC/Sβ⁺ genotypes (5/24, 20.8%). Among the five strokes occurring in HbSC/Sβ + patients, all were confirmed by brain MRI and corresponded to ischemic infarctions consistent with vascular occlusive patterns typical of sickle cell disease. No distinct radiological features specific to this subgroup were observed.

Baseline characteristics according to stroke status are presented in Table 1.

Table 1.

Baseline characteristics according to stroke status

Variable	Stroke (n = 24)	No Stroke (n = 151)	p-value
Age, median (IQR)	7 (3–17)	7 (2–17)	0.566
Male sex, n (%)	13 (54.2)	77 (50.9)	0.733
SS/Sβ⁰ genotype, n (%)	20 (83.3)	96 (63.6)	0.043
Asthma, n (%)	10 (41.7)	25 (16.6)	0.004
Irregular follow-up (< 75% visits/year), n (%)	14 (58.3)	50 (33.1)	0.017
Ferritin (µg/L), mean ± SD	58.6 ± 34.2	51.5 ± 32.2	0.342

Baseline demographic, clinical, and biological characteristics of the study population stratified by stroke status. Continuous variables are presented as means with standard deviations or medians with interquartile ranges, as appropriate. Categorical variables are presented as counts and percentages. Unadjusted odds ratios (OR) and 95% confidence intervals (CI) are shown for selected variables

Stroke occurred more frequently in children with SS/Sβ⁰ genotypes compared to SC/Sβ⁺ genotypes (83.3% vs. 63.6%; p = 0.043). Asthma was significantly more prevalent among children with stroke (41.7% vs. 16.6%; unadjusted OR 3.60; 95% CI: 1.44–9.02; p = 0.004), and irregular follow-up was also associated with stroke occurrence (58.3% vs. 33.1%; unadjusted OR 2.83; 95% CI: 1.16–6.89; p = 0.017). No significant differences were observed for age, sex, or ferritin levels in univariate analyses.

The final multivariable penalized logistic regression included all 175 children, among whom 24 had overt stroke.

In multivariable penalized logistic regression (Table 2), asthma remained associated with higher odds of overt stroke (adjusted OR 3.05; 95% CI: 1.12–8.31).

Table 2.

Multivariable penalized logistic regression for overt stroke

Variable	Adjusted OR	95% CI
Asthma	3.05	1.12–8.31
Ferritin (per SD)	1.58	0.99–2.63
Irregular follow-up (< 75% visits/year)	2.10	0.88–5.02
SS/Sβ⁰ genotype	2.42	0.78–7.48
Age (per SD)	1.29	0.74–2.26
Hydroxyurea	1.72	0.58–5.08

Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were estimated using penalized logistic regression (Firth method). The model included asthma status, standardized ferritin levels, genotype severity, frequency of follow-up, hydroxyurea treatment, and age as covariates selected a priori based on clinical relevance

In the multivariable penalized logistic regression model, asthma remained associated with higher odds of overt stroke (adjusted OR 3.05; 95% CI: 1.12–8.31). Standardized ferritin showed a non-significant trend toward higher odds of stroke (adjusted OR 1.58 per SD; 95% CI: 0.99–2.63), and irregular follow-up also showed a non-significant increase in the odds of stroke (adjusted OR 2.10; 95% CI: 0.88–5.02). Because the confidence intervals for ferritin, irregular follow-up, genotype severity, hydroxyurea treatment, and age crossed 1, these variables were not considered statistically significant in the adjusted model.

Genotype severity (SS/Sβ⁰) showed a non-significant trend toward higher odds of stroke (adjusted OR 2.42; 95% CI: 0.78–7.48), whereas hydroxyurea treatment and age were not independently associated with overt stroke in this model.

Adjusted associations between clinical and biological variables and stroke risk are illustrated in Fig. 2.

Fig. 2.

Adjusted odds ratios for variables associated with overt stroke in children with sickle cell disease. Forest plot showing adjusted odds ratios (aOR) and 95% confidence intervals for variables associated with overt stroke in children with sickle cell disease. Estimates were obtained using penalized logistic regression (Firth method). Hydroxyurea was not significantly associated with overt stroke. The observed estimate above 1 likely reflects confounding by indication, as hydroxyurea is preferentially prescribed to children with more severe disease or higher baseline clinical risk

Among the variables included in the adjusted model, asthma had the largest adjusted odds ratio, whereas ferritin and follow-up regularity showed non-significant associations.

Discussion

In this pediatric SCD cohort followed in French Guiana, physician-documented asthma was associated with higher odds of overt stroke and may represent a clinically identifiable marker of cerebrovascular vulnerability. This finding is consistent with previous studies reporting associations between asthma and severe SCD complications, including acute chest syndrome, increased healthcare utilization, and cerebrovascular events [6–8, 18].

In penalized multivariable analysis, asthma remained associated with higher odds of overt stroke (aOR 3.05; 95% CI 1.12–8.31) after adjustment for age, genotype category, hydroxyurea treatment, ferritin, and follow-up regularity. Because this was an observational retrospective analysis, this association should not be interpreted as proof that asthma directly causes stroke.

Hydroxyurea was not independently associated with overt stroke in adjusted analyses. This finding should not be interpreted as indicating harm, but rather may reflect confounding by indication, as hydroxyurea is typically prescribed to children with more severe disease or higher baseline clinical risk [2, 3, 5].

The observed association between asthma and overt stroke should be interpreted in light of the limited number of outcome events, which required a parsimonious modeling approach. The findings suggest that asthma may identify a subgroup of children with SCD requiring closer clinical assessment and further prospective evaluation [1, 5, 11, 21].

Previous studies have consistently reported associations between asthma and increased respiratory complications, particularly acute chest syndrome, as well as higher healthcare utilization in children with SCD [6–8]. The mechanisms linking asthma to cerebrovascular complications remain uncertain. Several biological pathways have been proposed to explain the observed association, although causal mechanisms remain uncertain [9–11]. However, this study was not designed to assess causal mechanisms, and asthma may also reflect a more severe underlying SCD phenotype rather than acting as a direct causal factor. Current American Society of Hematology guidelines emphasize the importance of stroke prevention through TCD screening but do not specifically incorporate asthma as a formal risk stratification criterion [1]. Therefore, asthma should be interpreted here as an associated clinical marker requiring further prospective evaluation.

Ferritin was included as an exploratory biological variable because it may reflect combined inflammatory and iron-related processes in sickle cell disease [12–14, 20]. In the present study, ferritin showed a non-significant trend toward higher odds of stroke after adjustment. This finding should be interpreted cautiously because ferritin is influenced by multiple factors, including transfusion exposure, iron metabolism, inflammation, infection, and disease severity [12, 14, 20]. Moreover, ferritin alone cannot adequately characterize the inflammatory or vascular biology underlying stroke in sickle cell disease. A more complete evaluation would require additional biomarkers of inflammation, hemolysis, endothelial activation, and iron overload [9–14, 20, 22–25]. Therefore, our findings do not support ferritin as a standalone marker of stroke risk but suggest that it may be useful to explore in future prospective studies using broader biomarker panels.

Follow-up regularity in this study reflected attendance at scheduled routine SCD hematology visits rather than asthma-specific care. Irregular follow-up showed a non-significant increase in the odds of stroke after adjustment and should therefore be interpreted cautiously. This variable may reflect broader barriers to continuity of care, including geographic distance, transportation difficulties, social vulnerability, and limited access to preventive monitoring, which have been described as important contributors to outcomes in SCD [15–17, 26]. However, because the association was not statistically significant, our findings should be viewed as exploratory and hypothesis-generating rather than definitive evidence that irregular follow-up independently increases stroke risk.

The originality of this study lies in integrating clinical comorbidity, exploratory biological indicators, and healthcare utilization patterns within the same analytical framework. These findings are consistent with previous reports from French Guiana emphasizing the contribution of both biological and contextual factors to cerebrovascular outcomes [21]. These findings suggest that cerebrovascular vulnerability in pediatric SCD may be associated with both clinical and healthcare-related factors.

Several limitations should be acknowledged. First, although the proportion of children with overt stroke was clinically important, the absolute number of stroke events was limited for multivariable modeling. The occurrence of 24 overt stroke cases among 175 children should not be interpreted as a low clinical frequency; rather, the limitation relates to the absolute number of outcome events available for adjusted statistical modeling. Because of the retrospective design, the study cannot establish causality. Asthma may contribute to cerebrovascular vulnerability through hypoxemia or inflammation, but it may also reflect a more severe underlying SCD phenotype [6–8, 18]. Similarly, ferritin and irregular follow-up showed non-significant trends and should not be interpreted as validated predictors of stroke [12–17, 20]. Several adjusted estimates had confidence intervals crossing 1 and should therefore be interpreted as exploratory findings requiring confirmation in larger cohorts with greater statistical power. Residual confounding cannot be excluded because several clinically relevant stroke-related variables were not consistently available, including longitudinal TCD findings, transfusion history and cumulative transfusion exposure, prior acute chest syndrome burden, vaso-occlusive crisis frequency, oxygen saturation, and detailed hydroxyurea adherence.

Second, asthma was defined using physician-documented diagnosis in routine medical records. Standardized asthma severity assessment, asthma-control scores, spirometric confirmation, and treatment data were not available for all participants. Misclassification of asthma status is therefore possible and may have influenced the observed association. Third, ferritin represents an imperfect biological marker and may be influenced by transfusion exposure, inflammation, infection, iron overload, and disease severity [12, 14, 20]. Fourth, stroke events in HbSC/Sβ⁺ genotypes were relatively uncommon (5/24, 20.8%) and should therefore be interpreted cautiously given the lower baseline cerebrovascular risk in this subgroup. Radiological findings in this subgroup were consistent with typical ischemic patterns observed in SCD. Finally, although stroke diagnosis was confirmed by brain MRI in all cases, the absence of systematic TCD screening represents a limitation, as TCD is a key tool for early identification of children at risk of stroke according to current international guidelines [1, 5]. The retrospective dataset did not consistently establish the temporal sequence between asthma diagnosis, ferritin measurement, hydroxyurea exposure, follow-up regularity, and stroke occurrence. Consequently, the variables examined should be interpreted as associated clinical characteristics rather than prospective predictors.

Despite these limitations, the study has several strengths. It was conducted within a defined territory, integrates multicenter data, and applies statistical methods adapted to a limited number of outcome events. The observed association between asthma and overt stroke provides a clinically relevant signal that warrants confirmation in future prospective studies.

Conclusion

In this multicenter pediatric SCD cohort from French Guiana, physician-documented asthma was associated with higher odds of overt stroke after adjustment. Ferritin levels and irregular continuity of care were not significantly associated with overt stroke in the adjusted analysis. Given the retrospective design, limited number of stroke events, and potential residual confounding, these findings should be considered exploratory. Larger prospective studies incorporating standardized respiratory assessment, longitudinal TCD screening, and detailed cerebrovascular and treatment-related variables are needed to confirm the observed association.

Abbreviations

ACS

Acute chest syndrome

aOR

Adjusted odds ratio

CI

Confidence interval

CNIL

Commission Nationale de l’Informatique et des Libertés

HbF

Fetal hemoglobin

HbSC

Hemoglobin SC disease

HbSS

Hemoglobin SS disease

HbSβ⁰

Sickle beta-zero thalassemia

HbSβ⁺

Sickle beta-plus thalassemia

MRI

Magnetic resonance imaging

OR

Odds ratio

SCD

Sickle cell disease

SD

Standard deviation

TCD

Transcranial Doppler

VIF

Variance inflation factor

VOC

Vaso-occlusive crisis

Authors' contributions

G.B : drafted the study protocol, collected data, performed data analysis, and wrote the manuscript. M.N : contributed to protocol validation, methodology development, and manuscript revision. C.M : contributed to data collection and manuscript revision. A.M : contributed to data collection and manuscript revision. P.F : contributed to data collection and manuscript revision. N.E : conceived the study, supervised the project, validated the methodology, and critically revised the manuscript.

Funding

This study did not receive any external funding.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This retrospective study used pseudonymized data collected during routine clinical care and was conducted in accordance with French regulations governing research not involving direct intervention on human participants. Under the applicable French regulatory framework, formal written informed consent and formal ethics committee approval were not required for this retrospective analysis of pseudonymized routine-care data. Patients and/or legal guardians were informed of the possible use of their medical data for research purposes and had the opportunity to object. The absence of objection was considered as authorization for the use of pseudonymized data. Data were analyzed in accordance with French data protection regulations and CNIL requirements. No study-specific ethics approval or exemption number was issued because the study qualified as a retrospective secondary analysis of pseudonymized routine-care data under the applicable French regulatory framework.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.