Intermittently Scanned and Continuous Glucose Monitor Systems: A Systematic Review on Psychological Outcomes in Pediatric Patients

Aim: To explore the impact of real-time continuous glucose monitoring (rtCGMs) or intermittently scanned/viewed CGM (isCGM) on psychological outcomes in children and caregivers, and to grade the level of evidence. Method: Systematic review of the literature from PubMed, Embase, Cochrane Library, Web of Science, CINAHL, Nursing reference center, Up to date, Google Scholar, and PsycINFO databases. The studies selected used validated questionnaires for investigating the psychological outcomes. We applied GRADE (Grading of Recommendations Assessment, Development and Evaluation) to rank the quality of a body of evidence. Results: A total of 192 studies were identified in the initial search and after the process of evaluation 25 studies were selected as appropriate to be included in this systematic review. We found in moderate quality studies that isCGM in adolescents can improve diabetes related distress, family conflicts, fear of hypoglycemia, and quality of life, while depression, anxiety, and quality of sleep have not yet been evaluated by validated questionnaires. In moderate—high quality studies, rtCGM technology does not impact on diabetes burden, diabetes specific family conflict, and depressive symptoms. The effect on fear of hypoglycemia, sleep quality, and anxiety is still debated and RCT studies powered to find significant results in psychological outcomes are lacking. RtCGM increases satisfaction and quality of life in parents and patients wearing rtCGM. Conclusion: these data present an interesting point to consider when families are deciding whether or not to start CGM use, choosing between rtCGM to reach a tighter metabolic control, or isCGM which allows greater benefits on psychological outcomes.


INTRODUCTION
The advent of real-time continuous glucose monitoring systems (rtCGMs) or intermittently scanned/viewed CGM (isCGM) is one of the major technological innovation for the treatment of Type I Diabetes (T1D). Real-time CGM allows individuals with diabetes to follow their glucose concentration simultaneously, and to obtain information on glucose trends and trajectories. Moreover, the systems can provide warnings on upcoming hypoglycemia or hyperglycemia as well as alarms for rapid glycemic excursions (1). Meta-analyses provided evidence for real-time CGM to lower hemoglobin A1c (HbA1C) levels without increasing hypoglycemic events (1).
Importantly, recent studies confirmed that the use of isCGM has a positive impact on glucose control, by limiting glucose variability, reducing hypoglycemia, and improving long-term glucose control (2).
In addition to the stand-alone rtCGM systems, the integrated combination of pump therapy with rtCGMs allows to automatically suspend insulin delivery in the case of upcoming hypoglycemia, thus reducing or avoiding nocturnal hypoglycemia (3).
Although a clear evidence that the benefits associated with the use of rtCGMs are strictly related to a near daily use (1,4,5), a constant rtCGM use remains problematic for many patients in the pediatric age group (6,7). Indeed, a better glycemic control is achieved by patients who use rtCGM for the majority of time, generally considered to be 70% or more (1,8). Nevertheless, recent data from the Type 1 Diabetes Exchange Clinic Registry still reports that only one third of T1D-affected youth regularly wears rtCGM, although there has been an increase of use from 2013 (4% of T1D youth) to 2015 (14%) and 2017 (31%) (9). Furthermore, rtCGM wearing declines significantly over-time among T1D users (10). Barriers to a regular rtCGM use in pediatrics are reported in the following Table: Barrier Description Physical barriers Pain due to sensor insertion, skin reactions to sensor, adhesive and lack of skin areas for sensor placement in young children (11,12) Clinical barriers Multiple alerts and alarms can lead to alarm fatigue Education barriers A well-experienced diabetes team has to ensure a proper training for patients and families and a continuous support in problem solving on ways to break down barriers; Financial barriers Lack of insurance coverage and high costs for rtCGM supplies (13) Psychological barriers related to rtCGM Diabetes distress/burden, diabetes-specific family conflicts, depressive symptoms, anxiety, fear of hypoglycemia, alarm fatigue, impaired sleep quality, and quality of life (QoL).
A deeper understanding of the factors related to technologies uptake and adherence remains a crucial topic of investigation. In particular, studies on psychological factors that may predict sensor success or interruption are still limited. On the contrary, identifying psychological issues related to the sensor use would support both diabetologists in tailoring the best treatment for each patient, and youth and families in setting realistic expectations. The impact of rtCGM and isCGM on psychological outcomes in children and caregivers remains controversial (6,14,15). This may be due to the fact that psychological measures are usually considered as secondary outcomes in trials involving CGMs (Laffel LM 2020 JAMA, Massa GG 2019, JDRF-CGM Study Group, Diabetes Care 2010), compared to the metabolic control (HbA1c, hypoglycemia, CGM glucose metrics). Moreover, different questionnaires are used to assess the outcomes in the published studies. Also, each area of investigation (depression, fear of hypoglycemia, QoL) could be explored by different validated measures, self-reported or administered by health care providers, as summarized in Table 1  .

AIM
The aim of this systematic literature review is to explore the impact of rtCGM or isCGM on psychological outcomes (diabetes distress/burden, diabetes-specific family conflicts, depressive symptoms, anxiety, fear of hypoglycemia, alarm fatigue, impaired sleep quality, quality of life, and satisfaction with the CGM system) in children and caregivers and to grade the level of evidence.

Types of Studies
We included RCTs, observational studies, prospective studies, cross-sectional studies, exploratory studies, mix of qualitative, and quantitative studies. We included only published studies.

Types of Participants
We included patients with T1D aged between 0 and 18 years and their caregivers. sleep quality and quality of life, satisfaction) vs. capillary glucose testing for glycemic assessment in children and caregivers. Comparison 3: rtCGM vs. isCGM on psychological outcomes (diabetes distress/burden, diabetes-specific family conflicts, depressive symptoms, anxiety, fear of hypoglycemia, alarm fatigue, impaired sleep quality and quality of life, satisfaction) in children and caregivers.

Outcomes
Psychological outcomes in children and caregivers included: diabetes distress/burden, diabetes-specific family conflicts, depressive symptoms, anxiety, fear of hypoglycemia, alarm fatigue, impaired sleep quality, quality of life, satisfaction.
A detailed description of outcomes and related measures is reported in Table 1  .

Search Methods
We conducted a systematic search of the literature according to the PICOS model (Population, Intervention, Comparison, Results, Study design). The study exclusion criteria were: -patients >18 years; patients with Type II Diabetes; -studies not meeting the established primary and secondary outcomes; -animal research studies; -devices: use of closed loop systems; -reviews, conference abstracts, full texts not available.
We did not apply language restrictions.
Sources used for literature review included: PubMed, Embase, Cochrane Library, Web of Science, CINAHL, Nursing reference center, Up to date, Google Scholar, and PsycINFO.
Articles published from 1/01/2006 to 31/12/2020 were considered for the current review. Search terms, or "mesh" (MEdical Subject Headings) for this systematic review included: "CGM AND distress, " "CGM AND sleep quality, " "CGM AND psychological variables, " "Glucose monitoring AND distress, " "Glucose monitoring AND sleep quality, " "Glucose monitoring AND psychological variables, " "Flash glucose monitoring AND distress, " "Flash glucose monitoring AND sleep quality, " "Flash glucose monitoring AND psychological variables." According to the PICOS detailed above, filters for participants' age (0-18 years), and study characteristics were activated.

Data Extraction and Management
Two review authors independently extracted data by using the forms integrated in the sources' systems.
The following characteristics were reviewed for each included study: • reference aspects: authorship(s); published or unpublished; year of publication; year in which study was conducted; other relevant papers cited; • study characteristics: study design; type, duration; informed consent; ethics approval; • population characteristics: age, number of participants; • intervention characteristics: type, duration, mode of use of rtCGM and isCGM; • evaluation of the outcomes as reported in Table 1  .
Disagreements were solved by discussion.

Assessment of the Certainty of the Evidence
We used the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation) to rank the quality of a body of evidence (www.gradeworkinggroup.org) for the following outcomes: diabetes distress/burden, diabetesspecific family conflicts, depressive symptoms, anxiety, fear of hypoglycemia, alarm fatigue, impaired sleep quality, quality of life, and satisfaction with the rtCGM and the isCGM systems.
Two review authors independently assessed the certainty of the evidence for each of the outcomes above. In the case of risk of bias in the study design, imprecision of estimates, inconsistency across studies, indirectness of the evidence, and publication bias, we had the option of decreasing the level of certainty by one or two levels according the GRADE guidelines (43).
The GRADE approach results in an assessment of the certainty of a body of evidence and allocation to one of four grades:

RESULTS
A total of 192 studies were identified following the literature review. After screening, we excluded 20 records as they were duplicates. When we reviewed titles and abstracts we excluded 112 records: 9 studies were published only in abstract form, 100 studies did not investigate the outcomes of interest ( Table 1), 3 studies were not available in the full text form. A total of 60 full-text manuscripts were assessed for eligibility: 27 studies were excluded as no data were available for the analysis, besides the ones reported in the abstracts; 4 studies were excluded as they reported data from the same cohort of patients; 4 studies were excluded as they resulted to be literature reviews when the full-texts were analyzed. A final number of 25 studies, 6 on isCGM, 19 on rtCGM, were included in this systematic review.
The PRISMA flow diagram in Figure 1 shows the process of study evaluation.
A summary of results from the studies included in this systematic review is reported in Tables 2, 3.

FAMILY CONFLICT IN THE MANAGEMENT OF DIABETES
This outcome is measured in 2 studies on isCGM use and in 5 studies on rtCGM use in youth and their caregivers.
IsCGM use was associated with a reduction in diabetes specific parent-child conflict and parental conflict in patients aged 13-20 years in 2 qualitative studies [ (45,46), Low].
RtCGM use was associated with both a reduction in family conflicts and an improvement in rtCGMs related family functioning in 2 studies included in the review [ (51,55), Moderate]. These benefits were related to a decrease in the workload associated to blood glucose monitoring (BGM) and

DEPRESSION
Depression in youth using rtCGM is evaluated in two studies. In a cross-sectional study on rtCGM use in adolescents, more depressive symptoms were reported by those who faced more barriers [(53), Moderate]. In a RCT in children 8-17 years old, rtCGM parent-proxy report of depression was significantly higher than that reported by BGM parents [(52), Moderate]. Data on depression in youths using isCGM are lacking.

ANXIETY
This outcome is measured in 3 studies on rtCGM use in youth. In a RCT evaluating children in the age 2-12 years and their parents, parental stress level was lower in the arm using rtCGM compared to the control group (51, Moderate). In another study including 16 children aged 2-17 years, rtCGM use was associated with an improvement in children and parents' anxieties [(56), Low].
In a RCT study, the group of youth with rtCGM reported more trait anxiety than BGM youth, whereas rtCGM adults reported less state and trait anxiety than BGM adults [(52), Moderate].
Data on anxiety in youths using isCGM are lacking.

SLEEP QUALITY
This outcome is measured in 7 studies on rtCGM use in youth. In an observational study, overall 67% of children with T1D met the criteria for poor sleep quality; a worse child sleep quality was associated with worse metabolic control and poorer parental sleep quality. Child sleep was not related to the use of diabetes-related technology (  The following themes were identified: (1) improved parental well-being: "peace of mind" while their adolescent slept; reduced diabetes-specific worry and improvement in sleep quality (2) reduced diabetes-specific parent-child conflict (3) facilitated parental role in management: easier to perform glucose checks; helped guide treatment decision isCGM has the potential to reduce diabetes management burden for both adolescents and parents. Barriers: premature sensor loss and sensor malfunction, isCGM costs.
Limitation were the small sample size. The parents included in this study were predominantly of European ethnicity and the findings may not apply to minority populations.
-Low - Frontiers in Pediatrics | www.frontiersin.org  In a qualitative study, 9 pairs of children and parents reported improved sleep quality with the sensor use [(61), Low]. A prospective study on 46 children and their parents found that kids who used rtCGM experienced fewer sleep disturbances than those who did not, but their parents had greater sleep disturbances related to a higher frequency of nocturnal blood glucose monitoring (NBGM) [(62), Moderate]. A RCT on youth aged 14-24 years using rtCGM, reported there were no differences in sleep quality between sensors users and non-users [(60), High]. Data on sleep quality in youths using isCGM are lacking.

ALARM FATIGUE
This outcome is measured in 5 studies on rtCGM use in youth. Parents of children aged 3-17 years using rtCGM reported both positive and negative responses for alarms: helpful when signaling hypoglycemia but annoying when repeatedly sounding during the night; thus, most parents reported they would like to louder alarms [(54), Low]. In a qualitative study, most parents reported clear clinical and psychological benefits associated with alarms alerting, but others noted that alarms could interfer with daily activities in the workplace or at school [(61), Low]. While alarms could reinforce a sense of hypoglycemic safety, some individuals expressed ambivalent views, especially those who perceived alarms as signaling personal failure to achieve optimal glycemic control [(61), Low]. Two additional studies included in the review highlighted that alarms can often cause annoyance and discomfort [(53, 63), Moderate]. Day caregivers, teachers or school nurses, generally appreciate alarm systems and these are not perceived as a source of distraction or disturbance but as a tool that simplifies the management of the disease [(48), Low].

QUALITY OF LIFE/WELL-BEING
Four studies reported on this outcome in patients with isCGM, as well as 9 studies in patients with rtCGM. The use of isCGM has been reported to improve QoL in children and adolescents [(59, 64), Moderate] as well as in their parents [(46, 65)  Three RCTs of high quality confirmed the satisfaction with rtCGM use (6,14,60). In the first RCT, 90% of parents of 4-9 years old children, reported a high degree of satisfaction with rtCGM: the use of rtCGM makes adjusting insulin easier, shows patterns in blood glucose not seen before, and makes them feel safer knowing that they will be warned about low blood glucose before it happens [(6), High]. In the second RCT, patients aged 14-24 years using rtCGM, reported higher glucose monitoring satisfaction compared to the BGM group over a 26-weeks study period [(60), High]. In the third RCT, in patients aged 7-17 years, satisfaction scores at 26 weeks were higher for both, youths and parents, with higher scores associated with a more frequent use of rtCGM [(14), High].
In a cross-sectional study using qualitative and quantitative methods, parents and caregivers of children aged 2-17 years, felt positive about rtCGM use [(48), Low].
Data on satisfaction in youths using isCGM are lacking.

DISCUSSION AND CONCLUSIONS
A large percentage of pediatric patients with T1D experiences negative emotions, including state of anxiety, fear, discouragement, and frustration for the burden of the disease management. The use of CGM systems improves glycemic control (60) but demands for extra efforts from patients and their parents. Therefore, it is important to assess if the use of rtCGM and isCGM systems is related to psychological issues (52). Studies on how isCGM and rtCGM impact the psychological outcomes in children and their caregivers were evaluated in this systematic review. Some limitations of the revised studies need to be addressed ( Table 2): (i) the sample size resulted small or not representative of the general population is some studies; (ii) psychological measures were included as secondary outcomes in most of the studies; thus, in some cases, the study design was not adequate to support significant results; (iii) some of the questionnaires used to measure the psychological outcomes were not previously validated. Also, questionnaires varied from one study to another.
Data on psychological outcomes in the pediatric population using isCGM systems are still limited, probably due to their recent availability on the market. The use of isCGM in adolescents can reduce psychological distress, family conflicts and fear of hypoglycemia (44,59) and improves QoL (59,65) as reported by a Saudi Arabia group (44) in moderate quality studies. Currently, there is no evidence of a negative impact of the isCGM system on the psychological outcomes evaluated in this review. However, results from our literature review highlighted the lack of data on depression, anxiety, and quality of sleep in pediatric patients using isCGM.
Most of the studies reported that the use of rtCGM did not increase diabetes burden in adolescents and their parents/caregivers with a moderate-high quality of evidence and using the PAID-T and P-PAID-T questionnaires (6,13,14,52,60). Likewise, rtCGM did not impact the diabetes specific family conflict, as measured by DFRQ and DFCS questionnaires in a moderate quality study (13,52). Furthermore, rtCGM did not change depressive symptoms assessed with CDI, CES-D (13), and PHQ8 questionnaires (53).
On the other hand, rtCGM resulted improving parental anxiety in a moderate quality RCT using the STAI questionnaire by Burckhardt et al. (51). However, these results were not confirmed in a moderate quality observational study using the same questionnaire, by Giani et al. (13).
Fear of hypoglycemia remains the most common diabetes-related issue among T1D, both for youth and their parents/caregivers. In a RCT (51), parental fear of hypoglycemia (FOH) evaluated by the HFS score resulted lower in the group using rtCGM. However, other moderate-high quality studies using the HFS and HCS questionnaire did not confirm this outcome (6,13,14,60).
In a RCT, adolescents' sleep quality measured with the PSQI questionnaire was not different in youth using rtCGM (60). On the contrary, parental sleep quality improved with the use of rtCGM, both when measured with the PSQI questionnaire as well by accelerometry devices in parents of adolescents and of young children, respectively (62).
Alarm fatigue was broadly evaluated in patients using rtCGM by non-validated interviews. In most cases, individuals reported clear clinical and psychological benefits to alarms setting (61), but in some contexts alarms resulted annoying and intrusive (53).
In most of the studies the perceived QoL assessed by the PedsQL in patients and caregivers, resulted improved by the use of rtCGM (55,62). In some other studies no variations in the PedsQL were reported (13,14), probably due to the number of variables that may influence the perceived QoL in diabetes or due to the short-term follow-up. An increased satisfaction related with the rtCGM use was assessed in both parents and youth with the DTSQ, CGM-SAT, and GMS questionnaires in moderate-high quality studies (6,14,51,60).
In conclusion, the benefits of isCGM and rtCGM use on glycemic control have been previously demonstrated (1,2,66,67). Findings from the studies included in this systematic review suggest that: (i) the use of isCGM in adolescents can improve diabetes related distress, family conflicts, FOH and perceived QoL; depression, anxiety, and quality of sleep have not yet been evaluated with validated questionnaires; (ii) the use of rtCGM does not impact diabetes burden, diabetes specific family conflict and depressive symptoms. The effect of rtCGM use on the fear of hypoglycemia, the sleep quality and the anxiety is still debated. Further RCT studies specifically powered to investigate psychological outcomes are needed. The use of rtCGM increases both satisfaction and perceived QoL in youth and their parents, although alarm fatigue need to be prevented with alarm targeting.
Altogether, these findings represent an interesting overview to consider when families are in the process of deciding whether or not to start CGM use.

AUTHOR CONTRIBUTIONS
RF and FM made a substantial contribution to the design of this literature review, in the acquisition of data, and their interpretation and analysis as well as in the writing of the manuscript. FM and RF selected the articles of this literary review. VC, MS, EM, and EG contributed to the critical revision of the manuscript for intellectual reasons and performed a thorough proofreading of the manuscript. All the authors have definitely approved the version to publish.