The impact of hypoglycemia on quality of life and related outcomes in children and adolescents with type 1 diabetes: A systematic review.

OBJECTIVE: To conduct a systematic review to examine associations between hypoglycemia and quality of life (QoL) in children and adolescents with type 1 diabetes.
METHODS: Four databases (Medline, Cochrane Library, CINAHL, PsycINFO) were searched systematically in November 2019 and searches were updated in September 2021. Studies were eligible if they included children and/or adolescents with type 1 diabetes, reported on the association between hypoglycemia and QoL (or related outcomes), had a quantitative design, and were published in a peer-reviewed journal after 2000. A protocol was registered the International Prospective Register of Systematic Reviews (PROSPERO; CRD42020154023). Studies were evaluated using the Joanna Briggs Institute's critical appraisal tool. A narrative synthesis was conducted by outcome and hypoglycemia severity.
RESULTS: In total, 27 studies met inclusion criteria. No hypoglycemia-specific measures of QoL were identified. Evidence for an association between SH and (domains) of generic and diabetes-specific QoL was too limited to draw conclusions, due to heterogenous definitions and operationalizations of hypoglycemia and outcomes across studies. SH was associated with greater worry about hypoglycemia, but was not clearly associated with diabetes distress, depression, anxiety, disordered eating or posttraumatic stress disorder. Although limited, some evidence suggests that more recent, more frequent, or more severe episodes of hypoglycemia may be associated with adverse outcomes and that the context in which hypoglycemia takes places might be important in relation to its impact.
CONCLUSIONS: There is insufficient evidence regarding the impact of hypoglycemia on QoL in children and adolescents with type 1 diabetes at this stage. There is a need for further research to examine this relationship, ideally using hypoglycemia-specific QoL measures.

Introduction

Type 1 diabetes is one of the most common chronic conditions among children and adolescents and requires a demanding treatment regimen (e.g., insulin administration several times a day, monitoring of glucose levels and regulation of food intake and physical activity) [1, 2]. The goal of diabetes management is to achieve and maintain recommended glycemic levels to prevent/delay acute and long-term complications [1]. However, treatment with insulin can lead to hypoglycemia (low blood glucose level) [3]. Hypoglycemia can cause immediate uncomfortable symptoms (e.g., shakiness, dizziness), and in severe cases lead to confusion, seizures and coma, where self-treatment is not possible. In addition, recurrent episodes of severe hypoglycemia (SH) have been associated with neurocognitive impairments, especially in young children [4].

Although rates of SH in children and adolescents have decreased significantly in the past two decades, due to improvements in insulin administration and monitoring technologies (e.g., continuous subcutaneous insulin infusion and continuous glucose monitoring) [5-7], a recent systematic review still reported an incidence of 1.21–30 events per 100 person-years in young people with type 1 diabetes [8]. Hypoglycemia is particularly challenging and complex to manage in children and adolescents with type 1 diabetes for several reasons: this group has less predictable eating, activity, and sleep patterns relative to adults; children’s diabetes is often (co-)managed by the parent; and young children may be unable to communicate their symptoms and needs [9]. Among adolescents, both hormonal changes leading to insulin resistance [10] and developmental changes, such as seeking independence from parents, that add to the burden of self-management, can lead to greater fluctuations in glucose levels and increase the risk of hypoglycemia [11].

Another important goal of pediatric diabetes management is to achieve and maintain optimal quality of life (QoL) [12]. While some studies have shown that hypoglycemia is negatively associated with QoL [13, 14], other studies have not found such an association [15, 16]. Although QoL is defined and assessed in many different ways across studies, it is recognized that QoL is a multidimensional, dynamic and subjective construct [17]. It has been argued that, to understand the impact of a condition on QoL, we need to ask people how satisfied they are with the areas of life that are important to them for their overall QoL, and then ask how these areas are affected by the condition, such as diabetes or, more specifically, hypoglycemia [18, 19]. It is therefore important to critically examine the range of patient-reported outcomes (PROs) used in studies, and to determine which are measuring the impact on QoL, and which are measuring related outcomes (such as diabetes-specific emotional distress or health status) rather than QoL [18]. Synthesis of the current evidence base is needed to determine the relationship between hypoglycemia and QoL-related outcomes.

Therefore, our aim was to conduct a systematic review to summarize and critically appraise the evidence regarding the association between hypoglycemia and QoL (and related outcomes) in children and adolescents with type 1 diabetes.

Methods

Search strategy

This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [20] and was registered on the International Prospective Register of Systematic Reviews (PROSPERO; CRD42020154023) database. A systematic search of Medline, Cochrane Library, CINAHL and PsycINFO databases was conducted in November 2019 and updated in September 2021, as part of a larger search strategy for five related systematic reviews examining the impact of hypoglycemia in various populations. Search terms included free-text and subject heading terms relating to the following concepts, separated by the Boolean operator “and”: (1) type 1 diabetes, (2) children and adolescents, (3) hypoglycemia and (4) QoL and related outcomes. There were no limits applied to date or language at the search stage. The search string is provided in S2 File.

Inclusion & exclusion criteria

Studies were eligible if they: (1) included children and/or adolescents with type 1 diabetes, majority aged ≤18 years (or mean age <18 years old), (2) assessed the history of hypoglycemia, (3) included outcomes of generic, diabetes-specific or hypoglycemia-specific QoL (or domains of QoL) or related outcomes (e.g., fear of hypoglycemia, depression, diabetes distress), (4) examined the association between hypoglycemia and QoL or related outcomes, (5) had a quantitative design, (6) were published in a peer-reviewed journal with full text available in English, (7) were published after 2000. The focus was limited to publications in the past two decades, as diabetes management strategies and rates of hypoglycemia have changed considerably in recent decades [5-7]. Studies were excluded if they: (1) focused on cognitive functioning [21] or neurodevelopmental disorders [22], or (2) only included proxy-report (e.g., by parents) of outcomes [23].

Screening, article selection, and data extraction

Abstract screening was completed by three reviewers, with 10% of the abstracts being double screened (AS, AC and MCL). MC completed full text-screening (with input from a second reviewer (MB) where queries arose), and 10% of the full-text records were independently screened by a third reviewer (KM). In case of disagreement, reviewers discussed until consensus was reached. Additionally, forward chaining (i.e., citation searching of included studies in Google Scholar) and backward chaining (i.e., reference list checking of all included studies) was undertaken to identify additional eligible papers. Data extraction was performed by MC and KS; extracted data included reference details, study details, participant characteristics, analysis, results and discussion points. Extracted data were checked by two independent reviewers (HC, MB) and consensus was reached in case of discrepancies.

Risk of bias assessment

Risk of bias was assessed (MC) by the analytical cross-sectional studies critical appraisal tool from the Joanna Briggs Institute (JBI) [24]. Risk of bias assessment was not used to exclude studies but was discussed and summarized to aid interpretation of the quality of the evidence base.

Data synthesis

Narrative synthesis was structured primarily by a conceptual framework of QoL (Table 1), wherein outcomes were grouped based on two dimensions [18]: 1) the scope of the measure (global, broad, specific): i.e. whether a questionnaire assesses global QoL (e.g., ‘overall QoL’), a broad domain of QoL (e.g., social functioning) or a specific domain of QoL (e.g., friends); and 2) the attribution of the measure (generic, diabetes- or hypoglycemia-specific): generic QoL measures ask people to rate areas of their life overall. These ratings can be affected by many factors including but also unrelated to diabetes, whereas diabetes-specific [or hypoglycemia-specific] QoL measures seek to attribute any impact to the condition, specifically asking: ‘how does diabetes [or hypoglycemia] impact on your QoL?’

Table 1

Overview of quality of life and related outcome measures in the included studies, by breadth and attribution.

Quality of Life (QoL) and related outcomes		Generic	Diabetes-specific	Hypoglycaemia-specific
		(no attribution)	(attribution to diabetes)	(attribution to hypoglycaemia)
Global QoL		• KINDL-R Total score [13]	• DISABKIDS DCGM-12 [13, 28]	None
		• PedsQL total score [16, 29–31]	• DQOLY total score [32]
			• DQOLY impact scale [32]
			• DQOLY Diabetes life satisfaction scale [32]
			• DQOLY Short Form total score [33]
Broad domains of QOL	Physical functioning	• KIDSCREEN 27: physical wellbeing [14]	None	None
		• KINDL R: physical [13, 34]
		• PedsQL: physical functioning [16, 31]
		• EQ5D VAS scale [14]
	Social functioning	• PedsQL: social functioning [31]	None	None
		• PedsQL: psychosocial functioning [16, 31]
	Psychological functioning	• KIDSCREEN 27: psychological well-being [14]	None	None
		• KINDL R: emotional wellbeing [13, 34]
		• PedsQL: emotional functioning [31]
		• KIDSCREEN-10 index [14]
Specific domains of QoL	Family	• KINDL R: family [13, 34]	None	None
		• KIDSCREEN 27: Autonomy and relationships with parents [14]
	Friends	• KINDL R: friends [13, 34]	None	None
		• KIDSCREEN 27: Relationships with friends or peers [14]
	School / Studies	• PedsQL: school functioning [31]	None	None
		• KINDL R: school [13, 34]
		• KIDSCREEN 27: school [14]
	Self-esteem	• KINDL R: self-esteem [13, 34]	None	None
	Sleep	• Adolescent Sleep/Wake scale [35]	None	None
Related psychological outcomes		• Screen for Child Anxiety-Related Disorders [36]	• DQOLY: Worries about diabetes [32, 37]	• Hypoglycaemia Fear Survey–child version (HFS-C) total scale [15, 38, 39]
		• ICD-10 anxiety disorder diagnosis [40]	• KINDL-R chronic illness scale [34]
				• HFS-C ‘worries about hypoglycaemia’ subscale [36, 38, 41, 42]
			• PedsQL DM: diabetes distress [15, 29, 30, 42, 45, 46]
		• State-Trait Anxiety Inventory for Children, Trait Subscale [38]		• HFS-C ‘fear of hypoglycaemia related behaviors’[36, 38, 41]
			• PedsQL DM: ‘diabetes symptoms’ [42]
				• Child Posttraumatic Stress
			• PedsQL DM: ‘diabetes management’ [42]	• Reaction Index (hypoglycaemia is referred to as the traumatic event) [47]
		• Center for Epidemiological Studies-Depression Scale [43, 44]
			• DISABKIDS impact scale [13, 28]
				• Child Hypoglycaemia Index-2 [44]
		• Children’s Depression Inventory, Short version [48]	• Diabetes Eating Problem Survey-Revised [50]
		• Adolescents–IV (DSM IV depression diagnosis) [49]

If a measure did not assess QoL but assessed a concept closely related to QoL (such as depressive symptoms, diabetes distress, FoH), it was classified as a related outcome. Diabetes distress refers to the negative emotions related to living with diabetes [25]. These related outcomes were grouped by the attribution of the measure (generic, diabetes- or hypoglycemia-specific outcome). Within each outcome group, study findings were summarized separately for SH and non-severe hypoglycemia (NSH) according to the authors’ definitions, and where possible by outcome type/questionnaire.

To enhance consistency and transparency in the narrative synthesis and to avoid vote counting based on statistical significance [26], the following considerations were taken into account to interpret the evidence per outcome: 1) whether definitions and recall periods of hypoglycemia varied between studies; 2) whether there was a valid assessment of QoL and/or related outcomes; 3) whether analyses were conducted for children and adolescents separately or together; 4) whether there were exclusion criteria that directly related to hypoglycemia or QoL outcomes; and 5) whether effect sizes were available: small (r≥0.10 and <0.30), moderate (r≥0.30 and <0.50), and large r≥0.50) [27].

It was determined that there was insufficient evidence to draw a conclusion for an outcome if: a) there were less than three studies examining the association, or b) there was considerable heterogeneity in definitions of hypoglycemia and sample characteristics across studies.

Results

Included studies

The searches yielded 1165 results. Title and abstract screening resulted in 217 potential includes. After full-text screening, 17 studies were included. An overview of the full-text papers that have been assessed for eligibility with reasons for exclusion is provided in S1 Table. Forward and backward chaining yielded 10 extra includes. In total, 27 studies were included for data extraction and synthesis. Fig 1 provides an overview of the screening and selection process.

Fig 1

PRISMA flowchart of the systematic search and screening, reasons for exclusions, and final number of included studies.

Study characteristics

The 27 studies included a total of N = 141,530 participants, with sample sizes ranging from N = 39 to N = 2,602, with the exception of two large-scale studies (N = 53,986 and N = 75,258). The studies were conducted in 18 countries, the majority conducted in USA (n = 6) and Germany (n = 4). One study included multiple countries in Europe, North America and Japan [37]. The age of participants ranged from 5–25 years. Most studies included participants between 8–18 years, although eight studies also included participants above 18 years, and four studies also included participants aged 5–7 years. One study included children aged 6–12 years and five studies included adolescents aged 12–18 years. Study characteristics are detailed in Table 2.

Table 2

Sociodemographic and clinical information and inclusion and exclusion criteria of the included studies.

Author, year Country	Study design; Sample size	Age in years Mean (SD), Range	Diabetes duration in years Mean (SD)	Diabetes management	Inclusion/Exclusion criteria	HbA1c (DCCT unit) Mean (SD)	Hypoglycaemia assessments
Adler et al. (2017) [35] Israel	Cross-sectional N = 45	14.9 (1.7) R (12.2–17.9)	5.9 (3.6)	MDI: 28.9% CSII: 71.1% CGM 35.6%	Included: age 6–30 years, diabetes duration: ≥1 year Excluded: psychiatric / neurological comorbidities, psychotropic medication, night shifts in the last 3 months, language difficulties	7.96 (1.47)	No. of nocturnal H episodes last month: Less than once/week 48.9% 1–2 times/week 17.8% ≥3 times/week 6.7%
Al Hayek et al. (2014) [36] Saudi Arabia	Cross-sectional N = 187	15.3 (1.6)	7.1 (5.2)	CSII 19.3% MDI 80.7%	Included: age 13–18 years, follow up for ≥12 months Excluded: psychopathological and medical instability, visual, hearing, or cognitive impairment	HbA1c >7 81.8% HbA1c ≤7 18.2%	Trouble with H past 12 months: 1–2 times: 7.5% 3–6 times: 34.9% 7–11 times: 16.6% ≥12 times: 41.8% Passed out due to H: 33.2% H episode while asleep: 82.9% H while awake but by themselves: 67.9% H in front of friends of strangers: 84% H when at school: 80.7%
Amiri et al. (2014) [39] Iran	Cross-sectional N = 61	9.2 (2.0) R (6.0–12.7)	3.2 (2.0) R (0.5–10.5)	NR	Included: age 6–12 years, diabetes duration≥6 months Excluded: other diseases (e.g., thyroid, celiac)	NR	Mean number of SH (past 3 months): 1.4 SD 5.4, range 0–36
Caferoglu et al. (2016) [16] Turkey	Cross-sectional N = 70	Median 13.0 R (11.00–15.00)	Median 3.5R (2.0–6.0)	MDI 100%	Included: aged 8–18 years, diabetes duration ≥1 year, using MDI Excluded: mental retardation and/or other chronic diseases (coeliac disease, hypothyroidism etc.)	Median 7.80, R (7.10–9.03)	Median and (Q1-Q3) number of NSH episodes 2.50 (0.00–5.25)
Coolen et al. (2021) [42] The Netherlands	Cross-sectional N = 96	15.2 (1.6) R 12–18	7.0 (4.3)	MDI:19% CSII: 81% CGM: 33%	Included: diabetes duration ≥ 6 months, no intellectual disabilities	7.5 (.9) R 5.3–10.4	No SH past 12 months: 80% SH past 12 months: 20% Mean number SH past 12 months: 0.7(2.4). Mean number of NSH past 6 months: 17.4 (29.9)
Dłużniak-Gołaska et al. (2019) [46] Poland	Cross-sectional N = 197	13.9 (2.3) R (8–18)	<5 years: 45.7% ≥5 years: 54.3%	CSII 100% CGM 31%	Included: diabetes duration ≥1 year, CSII treatment Excluded: other chronic diseases (e.g., coeliac disease)	NR	No/several times a month: 131 Several times a week/every day: 66
Galler et al. (2021) [40] Germany, Austria, Switzerland, and Luxembourg	Observational N = 75,258	16.4 R 13.1–17.7	6.0 R 3.3–9.4	CSII: 41%	Included: diabetes duration ≥1 year from 431 participating centers between 1995 until June 2019	7.9 R 7.1–9.0	Rate of SH/patient year (95% CI): 12.8 (12.4; 13.3)
Gonder-Frederick et al. (2006) [38] USA	Cross-sectional N = 39	15.4 (1.5)	7.0 (4.0)	CSII 36%	Included: age 12–17 years, diabetes duration ≥1 year Excluded: significant comorbidity (e.g., cystic fibrosis) and cognitive or learning disabilities	NR	Mean number NSH in past 12 months: 6.74, SD 5.03 Mean number SH past 12 months; 0.46, SD 2.11
Hanberger et al. (2009) [28] Sweden	Cross-sectional N = 93 children N = 145 adolescents	13.2 (3.9) R (8–19.6)	5.1 (3.8) R (0.3–17.6)	CSII 17%	NR	7.1(1.2) R (4.0–10.7)	NR
Hassan et al. (2017) [33] Egypt	Cross-sectional N = 150	12.3 (1.8) R (10–18)	<3 years: 46.7% 3–5 years: 34.7% >5 years: 18.6%	NR	Included: age 10–18 years, diabetes duration ≥1 year, completed diabetes education program	<7.5, 42.7% 7.5–9.0, 32% >9.0, 25.3%	SH with coma: 7% SH without coma: 93%
Hoey et al. (2001) [37] Multi country (17 countries in Europe, Japan and North America)	Cross-sectional N = 2101	13.8 R (10–18)	5.2	NR	Included: age 10–18 years, born between 1980–1987	8.7 (1.7) R (4.8–17.4)	Incidence of SH = 15.6 /100 patient years
Johnson et al. (2013) [15] Australia	Cross-sectional N = 196	11.8 (3.7)	4.8 (3.5)	CSII 34.8%	Included: age 8–18 years old, diabetes duration ≥6 months, recent clinic attendance Excluded: significant comorbid condition, parent unable to answer the questionnaire	8.0 (0.9)	SH: 18.8%
Jurgen et al. (2020) [44] USA	Cross-sectional N = 83	13.87 (3.21)	NR	CSII: 45% MDI: 24% 2 daily injections: 31%	Included: age 8–20 years, diabetes duration ≥1 year Excluded: type 2 diabetes, under 18 without parent, no HbA1c measurement, no blood glucose meter	9.5 (1.8)	SH: 12.8%
Kalyva et al. (2011) [29] Greece	Cross-sectional N = 117	10.9 (4.0) R (5–18)	NR	MDI 99% CSII 1%	Included: age 5–18 years, diabetes duration ≥1 year	8.05 (1.39) R (5.5–11.9)	Mean number of NSH episodes 5.82 SD 1.08, R 0–7
Lawrence et al. (2012) [45] USA	Cross-sectional N = 2,602	13.6 (4.1)	5.2 (3.9)	MDI 50% CSII 22%	Included: age >5 years, diabetes duration ≥1 year Excluded: not taking insulin, no HbA1c measurements	Good glycemic control, n = 32.3% Intermediate glycemic control, 47.6% Poor glycemic control = 20.1%	0 SH = 88.1% 1 SH = 6.6% ≥ 2 SH = 5.3%
Matziou et al. (2010) [32] Greece	Cross-sectional N = 98	14.9 (2.4)	7.3 (4.0)	CSII 32.7%	Included: age 11–18 years diabetes duration ≥6 months Excluded: psychiatric disorders	NR	NSH in past 3 months: 23.5% No NSH in past 3 months: 76.5%
Murillo et al. (2017) [14] Spain	Cross-sectional N = 136	13.5 (2.9)	5.0 (3.7)	MDI 98.5% CSII 1.5%	Included: age 8–19 years, diabetes duration ≥6 months Excluded: cognitive problems	NR	SH in past 3 months: 2.2% No SH in past 3 months: 97.8%
Naughton et al. (2008) [31] USA	Cross-sectional N = 2,188	14.6 (3.6)	6.2 (3.9)	Oral /no diabetes medications 0.6% MDI 76.9% CSII 22.5%	Included age≤20 years, resident in geographical center population, member of the participating health plan Excluded: diabetes as secondary to another condition	NR	0 SH in past 6 months: 88.1% 1 SH in past 6 months: 6.4% ≥2 SH in past 6 months: 5.5%
Nip et al. (2019) [50] USA	Cross-sectional N = 2,156	17.7 (4.3) R (10–25)	NR	CSII 55% CGM 18.5%	Included: diabetes duration ≥5 years, diagnosed between 2002–2008 Excluded: type 2 diabetes not on insulin.	NR	NR
Plener et al. (2015) [49] Germany/Austria	Observational N = 53,986	NR	5.77	NR	Included: Age <25 years	NR	Rate of SH/patient year (95% CI)—Depression: 0.56 (0.52–0.58), No depression: 0.20 (0.19–0.20) Rate of SH coma/patient year (95% CI)—Depression: 0.04 (0.03–0.05), No depression: 0.03 (0.03–0.03)
Riaz et al. (2017) [43] Pakistan	Cross-sectional N = 104	15.8 (3.1)	5.1 (4.0)	NR	Included: age 12–20 years, diabetes duration ≥1-year, recent clinic attendance Excluded: comorbid mental disorders or receiving psychotherapy	10.3 (3.5)	SH in past six months = 20.2%
Serkel-Schrama et al. (2016) [30] The Netherlands	Cross-sectional online survey N = 129	14.0(2.0) R (12–18)	6.0 (4.0) R (0–18)	CSII 71%	Included: age 12–18 years, self-reported type 1 diabetes, sufficient language skills	NR	No SH in last 12 months: 78% ≥1 SH last in 12 months: 12%
Shepard et al. (2014) [41] USA	Observational (validation study) N = 2591	10.6 (3.3) R (6–18)	5.2 (3.3)	MDI 60% CSII 40%	Included: diabetes duration ≥1 year, 4 BG readings/day for 4 weeks Excluded: medical comorbidities (e.g., asthma, cystic fibrosis), cognitive or learning disabilities	8.01 (0.97)	NR
Sismanlar et al. (2012) [47] Italy	Cross-sectional N = 42	M 13.67, SD 2.39	3.8 R (1–12)	NR	Included: age 8–18 years	7.9	SH: 28.6% H attacks in last month CTPS-RI<40: 7.11 (6.89), CPTS-RI ≥40: 13.57 (15.34)
Stahl-Pehe et al. (2013) [13] Germany	Cross-sectional N = 840	M 16.3, SD 2.3 R (11.3–21.9)	M 13.3, SD 2.0, R (10.0–17.7)	CSII: 46.9% MDI 53.1%	Included: age 11–21 years, age of onset <5 years, diagnosed between 1993–1999, diabetes duration ≥10 years	8.3 (1.4) R (5.6–15.4)	No SH in the last year: 41.7% SH in the last year (incl. last six months): 34.1% SH in last month (incl. last week): 24.3%
Strudwick et al. (2005) [48] Australia	Cross-sectional N = 84	10.1 R (6–15)	6.9	NR	Included: age of onset <6 years, treatment at the center Excluded: neurologic or significant health problems unrelated to diabetes, psychiatric condition, developmental delay	NR	SH with seizures: 48.8% Number of SH: M; 2.5, SD; 2.2
Wagner et al. (2005) [34] Germany	Cross-sectional N = 68	8–12 years: 72% 13–16 years 28%	M 4.2, SD 2.8, R (0.42–11.33)	MDI 100%	Included: age 8–16 years, diabetes duration ≥5 months	NR	SH: 19.6/100 patient years

CGM, continuous glucose monitoring; CSII, continuous subcutaneous insulin infusion; H, hypoglycemia; MDI, Multiple daily injections; NR, not reported; SD, standard deviation; SH, severe hypoglycemia.

a Aggregation of five studies.

All studies had a cross-sectional design. Assessment of hypoglycemia relied mostly on retrospective self-report (n = 19, 70%), with recall periods ranging from the past month (n = 4) to the past three (n = 5), six (n = 5) or 12 months (n = 7), to period since diagnosis (n = 1). Hypoglycemia was reported by the child or adolescent with diabetes (n = 10, 34%), their parent(s) (n = 7, 24%), or both (n = 1, 4%); or based on a combination of self-report and glucose meter data (n = 2, 8%). Six studies (22%) focused on hypoglycemia that involved coma or seizures, assessed via medical records. Two studies (7%) did not specify how hypoglycemia data were derived.

Twenty-one studies (78%) examined SH, defined as episodes: 1) where assistance of others was needed (n = 4); 2) resulting in confusion or seizures/coma (n = 7), or 3) characterized by a combination of these definitions (n = 8). Four studies did not specify a definition of SH. Ten studies (37%) examined “moderate” hypoglycemia, which will be referred to as “non-severe” hypoglycemia (NSH) throughout this review. Although it is recognized that NSH is usually referred to as “self-treated” hypoglycemia [51], that is not appropriate when describing hypoglycemia in (younger) children, as their parents often need to help regardless of the severity of the episode. Twelve studies (44%) used a continuous measurement of hypoglycemia (e.g., frequency of SH in the past 6 months), and fifteen (55%) reported on categorical measurement of hypoglycemia (e.g., absence or presence of SH).

The studies included 19 instruments to assess QoL and related outcomes (Table 1). The most commonly used were the Hypoglycemia Fear Survey Child Version (HFS-C) (n = 6) and the Pediatric Quality of Life Inventory (PedsQL) Generic (n = 4) and Diabetes (n = 6) modules. An overview of all scales being used in the studies can be found in S2 Table.

Of the 27 studies, 93% included participants with a medically-verified diagnosis of type 1 diabetes. Most provided adequate details of their inclusion and exclusion criteria (89%) and participants and settings (74%). In 52% of the studies, hypoglycemia was defined in accordance with the current International Society for Pediatric and Adolescent Diabetes (ISPAD) definition; namely, SH as an event with severe cognitive impairment (including coma and seizures) requiring assistance by others, and NSH as events with a blood glucose value ≤3.9 mmol/L (70 mg/dL) [52]. Most studies (81%) used statistical analyses appropriate to their data and, while all studies identified confounding factors, 67% adjusted analyses accordingly. Most studies (70%) used psychosocial outcome measures that were psychometrically valid and reliable instruments for use with children and adolescents with type 1 diabetes. In 11% of the studies, both validated and non-validated measures [13, 28, 36] were used, while 19% included measures that were not validated in adolescents with type 1 diabetes [14, 34, 35, 43, 47]. A full overview of the risk of bias assessment is presented in S3 Table.

Narrative synthesis

Table 3 provides a summary of the main findings of each study.

Table 3

Hypoglycemia definition, measurement and relationship with quality of life and related outcomes.

Author, year [ref]	Hypoglycaemia definition	Hypoglycaemia measurement	Recall period (months)	QoL domain or related outcome	Instrument	Findings: Association between hypoglycaemia and QoL / related outcome
Adler et al. (2017) [35]	Nocturnal H: BG levels <70 mg/dL or symptomatic H	No. nocturnal H episodes; self or parent reported	1	Sleep quality	ASWS	N.S. for sleep quality (data NR)
Al Hayek et al. (2014) [36]	Frequency of trouble with H episodes Passed out due to H H episode while asleep H episode while you were awake but by yourself H in front of friends or strangers? H when you were at school?	Categorical (1–2, 3–6, 7–11, >11) and yes vs. no; self-reported	12 Ever	Worries about H; H related behavior; panic disorder; generalized anxiety disorder; separation anxiety disorder; social anxiety disorder; significant school avoidance	HFS -C SCARED	1Pass out due to H associated with H related behaviors (β = 0.502***), separation (β = 0.189**) and school anxiety (β = -0.271***) H while asleep associated with worries about H (β = -0,508**) GAD (β = -0.253, p**) and separation anxiety (β = -0.274**) H while awake associated with H related behaviors (β = -0.300*), worries about H (β = -0.508**), panic disorder (β = -0.318***), GAD (β = -0.206**) and social anxiety (β = -0.388***) H in front of friends associated with panic disorder (β = 0.595***), GAD (β = 0.537***), separation anxiety (β = 0.321**), social anxiety (β = 0.362**) and school anxiety (β = 0.303***). H at school associated with H related behaviors (β = -0.312*), panic disorder (β = -0.284***), GAD (β = -0.177*), separation anxiety (β = -0.232**) and social anxiety (β = -0.367***) All other associations are N.S. Covariates: age, gender, education, exercise, treatment type, duration of T1D, HbA1c, passing out due to H, H as a big problem, H in front of friends and strangers and H at school
Amiri et al. (2014) [39]	SH: H with unconsciousness or consciousness but needing parent’s help for treatment due to mental confusion and disorientation	No. of SH episodes; parent-reported	3	FoH Worries about H H related behaviors	HFS-C	N.S. for FoH (data NR)
Caferoglu et al. (2016) [16]	NSH: BG levels < 70 mg/dL, without seizures or coma	No. of NSH episodes; collected in interviews and checked with records from glucometers	1	Physical functioning; psychosocial functioning; general QoL	PedsQL	N.S. for psychosocial functioning, physical functioning and general QoL (p>0.05)
Coolen et al. (2021) [42]	SH: H when your blood glucose was so low that you were unable to recognize symptoms, ask for help, or treat yourself due to mental confusion or unconsciousness NSH: H when your blood glucose was so low that it interfered with what you were doing, and you had to wait a while to recover	No. of SH and NSH episodes; Self-reported	SH: 12 NSH: 6	Worries about H DD Diabetes symptoms Diabetes management	HFS-C PedsQL DM	↑ SH associated with ↑ worries about H** (r = 0.32) N.S. for NSH and worries about H (r = 0.17, p>0.05) N.S. for SH and NSH and diabetes distress, diabetes symptoms, or diabetes management (p>.05). Covariates include age, gender, HbA1c, frequencies of H, perceived severity of H, fear of hypoglycaemia
Dłużniak-Gołaska et al. (2019) [46]	NSH: BG levels < 70 mg/dL	No/several times a month vs. Several times a week/every day; self-reported	NR	DD	PedsQL- DM	N.S. for DD (p>0.05) Covariates: method of controlling glycemia, daily insulin dose, hyperglycemia, carbohydrate exchanges (CE) calculation and infections
Galler et al. (2021) [40]	SH: loss of consciousness or seizure or requiring assistance from another person to actively administer carbohydrates, glucagon, or intravenous glucose)	No. of SH episodes	NR	Anxiety disorders	ICD-10 German Modification	N.S. for rates of hypoglycaemia per 100 patient years between those with and without anxiety disorders (p>0.05) Covariates: age, sex, diabetes duration, migratory background, type of insulin therapy, and treatment year and depression
Gonder- Frederick et al. (2006) [38]	NSH: BG so low that it interfered with the adolescent’s ability to function, but did not become so mentally disoriented that self-treatment was not possible SH: BG resulting in neuroglycopenia that interfered with the adolescent’s ability to self-treat due to mental disorientation, unconsciousness, or seizure H in situations where the parent was not present (e.g., while sleeping, alone, at school, and in social situations)	No. of H episodes (severe and moderate); parent-reported	12	FoH Worries about H H related behaviors Trait Anxiety	HFS C STAIC	SH with unconsciousness ↑ FoH vs. no SH with unconsciousness* ↑ SH associated with ↑ worries about H** and FoH** Only for girls after adjustment for gender (Total: r = .59*; Worries: r = .55*) ↑ H episodes in social situations associated with ↑ trait anxiety (r = 0.37*) ↑ SH associated with ↑ FoH and ↑ worries about H** N.S. for SH and H related behaviors or trait anxiety (data NR) N.S. for H and FoH, worries about H, H related behaviors and trait anxiety (data NR) Covariates: trait anxiety scores frequency of H over the past year frequency of H, SH, episodes in situations where the child was likely alone) and gender
Hanberger et al. (2009) [28]	SH: needing assistance from another person	No SH vs. SH; self-reported	12	Diabetes-specific QoL and DD	DISABKIDS -DCGM-12 DISABKIDS Diabetes Module	N.S. differences for diabetes-specific QoL and DD (data NR) Covariates: gender, age, duration, HbA1c, frequency of BG tests, parents living together or not, mother’s educational level, use of insulin pump and center SH only associated with ↓ diabetes-specific QoL in single parent families, for adolescents (B = -1.22*) and children (B = -0.92*)
Hassan et al. (2017) [33]	SH with or without coma	SH with coma vs. SH without coma); taken from the medical record	NR	Diabetes-specific QoL	DQOL-Y	SH with coma vs. without coma associated with ↓ diabetes-specific QoL*
Hoey et al. 2001 [37]	SH: seizures or unconsciousness	No SH vs. ≥1 SH; self-reported	3	Worries about diabetes	DQOL-Y	≥1SH associated with ↑ worries about diabetes than no SH (B = 4.2*)
Johnson et al. (2013) [15]	SH: event resulting in a seizure or coma	No SH vs. ≥1 SH; taken from Western Australia Childhood Diabetes Database	NR	DD FoH	PedsQL-DM HFS-C	N.S. for DD or FoH (p>0.05) Covariates: age and diabetes duration
Jurgen et al. (2020) [44]	SH: seizure or loss of consciousness	Parent reported	NR	FoH Depression	CHI-2 CES-DC	N.S. for FoH and depressive symptoms (r < .15, p>.05)
Kalyva et al. (2011) [29]	NSH: BG levels < 60 mg/dL without seizures or coma	No. of NSH episodes; parent-reported	1	General QoL DD	PedsQL PedsQL-DM	N.S. for general QoL or DD (p>0.05) Covariates: gender, age of onset episodes, number of hyperglycemic episodes, and HbA1c
Lawrence et al. (2012) [45]	SH: event requiring assistance of another person	No SH vs. 1 SH No SH vs. ≥ 2 SH; parent-reported	6	DD	PedsQL-DM	≥ 2SH vs. no SH associated with ↑ DD** N.S. difference in no SH vs. 1 SH and DD (p>0.05)
Matziou et al. (2010) [32]	NSH: BG values <3.9 mmol/L (70 mg/ dL)	No NSH vs. ≥1 H; self-reported	3	Life satisfaction; disease impact; disease related worries; diabetes- specific QoL	DQOLY	N.S. for diabetes life satisfaction, disease impact, disease related worries and diabetes-specific-QoL (p>0.05)
Murillo et al. (2017) [14]	SH: BG levels <60 mg/dl with decreased level of consciousness requiring glucagon or the help of others	No SH vs. SH; taken from medical record	3	General QoL, health status, physical wellbeing; psychological wellbeing; parents/autonomy peers; school	EQ5D VAS KIDSCREEN-10 index KIDSCREEN 27	SH vs. no SH associated with ↓ general QoL (ES 1.28*) N.S. for health status, physical wellbeing, psychological wellbeing, parents/autonomy, peers and school (p>0.05)
Naugthon et al. (2008) [31]	SH: event requiring assistance of another person	No SH vs. 1 SH No SH vs. ≥2 SH; self-reported	6	Overall generic QoL; psychosocial; social; school; physical health; emotional	PedsQL	≥ 2 SH vs. no SH associated with ↓ physical health (β = -4.00***) N.S. for physical health between those with 1 SH vs. no SH and between those with 1 or ≥2 SH vs. no SH on general-QoL, social functioning, school functioning, emotional functioning and psychosocial functioning (p>0.05) Covariates: sex, race/ethnicity, age, highest level of parent education, and type of health insurance, BMI z score, duration of diabetes, type of diabetes treatment, HbA1c level, number of comorbid conditions, emergency department visits, and hospitalizations in the preceding 6 months
Nip et al. (2019) [50]	SH: event requiring assistance of another person	No. of SH; self-reported	6	Overall eating behavior	DEPS-R	N.S. difference in frequency of SH between those with DEB vs. without DEB (data NR)
Plener et al. (2015) [49]	SH with need of assistance of other persons, defined by unconsciousness, seizures, or application of glucagon or intravenous glucose	Rate of SH/patient year, rate of SH coma/patient year; taken from patient registries	H/patient year, recorded prospectively	Depression (diagnosis or symptoms)	ICD-10 and DSM-IV	SH /patient year ↑ in those with depression vs. without depression**N.S. for SH coma/patient year (p>0.05)
Riaz et al. (2017) [43]	SH and hospitalizations due to H	No SH vs. SH No hospitalization due to H vs. hospitalizations due to H	6	Depression	CES-D	N.S. for SH or hospitalizations due to H (p>0.05)
Serkel-Schrama et al. (2016) [30]	N/A	No SH vs. SH; parent-reported	12	General QoL and DD	PedsQL PedsQL-DM	SH vs. NO SH associated with ↑ DD (r = -0.19*) N.S. for generic QoL (p>0.05)
Shepard et al. (2014) [41]	SH (N/A) SH episodes requiring medical attention and NSH: % of readings <70 mg/dl	No. of SH episodes; Parent-reported	12	Helplessness; avoidance; maintaining high BG; social consequences	HFS C	↑ SH associated with ↑ helplessness (r = 0.19**) N.S. for SH and maintaining high BG, avoidance and worry about negative social consequences (data NR) Those who needed medical attention due to H vs. those without reported ↓ avoidance* N.S. for medical attention due to H and helplessness, maintain high BG and worry about negative social consequences (data NR) Children scoring in the highest tertile vs. the lowest tertile of maintain high BG had ↑ SH episodes* N.S. for SH episodes, medical treatment due to H and % of readings <70 mg/dl and avoidance (p>0.05) and for medical treatment due to H and % of readings <70 mg/dl and maintaining high BG (p>0.05)
Sismanlar et al. (2012) [47]	NSH: BG levels <60mg/dl SH: H plus one of the following: BG levels ≤30 mg/dl, loss of consciousness, requirement of glucagon injection parenteral treatment at hospital	No. of SH; taken from BG charts and patients’ home notes	1	PTSD	CPTS-RI	↑ SH associated with ↑ PTSD (ß = 0.450*) N.S. for any SH and PTSD (data NR) N.S. difference in SH in last month or any SH between those with severe PTSD and those with mild/moderate PTSD (p>0.05)
Stahl-Pehe et al. (2013) [13]	N/A	No SH vs. SH in past 12 months No SH vs. SH in past month; self-reported	12	Physical wellbeing; emotional wellbeing; self-esteem; family; friends; school; general QoL; diabetes impact; diabetes treatment; overall diabetes specific QoL	KINDL-R DISABKIDS	SH past year vs. no SH associated with ↓ quality of relationship friends (β = -3.1*) SH past month vs. no SH associated with ↓ emotional wellbeing (β = -4.2**), ↓ school functioning (β = -4.1*), ↓ general QoL (β = -3.0**), ↓ diabetes-specific QoL(β = -4.5**) ↓ diabetes impact (β = -3.8*) and ↓ diabetes treatment (β = -6.6**) N.S. association for SH past year or month vs. no SH and physical wellbeing, self-esteem, relationship with family (p>0.05) N.S. for SH past year and school functioning, diabetes-specific QoL, diabetes impact and diabetes treatment, general QoL emotional wellbeing (p>0.05) N.S. for SH past month and relationship with friends (p>0.05) Covariates: sex, age group, socioeconomic status, family structure, HbA1c level, insulin regimen, treatment satisfaction, weight status, and history of hospitalization
Strudwick et al. (2005) [48]	SH: resulting in seizure or coma	SH without seizure vs. SH with seizure; taken from medical record	Collected at clinics every 3 months	Depression	CDI -S	N.S. for depressive symptoms (data NR)
Wagner et al. (2005) [34]	SH: episodes with severe neurological dysfunction (e.g. seizures, loss of consciousness, disorientation, inability to arouse from sleep) that require intervention with glucagon or intravenous dextrose or milder forms of hypoglycaemia associated with neurological dysfunction that were not recognized or self-treated	No. of SH episodes	NR	Physical; psychological; wellbeing; self-esteem; family; friends; school, illness related distress	KINDL-R	N.S. for physical wellbeing, psychological wellbeing, self-esteem, family, friends, school and illness related distress (data NR) Covariates: age and gender

ASWS, Adolescent Sleep Wake Scale; CDI-S, Children’s Depression Inventory, Short version; CES-D, Center for Epidemiological Studies-Depression Scale; CHI-2, Child Hypoglycemia Index 2; CPTS-RI, Child Posttraumatic Stress Reaction Index, DEPS-R, Diabetes Eating Problem Survey-Revised; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders; DQOLY, Diabetes Quality of Life for Youth scale; EQ-5D, EuroQoL 5 Dimensions; HFS-C, Hypoglycemia Fear Survey-Children version; ICD-10, International Classification of Diseases -10, PedsQL, Pediatric Quality of Life Inventory; PedsQL-DM, Pediatric Quality of Life Inventory-Diabetes Module; SCARED, Screen for Child Anxiety Related Emotional Disorders; STAIC, State-Trait Anxiety Inventory for Children.

BG, blood glucose; DD, diabetes distress; FoH, fear of hypoglycemia; H, hypoglycemia; SH, severe hypoglycemia; No., number; N.S., Not significant (p>0.05); PTSD, Post-Traumatic Stress Disorder; QoL, quality of life, sig., significantly.

a Multivariate analysis are displayed only.

*p<0.05,

**p<0.01,

***p<0.001.

Global QoL

Table 1 shows that both generic measures and diabetes-specific measures of global QoL were used. One study used a non-validated questionnaire [13]. The age of the participants in these studies ranged from 11–21 years, and one study conducted analysis for children and adolescents separately [30].

Severe hypoglycemia. Three studies examined the relationship between SH and generic QoL using the KINDL-R [13] or the PedsQL [30, 31]. One study showed that those with SH (not further defined) in the past month reported significantly lower QoL than those without SH, but this was not observed for SH in the past year [13]. Two studies found no significant differences in generic QoL between groups with and without SH (not further defined [30] or episodes requiring assistance from others [31]) in the past 6 [31] to 12 months [30].

Three studies explored the association between SH and diabetes-specific QoL using the DISABKIDS DCGM-12 [13, 28] or the DQOL-Y [33]. In two studies, SH (not defined [13] or episodes requiring assistance [28]) in the past 12 months was not associated with diabetes-specific QoL after adjustment for covariates (e.g., age, gender, HbA1c). However, one of these studies indicated that those who experienced SH (not further defined) in the past month reported significantly lower diabetes-specific QoL than those who had not [13]. The third study found that SH with coma since diagnosis was significantly associated with lower diabetes-specific QoL [33].

Non-severe hypoglycemia. One study found no significant differences diabetes-specific QoL scores on the DQOL-Y, between those who experienced NSH (glucose levels below 70 mg/dl) in the past three months and those who did not [32].

Two studies reported no significant association between frequency of NSH (glucose levels below 60 or 70 mg/dl) in the past month and generic QoL (PedsQL) after adjusting for covariates such as gender, hyperglycemia and age of onset of diabetes [16, 29].

Broad and specific domains of QoL

Table 1 shows that studies examined three broad domains of QoL (psychological, physical, or social functioning), and/or the following specific domains of QoL: school, family, friends, self-esteem and sleep. Three studies used non-validated QoL questionnaires [13, 14, 34]. The participants’ age range was 8–21 years, one study only included adolescents aged 12–18 [35].

Severe hypoglycemia. Four studies examined the relationship between SH (not further defined [13], or inability to self-treat due to neurological dysfunction [14, 34] or requiring assistance from others [31]) and broad domains (physical, psychological, social), or specific domains (self-esteem, family, friends or school) of QoL.

Three studies found no significant relationship between SH in the past 1–12 month(s) and physical functioning, [13, 14, 34]. In contrast, one study indicated that those with two or more episodes of SH in the past six months reported significantly lower physical functioning than those without SH, but not for those who only had one SH [31].

Three studies found no significant relationship between SH in the past six [31] to 12 months and psychological functioning [13, 31, 34]. However, one study examined various recall periods and found that SH in the past month was significantly associated with lower psychological functioning [13]. The fourth study reported that those with SH in the past three months reported significantly lower psychological functioning than those without [14]. Two studies examined the association between in the past 1–12 months and self-esteem and found no significant results [13, 34].

One study reported no significant associations between SH in the past six months and social functioning [31]. Three studies reported no significant associations between SH in the past 1–12 months and relationships with family [13, 14, 34]. None of the studies reported a significant association between SH in the past 3–12 months and school [13, 14, 31, 34], although one study indicated that SH in the past month was significantly associated with lower school functioning [13]. Three studies examined the association between SH and quality of friendship [13, 14, 34]. One found that SH in the past year was significantly associated with lower quality of friendship, but this was not observed for SH in the past month [13]. Two studies found no significant association between SH and quality of friendship in the past 3–12 months [14, 34].

Non-severe hypoglycemia. Two studies examined associations of NSH and domains of QoL using the PedsQL [16] or the ASWS [35]. The first study found no significant associations between NSH (glucose levels below 70 mg/dl) in the past month and physical functioning or psychosocial functioning [16]. The second study found no association between nocturnal hypoglycemia (glucose levels below 70 mg/dl or symptomatic hypoglycemia) in the past month and adolescents’ sleep quality [35].

Related outcomes-hypoglycemia-specific

Table 1 shows that although hypoglycemia-specific QoL was not assessed, related outcomes were assessed, including fear of hypoglycemia (FoH), and hypoglycemia-specific post-traumatic stress symptoms. One study used a non-validated questionnaire [47]. The participants’ age range was 6–20 years. Three studies specifically focused on adolescents aged 12–18 [36, 38, 42] and one on children aged 6–12 [39].

Severe hypoglycemia. Seven studies examined the association between SH and FoH measured with the HFS-C [15, 36, 38, 39, 41, 42] or the CHI-2 [44].

Four studies examined relationships between SH and worries about hypoglycemia [36, 38, 41, 42] Three of these studies reported significant, small-to-medium, positive correlations between frequency of SH (not further defined [41] or inability to self-treat due to mental disorientation or seizures [38, 42]) in the past 12 months and greater worries about hypoglycemia. However, in one study, this only remained statistically significant for female adolescents after controlling for gender [38]. The fourth study found no significant difference in worries about hypoglycemia between adolescents who never lost consciousness and those who ever lost consciousness due to SH, after controlling for covariates such as age gender and other types of hypoglycemia [36].

Three of the studies also explored associations between SH and FoH related behaviors [36, 38, 41]. One study reported no significant association between frequencies of SH episodes (inability to self-treat due to mental disorientation or seizures) and FoH related behaviors [38]. The second study indicated that those who had passed out due to hypoglycemia significantly reported more hypoglycemia related avoidance behaviors compared to those who had never passed out [36]. In contrast, the third study reported that those who needed medical attention due to SH reported significantly less hypoglycemia related avoidance behaviors than those who did not [41].

Three of the eight studies examined associations between SH (inability to treat due to mental confusion or unconsciousness in the past three months [39] or SH resulting in seizures or coma [15, 44]) and overall FoH, but found no significant associations [15, 39, 44].

An additional study found that frequency of SH (loss of consciousness or requirement of glucagon) in the past month was a significant predictor of self-reported post-traumatic stress (PTSD) assessed with the CPTS-RI after adjustment for age and family history of diabetes [47].

Non-severe hypoglycemia. Four studies explored the relationship between NSH and HFS-C subscale scores [36, 38, 41, 42]. Three of these studies reported no significant associations between frequency of NSH (glucose values below 70 mg/dl [41] or interfering with ability to function [38, 42]) and FoH. The fourth study found that frequency of NSH and ‘hypoglycemia while at school’, ‘awake’ or ‘asleep’ were significantly associated with at least one of the HFS-C scales, after adjustment for clinical factors and other types of hypoglycemia (e.g., passing out because of hypoglycemia). This was not observed for ‘hypoglycemia in front of friends’ [36].

Related outcomes—diabetes-specific

Table 1 shows that studies assessed the relationship between hypoglycemia worries attributed to diabetes, diabetes-related disordered eating and diabetes distress. One study used a non-validated questionnaire [34]. The participants’ age range was 5–21 years. Two studies focused on adolescents aged 12–18 [30, 42] and one study conducted analysis for children and adolescents separately [28].

Severe hypoglycemia. Eight studies investigated the association between SH and diabetes distress [13, 15, 28, 30, 34, 37, 42, 45]. Four of these studies used the PedsQL DM [15, 30, 42, 45]. One of these reported that SH (not further specified) in the past 12 months was significantly associated with higher diabetes distress, compared to those without SH, with a small effect size [30]. This was confirmed for those who experienced two or more SH episodes (requiring assistance from others) in the past six months, but not for only one SH [45]. In contrast the other two studies reported no significant association between SH (inability to self-treat due to mental confusion) in the past 12 months) [42] or SH (resulting in seizure or coma) since diagnosis [15] and diabetes distress.

Two of the studies using the DISABKIDS Diabetes Module found a significant association between SH (not further defined [13] or requiring assistance from others [28]) and greater diabetes distress if hypoglycemia was experienced in the past month [13] but not in the past year [13, 28]. One study reported no significant association between SH (inability to self-treat due to neurological dysfunction) and illness-related distress using the KINDL-R [34].

An additional study (using the DQOL-Y) reported that those who had SH involving seizures or coma in the past three months reported significantly more worries about diabetes than those without [37].

In addition, in one study frequency of SH (requiring assistance from others) in the past 6 months did not significantly differ between those with and without disordered eating measured with the DEPS-R [50].

Non-severe hypoglycemia. Four studies examined the association between NSH (glucose concentrations below 60 or 70 mg/dl [29, 32, 46] or interfering with ability to function [42]) in the past 1–6 months and diabetes distress using the PedsQL DM [29, 42, 46] or the DQOL-Y [32]. None of these studies reported a significant association between NSH and diabetes distress.

Related outcomes–generic

Table 1 shows that generic outcomes including anxiety or depression symptoms, or diagnosis were examined in the studies. Some of the studies used measures that are not validated in young people with diabetes [36, 38, 43, 44]. The participants’ age range was 0–25 years.

Severe hypoglycemia. Three studies reported no significant association between SH and depressive symptoms; the first explored the association between SH in the past 6 months (not further defined) and CDI-S scores [48] and the other two explored the association between SH resulting in coma or seizure and CES-D scores [43, 44]. In contrast, another study reported a significant positive relationship between SH (requiring assistance from others and unconsciousness or application of glucagon) in the past year and a DSM-IV depression diagnosis [49].

Two studies investigated the associations between SH and anxiety symptoms assessed by the SCARED [36] or an ICD-10 anxiety disorder diagnosis [40]. The first study reported that a history of passing out due to SH was significantly associated with greater symptoms of separation anxiety and school avoidance, but not with panic disorder, generalized anxiety or social anxiety [36]. The second study reported no significant associations between SH (loss of consciousness) and diagnosis of anxiety disorders [40].

Non-severe hypoglycemia. Two studies examining associations between hypoglycemia in different situations and various anxiety types (using the SCARED [36] or STAIC [38]) found that having ‘hypoglycemia while at school’, ‘in front of strangers’, ‘while awake’ or ‘asleep’ [36] was significantly associated with greater symptoms anxiety, for example social anxiety or separation anxiety [36] and that hypoglycemia in social situations was significantly associated with higher trait anxiety, with a moderate effect size [38].

Discussion

To our knowledge, this is the first systematic review that critically examines evidence on the relationship between hypoglycemia and QoL and related outcomes among children and adolescents with type 1 diabetes. Results of this review show that evidence regarding an association between SH and (domains of) generic QoL is inconclusive, while the evidence suggests no association between NSH and generic QoL. For diabetes-specific QoL, the evidence was too limited to draw conclusions. None of the studies used hypoglycemia-specific QoL measures to explore the association between hypoglycemia and QoL. In addition, there was some evidence suggesting an association between SH in the past 12 months and greater worries about hypoglycemia, and no association between NSH and diabetes distress. There was insufficient evidence to draw conclusions regarding the relationship between hypoglycemia and diabetes distress (for SH), FoH worries (for NSH), FoH-related behaviors and total FoH, anxiety, depression, disordered eating and PTSD.

A possible explanation for inconsistent findings is the heterogeneity in definitions of and recall periods for hypoglycemia and measures used to assess QoL across studies. This variation limits the ability to compare studies and draw conclusions. Several key limitations of the existing evidence base were identified, such as cross-sectional designs, low statistical power, lack of reporting of effect sizes (and thus limited information on the clinical value of the observed statistically significant differences), lack of information on the definition or frequency of hypoglycemia, and the self-report of hypoglycemia over several months or even back to diagnosis, which might have led to recall bias. The key recommendation for future studies is to use a definition of hypoglycemia as recommended by current guidelines. Future studies should also use longitudinal /prospective study designs and modern methods, such as continuous glucose monitoring, for a more objective assessment of hypoglycemia that does not rely on recall of episodes, to determine the direct, day-to-day impact of hypoglycemia on various domains of QoL in children and adolescents with type 1 diabetes.

Although the current evidence suggests no clear association between hypoglycemia and some outcomes, it is important to note that studies were more likely to show statistically significant associations between hypoglycemia and outcomes when SH was experienced recently (in the past 1–3 months), more frequently, or when it involved convulsions, unconsciousness, or coma. In addition, some studies suggested that the context in which hypoglycemia takes places (e.g., in social situations) might have implications for its impact. However, this was only based on a few studies, some of which have methodological limitations. Thus, more evidence is needed to confirm these associations.

Although emerging evidence shows the importance of self-treated hypoglycemia in relation to QoL and related outcomes in adults with diabetes (50, 51), current evidence on this relationship in youth with type 1 diabetes suggested no association between NSH and QoL. However, this should be interpreted with caution, as these studies are limited by the use of generic and diabetes-specific QoL questionnaires, while hypoglycemia-specific QoL measures may be more sensitive to the impact of NSH. Different research designs, that minimize recall bias and assess the impact closer to the occurrence NSH are needed to understand the association between NSH and QoL. In addition, this review identified only one study that explored the association between hypoglycemia while asleep and sleep quality (28). This highlights the need for more studies that investigate such relationships.

Although QoL has been considered as a key outcome in pediatric diabetes care [12], only two studies had a primary aim to examine the impact of hypoglycemia on QoL [15, 42]. Fifteen of the 27 studies aimed to explore QoL, however, only seven of these studies included measures that actually assess QoL, whereas the others focused on particular domains of QoL or measured related outcomes such as diabetes distress [13, 15, 28, 30, 34, 37, 42, 45] or health status [14], rather than QoL. Even though other studies included in this review have focused on identifying sociodemographic and clinical factors that are associated with QoL, it is difficult to identify the impact of hypoglycemia specifically in these studies [13, 14, 16, 28, 30–34, 37, 45, 46]. Importantly, some of the studies that explored the impact of hypoglycemia on QoL as a secondary aim had very low rates of hypoglycemia in their samples. To truly understand the impact of hypoglycemia on QoL, a questionnaire that assesses how hypoglycemia affects domains of life that are important to the individual should be used [18]. Given that there are currently no hypoglycemia-specific QoL measures that are designed to assess the impact of hypoglycemia on QoL in children and adolescents with type 1 diabetes, these need to be developed and would need to be age appropriate and to incorporate specific domains that are important to young people with diabetes. There might be other domains of importance to young people’s QoL, such as leisure activities, that were not included in questionnaires used in current studies.

Finally, the majority of studies included in this review pooled children and adolescents together when examining the link between hypoglycemia and QoL or related outcomes. Although these studies usually included age-appropriate assessments of outcomes, the impact of hypoglycemia on these outcomes might be different for children and adolescents. While younger children often rely on their parents for decisions about diabetes management, these responsibilities are usually transferred to the child during adolescence [53, 54]. During this challenging process of transferring responsibilities, the burden of self-management for the adolescents increases and can lead to increased hypoglycemia, which can interfere with other demands and lead to family conflicts, reduced self-efficacy and increased FoH, all aspects that can compromise QoL in adolescents with diabetes [42, 55]. Future studies should thus explore if the relationship between hypoglycemia and QoL is different in different age groups. Additionally, adolescence is characterized by a strong desire to be accepted by peers [54]. Episodes of hypoglycemia in this age group could be experienced as embarrassing and mark out adolescents with diabetes as different. Hypoglycemia has indeed previously been associated with higher stigma in young people with diabetes [56], which can lead to poorer psychosocial and medical outcomes [57]. Future studies need to explore the role of stigma as a possible mechanism by which hypoglycemia impacts on QoL.

Strengths and limitations

Strengths of this review include the systematic and comprehensive search of multiple databases, and the application of a conceptual framework of QoL to categorize outcome measures in order to critically appraise the evidence. This allows for a more detailed understanding of the various ways in which hypoglycemia can impact on QoL and related outcomes and highlights the gaps in the evidence base. This review also has some limitations. Although the inclusion of a wide range of outcomes provided an overview of all the available evidence related to the impact of hypoglycemia on QoL, it also made it difficult to compare studies directly. Further, the heterogeneity across studies and the lack of effect sizes reported in studies, precluded the possibility of meta-analysis. The inclusion of only quantitative studies that were published in English may have introduced some bias, although only six studies were excluded for this reason.

Implications for clinical practice

The implications for clinical practice that can be drawn from this review are limited due to the inconclusive and relatively small evidence-base. However, some evidence suggests that more recent episodes of hypoglycemia might have an impact on various outcomes. This may be useful for clinicians, as they could ask specifically about hypoglycemia and its impact in the weeks/months following episodes of SH.

Conclusion

This systematic review shows that there is insufficient evidence on the relationship between hypoglycemia and (domains of) generic and diabetes-specific QoL in children and adolescents with type 1 diabetes. This is largely because heterogeneity and methodological limitations across studies hamper the ability to draw strong conclusions. Importantly, none of the studies used a measure designed specifically to assess the impact of hypoglycemia on QoL. Additionally, there seems to be an association between SH and greater worry about hypoglycemia, while the evidence is too limited for other related outcomes. Although limited, some evidence suggests that issues such as timing and context of hypoglycemia might influence its impact. Future research should focus on the development of measures that can assess the impact of hypoglycemia in children and adolescents with type 1 diabetes and use agreed definitions of hypoglycemia that increase comparability between studies.

Protocol as registered on PROSPERO.

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Full search strategy.

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Overview of full text papers assessed for eligibility with reasons for exclusion.

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Overview of scales being used across studies.

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Quality assessment of the included studies.

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13 Sep 2021

PONE-D-21-24300The impact of hypoglycemia on quality of life and related outcomes in children and adolescents with type 1 diabetes: a systematic reviewPLOS ONE

Dear Dr. Coolen,

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Reviewer #1: In data analysis , some terms needs to be explained as "diabetes distress"

Regarding the conclusion of the study , why did the authors mentioned that the was insufficient evidence on the relationship between hypoglycemia and QOL despite that we can see from the studies involved in the meta- analysis systematic review that QOL was significantly affected in hypoglycemia.

Reviewer #2: The authors review very important topic for any pediatric diabetologist.

my main concern is in the methodological aspects & results presentation:

1- the process of systematic review entitles essentially duplicate independent review at all stages: title & abstract screening, full text assessment, data extraction. unfortunately the authors only did single review at all stages despite that the total number of articles is considered low which leads to big chance in missing important literature. Please re-do the search according to the proper steps.

2- the authors excluded articles that used parental proxy report. This lead essentially to the exclusion of the young children from the report of the review. I don't see a reason for such an exclusion for an important age group.

3- the authors choose to report on too many outcomes that lead to missing the big picture.

Typically when choosing outcomes the Cochrane recommends not exceeding 7 outcomes. additionally, majority of outcomes are considered a subgroup of interest & I don't see justification to report them separately, and splitting the report based on the type of the scale ( generic vs. DM specific) is not practical.

I would recommend re-doing the analysis and performing meta-analysis based on fewer outcomes pooled via SMD (standardized mean difference) and showing 1 or 2 subgroups:

1- overall quality of life. possible subgroup using type of the scale ( generic vs. DM specific)

2- hypoglycemia fear . possible subgroup using hypoglycmeia type

reporting sub-scales of quality of life is discouraged because those sub-scales in general are used to drive a total score, and to be able to do such analysis the sub-scale will need to be validated for such use.

Heterogeneity in such a review is expected because of the advances in the technology and DM treatment, type of hypoglycemia report, age groups, HbA1c. Therefore, authors are encouraged to explore those factors rather than not doing the meat-analysis.

4- It will be useful to add in appendix type of scales reported in the paper, description of the scale, the cronbach alpha

5- following the adjustments recommended please restructure the results in a comprehensible easy way to read, not all results need to be described. you just need to focus on the main outcomes and leave the other s in the table.

**********

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28 Oct 2021

Responses to reviewer comments:

Comment 1. Date of search was November 2019 (about 2 years ago); authors should update their review to include possible recent publications in 2020 and 2021, such as (Gordon, J., Beresford-Hulme, L., Bennett, H., Tank, A., Edmonds, C., & McEwan, P. (2020). Relationship between hypoglycaemia, body mass index and quality of life among patients with type 1 diabetes: Observations from the DEPICT clinical trial programme. Diabetes, obesity & metabolism, 22(5), 857–865) and (Coolen M, Aalders J, Broadley M, Aanstoot HJ, Hartman E, Hendrieckx C, Nefs G, Pouwer F. Hypoglycaemia and diabetes-specific quality of life in adolescents with type 1 diabetes. Diabet Med. 2021 Aug;38(8):e14565).

Response 1: We agree that it is important to update our search to include possible recent publications. We have conducted an update of our search, which resulted in 3 extra included articles. We have updated the details in the review accordingly. However, the publication from Gordon et al., 2020 was not included, as this study was conducted in adults with type 1 diabetes aged 18-75 years, and for that reason does not meet the eligibility criteria for inclusion in this review.

Comment 2: Authors should provide a list of publications assessed for eligibility, with reasons for exclusion of many of them.

Response 2: We agree that transparency of the review process is important, therefore we have uploaded the list of papers that were screened during the full text screening stage, with reasons for exclusion. This is added as a supplementary table (Table S1) and referred to in the manuscript on p8, line 160-161.

Comment 3: Reviewer #1: In data analysis, some terms need to be explained as "diabetes distress"

Response 3: We agree with the reviewer that it is important to clarify the constructs that are being measured. A recent review defines diabetes distress as ‘the negative emotional or affective experience resulting from the challenge of living with the demands of diabetes’ (1). We have added this definition into the data analysis section, indicated by track changes in the manuscript (p5, line 139-140).

Comment 4: Regarding the conclusion of the study, why did the authors mentioned that the was insufficient evidence on the relationship between hypoglycemia and QoL despite that we can see from the studies involved in the meta- analysis systematic review that QoL was significantly affected in hypoglycemia.

Response 4: As we have described in the methods sections, we used the following approach to interpret the evidence and to draw conclusions: “It was determined that there was insufficient evidence to draw a conclusion for an outcome if: a) there were less than three studies examining the association, or b) there was considerable heterogeneity in definitions of hypoglycemia and sample characteristics across studies.”

For the relationship between hypoglycemia and generic QoL, there were only three studies with important limitations, such as the use of a non-validated questionnaire to assess QoL, or lack of information on the definition of hypoglycemia. In addition, there was considerable heterogeneity in definitions of hypoglycemia, recall periods and age groups included, among the three studies that examined generic QoL.

As we have addressed in the discussion, there was some evidence suggesting that more recent, more frequent, or more severe episodes of hypoglycemia may be associated with lower QoL and related outcomes:

“Although the current evidence suggests no clear association between hypoglycemia and some outcomes, it is important to note that studies were more likely to show statistically significant associations between hypoglycemia and outcomes when SH was experienced recently (in the past 1-3 months), more frequently, or when it involved convulsions, unconsciousness, or coma.”

Comment 5: Reviewer #2: The authors review very important topic for any pediatric diabetologist.

Response 5: We thank the reviewer for taking the time to read our manuscript and for these kind words.

Comment 6: my main concern is in the methodological aspects & results presentation:

1- the process of systematic review entitles essentially duplicate independent review at all stages: title & abstract screening, full text assessment, data extraction. unfortunately, the authors only did single review at all stages despite that the total number of articles is considered low which leads to big chance in missing important literature. Please re-do the search according to the proper steps.

Response 6: We agree that it is important to minimize the chances of errors during the review process. We wish to clarify that each step was conducted (in full or in part) by at least 2 people. As also described in the method section of this review, 10% of the abstracts were double screened by a third independent reviewer. Full text screening was conducted by MC (with input from a third reviewer MB), with 10% of the full text records being independently screened by a third reviewer (KM). Data extraction was conducted by MC and KS, and extracted data was checked by two independent reviewers (HC and MB). These steps were taken to minimize errors in the process. In addition, single-screening conducted by experts is methodologically sound (2), so double-screening 10% of the records was deemed to be sufficiently rigorous.

Comment 7: 2- the authors excluded articles that used parental proxy report. This lead essentially to the exclusion of the young children from the report of the review. I don't see a reason for such an exclusion for an important age group.

Response 7: We partially agree with this reviewer’s comment. As QoL is a highly individual and subjective construct, it is recommended to assess this from the individual’s perspective whenever possible (3, 4). There are inevitable differences between parental proxy report and children’s self-report in terms of QoL, and parents tend to rate their children’s QoL lower than children do, especially in more subjective areas such as emotional and social functioning (3, 5). In addition, parental variables, such as their health, education, socioeconomic status, but also their psychological well-being may influence their proxy report of their child’s quality of life (3).

Although parental proxy report can be informative and used to complement self-report, it should only be used as a primary outcome in cases where the child is too young or too ill to self-report (3). With regards to minimum age, it is shown that children from the age of 5 can self-report on their QoL in a valid and reliable way, whenever age-appropriate questionnaires are used (6).

In the full-text screening of this review, only 2 articles were excluded for the reason of proxy report. In addition, of the 27 studies that are included in this review, five studies also assessed parental proxy report. Of these five studies, three included children under the age of 8 years old. Therefore, we believe that our review still provides an overall picture of children and adolescents with type 1 diabetes across different age groups.

The scope for this systematic review was to explore the impact of hypoglycemia on QoL and related outcomes in children and adolescents with type 1 diabetes. While we agree with the reviewer that adding the parental proxy report could complement the child’s self-report, the aim of this review was to explore the concept of QoL as broadly as possible. To avoid including too many outcomes, it was decided to only explore self-report of QoL within the scope of this review.

Comment 8: 3- the authors choose to report on too many outcomes that lead to missing the big picture.

Typically when choosing outcomes the Cochrane recommends not exceeding 7 outcomes. additionally, majority of outcomes are considered a subgroup of interest & I don't see justification to report them separately, and splitting the report based on the type of the scale (generic vs. DM specific) is not practical.

Response 8: We thank the reviewer for this comment. While we agree there are several outcomes included in the review, we believe there are clear conceptual and methodological grounds for this. One of the issues in past research is that studies used QoL as a synonym for other constructs, such as diabetes distress or health status. Though these outcomes are related to QoL, these are distinct and unique concepts that cannot be used as a substitute to assess QoL (4). To address this confusion in the literature, and thus to include all possible studies that focus on QoL or related outcomes in this population, the search string was quite broad and related outcomes were not predefined.

Generic QoL and diabetes-specific QoL are two different constructs (4). While generic QoL comprises a broad spectrum of different domains of life, diabetes-specific QoL measures refer to the impact of diabetes on QoL and are more sensitive to how specific issues of diabetes treatment and management can impair QoL (7). Results of a systematic review on QoL in children and adolescents with type 1 diabetes indicated that although there was no difference in generic QoL between them and their peers without diabetes, there were specific impacts of diabetes on daily functioning and psychological wellbeing (8).

Therefore, there is a need to report generic and diabetes-specific QoL separately, to address these current problems in the literature and to clearly indicate the gaps in the field. The decisions not to include parent proxy-report outcomes and not to conduct meta-analyses, were based on our acknowledgement of the broad scope of outcomes included in the review.

Comment 9: I would recommend re-doing the analysis and performing meta-analysis based on fewer outcomes pooled via SMD (standardized mean difference) and showing 1 or 2 subgroups:

1- overall quality of life. possible subgroup using type of the scale (generic vs. DM specific)

2- hypoglycemia fear. possible subgroup using hypoglycemia type

Response 9: We thank the reviewer for this comment. Initially, we opted to do a meta-analysis if the final includes reported sufficient information to do so. However, due to the heterogeneity in outcomes, definitions of hypoglycemia and age groups across studies, a narrative synthesis was the most appropriate approach to synthesis. As suggested in the Cochrane guidelines (9), the research question determines whether a combination of outcomes has a meaningful interpretation. If studies that are too diverse are included in a meta-analysis, differences in effects may be obscured.

The purpose of this review was to summarize the evidence for an association between hypoglycemia and a broad range of outcomes (both specifically measuring QoL or its subdomains, and measuring outcomes closely related to, but conceptually distinct from, QoL). The outcomes within this systematic review are too diverse and distinct from one another to warrant a meta-analysis. The “exposure” (hypoglycemia) was also highly heterogeneous in its definition and measurement across studies. If we were to perform a meta-analysis, this could only be done on some outcomes, which would still mean that the majority of the evidence would be summarized in a narrative synthesis.

If we followed the suggestion of the reviewer, we would only be comparing three studies, some of which have used different measures. While comparisons are often made between different measures, these are not always valid comparisons. Therefore, we believe that in this systematic review, pooling outcomes together would not result in meaningful findings.

Comment 10: reporting sub-scales of quality of life is discouraged because those sub-scales in general are used to drive a total score, and to be able to do such analysis the sub-scale will need to be validated for such use.

Response 10: We hold the opinion that it is of great of interest to report on the subscales separately. The total score is less sensitive to specific impacts, and by only reporting the total scores the impact of QoL on individual domains could be masked.

The aim of this review was to explore the impact of hypoglycemia on QoL. Since QoL is comprised of different domains (4), it is relevant in relation to our aim to explore whether some areas might be more (or less) impacted by hypoglycemia. It could be that, for example, there is no impact on global QoL, but there is an impact on some domains of QoL. These subtle differences would not be reflected if we only reported on the total scores. In addition, we believe it is reasonable to use the subscales when there are psychometric properties available for them, which is the case for the scales included in this review (10, 11).

Comment 11: Heterogeneity in such a review is expected because of the advances in the technology and DM treatment, type of hypoglycemia report, age groups, HbA1c. Therefore, authors are encouraged to explore those factors rather than not doing the meat-analysis.

Response 11: We agree that this is an interesting and relevant question. However, across studies included in this review, 25% did not information on participants treatment regimen, and 85% did not report on glucose monitoring methods. For the studies that did provide this information, analyses between hypoglycemia and QoL or related outcomes were not conducted separately for these groups which precludes the ability to conduct subgroup analyses. While the use of technology has shown promising results for some people with diabetes in relation to minimizing hypoglycemia, many people with diabetes are regularly experiencing hypoglycemia (12). Similarly, studies have shown that HbA1c is an unreliable risk factor for hypoglycemia (13, 14); one can experience hypoglycemia regardless of one’s HbA1c. Since the aim of this review is to explore the association between hypoglycemia and QoL, we believe that, although interesting, these questions are outside of the scope of this review. Additionally, type of hypoglycemia report and age groups are discussed in the discussion section of this paper:

“Future studies should also use longitudinal /prospective study designs and modern methods, such as continuous glucose monitoring, for a more objective assessment of hypoglycemia that does not rely on recall of episodes, to determine the direct, day-to-day impact of hypoglycemia on various domains of QoL in children and adolescents with type 1 diabetes.”

“The majority of studies included in this review pooled children and adolescents together when examining the link between hypoglycemia and QoL or related outcomes. Although these studies usually included age-appropriate assessments of outcomes, the impact of hypoglycemia on these outcomes might be different for children and adolescents.”

Comment 12: 4- It will be useful to add in appendix type of scales reported in the paper, description of the scale, the Cronbach alpha.

Response 12: We thank the reviewer for this suggestion and agree it could be helpful for the reader to have an overview of the scales that are reported in the paper, given the variety of scales used across studies. We have added a supplementary table (Table S2) with an overview of the scales and their subscales and referred to this in the manuscript (p9, line 191-192). As cronbach’s alpha is different for each study in which the scale has been used, it is not possible to give a general alpha for the scale, but we have indicated in the table whether the scales are validated for use in children and adolescents with type 1 diabetes.

Comment 13: 5- following the adjustments recommended please restructure the results in a comprehensible easy way to read, not all results need to be described. you just need to focus on the main outcomes and leave the others in the table.

Response 13: We agree that it is important to describe the results in a comprehensible and easy to read way. We also believe it is important to provide the reader with necessary for interpretation of the findings. We have used a consistent approach in the narrative synthesis, to avoid bias in reporting the results. As the aim of this review was to explore the relationship between hypoglycemia and QoL, it is of great importance how these key constructs, (i.e., hypoglycemia and QoL) have been assessed across different studies. This identifies key gaps in the literature that should be addressed in future studies, which are described in the discussion section of this manuscript. In addition, this is in line with items 20c and 20d from the PRISMA Checklist, that suggest all results should be presented.

To address the reviewer’s comment, we have taken another look at the results section and have taken out details that were considered less important and were not imperative to interpret findings, indicated by track changes in the manuscript.

Additional comment from the authors: During the revision process, we found that one of the previously included studies actually met one of our exclusion criteria (Northam et al, 2010, ref #47 in the submitted manuscript) did not meet the inclusion criteria, so this study has been removed from analysis. This results in a total of 27 studies.

References

1. Skinner TC, Joensen L, Parkin T. Twenty-five years of diabetes distress research. Diabetic Medicine. 2020;37(3):393-400.

2. Waffenschmidt S, Knelangen M, Sieben W, Bühn S, Pieper D. Single screening versus conventional double screening for study selection in systematic reviews: a methodological systematic review. BMC medical research methodology. 2019;19(1):132.

3. Sherifali D, Pinelli J. Parent as proxy reporting: implications and recommendations for quality of life research. Journal of family nursing. 2007;13(1):83-98.

4. Speight J, Holmes-Truscott E, Hendrieckx C, Skovlund S, Cooke D. Assessing the impact of diabetes on quality of life: what have the past 25 years taught us? Diabetic medicine : a journal of the British Diabetic Association. 2020;37(3):483-92.

5. Eiser C, Morse R. Can parents rate their child's health-related quality of life? Results of a systematic review. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation. 2001;10(4):347-57.

6. Varni JW, Limbers CA, Burwinkle TM. How young can children reliably and validly self-report their health-related quality of life?: an analysis of 8,591 children across age subgroups with the PedsQL 4.0 Generic Core Scales. Health and quality of life outcomes. 2007;5:1.

7. Patrick DL, Deyo RA. Generic and disease-specific measures in assessing health status and quality of life. Medical care. 1989;27(3 Suppl):S217-32.

8. Nieuwesteeg A, Pouwer F, van der Kamp R, van Bakel H, Aanstoot HJ, Hartman E. Quality of life of children with type 1 diabetes: a systematic review. Curr Diabetes Rev. 2012;8(6):434-43.

9. McKenzie J, Brennan S. Chapter 12: Synthesizing and presenting findings using other methods. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane: 2021. Available from: www.training.cochrane.org/handbook. [Accessed 4 January 2021].

10. Varni JW, Burwinkle TM, Jacobs JR, Gottschalk M, Kaufman F, Jones KL. The PedsQL in type 1 and type 2 diabetes: reliability and validity of the Pediatric Quality of Life Inventory Generic Core Scales and type 1 Diabetes Module. Diabetes care. 2003;26(3):631-7.

11. Hullmann SE, Ryan JL, Ramsey RR, Chaney JM, Mullins LL. Measures of general pediatric quality of life: Child Health Questionnaire (CHQ), DISABKIDS Chronic Generic Measure (DCGM), KINDL-R, Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales, and Quality of My Life Questionnaire (QoML). Arthritis care & research. 2011;63 Suppl 11:S420-30.

12. Cherubini V, Rabbone I, Lombardo F, Mossetto G, Orsini Federici M, Nicolucci A. Incidence of severe hypoglycemia and possible associated factors in pediatric patients with type 1 diabetes in the real-life, post-Diabetes Control and Complications Trial setting: A systematic review. Pediatr Diabetes. 2019;20(6):678-92.

13. Karges B, Kapellen T, Wagner VM, Steigleder-Schweiger C, Karges W, Holl RW, et al. Glycated hemoglobin A1c as a risk factor for severe hypoglycemia in pediatric type 1 diabetes. Pediatric diabetes. 2017;18(1):51-8.

14. Cooper MN, O'Connell SM, Davis EA, Jones TW. A population-based study of risk factors for severe hypoglycaemia in a contemporary cohort of childhood-onset type 1 diabetes. Diabetologia. 2013;56(10):2164-70.

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19 Nov 2021

The impact of hypoglycemia on quality of life and related outcomes in children and adolescents with type 1 diabetes: a systematic review

PONE-D-21-24300R1

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Reviewer #1: All comments have been addressed

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Reviewer #1: Yes

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English editing is still required

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23 Nov 2021

PONE-D-21-24300R1

The impact of hypoglycemia on quality of life and related outcomes in children and adolescents with type 1 diabetes: a systematic review

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Participant organisation name	Scientific person(s) in charge
STICHTING RADBOUD UNIVERSITAIR MEDISCH CENTRUM	Prof. Cees Tack
	Dr Bastiaan de Galan
King’s College London	Prof. Stephanie Amiel
	Dr Pratik Choudhary
Medical University of Graz	Prof. Thomas Pieber
	Dr Julia Mader
University of Cambridge	Dr Mark Evans
Montpellier University Hospital	Prof. Eric Renard
University of Southern Denmark	Prof. Frans Pouwer
	Prof. Jane Speight
University of Lausanne	Prof. Bernard Thorens
University of Sheffield	Prof. Simon Heller
	Prof. Alan Brennan
Nordsjællands University Hospital Hillerød	Prof. Ulrik Pedersen-Bjergaard
University of Dundee	Prof. Rory McCrimmon
European Research and Project Office GmbH	Jakob Haardt
Swiss Institute of Bioinformatics	Dr Mark Ibberson
University of Padova	Prof. Giovanni Sparacino
University of Edinburgh	Prof. Helen Colhoun
Novo Nordisk A/S	Dr Stephen Gough
Eli Lilly and Company Limited	Dr Zvonko Milicevic
Abbott Laboratories	Dr Mahmood Kazemi
Medtronic International Trading Sàrl	Dr Ohad Cohen
JDRF International	Dr Sanjoy Dutta
International Diabetes Federation	Dominique Robert
Unitio, Inc.	Dr Wendy Wolf
The Leona M. and Harry B. Helmsley Charitable Trust	Dr Sean Sullivan