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PMC Articles

Real-world experience with the use of diazoxide among people living with congenital hyperinsulinism and their caregivers

PMCID: PMC12410177

PMID:

Abstract

Introduction Congenital hyperinsulinism (HI) is a rare disease that causes severe hypoglycemia. Diazoxide is the first-line treatment; however, many individuals using diazoxide continue to experience hypoglycemia. Diazoxide is associated with side effects that impact life and well-being. Methods The study utilized a mixed-methods approach combining structured, survey-based cross-sectional quantitative data from the HI Global Registry (HIGR) (n=165, 89% were caregivers), of whom 75% reported current diazoxide use, with qualitative interviews with caregivers (n=12) and individuals with HI (n=6). This is the first mixed-methods study to focus on the experience of diazoxide treatment as reported by the individual taking the medicine and/or their caregiver. Results Of HIGR participants, 93% reported at least one side effect, including hypertrichosis (89%), loss of appetite (40%), facial changes (23%), and swelling (22%) with diazoxide use. In HIGR, 37% of people currently on diazoxide reported experiencing hypoglycemia up to several times per week. Interview participants described how these side effects, the drug’s taste, and feeding difficulties associated with HI and diazoxide adversely impacted daily life. Discussion Diazoxide is commonly used by families living with HI, but a significant proportion reported hypoglycemia. Individuals who experienced better glycemic control with the drug were less critical of side effects. Combining HIGR data with in-depth interviews facilitated understanding of day-to-day life, which can help implement measures to better support families managing HI. This study prompts the need for improved treatment options and for clinicians to utilize the International HI Care Guideline to optimize diazoxide therapy.

Full Text

Congenital hyperinsulinism (HI) is a rare disease characterized by excessive insulin secretion that leads to severe hypoglycemia. HI occurs in approximately 1 in 28,000 births in most countries, and is the most frequent cause of prolonged hypoglycemia in newborns and children (1, 2). Early diagnosis and effective management of this disease are necessary to avoid prolonged hypoglycemia, which is associated with an elevated risk of brain damage, seizures, developmental delay, and death (3, 4). HI usually presents in the newborn period (5, 6). A diagnosis of HI relies on the demonstration of a biochemical profile consistent with inappropriate secretion/actions of insulin during a spontaneous or provoked episode of hypoglycemia, including detectable plasma insulin/C-peptide, low plasma levels of free fatty acids and beta-hydroxybutyrate, and a glycemic response to a pharmacologic dose of glucagon (7, 8). Management of HI involves vigilant glucose monitoring and can include medications, surgery, and/or feeding plans to minimize, and optimally prevent, hypoglycemia (8, 9).
Diazoxide is the first-line treatment for HI, and is the only medication for HI approved by the United States Food and Drug Administration and European regulatory authorities (8). Diazoxide blunts insulin secretion by activating ATP-sensitive potassium (KATP) channels and hyperpolarizing the β-cell plasma membrane (10, 11). An individual is considered responsive to diazoxide by demonstrating a reversal in hypoketotic hypoglycemia (8). Up to 60% of individuals with HI are unresponsive to diazoxide (12–17); unresponsiveness often results from KATP channel defects, secondary to inactivating pathogenic variants in ABCC8 and KCNJ11, the genes encoding the channels, although other forms of genetic HI may also be diazoxide-unresponsive (12). Responsiveness is not universally assessed according to the standards described in the international HI care guidelines, which may be a contributing factor as to why some individuals on diazoxide may continue to experience hypoglycemia. Data from the HI Global Registry (HIGR) have shown that up to 32% of people currently taking diazoxide report hypoglycemia (blood glucose level below 70 mg/dL) multiple times a week or more frequently (6, 18).
Several studies have reported that side effects accompany diazoxide treatment (13, 19, 20). It is estimated that up to 9.7% of individuals discontinue use due to serious side effects impacting the cardiovascular/respiratory, hematologic, or gastrointestinal system (21). Individuals with perinatal stress-induced hyperinsulinism have higher rates of serious side effects (8, 16, 21, 22). The most frequently reported side effect of diazoxide is hypertrichosis, impacting up to 84% of people taking diazoxide (6). Changes in facial features are reported in up to 24% of people (9, 19, 23). Fluid accumulation, pulmonary hypertension, and pulmonary overload, which may become life-threatening, have also been observed (21, 24–27). The use of a diuretic to mitigate fluid retention is the current standard of care on initiation of diazoxide (8, 19). Other reported side effects include cardiac failure (28, 29), neutropenia, thrombocytopenia, and hyperuricemia (21, 25, 30). To monitor the occurrence of side effects, clinicians are advised to perform periodic echocardiograms, complete blood counts, and serum uric acid analysis on individuals who are prescribed diazoxide (8, 9, 27).
Multiple reports suggest an increase in feeding difficulty after diazoxide initiation (22, 31). Feeding difficulties are also a feature of HI; therefore, it is difficult to determine whether this is a feature of the disease or the treatment (18, 32). Moreover, gastrointestinal reactions have been reported in individuals receiving diazoxide, which may further exacerbate challenges in encouraging nutritional intake, which is critical to maintaining euglycemia (21, 33–35). Some diazoxide users were also tube fed; tube feeding may be required to ensure swift and easy access to nutritional support to maintain glycemic control (31).
In previous publications that have included the patient voice, there was some evidence that caregivers and individuals with HI taking diazoxide experienced a psychosocial burden due to the impact of the visible side effects, such as hair growth, which may trigger social distress and stigmatization for families (18, 32). Despite the acknowledgment of diazoxide’s side effects by clinicians and families affected by HI, the impact of these side effects is not adequately reported in the literature. There is a growing interest in including patient-reported data and the impact of treatments on a patient’s quality of life in research and clinical studies, often in the context of regulatory decision-making. However, this work has often not been conducted for treatments already on the market. Prior to this study, no study specifically asked caregivers and patients with HI about their experiences with diazoxide. The aim of this research was to better understand the real-world impact of diazoxide and its side effects on people living with HI and on their caregivers through their own words, including the impact on glycemic control, daily routines, and quality of life.
HIGR was launched in October 2018 as the first global patient-powered HI registry (6). The registry is available in eight languages and contains 13 patient and/or caregiver surveys that collect information through multiple-choice and open-ended questions on the experience of HI over a person’s lifetime and one physician-reported survey (6). HIGR recruitment is ongoing through Congenital Hyperinsulinism International’s (CHI) virtual platforms and in-person at patient-family conferences and HI clinics. Participation is open to individuals over the age of 18 who have received a diagnosis of HI and caregivers of children (younger than 18 years) with HI who are reporting on their child’s experiences and the impact on their own quality of life.
HIGR surveys were created by an international team of HI experts, including family members of children with HI, clinicians, and researchers, based on the literature and lived experiences (6). No tool has yet been validated for HI research; however, the HIGR quality of life surveys were based on validated tools, including PedsQL and DisabKids (37, 38). The surveys are cross-sectional and largely retrospective. A few surveys, including quality of life and glucose monitoring, are longitudinal. In this study, we included responses from the most recent survey submissions.
A total of 50 people expressed interest in participating in the study. Of this group, 26 were identified as eligible to participate, and 22 people were invited to participate; these 22 people represented a range of ages and primary treatment centers. Four did not respond to requests to schedule interviews prior to data saturation for the study being met. In total, 18 people participated in the qualitative interviews. Of this group, 12 were caregivers of individuals living with HI, three were children aged 10–12 years, and three were young adults living with HI (
).
Qualitative data analysis combined Van Manen and grounded theory strategies, including immersive reading, open coding, thematic identification, interpretative analysis, and integration to create a comprehensive narrative (39–41). Data analysis was completed manually by two authors using Delve, a qualitative data analysis software program. Open coding focused on identifying keywords or phrases, which were then contextualized through axial and selective coding to generate codes and subcodes to create the final codebook. Peer debriefing was completed throughout coding with individuals who were familiar with diazoxide as well as with those who were not, to ensure methodological consistency, clarity of interpretation of the data, and reproducibility. Interview participants were assigned a participant identifier to ensure anonymity, and basic demographic data were recorded (
). Interview participants lived in Australia, Canada, Italy, the United Kingdom, the United States, and the Caribbean. Based on the risk of identifiability, the specific country in the Caribbean has not been shared, and the countries of residence were not recorded in
.
Quotes were edited to improve clarity without changing their meaning (e.g., removing
“like”). Quotes have been anonymized, but were attributed to the participant via their identifier, which includes a letter code specifying whether the participant is a caregiver (CG) or a person with HI (HI), and the age of the person with HI. An example of the qualitative codebook and the themes that emerged are available in
.
In total, 165 HIGR participants reported either current use (n = 123) or past use (n = 42) of diazoxide (
). Throughout the manuscript, we will refer to individuals who were currently taking diazoxide at the time of the study; this does not indicate current use today. In HIGR, about one-third of individuals who were currently taking diazoxide were aged 1–3 years (34%); of these, 62% were from North America (of whom 88% were from the United States) and 59% were White. All individuals in HIGR taking diazoxide and all the interview participants indicated diffuse or atypical forms of HI. The genetic background of the HIGR participants varied. KATP channel variants were present in 22% of individuals currently taking diazoxide and 45% of the past use group. In the current use group, 32% of participants received negative genetic testing results, and 22% either had no genetic testing or did not report genetic testing. For individuals in HIGR, 29% had taken diazoxide for 6 years or longer (
). The patients’ ages ranged from 1 year to 26 years for interview participants. Five of these individuals began diazoxide within the first month of life, and seven of them within the first year of life (
). Two people with HI were previous diazoxide users.
Taste of diazoxide was frequently commented upon, with patients and caregivers describing this medicine as tasting like “chemical milk,” “charcoal with licorice,” or “very dirty water,” and using words like “bitter,” “sour,” “gross,” and “disgusting” (
). The taste contributed to additional challenges, leading to families developing strategies to mitigate the residual taste.
The complex relationship between HI, diazoxide, feeding issues, and gastrointestinal problems emerged as a prominent theme in the interviews. This finding correlated with HIGR participants currently taking diazoxide (n = 111), of whom 64% reported feeding issues (
), and 28% reported five or more feeding issues on a regular basis. The most common feeding issues experienced included poor appetite (29%), refusing to eat (19%), and gagging (13%). However, 22% of these 111 individuals had experienced resolution of all feeding issues, suggesting temporal improvement. Of those participants currently on diazoxide with resolved feeding issues (n = 24), 83% reported that the feeding issues were resolved by age 7. The most common feeding issues discussed in the interviews were poor appetite and refusal to eat (
).
Ensuring that the person with HI ate enough before bedtime was mentioned by four interviewees. HIGR survey participants currently taking diazoxide (n=109) were asked about the length of fasting tolerance before their blood glucose level dropped below 70 mg/dL (3.9 mmol/L, 0.7 g/L): responses showed that 53% of the 109 people with HI could last 4 hours or less during daytime and 36% could not go more than 8 hours overnight. Pre-bedtime snacks were often discussed as part of the routine (
).
For individuals with HI, tube feeding is often used to maintain blood glucose levels; for some, it is used to support nutritional needs resulting from feeding issues. Of HIGR participants currently using diazoxide (n = 112), 42% have used tube feeding, including 10% who utilized tube feeding at the time of the study. Tube feeding methods included one or more of the following: the use of a nasogastric or orogastric tube, a gastrostomy tube or button, a jejunostomy tube, and/or total parenteral nutrition (
). One individual in the qualitative study was currently using tube feeding, and three others had used tube feeding at some point.
Among HIGR survey participants who were currently using diazoxide and who reported on their comorbid conditions (n = 81), 73% reported having at least one other diagnosed medical condition (
). The most frequently reported comorbidities included attention deficit hyperactivity disorder (28%), epilepsy (22%), and autism spectrum disorder (20%). Of the participants with no comorbidities at the time of the survey (n = 22), 64% were 6 years or younger, suggesting that a comorbid condition may not yet have been identified.
Of those current diazoxide users in HIGR who also reported on their diagnosed comorbid conditions (n = 59), gastrointestinal comorbidities were reported by 22% (
) and included gastroesophageal reflux, gastrointestinal motility disorder, and inflammatory bowel disease. No respondent specified whether these conditions were explicitly linked to their HI or diazoxide use. In the qualitative interviews, gastrointestinal issues ranged from minor to severe, including one person who received a diagnosis from a neurologist of abdominal migraines. Multiple caregivers described their child as being “a spitty baby” or having “reflux issues”. Vomiting was discussed as a common problem associated with taking diazoxide (
).
Of participants in HIGR who had ever taken diazoxide (n = 160), 94% reported at least one side effect while taking the drug; of these, at least 15% reported that they stopped taking the drug, temporarily or permanently, owing to the side effects they experienced. Of individuals currently taking diazoxide who experienced side effects (n = 113), 49% reported having experienced at least three, and one person experienced 11 side effects. The frequency of side effects experienced by HIGR participants is listed in
. All individuals in the interviews indicated that they or their child experienced some side effects associated with diazoxide, using phrases like “pretty nasty” and “gnarly” to describe them.
An increase in body hair growth was reported as a side effect for 89% of the 121 current diazoxide users in HIGR (
), and the effect on hair was described in all but one interview. This included both positive and negative descriptions of “excess hair,” “hair darkening,” “hair growth,” and “nice hair”; three parents said that their child looked like a monkey. Hair growth was commonly described as occurring all over the body and specifically cited as growing on the back, forehead, legs, arms, hands, upper lip, eyebrows, mustache, and pubic area.
For some participants, one of the more concerning side effects was swelling, which was experienced by 22% of the 121 HIGR participants currently taking diazoxide (
). Many participants described their child or themselves as looking puffy or swollen (
). Although this was most visible in their face, it raised concerns about the impact of fluid retention on other body systems that could not be visually identified.
One of the adult participants was especially focused on how fluid retention impacted her self-image and the lengths she went to mitigate this side effect, including taking dandelion root and a diuretic and undergoing lymphatic drainage massage (
). Of the 15 people whose swelling was described in the interviews, 11 had used a diuretic at some point, but a few had discontinued use as they got older.
Of the 15 individuals discussed during the interviews, 10 commented about diazoxide-related facial changes or features. Of the 121 HIGR participants taking diazoxide, 23% reported facial changes (
). These were often discussed by comparing the child with HI with their other siblings or noting similarities between the person and others on diazoxide in the HI community (
).
In the interviews, additional side effects such as dry skin, eczema and skin darkening were considered, but specific attribution to diazoxide did not carry certainty. Of the 121 HIGR participants currently taking diazoxide, 11% reported skin rash as a side effect (
). In the interviews, two individuals indicated that their child broke out into a rash when they first started taking the medication, and one of them said that their child still deals with occasional rashes. Another individual discussed a long duration of unexplained pain that has lessened but not fully resolved. Another individual indicated they had a short-term thrombocytopenia problem that resolved. One of the adults with HI articulated additional effects of the medication on her emotional state (
).
Safety fasts were a prominent subject for seven of the interview participants. Most people found safety fasts helpful in providing a baseline understanding of their child’s fasting tolerance. However, two people stated that the in-hospital fasting environment was stressful and inconsistent with “real life”. Among HIGR participants who had experienced in-hospital fasting (n = 39), only 38% believed the procedure to be consistent with at-home fasting (this is a newly launched question with limited data). The frequency and importance of clinical safety fasts varied between participants (
).
A few parents reported that they had initiated conversations about fasting with their clinicians. Often, this was triggered by conversations with other parents at conferences or on social media, led to a desire for similar safety fasts conducted for their children (
).
When individuals were asked whether they were confident that diazoxide provided them or their child with adequate glycemic control, diazoxide was noted as an important component, but not a stand-alone solution. The largest benefit from diazoxide therapy was perceived as the ability of the family to normalize their routines and have fewer disruptive medical events (
).
The frequency of dysglycemia was reported by 110 HIGR participants currently taking diazoxide. A blood glucose level below 70 mg/dL (3.9 mmol/L) was reported by 37% of these participants as occurring up to several times per week, including 18% of the participants, who experienced this more than once a day. Only 3% of the 110 participants reported no longer experiencing blood glucose levels of below 70 mg/dL (
). Although less common than a low blood glucose event, a blood glucose level above 180 mg/dL (10 mmol/L) was experienced at least occasionally by 53% of the 110 HIGR participants currently taking diazoxide, with 24% of these reporting a frequency of this level at least one per month. When asked to describe glycemic trends during the interviews, responses focused on blood glucose ranges or the identifiable patterns that led to increased low blood glucose readings (
).
Exercise, sickness, seasonal patterns, and weather changes were discussed as potential reasons for a decrease in glucose control and an increase in parental anxiety (
). Most participants did not express an expectation that diazoxide would fully address the variations caused by these factors.
When the 101 caregivers in HIGR were asked how caring for someone with HI affected their decision to have additional children, 67% reported delaying or choosing not to have additional children. Caregivers also reported changes in their own health (
).
One significant impact on day-to-day life was parents’ feeling that they could safely trust others to watch or care for their child; this also impacted the parents’ social lives overall (
). When 24 caregivers were recently asked in HIGR whether they feel comfortable allowing others to care for their child (i.e. babysitting), 71% responded “seldom” or “never.” In some interviews, this discomfort was described as being motivated by the caregiver’s fear or a lack of trust due to the complexity of care needs. However, people indicated that they became more comfortable over time as their child was able to communicate more, the family established routines to better manage the child’s HI, and the child was more compliant with taking their medication. Over time, parents also identified care partners they could trust, including grandparents and specially trained babysitters. Three people noted that they had found nurses or nursing students who were able to serve as part-time babysitters and who the caregivers were comfortable leaving their child with.
Individuals expressed concern about their child with HI in daycare and school settings (
). Some individuals expressed that their school was supportive, especially during mealtimes or with glucose checks. However, others reported that the school was unwilling to support their child’s needs, and that they were told they must be available to pick the child up if they had a low glucose reading, or that they must be present for special events or school trips (
).
In the interviews, all of the career decisions reported within families were specific to changes made by the mother. Many caregivers spoke about either leaving their previous job, limiting their employment, or making career decisions based on needing to be available for care needs (
). In HIGR, caregivers reflected on the impact of HI on their career and household finances (
).
Families tried to maintain consistency and glycemic stability through use of a rigid regular routine; therefore, illness and other disruptions, increased activity, and social activities introduced anxiety and the potential for additional medical problems. Emergency room visits and hospitalizations presented a constant threat to the families and represented an underlying fear of potential brain damage or death. Hospitalizations were a burden not only to families, but also contribute to higher costs to healthcare systems (42, 43). Individuals who were able to maintain better glycemic control were more willing to accept the taste and the side effects of diazoxide.
The most frequently reported side effects from HIGR are consistent with published evidence (8, 19, 21, 24, 33) as are the smaller proportion reporting more severe side effects, including thrombocytopenia and pulmonary hypertension. Additionally, this study provides context and impact from the caregiver’s perspective, reinforcing the patient/caregiver voice in the management of HI, a complex, long-term condition associated with the risk of neurodisability (3, 4, 18, 25, 32).
While changes in physical appearance are well recognized in patients using diazoxide over prolonged periods (5, 8, 9, 18, 27, 44). This study is the first to acknowledge the social stigma and impact on self-esteem, prompting the need for clinicians to address these concerns and support patients in how they cope. As drug adherence is generally well correlated with side effect profile (45), patient-facing understanding of long-term therapy implications, including psychosocial ramifications, needs to be explored for improved and tolerable treatment outcomes. Although some studies have investigated long-term use (46), parents reported concerns about other unknown aspects of diazoxide, therefore additional studies should be conducted, and better information should be provided to patients to further alleviate their concerns.
A large proportion of HIGR participants currently taking diazoxide (64%) experienced feeding problems previously reported in other studies (46). This study reinforced the context of gastrointestinal adverse impact by interview participants discussing force-feeding, increased anxiety around mealtimes, and vomiting associated with overeating. These narratives have not been reported but need to be understood to plan holistic patient care. This study did not explore long-term dietary patterns and an individual’s relationship with food, but one adult reported their diagnosis of anorexia. The complex relationship between the illness manifestations, treatment effects, and side effects on gastrointestinal manifestations has not been well characterized; our study findings provide insight into the acceptance and adaptations of imperfect therapy, indicating the need to explore the social perspectives for new therapies in development. Additionally, new therapies should strive to eliminate the need for supplemental nutrition to maintain euglycemia and reduce feeding issues and gastrointestinal distress.
An important angle, rarely reported in published evidence, is the caregiver burden (mainly affecting mothers), which can cause anxiety and stress, often due to the need to adhere to stringent routines. Mothers reported on disrupted sleep, their added stress of participating in social activities, and the other ways HI impacted their parenting methods. The finding is not surprising, considering that mothers assume greater responsibility for managing chronic illness (47–50). Further, 93% of people populating HIGR were mothers and only mothers participated in qualitative interviews. Interestingly, the children in the study did not report experiencing the stress and anxiety their mothers did.
As a cross-sectional study, individuals were not followed over time, but the qualitative interviews were designed to include viewpoints at different phases of life. However, the sample size in each age category was small, precluding meaningful longitudinal narratives. It is possible that additional themes might have emerged with interviews over a wider age span. However, the conjunction of registry review and qualitative interview provides reasonable robustness to our data. Nonetheless, the study team recognizes the need to widen interview participation from different countries to capture the impact in different family, social, cultural, and economic settings. This is particularly important as diazoxide is deemed an essential medicine by the World Health Organization, but access is still limited or unavailable in many countries (9, 18, 32, 36). Geopolitical factors including healthcare affordability and overall access may further impact the generalizability of the results. However, through the advocacy and research work of CHI (32, 36), the authors are aware of ongoing access issues and are working on expanding participation within these communities, including by expanding the number of languages.
Caregiver responses in HIGR may have been subject to recall bias. However, caregivers and patients living with a rare disease are often highly engaged in managing the condition and often keep extensive records (51–53); therefore, it is unlikely that HIGR responses were significantly influenced by recall bias. Recruitment and retention are common problems in rare disease registries. To address these challenges, CHI conducts continuous engagement for HIGR.
The results of this study have implications for medical professionals and families living with HI. To optimize diazoxide efficacy and minimize side effects, the study suggests the need for greater adoption of the International HI Care Guidelines and for stronger dialogue between families and professionals (8). The study also points to the considerable psychosocial impact, both for the parents and children living with HI, with implications for monitoring and treating mental health, the need for support structures, and awareness of changing perspectives between childhood and adolescence with long-term use of diazoxide. Within the study, some individuals spoke about the value of connecting with other families, but more family-oriented resources can be developed and disseminated to schools and other caretakers. The study showed there is a clear unmet need for improved novel therapies for HI. Many individuals with HI and their families are striving for a future where their lives are unburdened by the constant focus on euglycemia, and the inescapable efforts to maintain it, to prevent the negative consequences of HI.

Sections

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A diagnosis of HI relies on the demonstration of a biochemical profile consistent with inappropriate secretion/actions of insulin during a spontaneous or provoked episode of hypoglycemia, including detectable plasma insulin/C-peptide, low plasma levels of free fatty acids and beta-hydroxybutyrate, and a glycemic response to a pharmacologic dose of glucagon (7, 8). Management of HI involves vigilant glucose monitoring and can include medications, surgery, and/or feeding plans to minimize, and optimally prevent, hypoglycemia (8, 9).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"B8\", \"B10\", \"B11\", \"B8\", \"B12\", \"B17\", \"B12\", \"B6\", \"B18\"], \"section\": \"Introduction\", \"text\": \"Diazoxide is the first-line treatment for HI, and is the only medication for HI approved by the United States Food and Drug Administration and European regulatory authorities (8). Diazoxide blunts insulin secretion by activating ATP-sensitive potassium (KATP) channels and hyperpolarizing the \\u03b2-cell plasma membrane (10, 11). An individual is considered responsive to diazoxide by demonstrating a reversal in hypoketotic hypoglycemia (8). Up to 60% of individuals with HI are unresponsive to diazoxide (12\\u201317); unresponsiveness often results from KATP channel defects, secondary to inactivating pathogenic variants in ABCC8 and KCNJ11, the genes encoding the channels, although other forms of genetic HI may also be diazoxide-unresponsive (12). Responsiveness is not universally assessed according to the standards described in the international HI care guidelines, which may be a contributing factor as to why some individuals on diazoxide may continue to experience hypoglycemia. Data from the HI Global Registry (HIGR) have shown that up to 32% of people currently taking diazoxide report hypoglycemia (blood glucose level below 70 mg/dL) multiple times a week or more frequently (6, 18).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"B13\", \"B19\", \"B20\", \"B21\", \"B8\", \"B16\", \"B21\", \"B22\", \"B6\", \"B9\", \"B19\", \"B23\", \"B21\", \"B24\", \"B27\", \"B8\", \"B19\", \"B28\", \"B29\", \"B21\", \"B25\", \"B30\", \"B8\", \"B9\", \"B27\"], \"section\": \"Introduction\", \"text\": \"Several studies have reported that side effects accompany diazoxide treatment (13, 19, 20). It is estimated that up to 9.7% of individuals discontinue use due to serious side effects impacting the cardiovascular/respiratory, hematologic, or gastrointestinal system (21). Individuals with perinatal stress-induced hyperinsulinism have higher rates of serious side effects (8, 16, 21, 22). The most frequently reported side effect of diazoxide is hypertrichosis, impacting up to 84% of people taking diazoxide (6). Changes in facial features are reported in up to 24% of people (9, 19, 23). Fluid accumulation, pulmonary hypertension, and pulmonary overload, which may become life-threatening, have also been observed (21, 24\\u201327). The use of a diuretic to mitigate fluid retention is the current standard of care on initiation of diazoxide (8, 19). Other reported side effects include cardiac failure (28, 29), neutropenia, thrombocytopenia, and hyperuricemia (21, 25, 30). To monitor the occurrence of side effects, clinicians are advised to perform periodic echocardiograms, complete blood counts, and serum uric acid analysis on individuals who are prescribed diazoxide (8, 9, 27).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"B22\", \"B31\", \"B18\", \"B32\", \"B21\", \"B33\", \"B35\", \"B31\"], \"section\": \"Introduction\", \"text\": \"Multiple reports suggest an increase in feeding difficulty after diazoxide initiation (22, 31). Feeding difficulties are also a feature of HI; therefore, it is difficult to determine whether this is a feature of the disease or the treatment (18, 32). Moreover, gastrointestinal reactions have been reported in individuals receiving diazoxide, which may further exacerbate challenges in encouraging nutritional intake, which is critical to maintaining euglycemia (21, 33\\u201335). Some diazoxide users were also tube fed; tube feeding may be required to ensure swift and easy access to nutritional support to maintain glycemic control (31).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"B18\", \"B32\"], \"section\": \"Introduction\", \"text\": \"In previous publications that have included the patient voice, there was some evidence that caregivers and individuals with HI taking diazoxide experienced a psychosocial burden due to the impact of the visible side effects, such as hair growth, which may trigger social distress and stigmatization for families (18, 32). Despite the acknowledgment of diazoxide\\u2019s side effects by clinicians and families affected by HI, the impact of these side effects is not adequately reported in the literature. There is a growing interest in including patient-reported data and the impact of treatments on a patient\\u2019s quality of life in research and clinical studies, often in the context of regulatory decision-making. However, this work has often not been conducted for treatments already on the market. Prior to this study, no study specifically asked caregivers and patients with HI about their experiences with diazoxide. The aim of this research was to better understand the real-world impact of diazoxide and its side effects on people living with HI and on their caregivers through their own words, including the impact on glycemic control, daily routines, and quality of life.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"B6\", \"B6\"], \"section\": \"HI global registry\", \"text\": \"HIGR was launched in October 2018 as the first global patient-powered HI registry (6). The registry is available in eight languages and contains 13 patient and/or caregiver surveys that collect information through multiple-choice and open-ended questions on the experience of HI over a person\\u2019s lifetime and one physician-reported survey (6). HIGR recruitment is ongoing through Congenital Hyperinsulinism International\\u2019s (CHI) virtual platforms and in-person at patient-family conferences and HI clinics. Participation is open to individuals over the age of 18 who have received a diagnosis of HI and caregivers of children (younger than 18 years) with HI who are reporting on their child\\u2019s experiences and the impact on their own quality of life.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"B6\", \"B37\", \"B38\"], \"section\": \"HI global registry\", \"text\": \"HIGR surveys were created by an international team of HI experts, including family members of children with HI, clinicians, and researchers, based on the literature and lived experiences (6). No tool has yet been validated for HI research; however, the HIGR quality of life surveys were based on validated tools, including PedsQL and DisabKids (37, 38). The surveys are cross-sectional and largely retrospective. A few surveys, including quality of life and glucose monitoring, are longitudinal. In this study, we included responses from the most recent survey submissions.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"T1\"], \"section\": \"Qualitative methodology: interviews\", \"text\": \"A total of 50 people expressed interest in participating in the study. Of this group, 26 were identified as eligible to participate, and 22 people were invited to participate; these 22 people represented a range of ages and primary treatment centers. Four did not respond to requests to schedule interviews prior to data saturation for the study being met. In total, 18 people participated in the qualitative interviews. Of this group, 12 were caregivers of individuals living with HI, three were children aged 10\\u201312 years, and three were young adults living with HI (\\n).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"B39\", \"B41\", \"T1\", \"T1\"], \"section\": \"Qualitative methodology: interviews\", \"text\": \"Qualitative data analysis combined Van Manen and grounded theory strategies, including immersive reading, open coding, thematic identification, interpretative analysis, and integration to create a comprehensive narrative (39\\u201341). Data analysis was completed manually by two authors using Delve, a qualitative data analysis software program. Open coding focused on identifying keywords or phrases, which were then contextualized through axial and selective coding to generate codes and subcodes to create the final codebook. Peer debriefing was completed throughout coding with individuals who were familiar with diazoxide as well as with those who were not, to ensure methodological consistency, clarity of interpretation of the data, and reproducibility. Interview participants were assigned a participant identifier to ensure anonymity, and basic demographic data were recorded (\\n). Interview participants lived in Australia, Canada, Italy, the United Kingdom, the United States, and the Caribbean. Based on the risk of identifiability, the specific country in the Caribbean has not been shared, and the countries of residence were not recorded in \\n.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"SM1\"], \"section\": \"Qualitative methodology: interviews\", \"text\": \"Quotes were edited to improve clarity without changing their meaning (e.g., removing\\n\\u201clike\\u201d). Quotes have been anonymized, but were attributed to the participant via their identifier, which includes a letter code specifying whether the participant is a caregiver (CG) or a person with HI (HI), and the age of the person with HI. An example of the qualitative codebook and the themes that emerged are available in \\n.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"T2\", \"T2\", \"T1\"], \"section\": \"Participants\", \"text\": \"In total, 165 HIGR participants reported either current use (n = 123) or past use (n = 42) of diazoxide (\\n). Throughout the manuscript, we will refer to individuals who were currently taking diazoxide at the time of the study; this does not indicate current use today. In HIGR, about one-third of individuals who were currently taking diazoxide were aged 1\\u20133 years (34%); of these, 62% were from North America (of whom 88% were from the United States) and 59% were White. All individuals in HIGR taking diazoxide and all the interview participants indicated diffuse or atypical forms of HI. The genetic background of the HIGR participants varied. KATP channel variants were present in 22% of individuals currently taking diazoxide and 45% of the past use group. In the current use group, 32% of participants received negative genetic testing results, and 22% either had no genetic testing or did not report genetic testing. For individuals in HIGR, 29% had taken diazoxide for 6 years or longer (\\n). The patients\\u2019 ages ranged from 1 year to 26 years for interview participants. Five of these individuals began diazoxide within the first month of life, and seven of them within the first year of life (\\n). Two people with HI were previous diazoxide users.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"f1\"], \"section\": \"Diazoxide administration\", \"text\": \"Taste of diazoxide was frequently commented upon, with patients and caregivers describing this medicine as tasting like \\u201cchemical milk,\\u201d \\u201ccharcoal with licorice,\\u201d or \\u201cvery dirty water,\\u201d and using words like \\u201cbitter,\\u201d \\u201csour,\\u201d \\u201cgross,\\u201d and \\u201cdisgusting\\u201d (\\n). The taste contributed to additional challenges, leading to families developing strategies to mitigate the residual taste.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"T3\", \"f2\"], \"section\": \"The impact of HI and diazoxide on diet and gastrointestinal health\", \"text\": \"The complex relationship between HI, diazoxide, feeding issues, and gastrointestinal problems emerged as a prominent theme in the interviews. This finding correlated with HIGR participants currently taking diazoxide (n = 111), of whom 64% reported feeding issues (\\n), and 28% reported five or more feeding issues on a regular basis. The most common feeding issues experienced included poor appetite (29%), refusing to eat (19%), and gagging (13%). However, 22% of these 111 individuals had experienced resolution of all feeding issues, suggesting temporal improvement. Of those participants currently on diazoxide with resolved feeding issues (n = 24), 83% reported that the feeding issues were resolved by age 7. The most common feeding issues discussed in the interviews were poor appetite and refusal to eat (\\n).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"f2\"], \"section\": \"The impact of HI and diazoxide on diet and gastrointestinal health\", \"text\": \"Ensuring that the person with HI ate enough before bedtime was mentioned by four interviewees. HIGR survey participants currently taking diazoxide (n=109) were asked about the length of fasting tolerance before their blood glucose level dropped below 70 mg/dL (3.9 mmol/L, 0.7 g/L): responses showed that 53% of the 109 people with HI could last 4 hours or less during daytime and 36% could not go more than 8 hours overnight. Pre-bedtime snacks were often discussed as part of the routine (\\n).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"T3\"], \"section\": \"The impact of HI and diazoxide on diet and gastrointestinal health\", \"text\": \"For individuals with HI, tube feeding is often used to maintain blood glucose levels; for some, it is used to support nutritional needs resulting from feeding issues. Of HIGR participants currently using diazoxide (n = 112), 42% have used tube feeding, including 10% who utilized tube feeding at the time of the study. Tube feeding methods included one or more of the following: the use of a nasogastric or orogastric tube, a gastrostomy tube or button, a jejunostomy tube, and/or total parenteral nutrition (\\n). One individual in the qualitative study was currently using tube feeding, and three others had used tube feeding at some point.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"T4\"], \"section\": \"The impact of HI and diazoxide on diet and gastrointestinal health\", \"text\": \"Among HIGR survey participants who were currently using diazoxide and who reported on their comorbid conditions (n = 81), 73% reported having at least one other diagnosed medical condition (\\n). The most frequently reported comorbidities included attention deficit hyperactivity disorder (28%), epilepsy (22%), and autism spectrum disorder (20%). Of the participants with no comorbidities at the time of the survey (n = 22), 64% were 6 years or younger, suggesting that a comorbid condition may not yet have been identified.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"T4\", \"f2\"], \"section\": \"The impact of HI and diazoxide on diet and gastrointestinal health\", \"text\": \"Of those current diazoxide users in HIGR who also reported on their diagnosed comorbid conditions (n = 59), gastrointestinal comorbidities were reported by 22% (\\n) and included gastroesophageal reflux, gastrointestinal motility disorder, and inflammatory bowel disease. No respondent specified whether these conditions were explicitly linked to their HI or diazoxide use. In the qualitative interviews, gastrointestinal issues ranged from minor to severe, including one person who received a diagnosis from a neurologist of abdominal migraines. Multiple caregivers described their child as being \\u201ca spitty baby\\u201d or having \\u201creflux issues\\u201d. Vomiting was discussed as a common problem associated with taking diazoxide (\\n).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"T5\"], \"section\": \"Side Effects\", \"text\": \"Of participants in HIGR who had ever taken diazoxide (n = 160), 94% reported at least one side effect while taking the drug; of these, at least 15% reported that they stopped taking the drug, temporarily or permanently, owing to the side effects they experienced. Of individuals currently taking diazoxide who experienced side effects (n = 113), 49% reported having experienced at least three, and one person experienced 11 side effects. The frequency of side effects experienced by HIGR participants is listed in \\n. All individuals in the interviews indicated that they or their child experienced some side effects associated with diazoxide, using phrases like \\u201cpretty nasty\\u201d and \\u201cgnarly\\u201d to describe them.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"T5\"], \"section\": \"Side effect: hair\", \"text\": \"An increase in body hair growth was reported as a side effect for 89% of the 121 current diazoxide users in HIGR (\\n), and the effect on hair was described in all but one interview. This included both positive and negative descriptions of \\u201cexcess hair,\\u201d \\u201chair darkening,\\u201d \\u201chair growth,\\u201d and \\u201cnice hair\\u201d; three parents said that their child looked like a monkey. Hair growth was commonly described as occurring all over the body and specifically cited as growing on the back, forehead, legs, arms, hands, upper lip, eyebrows, mustache, and pubic area.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"T5\", \"f3\"], \"section\": \"Side effect: swelling and fluid retention\", \"text\": \"For some participants, one of the more concerning side effects was swelling, which was experienced by 22% of the 121 HIGR participants currently taking diazoxide (\\n). Many participants described their child or themselves as looking puffy or swollen (\\n). Although this was most visible in their face, it raised concerns about the impact of fluid retention on other body systems that could not be visually identified.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"f3\"], \"section\": \"Side effect: swelling and fluid retention\", \"text\": \"One of the adult participants was especially focused on how fluid retention impacted her self-image and the lengths she went to mitigate this side effect, including taking dandelion root and a diuretic and undergoing lymphatic drainage massage (\\n). Of the 15 people whose swelling was described in the interviews, 11 had used a diuretic at some point, but a few had discontinued use as they got older.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"T5\", \"f3\"], \"section\": \"Side effect: facial changes\", \"text\": \"Of the 15 individuals discussed during the interviews, 10 commented about diazoxide-related facial changes or features. Of the 121 HIGR participants taking diazoxide, 23% reported facial changes (\\n). These were often discussed by comparing the child with HI with their other siblings or noting similarities between the person and others on diazoxide in the HI community (\\n).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"T5\", \"f3\"], \"section\": \"Additional side effects\", \"text\": \"In the interviews, additional side effects such as dry skin, eczema and skin darkening were considered, but specific attribution to diazoxide did not carry certainty. Of the 121 HIGR participants currently taking diazoxide, 11% reported skin rash as a side effect (\\n). In the interviews, two individuals indicated that their child broke out into a rash when they first started taking the medication, and one of them said that their child still deals with occasional rashes. Another individual discussed a long duration of unexplained pain that has lessened but not fully resolved. Another individual indicated they had a short-term thrombocytopenia problem that resolved. One of the adults with HI articulated additional effects of the medication on her emotional state (\\n).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"f4\"], \"section\": \"Ongoing monitoring of HI and the impact of diazoxide\", \"text\": \"Safety fasts were a prominent subject for seven of the interview participants. Most people found safety fasts helpful in providing a baseline understanding of their child\\u2019s fasting tolerance. However, two people stated that the in-hospital fasting environment was stressful and inconsistent with \\u201creal life\\u201d. Among HIGR participants who had experienced in-hospital fasting (n = 39), only 38% believed the procedure to be consistent with at-home fasting (this is a newly launched question with limited data). The frequency and importance of clinical safety fasts varied between participants (\\n).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"f4\"], \"section\": \"Ongoing monitoring of HI and the impact of diazoxide\", \"text\": \"A few parents reported that they had initiated conversations about fasting with their clinicians. Often, this was triggered by conversations with other parents at conferences or on social media, led to a desire for similar safety fasts conducted for their children (\\n).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"f5\"], \"section\": \"Glycemic control and individual glucose monitoring\", \"text\": \"When individuals were asked whether they were confident that diazoxide provided them or their child with adequate glycemic control, diazoxide was noted as an important component, but not a stand-alone solution. The largest benefit from diazoxide therapy was perceived as the ability of the family to normalize their routines and have fewer disruptive medical events (\\n).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"T6\", \"f5\"], \"section\": \"Glycemic control and individual glucose monitoring\", \"text\": \"The frequency of dysglycemia was reported by 110 HIGR participants currently taking diazoxide. A blood glucose level below 70 mg/dL (3.9 mmol/L) was reported by 37% of these participants as occurring up to several times per week, including 18% of the participants, who experienced this more than once a day. Only 3% of the 110 participants reported no longer experiencing blood glucose levels of below 70 mg/dL (\\n). Although less common than a low blood glucose event, a blood glucose level above 180 mg/dL (10 mmol/L) was experienced at least occasionally by 53% of the 110 HIGR participants currently taking diazoxide, with 24% of these reporting a frequency of this level at least one per month. When asked to describe glycemic trends during the interviews, responses focused on blood glucose ranges or the identifiable patterns that led to increased low blood glucose readings (\\n).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"f5\"], \"section\": \"Glycemic control and individual glucose monitoring\", \"text\": \"Exercise, sickness, seasonal patterns, and weather changes were discussed as potential reasons for a decrease in glucose control and an increase in parental anxiety (\\n). Most participants did not express an expectation that diazoxide would fully address the variations caused by these factors.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"T7\"], \"section\": \"Impact of disease and medication on daily functioning and quality of life\", \"text\": \"When the 101 caregivers in HIGR were asked how caring for someone with HI affected their decision to have additional children, 67% reported delaying or choosing not to have additional children. Caregivers also reported changes in their own health (\\n).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"f6\"], \"section\": \"Impact of disease and medication on daily functioning and quality of life\", \"text\": \"One significant impact on day-to-day life was parents\\u2019 feeling that they could safely trust others to watch or care for their child; this also impacted the parents\\u2019 social lives overall (\\n). When 24 caregivers were recently asked in HIGR whether they feel comfortable allowing others to care for their child (i.e. babysitting), 71% responded \\u201cseldom\\u201d or \\u201cnever.\\u201d In some interviews, this discomfort was described as being motivated by the caregiver\\u2019s fear or a lack of trust due to the complexity of care needs. However, people indicated that they became more comfortable over time as their child was able to communicate more, the family established routines to better manage the child\\u2019s HI, and the child was more compliant with taking their medication. Over time, parents also identified care partners they could trust, including grandparents and specially trained babysitters. Three people noted that they had found nurses or nursing students who were able to serve as part-time babysitters and who the caregivers were comfortable leaving their child with.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"T8\", \"f6\"], \"section\": \"Diazoxide and HI at daycare and school\", \"text\": \"Individuals expressed concern about their child with HI in daycare and school settings (\\n). Some individuals expressed that their school was supportive, especially during mealtimes or with glucose checks. However, others reported that the school was unwilling to support their child\\u2019s needs, and that they were told they must be available to pick the child up if they had a low glucose reading, or that they must be present for special events or school trips (\\n).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"f7\", \"T8\"], \"section\": \"Caregiver career decisions\", \"text\": \"In the interviews, all of the career decisions reported within families were specific to changes made by the mother. Many caregivers spoke about either leaving their previous job, limiting their employment, or making career decisions based on needing to be available for care needs (\\n). In HIGR, caregivers reflected on the impact of HI on their career and household finances (\\n).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"B42\", \"B43\"], \"section\": \"Discussion\", \"text\": \"Families tried to maintain consistency and glycemic stability through use of a rigid regular routine; therefore, illness and other disruptions, increased activity, and social activities introduced anxiety and the potential for additional medical problems. Emergency room visits and hospitalizations presented a constant threat to the families and represented an underlying fear of potential brain damage or death. Hospitalizations were a burden not only to families, but also contribute to higher costs to healthcare systems (42, 43). Individuals who were able to maintain better glycemic control were more willing to accept the taste and the side effects of diazoxide.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"B8\", \"B19\", \"B21\", \"B24\", \"B33\", \"B3\", \"B4\", \"B18\", \"B25\", \"B32\"], \"section\": \"Discussion\", \"text\": \"The most frequently reported side effects from HIGR are consistent with published evidence (8, 19, 21, 24, 33) as are the smaller proportion reporting more severe side effects, including thrombocytopenia and pulmonary hypertension. Additionally, this study provides context and impact from the caregiver\\u2019s perspective, reinforcing the patient/caregiver voice in the management of HI, a complex, long-term condition associated with the risk of neurodisability (3, 4, 18, 25, 32).\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"B5\", \"B8\", \"B9\", \"B18\", \"B27\", \"B44\", \"B45\", \"B46\"], \"section\": \"Discussion\", \"text\": \"While changes in physical appearance are well recognized in patients using diazoxide over prolonged periods (5, 8, 9, 18, 27, 44). This study is the first to acknowledge the social stigma and impact on self-esteem, prompting the need for clinicians to address these concerns and support patients in how they cope. As drug adherence is generally well correlated with side effect profile (45), patient-facing understanding of long-term therapy implications, including psychosocial ramifications, needs to be explored for improved and tolerable treatment outcomes. Although some studies have investigated long-term use (46), parents reported concerns about other unknown aspects of diazoxide, therefore additional studies should be conducted, and better information should be provided to patients to further alleviate their concerns.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"B46\"], \"section\": \"Discussion\", \"text\": \"A large proportion of HIGR participants currently taking diazoxide (64%) experienced feeding problems previously reported in other studies (46). This study reinforced the context of gastrointestinal adverse impact by interview participants discussing force-feeding, increased anxiety around mealtimes, and vomiting associated with overeating. These narratives have not been reported but need to be understood to plan holistic patient care. This study did not explore long-term dietary patterns and an individual\\u2019s relationship with food, but one adult reported their diagnosis of anorexia. The complex relationship between the illness manifestations, treatment effects, and side effects on gastrointestinal manifestations has not been well characterized; our study findings provide insight into the acceptance and adaptations of imperfect therapy, indicating the need to explore the social perspectives for new therapies in development. Additionally, new therapies should strive to eliminate the need for supplemental nutrition to maintain euglycemia and reduce feeding issues and gastrointestinal distress.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"B47\", \"B50\"], \"section\": \"Discussion\", \"text\": \"An important angle, rarely reported in published evidence, is the caregiver burden (mainly affecting mothers), which can cause anxiety and stress, often due to the need to adhere to stringent routines. Mothers reported on disrupted sleep, their added stress of participating in social activities, and the other ways HI impacted their parenting methods. The finding is not surprising, considering that mothers assume greater responsibility for managing chronic illness (47\\u201350). Further, 93% of people populating HIGR were mothers and only mothers participated in qualitative interviews. Interestingly, the children in the study did not report experiencing the stress and anxiety their mothers did.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"B9\", \"B18\", \"B32\", \"B36\", \"B32\", \"B36\"], \"section\": \"Limitations\", \"text\": \"As a cross-sectional study, individuals were not followed over time, but the qualitative interviews were designed to include viewpoints at different phases of life. However, the sample size in each age category was small, precluding meaningful longitudinal narratives. It is possible that additional themes might have emerged with interviews over a wider age span. However, the conjunction of registry review and qualitative interview provides reasonable robustness to our data. Nonetheless, the study team recognizes the need to widen interview participation from different countries to capture the impact in different family, social, cultural, and economic settings. This is particularly important as diazoxide is deemed an essential medicine by the World Health Organization, but access is still limited or unavailable in many countries (9, 18, 32, 36). Geopolitical factors including healthcare affordability and overall access may further impact the generalizability of the results. However, through the advocacy and research work of CHI (32, 36), the authors are aware of ongoing access issues and are working on expanding participation within these communities, including by expanding the number of languages.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"B51\", \"B53\"], \"section\": \"Limitations\", \"text\": \"Caregiver responses in HIGR may have been subject to recall bias. However, caregivers and patients living with a rare disease are often highly engaged in managing the condition and often keep extensive records (51\\u201353); therefore, it is unlikely that HIGR responses were significantly influenced by recall bias. Recruitment and retention are common problems in rare disease registries. To address these challenges, CHI conducts continuous engagement for HIGR.\"}, {\"pmc\": \"PMC12410177\", \"pmid\": \"\", \"reference_ids\": [\"B8\"], \"section\": \"Future directions\", \"text\": \"The results of this study have implications for medical professionals and families living with HI. To optimize diazoxide efficacy and minimize side effects, the study suggests the need for greater adoption of the International HI Care Guidelines and for stronger dialogue between families and professionals (8). The study also points to the considerable psychosocial impact, both for the parents and children living with HI, with implications for monitoring and treating mental health, the need for support structures, and awareness of changing perspectives between childhood and adolescence with long-term use of diazoxide. Within the study, some individuals spoke about the value of connecting with other families, but more family-oriented resources can be developed and disseminated to schools and other caretakers. The study showed there is a clear unmet need for improved novel therapies for HI. Many individuals with HI and their families are striving for a future where their lives are unburdened by the constant focus on euglycemia, and the inescapable efforts to maintain it, to prevent the negative consequences of HI.\"}]"

Metadata

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