Medical comorbidities in children and adolescents with autism spectrum disorders and attention deficit hyperactivity disorders: a systematic review

Medical disorders occur more often in adult psychiatric patients than in the general population [1]. Moreover, somatic symptoms may cause or enhance psychiatric symptoms [2‐4]. A comprehensive review of comorbidity of mental and medical disorders in adults was presented by The Robert Wood Johnson Foundation in 2011, which included its the prevalence, origins and models for effective treatment [5]. More than 68% of adults with a mental disorder had at least one medical condition. Thereby, comorbidity was associated with elevated symptom burden, functional impairment, decreased length and quality of life and increased costs. The pathways between psychiatric symptoms and medical disorders are mostly, if known, complex and bidirectional. For example, adults with hypothyroidism are at risk for mood disorders [6, 7], and patients with schizophrenia and bipolar disorder have an increased risk of developing metabolic syndrome, due to their psychiatric disease as well as the use of antipsychotic drugs [8, 9]. Moreover, adults with mental health problems are more likely to have sedentary lifestyles and poor diets [5]. Different studies showed that patients with schizophrenia, bipolar disorder, or major depression, report less physical activity compared with those without mental disorders, and tend to eat foods that are high in fat and calories while avoiding fruits and vegetables [10, 11].

The increased risk for mental health problems has also been found in children with medical disorders. Findings of the Isle of Wight studies of Sir Michael Rutter and colleagues [12] starting in 1964–1965, already reported that 12% of children with somatic disorders (non-neurological) exhibited mental health problems compared to 7% of children in the general population [13, 14]. Also, significantly higher rates of mental health problems were reported in children with epilepsy: 29% in children with uncomplicated epilepsy and 58% in those with complicated epilepsy (i.e., structural brain abnormalities and seizures).

Several systematic reviews have been published on the association between specific medical disorders and child psychiatric disorders, for instance on the association between epilepsy and psychopathology [15], atopic diseases and mental health [16, 17], inflammation and neuropsychiatry [18], headaches/migraine and psychopathology [19, 20], HIV/AIDS and mental health [21], gastro-intestinal dysfunction and ASD [22], immune factors and ASD [23], phenylketonuria and ADHD [24]. Aldinger and colleagues aimed to identify clustering of medical disorders in children with autism. In this study, the prevalence of medical conditions ranged from 10.7 to 77.4%. A co-occurrence of sleeping problems and gastro-intestinal disturbances in children with autism was found. Also, the co-occurrence of gastro-intestinal disturbances, seizures and sleep problems predicted more severe behavioral symptoms in children with ASD [25]. Buie et al. concluded that medical disorders, such as gastro-intestinal problems, occur commonly in individuals with ASD [26]. However, medical conditions may remain undiagnosed in children with ASD due to atypical presentation of symptoms. Nonverbal or minimally verbal ASD individuals cannot verbally express pain or discomfort and instead often demonstrate their level of discomfort through disruptive behaviors, including aggressions and self-injury [26]. Even patients with ASD who acquire verbal communication skills may have difficulty describing subjective experiences or symptoms. Clinicians should be aware that problem behavior in ASD may be the primary or sole symptom of the underlying medical disorder. Even more so, Schieve and colleagues showed that children with specific developmental delays (autism, ADHD, learning disorder and intellectual disability) were more likely to have certain medical conditions than children without these delays [27]. Based on this finding, Schieve and colleagues state that children with developmental delays require increased pediatric health services and specialist services, both for their core functional deficits as for their health problems [27]. However, these results were based on parents or caregivers report, without clinical confirmation on developmental delays or medical conditions.

Following the data from reviews and clinical studies, Merikangas and colleagues performed a study on comorbidity of mental and physical conditions and functional impairments in 9014 children and adolescents [28]. In particular, a strong association between ADHD and neurologic disorders (seizures and epilepsy) was found. This association between neurologic disorders that affect brain systems and behavioral disorders is in line with other studies examining developmental disorders such as autism, ADHD, and neurobehavioral problems [29, 30]. It may implicate dysfunction in the underlying network and common genetic and/or environmental risk factors [31‐34].

In a previous pilot study we evaluated the outcome of medical screening at referral in children and adolescents with different psychiatric disorders. This screening revealed new somatic findings in 56% of the subjects [35]. These findings included a broad spectrum of medical concerns, including weight and length problems, high levels of thyroid hormone, dyslipidemia, anemia, vitamin D and vitamin B12 deficiency and dysmorphic anomalies. Some of these results required consultation from other medical specialists, whereas others had direct implications for daily medical practice, such as adjustments in psychopharmacologic treatment and/or participation in prevention programs for overweight.

These findings all contribute to the increasing awareness about the association between somatic and mental symptoms in developmental disorders and may suggest potential mechanisms such as common genetic pathways [28]. Also, the simultaneous assessment of medical and psychiatric disorders could be of major value. It seems important that the interpretation of meaningful somatic findings is done by clinicians who are able to relate these findings to differential diagnostic considerations for both medical and psychiatric interventions.

Most of the available literature on medical disorders in child and adolescent psychiatric disorders relates to ASD and ADHD, but there is a lack of integration of existing data, hampering the interpretation of findings. Therefore, this systematic review focuses on the association of medical disorders with autism and/or ADHD in children and adolescents and provides recommendations for future studies. Our hypothesis is that children with ADHD and ASD are at increased risk for a broad spectrum of medical disorders.

The initial search yielded in total 5278 papers (1783 and 3495 hits, respectively, of which 55 duplicates). 4665 papers were excluded according to the title and/or the abstract and 451 were excluded based on the full text. The remaining 104 papers were scored of which 29 papers were considered of high quality (5 or 6 points) and presented in this review. Two of these 29 papers focused on both ADHD and ASD, and are therefore listed in both tables (see Fig. 1).

Table 1 presents the papers that studied the association between ASD and medical disorders: 5 papers on immunology, 6 papers on gastroenterology, 1 paper on neurology and 2 papers on other medical disorders (see Table 1). In Table 2, the papers are listed that studied ADHD and medical disorders: 12 papers on immunology, 1 paper on neurology and 4 papers on other medical disorders (see Table 2).

The main finding of this systematic review is that medical disorders in children with ASD and ADHD appear to be widespread, e.g., can manifest across different medical areas, such as immunology, neurology and gastroenterology. Although it was not possible to extract prevalence data for the medical disorders, a reasonable number of studies could be included in this review, which supports the notion that children and adolescents with developmental disorders such as ADHD and ASD often suffer from medical disorders that needs to be investigated and addressed [67]. Likewise, children with medical disorders are at increased risk for developmental disorders, which are unfortunately not often recognized [52, 68]. Nevertheless, it is clear that these children require multidisciplinary medical services, including psychiatric help [28].

Increased awareness about the prevalence and types of comorbidity of medical disorders in developmental disorders is important for several reasons. It is first of all relevant for treatment and care for patients and their parents. Also, it may provide important information for fundamental research and could help to create a better understanding of the disease etiology of ASD and ADHD. Furthermore, insight in specific patterns of comorbidity may have important implications for the development of effective interventions for these disorders [5].

However, most of the studies that were identified by our initial search did not reach the required level of quality to come to more profound interpretations, because they were hampered by limitations in study design, in limited case–control matching and/or relied on parent, teacher or self-report of symptoms rather than systematic diagnostic assessments by experts.

First, most studies provide cross-sectional data thus limiting assessment of temporality and inference of causal pathways for the various conditions studied. Second, most studies examine the impact of a single medical comorbid condition, and studies that looked at a broad range of comorbid medical conditions are scarce. Third, the included studies sometimes show inconsistent results.

There are also limitations related to the design of this systematic review. First of all, given the amount of research in child psychiatry, it has been decided to limit the current systematic review to the two main developmental disorders: ASD and ADHD. Consequently, other psychiatric disorders, such as Gilles de la Tourette syndrome or tic disorders were not included in this review. As for sleeping disorder, it was decided to exclude these from the review since sleeping disorders are frequently not viewed as specific medical disorder, but rather as part of a symptom complex of several neuropsychiatric disorders. For a recent review on sleeping disorders in children with neurodevelopmental disorders, see the study by Blackmer and colleagues [69].

Second, strict criteria for methodologic quality of the studies were used for the inclusion and consequently only 29 studies were selected, out of more than 4000 studies that were identified in our initial search. Third, we excluded studies that were not published in English, which might have led to the exclusion of potentially relevant studies.

Bearing these limitations in mind, several strong aspects about this systematic review allow us to conclude that a valuable overview of data is provided. First, the methodologic quality and strength of evidence of the various studies has been assessed in a systematic manner by using a standardized set of criteria. This helps to appreciate individual studies in a correct manner. Second, two raters independently assessed the quality of the studies, selected from two databases, with a standardized set of criteria. An additional rater was consulted in case of a difference in scoring by the other two raters. Third, by using a predefined search strategy, the potential for bias was reduced.

In conclusion, medical comorbidity in children and adolescents with ASD and ADHD appears to occur in numerous medical areas [27, 70]. This should lead to a critical view on current health care systems, which are often marked by clear divisions between medical disciplines. The data of this review clearly point to a multidisciplinary and integrated approach for children and adolescents with ASD and ADHD. Moreover, collaborative care models should be recommended including both a psychiatric and medical approach; that is treatment models including screening for ADHD and ASD in primary care settings, and screening for common medical conditions in child and adolescent psychiatry. Thereby, clinicians should be aware that problem behavior in developmental disorders may be the only symptom of the underlying somatic disorder. Furthermore, prevention programs are needed to address common risk factors for comorbid conditions, such as obesity, underweight, vitamin deficiency, hypo or hyperthyroidism and dyslipidemia. Identifying and treating somatic and psychiatric comorbidities will improve behavior and overall improve quality of life for both patient and family.

Also, developmental disorders such as autism can be a feature of several underlying genetic syndromes, many of which also entail somatic symptoms. As such, a careful analysis of the combination of ASD and somatic disorders requires an extensive diagnostic scheme to detect such genetic syndromes to consider referral to a clinical geneticist. For a review on this specific topic, see the study by Cohen and colleagues [71].

With respect to research in ASD and ADHD, future studies should not only focus on psychiatric symptoms, but provide a broader evaluation of medical disorders, preferably with longitudinal studies. Likewise, it would also be worth to study a specific group of medical disorders and comorbid ADHD and/or ASD. This may ultimately help to provide a more personalized treatment approach and broaden our insight in etiological aspects of ASD and ADHD.