Humanistic Burden of Informal Caregivers of Children and Young Adults with Newly Diagnosed Type 1 Diabetes (T1D): A Systematic Literature Review (SLR)

OBJECTIVES: To describe the humanistic and economic burden of informal caregivers of children, adolescents, and young adults newly diagnosed with T1D. METHODS: An SLR was conducted in MEDLINE®, Embase®, and PsycInfo® (search date: December 7, 2021) to identify clinical and observational studies assessing the humanistic burden experienced by informal caregivers (i.e., persons who provide unpaid care) of children, adolescents, and young adults aged 6 to 21 who were diagnosed with T1D within three months. RESULTS: Four prospective cohort studies and one randomized controlled trial (RCT) were included. Caregiver sample size ranged from 59 to 191. Duration of T1D was 2 to 6 weeks. Among parents of children aged ≤ 11 years, mothers had a moderate posttraumatic stress disorder symptom severity (mean score: 11.9; standard deviation [SD]: 7.4), while fathers experienced mild severity (8.4; SD: 6.2; p < 0.001; Posttraumatic Diagnostic Scale). Mothers experienced clinically significant symptoms (defined as score >5) of anxiety (mean score: 7.5), social dysfunction (7.5), and somatic symptoms (5.1; General Health Questionnaire [GHQ]-28). Fathers showed clinically significant anxiety (5.5


Introduction
T1D is an autoimmune disease characterized by the destruction of pancreatic beta cells by the immune system, leading to rapid decline of endogenous insulin production and secretion [1]. Very often onset of T1D occurs in childhood or adolescence with the peak between 10 and 15 years of age [2]. There is no disease-modifying therapy approved for newly diagnosed T1D so far, and disease management requires life-long insulin replacement therapy [3]. Despite the availability of injectable insulin and insulin pumps for the management of T1D, the burden of disease remains very high and people with T1D typically develop long term complications and have decreased life span expectancy [4]. Newly diagnosed T1D patients often require significant caregiving and this is particularly the case in children. Informal care is often provided by immediate family members, such as parents in the case of children with T1D. Studies globally have shown that caring for a child with T1D is associated with elevated levels of parental psychological distress [5]. This is particularly significant in an early period after diagnosis, as disease onset is sudden and unexpected in the vast majority of cases. Previous studies have identified this complex burden and recommended targeted psychosocial interventions for informal caregivers and care partners [6][7][8]. However, the significant and rapid developments in technology and disease management calls for an updated assessment of the humanistic and economic burden among informal caregivers of children, adolescents, and young adults living with T1D.

Methods
An SLR was conducted by searching MEDLINE®, Embase®, and PsycInfo® from database inception to December 6, 2021 (Figure 1) using MeSH terms and keywords for "type 1 diabetes" and "caregiver" or "parent". Additionally, gray literature searches were conducted (via Embase) for abstracts published in the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) conferences from 2020 to 2021. The review was performed in line with PRISMA 2020 guidelines without registration. Internal protocol was developed but not registered.
The overarching goal of this SLR was to describe and characterize the landscape of evidence on the humanistic burden of informal caregivers or parents of children, adolescents, and young adults (ages 6 to 21) who have been newly diagnosed with T1D within approximately three months. Specifically, we aimed to describe the impact of T1D symptoms on the caregiver burden.
After the exclusion of duplicates, two investigators reviewed all abstracts and proceedings identified through the searches and applied the following PICO criteria to assess eligibility:

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Studies were included if the population included informal caregivers (i.e., persons who provide unpaid care) of children, adolescents, and young adults aged 6 to 21 who were diagnosed with T1D within three months.

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Studies with any intervention or no intervention were included.
• Included studies had any comparator or no comparator.

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The full-text studies identified for eligibility included outcomes regarding informal caregiver perspective, symptoms, and burden.

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Study types were randomized and non-randomized clinical trials, observational studies, and qualitative research.

Screening
Reports of included studies (n = 6) of which 5 unique studies were included in review Included Reports not retrieved (n = 1)

Records
A preliminary conceptual framework, based on only studies included within the SLR, was developed to illustrate the humanistic burden associated with informal caregiving for people living with T1D.

Results
Of the five primary studies [9][10][11][12][13] included, four were prospective cohort studies and one was a randomized controlled trial (RCT) ( Table 1). No qualitative studies were identified that met the eligibility criteria. As well, none of the included studies reported on economic burden. Three studies were conducted in the United States, one in Switzerland, and one in Australia. Study follow-up ranged from 14 weeks to 312 weeks (median: 48 weeks).

Patient Characteristics
The mean age of children with T1D across studies ranged from 7.6 years to 13.2 years (median: 9.1 years). The proportion of female children was reported across three studies and ranged from 39% to 53.7%. Most children were living with both their biological parents, 86.5% [9] and 84.9% [12]. Newly diagnosed with T1D was defined as within 2 weeks after diagnosis [9], within the first 6 weeks of diagnosis [13] or within three months [10][11][12].
Baseline characteristics of children are summarized in Table 2.

Caregiver Characteristics
The mean age of informal caregivers was 38 years as per Sullivan-Bolyai 2015 [10], while another study by Kovacs 1990 [11] reported median maternal and paternal age as 37.6 years and 40 years, respectively ( Table 2). The proportion of female caregivers ranged from 50.5% [9] to 100% [11]. Most informal caregivers had an intact family or were married.

Parents of Children Aged ≤11 Years
In Landolt 2005 [9] among parents of children aged ≤11 years, 22.4% and 79.6% of mothers, and 14.6% and 56.3% of fathers met the DSM-IV criteria for full posttraumatic stress disorder (PTSD) and subclinical PTSD, respectively. Mothers had a moderate PTSD symptom severity (mean score: 11.9; standard deviation [SD]: 7.4), while fathers experienced mild severity (8.4; SD: 6.2) as measured by the Posttraumatic Diagnostic Scale. This difference was statistically significant (p < 0.001).
Northam 1996 [12] examined psychosocial and family functioning in parents of children with newly diagnosed T1D within 3 weeks after discharge from hospitalization. Symptoms of anxiety, social dysfunction, depression, and somatic symptoms were measured using the General Health Questionnaire (GHQ-28). Mothers experienced clinically significant symptoms (defined as score >5) of anxiety (mean score: 7.5), social dysfunction (7.5), and somatic symptoms (5.1), while fathers showed clinically significant anxiety (5.5) and social dysfunction (7.7) only.
Sullivan-Bolyai 2015 [10] examined the efficacy of the Parent Education Through Simulation-Diabetes (PETS-D), which is a series of parent education vignette sessions using human patient simulation, and parent education sessions using vignettes only. Results from the RCT indicated that caregivers in both intervention groups experienced a greater fear of hypoglycemia at diagnosis as measured by the Hypoglycemia Fear Survey for Parents (HFS-P), which decreased over time. At diagnosis, both intervention groups showed similar levels of fear, and at 6 and 14 weeks, levels of fear in caregivers in the PETS-D intervention group were slightly higher than those in the vignette only intervention group. Additionally, among a subgroup of informal caregivers with children younger than 6 years old, fear of hypoglycemia was significantly higher in the PETS-D intervention group than in the vignette only intervention group over time (p = 0.03).

Parents of Children Aged >11 Years
Kovacs 1990 [11] investigated if mothers of children aged >11 years with newly diagnosed T1D experienced symptoms of depression. The mean Beck Depression Inventory (BDI) score for mothers 2-3 weeks after receiving their child's diagnosis was 8.75 (SD: 7.62), indicating the mothers were not clinically depressed (BDI scores range from 0 to 63, with a score between 0 and 9 indicating that a person is not depressed).
Northam 1996 [12] showed that parents of children aged >11 years experienced clinically significant (GHQ score of greater than 5) social dysfunction as measured by GHQ-28 with a mean score of 7.6 for mothers and 7.1 for fathers. In addition, mothers showed clinically significant symptoms of anxiety (mean: 5.4).
Yi-Frazier 2018 [13] measured acute diabetes-specific stress by asking caregivers "What is your overall stress level about your child's diabetes right now?" on a Likert scale from 1 to 10, with a score of 1 indicating not at all stressed, a score of 5 moderately stressed, and a score of 10 extremely stressed. At time of diagnosis, the mean diabetes-specific stress score as rated by informal caregivers was 6.4, and this decreased to 3.5 at 3 months.

Preliminary Conceptual Framework on Caregiver Burden
Relevant burden and impact concepts identified from the included studies were used to develop a preliminary conceptual framework of the caregiver burden in newly diagnosed T1D. Burden and impacts were categorized under overarching categories of factors, including (i) treatment factors, (ii) psychosocial factors, (iii) caregiver emotional functioning, (iv) disease-related factors, and (v) sociodemographic factors ( Figure 2): Treatment factors include parent education through simulation (n = 1) and one-to-one education (n = 1).
(iii) The overarching category of caregiver emotional functioning includes seven dimensions, and in particular anxiety (n = 2), depression (n = 2), and others.
(v) Sociodemographic factors include the parent role: mother or father (n = 1) and patient age (n = 1).

Discussion
The aim of this SLR was to describe and characterize the landscape of evidence on the humanistic and economic burden of informal caregivers or parents of children, adolescents, and young adults (ages 6 to 21), who have been newly diagnosed with T1D within approximately three months. The SLR captured a small number of studies, the majority of which were single-center prospective cohort studies and conducted in the United States. Across the included publications, children with T1D had a median age of 10.5 years (ranging from 7.6 to 13.2) and were mostly male. Included informal caregivers of children with T1D were mostly middle-aged and female. Most of the caregivers had an intact family or were married.
In terms of informal caregiver burden outcomes, measures used varied widely across studies. Amongst parents of children aged 11 years or younger, parents showed mild symptoms of PTSD and clinically significant symptoms of anxiety, social dysfunction, and somatic symptoms. For both mothers and fathers, fear of hypoglycemia was highest at diagnosis and decreased over time within three months. Amongst parents of children older than 11 years, parents showed clinically significant symptoms of anxiety and social dysfunction. No signs of depression were noted.
In addition, a preliminary conceptual framework of caregiver burden in newly diagnosed T1D was developed using the five included studies. Concepts identified included treatment factors, psychosocial factors, diseaserelated factors, and sociodemographic factors. To the best of our knowledge, there is no other similar conceptual framework for a similar population available in the literature. This framework can act as a starting step to understand the dynamics of disease burden for this population, and can be further developed and validated by organizing focus groups with patients, caregivers, and healthcare providers.
The present review had several strengths. Firstly, all stages of the review were carried out in accordance with standard recommendations for the conduct of SLRs [14,15]. Secondly, the literature search and screening were comprehensive. Although the final evidence base was small, all main databases and conference proceedings were covered during the searches and study selection. However, this review is not without limitations. Firstly, there was a paucity of evidence on the humanistic burden to informal caregivers within the short period of time just after diagnosis. This is despite the evidence that the level of stress and psychological burden typically peaks shortly after diagnosis [9,11,12,13]. Furthermore, none of the included studies reported on economic burden, indicating an evidence gap regarding newly diagnosed T1D. The caregiver burden outcome measures also varied widely across included studies, and only one study examined an intervention for caregivers, leading to difficulty in comparing findings across studies. Additionally, some dimensions, such as intensity of children diabetes, experience of disease from caregivers, or treatment perspectives were not reported in literature. Finally, the preliminary conceptual framework that was developed based on the included literature is the first preliminary conceptual framework analyzing the humanistic burden of caregivers of pediatric, adolescent, and young adult patients with newly diagnosed T1D. However, the preliminary conceptual framework has limitations because of the small number of included studies. Certain concepts may be missing from the preliminary conceptual framework as they were not identified in the current evidence base, including caregiver and patient characteristics and coping strategies. Additionally, the current conceptual framework requires more investigation with patients, caregivers, and healthcare providers to understand the dynamic of caregiver burden.
Due to these limitations, any conclusions regarding the findings related to informal caregiver burden and predictors of burden need to be interpreted cautiously.

Conclusions
Overall, this SLR highlights that parents of children, adolescents, and young adults with newly diagnosed T1D experience caregiver burden, with mothers experiencing a greater burden than fathers. Informal caregiver burden was found to be highest at diagnosis, with a slight decrease observed over time. Due to the paucity of evidence, our review uncovered existing gaps in the knowledge, and need of systematic approach to evaluate psychological and economic burden of T1D. This could become even more important in the future with development of new disease-modifying therapies and further improvement of technology in the field of T1D.