Quality of life in children and adolescents with hemophilia A: A systematic review and meta-analysis

Background Various instruments have been used to assess health-related quality of life (HRQoL) in children and adolescents with hemophilia A. Objective We systematically reviewed the literature to summarize HRQoL measurement instruments and outcomes in this population. Methods MEDLINE, Embase, Cochrane CENTRAL, and LILACS databases were searched. Studies published from 2010 to 2021, reporting HRQoL assessed by generic or hemophilia-specific instruments in individuals aged 0 to 18 years were included. Two independent reviewers performed screening, selection, and data abstraction. Data were meta-analyzed using the generic inverse variance method with the random-effects model for single-arm studies reporting instrument-specific mean total HRQoL scores. Prespecified subgroup meta-analyses were performed. Heterogeneity among studies was assessed using the I2 statistic. Results Six instruments were identified in 29 studies meeting the following inclusion criteria: 4 generic instruments (PedsQL [5 studies], EQ-5D-3L [3 studies], KIDSCREEN-52 [1 study], and KINDL [1 study]) and 2 hemophilia-specific instruments (Haemo-QoL [17 studies] and CHO-KLAT [3 studies]). The overall risk of bias was moderate to low. There was a substantial variability in the primary outcome (mean total HRQoL score) among studies using the same instrument (Haemo-QoL), with scores ranging from 24.10 to 89.58 on a scale from 0 to 100 (higher scores indicating higher HRQoL). Meta-regression with 14 studies using the Haemo-QoL questionnaire demonstrated that 79.34% (R2) of the observed 94.67% total heterogeneity (I2) was explained by the proportion of patients receiving effective prophylactic treatment. Conclusion HRQoL assessment in young people with hemophilia A is heterogeneous and context specific. The proportion of patients on effective prophylactic treatment is positively correlated with HRQoL. The review protocol was registered prospectively with PROSPERO (CRD42021235453).


| I N T R O D U C T I O N
Hemophilia A is a congenital life-threatening disorder caused by an inherited deficiency of factor (F)VIII [1]. It is characterized by spontaneous and post-traumatic bleeding events into the joints, muscles, and soft tissues, which can lead to disability. The challenges experienced by children and adolescents with hemophilia A can seriously affect their quality of life (QoL) in a wide range of health, physical, social, and educational settings. Parental restriction of the child's or adolescent's activities to prevent trauma, frequent absences from school due to repeated bleeding episodes, and the accompanying pain or discomfort associated with a bleeding episode are factors that limit or interfere with physical functioning, social and intellectual development, and academic performance [2,3]. Children and adolescents with hemophilia also experience difficulties that include frequent hospital visits, frequent injections, and inability to fully participate in daily activities [4][5][6].
Health-related QoL (HRQoL) is a multidimensional construct that includes a subjective assessment of the impact of health and illness on daily physical, social, cognitive, and emotional functioning [7]. Measurement of HRQoL is essential to fully understand the impact of a chronic disease and its treatment on clinical outcomes [1], and it should be included as an outcome in research and in the evaluation of treatment options for persons with hemophilia [8,9]. HRQoL questionnaires have long been used in adult populations and are gaining increasing acceptance among clinicians for use in children and adolescents [10][11][12]. Adult and pediatric HRQoL questionnaires can differ substantially in content and relevant dimensions, and the latter may also vary considerably with the age of the child [13].
Although age-and disease-specific HRQoL questionnaires have been developed [14][15][16], generic instruments have been most commonly used to assess HRQoL in patients with chronic conditions, such as the 36-item Short Form Health Survey for adults and the Pediatric Quality of Life Inventory (PedsQL) for children and adolescents [9,17,18]. Therefore, the challenge remains as to how to choose the best assessment tool for a particular chronic condition [1,5], and systematic reviews can be a useful starting point for identifying these tools [19].
In hemophilia, specifically, several systematic reviews have been published on the health and patient-reported outcome measures [11,[19][20][21], but most of the studies are population specific and do not report the HRQoL measurement properties in children and adolescents [5]. Because clinical evaluation may not be sufficient to adequately characterize hemophilia A-related morbidity in children and adolescents, identifying tools that capture these features is important to guide HRQoL assessment and therapeutic care programs in the pediatric population with hemophilia A.
In the present systematic review, we aimed to identify and investigate existing instruments used to assess HRQoL in children and adolescents with hemophilia A and to summarize available QoL assessments.

| M E T H O D S
We developed this systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [22] statement and the methods for systematic reviews proposed by the Cochrane Collaboration [23]. The review protocol was registered prospectively with PROSPERO (CRD42021235453). indices, and synonyms, or by combining them with Boolean operators ("AND" and "OR"): "Hemophilia A," "Congenital Hemophilia A," "Classic Hemophilia," "Factor VIII Deficiency, "Quality-Adjusted Life Years," "Quality of Life," "utility," and "disability adjusted life year." We did not include terms related to the intervention or study design to increase the search sensitivity. We set no language restrictions, but we only considered articles in the English, Portuguese, and Spanish for inclusion. We also hand searched the reference lists of all articles included in this review and of all reviews published on the subject for additional studies. Search strategy is provided in Supplementary Table 1. We cross-checked the results of the database searches to locate and eliminate duplicate entries.

| Eligibility criteria and study selection
Studies eligible for inclusion in this review were randomized controlled trials and observational studies (cohort, cross-sectional, case control, or case series) published in English, Portuguese, or Spanish that recruited a minimum of 30 patients aged <18 years with hemophilia A and reported on the results of HRQoL assessment or condition-specific QoL assessment or utility/disutility assessment. Conference abstracts were Essentials • A systematic review on the quality of life (QoL) of children with hemophilia A was lacking.
• We searched major databases for studies reporting QoL in children with hemophilia A.
• QoL for this population varied according to the access to preventive measures.
• Better QoL was related to a higher proportion of patients receiving preventive therapy. considered for inclusion if they provided sufficient information about the primary outcome (mean total HRQoL score). There were no restrictions regarding the intervention used. Studies with or without a comparison group were also eligible for inclusion. We excluded the following study designs: guidelines, editorials, book chapters, commentaries, letters, notes, and study protocols.
We limited the review scope to persons with hemophilia A because this is the most prevalent form of hemophilia. Furthermore, restriction to 1 type of disease is likely to reduce the expected heterogeneity among studies.
The primary outcome of this review was the instrument-specific mean total HRQoL score of persons with hemophilia A, which was evaluated according to the study design and intervention. Secondary outcomes included the instrument used and the instrument-specific mean domain scores associated with better and worse HRQoL in a particular study.  Scale (NOS), which contains 8 questions and assesses methodological quality using a star rating system that allocates a maximum of 9 stars across 3 categories: selection, comparability of the groups, and ascertainment of outcome (cohort studies) or exposure (case-control studies) [24]. Treatment-comparative cross-sectional studies were assessed with the NOS adapted for cross-sectional studies, which uses a similar star rating system (maximum of 10 stars) [25]. Noncomparative cohort and cross-sectional studies were assessed with the same scales with the exclusion of domains pertinent to comparative studies, resulting in a maximum of 6 and 8 stars for cohort and cross-sectional studies, respectively. Studies reaching 50% to 75% of the maximum number of stars for the given NOS were classified as having a moderate risk of bias, and those reaching 75% or more were classified as having a low risk of bias. We used the revised Cochrane risk of bias tool for randomized trials (RoB 2.0) to assess the randomized controlled trials [26].

| Data analysis
We conducted qualitative and quantitative syntheses of the available evidence. For each included article, we collected data on which the Study publication does not present results for the TAPQOL applied to patients aged 0 to 5 y, but the authors report that there were no differences in HRQoL between boys with and without hemophilia as measured with the TAPQOL instrument. c Distribution of regular FVIII intravenous infusions according to treatment regimen by age group [36]: 91.2% prophylaxis and 8.8% on-demand in the 4 to 7 y age group; 100% prophylaxis in the 8 to 12 y age group; and 85.1% prophylaxis and 14.9% on-demand in the 13 to 16 y age group.
T A B L E 2 Risk of bias assessment according to the study design.
Author  hemophilia (Haemo-QoL)-we analyzed the scores as 100 minus the reported score because, originally, higher scores indicated worse HRQoL in this specific instrument-and the three-level version of the EuroQol fivedimensional descriptive system for HRQoL states (EQ-5D-3L)-we analyzed the scores after multiplying them by 100 because, originally, the mean total HRQoL scores were reported on a scale from 0 to 1. We conducted other prespecified subgroup meta-analyses using the same methods.
For studies presenting direct group comparisons regarding the mean total HRQoL scores, we analyzed the standardized mean difference (SMD) of HRQoL scores between the groups being compared. We used an inverse variance random-effects model for meta-analysis.
We assessed heterogeneity among studies using the I 2 statistic, where scores > 75% indicated high heterogeneity. We performed a meta-regression analysis for prespecified quantitative covariates whenever an unexplained high heterogeneity was found. We assessed the potential for publication bias by visually inspecting the funnel plots and using the Begg's rank correlation test.

| R E S U L T S
The initial search yielded 2220 records, of which 2155 remained after adjusting for duplicates. After screening the titles and abstracts, 98 studies were retrieved for full text reading, of which 29 met the inclusion criteria for the present review. Figure 1 shows the flow diagram of the study selection process. NOS for comparative cohort studies (maximum 9 points) and adaptation for comparative cross-sectional studies (maximum 10 points); domains pertinent to comparative studies were not included in the assessment of single-arm studies, resulting in maximum values of 6 and 8 points for the assessments of noncomparative cohort and cross-sectional studies, respectively.
AZEREDO-DA-SILVA ET AL. Children (0-12 y) showed no significant impairment in HRQoL compared with healthy peers. Adolescent boys (13-18 y) with CBDs reported slightly better HRQoL on the total and emotional functioning scales than healthy peers (small-moderate effect sizes). In contrast, adolescent girls experienced worse HRQoL on the total, social functioning, and psychosocial health scales than healthy peers (moderate effect sizes). No differences were found in HRQoL between severity groups, but more problem behavior was observed in young boys (0-5 y) with severe hemophilia. Male sex, participation in sports, and school attendance were positively associated with HRQoL. Parental country of birth, type of treatment, and number of bleeds were not associated with HRQoL. 5 Baek et al. [ T A B L E 3 (Continued)
(Continues) The "Family" and "Other persons" domains were highly impaired in children aged 6-7 y. QoL was also impaired in "Family" and "Friends" compared with "Physical health" and "Feeling" domains in children aged 8-12 y. 10  HRQoL was compared between children with and without hemophilia (control group), with no comparison regarding treatment options. A significant difference was observed between children (aged 8-12 y) in the hemophilia group and those in the control group in 1 dimension of the selfreported HRQoL: the hemophilia group showed a significantly lower mean score for "moods and emotions" (48.20) than the control group (52.40) (P = .023). In contrast, no significant difference was observed in any of the self-assessed HRQoL dimensions between these groups in the adolescent category (13-18 y of age). Alternatively, parentreported HRQoL differed significantly between patients and controls in several dimensions. In particular, in the lower age category (8-12 y of age), the hemophilia parents' group had significantly lower scores than the parents' control group for "moods and emotions" (43.40 and 49.60, respectively; P = .042), "social support and peers" (47.60 and 54.00; P = .041), "self-perception" (45.10 and 50.30; P = .026), and "school environment" (49.00 and 54.60; P = .048). However, no significant differences in any of these dimensions were noted in the records of parents of adolescents. There were no significant differences between the CHO-KLAT scores of 12 proxy and child selfreports (P = .440 and P = .275, respectively). CHO-KLAT scores were higher at follow-up than at baseline, but no statistical significance was observed. Hemophilia decreased HRQoL in patients, but this effect weakened at year 4 compared with baseline (primary outcome). In addition, HRQoL was influenced by bleeding rates, physical activity (Continues) AZEREDO-DA-SILVA ET AL.

ID
Author/year/country/ publication type QoL assessment tool Respondents a Mean overall score (± SD or range) b Key HRQoL findings restriction, financial burden, and treatment (secondary exploratory outcomes). Prophylactic treatment was a key factor contributing to eventfree survivor prognosis and optimal therapy for persons with hemophilia. 24 Gringeri et al. [50]/2011/Italy/ Peer-reviewed journal article Haemo-QoL I (4-7 y), II (8-12 y), and III (13-16 y) Patient self-report and parent/caregiver report Mean total Haemo-QoL score (all patients): -patient-reported: 29.97 ± 9.30 -parent-reported: 28.70 ± 11.20 A significant difference was found between children and adolescents on episodic treatment vs prophylaxis for the "Family" domain (P < .029, Student's t-test), which was more impaired in the episodic treatment group (44.00 ± 22.60) than in the prophylaxis group (11.27 ± 8.70). Moreover, children on episodic treatment felt "often" or "always" more overprotected both by their mother (80.0% vs 11.0%) and father (80.0% vs 20.0%) than children on prophylaxis. In the episodic treatment group, 20.0% of children and adolescents perceived that their parents had "often" or "always" to limit their work or leisure time because of their hemophilia compared with none in the prophylaxis group, whereas only 10% perceived that their parents had only "sometimes" their work or leisure time limited. HRQoL scores were widely below 40 for children and below 50 for their caregivers in all dimensions. "Family" and "Treatment" had the highest scores (mean scores of 57.70 and 46.20, respectively), suggesting reduced QoL in these dimensions in children aged 4-7 y. The most impaired Haemo-QoL domain in children aged 8-12 y was "Perceived support" (mean score of 40.63), whereas older children showed greater impairment in the "Family" and "Treatment" domains, but much less than that of younger children (mean score of 36.10 in both domains). The least impaired domains were "Selfview," "Other persons," and "Relationships" in the 3 groups. Among Haemo-QoL subscales, "Perceived

ID
Author/year/country/ publication type QoL assessment tool Respondents a Mean overall score (± SD or range) b Key HRQoL findings support" in the age group 8-12 y and "Sports/ school" and "Relationships" in the adolescent group were strongly associated with the number of hemarthroses over the previous 12 mos. 27  There was no significant difference in child or parent Haemo-QoL scores between the age groups (P = .200). Forty-four patients (88.0%) had different degrees of anemia. The degree of anemia was significantly correlated with child Haemo-QoL scores (r = 0.29, P = .040), mainly with "View" and "School" domain scores. Both child and parent Haemo-QoL scores were significantly correlated with the factor activity level, disease duration, duration of joint disease, number of bleeding events in the past year, and number of joints affected. Five patients (10.0%) underwent synovectomy. The Haemo-QoL score was significantly lower after intervention (P = .043), especially in the "Physical health," "Feeling," "View," "Family," "School and sports," "Treatment," and "Dealing" domains. HRQoL in children was generally good, with the highest impairments in boys aged 8-12 y. Boys aged 8-16 y reported good physical performance (80.00 ± 16.00), with the highest impairments in the "endurance" and "mobility" domains. Boys who engaged in sports had significant better physical performance and HRQoL than boys who did not. Sedentary lifestyle had a negative impact on subjective physical performance and number of days lost of children. Among children, PedsQL scores generally decreased with increasing disease severity, and no significant differences were found between persons with severe hemophilia receiving prophylaxis (mean total PedsQL: 84.10 ± 14.20) and on-demand treatment (mean total PedsQL: 86.50 ± 12.40). In children, the mean total PedsQL scores as well as mean scores across all PedsQL subscales decreased as the severity of joint pain increased, with statistically significant (P < .050) and minimally (Continues) AZEREDO-DA-SILVA ET AL.
risk of bias (6 of 6 stars) on the corresponding adapted NOS. Three treatment-comparative cohort studies had a median of 5 of 9 stars on the original NOS for cohort studies. The only randomized controlled trial, conducted by Gringeri et al. [50], had an overall low risk of bias on the Cochrane RoB 2.0 tool ("some concerns" in the domain "deviation from the intended intervention"). The results of the risk of bias assessment according to the study design are presented in Table 2 [6,27-54].
There was a substantial variability in the primary outcome (mean total HRQoL score) among studies that used the same instrument.
Scores ranged from as low as 24.10 to as high as 89.58 on a scale from 0 to 100, where higher scores indicate better HRQoL. Table 3 [6,  shows the total HRQoL scores and a brief description of the main findings of each study.
The subgroup meta-analysis according to specific HRQoL assessment instruments demonstrated that high heterogeneity persisted even among studies that used the same instrument to assess HRQoL. Figure 2 shows the total and subgroup meta-analyses for the total HRQoL scores by the type of instrument.
Additional subgroup meta-analyses according to specific age Overall score or general physical health score if overall score is unavailable.  Table 4 31,37,42].
Regarding the QoL domains that most influenced the overall QoL assessment, the domains "View," "Others," and "Relationships" had the highest QoL scores for the age groups 0 to 7 years, 8 to 12 years, and 13 to 18 years, respectively. The domains "Family" (overprotection) and "Perceived support" had the lowest QoL scores for the age groups 0 to 7 years and 8 to 18 years, respectively. Table 5 shows the frequency of the

| D I S C U S S I O N
To the best of our knowledge, this is the most comprehensive systematic review of HRQoL assessment in children and adolescents with hemophilia A conducted to date. Two recent reviews evaluating HRQoL among children and adolescents with hemophilia A presented distinct scopes: one focused on the comparative effectiveness of hemophilia A treatments and the other was not a hemophilia-specific review [56,57]. In addition, the last systematic review that assessed HRQoL questionnaires for children and adolescents with hemophilia A was published in 2017 [5]. Therefore, the present systematic review represents a necessary update.
In general, studies of moderate quality were considered. The risk of bias ranged from low to moderate, and the risk of publication bias was considered to be low. . Relationships: related to romantic partnership due to hemophilia (Haemo-QoL). Self-perception: related to satisfaction and worries with patient's own body, clothes, and general appearance (KIDSCREEN-52). Social: related to problems with social functioning (Haemo-QoL; PedsQL). School: related to participating in different types of physical and leisure activities and intellectual activities inside School (Haemo-QoL; PedsQL; KINDL). Sports: related to participating in different types of physical and leisure activities outside School (Haemo-QoL). Support (perceived support): related to consideration and understanding from others in relation to hemophilia (Haemo-QoL). Treatment: related to the satisfaction with and acceptance of the treatment, health care management, and injection-related constraints (Haemo-QoL). View: related to the attitude toward others and the impact of hemophilia on ability to do things (Haemo-QoL).Note: none of the 3 studies that used the CHO-KLAT instrument reported detailed results per instrument domain.
HRQoL, health-related quality of life; QoL, quality of life. a Fourteen subgroups from 13 studies (considering both arms from the randomized trial by Gringeri et al. [50]); 268 patients assessed in 11 countries. b Fifteen subgroups; 534 patients assessed in 13 countries. c Thirteen subgroups from 15 studies; 334 patients assessed in 11 countries.
subgroups of patients. Some particularly noteworthy findings from individual studies are as follows: • HRQoL tends to be better in children and adolescents with hemophilia A than in adults with the disease [1,13,14].
• Pain associated with joint bleeding seems to be the most important variable in explaining the reduction in perceived QoL related to physical health [2,5,23,26,42].
• HRQoL estimates obtained from parents/caregivers tend to be closely related to those obtained directly from children and adolescents [3,19,23,31].
• Sports and school attendance are positively associated with QoL [4].
• QoL of children and adolescents with hemophilia receiving prophylactic treatment in high-quality care settings appears to be comparable with that of children and adolescents without hemophilia; however, this finding should be regarded with caution because of a possible "disability paradox" that has been described in this population [4,58].
• There is a trend toward deterioration in QoL with increasing age among children and adolescents [8].
• A lower proportion of patients receiving prophylactic treatment appears to be associated with worse HRQoL in the "Family" domain (overprotection) [4,36,48].
• Children and adolescents receiving on-demand treatment report feeling overly protected by their parents and with greater restriction of physical activity than those receiving prophylactic treatment [52].
• Patients who participate in sports have significantly better QoL than those who do not [37].
The limitations of this systematic review should also be considered. First, the high heterogeneity among studies prevented us from reliably providing a useful summary effect size estimate. Second, although the meta-regression analysis was able to explain much of the heterogeneity among studies, significant inconsistencies persisted.
The assessment of the risk of bias of noncomparative studies was limited by the use of adapted scales without previous validation for this purpose. Finally, the search strategy used in the current systematic review focused on terms for QoL. We did not search for studies reporting QoL outcomes associated with specific products or treatment regimens. We acknowledge that studies reporting QoL