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Do autistic patients change healthcare services utilisation through the transition age? An Italian longitudinal retrospective study

Objectives This paper aims to provide an estimate of the prevalence rate of autism spectrum disorder (ASD) in 8-year-olds in 2017 based on administrative databases and to investigate the change in healthcare service use during the healthcare transition age of 18. Design This research is based on a longitudinal retrospective cohort study. Setting The data is drawn from the Italian Administrative Healthcare Database (2010–2017). Participants We identified 5607 ASD patients; 331 ASD patients from 2012 to 2015 in the calendar year of their 18th birthday were selected and their health service utilisation during a 5-year period—ranging from 2 years preceding and succeeding their 18th year—were investigated. Interventions None. Primary and secondary outcome measures Prevalence, incidence and proportion of ASD patients receiving specific healthcare services were included in the outcome measures. Results Prevalence of ASD at age 8 was 5.4/1000. Global access to health and social services was lower both before and after age 18 (46.5% at 16; 68.0% at 18; 54.1% at 20). The percentage of patients receiving a neuropsychiatric consultation decreased after age 18 (30.8% at 18; 5.4% at 20). Community mental health services (CMHS) utilisation rate increased above 18 years of age. Regarding psychiatric visits, for both outpatient and CMHS, an increase was observed from 17.8% at age 18 to 25.4% at age 20. The utilisation of rehabilitation services decreased with age, dropping from 17.8% at age 16 to 1.8% at age 20. Psychiatric outpatient services remained stable across ages at about 14%. Conclusion Our findings suggest that ASD patients changed clinical reference services with age from neuropsychiatric and rehabilitative services towards psychiatric and community-based services as they transitioned from paediatric to adult healthcare services.


INTRODUCTION
Autism spectrum disorder (ASD) is a brain-based chronic neurodevelopmental disorder, with lifelong impacts, characterised and diagnosed by impairments in social communication and social interaction with the presence of restricted, repetitive behaviours or interest [1]. ASD is a serious condition resulting in a significant burden for individuals, families and society [2,3]. Onset of ASD typically occurs by age 3, although some studies suggest that symptoms can emerge between 6 and 18 months of age and may not be full manifested until school age [4,5].
Children, adolescents and adults with ASD can often present a number of comorbidities including psychiatric conditions, intellectual disabilities, development delay, epilepsy, anxiety, language and motor difficulties and depression [6][7][8][9]. Moreover, an increase in mortality has been observed compared with the general population [10].
The aetiology of ASD remains largely unexplained. It seems to be highly hereditable [11] and some environmental risk factors [12] and parental age [13] may be involved [14]. The prevalence of ASD has increased in the last decades, although the reasons for this increase are not fully understood. It might be related to etiologic, nonetiologic and administrative factors (e.g. alternated diagnostic criteria, improved access at services and increased public and scientific interest [8,15,16]).
In 2010, [17] the prevalence rate for children aged 8 was estimated to be 3.9 per 1000 for boys and 0.8 per 1000 for girls. The annual incidence rates in 2010 [18] in children aged 2-8 was 1.02 per 1000 in boys aged 2-8 and 0.21 per 1000 in girls.
A review published in 2012 [19] estimated the global prevalence of ASD to be about 1% (62/10000); a more recent study has estimated the prevalence to be 1.5 in developed countries [14,17,20]. In 2014 [20] a prevalence rate of 16.8 per 1000 was estimated for children aged 8.
Treatments of ASD vary across the word and even within country regions and it seems that parents with a lower educational level are less successful in obtaining specialist interventions that could improve the outcome [8].
Treatments of ASD include early parent-mediated interventions, behavioural and social treatment. Evidence based pharmacology in ASD is currently limited to the treatment of co-occurring behaviour or diagnosis and not ASD itself [8]. Risperidone [21], Aripiprazole [22] have improved symptoms of irritability or agitation in children and adolescents with ASD. Methylphenidate [23] , Atomoxetine [24] Guafacine [25] have shown a benefit for ADHD symptoms in ASD. However, the use of such drugs presents some adverse effects and their use has been indicated during a specific age period. While autism is generally considered a disorder of childhood, the rise in ASD prevalence in the last decades in children is resulting in an increased number of subject with ASD transitioning from paediatric to young adult medical services and this means that autism is rapidly becoming a disorder of adulthood as well [26]. There are evidences that for young people with special healthcare needs, such as autism, transitioning form paediatric to adult healthcare remains a problem [27,28]. The transition process may be especially difficult for young people whose special healthcare needs involve mental health, development disabilities of intellectual disabilities [28].
Moreover, the lack of clarity on adult ASD treatment guidelines increases the complexity of healthcare delivery and a involves a problematic transition from paediatric to adult healthcare [29].
Administrative claims data can be plentiful, comprehensive, cost efficient and free from some of biases that accompany other types of data, such as surveys or self-reports [30]. Analyses of administrative healthcare databases have the potential to include large number of subjects and have been successfully used in the study of health outcomes associated with a variety of conditions [30,31]. Studies conducted in US [32] and Canada [33,34] indicated that administrative claims data were able to clearly identify children with ASD.
The purpose of this paper is to use administrative databases derived from the largest Northern Italian population to a) provide an estimate of the prevalence of ASD at 8 years of age and b) investigate the change in healthcare services use by ASD patient during the transitioning from paediatric towards young adult healthcare services.

Data collection
A retrospective cohort study was conducted using the Administrative Healthcare Database of the Health Protection  Co-occurring conditions ( Table 2) were about 22% at 16 years of age and remained constant among ages (p-value 0.7) as epilepsy (p-value 0.8); no differences were found for the gender (p-value 0.5) and deprivation index. On the contrary, other psychiatric diagnoses increased from 42.6% at 16 years of age to 66.5% at 18 (p-value <0.001), females had a greater risk than males (p-value 0.003) and no differences were found for the deprivation index.
Schizotypal and delusional disorders increased from 11.2% at 16 years old to 26.3% at 18 (p-value 0.001); at 16 years old about 30% of ASD had intellectual disabilities, and that percentage increased with age reaching 39% at 20 (p-value <0.001). We found greater risk for females regarding mood affecting disorders (F30-F39, p-value 0.001) and disorders of adult personality and behaviour ( F60-F69, p-value 0.009).
The percentage of ASD patient with at least one health services utilization by age where reported in Table 3. Global access to health and social services decrease both before and after aged 18 (Table 3), with comparable level at 16 and 20 years of age (p-value 0.08).
The percentage of patients receiving a neuropsychiatric visit in outpatient services ( if the latter did not reach a statistical significance. It should be noted that neuropsychiatric and psychiatric hospital admissions together remained stable across ages (9.4% at 16 to 6.6% at 20, OR 20vs18 =0.59; 95%CI 0.35-1.01). The utilisation of residential and semi-residential services was constant across ages (from 6.6% to 6.0%, OR 20vs18 =0.66; 95%CI 0.43-1.01).
Over than 40% of ASD patients had antipsychotics drug prescriptions, and the percentage increased, even without being statistically significant, with age. Antipsychotics (about 30%) and antiepileptics (about 20%) were the most prescribed drugs and the percentage did not show a statistically significant increase with age. In detail, risperidone (15%) and aripiprazole (from 5% to 10.5) were the antipsychotic drugs most frequently prescribed.
Valproic acid was the most frequent prescription in epileptic drugs (about 20% of ASD patients) and no statistically significant differences were found across ages. Nor any significant differences were found neither by gender nor by deprivation index.

DISCUSSION
Autism is among the most considerable public health problems and between the diagnosis and the age of 18, the Italian healthcare system provides an efficient management model based on child neuropsychiatry.
The results from this study, based on the innovative and integrated use of healthcare and social databases, show that, however, in the transition to adult age, there is a change in the models for taking care of a child diagnosed with autism.
The use of administrative databases allowed us to study real-word diagnostic patterns of a large and unselected population. However, the diagnoses in this analysis were made by physicians specialised in a variety of disciplines, which may lead to a diagnostic imprecision. Indeed, the estimated prevalence at 8 years old (0.54%) is lower than the autism prevalence of 1.68% reported by the most recent study [20]. Nevertheless, our estimation is very close to a value estimated in less recent years [18,36,37] and are similar to the prevalence estimated from administrative databases in Germany during 2012 [38] for age groups ranging from 6 to 11 years old (0.6%) and in France 0.35% from register based data [39]. In Italy, few studies reporting autism prevalence have been carried out; in a recent paper, Narzisi [40] estimated a prevalence of 0.8% in 7-9 year olds. This figure is higher than ours, but the different study setting might have influenced the results, as Narzisi based the study on a sample at the community level.
However, if we considered only children included in Narzisi et al. with both certified disability and ASD, a prevalence of 0.65% would be assessed and this is much closer to our estimate. Since ASD is generally diagnosed after 1 year of age and our administrative data started from 2010, we believe that only a small part of ASD diagnosed patients being 8 years old in 2017 was not included. Our underestimation of ASD may be due to a number of reasons: 1) a delay of diagnosis after 8 years old, 2) a lack of recorded diagnosis in administrative databases, 3) a limited tendency to register the autism diagnosis in Lombardia by physicians; 4) a misclassification diagnosis or 5) only more serious cases were diagnosed by physicians of the NHS.
With respect to incidence, we estimated for 2017 an annual incident rate of about 2/1000 from children aged 2-8, but we were able to find only one study for comparison [18], which estimated an annual incidence of 1.02/1000 in boys and 0.21/1000 in girls aged 2-8. This figure is lower than ours, however it is referred to 2010, and the incidence of ASD in these years could have increased. Furthermore, we were able to estimate an incidence for Our study investigated the differences in rates of comorbidity and healthcare services utilisation in a selected retrospective longitudinal cohort of ASD patients from 16 to 20 years old.
Giving that fact, the recruited ASD cohort included selected ASD subjects who had been recruited as patients with health/social care services utilisation over seven years (from 2010 to 2017). Thus, the finding in that cohort could not be connected to general ASD patients during the transition age but to ASD patients who were included in a health/social services pathway and, perhaps, with more serious conditions. In that view, our findings of a high rate (up to 66.5%) of psychiatric conditions (including mental retardation) were not completely surprising, even if higher than those reported in other studies (34% [41], 54% [7], 65% [37]). In detail, the percentage of anxiety previously reported [41] was similar (14.4%) to ours (19.3%), as well as depression (9.9 vs 13.3 ). The percentage of epilepsy (9%) is comparable with other studies about the transition age in ASD [41].
In Italy, patients remain in charge of paediatric healthcare services until 18  In conclusion, we did not observe a decrease in healthcare services utilisation as recently reported by Nathenson et al [42].
The percentage of ASD people who received at least one service related to an ED remains stable with age, although a slight increase in 17-19 olds was observed. This suggests that even if the therapeutic references may have changed with age, this did not imply a greater need of the ED.
Even if the current evidence for the effectiveness of antipsychotics drugs in ASD is only moderate [8], neuroleptic drugs were frequently used in this cohort of ASD patients and their consumption remained stable across ages; moreover, our findings were similar to frequencies reported in other studies [37]. ADHD drugs were less prescribed ( less than 0.6%) with respect to other reported prescription rates in ASD patients (about 15%) even considering the patients' age [43], this may reflect a generally low consumption in Italy of such drugs in childhood [44].

Strengths and Limitations
The current study used large administrative databases, which made it possible to study real-word diagnostic patterns of a large and unselected population, without non-responses, interviews or recall bias issues. However, we must note that we could not include any service utilisation outside the NHS. Furthermore, diagnoses in administrative databases are made by physicians specialised in a variety of disciplines and were not validated, Rehabilitation interventions database did not systematically report the type of services provided (i.e. speech therapy, rehabilitation, occupational therapy). As co-occurring conditions, we could include only selected items from the Co-payment Exemption Register and psychiatric conditions were reported in the general category.
The 16-20 age range provides an opportunity to investigate ASD patients during the transition from paediatric toward to young adult services and we were able to follow longitudinally a selected group of ASD patients in transition age without the birth cohort effect. Unfortunately, our cohort was limited to adolescents with ASD who had had at least one healthcare service consumption with a diagnosis code related to ASD starting from 2010, so ASD patients who did not use healthcare services during this period would not be included. Accordingly, our findings may not be applied to all ASD patients in transition age but represented ASD patients with some healthcare service connection.
Our study suggested a change in the "therapeutic references" but we did not find a reduction in the use of healthcare services with age. However, we were not able to include a survey on caregivers in order to investigate the actual difficulty in managing this transition. Moreover, psychiatric healthcare services may not be the proper type of support considering the special needs (such as speech therapy, rehabilitations, occupational therapy) of these patients.

Strengths and limitations of this study
 Longitudinal retrospective cohort study based on Administrative Healthcare Database: realworld diagnostic patterns of a large and unselected population (3.5 million habitants)  Estimation of prevalence and incidence rates, differences in comorbidity, and healthcare services utilisation in an unselected retrospective longitudinal cohort of ASD patients from 16 to 20 years of age  Diagnosis codes and healthcare services utilisation were based only on the administrative data Onset of ASD typically occurs by age 3, although some studies suggest that symptoms can emerge between 6 and 18 months of age and may not be fully manifested until school age [2,3].
The aetiology of ASD remains largely unexplained. It seems to be highly heritable [8] and some environmental risk factors [9] and parental age [10] may be involved [11]. The prevalence of ASD has increased in the last decades, although the reasons for this increase are not fully understood. It might be related to etiologic, non-etiologic, and administrative factors (e.g. modified diagnostic criteria, improved access to services, and increased public and scientific interest [6,12,13]).
A review published in 2012 [14] estimated the global prevalence of ASD to be about 1% (62/10000); a more recent study has estimated the prevalence to be 1.5% in developed countries [11,15,16]. In 2014 [15], a prevalence rate of 16.8 per 1000 was estimated for children aged 8.
Treatments for ASD vary across the world and even within country regions and it has been reported that parents with a lower educational level are less successful in obtaining specialist interventions that could improve outcomes [6]. Treatments for ASD include early parent-mediated interventions and behavioural and social treatments. Evidence-based pharmacology in ASD is currently limited to the treatment of co-occurring behaviours or diagnoses and not ASD itself [6]. Risperidone [17] and aripiprazole [18] have improved symptoms of irritability or agitation in children and adolescents with ASD. Methylphenidate [19], atomoxetine [20], and guanfacine [21] have shown a benefit for ADHD symptoms in ASD. However, the use of such drugs presents some adverse effects and their use has been indicated during a specific age period.
While autism is generally considered a disorder of childhood, the rise in ASD prevalence in the last decades has produced an increase of individuals with ASD transitioning from paediatric to young adult medical services resulting in autism rapidly becoming a disorder of adulthood as well [22]. There is evidence that for young people with special healthcare needs, such as autism, transitioning form paediatric to adult healthcare represents a problem [23,24].
The transition process may be especially difficult for young people whose special healthcare needs involve mental health, developmental disabilities, or intellectual disabilities [24].
Moreover, the lack of ASD treatment guidelines for adult patients increases the complexity of healthcare delivery and involves a problematic transition from paediatric to adult healthcare [25]. Very often, the transition to adulthood in people with ASD results in poor outcomes across multiple domains including employment, education, healthcare, social engagement, and independent living [26,27], even in the presence of healthcare transition services [28]. This may represent problems both for parents [27] and patients [29].
Often the transition from the paediatric to adult healthcare system coincides with an exit from the educational system (i.e. high school) where adolescents may receive daily support that may further affect service usage. However, to our knowledge, only a few studies have described changes in healthcare service usage during the transition to adulthood in people with ASD [24,26,30]. Administrative claims data can be plentiful, comprehensive, cost efficient, and free from some of the biases that accompany other types of data, such as surveys or self-reports [31].
Analyses of administrative healthcare databases have the potential to include a large number of individuals and have been successfully used in the study of health outcomes associated with a variety of conditions [31,32]. Studies conducted in the US [33] and Canada [34,35] have indicated that administrative claims data were able to clearly identify children with ASD.
The purpose of this paper is to provide an estimate of the prevalence of ASD at 8 years of age using administrative databases derived from the largest Northern Italian population.
Further, this study investigated the change in healthcare services use during the transition from the paediatric to young adult healthcare systems.

Data collection
A retrospective cohort study was conducted using the Administrative Healthcare These databases can be linked through a unique identifier code; demographic information was obtained by record linkage using a unique identifier code with patients' master ASD patients were defined as individuals having a reported diagnosis of ASD (ICD-9 codes 299.00 to 299.99 or their ICD-10 equivalents) in at least one of the databases during the study period [35]. For each patient, the calendar year of birth was used as an approximate age value at the time of service utilisation.

Statistical analysis Prevalence and incidence rates estimation
Prevalence rates at age 8 and 2-8 years incidence rates based on administrative databases were estimated for 2017. The prevalence rate was obtained by dividing the number of children 8 years old diagnosed as ASD in 2017 or previously, by the population size -of the same age -in the study area at 1 January 2018 based on the Italian National Institute of Statistics.
The annual incidence rates were obtained by dividing the annual number of children aged 2-8 years newly diagnosed by the general population subtracting the number of ASD diagnoses in preceding years. Binomial 95% confidence intervals (95%CI) were calculated for the prevalence and incidence rates.

Consumptions and outcome models
We selected ASD patients from 2012 to 2015 in the calendar year of their 18 th birthday, and we investigated Health Services utilisation during a 5-year period: the two years preceding and succeeding their 18 th year as well as the year of their 18 th birthday (i.e. aged from 16 to 20).
We investigated the percentage of co-occurring conditions related to other psychiatric diseases; as an outcome variable, we investigated access to services (i.e. outpatient, rehabilitation interventions, community/social services, ED access, hospital admissions, and neuroleptic drug consumption). With regard to neuroleptic drug consumption, we investigated the percentages of ASD patients who had at least one prescription for any psychotropic substances according to the anatomical therapeutic chemical (ATC) classification. We selected all substances with ATC code "N" (nervous system) excluding anaesthetics (N01) and analgesics (N02). In addition, we included antidepressants (N06A), antipsychotics (N05), anxiolytics/tranquillisers (N05B, N05CD, N05CF), ADHD medication (N06BA), and antiepileptics (N03A) as separate groups.
The binary responses of co-occurring diseases, other psychiatric diagnoses, service consumptions, and outcomes at ages 16-20 were modelled by repeated measurements using a generalised estimating equation (GEE) approach with a dichotomic response variable. The binary responses for individual ASD patients were assumed to be equally correlated, so an

Patient and public involvement
Neither patients nor the public were involved in the design or conduct of this study.
Ethics approval was not required given that ATS has among its institutional functions the evaluation of the care pathways of autistic patients transitioning to adulthood which is considered a critical element to monitor at present in NHS. Patient identity was masked by anonymization according to the standard ISO 25237:201. Their unique identification number (fiscal code) was transcoded into a string by the Information System of ATS, which had no role in analysing the data.

RESULTS
In the period between 2010 and 2017, we identified 5,607 patients (4,109 male and We found a greater risk for females regarding mood affecting disorders (F30-F39, p-value <0.001) and disorders of adult personality and behaviour (F60-F69, p-value=0.009).
The percentage of ASD patients with at least one access to health services by age is reported in Table 3. Global access to health and social services are lower both before and after age 18 (Table 3), with comparable levels at 16 and 20 years of age (p-value=0.08).
The percentage of patients receiving a neuropsychiatric consultation ( More than 40% of ASD patients had neurological drug prescriptions, and the percentage increased with age, although the increase was not statistically significant. Antipsychotics (about 30%) and antiepileptics (about 20%) were the most commonly prescribed drugs and these percentages did not show a statistically significant increase with age. In detail, risperidone (15%) and aripiprazole (from 5% to 11.5%) were the antipsychotic drugs most frequently prescribed. Valproic acid was the most frequent epileptic drug prescribed (about 20% of ASD patients) and no statistically significant differences were found across ages.

DISCUSSION
Autism is a considerable public health problem and between the initial diagnosis and the age of 18, the Italian healthcare system provides an efficient management model based on child neuropsychiatry. Child neuropsychiatry is devoted to neurological, behavioural, emotional, and psychiatric disorders in childhood and adolescence while psychiatry units usually are devoted only to psychiatric disorders, particularly in adulthood. The results from this study, based on the innovative and integrated use of healthcare and social databases, show that, in the transition to adulthood, there is a change in the models used in taking care of a child diagnosed with autism.
The use of administrative databases allowed us to study real-word diagnostic patterns of a large and unselected population. However, the diagnoses used in this analysis were made by physicians specialised in a variety of disciplines, which may lead to diagnostic imprecision.
Indeed, the estimated prevalence of ASD at 8 years of age (0.54%) is lower than the autism prevalence of 1.68% reported by the most recent study [15]. Nevertheless, our estimate is very close to a value estimated in less recent years [37][38][39] and is similar to the prevalence reported using administrative databases in Germany during 2012 [40] for age groups ranging from 6 to 11 years (0.6%) and in France (0.35%) from register-based data [41]. In Italy, few studies reporting autism prevalence have been carried out; in a recent paper, Narzisi et al. [42] estimated a prevalence of 0.8% in 7-9 year olds. This figure is higher than ours, but the different is much closer to our estimate. Since ASD is generally diagnosed after 1 year of age and our data started from 2010, we believe that only a small number of ASD-diagnosed patients who were 8 years old in 2017 were not included. Our underestimation of ASD may be due to a number of reasons: 1) a delay of diagnosis to after 8 years old; 2) a lack of recorded diagnosis in administrative databases; 3) a limited tendency to register the autism diagnosis in Lombardy by physicians; 4) a misclassification of the diagnosis; or 5) only more serious cases were diagnosed by physicians of the NHS.
With respect to incidence, we estimated for 2017 an annual incidence rate -based on administrative databases -of about 2/1000 for children aged 2-8, but we were able to find only one study for comparison [37], which estimated an annual incidence of 1.02/1000 in boys and 0.21/1000 in girls aged 2-8. This figure is lower than ours, however it referred to 2010, and the incidence of ASD in the subsequent years could have increased. Furthermore, we were able to estimate an incidence for children 2 trend for ASD diagnoses reported in administrative claims that will be reflected in the prevalence of the following years. However, the increase of ASD is more related to administrative changes [13] given that fewer symptoms of autism are now required for diagnosis and that a child with a diagnosis of ASD much more often receives support at school and in the community [43], rather than a factor affecting pathogenesis.
Our study investigated the differences in rates of comorbidity and healthcare services utilisation in a selected retrospective longitudinal cohort of ASD patients from 16 to 20 years old. Given that fact, the ASD cohort used in this study included selected individuals who had been patients with health/social care services utilisation over seven years (from 2010 to 2017).
Thus, the findings in this cohort could not be connected to general ASD patients during the transition age but to ASD patients who were included in a health/social services pathway and, perhaps, having more serious conditions. Thus, our findings of a high rate (up to 66.5%) of psychiatric conditions (including mental retardation) were not completely surprising, even if higher than those reported in other studies (34% [44], 54% [5], 65% [39]). In detail, the percentage of anxiety previously reported in a previous study [44] was similar (14.4%) to ours (19.3%), as well as depression (9.9% vs 13.3%). The percentage of individuals with epilepsy in our study (9%) is comparable with other studies examining the transition age in ASD [44].
However, it must be taken into account that the diagnosis of other psychiatric conditions was also based on administrative data and thus may depend, at least in part, on which services and specialists were more involved in each patients' care.
In Italy, patients remain in charge of paediatric healthcare services until 18  services utilisation as recently reported by Nathenson et al. [30]. Moreover, psychiatric healthcare services may not be the proper type of support considering the special needs (such as speech therapy, rehabilitation, and occupational therapy) of these patients.
The percentage of individuals with ASD who received at least one service related to an ED remains stable with age, although a slight increase in 17-19 year olds was observed. This suggests that even if the therapeutic references may have changed with age, this did not imply a greater need of the ED.
Even if the current evidence for the effectiveness of antipsychotic drugs in ASD is only moderate [6], neuroleptic drugs were frequently used in this cohort of ASD patients and their consumption remained stable across ages; moreover, our findings were similar to frequencies reported in other studies [39]. ADHD drugs were less prescribed (less than 0.6%) with respect to other reported prescription rates in ASD patients (about 15%) even considering the patients' age [45]; this may reflect a generally low consumption in Italy of such drugs in childhood [46].

Strengths and Limitations
The current study used large administrative databases, which made it possible to study real-world diagnostic patterns of a large and unselected population, without non-responses, interviews, or recall bias issues. However, we must note that we could not include any service utilisation outside the NHS. Furthermore, diagnoses in administrative databases are made by physicians specialised in a variety of disciplines and were not validated, which may lead to diagnostic imprecision. In addition, some diagnoses may not have been reported. With regard to the estimated rate of ASD patients who used healthcare services, we investigated what type of diagnosis these outcomes were associated with and which were the reasons for such services.
However, the CSS and rehabilitation interventions database did not systematically report the type of services provided (i.e. speech therapy, rehabilitation, occupational therapy). The 16-20 age range provides an opportunity to investigate ASD patients during the transition from paediatric to young adult services and we were able to follow longitudinally a selected group of ASD patients in transition age without the birth cohort effect. Unfortunately, our cohort was limited to adolescents with ASD who had had at least one healthcare service consumption with a diagnosis code related to ASD starting from 2010, so ASD patients who did not use healthcare services during this period would not be included. Accordingly, our findings may not be applied to all ASD patients in transition age but represented ASD patients with some healthcare service connection.
Our study suggested a change in the "therapeutic references" but we did not find a reduction in the use of healthcare services with age. However, we were not able to include a survey of caregivers in order to investigate any actual difficulties in managing this transition.

CONCLUSION
Our findings suggest that ASD patients change "therapeutic references" with age from neuropsychiatric and rehabilitative services towards psychiatric and community-based services.
The rise in prevalence -based on administrative data -of ASD in children might lead to a large number of adolescents who will be entering the young adult's healthcare system in the future and will require specific support. More studies are needed to investigate the actual needs of ASD patients in order to plan future public healthcare policies and interventions. 9c53-4491-b5b7-0a6d43fdcd43, page 68), which is considered a critical element to monitor at present in the Regional and National Italian Health System. Therefore, the Agency of Health Protection of Milan is allowed to use the anonymized administrative data to perform the evaluation of the services provided to autistic patients residing in the covered area. Patient identity was masked by anonymization according to the standard ISO 25237:201. Their unique identification number (fiscal code) was transcoded into a string by the Information System of the Agency of Health Protection, which had no role in analysing the data.

Competing interests:
The research being reported in this publication was supported by Roche.
The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The author reports no other conflicts of interest in this work.        Describe any efforts to address potential sources of bias 8   Conclusions: Our findings suggest that ASD patients changed "therapeutic references" with age from neuropsychiatric and rehabilitative services towards psychiatric and community-based services as they transitioned from paediatric to young adult's healthcare services.
Keywords: Autism spectrum disorder; Epidemiology; Administrative databases; Health outcomes; Health service research

Strengths and limitations of this study
 Longitudinal retrospective cohort study based on Administrative Healthcare Database: realworld diagnostic patterns of a large and unselected population (3.5 million habitants)  Estimation of prevalence and incidence rates, differences in comorbidity, and healthcare services utilisation in an unselected retrospective longitudinal cohort of ASD patients from 16 to 20 years of age  Diagnosis codes and healthcare services utilisation were based only on the administrative data Onset of ASD typically occurs by age 3, although some studies suggest that symptoms can emerge between 6 and 18 months of age and may not be fully manifested until school age [2,3].
The aetiology of ASD remains largely unexplained. It seems to be highly heritable [8] and some environmental risk factors [9] and parental age [10] may be involved. The prevalence of ASD has increased in the last decades, although the reasons for this increase are not fully understood. It might be related to etiologic, non-etiologic, and administrative factors (e.g. modified diagnostic criteria, improved access to services, and increased public and scientific interest [6,11,12]).
A review published in 2012 [13] estimated the global prevalence of ASD to be about 1% (62/10000); a more recent study has estimated the prevalence to be 1.5% in developed countries [14][15][16]. In 2014 [15], a prevalence rate of 16.8 per 1000 was estimated for children aged 8.
Treatments for ASD vary across the world and even within country regions and it has been reported that parents with a lower educational level are less successful in obtaining specialist interventions that could improve outcomes [6]. Treatments for ASD include early parent-mediated interventions and behavioural and social treatments. Evidence-based pharmacology in ASD is currently limited to the treatment of co-occurring behaviours or diagnoses and not ASD itself [6]. Risperidone [17] and aripiprazole [18] have improved symptoms of irritability or agitation in children and adolescents with ASD. Methylphenidate [19], atomoxetine [20], and guanfacine [21] have shown a benefit for ADHD symptoms in ASD. However, the use of such drugs presents some adverse effects and their use has been indicated during a specific age period.
While autism is generally considered a disorder of childhood, the rise in ASD prevalence in the last decades has produced an increase of individuals with ASD transitioning from paediatric to young adult medical services resulting in autism rapidly becoming a disorder of adulthood as well [22]. There is evidence that for young people with special healthcare needs, such as autism, transitioning form paediatric to adult healthcare represents a problem [23,24].
The transition process may be especially difficult for young people whose special healthcare needs involve mental health, developmental disabilities, or intellectual disabilities [24].
Moreover, the lack of ASD treatment guidelines for adult patients increases the complexity of healthcare delivery and involves a problematic transition from paediatric to adult healthcare [25]. Very often, the transition to adulthood in people with ASD results in poor outcomes across multiple domains including employment, education, healthcare, social engagement, and independent living [26,27], even in the presence of healthcare transition services [28]. This may represent problems both for parents [27] and patients [29].
Often the transition from the paediatric to adult healthcare system coincides with an exit from the educational system (i.e. high school) where adolescents may receive daily support that may further affect service usage. However, to our knowledge, only a few studies have described changes in healthcare service usage during the transition to adulthood in people with ASD [24,26,30]. Administrative claims data can be plentiful, comprehensive, cost efficient, and free from some of the biases that accompany other types of data, such as surveys or self-reports [31].
Analyses of administrative healthcare databases have the potential to include a large number of individuals and have been successfully used in the study of health outcomes associated with a variety of conditions [31,32]. Studies conducted in the US [33] and Canada [34,35] have indicated that administrative claims data were able to clearly identify children with ASD.
The purpose of this paper is to provide an estimate of the prevalence of ASD at 8 years of age using administrative databases derived from the largest Northern Italian population.
Further, this study investigated the change in healthcare services use during the transition from the paediatric to young adult healthcare systems.

Data collection
A retrospective cohort study was conducted using the Administrative Healthcare These databases can be linked through a unique identifier code; demographic information was obtained by record linkage using a unique identifier code with patients' master ASD patients were defined as individuals having a reported diagnosis of ASD (ICD-9 codes 299.00 to 299.99 or their ICD-10 equivalents) in at least one of the databases during the study period [35]. For each patient, the calendar year of birth was used as an approximate age value at the time of service utilisation.

Statistical analysis Prevalence and incidence rates estimation
Prevalence rates at age 8 and 2-8 years incidence rates based on administrative databases were estimated for 2017. The prevalence rate was obtained by dividing the number of children 8 years old diagnosed as ASD in 2017 or previously, by the population size -of the same age -in the study area at 1 January 2018 based on the Italian National Institute of Statistics.
The annual incidence rates were obtained by dividing the annual number of children aged 2-8 years newly diagnosed by the general population subtracting the number of ASD diagnoses in preceding years. Binomial 95% confidence intervals (95%CI) were calculated for the prevalence and incidence rates.

Consumptions and outcome models
We We investigated the percentage of co-occurring conditions related to other psychiatric diseases; as an outcome variable, we investigated access to services (i.e. outpatient, rehabilitation interventions, community/social services, ED access, hospital admissions, and neuroleptic drug consumption).

Patient and public involvement
Neither patients nor the public were involved in the design or conduct of this study.

RESULTS
In the period between 2010 and 2017, we identified 5,607 patients (4,109 male and We found a greater risk for females regarding mood affecting disorders (F30-F39, p-value <0.001) and disorders of adult personality and behaviour (F60-F69, p-value=0.009).
The percentage of ASD patients with at least one access to health services by age is reported in Table 3. Global access to health and social services are lower both before and after age 18 (Table 3), with comparable levels at 16 and 20 years of age (p-value=0.08).
The percentage of patients receiving a neuropsychiatric consultation ( More than 40% of ASD patients had neurological drug prescriptions, and the percentage increased with age, although the increase was not statistically significant. Antipsychotics (about 30%) and antiepileptics (about 20%) were the most commonly prescribed drugs and these percentages did not show a statistically significant increase with age. In detail, risperidone (15%) and aripiprazole (from 5% to 11.5%) were the antipsychotic drugs most frequently prescribed. Valproic acid was the most frequent epileptic drug prescribed (about 20% of ASD patients) and no statistically significant differences were found across ages. The use of administrative databases allowed us to study real-word diagnostic patterns of a large and unselected population. However, the diagnoses used in this analysis were made by physicians specialised in a variety of disciplines, which may lead to diagnostic imprecision.

DISCUSSION
Indeed, the estimated prevalence of ASD at 8 years of age (0.54%) is lower than the autism prevalence of 1.68% reported by the most recent study [15]. Nevertheless, our estimate is very close to a value estimated in less recent years [37][38][39] and is similar to the prevalence reported using administrative databases in Germany during 2012 [40] for age groups ranging from 6 to 11 years (0.6%) and in France (0.35%) from register-based data [41]. In Italy, few studies reporting autism prevalence have been carried out; in a recent paper, Narzisi et al. [42] estimated a prevalence of 0.8% in 7-9 year olds. This figure is higher than ours, but the different With respect to incidence, we estimated for 2017 an annual incidence rate -based on administrative databases -of about 2/1000 for children aged 2-8, but we were able to find only one study for comparison [37], which estimated an annual incidence of 1. trend for ASD diagnoses reported in administrative claims that will be reflected in the prevalence of the following years. However, the increase of ASD is more related to administrative changes [12] given that fewer symptoms of autism are now required for diagnosis and that a child with a diagnosis of ASD much more often receives support at school and in the community [43], rather than a factor affecting pathogenesis.
Our study investigated the differences in rates of comorbidity and healthcare services utilisation in a retrospective longitudinal cohort of ASD patients from 16 to 20 years old. Given that fact, the ASD cohort used in this study included individuals who had been patients with health/social care services utilisation over seven years (from 2010 to 2017). Thus, the findings in this cohort could not be connected to general ASD patients during the transition age but to ASD patients who were included in a health/social services pathway and, perhaps, having more serious conditions. Thus, our findings of a high rate (up to 66.5%) of psychiatric conditions (including mental retardation) were not completely surprising, even if higher than those reported in other studies (34% [44], 54% [5], 65% [39]). In detail, the percentage of anxiety previously reported in a previous study [44] was similar (14.4%) to ours (19.3%), as well as Even if the current evidence for the effectiveness of antipsychotic drugs in ASD is only moderate [6], neuroleptic drugs were frequently used in this cohort of ASD patients and their consumption remained stable across ages; moreover, our findings were similar to frequencies reported in other studies [39]. ADHD drugs were less prescribed (less than 0.6%) with respect to other reported prescription rates in ASD patients (about 15%) even considering the patients' age [47]; this may reflect a generally low consumption in Italy of such drugs in childhood [48].

Strengths and Limitations
The current study used large administrative databases, which made it possible to study real-world diagnostic patterns of a large and unselected population, without non-responses, interviews, or recall bias issues. However, we must note that we could not include any service utilisation outside the NHS. Furthermore, diagnoses in administrative databases are made by physicians specialised in a variety of disciplines and were not validated, which may lead to diagnostic imprecision. In addition, some diagnoses may not have been reported. With regard to the estimated rate of ASD patients who used healthcare services, we investigated what type of diagnosis these outcomes were associated with and which were the reasons for such services.
However, the CSS and rehabilitation interventions database did not systematically report the type of services provided (i.e. speech therapy, rehabilitation, occupational therapy).
The 16-20 age range provides an opportunity to investigate ASD patients during the transition from paediatric to young adult services and we were able to follow longitudinally a group of ASD patients in transition age without the birth cohort effect. Unfortunately, our cohort was limited to adolescents with ASD who had had at least one healthcare service consumption with a diagnosis code related to ASD starting from 2010, so ASD patients who did not use healthcare services during this period would not be included. Accordingly, our findings may not be applied to all ASD patients in transition age but represented ASD patients with some healthcare service connection.
Our study suggested a change in the "therapeutic references" but we did not find a reduction in the use of healthcare services with age. However, we were not able to include a survey of caregivers in order to investigate any actual difficulties in managing this transition.

CONCLUSION
Our findings suggest that ASD patients change "therapeutic references" with age from neuropsychiatric and rehabilitative services towards psychiatric and community-based services.
The rise in prevalence -based on administrative data -of ASD in children might lead to a large number of adolescents who will be entering the young adult's healthcare system in the future and will require specific support. More studies are needed to investigate the actual needs of ASD patients in order to plan future public healthcare policies and interventions. We would like to thank Editage (www.editage.com) for English language editing. Funding: The research being reported in this publication was supported by Roche. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The etiology of ASD remains largely unexplained. It seems to be highly heritable [8], and some environmental risk factors [9] and parental age [10] may be involved. The prevalence of ASD has increased in the last decades, although the reasons for this increase are not fully understood. It might be related to etiologic, non-etiologic, and administrative factors (e.g. modified diagnostic criteria, improved access to services, and increased public and scientific interest [6,11,12]).
A review published in 2012 [13] estimated the global prevalence of ASD to be about 1% (62/10000); a more recent study has estimated the prevalence to be 1.5% in developed countries [14][15][16]. In 2014 [15], a prevalence rate of 16.8 per 1000 was estimated for children aged 8.
Treatments for ASD vary across the world and even within country regions, and it has been reported that parents with a lower educational level are less successful in obtaining specialist interventions that could improve outcomes [6]. Treatments for ASD include early parent-mediated interventions and behavioral and social treatments. Evidence-based pharmacology in ASD is currently limited to the treatment of co-occurring behaviors or diagnoses, not ASD itself [6]. Risperidone [17] and aripiprazole [18] have improved symptoms  [19], atomoxetine [20], and guanfacine [21] have shown a benefit for ADHD symptoms in ASD.
However, the use of such drugs presents some adverse effects, and their use has been indicated for a specific age period.
While autism is generally considered a disorder of childhood, the rise in ASD prevalence in the last decades has produced an increase of individuals with ASD transitioning from pediatric to young adult medical services resulting in autism rapidly becoming a disorder of adulthood as well [22]. There is evidence that for young people with special healthcare needs, such as autism, transitioning form pediatric to adult healthcare can be problematic [23,24]. The transition process may be especially difficult for young people whose special healthcare needs involve mental health, developmental disabilities, or intellectual disabilities [24]. Moreover, the lack of ASD treatment guidelines for adult patients increases the complexity of healthcare delivery and involves a complicated transition from pediatric to adult healthcare [25]. Very often, the transition to adulthood in people with ASD results in poor outcomes across multiple domains including employment, education, healthcare, social engagement, and independent living [26,27], even in the presence of targeted healthcare transition services [28]. This may represent problems both for parents [27] and patients [29].
Often the transition from the pediatric to the adult healthcare system coincides with an exit from the educational system (i.e. high school) where adolescents may receive daily support that further affects service usage. However, to our knowledge, only a few studies have described changes in healthcare service usage during the transition to adulthood in people with ASD [24,26,30]. Administrative claims data can be plentiful, comprehensive, cost efficient, and free from some of the biases that accompany other types of data, such as surveys or self-reports [31].
Analyses of administrative healthcare databases have the potential to include a large number of individuals and have been successfully used in the study of health outcomes associated with a variety of conditions [31,32]. Studies conducted in the US [33] and Canada [34,35] have indicated that administrative claims data were able to clearly identify children with ASD.
The purpose of this paper is to provide an estimate of the prevalence of ASD at 8 years of age using administrative databases derived from the largest Northern Italian population.
Further, this study investigated the change in healthcare services use during the transition from the pediatric to young adult healthcare systems.

Data collection
A retrospective cohort study was conducted using the Administrative Healthcare  ASD patients were defined as individuals having a reported diagnosis of ASD (ICD-9 codes 299.00 to 299.99 or their ICD-10 equivalents) in at least one of the databases during the study period [35]. For each patient, the calendar year of birth was used as an approximate age value at the time of service utilization.

Statistical analysis Prevalence and incidence rates estimation
Prevalence rates were estimated for 2017 at age 8 and incidence rates ranging from 2-8 years of age, based on administrative databases. The prevalence rate was obtained by dividing the number of children 8 years old diagnosed with ASD in 2017 or previously, by the population size-of the same age-in the study area as of 1 January 2018, based on the Italian National Institute of Statistics.
The annual incidence rates were obtained by dividing the annual number of children aged 2-8 years, newly diagnosed, by the general population and subtracting the number of ASD diagnoses in preceding years. Binomial 95% confidence intervals (95% CI) were calculated for the prevalence and incidence rates.

Consumptions and outcome models
We selected ASD patients from 2012 to 2015 in the calendar year of their 18 th birthday, and we investigated health services utilization during a 5-year period: the four years bracketing their 18 th year and the 18 th year (i.e. aged from 16 to 20). We investigated the percentage of cooccurring conditions related to other psychiatric diseases; as an outcome variable, we investigated access to services (i.e. outpatient, rehabilitation interventions, community/social services, ED access, hospital admissions, and neuroleptic drug consumption). Co-occurring conditions were identified using the chronicity database [36] that covers the 13 main comorbidity conditions (hypertension, diabetes, dyslipidemia, COPD, heart failure, renal failure, neoplasms, cardiovascular diseases, inflammatory bowel disease, chronic liver diseases, chronic neurological diseases, autoimmune diseases, and endocrine and metabolic diseases). The proportion of ASD patients with a co-occurring psychiatric diagnosis was estimated by searching for psychiatric diagnoses (ICD-10 code: F00 to F99 with F84, autistic disorder, excluded and their ICD-9 conversion according to the database encoding) in the AHD-ATS databases; we assumed that the psychiatric conditions persisted over time after the first psychiatric diagnoses were recorded.
As outcomes, we investigated consumption of outpatient services (psychiatric, neurologic, and neuropsychiatric visits; tests and psychological services), ED admissions, rehabilitation interventions, CMHS interventions, hospital admissions (psychiatry and neuropsychiatric hospitalization), residential services, and CSS utilizations.
The binary responses of co-occurring diseases, other psychiatric diagnoses, service consumptions, and outcomes at ages 16-20 were modelled by repeated measurements using a generalized estimating equation (GEE) approach with a dichotomic response variable. The binary responses for individual ASD patients were assumed to be equally correlated; thus, an  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   9 exchangeable correlation structure was assumed. Ages were modelled first as a categorical variable with age 18 as reference. Regressions for co-occurring diseases and other psychiatric diagnoses were adjusted by a gender and deprivation index; in addition, logistic regressions for service consumption and outcomes were adjusted for co-occurring diseases and other psychiatric diagnoses.

Patient and public involvement
Neither patients nor the public were involved in the design or conduct of this study.
We included all patients (331) who were 18 years old between 2012 and 2015 (Table   1), of whom 257 (77.64%) were male and 74 (22.36%) were female. Regarding the deprivation index, at 18 years of age, 11.18% were in the least deprived quintile, while 20.24% were in the most deprived quintile; no differences were found in the quintile distribution by calendar year (p = 0.2).
Schizotypal and delusional disorders increased from 11.2% at 16 years old to 26.3% at age 18 (p = 0.001); at 16 years old about 30% of individuals with ASD had intellectual disabilities, and that percentage increased with age reaching 39% at 20 years (p < 0.001). We found a greater risk for females regarding mood affecting disorders (F30-F39, p < 0.001) and disorders of adult personality and behavior (F60-F69, p = 0.009).
The percentage of ASD patients with at least one instance of access to health services by age is reported in Table 3. Global access to health and social services are lower both before and after age 18 (Table 3), with comparable levels at 16 and 20 years of age (p = 0.08).
The percentage of patients receiving a neuropsychiatric consultation (Table 3) 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  More than 40% of ASD patients had neurological drug prescriptions, and the percentage increased with age; however, the increase was not statistically significant. Antipsychotics (about 30%) and antiepileptics (about 20%) were the most commonly prescribed drugs, and these percentages did not show a statistically significant increase with age. In detail, risperidone (15%) and aripiprazole (from 5% to 11.5%) were the antipsychotics drugs most frequently prescribed. Valproic acid was the most frequent epileptic drug prescribed (about 20% of ASD patients); no statistically significant differences were found across ages.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   12 Autism is a major topic in public health debates and between the initial diagnosis and the age of 18, the Italian healthcare system provides an efficient management model based on child neuropsychiatry. Child neuropsychiatry is devoted to neurological, behavioral, emotional, and psychiatric disorders in childhood and adolescence while psychiatry units usually are devoted only to psychiatric disorders, particularly in adulthood. The results from this study, based on the innovative and integrated use of healthcare and social databases, show that, in the transition to adulthood, there is a change in the models used in taking care of a child diagnosed with autism.

DISCUSSION
The use of administrative databases allowed us to study real-word diagnostic patterns of a large and unselected population. However, the diagnoses used in this analysis were made by physicians specialized in a variety of disciplines, which may lead to diagnostic imprecision.
Indeed, the estimated prevalence of ASD at 8 years of age (0.54%) is lower than the autism prevalence of 1.68% reported by the most recent study [15]. Nevertheless, our estimate is very close to a value estimated in less recent years [37][38][39]. It is also similar to the prevalence reported using administrative databases in Germany during 2012 [40] for age groups ranging from 6 to 11 years (0.6%) and in France (0.35%) from register-based data [41]. In Italy, few studies reporting autism prevalence have been carried out; in a recent paper, Narzisi et al. [42] estimated a prevalence of 0.8% in children aged 7-9. This figure is higher than ours, but the different study setting might have influenced the results, as Narzisi et al. based theirs on a sample extracted at the community level. However, if we considered only children included in Narzisi et al. with both certified disability and ASD, a prevalence of 0.65% would be assessedmuch closer to our estimate. Since ASD is generally diagnosed after 1 year of age and our data started from 2010, we believe that only a small number of ASD-diagnosed patients who were 8 years old in 2017 were not included. Our underestimation of ASD may be due to a number of reasons: 1) a delayed diagnosis after 8 years old; 2) a lack of recorded diagnosis in  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  With respect to incidence, we estimated for 2017 an annual incidence rate-based on administrative databases-of about 2/1000 for children aged 2-8, but we were able to find only one study for comparison [37], which estimated an annual incidence of 1.02/1000 in boys and 0.21/1000 in girls aged 2-8. This figure is lower than ours; however, it referred to 2010 and the incidence of ASD in the subsequent years could have increased. Furthermore, we were able to estimate an incidence for children 2-6 years old between 2015 and 2017, and we estimated (data not shown) 4.30/1000 for 2015, 4.70 for 2016, and 7.30 for 2017. This suggests an increasing trend for ASD diagnoses reported in administrative claims that will be reflected in the prevalence of the following years. However, the increase of ASD is more related to administrative changes [12] given that fewer symptoms of autism are now required for diagnosis and that a child with a diagnosis of ASD much more often receives support at school and in the community [43], rather than a factor affecting pathogenesis.
Our study investigated the differences in rates of comorbidity and healthcare services utilization in a retrospective longitudinal cohort of ASD patients from 16 to 20 years old. The ASD cohort used in this study included individuals who had been patients with health/social care services utilization over seven years (from 2010 to 2017). Thus, the findings in this cohort could not be connected to general ASD patients during the transition age but to ASD patients who were included in a health/social services pathway and, perhaps, having more serious conditions. Thus, our findings of a high rate (up to 66.5%) of psychiatric conditions (including mental retardation) were not completely surprising, even if higher than those reported in other studies (34% [44]; 54% [5]; 65% [39]). In detail, the percentage of anxiety previously reported in a previous study [44] 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   14 13.3%). The percentage of individuals with epilepsy in our study (9%) is comparable with other studies examining the transition age in ASD [44]. We observed a high percentage of schizophrenia, schizotypal, and delusional disorders (over 20%) compared to other studies (between 8% in adults [5,45,46] and 17% in 22-40 years old [7]). This could be related to a change from child neuropsychiatry services to psychiatry services in the young adult phase where personality disorders may be over-diagnosed. Moreover, it must be considered that the diagnosis of other psychiatric conditions was also based on administrative data and thus may depend, at least in part, on which services and specialists were more involved in each patients' care. Surprisingly, we observed an increasing rate of intellectual disability from 16 years to 20; two possible causes should be considered. On one hand, this trend may be related to the end of the pediatric co-payment exemption at age 18 that previously could overwrite other causes of exemption. On the other hand, the end of compulsory education may cause an increase of intellectual assessment request in order to provide a more specific daily support. In Italy, patients remain in charge of pediatric healthcare services until 18 years of age; however, starting at 16 years of age there may be some overlap in healthcare systems. The results of this study suggest that the type of medical services used for ASD patients changes between 16 and 20 years. Further, comparison between ages showed that general healthcare services utilization increases from 16 to 18 years old and subsequently decreases.
Neuropsychiatric and rehabilitation services decreased with age as ASD patients began treatment with CMHS and CSS; this suggests a change in the care path for these people. Indeed, the percentage of ASD patients with at least one CMHS treatment increased from 18 to 20 years of age. Also, the percentage of ASD patients having psychiatric visits in outpatient care services or CMHS increased from 12.7% at 16 years old to 25.4% at 20 years old. This change in patients' reference services was also confirmed by the decreased rate of ASD patients with neuropsychiatric hospitalization and the corresponding increase of psychiatric hospitalization,  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  remained stable across ages. This suggests, together with the higher global access observed at age 18, that ASD patients and their families might look for new clinical reference services around the 18 th year and then settle down, even if long-term observation may be necessary. In conclusion, we did not observe a decrease in healthcare services utilization as recently reported by Nathenson et al. [30]. Moreover, psychiatric healthcare services may not be the proper type of support considering the special needs (such as speech therapy, rehabilitation, and occupational therapy) of these patients.
The percentage of individuals with ASD who received at least one service related to an ED remains stable with age, although a slight increase in 17-19 year olds was observed. This suggests that even if the clinical reference services changed with age a greater need of the ED was not implied.
Even if the current evidence for the effectiveness of antipsychotic drugs in ASD is only moderate [6], neuroleptic drugs were frequently used in this cohort of ASD patients and their consumption remained stable across ages; moreover, our findings were similar to frequencies reported in other studies [39]. ADHD drugs were less prescribed (less than 0.6%) with respect to other reported prescription rates in ASD patients (about 15%) even considering the patients' age [47]; this may reflect a generally low consumption in Italy of such drugs in childhood [48].

Strengths and Limitations
The current study used large administrative databases, which made it possible to study real-world diagnostic patterns of a large and unselected population without non-responses, interviews, or recall bias issues. However, we must note that we could not include any service utilization outside the NHS. Furthermore, diagnoses in administrative databases are made by physicians specialized in a variety of disciplines and were not validated, which may lead to diagnostic imprecision. In addition, some diagnoses may not have been reported. With regard  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  to the estimated rate of ASD patients who used healthcare services, we investigated what type of diagnosis these outcomes were associated with and the reasons for such services. However, the CSS and rehabilitation interventions database did not systematically report the type of services provided (i.e. speech therapy, rehabilitation, occupational therapy).
The 16-20 age range provides an opportunity to investigate ASD patients during the transition from pediatric to young adult services, and we were able to follow longitudinally a group of ASD patients in transition age without the birth cohort effect. Unfortunately, our cohort was limited to adolescents with ASD who had had at least one healthcare service contact with a diagnosis code related to ASD starting from 2010; thus, ASD patients who did not use healthcare services during this period would not be included. Accordingly, our findings may not be applied to all ASD patients in transition age but represented ASD patients with some healthcare service connection.
Our study suggested a change in the clinical reference services, but we did not find a reduction in the use of healthcare services with age. However, we were not able to include a survey of caregivers in order to investigate any actual difficulties in managing this transition.

CONCLUSION
Our findings suggest that ASD patients change clinical reference services with age from neuropsychiatric and rehabilitative services towards psychiatric and community-based services.
The rise in prevalence, based on administrative data, of ASD in children might lead to a large number of adolescents who will be entering the young adult's healthcare system in the future and will require specific support. More studies are needed to investigate the actual needs of ASD patients in order to plan future public healthcare policies and interventions.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  Compliance with Ethical Standards : The data are administrative ones, so no informed consent was necessary. The Agency of Health Protection has among its institutional functions, established by the Lombardy Region legislation, the evaluation of the care pathways of autistic patients transitioning to adulthood (DRG 7600, 20 Dec 2017, available at http://www.regione.lombardia.it/wps/wcm/connect/cf479d70-9c53-4491-b5b7-0a6d43fdcd43/DGR2017_7600_regole_2018.pdf?MOD=AJPERES&CACHEID=cf479d70-9c53-4491-b5b7-0a6d43fdcd43, page 68), which is considered a critical element to monitor at present in the Regional and National Italian Health System. Therefore, the Agency of Health Protection of Milan is allowed to use the anonymized administrative data to perform the evaluation of the services provided to autistic patients residing in the covered area. Patient identity was masked by anonymization according to the standard ISO 25237:201. Their unique identification number (fiscal code) was transcoded into a string by the Information System of the Agency of Health Protection, which had no role in analysing the data.

Funding:
The research being reported in this publication was supported by Roche. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.