Introduction
Type 1 diabetes is the predominant form of diabetes in childhood and is increasing worldwide [
1]. Several studies have suggested a link between childhood-onset type 1 diabetes and increased risk of neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD) and intellectual disability [
2‐
4].
Neurodevelopmental disorders are a group of conditions classified together by the Diagnostic and Statistical Manual of Mental Disorders (5th edition) [
5] because of their common onset during childhood, high comorbidity rate of 20–80% and essential overlap of contributing factors across specific diagnoses [
6].
Although the aetiology of neurodevelopmental disorders is often attributed to genetic factors in the general population [
7,
8], a different biological mechanism may be more plausible in type 1 diabetes. In our previous study, statistically significant increased risk of neurodevelopmental disorders (HRs 1.5–1.7) was observed in individuals with childhood-onset type 1 diabetes, but not in their healthy siblings. This suggests that diabetes-related factors play important roles in the aetiology of neurodevelopmental disorders in individuals with diabetes rather than shared genetic and environmental influences [
2].
Glucose metabolism is essential for brain development and function [
9], and its disturbance during childhood may have negative consequences. Adverse effects of dysglycaemic insults on central nervous system development in children and adolescents with type 1 diabetes have long been recognised [
10‐
12]. Several studies have shown that poor glycaemic control is related to impairments in neurocognitive functions, such as attention (the ability to focus selectively on certain information and sustain that focus while disregarding other perceivable stimuli), working memory (capacity to temporarily store information in order to execute cognitive tasks) and intellectual abilities [
13‐
15]. Yet, it remains unknown whether these neurocognitive deficits can be translated into increased risk of medical diagnosis of neurodevelopmental disorders or merely indicate subclinical difficulties.
Many children and adolescents in high-income countries fail to achieve the recommended target of HbA
1c [
16]. Diabetes guidelines emphasise the importance of appropriate glycaemic control to avoid microvascular and microvascular complications [
17]. Nevertheless, there is limited evidence regarding whether maintaining adequate glycaemic control similarly benefits paediatric patients through reduced psychological morbidity risk. A better understanding of the relationship between glycaemic control and the risk of neurodevelopmental disorders is also crucial for future evidence-based recommendations on neurodevelopmental follow-ups, and early interventions. A recent Danish population-based study found that poor glycaemic control with an average HbA
1c level of >8.6% (>70 mmol/mol) predicted a higher risk of psychiatric morbidity in individuals with type 1 diabetes [
18], but this study was unable to specifically address the risk of neurodevelopmental disorders, which are aetiologically distinct from other psychiatric disorders [
19].
In this study, we used Swedish registers, which have high coverage and contain prospectively collected information on HbA1c measurements and medical diagnoses, to investigate the effect of childhood-onset type 1 diabetes on the subsequent risk of neurodevelopmental disorders, and the role of glycaemic control in this association.
Discussion
In this large population-based cohort study, we found that individuals with childhood-onset type 1 diabetes were at higher risk of neurodevelopmental disorders compared with their peers from the general population and that this risk increased at higher mean HbA1c levels. We also demonstrated that poor glycaemic control, which was assessed using time-varying HbA1c, was an independent risk factor for subsequent neurodevelopmental disorders in childhood-onset type 1 diabetes.
To date, two population-based studies have evaluated the risk of neurodevelopmental disorders in individuals with childhood-onset type 1 diabetes compared with the general population. In our previous study of 17,122 children and adolescents with type 1 diabetes, we observed 1.5–1.7-fold increased risk of ADHD, ASD and intellectual disability diagnosed before the age of 18 years [
2,
26]. A Danish study of 5084 patients with childhood-onset type 1 diabetes reported slightly (statistically non-significant) increased risk of ADHD in girls (HR
adjusted 1.12 [95% CI 0.81, 1.56]) and ASD in boys (HR
adjusted 1.09 [95% CI 0.82, 1.46]) diagnosed after diabetes onset [
26].
Our current study, consisting of 8430 individuals with childhood-onset type 1 diabetes and with a focus on the first event of neurodevelopmental disorders diagnosed after diabetes onset, observed statistically significantly elevated risks with adjusted HRs ranging from 1.27 to 1.30. The somewhat lower HRs observed in the current study, compared with our previous study [
2], could be explained by the exclusions of patients with chromosomal abnormalities and patients with neurodevelopmental disorders prior to diabetes onset, and a focus on recent years (the current study included type 1 diabetes diagnosed 1995–2013 as opposed to 1973–2009 in our previous study). Another study from the Danish group observed an association between high mean HbA
1c level (>8.6% [>70 mmol/mol]) during the first 2 years after diabetes onset and later diagnosis of any psychiatric disorders. Yet, the summarised outcome ‘any psychiatric disorders’ included a wide range of diagnoses with different aetiological backgrounds, such as neurodevelopmental disorders but also depression and anxiety [
18]. Our study is the first presenting specific risks of neurodevelopmental disorders in childhood-onset type 1 diabetes compared with the general population and within patients. A novel aspect of the current study is the monotonic increase in the risk of all types of neurodevelopmental disorders with higher HbA
1c values, which may be explained by the use of the time-varying HbA
1c in our analysis. This method of estimation of glycaemic control is known to be more accurate than using mathematical mean or single measurement of HbA
1c [
27].
Our findings suggest that maintaining adequate glycaemic control is important for controlling potential psychological burdens in childhood-onset type 1 diabetes, since patients with adequate glycaemic control showed no statistically significant difference in risk of any neurodevelopmental disorders compared with the general population. Notably, risks of any neurodevelopmental disorders and ADHD gradually increased at higher glycaemic control, and nearly doubled in patients with poor glycaemic control compared with their peers without type 1 diabetes. Although in the comparison with the general population, statistically significantly increased risk of ASD was only found in patients with adequate glycaemic control, this result was not confirmed when we restricted our analysis to individuals with type 1 diabetes only, where the risk was almost tripled (HRadjusted 2.84) in patients with poor glycaemic control compared with those adequately controlled. We noted that there was limited statistical power in these analyses, but we cannot exclude the possibility that some of these results were a result of patients with type 1 diabetes with high awareness of disease management more frequently and willingly seeking advice from medical professionals, and thus being more likely to be psychiatrically evaluated and receive a timely diagnosis than their peers without type 1 diabetes.
Several possible mechanisms may explain the observed increased risk of neurodevelopmental disorders in individuals with type 1 diabetes, especially in those with poor glycaemic control. Studies have found inadequate growth of grey and white matter, of both microstructure and volume, in children with type 1 diabetes, especially in those with chronic hyperglycaemia (i.e. poor glycaemic control) [
28‐
30]. A similar pattern of hindered growth of cortical surface area and hippocampus volume has also been reported in other studies [
29,
31]. On one hand, the compromised brain growth and neurodevelopment in type 1 diabetes may lead to altered neuropsychological functions, and subsequently clinically diagnosed neurodevelopmental disorders. Abnormalities in the above-mentioned brain structures are commonly present in individuals with neurodevelopmental disorders [
32], for instance, hippocampus deficits are often found in individuals with ADHD and ASD, and correspond with memory and executive impairments [
33]. On the other hand, it may worsen the pre-existing subthreshold symptoms of the undiagnosed neurodevelopmental disorders so they become clinically significant. Moreover, detection bias may contribute to the observed association, as individuals with type 1 diabetes need to be closely monitored and thus have increased contact with healthcare providers as well as mental health services. To address this, we performed a sensitivity analysis by excluding neurodevelopmental disorders diagnosed within 1 year after diabetes diagnosis. The magnitude of risk estimates remained similar although with some loss of statistical power. Furthermore, we cannot rule out reverse causation between neurodevelopmental disorders and glycaemic control. Since the manifestations of neurodevelopmental disorders change with age and over time [
34], patients with type 1 diabetes with undiagnosed neurodevelopmental disorders may have inferior neuropsychological functions that can negatively affect their abilities to manage their diabetes, resulting in poor glycaemic control.
This is the first large nationwide register-based study with prospectively collected data specifically investigating the association of childhood-onset type 1 diabetes and neurodevelopmental disorders, while determining the role of glycaemic control in this association. The selection of matched reference individuals from the general population and the exact matching allowed us to control for possible confounding from sex, birth year and birth county. The study took place in Sweden, a country with a tax-funded healthcare system with universal access and free-of-charge paediatric care, which reduced possible confounding from socioeconomic factors [
35]. This is important since earlier research indicated a link between low socioeconomic status and both poor glycaemic control [
36] and neurodevelopmental disorders [
37]. In our study, we adjusted for socioeconomic status, using parental education as a proxy.
Our study also has some limitations. Reverse causation between neurodevelopmental disorders and glycaemic control cannot be fully ruled out in an observational study. Moreover, because of the registration-based nature of the study, we could not monitor the glycaemic control of every patient precisely from diabetes diagnosis. To address this concern, we repeated the analysis in patients with first HbA
1c documented within the first 3 months after diagnosis, as HbA
1c primarily reflects 3-month average glycaemic control [
38], and observed similar associations. Additionally, because of the lack of data, we were not able to control for prenatal exposure to maternal gestational diabetes, which is a potential risk factor for neurodevelopmental disorders in offspring [
39]. Despite our large sample size of individuals with childhood-onset type 1, we had limited statistical power to examine co-occurrence of neurodevelopmental disorders and levels of intellectual disability as outcomes. Among patients with diabetes diagnosed with subsequent neurodevelopmental disorders, only 22 (5%) received two or more diagnoses on the same date, and this corresponded to 201 (6%) among matched reference individuals. In total, 40 patients with diabetes were diagnosed with intellectual disability, among whom 34 (85%) were mild and 6 (15%) were moderate to severe. This was similar to levels of intellectual disability diagnosed in the matched reference individuals (271 [88%] mild and 36 [12%] moderate to severe). Also, we do not have data on other neurodevelopmental disorders such as communication or specific learning disorders, and we had limited statistical power to evaluate the association between exposure to severe hypoglycaemia or diabetic ketoacidosis and later risk of neurodevelopmental disorders, which have been previously associated with intellectual disability and ADHD. Besides, HbA
1c values were not available for the matched reference individuals. Given the relatively young age of the study sample, prediabetes and undiagnosed type 2 diabetes, and thus the HbA
1c levels of the matched reference individuals, were presumed to be close to normal. Although we cannot fully exclude the possibility of a bias towards underestimation of risk due to disturbed glucose metabolism from other reasons in the matched reference individuals, we were similarly unable to evaluate the optimal HbA
1c target regarding future risk of neurodevelopmental disorders. We used the current cut-off to be consistent with a previous Danish study [
18], but a similar pattern of association was observed when glycaemic control was categorised differently (ESM Table
8 and
9).
Several implications for clinicians may be derived from the present study. First, our findings further support existing evidence that individuals with childhood-onset type 1 diabetes are at higher risk of neurodevelopmental disorders. Second, we demonstrated that glycaemic control is an independent risk factor for clinically diagnosed neurodevelopmental disorders. Thus, optimal diabetes management along with psychological care is crucial for children and adolescents with type 1 diabetes. Paediatricians should be aware of the relationship between treatment adherence in individuals with type 1 diabetes and impairment in executive functions. Neurocognitive assessment for neurodevelopmental disorders should be offered to children and adolescents with self-management difficulties, suboptimal glycaemic control, and unexplained academic problems. Appropriate educational adjustment, and social and family support, should be available to individuals with childhood-onset type 1 diabetes and neurodevelopmental disorders.
Future longitudinal studies, with information on a wider range of diabetes-related factors such as episodes and severity of acute complications, are warranted in order to gain more insights into the aetiology of neurodevelopmental disorders in childhood-onset type 1 diabetes. Research on strategies that can integrate paediatric psychological services and diabetes care are needed for prevention and early detection of the comorbidity.
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