CLINICAL REPORT Guidance for the Clinician in Rendering Pediatric Care

Identification, Evaluation, and Management of Children With Autism Spectrum Disorder Susan L. Hyman, MD, FAAP,a Susan E. Levy, MD, MPH, FAAP,b Scott M. Myers, MD, FAAP,c COUNCIL ON CHILDREN WITH DISABILITIES, SECTION ON DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder abstract with reported prevalence in the United States of 1 in 59 children (approximately 1.7%). Core deficits are identified in 2 domains: social aGolisano Children’s Hospital, University of Rochester, Rochester, New b communication/interaction and restrictive, repetitive patterns of behavior. York; Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; and cGeisinger Autism & Developmental Medicine Institute, Danville, Children and youth with ASD have service needs in behavioral, educational, Pennsylvania health, leisure, family support, and other areas. Standardized screening for Clinical reports from the American Academy of Pediatrics benefit from ASD at 18 and 24 months of age with ongoing developmental surveillance expertise and resources of liaisons and internal (AAP) and external reviewers. However, clinical reports from the American Academy of continues to be recommended in primary care (although it may be performed Pediatrics may not reflect the views of the liaisons or the in other settings), because ASD is common, can be diagnosed as young as organizations or government agencies that they represent. 18 months of age, and has evidenced-based interventions that may improve Drs Hyman, Levy, and Myers all participated in development of the outline of material to be covered, generation of content, and editing of function. More accurate and culturally sensitive screening approaches are the document; and all authors approved the final manuscript as needed. Primary care providers should be familiar with the diagnostic criteria submitted. for ASD, appropriate etiologic evaluation, and co-occurring medical and The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking behavioral conditions (such as disorders of sleep and feeding, gastrointestinal into account individual circumstances, may be appropriate. tract symptoms, obesity, seizures, attention-deficit/hyperactivity disorder, All clinical reports from the American Academy of Pediatrics anxiety, and wandering) that affect the child’s function and quality of life. There automatically expire 5 years after publication unless reaffirmed, is an increasing evidence base to support behavioral and other interventions revised, or retired at or before that time. to address specific skills and symptoms. Shared decision making calls for This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed collaboration with families in evaluation and choice of interventions. This conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process single clinical report updates the 2007 American Academy of Pediatrics approved by the Board of Directors. The American Academy of clinical reports on the evaluation and treatment of ASD in one publication with Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication. an online table of contents and section view available through the American Academy of Pediatrics Gateway to help the reader identify topic areas within DOI: https://doi.org/10.1542/peds.2019-3447 the report. Address correspondence to Susan L. Hyman. E-mail: susan_hyman@ urmc.rochester.edu

To cite: Hyman SL, Levy SE, Myers SM, AAP COUNCIL ON CHILDREN WITH DISABILITIES, SECTION ON DEVELOPMENTAL INTRODUCTION AND BEHAVIORAL PEDIATRICS. Identification, Evaluation, and Autism spectrum disorder (ASD) is a category of neurodevelopmental Management of Children With Autism Spectrum Disorder. Pediatrics. 2020;145(1):e20193447 disorders characterized by social and communication impairment and

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020:e20193447 FROM THE AMERICAN ACADEMY OF PEDIATRICS restricted or repetitive behaviors.1 criteria after publication of the in children at different ages. What is ASD affects more than 5 million Diagnostic and Statistical Manual of reported is age at recognition of Americans, with an estimated Mental Disorders, Fifth Edition (DSM- symptoms, not the actual onset. As prevalence of approximately 1.7% in 5)1 in 2013. The DSM-5 established a result, prevalence is more typically children.2 The care needs of children a single category of ASD to replace reported than incidence, reflecting with ASD are significant, affect the subtypes of autistic disorder, rates of ASD in the population at parents and siblings as well, and Asperger syndrome, and pervasive a point in time. require substantial community developmental disorder not The reported prevalence of children resources. Direct and indirect costs of otherwise specified in the Diagnostic with ASD has increased over time, caring for children and adults with and Statistical Manual of Mental and primary care providers are often ASD in the United States in 2015 were Disorders, Fourth Edition, Text asked about the reasons for this estimated to be $268 billion, more Revision (DSM-IV-TR). With the increase. This increase may be than the cost of stroke and current reported prevalence rate of 1: attributable to several factors, hypertension combined.3 The lifetime 59 children (approximately 1.7%), all including broadening in the cost of education, health, and other primary care providers can expect to diagnostic criteria with ongoing service needs for an individual with have children and youth with ASD in revisions of the Diagnostic and ASD ranges from $1.4 to $2.4 million their practices.2 As noted in earlier Statistical Manual of Mental Disorders dollars, depending on whether he or clinical reports, the primary care (DSM), the more inclusive definition she has any co-occurring intellectual provider has critical access to the of pervasive developmental disorder disabilities.4 To deliver timely and child in the context of the medical with the adoption of the Diagnostic effective medical, behavioral, home to identify symptoms of ASD and Statistical Manual of Mental educational, and social services early in childhood, support the family Disorders, Fourth Edition (DSM-IV) in across the lifespan means that through the process of diagnosis and 1994,8 increased public awareness of primary care providers must intervention, address etiologic the disorder and its symptoms, understand the needs of individuals evaluations, help the family recommendations for universal with ASD and their families. ASD is understand how to interpret the screening for ASD,5,9 and increased more commonly diagnosed now than evidence supporting different availability of early intervention and in the past, and the significant health, interventions so they can effectively school-based services for children educational, and social needs of engage in shared decision-making, with ASD. In part, the increasing individuals with ASD and their and manage co-occurring medical numbers of children with a diagnosis families constitute an area of critical conditions that may influence of ASD may reflect diagnostic need for resources, research, and outcome and affect daily function. substitution, the recognition of ASD in professional education. The primary care provider can help children previously primarily minimize disparities in age of diagnosed with intellectual disability In the 12 years since the American diagnosis of African American and or a co-occurring genetic syndrome.10 Academy of Pediatrics (AAP) Hispanic children and be alert to the A true increase in the prevalence of published the clinical report potential for gender bias in symptom ASD associated with other biological “Identification and Evaluation of recognition.7 This updated document risk factors is also possible. Children With Autism Spectrum aims to provide primary care Disorders”5 and its companion, providers with a summary of current Prevalence rates in US populations “Management of Children With information in a single report that are similar to those of other Autism Spectrum Disorders,”6 will help guide them in providing industrialized countries,11 and lower reported prevalence rates of ASD in a medical home for the patient rates are reported in resource-limited children have increased, with ASD. countries, where epidemiological data understanding of potential risk are more difficult to collect.12 Data on factors has expanded, awareness of national samples suggest that the co-occurring medical conditions and SECTION 1: PREVALENCE prevalence of ASD is stabilizing.2,13 genetic contribution to etiology has Incidence is the onset of new Ongoing epidemiological studies help improved, and the body of research diagnoses over time in a selected to understand changes in the supporting evidence-based cohort. Without consistent reported prevalence over time. interventions has grown substantially. longitudinal data in a specified Epidemiological data help to predict This updated clinical report builds on cohort, incidence cannot be the need for services and identify previous reports and guidance for determined. Because of the potential risk factors. Surveillance care of children and youth with ASD. heterogeneity of symptoms and methods include regional, state, It also reflects changes in diagnostic severity in ASD, it may be diagnosed and/or national registry systems;

Downloaded from www.aappublications.org/news by guest on October 1, 2021 2 FROM THE AMERICAN ACADEMY OF PEDIATRICS records- or services-based analyses; as having ASD before 3 years of age. developmental and behavioral surveys; and other methods, including Diagnosis later than 6 years of age disorders and symptoms. In the years population-based case findings. was reported in one-third to half of since the 2007 AAP clinical reports on children. Later age at diagnosis was ASD, both professional education and In 2000, the US Centers for Disease associated with reported mild public awareness have promoted Control and Prevention (CDC) presentation.16 recognition of symptoms that might established the Autism and lead to early identification of ASD, CDC surveillance data published in Developmental Disabilities use of standardized screening 2014 revealed that white, non- Monitoring (ADDM) Network as approaches, and management of Hispanic children were approximately a population-based public health associated medical and behavioral 20% more likely to be identified with surveillance system to estimate the features of ASD from infancy through ASD before the case review than were prevalence of ASD in children 8 years adolescence. of age. ADDM reports published in non-Hispanic African American 2014 and 2016 revealed comparable children and were about 50% more fi prevalence rates (approximately 1 in likely to be identi ed with ASD than Core Symptoms 14 68),14,15 but the report published in were Hispanic children. Recent Although symptoms of ASD are 20182 revealed a slightly increased prevalence data reveal increasing neurologically based, they manifest as rate (1 in 59). Additional data over rates of ASD in Hispanic and African behavioral characteristics that time will help determine if rates have American children. This may reflect present differently depending on age, stabilized. The data also revealed more widespread awareness of the language level, and cognitive abilities. some variation in prevalence rates symptoms among parents, schools, Core symptoms cluster in 2 domains across the participating states, with and health care providers and (social communication/interaction the highest rates in the locations improved rates of screening in health 2 and restricted, repetitive patterns of where both educational and health supervision care. Studies examining behavior), as described in the DSM- records were available for chart the effects of race and ethnicity on fl 7 5.1 Atypical development in several abstraction and standardized age at diagnosis are con icting, but functional areas contribute to application of diagnostic criteria. earlier diagnosis of ASD is associated Regional variation in prevalence may with higher socioeconomic status and symptoms of ASD. Abnormalities in also reflect availability of services, access to services. African American understanding the intent of others, local provider practices for ASD and Hispanic children diagnosed with diminished interactive eye contact, screening, educational policies, school ASD by age 4 years were more likely and atypical use and understanding and/or community resources, and to have coexisting intellectual of gesture presage atypical insurance mandates, among other disability than were white, non- development of social communication factors. The CDC also published data Hispanic children, suggesting that and pretend play as well as interest in on the prevalence of ASD in children some African American and Hispanic other children. Symptoms of ASD are fi who were 4 years of age in 2010. A children with ASD and average to further shaped by de cits in imitation lower prevalence rate for diagnosis above-average intelligence may not and of processing information across fi 17 (1.34%) was reported in these have been identi ed. sensory modalities, such as vision children (approximately 30% less (gesture) and hearing (language). than that of children 8 years of age). Repetitive behaviors and The lower identified prevalence and SECTION 2: CLINICAL SYMPTOMS perseveration may be primary higher proportional rate of children Despite advances in understanding compulsions but may also be related 4 years of age with ASD and the neurobiology and genetics of ASD, to atypical processing of sensory intellectual disabilities may be the diagnosis of ASD continues to be information or may reflect a desire to attributable, in part, to later diagnosis based on identifying and reporting instill predictability when an of children with ASD and average- behaviorally defined clinical individual does not understand the range cognitive abilities.16 The symptoms. The challenges in intent of others. The CDC “Learn the National Survey of Children’s Health determining accurate prevalence Signs. Act Early” Web site provides (2011–2012) and the National Survey rates, in part, relate to the need for free resources to help families of Children with Special Health Care consistency in clinical diagnosis of recognize developmental concerns, Needs (2009–2010) were analyzed a very heterogeneous disorder. In including autism (https://www.cdc. for the age the parents reported 2013, the DSM-5 consolidated the gov/ncbddd/actearly/), and Autism diagnosis as well as for parent- diagnosis of ASD into a single Navigator (www.autismnavigator. reported subjective severity. The category and emphasized the com) has a video glossary of early minority of children were identified importance of identifying coexisting symptoms in toddlers.

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 3 Approximately one-quarter of paired with inconsistency in their agreement of surveillance data by children with ASD will be reported to application across research sites using DSM-IV-TR and DSM-5 criteria. have a regression in language or supports the decision to consolidate The DSM-5 criteria have been shown social skills, most typically between the subgroups into 1 diagnostic to appropriately identify younger 18 and 24 months of age.18,19 The category, ASD, in the DSM-5. The children and those with mild reason for this loss of previously DSM-IV divided the symptoms of ASD symptoms.25,27 These children with acquired milestones is not yet known. into 3 areas: qualitative impairment milder cognitive and adaptive Although medical evaluation of loss of of social reciprocity, qualitative symptoms may be the ones most milestones is indicated, a history of impairment of communication, and likely to have significant change with regression in language and social restricted and repetitive behaviors. In early intervention services. interaction in children with ASD the DSM-5, core symptoms were within the expected age range is not divided into 2 domains (social The DSM-5 also introduced an likely to be attributable to seizures or communication and social interaction approach to severity rating, which is neurodegenerative disorders. Note and restrictive, repetitive patterns of summarized in Table 2. Severity that the processes underlying behaviors).23 To fulfill diagnostic rating reflects the impairment of the regression are not yet well criteria for ASD by using the DSM-5, ASD symptoms and the resultant understood. Current theories include all 3 symptoms of social affective service needs of the individual. synaptic “over pruning” in response difference need to be present in Severity rating is not a quantifiable to genetic factors.20 addition to 2 of 4 symptoms related score that can be used to monitor to restrictive and repetitive progress at this time; in clinical use, it Diagnostic Criteria: DSM-5 behaviors. Examples in Table 1 are often reflects the impact of cognitive The DSM has been central in illustrative but not exhaustive. The limitations.28 Measures have been establishing criteria for diagnosing recognition of symptoms of ASD published that attempt to capture mental and behavioral disorders. The related to sensory processing led to severity of core symptoms29,30 and diagnosis of infantile autism was the inclusion of sensory symptoms, allow for measurement of introduced in the Diagnostic and such as hyper- or hyporeactivity to improvement with intervention.31 To Statistical Manual of Mental Disorders, sensory input or unusual interests in date, no single measure adequately Third Edition nearly 30 years after sensory aspects of the environment. reflects the combination of medical, the first edition of the DSM was Examples include apparent behavioral, and educational severity published in 1952. The initial indifference to pain or temperature; in a fashion that will help clinicians descriptions were narrow and sensitivity to sound, taste, or textures; and families determine progress with referred to individuals with profound and intense visual interest in objects intervention across multiple impairment. Publication of the DSM- or movement. The DSM-5 notes that functional domains. Coexisting IV in 1994 expanded the diagnosis to a diagnosis may be made at older medical disorders also affect the a spectrum of symptoms called ages, when the demands of the social perception of severity and the pervasive developmental disorders or school environment may result in prognosis for children with (PDDs), which included the diagnoses functional impairment. a diagnosis of ASD. The DSM-5 of autistic disorder, Asperger includes course specifiers that help disorder, pervasive developmental Almost all individuals with describe the variation in symptoms of disorder not otherwise specified a diagnosis of autistic disorder or individuals with ASD. Course (PDD-NOS), childhood disintegrative Asperger syndrome by using DSM-IV specifiers include the presence or disorder, and Rett disorder. The PDDs criteria would be diagnosed with ASD absence of intellectual impairment, included individuals with lower- and by using DSM-5 criteria.24 To language impairment, catatonia, higher-functioning cognitive skills. determine if the same patients would medical conditions, and known PDD-NOS was a diagnostic category be identified by the DSM-IV and DSM- genetic or environmental etiologic requiring some, but not all, of the core 5 criteria, the CDC ADDM Network factors. Patients with Rett syndrome symptoms necessary for other looked at its chart abstraction data on are no longer automatically diagnoses in this category. 8-year-old children.25 This analysis considered to have a diagnosis of ASD Subsequent research has revealed that more than 80% of according the DSM-5, although demonstrated that the subgroupings children diagnosed with PDD-NOS individuals with this neurogenetic within PDD were not reproducible would also be diagnosed with ASD.25 disorder may also meet diagnostic across research sites by using the It is possible that the narrative in the criteria for ASD. Specific genetic same diagnostic data21,22 and were charts that were abstracted was causes of ASD should be recorded as not stable over time. The overlap influenced by knowledge of the DSM- specifiers for individuals with ASD between DSM-IV–defined subgroups IV criteria.26 There is a high level of when identified. The DSM-5 promotes

Downloaded from www.aappublications.org/news by guest on October 1, 2021 4 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 1 DSM-5 Criteria for Autism Spectrum Disorder Domains Criteria: Deficits Examples A. Persistent deficits in social communication and social 1. Social-emotional reciprocity Abnormal social approach and failure of normal back- interaction across multiple contexts, as manifested and-forth conversation; reduced sharing of interests, by the following, currently or by history; must have emotions, or affect; failure to initiate or respond to all 3 symptoms in this domain social interactions 2. Nonverbal communicative behaviors Poorly integrated verbal and nonverbal communication; used for social interaction abnormalities in eye contact and body language or deficits in understanding and use of gestures; total lack of facial expressions and nonverbal communication 3. Developing, maintaining, and Difficulties adjusting behavior to suit various social understanding relationships contexts; difficulties in sharing imaginative play or in making friends; absence of interest in peers B. Restricted, repetitive patterns of behavior, interests, 1. Stereotyped or repetitive motor Simple motor stereotypies, lining up toys or flipping or activities, as manifested by at least 2 of the movements, use of objects, or speech objects, echolalia, idiosyncratic phrases following, currently or by history; must have 2 of the 4 symptoms 2. Insistence on sameness, inflexible Extreme distress at small changes, difficulties with adherence to routines, or ritualized transitions, rigid thinking patterns, greeting rituals, patterns or verbal nonverbal behavior need to take same route or eat food every day 3. Highly restricted, fixated interests that Strong attachment to or preoccupation with unusual are abnormal in intensity or focus objects, excessively circumscribed or perseverative interest 4. Hyper- or hyporeactivity to sensory Apparent indifference to pain/temperature, adverse input or unusual interests in sensory response to specific sounds or textures, excessive aspects of the environment smelling or touching of objects, visual fascination with lights or movement Symptoms must be present in the early developmental period (but may not become fully manifest until social demands exceed limited capacities or may be masked by learned strategies in later life). Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning. These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Intellectual disability and ASD frequently co-occur; to make comorbid diagnoses of ASD and intellectual disability, social communication should be below that expected for the general developmental level. Specify whether: with or without accompanying intellectual impairment, language impairment or associated with a known medical or genetic condition or environmental factor. Add code 293.89 if catatonia is also present. Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (copyright 2013). American Psychiatric Association. All Rights Reserved. notation of all coexisting diagnoses as and social communication disorder continues to include the subtypes of specifiers. are similar and different in terms of diagnoses as defined by the DSM-IV.33 etiology, prognosis, and treatment. The DSM-5 provides the clinician with Social pragmatic communication Evaluation of pragmatic (social) criteria and definitions for diagnosis disorder is a new diagnosis described language use by a speech-language of ASD and should guide the clinician within the DSM-5 that describes pathologist provides additional in the diagnosis and management individuals who exhibit functionally information to consider this of ASD. impairing symptoms in social diagnosis.32 The characteristics of language use but do not have habitual social pragmatic communication Co-occurring Symptoms and 1 Conditions or repetitive behaviors. Individuals disorder and how best to address who are affected must have deficits in symptoms require additional study. Co-occurring conditions are common using language for social purposes, in children with ASD and may have impaired ability to match their Although the DSM-5 provides the great effects on child and family communication style with the context criteria and definitions to accurately functioning and clinical management for communication, difficulty assign mental health and behavioral (see also Section 5: Interventions). following the conventional rules for diagnoses, the International Examples include medical conditions conversation, and difficulty with Classification of Diseases, 10th such as sleep disorders and seizures; idioms and unstated meanings in Revision, Clinical Modification is the other developmental or behavioral language (Table 3). As with ASD, the standardized code set used for diagnoses, such as attention-deficit/ symptoms cannot be better explained payment as well as for statistical hyperactivity disorder (ADHD), by another DSM-5 diagnosis. tracking through electronic medical anxiety, and mood disorders; and Research and experience with DSM-5 records. The International behavioral disorders, such as food diagnoses over time will give Classification of Diseases, 10th refusal, self-injury, and aggression.34 clinicians a better sense of how ASD Revision, Clinical Modification Approximately 30% of children with

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 5 TABLE 2 ASD Symptoms by Level of Severity Severity Level Social Affective Restricted and Repetitive Behaviors Level 1. “Requiring Without supports in place, deficits in social communication cause Inflexibility of behavior causes significant interference with support” noticeable impairments. Difficulty initiating social interactions, functioning in one or more contexts. Difficulty switching and clear examples of atypical or unsuccessful response to between activities. Problems of organization and planning social overtures of others. May appear to have decreased hamper independence. interest in social interactions. Level 2. “Requiring Marked deficits in verbal and nonverbal social communication Inflexibility of behavior, difficulty coping with change, or other substantial support” skills. Social impairments apparent even with supports in restricted and repetitive behaviors appear frequently enough to place. Limited initiation of social interactions and reduced or be obvious to the casual observer and interfere with abnormal responses to social overtures from others. functioning in a variety of contexts. Distress and/or difficulty changing focus or action. Level 3. “Requiring very Severe deficits in verbal and nonverbal social communication Inflexibility of behavior, extreme difficulty coping with change, or substantial support” skills cause severe impairments in functioning, very limited other restricted and repetitive behaviors markedly interfere initiation of social interactions, and minimal response to social with functioning in all spheres. Great distress at or difficulty overtures from others. with changing focus or action. Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (copyright 2013). American Psychiatric Association. All Rights Reserved. a diagnosis of ASD will also have 3 years of age, especially if they have Approximately 9% of children who intellectual disability,2 and 30% are average or above-average cognitive are diagnosed with ASD in early minimally verbal.35 Increasingly, abilities.38 Across early childhood childhood may not meet diagnostic researchers and clinicians recognize development, communication skills criteria for ASD by young adulthood. how co-occurring disorders help and social affective symptoms may Youth who no longer meet criteria for identify phenotypic differences improve, whereas repetitive ASD are more likely to have a history within populations affected by ASD, behaviors may change, possibly of higher cognitive skills at 2 years of fl fl which can in uence prognosis and re ecting maturation and/or age, to have participated in earlier 39 choice of interventions. intervention. In general, young intervention services, and to have children with ASD with language demonstrated a decrease in their Prognosis impairment appear to have more repetitive behaviors over time.41 A The prognosis and trajectory of social difficulty than do children with change in clinical diagnosis (eg, to development for a young child ASD without language impairment. ADHD or obsessive-compulsive diagnosed with ASD typically cannot Children with ASD and intellectual be predicted at the time of diagnosis. disability have the most difficulty disorder [OCD]) is more likely in However, most children ($80%) who developing social competence.40 The children who were diagnosed with are diagnosed with ASD after prognosis for children with ASD in ASD before 30 months of age or had a comprehensive evaluation at less phenotypic and demographic a diagnosis of PDD-NOS per the DSM- 42,43 than 3 years have retained their subgroups (eg, girls, racial and IV. Severity scores are most likely diagnosis.36,37 It may be more ethnic subgroups, children with to improve in youth who have had the difficult to recognize mild symptoms macrocephaly) needs additional greatest increase in tested verbal of ASD in children younger than study. IQ.44 Executive function difficulties

TABLE 3 DSM-5 Social (Pragmatic) Communication Disorder (DSM-5 315.39) A. Persistent difficulties in the social use of verbal and nonverbal communication as manifested by all of the following: 1. Deficits in using communication for social purposes, such as greeting and sharing information, in a manner that is appropriate for the social context. 2. Impairment of the ability to change communication to match context or the needs of the listener, such as speaking differently in a classroom than on the playground, talking differently to a child than to an adult, and avoiding use of overly formal language. 3. Difficulties following rules for conversation and storytelling, such as taking turns in conversation, rephrasing when misunderstood, and knowing how to use verbal and nonverbal signals to regulate interaction. 4. Difficulties understanding what is not explicitly stated (eg, making inferences) and nonliteral or ambiguous meanings of language (eg, idioms, humor, metaphors, multiple meanings that depend on the context for interpretation). B. The deficits result in functional limitations in effective communication, social participation, social relationships, academic achievement, or occupational performance, individually or in combination. C. The onset of the symptoms is in the early developmental period (but deficits may not become fully manifest until social communication demands exceed limited capacities). D. The symptoms are not attributable to another medical or neurologic condition or to low abilities in the domains or word structure and grammar and are not better explained by ASD, intellectual disability (intellectual developmental disorder), global developmental delay, or another mental disorder. Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (copyright 2013). American Psychiatric Association. All Rights Reserved.

Downloaded from www.aappublications.org/news by guest on October 1, 2021 6 FROM THE AMERICAN ACADEMY OF PEDIATRICS are associated with poorer adaptive TABLE 4 Red Flags: Early Symptoms of ASD 45 outcomes, independent of IQ. Symptom Measured intelligence (eg, IQ) and By 12 months • Does not respond to name language ability in childhood tend to By 14 months • Does not point at objects to show interest predict outcome in adulthood.46 By 18 months • Does not pretend play However, reported quality of life in General • Avoids eye contact and may want to be alone • ’ high-functioning adults with ASD was Has trouble understanding other peoples feelings or talking about their own feelings • Has delayed speech and language skills associated more with the presence of • Repeats words or phrases over and over (echolalia) family and community supports than • Gives unrelated answers to questions their symptoms related to ASD.47 • Gets upset by minor changes • Has obsessive interests • Makes repetitive movements like flapping hands, rocking, or spinning in circles SECTION 3: SCREENING AND DIAGNOSIS • Has unusual reactions to the way things sound, smell, taste, look, or feel The AAP recommends screening all Information from this table is adapted from http://www.cdc.gov/ncbddd/autism/signs.html. children for symptoms of ASD through a combination of developed by the CDC may help primary pediatric care have increased developmental surveillance at all educate families about developmental steadily. In the 2015 AAP survey of visits and standardized autism- and behavioral milestones (https:// screening practices, almost three- specific screening tests at 18 and www.cdc.gov/ncbddd/actearly/ quarters of pediatricians who 24 months of age in their primary index.html). Developmental responded reported routine ASD care visits5 because children with surveillance alone is not sufficient to screening.54 Pediatricians ASD can be identified as toddlers, and identify children who need further increasingly report including office early intervention can and does evaluation because children with ASD staff for efficient workflow, including influence outcomes.48 This autism- may not demonstrate characteristic administration and scoring of specific screening complements the symptoms in brief office visits,50 and screening tests. Although time and recommended general developmental caregivers may not volunteer social remuneration remain as concerns, screening at 9, 18, and 30 months of and emotional concerns unless fewer pediatricians rate these as age.9 Efficient screening of all specifically asked. Use of barriers. Referral for and tracking of children would be aided by inclusion a standardized screening tool for ASD evaluation and services remain of valid screening tools in the can help families identify potential a challenge associated with lack of electronic health record with symptoms. In a large study evaluating office-based systems for making appropriate compensation for the universal screening with the Modified referrals and after screen-positive staff and professional time necessary Checklist for Autism in Toddlers outcomes.43 to complete the administration, (M-CHAT), researchers asked The authors of the 2019 AAP scoring, and counseling related to physicians to note whether they were 49 developmental surveillance and screening. concerned about ASD. Sensitivity of screening clinical report discuss physician clinical concern was low Screening tools are designed to help strategies for billing for screening (0.244; 30 of 123 cases; 95% caregivers identify and report and counseling in primary care.49 confidence interval 0.17–0.32). The symptoms observed in children at The following sections describe sensitivity of the M-CHAT when used high risk for ASD. The screens are toolscommonlyusedtoscreenand as directed in this low-risk population based on early manifestations of diagnose ASD and emphasize the was 0.91.51 Accurate early symptoms of core deficits related to importance of ongoing identification has been a goal of the social communication. Some of these surveillance, especially in children AAP since the publication of the 2 early symptoms that may alert the at high risk. previous autism clinical reports in provider to the risk for ASD have 2007, with focused continuing been called “red flags” (Table 4). medical education and a tool kit (AAP Screening Developmental surveillance for ASD Autism Toolkit: https://toolkits. Results of a screening test are not includes asking caregivers about solutions.aap.org/toolkits.aspx). The diagnostic; they help the primary care concerns they have about their child’s goal of universal screening, including provider identify children who are at development or behavior, informal screening for ASD, has been risk for a diagnosis of ASD and observation, and monitoring of supported by public health agencies52 require additional evaluation. General symptoms in the context of routine and family support organizations.53 developmental screening tools used health supervision. The “Learn the Rates of screening for both for screening at ages 9, 18, and Signs. Act Early” parent resources developmental delays and ASD in 30 months identify language,

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 7 cognitive, and motor delays but may Screening by Age Group ASD. Pediatricians can help families not be sensitive to social symptoms Children Younger Than Age 18 Months with management of these symptoms. associated with identification of 43,55 Earlier diagnosis of ASD may lead to ASD. This limitation associated Children Ages 18 to 30 Months earlier treatment. The M-CHAT is the with general developmental 56 most studied and widely used tool The most commonly used screening is why ASD-specific tools for screening toddlers for ASD. questionnaire-based screening tool is are needed to capture differences in Additional tools are under the M-CHAT. It has been further social interaction, play, and investigation and are listed in Table 6 validated, and the scoring has been repetitive behaviors. See the AAP as promising autism screening tests. modified for ease of administration in clinical report “Promoting Optimal Language delay can be identified by primary care settings for children Development: Identifying Infants 51 using the Infant and Toddler ages 16 to 30 months. The Modified and Young Children With Checklist (parent questionnaire) in Checklist for Autism in Toddlers, Developmental Disorders Through low-risk infants and toddlers between Revised with Follow-Up (Questions) Developmental Surveillance and 12 and 18 months of age.43,59 This (M-CHAT-R/F) eliminates 3 questions Screening,”49 Table 1 (developmental questionnaire might be useful in from the previous version. Children screening tests; a description of identifying infant siblings of children who score $8 are at high risk for ASD general developmental and with ASD who are at increased risk or another developmental disorder behavioral screening tests), and for ASD. Additional research may and should be referred immediately Table 5 in this report for resources allow for screening of toddlers as for diagnostic assessment. For and guidance on developmental young as 12 months by using parent- children with scores of 3 to 7, publicly screening. administered questionnaires such the available scripted follow-up interview questions are required for the items Parent-completed questionnaires Communication and Symbolic fi scored as positive. Children who are the most common screening Behavior Scales Development Pro le continue to have 3 to 7 items positive tests used in primary care. and the Infant and Toddler 58 for ASD diagnosis after clarifying Commonly used autism-specific Checklist. follow-up questions have a 47% risk screening tools that are based on Primary care providers are tasked of having ASD diagnosed and a 95% questionnaires and observation are with identifying all children who chance of being identified with some summarizedinTable6.Many would benefit from early other developmental delay that would clinician-administered screening intervention, not just children at risk benefit from intervention. Children tests require specifictraining(eg, for ASD (see the AAP clinical report screened with the M-CHAT-R/F are the Screening Tool for Autism in “Promoting Optimal Development: identified with ASD at younger ages Toddlers and Young Children Identifying Infants and Young than predicted by national [STAT]).5,57 A clinician- Children With Developmental statistics.49 Children who do not pass administered test like the STAT Disorders Through Developmental ASD screening tests or who score as increases the likelihood of an ASD Surveillance and Screening”49 for at risk for a diagnosis should be diagnosis on further testing and further information). It is important referred for both diagnostic may be used to support to identify all clinically significant assessment and intervention services. a preliminary diagnosis of ASD to delays in children with referral for Adefinitive diagnosis is not necessary obtain services.58 Identification of appropriate diagnostic evaluation and to institute services for documented infants and toddlers at risk for ASD intervention. Problems with sleep, delays that would be served through based on neurophysiologic makers eating, constipation, and state early intervention or school services. or other biomarkers is discussed in regulation are common in the general Although the M-CHAT-R/F appears to the subsection The Biology of ASD in population but may be particularly be useful for general screening of Section 4: Etiologic Evaluation. challenging in young children with diverse populations,60 decreasing the disparity in early diagnosis will TABLE 5 Resources and Guidance for Developmental Screening require adapting and validating • measures and addressing cultural and AAP Bright Futures: Guidelines for the Health Supervision of Infants, Children, and Adolescents 61 • AAP early childhood screening linguistic barriers to screening. • AAP clinical report: “Promoting Optimal Development: Identifying Infants and Young Children With Developmental Disorders Through Developmental Surveillance and Screening”49 Measures under development may • Additional guidance for developmental and behavioral screening can be found in “Birth to 5: Watch provide rapid screening while Me Thrive!” which contains helpful information for the primary care provider about how to present addressing clinician concerns for the results of developmental screening (available at: https://www.acf.hhs.gov/sites/default/files/ecd/ compatibility with an electronic pcp_screening_guide_march2014.pdf). record system and open access.62

Downloaded from www.aappublications.org/news by guest on October 1, 2021 8 FROM THE AMERICAN ACADEMY OF PEDIATRICS EITISVlm 4,nme ,Jnay2020 January 1, number 145, Volume PEDIATRICS TABLE 6 Commonly Used ASD Screening Tests Autism Screening Description Age Range Average No. Administration Forms Available Psychometric Scoring Method Cultural Source Key References Tests Items Time EHR compatible Properties Considerations M-CHAT-R/F Parent-completed 16–30 mo 20 5–10 min Yes Standardization Risk categorization Available in http://mchatscreen. Ref 51 questionnaire sample included for questionnaire multiple com/ designed to 16 071 children (pass/need languages; identify children screened; 115 interview/ fail); see test at risk for had positive after interview information autism from the screen results, (pass/fail) for details general 348 needed population; evaluation, 221 Downloaded from follow-up were evaluated, clinician- and 105 administered diagnosed with questions and an ASD; validated repeat by using the ADI- questionnaire R, ADOS-G, CARS, www.aappublications.org/news required for and DSM-IV-TR; specificity sensitivity: 0.91; specificity: 0.95 for low-risk 18- and 24-mo-old children with follow-up questionnaire and interview; 45% of children

byguest on October1,2021 with a score $3 on the initial screen and $2 on follow-up had ASD; 95% had clinically significant developmental delay SCQ Parent-completed 41 y405–10 min No Validated by using Risk categorization Available in Western Refs 77 and 572 questionnaire; the ADI-R and (pass/fail) multiple Psychological designed to DSM-IV on 200 languages; Corporation: www. identify children subjects (160 see test wpspublish.com at risk for ASD with pervasive information from the general developmental for details. population; disorder, 40 based on items without pervasive in the ADI-R developmental disorder); for use in children with mental age of at 9 10 TABLE 6 Continued Autism Screening Description Age Range Average No. Administration Forms Available Psychometric Scoring Method Cultural Source Key References Tests Items Time EHR compatible Properties Considerations least 2 y and chronologic age 41 y; available in 2 forms: lifetime and current. overall test: sensitivity: 0.85 (moderate), Downloaded from specificity: 0.75 (moderate); sensitivity can be improved with lowering cutoff for children www.aappublications.org/news younger than 5 y and 5–7y, specificity poor for younger children STAT Clinician-directed, 24–35 mo; 12 20–30 min No Validated by 12 activities to English http://stat. Refs 573 and interactive, and ,24 mo comparison with observe early vueinnovations. 574 observation (exploratory) ADOS-G results in social- com/ measure; 52 children 24–35 communicative requires training mo (26 with behavior; risk

byguest on October1,2021 of clinician for autism, 26 with categorization standardized developmental (high risk/low administration; delay); sensitivity: risk) not for 0.83, specificity: population 0.86, PPV: 0.77, screening NPV: 0.90, for ,24 mo: sensitivity: 0.95, RMTEAEIA CDM FPEDIATRICS OF ACADEMY AMERICAN THE FROM specificity: 0.73, PPV: 0.56, NPV: 0.97; screening properties improved for children .14 mo Promising autism screening tests The Infant/Toddler Parent 6–24 mo 24 15 min No PPV DD: 0.43 (6–8 Identifies language Available in Paul H. Brookes Ref 59 Checklist questionnaire: mo); PPV DD: 0.79 delays (alone/ multiple Publishing Co Inc: (Communication screens for (21–24 mo) with ASD); risk languages; 800-638-3775 or and Symbolic language delay for ASD; risk see test www. Behavior Scales status for social, EITISVlm 4,nme ,Jnay2020 January 1, number 145, Volume PEDIATRICS TABLE 6 Continued Autism Screening Description Age Range Average No. Administration Forms Available Psychometric Scoring Method Cultural Source Key References Tests Items Time EHR compatible Properties Considerations Developmental speech, symbolic information brookespublishing. Profile) composites, and for details com total score Early Parent 12–36 mo 47 10–15 min No Sensitivity: Investigation English https:// Not in peer- Screening for questionnaire: 0.85–0.91; ongoing of firstwordsproject. reviewed Autism and research edition, specificity: subset (24 com/screen- literature Communication 47 items 0.82–0.84; PPV: items) my-child/ Disorders 0.55–0.81; NPV: Downloaded from 0.88–0.98 First-Year Inventory Parent 12 mo 63 10 min No Sensitivity, Scores at risk; English https://www.med.unc. Ref 575 questionnaire; specificity, PPV promising in edu/ahs/pearls/ promising in not reported high-risk (infant research/first- high-risk sibling) cohort year-inventory-fyi- population to (Rowberry development/ www.aappublications.org/news identify risk in et al575 ) 12-mo-old infants Parent’s Parent 16–35 mo 7 ∼5 min Available Sensitivity: 3 of 7 symptoms in Available in Free download from Publications Observations of questionnaire through 83%–93%, at-risk range multiple www.theswyc.org and User’s Social used to assess patient tools, average 88.5%; languages; Manual Interactions autism risk; ASD epic, and specificity: see test available at screening CHADIS; 42%–75%, information www. included on 18-, available for average 56.9% for details theswyc.org; 24-, and 30-mo free Refs 576 and

byguest on October1,2021 The Survey of download as 577 Well-Being of pdfs from Young Children: www. forms theswyc.org Rapid Interactive Clinician 12–36 mo 9 20–30 min No Cutoff .15; 9 interactive English https://umassmed. Ref 578 Screening Test observation: interactive sensitivity: 1; activities; total edu/AutismRITA-T/ for Autism in administered by items specificity: 0.84; score summed, about-the-test/ Toddlers 13 trained examiner PPV: 0.88; NPV: cutoff score of 15 0.94; needs (for that sample) further study in larger samples The AAP does not approve/endorse any specific tool for screening purposes. This table is not exhaustive, and other tests may be available. ADOS-G, Autism Diagnostic Observation Schedule – Generic; CARS, Childhood Autism Rating Scale; CHADIS, Comprehensive Health and Decision Information System; EHR, electronic health record; ICD-10, International Classification of Diseases, 10th revision; IMFAR, International Meeting for Autism Research; NPV, negative predictive value; PPV, positive predictive value. 11 Further adaptations of the AAP continues to recommend Barriers to Identifying Risk for ASD Communication Symbolic Behavior screening using the most valid of Children with milder symptoms Scale for use in screening for current measures at 18 and and/or average or above-average language delays in addition to ASD 24 months of age. Pediatricians intelligence may not be identified have the potential to identify children cannot assume that early intervention with symptoms until school age, at risk for both disorders (functional systems will screen participants when differences in social language communication; ages 6–24 being served for language or global 49,59 or personal rigidities affect function. months). Use of this or other delays for ASD at the recommended Some children who are later screening tools may be coupled with ages. Universal screening is diagnosed with ASD are initially the online support of a video glossary recommended because symptoms of believed to have precocious language, fi of symptoms of ASD, such as that in ASD can be identi ed in early reading, or math skills, and it is not the Autism Navigator (http://www. childhood, and a diagnosis of ASD by until the social demands of school autismnavigator.com/). These and skilled professionals is accurate in that the social language symptoms other online approaches to support children as young as 18 months of 65 become problematic. It has also been screening strategies may be age. Diagnostic stability is high for suggested that girls may have lesser integrated into efficient patterns of children who are diagnosed with ASD 43 intensity of symptoms and fewer practice. Results of screening at 18 to 36 months of age. Early externalizing behaviors. These conducted online, in community screening does not identify many differences may, in part, result in settings, and in preschools should be children with milder symptoms and underdiagnosis in girls.70 Specific communicated to the primary care typical cognitive ability as at risk for coexisting conditions may prevent provider to ensure appropriate ASD; therefore, ongoing surveillance 16 clinicians from recognizing symptoms evaluation of etiology, co-occurring remains necessary. Participation in of ASD in early childhood. For conditions, referral for diagnosis, and early intervention in general is example, 1 study revealed that follow-up to ensure that intervention greatest among children who had children who were initially identified 49 66 is accessed. screening and surveillance. with ADHD in primary care were diagnosed with ASD 3 years later A systematic review by the US Children Older Than 30 Months compared with children who did not Preventive Services Task Force At present, for children older than have earlier symptoms of ADHD.69 (USPSTF) concluded that the 30 months, there are no validated Recognition and referral for older literature on existing screening tools screening tools available for use in children with social-skill deficits did not demonstrate sufficient pediatric practice, nor are there would be facilitated by the specificity to justify universal current recommendations by the AAP development of accurate and brief screening.63 The USPSTF noted that for universal screening for ASD in screening tests for use in primary no study has directly examined that age group. The Social care and school settings. whether children with ASD detected Communication Questionnaire (SCQ) by early screening have better (see Table 6) has been studied in Population surveillance data reveal outcomes than those detected by different populations (eg, clinical later age at diagnosis for African other means. However, such a study sample, population reference sample, American and Hispanic children, would require random assignment of community sample, and convenience suggesting that there are barriers to large representative samples from sample), with best results in screening and surveillance and across the country to either population samples67 when using the referral for diagnosis in groups with a screening or nonscreening lifetime version, and appears to have other unmet health needs.2 Race, condition, with follow-up of long- reasonable psychometric properties. ethnicity, and socioeconomic status term outcomes and societal costs. However, questionnaires like the SCQ did not affect the accuracy of routine Given that early treatment of children may identify symptoms that overlap screening tests for ASD in low-risk younger than 36 months has been with other conditions, such as ADHD, toddlers, suggesting that screening shown to result in positive that affect function at school age.68,69 with appropriate supports for follow- outcomes,43,64 such a study would be Further validation of population- up care can lower the age at diagnosis challenging to support. The USPSTF based screening tools for children in diverse populations.60 Language concluded that further research is older than 30 months is needed barriers, inaccurate translations, and indicated to evaluate the appropriate before recommendations for low parental literacy may ages and populations of children who universal screening of school-aged compromise use of parent-completed should be screened for ASD and that children can be made. At this time, questionnaires.71 Limited more accurate and culturally sensitive ongoing surveillance in the context of understanding of cultural differences measures should be developed. The primary care is recommended. experienced by the patient’s family

Downloaded from www.aappublications.org/news by guest on October 1, 2021 12 FROM THE AMERICAN ACADEMY OF PEDIATRICS and lack of trust in the health care function. Formal assessment of Elevated scores may be seen with provider may further limit language, cognitive, and adaptive greater severity of symptoms of identification and reporting of abilities and sensory status is an ASD as well as with intellectual symptoms of autism.72 Screening important component of the disability, communication tools need to be developed for diagnostic process. difficulties, and behavioral populations of individuals whose challenges. Short clinical visits may not allow primary language is not English and even a skilled clinician the who are also sensitive to cultural Structured observation of symptoms opportunity to accurately recognize barriers that may limit reporting of of ASD during clinical evaluation is symptoms of ASD.50 An accurate symptoms of ASD.73 helpful to inform the diagnostic history needs to reflect a longitudinal application of the DSM-5 criteria. experience with the individual and Diagnostic Evaluation Validated observation tools used to reflect the effects of symptoms on the provide structured data to confirm Once a child is determined to be at patient’s ability to function in family, the diagnosis include the Autism risk for a diagnosis of ASD, either by peer, and school settings. This history Diagnostic Observation Schedule, screening or surveillance, a timely is obtained by interview with the Second Edition (ADOS-2) and the referral for clinical diagnostic patient and caregivers, reports of Childhood Autism Rating Scale, evaluation and early intervention or behavior in other environments (such Second Edition (CARS-2).86 No single school services, depending on his or as school), and descriptions of observation tool is appropriate for all her age, is indicated.74 Children with behavior during formal testing. The clinical settings. The observation tool developmental delay with or without history of symptoms of ASD can be is meant to support application of the an ASD diagnosis should be referred supported by questionnaires such as DSM-5 criteria informed by history to early intervention or school the SCQ77 or Social Responsiveness and other data. services, in which cognitive and Scale (SRS).78 None of these language testing may be completed. fi questionnaires is suf cient alone to The ADOS-2 was developed to elicit The primary care provider should make a diagnosis of ASD, but all atypical social language and discuss with the family the provide a structured approach to behaviors. With the ADOS-2, modules importance of both the assessment of elicit symptoms of ASD. Measures are specific for use across the age developmental status and evaluation such as the Behavior Assessment span of toddlers to adults.87,88 The for an ASD diagnosis and assist the 79 System for Children, Diagnostic ADOS-2 requires intensive training to family in navigating through the Interview for Social and accurately administer and score and process, including connecting them Communication Disorders takes 30 to 45 minutes to administer. with community resources. Families 80,81 (DISCO), and the Child Behavior It is often a component of both with low income or language barriers 82 Checklist are used to assess research and clinical evaluations. The may need additional attention to take children and youth for other information obtained from the ADOS- the next steps. behavioral health conditions but may 2 is used by the clinician in also identify behavioral profiles Although most children will need to conjunction with the history of peer consistent with ASD. see a specialist, such as interactions, social relationships, and a developmental-behavioral or In some clinical and research functional impairment from neurodevelopmental pediatrician, settings, the behaviors associated symptoms to determine if the DSM-5 psychologist, neurologist, or with ASD are reported through the criteria are met. The CARS-2 is psychiatrist, for a diagnostic Autism Diagnostic Inventory- another structured approach evaluation, general pediatricians and Revised (ADI-R), a lengthy, a clinician might use to support child psychologists comfortable with semistructured parent a clinical diagnosis of ASD.89 The application of the DSM-5 criteria can interview.83,84 It supports clinician completes a 15-point scale make an initial clinical diagnosis. a knowledgeable clinician in that is based on history and Having a clinical diagnosis may applying diagnostic criteria of ASD. observation. The ADOS-2, CARS-2, facilitate initiation of services. At this The SCQ was designed to elicit and SRS (Parent and Teacher) all rate time, there are no laboratory tests similar information to the ADI-R in children similarly in approximately that can be used to make a diagnosis an abbreviated questionnaire half of identified cases.90 The of ASD, so careful review of the child’s format. The SRS is a 65-item integration of historical information behavioral history and direct questionnaire that may be used to and objective observation by observation of symptoms are measure autistic traits on a clinician trained to diagnose autism necessary.75,76 To meet diagnostic a continuum as part of a more and related conditions to inform the criteria, the symptoms must impair complete evaluation of ASD.78,85 DSM-5 diagnostic criteria is the

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 13 critical element to diagnostic and nonverbal communication for problems, or inattention. Appropriate evaluation. social interaction. Formal assessment amplification should be offered, if of communication by a speech or indicated. The clinical utility of Evaluation of Co-occurring language pathologist at the time of auditory processing evaluations Developmental Conditions diagnosis should include the available in current practice remain Patients with ASD may have documentation of expressive and an area of study.100,101 intellectual disabilities, learning receptive language skills as well as disabilities, ADHD, anxiety disorders, the pragmatic or conversational use Sensory Assessment: Vision 92 or speech and language disorders, of language. Visual function should be considered among others. These conditions may in the initial evaluation of children Adaptive Function Testing influence the presentation of the who are visually inattentive, have symptoms of ASD. These conditions A caregiver report and/or teacher stereotypical behaviors (such as eye may influence the presentation of report of adaptive functioning poking or close visual scrutiny), or do symptoms of ASD and may influence complements objective cognitive not make eye contact. Decreased the social and functional impairment testing. Determining the extent that visual acuity may affect interactive of the individual in different ways at ASD affects daily function is gaze and require accommodations in different ages. Valid assessment of necessary to establish eligibility for the educational setting.102 Children cognitive and language ability is an some publicly funded programs as with visual impairment may also important component of the well as to identify and monitor demonstrate stereotyped motor diagnostic evaluation. In the United developmental goals for treatment. behaviors. States, early intervention services and Adaptive behaviors are typically school systems will evaluate children delayed in people who have Sensory Assessment: Sensory in these domains to assess intellectual disability with ASD but Processing educational needs. In some areas, can be impaired in people with ASD The DSM-5 includes sensory 93,94 initial evaluations are performed in and an average-range IQ. symptoms in the diagnostic criteria clinical settings and paid for by Commonly used adaptive measures for ASD. The DSM-5 does not include insurance. include the Vineland Adaptive sensory processing disorder as Behavior Scales and the Adaptive a discrete diagnosis. Commonly used Cognitive Testing 95 Behavior Assessment System. evaluation tools (such as the Short A range of standardized measures are Sensory Profile and others) quantify Motor Assessment used to determine developmental parent perception of sensory levels of younger children and IQ in Children with ASD are more likely to differences relative to smell, taste, children older than 3 years. The have mild delays in gross motor skills vision, hearing, and touch.103,104 In intelligence test selected by the and coordination compared with addition to capturing what is psychologist will depend on the age children in the general population conventionally considered as and language level of the child. and may meet DSM-5 criteria for a sensory disturbance, questionnaires Administration of a valid cognitive developmental coordination disorder that are used to assess sensory 96 test is important in ascribing in addition to ASD. General symptoms also capture motor symptoms to ASD as part of the initial screening tests or adaptive measures hyperactivity and hypoactivity as diagnosis but also helps to establish may suggest motor delays that would sensory-seeking or sensory-avoiding co-occurring diagnoses with ASD, benefit from formal evaluation by an behaviors. These latter symptoms such as intellectual disability. There occupational or physical therapist. A may reflect co-occurring ADHD. are valid tests that can be used in relationship of early motor delays and Sensory symptoms may be more children who are nonverbal. Although subsequent language and adaptive evident at younger ages and may the prevalence of a diagnosis of ASD development in children with ASD define subtypes of the disorder.105,106 is increased in children with an has been proposed.97,98 intellectual disability,91 other children diagnosed with intellectual disability Sensory Assessment: Hearing SECTION 4: ETIOLOGIC EVALUATION may have some symptoms of ASD Children with language delay or Children with a diagnosis of ASD without meeting diagnostic criteria inattention to language should have should be assessed for potential for the disorder. an evaluation of their hearing as part etiology and common coexisting of their initial evaluation.99 Hearing medical conditions. At the time of the Language Testing loss may co-occur with ASD and 2007 AAP clinical reports on autism, Inherent in the core symptoms of ASD needs to be considered in children karyotype and DNA testing for fragile are differences in the use of verbal with language delays, behavior X syndrome were the state-of-the-art

Downloaded from www.aappublications.org/news by guest on October 1, 2021 14 FROM THE AMERICAN ACADEMY OF PEDIATRICS etiologic investigations. Soon TABLE 7 Potential Benefits of Establishing a Genetic Etiologic Diagnosis thereafter, chromosomal microarray • Improving accuracy of counseling provided to patients and families: (CMA) was endorsed by the American o Prognosis or expected clinical course College of Medical Genetics and o Recurrence risk for the family and the individual affected • fi Genomics and the American Academy Providing condition-speci c family support, such as: o Improving psychosocial outcomes for patients and their families (eg, knowledge and sense of of Child and Adolescent Psychiatry as empowerment, parental quality of life) the most appropriate initial test for • Preventing morbidity and treating medical conditions associated with the genotype, such as: etiologic evaluation of children with o Conditions or anomalies likely to be present at diagnosis ASD.76,107–110 Despite rapid o Conditions that may develop later • fi technological advances in Re ning treatment options, including: o Avoiding therapeutic interventions that may be based on unfounded etiologic theories neuroimaging and other areas, many o Avoiding ineffective or potentially harmful treatments of the recommendations for clinical o Providing access to emerging etiology-specific treatments evaluation published in 2007 are • Facilitating acquisition of needed services and access to research treatment protocols unchanged. This section summarizes • Avoiding additional diagnostic tests, which may be unnecessary, expensive, and/or uncomfortable recent advances in understanding the Adapted from Sun F, Oristaglio J, Levy SE, et al. Genetic Testing for Developmental Disabilities, Intellectual Disability, and etiologies of ASD and how they Autism Spectrum Disorder. Rockville, MD: Agency for Healthcare Research and Quality (US); 2015; Amiet C, Couchon E, Carr K, Carayol J, Cohen D. Are there cultural differences in parental interest in early diagnosis and genetic risk translate into recommendations for assessment for autism spectrum disorder? Front Pediatr. 2014;2:32; Srivastava S, Cohen JS, Vernon H, et al. Clinical clinical practice. whole exome sequencing in child neurology practice. Ann Neurol. 2014;76(4):473–483; Iglesias A, Anyane-Yeboa K, Wynn J, et al. The usefulness of whole-exome sequencing in routine clinical practice. Genet Med. 2014;16(12):922–931; Lingen M, Albers L, Borchers M, et al. Obtaining a genetic diagnosis in a child with disability: impact on parental quality of life. Clin Medical Workup of the Child With ASD Genet. 2016;89(2):258–266; Riggs ER, Wain KE, Riethmaier D, et al. Chromosomal microarray impacts clinical manage- Genetic Testing ment. Clin Genet. 2014;85(2):147–153; and ACMG Board of Directors. Clinical utility of genetic and genomic services: a position statement of the American College of Medical Genetics and Genomics. Genet Med. 2015;17(6):505–507. Advances such as the development of CMA and next-generation sequencing physical examination should include abnormalities.109 Genetic evaluation technologies and the application of assessment of growth relative to should be recommended and offered these technologies to well- typical curves (including head to all families as part of the etiologic characterized patient cohorts have circumference), dysmorphic features, workup. A stepwise general approach led to progress in the understanding organomegaly, skin manifestations of is provided in Table 8 as a practical of the complex genetics of ASD and neurocutaneous disorders (eg, guideline.110,120 The presence of other neurodevelopmental disorders tuberous sclerosis and dysmorphic features or intellectual in the last decade. Identifying neurofibromatosis), and neurologic disability is generally associated with a genetic etiology provides clinicians with more information for families about prognosis and recurrence risk TABLE 8 Genetic Etiologic Investigations in Patients With ASD and may help to identify and treat or Step Genetic Etiologic Investigations prevent co-occurring medical conditions, guide patients and 1 Consider referral for pediatric genetics evaluation fi 2 Comprehensive history (including 3-generation family history with emphasis on individuals with families to condition-speci c ASD and other developmental, behavioral and/or psychiatric, and neurologic diagnoses) resources and supports, and avoid Physical examination (including dysmorphology, growth parameters [including head ordering unnecessary tests circumference], and skin examination) (Table 7).111–117 Most parents find • If syndrome diagnosis or metabolic disorder is suspected, go back to step 1 (genetics and/ this information to be useful.118 As or metabolism referral) and/or order the appropriate targeted testing • Otherwise, proceed to step 3 research progresses, genetic testing 3 Laboratory studies may contribute to identifying • Discuss and offer CMA analysis effective interventions related to • Discuss and offer fragile X analysis; if family history is suggestive of sex-linked intellectual specific etiologies. disabilities, refer to genetics for additional testing • If patient is a girl, consider evaluation for Rett syndrome, MECP2 testing Etiologic investigation begins with • If these studies do not reveal the etiology, proceed to step 4 a careful medical, developmental- 4 Consider referral to genetics, workup might include WES behavioral, and family history and Adapted from Schaefer GB, Mendelsohn NJ; Professional Practice and Guidelines Committee. Clinical genetics evaluation a thorough physical and neurologic in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15(5):399–407; 109 Srivastava S, Love-Nichols JA, Dies KA, et al; NDD Exome Scoping Review Work Group. Meta-analysis and multidisciplinary examination. The history should consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental include potential prenatal exposure to disorders [published online ahead of print June 11, 2019]. Genet Med. and Shevell M, Ashwal S, Donley D, et al; Quality teratogens (such as medications, Standards Subcommittee of the American Academy of Neurology; Practice Committee of the Child Neurology Society. Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Sub- alcohol, drugs) and other factors that committee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 109,119 increase risk for ASD. The 2003;60(3):367–380.

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 15 increased likelihood of finding individuals with ASD are provided in have consistently been used to a genetic abnormality.121 However, Supplemental Table 14. identify a molecular diagnosis in 26% authors of some clinical studies have to 29% of individuals for whom Because fragile X syndrome increases identified similar yield for genetic neurodevelopmental disorders were risk for ASD, DNA testing for fragile X testing in children without these risk the primary indication for syndrome should be recommended – factors.122,123 testing.143 145 Authors of studies of for all children with ASD, but clinical populations with ASD have In some cases, individuals with especially for boys and children with reported diagnostic yields of 8% to clinical genetic syndromes, such as a suggestive family history of male 20%.121,144 The yield of WES is fragile X syndrome, tuberous sclerosis members with intellectual disability. higher when both the parents and the complex, and others (such as those Physical examination might reveal the child who is affected are evaluated144 described in Supplemental Table 13), common features of a large head size, to allow for comparison of the child also meet criteria for ASD.124,125 prominent jaw, large ears, with parents who are unaffected. When a specific syndrome or ligamentous laxity, and, in male metabolic disorder is suspected, the patients, large testes after puberty. Some geographic areas may have clinician should proceed with the The cytosine-guanine-guanine limited availability of pediatric appropriate targeted testing or trinucleotide repeat expansion that is subspecialists (eg, in genetics or referral to a pediatric geneticist or responsible for fragile X syndrome is metabolism) who can guide the neurologist. For example, a girl with not detected on CMA and must be genetic workup, so primary care significant developmental delays, ordered as a separate test. The providers may be in the position to deceleration in head growth velocity, current estimate is that consider and direct etiologic and characteristic midline hand approximately 0.45% of individuals evaluation. The complexity of genetic movements should prompt genetic with ASD have the full mutation for testing is such that most primary care testing for a mutation or deletion or fragile X syndrome, and many of them providers may want to consult with – duplication of MECP2, the gene are female.130,132,135 137 Because a specialist to plan testing and implicated in Rett syndrome.109,126 fragile X syndrome testing is interpret results. The clinical etiologic Another specific example would be relatively inexpensive and the evaluation should be tailored to the a boy with ASD with marked condition has important genetic individual patient, taking into macrocephaly and pigmented counseling implications, it is consideration information from macules on the penis, findings that reasonable to consider testing both the history and physical would warrant sequencing and male and female patients with ASD, at examination109,110 and the values and deletion or duplication analysis of the least until more data become wishes of the family. The stepwise PTEN gene.127 Descriptions of these available to clarify the issue. general approach summarized in and other clinical syndromes Table 8 can be used to guide this When the history and physical associated with ASD are provided in process. examination, CMA, and fragile X Supplemental Table 13. analysis do not identify an etiology, It is important for families to CMA is recommended if the etiology the next step at this time in the understand that genetic tests may for developmental disability is not etiologic evaluation for ASD is whole- explain the cause of their child’s ASD known. CMA identifies copy number exome sequencing (WES). WES or provide information about the variants (CNVs) at this time, which technology allows for the statistical risk of ASD, but they are are DNA duplications or deletions identification of single-nucleotide not diagnostic of ASD; the diagnosis that alter the function of genes variants, including pathogenic loss-of- of ASD is made on the basis of clinical (Table 8, step 2). CMA reveals function mutations and missense symptoms. Unlike CMA and WES, adefinitively pathogenic CNV mutations, which have been found to commercially marketed tests may not – in 5.4% to 14% (median 9%) of be associated with ASD.138 142 have the potential to provide individuals with ASD in clinical Examples of ASD risk genes identified a molecular etiologic diagnosis. samples.121,128–135 When CNVs of or confirmed in WES studies are Genomic testing technology is uncertain significance are included, provided in Supplemental Table 15. evolving rapidly, as is our approximately 17% to 42% of As with other tests, clinicians understanding of the genetic patients with ASD have findings on ordering this test should be familiar architecture of ASD, and these the CMA. Some of the variants of with both pretest counseling and recommendations for testing will uncertain significance may be interpretation of the results. A genetic need to be updated as new studies determined as pathogenic in the counselor is helpful in explaining the are published.146 For example, it is future. The most commonly identified reason for testing as well as the anticipated that CMA and WES will recurrent pathogenic CNVs among results. Large clinical WES studies soon be combined because of

Downloaded from www.aappublications.org/news by guest on October 1, 2021 16 FROM THE AMERICAN ACADEMY OF PEDIATRICS improvements in accurate require intervention.159,160 The need metabolic conditions that may be identification of CNVs using sequence for clinical MRI should be directed by associated with an ASD phenotype data and that sequencing of the a history and physical examination. are provided in Supplemental exome will be replaced by sequencing MRI may be indicated in the Table 16. There is no evidence at this of the entire genome as issues with evaluation of atypical regression, time for routine testing of hair, blood, interpretation and cost become more microcephaly, macrocephaly, seizures, or urine for environmental toxins or manageable.121,130,147–150 intracranial manifestations of genetic heavy metals outside of laboratory disorders, abnormal neurologic screening for lead exposure.169 Parents of a child with ASD should be examination, or other clinical counseled regarding recurrence risk indications.76,109,161,162 Imaging EEG in subsequent offspring, and the technology used to examine brain nature of the counseling depends Children with ASD have an increased structure and function provides greatly on whether a specific genetic risk for seizures, and EEG valuable insight into the neurobiology cause of the child’s ASD has been abnormalities are common in the of ASD in research settings and may identified. When a specific genetic absence of clinical seizures (see lead to useful clinical applications in etiology has been determined, the Seizures section for more the future. 170–175 family can be provided with information). However, EEG is information about the risk of Metabolic Testing not recommended as a routine recurrence in subsequent offspring. baseline evaluation in the absence of The yield of routine metabolic testing However, when genetic testing has clinical concern about seizures, for children with ASD is low and not not been completed or has not – atypical regression, or other recommended for regular use.163 167 revealed the etiology of the child’s neurologic symptoms on history or However, large population-based ASD, recurrence risk counseling is examination that would suggest an studies are lacking, so accurate 161,170,172,176 based on group averages derived EEG is indicated. Late or prevalence and diagnostic yield from the existing literature. For atypical loss of language, as might be estimates are not available. Metabolic a couple with 1 child with ASD of observed in electrical status workup should be informed by unknown cause, the current best epilepticus of sleep with loss of history, family history, symptoms, and estimate of recurrence in language, should be evaluated with an examination and might include 161,170,172,176 a subsequent child is approximately overnight EEG. Primary measurement of fasting plasma amino 10% (range 4%–14%151–153). If care clinicians should discuss the acid levels, urine organic acid levels, a couple already has $2 children with increased risk and the signs and and acylcarnitine metabolite levels ASD of unknown etiology (idiopathic), symptoms of seizures with the and other testing for specific the chance of a subsequent child families of children diagnosed with metabolic disorders. History of having ASD may be as high as 32% to ASD, maintain a high index of clinical atypical regressions (later than 36%.151,154 However, the risk is not suspicion for seizures, and consult 2 years of age, motor regression, or limited to ASD. Siblings of children with a pediatric neurologist when multiple regressions), family history with ASD who do not have ASD concerned about atypical regression of early childhood death or diagnosed 170,172,176 themselves may have a 20% to 25% or the possibility of seizures. metabolic disorders, and physical risk for language disorders and other features, such as significant hypotonia neurodevelopmental and psychiatric The Biology of ASD or weakness, visual and hearing disorders.152,155,156 impairment, and dysmorphic Genetics and ASD features, would suggest consultation ASD is clinically and etiologically Neuroimaging with a specialist to guide evaluation heterogeneous yet highly heritable. Specific clinical neuroimaging for metabolic or mitochondrial The rate of ASD in siblings is much findings are not more prevalent in disorders.109,168 Children who higher than the rate in the general ASD compared with other present with motor delay should be population. Twin studies demonstrate neurodevelopmental disorders, nor evaluated with creatine kinase substantially higher concordance do specific abnormalities correlate and thyroid-stimulating hormone rates for symptoms of ASD in with clinical, etiologic, or testing, according to AAP monozygotic twins than in dizygotic pathophysiological aspects of recommendations.9,49 Although twins.177 A meta-analysis involving ASD.120,157,158 Incidental findings are metabolic disorders are uncommon 6413 twin pairs revealed a 98% common in neuroimaging studies causes of ASD, the potential impact is concordance in monozygotic twins, obtained in the workup of children high because treatment may be a 53% to 67% concordance in diagnosed with ASD but rarely available and the inheritance pattern dizygotic twins, and heritability provide etiologic information or may be known.109,124 Examples of estimates from 64% to 91%.177,178

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 17 Siblings may also be at risk for intracellular signaling, transcription Genes, Immunologic Exposures, and ASD symptoms related to ASD that do not regulation, and chromatin 139,190,191,196 It has been proposed that children meet the threshold for a diagnosis of remodeling. It is with ASD-associated CNVs may be fi ASD and have been described as the important to note that no speci c more susceptible to environmental 141,179 fi broader autism phenotype. mutation has been identi ed that is insult in the form of maternal These data provide strong evidence unique to ASD; there is substantial immune activation. Report of for a genetic contribution to ASD genetic overlap between ASD and 180–184 maternal infection or fever during risk. other neurodevelopmental disorders, pregnancy may be associated with including intellectual disability, Risk for ASD also is increased in the – increased severity of ASD-related epilepsy, and schizophrenia.197 204 children of both older fathers and symptoms in offspring who are – 217 older mothers.185 187 The increased affected. The pathogenic role of risk with parental age may be related Genes, Environmental Exposures, and circulating maternal antibodies to germline mutations in older ASD directed to fetal brain tissue and the fathers.143,188 Mechanisms mediating potential value of maternal antibody The potential environmental factors the effect of advancing maternal age panels as biomarkers of ASD are that may be related to increased 218–222 on ASD risk are less clear.143 currently being studied. Unless reported prevalence of ASD is an area Increased maternal and paternal age otherwise indicated (eg, history of active study that, as yet, is without are independently associated with suggestive of autoimmune or firm conclusions.119 Environmental ASD risk, and a joint effect seems to immunologic disorder), no immune – factors associated with ASD include in occur as well.185 187 testing is recommended in the utero exposure to medications such etiologic workup of a child with ASD. Important aspects of the genetics of as valproate and thalidomide. Other ASD are still poorly understood, prenatal influences, such as short Epigenetics including the role of common interpregnancy interval, multiple variants, epistasis (gene-gene gestation, maternal obesity, Epigenetic modifications, such as interactions), and environmental gestational bleeding, gestational DNA methylation and modification of genotype effects. In diabetes, advanced parental age, and posttranslational histone contrast, advances such as CMA and infections (eg, rubella and modification, produce heritable next-generation sequencing cytomegalovirus), may be associated changes in gene expression that do – technologies have resulted in with increased risk for ASD.205 209 not involve a change in the DNA identification of large-effect Perinatal factors, such as preterm sequence. Some genetic disorders (pathogenic) rare variants that birth, low birth weight, fetal growth associated with ASD (eg, Rett appear to be causally associated with restriction (ie, small for gestational syndrome; CHARGE syndrome; 15q ASD, including CNVs, which are age), intrapartum hypoxia, and duplication; Angelman syndrome; and deletions or duplications $1000 bp neonatal encephalopathy, are fragile X syndrome), involve genes in size that alter the dosage of genes, associated with increased ASD that either encode epigenetic – and sequence-nucleotide risk.205,210 212 Environmental factors regulators or are sensitive to variants.189–192 Pathogenic rare may present independent risk to alterations in their epigenetic variants may arise de novo or be prenatal brain development or may regulation.223,224 Because epigenetic inherited as autosomal dominant, affect gene function in individuals modifications can be influenced by autosomal recessive, or X-linked with genetic predisposition.213 environmental factors, such as mutations. Researchers of CMA and Population-level associations with prenatal maternal exposures and WES studies have established that ASD have been examined for postnatal experience, they represent although de novo and inherited rare organophosphates and certain other 1 interface between genes and variants of large effect size are pesticides, metals, volatile organic environment. However, epigenetic collectively common, no individual compounds, and air pollution, modifications are not the only pathogenic variant accounts for more particularly particulate matter and mechanisms by which gene – than 1% of cases of ASD.* Genes that nitrogen dioxide.214 216 Research on expression is regulated, and contribute to ASD are involved in environmental exposures may be of epigenetics should not be conflated a variety of biological functions, with great importance in identifying with the broader category of convergence on aspects of brain modifiable risk factors related to ASD environmental effects.223,225 development and function, including and other developmental disorders. It Currently, the evidence that alteration synaptic structure and function, is prudent to limit exposure of of gene expression by environmental children and pregnant women to factors plays a causal role in ASD is – * Refs 121, 144, 189–195. known neurotoxicants. very limited.223 228 Investigation of

Downloaded from www.aappublications.org/news by guest on October 1, 2021 18 FROM THE AMERICAN ACADEMY OF PEDIATRICS the role of epigenetic and other Brain Structure and ASD: Early Brain Overgrowth fi Neuropathology nongenetic modi cations that Cross-sectional and longitudinal alter gene activity without Neuropathological research has been studies suggest that as a group, changing the DNA sequence is an limited by the small number of children later diagnosed with ASD active area of etiologic research postmortem brains available for may have an average or below- in ASD. study. Developmental brain average head circumference at birth, abnormalities in people with ASD are with an acceleration in brain growth 256 Vaccines reported in the cerebral neocortex; before 2 years of age. This rapid limbic system structures, including brain growth leads to significantly fi The scienti c literature does not the hippocampal formation and above-average head circumferences support an association of amygdala; basal ganglia; thalamus; and MRI brain volumes in toddlers, vaccination as an environmental brainstem; and cerebellum. These followed by a plateau in brain growth, factor that increases the risk for brain abnormalities include dysplasia, with brain volumes in adolescence ASD. Children with ASD should be altered neurogenesis, and abnormal and adulthood similar to those of – vaccinated according to the neuronal migration.249 251 The vast controls.257,258 Almost 16% of young recommended schedule. majority of abnormalities described children with ASD have a head Epidemiological studies do not originate during prenatal brain circumference greater than the 97th demonstrate any association of the development.249,251,252 Findings in percentile.258 A preliminary study measles-mumps-rubella vaccine, the cerebral cortex may include focal suggested that infant siblings of mercury exposure by thimerosal- disruption of neuronal migration, children with ASD who exhibited containing vaccines, aluminum in minicolumnar abnormalities, and a larger head circumference at vaccines, or increased level of variations in neuronal 12 months and showed more slowing immunologic exposure attributable density.249,251,252 A decreased of head circumference growth from to a larger number of vaccines number of Purkinje cells in the 12 to 24 months had an increased (either given at 1 time or cerebellum is 1 of the most 214,229–246 chance of demonstrating symptoms cumulatively) with ASD. consistently reported of ASD.259,260 Although this finding Vaccines used for children in the neuropathologic findings associated raises the possibility that patterns of United States have not contained with ASD. Although it was initially brain growth might be used for early thimerosal since 2001. The authors thought to be of prenatal onset, fi 234 identi cation, the rate of head growth of a 2012 Cochrane review and evidence now indicates that this did not predict which infants a 2014 quantitative meta-analysis phenomenon is more likely to be an developed ASD in the first 3 years of of pooled data from cohort studies acquired process that occurs life in a large prospective study of involving 1 256 407 children and postnatally, potentially related to high-risk infants.261 It is possible that case-control studies involving 9920 seizures, medications, and/or a large head size is unrelated to ASD fi children reviewed the scienti c ischemia near the time of death or and/or may be part of general literature and came to this factors other than ASD.249 No uniform 262–265 231 somatic overgrowth. conclusion. Evidence implicating neuropathology has been identified in “ ” immunizations as a second hit people with ASD. conferring ASD risk in genetically Neuroimaging Patterns Associated susceptible subgroups is lacking. It With ASD in Research Studies has been shown that the measles- Biomarkers Although there are conflicting mumps-rubella vaccine is not Objectively measured biological findings, structural MRI volumetric associated with increased risk for characteristics, or biomarkers, of ASD studies suggest that young children ASD, even among children who are could potentially be used to predict with ASD differ from controls in total already at higher risk because of ASD risk, enhance screening, and brain volume, cortical gray and white having an older sibling with ASD.229 permit presymptomatic detection. matter volume (particularly frontal, Media coverage of vaccine issues Their use could improve the temporal, and cingulate cortices), may inflate the perception of reliability and validity of clinical extraaxial cerebral spinal fluid uncertainty by equal coverage of diagnosis (identifying clinically volume, and amygdala volume.266–271 vaccine proponents and opponents. meaningful subgroups that would A research-level analysis also has The overwhelming weight of allow for prediction of prognosis or identified asymmetries in multiple evidence supports vaccine safety.247 treatment response), identify brain structures in people with Communicating information about mechanisms for developing ASD.272 Diffusion tensor imaging has vaccine safety is a critical treatment, and confirm the need for been used to identify altered patterns component of pediatric practice.248 a specific intervention.221,253–255 in white matter by 6 months of age in

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 19 infants later diagnosed with Other Potential Biomarkers repetitive behaviors and interests)1 ASD.270,273 Functional MRI has and co-occurring associated Although some studies have 292-294 demonstrated differences in people attempted to differentiate people impairments ; (2) maximize with ASD relative to controls in with and without ASD on the basis of functional independence by fi ef ciency of visual processing, differences in laboratory profiles of facilitating learning and acquisition of executive function, language, and platelet serotonin, plasma melatonin, adaptive skills; and (3) eliminate, basic and complex social processing urine melatonin sulfate, redox status, minimize, or prevent problem skills.274,275 Functional MRI in behaviors that may interfere with placental trophoblast inclusions, and 6,295,296 research settings demonstrate immune function, currently no functional skills. Treatments differences in the mechanisms of diagnostic laboratory tests have been should be individualized, attention to social stimuli, approved for ASD.286,287 To date, developmentally appropriate, and modulation in response to task none of these potential biomarkers intensive, with performance data demands or intensity of stimuli, under study has sufficient evidence to relevant to treatment goals to 6,297 and executive function in people be recommended. evaluate and adjust intervention. with ASD.274 Functional All interventions should be based on underconnectivity has also been Biomarkers: Future Directions sound theoretical constructs, rigorous demonstrated across a wide variety Proposed biomarkers for ASD risk methodologies, and objective fi of the brain regions that support include genetic and biochemical scienti c evidence of effectiveness. language, executive function, findings in blood, urine, or brain Since the publication of the 2007 AAP social cognition, emotion tissue; placental pathology; maternal clinical reports on autism, processing, and motor tasks, autoantibody profiles; structural and a substantial published literature has especially for long-range, frontal- functional MRI patterns; examined the effectiveness of 274,276,277 48,295,297,298 posterior networks. electrophysiological test results on interventions. Legal EEG, including event-related mandates in education law in the Electrophysiologic Testing and United States, which include the Measurement of Eye Tracking potentials; responses in eye tracking; and physical parameters such as head Individuals with Disabilities Electrophysiologic research studies circumference growth trajectory. Education Improvement Act of 2004 – demonstrate differences in auditory Although none of these proposed (IDEA) (Public Law 108 446) and the processing (including language biomarkers has demonstrated No Child Left Behind Act of 2001 – processing), visual processing sufficient predictive validity for (Public Law 107 110) and its (including face processing), clinical use at this time,221,253–255,288 successor, the Every Student Succeeds – somatosensory response, the search for biomarkers is a major Act of 2015 ( Public Law 114 95), multisensory integration, research focus. Biomarker research require the use of practices supported fi attentional shifting, selective has important ethical issues,253 and by scienti cally based research (IDEA attention, recognition memory, and concerns have appropriately been and the No Child Left Behind Act of neural connectivity in people with raised regarding premature 2001) or evidence-based practices 278–281 ASD. Continuous measures translation of research data into (Every Student Succeeds Act of 2015) of resting-state and task-related commercially available tests (https://www.ed.gov/). Early quantitative EEG are used to marketed to patients and intervention services under part C of calculate and describe spectral families.221,253,289,290 However, the IDEA provide for assessment and power, complexity, and coherence. capabilities to screen large numbers intervention for children younger Although promising, the clinical of bioactive compounds, examine the than 3 years with developmental utility of these measures as entire genome, and simultaneously delays, including ASD. biomarkers requires additional analyze large data sets have 279 study. Eye tracking has been accelerated research into the Interventions for children with ASD used to determine if infants who neurobiology of ASD and may result are provided through educational are younger siblings of children in the identification of valid practices, developmental therapies, with ASD and, therefore, biomarkers.221,255,291 and behavioral interventions. at increased risk for ASD exhibit Treatment strategies may vary by the differences in fixation on faces.282-284 age and strengths and weaknesses of Preliminary evidence suggests SECTION 5: INTERVENTIONS the child. For example, intervention that infants later diagnosed with The goals of treatment of children for a toddler with a recent diagnosis ASD exhibit a decline in gaze with ASD are to (1) minimize core of ASD may include behavioral and fixation from age 2 to age 6 deficits (social communication and developmental approaches months.285 interaction and restricted or (individually or in the context of

Downloaded from www.aappublications.org/news by guest on October 1, 2021 20 FROM THE AMERICAN ACADEMY OF PEDIATRICS comprehensive approach) and, as he Wong et al295 described 2 categories promoted. These interventions are or she progresses, involvement in of evidence-based interventions, the provided in a structured setting by an a specialized or typical preschool comprehensive treatment model adult, in naturalistic environments program. For older children, (CTM) and focused interventions. with peers, or as a component of intervention is more likely to occur in These interventions may be provided a more comprehensive approach.295 educational settings, with integration in different settings (eg, the home, Focused interventions may be of behavioral and developmental classroom, naturalistic environment, effective for promoting skill therapies to promote skill or community), by different providers development and development. In addition to variation (eg, developmental specialist, communication.295,297,304,305 by age of the child, interventions behavioral therapist, educator, or Pediatricians may be asked to advise differ in theoretical approach and trained parent), individually or in families on therapy choices or write scope (eg, focused and targeted or group settings, and by using a set prescriptions for therapies.306 It is comprehensive), settings and/or curriculum or guide. helpful for clinicians to have an modality of delivery (eg, individual understanding of intervention versus group or classroom, delivered The CTM uses a central conceptual framework to address a broad array terminology and of the evidence base by a professional versus a trained so they can effectively communicate parent, and school versus home of symptoms and is designed to address specific skill(s) or the rationale for medically indicated setting), and targets of treatment recommendations with intervention.48,297 Interventions may symptom(s). A CTM should be replicable, intense, and designed to families, educators, therapists, and be provided through public and/or other service providers as well as not-for-profit agencies, schools, and address multiple therapeutic goals over a period of time. Provision of with insurance companies, health early intervention services, and some care administrators, funding agencies, 299 services may occur in individual may be paid for through insurance. and policy makers.295 Families should be involved in the instruction or class settings selection of intervention approaches (specialized or inclusive), should This report describes various types of and remain an involved participant in include parents, and may involve interventions provided for children technology-assisted intervention.303 subsequent educational and and youth with ASD. Additional research is needed to evaluate the therapeutic decisions. There is Applied behavior analysis (ABA), effectiveness of current approaches regional variation in the availability of developmental approaches, and/or and develop interventions that various types of therapy and naturalistic approaches may be used address core deficits of ASD. At the providers that sometimes results in in CTMs.303 Examples of CTMs time of diagnosis, parents of young long waits for service, less-than- include early intensive behavioral preschool children may ask their desired intensity, or inability to intervention, Treatment and provider to help them decide what obtain a desired intervention Education of Autistic and Related type of intervention they should elect. altogether. By law, students with ASD Communication-Handicapped Two common theoretical approaches should receive an appropriate Children (TEACCH), and the Early to intervention for symptoms of ASD educational program, although it may Start Denver Model (ESDM).295,303 not include all of the components are ABA and developmental 296–298,307 desired by the family. Advocacy is Focused intervention practices are models. Although these often necessary to obtain desired designed to address a single or approaches have important fi services through schools or through limited range of skills, such as distinctions, they also have signi cant mechanisms paid for by insurance. It increasing social communication or overlap, and interventions is noted that many of the learning a specific task, and may be increasingly are incorporating aspects interventions in common use do not delivered over a short period of of both. There is considerable have a strong evidence base. Some time.295,297,303 Focused intervention regional variation in the availability of types of intervention may not be paid practices may be behavioral, various interventions. Table 9 for by insurance. developmental, and/or educational. describes common characteristics of Focused interventions may be empirically supported 296,297,308,309 Systematic reviews of the evidence grounded in principles of ABA, in interventions. fi base for treatment have been which speci c skills are taught in Approaches to Intervention completed on early intensive a stepwise progression by using intervention,44,300 medical principles of reinforcement or ABA treatments,301 behavioral developmental theory, in which the Most evidence-based treatment interventions,294,298 and evidence- emerging skills inherent in models are based on principles of based practice guidelines.292,302 neurobehavioral maturation are ABA. ABA has been defined as “the

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 21 TABLE 9 Characteristics of Effective Interventions Features of Practice Common Characteristics of Empirically Supported Interventions Assessment and goals Systematically assess skills Include input of family (shared decision-making) Select individualized measurable goals and instructional procedures on the basis of objective assessment of each child Use assessment-based, empirically supported instructional methods to build, generalize, and maintain skills and reduce problem behaviors Instructional methods Address core symptoms in social communication and restricted and repetitive behaviors as well as skill deficits Provide a student/teacher ratio low enough to address the child’s individualized goals Interventions should be by providers who are properly trained and should maintain fidelity with the treatment approach selected Ensure that multiple providers work collaboratively Services and supports Individualize services and support Make use of the child’s interests and preferences in determining reinforcement systems Incorporate preferred activities to increase engagement in activities Environment Provide a structured learning environment that helps children anticipate transition between activities, including a predictable routine and visual activity schedules Organize workspaces to minimize distraction and promote task completion Limit access to things that may distract a student The environment should promote opportunities for the student to initiate communication and interact with peers Behavioral Implement a functional behavioral analysis to identify the reasons why challenging behaviors occur and develop a behavior management improvement plan based on this assessment (IDEA-mandated approach) Teach children more appropriate responses using the behavior improvement plan Progress Systematically measure and document the individual child’s progress Adjust instructional strategies as necessary to enable acquisition of target skills Family support Involve and educate families so they can use the behavioral strategies at home and in the community Transition planning Plan for transitions in school settings and to adulthood (eg, from home-based early intervention to preschool services, preschool to elementary school, elementary school to middle school, middle school to high school, high school to work or postsecondary education, and home to community living) Adapted from Smith T, Iadarola S. Evidence base update for autism spectrum disorder. J Clin Child Adolesc Psychol. 2015;44(6):897–922; Myers SA, Pipinos II, Johanning JM, Stergiou N. Gait variability of patients with intermittent claudication is similar before and after the onset of claudication pain. Clin Biomech (Bristol, Avon). 2011;26(7):729–734; and Myers SM. Management of autism spectrum disorders in primary care. Pediatr Ann. 2009;38(1):42–49.

process of systematically applying environments that may be child led intensive behavioral intervention, is interventions based upon the and implemented in the context of supported by a few randomized principles of learning theory to play activities or daily routines and controlled trials (RCTs) and improve socially significant behaviors activities and are altered on the basis a substantial single-subject to a meaningful degree, and to of the child’s skill development (eg, literature.297 When only RCTs are demonstrate that the interventions pivotal response training, reciprocal considered, few interventions have employed are responsible for the imitation training, and sufficient evidence to be endorsed improvement in behavior.”310 The use others).297,309,312,313 To determine either for children younger than of ABA methods to treat symptoms of what intervention is most 12 years298 or for adolescents.314 ASD suggests that behaviors exhibited appropriate, the behavioral clinician Children younger than 12 years can be altered by programmatically works with the family and child to receiving more hours per week of reinforcing skills related to determine which skills to target for ABA were found to be more likely to communication and other skill development and maintenance and achieve the individualized goals acquisition.311,312 Thus, ABA what goals are appropriate. identified in their programs.315 In treatments may target development ABA programs are typically designed retrospective studies, more intense of new skills (eg, social engagement) and supervised by professionals ABA therapy was associated with and/or minimize behaviors (eg, certified in behavior analysis. The achieving optimal developmental aggression) that may interfere with 316 majority of states at this time have outcomes. Given the heterogeneity a child’s progress. licensure for board-certified behavior of the ASD phenotype, the service analysts with provisions for payment needs of children, youth, and adults ABA interventions vary from highly by insurance. ABA may be prescribed need to be individualized by using structured adult-directed approaches or recommended by a physician or available clinical data. (eg, discrete trial training or licensed psychologist. instruction, verbal behavior In some instances, a behavioral applications, and others) to A comprehensive ABA approach for intervention is needed to address interventions in natural younger children, also known as early acute serious problem behaviors that

Downloaded from www.aappublications.org/news by guest on October 1, 2021 22 FROM THE AMERICAN ACADEMY OF PEDIATRICS must be given priority, for example, Relationship-Based model). In 1 RCT a clinical measure of social behavior because of safety issues.295 Whether comparing parent coaching using this through an early intervention a student is getting formal ABA under approach to community intervention program.327 IDEA or not, a family can request that alone (N = 112) in children ages 2 to challenging behaviors be evaluated in 5 years, parents who were taught this Combined Approaches the school setting by using behavioral approach were less directive, and Common factors in combined principles through a functional their children were rated as more developmental and behavioral behavioral assessment. The target socially responsive, although IQ and approaches include use of principles symptoms to treat may then be language scores were no different of ABA to reinforce skill building; divided into component parts that are between groups, and half of the a systematic approach with a manual addressed in a stepwise fashion (task children in the control group for training practitioners who would analysis).313,317 Once the reasons for improved in their affective ratings.323 use the intervention in a standard the behavior are understood, A similar approach is relationship fashion; individualized treatment a behavior improvement plan may be development intervention,324 and goals for the child and means of implemented. more research is needed to evaluate measuring progress; child-initiated efficacy and community use. teaching, imitation, and modeling; Developmental Relationship–Focused and adult prompting that fades over Interventions Naturalistic Developmental Behavioral time to promote independence.296 It fi Intervention for young children also Intervention may be dif cult to advise parents on fi may be derived from developmental Naturalistic developmental speci c programs in community theory, which is focused on the behavioral interventions (NDBIs) settings because the way the program ’ is conducted may differ from the relationship between the caregiver s incorporate elements of ABA and 328 level of responsiveness and the developmental principles, such as research settings. However, it is child’s development of social emphasis on developmentally based always accurate to describe the communication.296,318–320 Through learning targets and foundational common characteristics of empirically interaction with others, children learn social learning skills, with delivery of supported interventions and to communicate and regulate interventions in the context of recommend that families seek emotions and establish a foundation naturally occurring social activities interventions that incorporate these for increasingly complex thinking and within natural environments. They features (Table 9). social interaction. Therefore, use child-initiated teaching episodes, Parent-Mediated Treatment or Parent developmental models designed to naturally occurring opportunities for Management Training promote social development in learning, and turn-taking interactions children with ASD are focused on the within play routines and implement Increasing evidence reveals that relationship between the child with ABA-based approaches to address focused interventions delivered by ASD and his or her caregiver through measurable goals.296 trained parents or other caregivers can be an important part of coaching to help increase 297,329–332 responsiveness to the adult (ie, the The most extensively studied NDBI a therapeutic program. interventionist or parent or approach is the ESDM, which More RCTs have been published on prepares children to learn in parent-mediated therapies than on caregiver) through imitating, 325 expanding on, or joining into child- naturalistic environments. In other nonpharmacologic initiated play activities. This approach a multisite trial of ESDM, early age at interventions. What is sometimes may address core symptoms of entry to therapy and more hours of called parent management training is total therapy were associated with divided into 2 categories: parent ASD, such as joint attention, 326 imitation, and affective social improved outcome. Of note, the 48 support and parent-mediated engagement.296,297,321,322 children randomly assigned to ESDM interventions. Parent support or community treatment in the interventions, which are knowledge- Developmental models for original trial were studied by using focused and provide indirect benefit intervention are focused on teaching event-related potentials and spectral to the child, include care coordination adults to engage in nondirective power on EEG while viewing faces as and psychoeducation. Parent- interactive strategies to foster opposed to objects and were mediated interventions, which are interaction and development of compared with typical controls on technique-focused and provide direct communication in the context of play. these tasks. This is an early benefit to the child, may target core One such approach is known as demonstration of improvement on symptoms of ASD or other behaviors DIRFloortime (The Developmental, a neurophysiologic measure or skills and may be built on ABA Individual Differences, and associated with improvement on approaches in natural settings.331

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 23 Training sessions for caregivers may aged pupils in inclusive settings for environmental and behavioral be delivered in the home, clinic, teaching social interaction.344–346 An supports.344 Research interventions school, or other community RCT of 294 preschool-aged children may not be comparable with settings or remotely by revealed that LEAP was associated community-provided school – – telehealth.297,329 331,333 337 An RCT with improvement in socialization, programs. Future research is needed involving 86 toddlers and their cognition, language, and challenging to address how best to provide primary caregivers demonstrated that behavior and that LEAP was superior evidence-based intervention in 10 weeks of hands-on parent training to a treatment-as-usual method.345 classroom settings. in joint attention, symbolic play, TEACCH class settings are visually engagement and regulation (an NDBI) Education in the Least Restrictive organized to promote engagement was superior to a parent-only Educational Environment and learning.344 The TEACCH psychoeducational intervention for Pediatricians have an important role approach to skill acquisition includes increasing joint engagement.338 A in advocating for children and youth assessment-based curriculum parent training approach may be used with special health care needs, development and an emphasis on to promote compliance with including ASD, in the educational structure, including predictable instruction, social communication, setting. Students have a right to a free organization of activities and use of and other identified goals of the and appropriate public education. visual schedules, organization of the caregiver, such as reducing Educational programs for school-aged – physical environment to optimize maladaptive behaviors.331,339 342 children with ASD should promote learning and avoid frustration (eg, by Including parents in the intervention language, academic, adaptive, and minimizing distractions and/or process is critically social skills development and prepare sensory dysregulation), and important.43,326,343 them for postsecondary education or adaptation and organization of employment.348 Most, but not all, materials and tasks to promote Educational Interventions students with ASD will have some independence from adult directions individualization of their education Classroom-Based Models or prompts.344,347 Instruction is under the guidance of an IEP It is the expectation that school-aged organized in a predictable fashion determined by the school children will be educated in and uses visual schedules with multidisciplinary team in conjunction classroom settings with supports for promotion of independence in with the family. Others may receive a broad effect on the symptoms of activities planned into the accommodation and/or ASD and associated deficits. instruction.347 This approach is environmental modifications under Educating students with ASD in the associated with a small, but Section 504 of the Rehabilitation Act least restrictive environment typically measurable, benefit in perceptual, of 1973.349 A medical diagnosis of requires an individualized program motor, verbal, and cognitive skills in ASD alone does not automatically that is modified to meet the students with ASD, with less translate into eligibility for school- Individualized Education Program measured effect on adaptive and based services. Functional (IEP) goals set by the family, student, motor function347 and challenging impairment that affects participation and school team. Some students who behaviors. Rigorous studies of in the typical curriculum is required do not qualify for an IEP by educational interventions for to qualify for supports in the educational criteria may be students with ASD at school age and educational setting and may lead to supported with accommodations beyond are necessary to understand an IEP for the educational handicap of through a Section 504 plan or with the effectiveness of different autism. Most youth with ASD and classroom-level accommodations. models.298 average-range intelligence will likely Many students with ASD are educated A comparison of the effects of LEAP require academic intervention in inclusive classrooms with and TEACCH classrooms with those of because of coexisting learning supports. Other school-aged children standard special education classes disabilities, executive function and youth benefit from disorder- taught by teachers familiar with ASD challenges, ADHD, motor processing specific approaches. Examples of revealed that the common features of deficits, the effects of their pragmatic classroom-based models include these interventions may be language differences on reading and Learning Experiences and Alternative responsible for improvements seen in writing, and/or challenges in Programs for Preschoolers and their all students. TEACCH was associated comprehension of spoken or written Parents (LEAP) and TEACCH.344 with more reported improvement in language.350 Attention to the needs of LEAP blends principles of ABA with ASD severity for students who had the individual student must be special and general education greater cognitive delays. This finding central to the IEP process. Social skills teaching techniques for elementary- may speak to the benefit of the of students with ASD may benefit

Downloaded from www.aappublications.org/news by guest on October 1, 2021 24 FROM THE AMERICAN ACADEMY OF PEDIATRICS from students being in class and on skills support considered in their Because child-mediated interventions the playground with peers with school and perhaps in other taught separately from social typical development.351,352 However, therapeutic settings if settings have not had consistently – spending more than 75% of their indicated.351,354 356 Although families beneficial effects, interventions have time in an inclusive educational identify the need to address social been developed for implementation setting alone was not sufficient in skill developments in settings outside in the social settings that include transition-aged youth to increase of school, the success of these types of peers, such as the classroom and rates of college attendance, high interventions is variable. playground. These interventions school graduation, or functional Interventions may be divided into demonstrate improved playground 353 ratings. How to best support adult-mediated (skill building with interaction between children with students with ASD in the least the individual child), peer-mediated and without ASD and improved restricted environment requires (skill building with the child and identification as friends by typical further study. typically developing classmates), and peers.351 Peer-mediated intervention mixed approaches. Child-directed for students with ASD have revealed Social Skills Instruction social skills interventions are often improved social connectedness and Social skills deficits may present delivered individually or in small reduced social isolation and provide differently depending on language groups with other children with evidence to support the use of these abilities, developmental level, and similar needs. Therapy may be interventions in the classroom and age. Examples of social skills deficits provided in behavioral health settings playground. An evidence-based include the following: to complement the social skills approach designed for group interventions at school. • challenges with entering, administration, the Program for the Education and Enrichment of sustaining, and exiting interactions; Interventions addressing social skills Relational Skills, may improve both • difficulty attending to, may increase the child’sknowledge teacher-reported social functioning understanding, and using of the cues for social behavior and nonverbal and verbal social cues, and adolescent-reported social teach strategies for social problem- 358 such as eye contact, facial solving. A popular method uses the cognition. Fewer studies are expressions, and gestures; social narrative to help a child define available to guide programs to promote social skills development • difficulty in understanding the social context of an anticipated for adults with ASD. However, the “unwritten” social rules of the or experienced situation, put it in Program for the Education and environment; perspective, and then develop statements on how it makes the child Enrichment of Relational Skills • not understanding the perspective feelandonwhattodoinresponseto group model has been demonstrated of others; the event and feelings.357 This to improve social skills in young • 359 struggling with negotiation, coached rehearsal strategy may be adults with ASD. fl compromise, and con ict included within other programmatic resolution; and approaches. Implementation may Families should be counseled to • problems with interactive play or use a cognitive behavioral include development of social skills participation in leisure activities. intervention strategy in which the with discrete goals and interventions child identifies feelings and thoughts in the IEP or educational plan as The importance of caregiver and learns to substitute more well as to be cognizant of potential involvement in teaching social skills socially appropriate alternatives.354 opportunities to promote social to preschool-aged children needs to Video- and computer-based social interaction in the natural be emphasized for families of young skill interventions may extend access environment and in the context of children with ASD. Reinforcing social 360 to intervention once an evidence other therapies. Implementing interaction is central to the success of base is established. A systematic IEP goals across the day and evidence-based ABA, developmental, review of RCTs of social skills generalizing specific skills to and NDBI approaches.296,354 Teaching training for children aged 6 to promote conversation and nonverbal and coaching social interaction 21 years revealed that interventions communication, such as providing involves both behavioral therapy and improved social competence and eye contact, directing facial speech and language therapy friendship quality but did not result expressions, and using appropriate approaches. in differences in emotional gestures, is important, independent School-aged children and adolescents recognition and social of age, and should involve both with ASD, including those with typical communication. Transfer of skills to the caregivers and professionals. academic skills, should have social other settings was inconsistent.356 More information about IEPs in

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 25 general can be found at http://www. onset of speech may be complicated individual is guided to wrightslaw.com/info/iep.index.htm. by general delays in development communicate.369,370 This differs from (intellectual disabilities) or coexisting AAC, in which the individual is taught Other Therapeutic Interventions speech disorders, such as childhood to communicate independently. Speech and Language Interventions apraxia of speech. Although using Future strategies to promote Delayed language is an early concern communicative spoken phrases communication are expected to for many children who are later before age 4 years is considered incorporate evolving knowledge diagnosed with ASD. The a good prognostic sign for language about sensory processing and communication symptoms included development in youth with ASD, connectivity of brain functions in in the DSM-5 criteria for ASD reflect emergence of phrase speech may people with ASD. fi occur to at least age 10 years, core de cits in social communication Children and youth with ASD often especially in children with preserved and interaction, such as failure of have deficits in pragmatic language nonverbal skills and evidence of back-and-forth communication, that can affect social interaction with fi social engagement.364 de cits in nonverbal communication adults and peers and academic (such as eye gaze and use of gesture), When children do not spontaneously performance as more complex fi dif culty adjusting behavior to suit speak, augmentative and alternative language becomes required for the social context, and restricted and communication (AAC) may be reading comprehension and analysis repetitive behaviors leading to introduced. Examples of AAC of information. In addition, literal perseverative vocalization, echolalia, strategies include sign language, the interpretation of language and and preoccupation with restricted Picture Exchange Communication difficulty in understanding the intent topics of interest. All children with System, and speech-generating of other people leads to behavioral ASD should have documentation of devices.365,366 The use of AAC may challenges in some people with ASD fi speci c coexisting speech and help promote social interaction and and affects success in school, leisure language diagnoses so that understanding of the purpose of activities, and employment. School- appropriate intervention might be communication and does not delay aged students with spoken language provided. onset of speech. Indeed, it may should have their pragmatic language Speech-language therapy is the most enhance emergence of spoken words assessed as part of their school- commonly identified intervention by pairing nonverbal and verbal related reevaluations, with provided for children with ASD.361 communication. consideration of pragmatic language testing if academic problems and The strategies used by speech- The Picture Exchange Communication inattention are noted in the language pathologists to reinforce System is used to build classroom. Interventions may include sound repetition and word use in communication through picture individual and group approaches that children with typical development are identification and exchange as include teaching and practicing often initially used with young communication. With training, conversation. The pediatrician may children with ASD. Such strategies pictures can be sequenced to build on refer the child for private speech- include reinforcement of speech communicaiton.367 Picture strips that language therapy if he or she is not sounds and communicative acts, sequentially explain medical eligible for services in school or if imitation of the sounds the child procedures, for example, take increased intensity of intervention is makes, and exaggerated imitation and advantage of this approach. Use of 362 desired. Although the impact of slowed tempo. The literature speech-generating devices and speech-language therapy on offers the most support for programs that use AAC on digital structural language improvement has approaches with preverbal children tablets also are increasing. These not been adequately studied, with ASD in which adult prompts are devices provide acoustic feedback to improvement in ratings of used for communication, prompt the child, and touch-screen tablets are conversational competence by fading, and reinforcement of their relatively inexpensive and portable. parents and of classroom learning own attempts at communication. Medical providers are often asked to skills by teachers supports the Intervention in naturalistic settings justify the purchase of touch-screen recommendation for social skills and and involvement of caregivers may tablets or AAC devices. It cannot be social language interventions for help reinforce the initiation of assumed that the use of AAC alone students with ASD.371 communication and functional use of will lead to functional oral sounds, gestures, and words. communication without a therapeutic A significant minority (up to 30%) of plan.368 Current scientific evidence Motor Therapies individuals with ASD ultimately do does not support the use of facilitated Children with ASD may have low not acquire verbal speech.363 Delayed communication in which a nonverbal muscle tone or a developmental

Downloaded from www.aappublications.org/news by guest on October 1, 2021 26 FROM THE AMERICAN ACADEMY OF PEDIATRICS coordination disorder. Although the Sensory Therapies occupational therapist, to work with ages for sitting and walking do not In 2012, the AAP published a clinical a child by using play and sensory differ between children with ASD report, “Sensory Integration activities to reinforce adaptive and children with typical Therapies for Children With responses. The therapist explains the fi ’ development, both ne and gross Developmental and Behavioral child s behaviors and responses to motor skills may be delayed in ” caregivers in sensory terms and 372 Disorders, providing important preschool-aged children with ASD. background information and provides them with strategies to help Attention to position in space in recommendations for the caregivers accommodate the ’ children with a coexisting diagnosis pediatricians.376 Since that child s sensory needs to decrease of ADHD may further complicate functional impairment and tolerate 373 publication, the DSM-5 criteria now delays in coordination. includes sensory symptoms in the environmental triggers. Advocates of Occupational therapy services may diagnostic criteria for ASD in these interventions claim that fi be indicated to promote ne motor recognition of the fact that individuals dysfunction in integration of sensory fi and adaptive skills, including self- with ASD have sensory challenges input contributes to inef ciencies in care, toy use, and handwriting. that may be related to repetitive and learning and to behavioral challenges Almost two-thirds of preschool-aged other challenging behaviors.377 and that therapeutic approaches to children with ASD are reported to Indeed, sensory symptoms exhibited sensory integration need to be receive occupational therapy by young children, such as food considered separately from focal 374 379 services. selectivity, covering their ears for sensory-based treatments. certain sounds, and visual scrutiny of Although sensory-based therapies are Similarly, some children with ASD aspects of objects, may be among the among the most commonly requested may have gross motor impairment 361 earliest differences families identify therapies by caregivers, the on formal testing that may benefit in their children’s development. evidence supporting their general use from therapeutic intervention 378,379 Sensory goals may be included in remains currently limited. As focused on building strength, fi treatment objectives for students with any other intervention, speci c coordination, motor planning, or with ASD. Adult-directed approaches goals for sensory-based therapies skill acquisition to promote safer fi provided through sensory-based should be identi ed, and outcomes mobility or play. Toe walking is interventions may be included in the should be monitored so that the common among children with ASD context of motor and behavioral utility for any given child can be as well as in other developmental 376 therapies and in educational settings. documented. disorders in early childhood. The Despite the increasing scientific etiology of toe walking in ASD is Medical Management of understanding of the neurobiological unclear, although sensory aversion Co-occurring Conditions basis for sensory symptoms in and habit or perseveration have Co-occurring medical and other individuals with ASD, empirical been proposed. Common interventions in common practice conditions, such as seizures, sleep interventions for toe walking may have modest evidence to support disorders, gastrointestinal (GI) include passive stretching, orthotics, 378 their general use at this time. disorders, feeding disorders, obesity, and casting. Impairment in gross Commonly used sensory-based catatonia, and others, have fi motor function may affect the interventions, including brushing of a signi cant effect on the health and quality of life for children and youth capacity of a child with ASD to the skin, proprioceptive stimulation with ASD and their families.380,381 In participate in leisure activities with by using weighted vests, or this section, the co-existing conditions the family or with peers and may kinesthetic stimulation (such as impair participation in sports or swinging or use of specialized seating, commonly observed in children and interactive play beyond the effect of such as a therapy ball, to modulate youth with ASD are described, and their social skills alone. Impaired level of arousal), are not yet anticipatory guidance and motor skills may further decrease supported in the peer-reviewed management strategies that primary opportunities for social skills literature. care providers may consider are development and active learning and provided.380 may be a risk factor for overweight Proponents of sensory integration and obesity.375 For motor therapies to therapies distinguish them from Seizures be provided in the educational interventions with sensory modalities There is both an increased risk for setting, a significant delay for age that because of the active engagement ASD among children and youth with affects function in school must be with the child in skill building or epilepsy and an increased risk for identified on a valid assessment desensitization. This type of therapy seizures in those with ASD. The measure. requires a trained clinician, often an pooled risk for ASD among children

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 27 with epilepsy is 6.3%, with almost were later diagnosed with ASD.388 Feeding Disorders 5 times as many in samples with the Because of language delays and Up to three-quarters of children with highest rates of co-occurring atypical sensory perception or report 173,382,383 ASD have problems related to eating, intellectual disabilities. The of pain, individuals with ASD may be including food selectivity based on fi rate of seizures among people with less likely to report speci cGI texture, color, or temperature; rituals ASD in community-based populations discomfort and may present with around food presentation; and has been reported to range from 7% agitation, sleep disruption, or other compulsive eating of certain to 23%, with rates as high as 46% behavioral symptoms rather than GI foods.397–399 Behavioral refusal may reported in clinically ascertained discomfort.387 Characteristics of ASD 170 also present as the child holding food samples. It has been suggested that might affect GI symptoms include in the mouth, volitional gagging, and that the risk for seizures is not resistance to change (feeding and emesis. Common related problems increased in individuals with ASD constipation), comorbid anxiety include pica (eating of nonfood items) without intellectual disability. Risk (pain, feeding, and motility and rumination (self-stimulatory 389 factors for the increased likelihood of disorders), and altered sensory emesis and reswallowing of stomach seizures in people with ASD include perception (pain, feeding, and contents). By age 16 months, children intellectual disability (as noted), constipation). At present, there is no who are later diagnosed with ASD are female sex, and lower gestational evidence of an association of ASD observed to be more selective in their 174 fi fi age. Speci c genetic disorders with celiac disease, speci c immune eating patterns than are other associated with ASD, such as tuberous dysfunction, or motility disorders (eg, toddlers.400 Problems around fl sclerosis, also may contribute to gastroesophageal re ux) in children mealtime behavior and food choice seizure risk in early childhood. Onset with ASD. often persist into adolescence. The is bimodally distributed, with most frequency of feeding challenges in fi rst seizures occurring in early It would be expected that these children and youth with ASD may childhood and in adolescence; 20% of disorders would occur at least as relate to the core symptoms of first seizures occur in adults with frequently among individuals with 170 restrictive and repetitive behavior ASD. Children with ASD and ASD as among individuals in the and differences in sensory perception seizures tend to have more behavioral general population, and they should related to smell, taste, and texture.401 challenges, independent of cognitive be considered when the child has 382 skills. Screening EEGs are not a history of GI symptoms or a change Children with developmental delays 390,391 recommended for patients who are in behavior. Ongoing research is may also have delayed oral motor asymptomatic. An overnight EEG focused on whether differences are skill development and may should be considered when the present in immunologic function, demonstrate food refusal of textures clinical history suggests seizures and motility, or the microbiome in that they cannot physically chew or 392–394 atypical regression. Response to individuals with ASD. swallow. Discomfort can lead to food conventional antiepileptic drug refusal, so initial evaluation should therapy varies greatly, with some Selective eating is common in include consideration of 386 reports suggesting an increased risk children with ASD. A limited diet gastroesophageal reflux, dental pain, fl for treatment-resistant epilepsy in may in uence GI symptoms, such as food allergies, lactose intolerance, and 395 individuals with early onset of constipation, and alter the significant constipation.387 If oral- seizures and delayed global intestinal microbiota. GI disorders motor concerns are observed, speech 384 development. should be considered in patients with or occupational therapy assessment is ASD if they present with typical GI indicated. GI Symptoms symptoms or with agitation, food GI symptoms, such as abdominal pain, refusal, or sleep disturbance.387,396 Because feeding problems are so constipation, diarrhea, The indicated GI workup will depend common among children with ASD, gastroesophageal reflux, and feeding on the specific symptoms. Children a dietary history should be obtained problems, are more commonly with ASD should be offered the same at health supervision visits. reported in children and adolescents approaches to treatment of GI Physiologic needs for macronutrients with ASD than in those with disorders as other children. and micronutrients are the same for developmental delay or typical Modifications of conventional children with ASD as for other development.385–387 A large interventions to accommodate for children. As with other children in the prospective cohort study revealed symptoms of ASD might include United States, insufficient intake of differences as early as 6 to 18 months consistent behaviorally informed fiber, vitamin D, and calcium are of age in stooling patterns and approaches for constipation and common.402 Rare cases of severe feeding behaviors in children who encopresis. nutritional deficiencies, such as

Downloaded from www.aappublications.org/news by guest on October 1, 2021 28 FROM THE AMERICAN ACADEMY OF PEDIATRICS rickets (vitamin D),403 scurvy eating patterns that may include persistence of pica in children and (vitamin C),404 and keratoconus energy-dense foods, and are more youth with ASD because of the risk (vitamin A),405 have been reported in likely to be prescribed medications, for toxic ingestions, risk for lead children with ASD with severe food such as atypical neuroleptics (or intoxication, potential for infection, aversions. If supplements are used to antipsychotic medication) and and the risk for mechanical ingestions correct for poor vitamin D or calcium anticonvulsants, that often contribute ranging from batteries to bezoars.418 intake, it is important to confirm that to excessive weight gain. Sleep Obstruction and perforation need to the dose is sufficient for the age and disorders may further predispose be considered in children with pica sex of the child.406 Food fortification them for obesity. Primary care who have acute abdominal in the United States may supply providers should monitor a child’s symptoms. Iron deficiency is adequate amounts of vitamins and age-specific BMI percentile in the associated with pica in the general minerals for some children with context of health supervision care and population.419 Laboratory monitoring selective diets, so additional address modifiable risk factors of blood lead and iron deficiency in multivitamins may not be through anticipatory guidance for children with pica is suggested in the necessary.407 Consultation with their patients with ASD. Programs context of primary care. Behavioral a registered dietitian may be helpful that address healthy weight for intervention includes reinforcing to be able to guide families regarding children and youth with typical appropriate behaviors, ensuring adult the nutritional sufficiency of their development may need to be supervision, and putting into place child’s diet. modified for successful use for environmental safeguards for patients with ASD.414 prevention. The clinician can counsel families about offering children routine meals Dental Health Sleep Problems and snacks, discouraging snacking Children with ASD commonly have Sleep disturbance is common in through the day, promoting self- unmet dental needs. Difficulty individuals with ASD and may be feeding, and using basic behavioral cooperating with hygiene and associated with exacerbation of approaches to encourage mealtime – professional care are reported problematic daytime behavior.420 427 structure and predictability with barriers for dental care. Even when Problems with initiating and minimal distraction. Children with insurance coverage is available, maintaining sleep are reported for ASD need to be offered new foods children with ASD have fewer visits 50% to 80% of children with ASD.428 multiple times to become familiar for routine care.415 There are limited Children who are later diagnosed with them. Feeding problems that data about the prevalence of caries or with ASD are reported to have had affect nutrition or family function or gingival disease in children with ASD. sleep problems by 30 months of that are specialized, such as mouth As with other children, anticipatory age.429 Sleep problems in individuals packing, rumination, severe pica, and guidance should include attention to with ASD persist; almost half of intense aversions, are likely to need dental hygiene and fluoride use, if adolescents with ASD continue to the support of professionals with appropriate, from a young age. have sleep symptoms.430 Adolescents expertise in behavior management Behavioral strategies may be helpful are more likely to have shorter sleep and/or oral-motor therapies (speech to prevent the need for dental care duration, daytime sleepiness, and or occupational therapy).408,409 Food under sedation. delayed sleep onset compared with refusal may stem from discomfort, so younger children with ASD, who are consultation with a gastroenterologist Pica more likely to have bedtime may be helpful. Gastrostomy-tube Children and youth with ASD may put resistance, parasomnias, and night- placement and nonoral feeding nonfood items in their mouths long waking. Reasons for the increased should only be considered after after the developmental period of frequency of sleep disturbances in appropriate behavioral intervention early childhood, when pica is children and youth with ASD may has failed. expected. Pica is reported in up to include differences in melatonin one-quarter of preschool-aged metabolism,431 developmental Obesity children with ASD and is documented disruption of other neurotransmitter Children and youth with ASD have to persist in individuals with systems critical to sleep, and lack of greater risk for overweight and intellectual disability.416,417 The social expectations, among other obesity than those in the general persistence of pica may be explanations. Genetic disorders, such population.410–413 People with ASD attributable to sensory differences, as Smith-Magenis syndrome, are have fewer opportunities and perseveration or obsession, and oral associated with both ASD and sleep perhaps less interest for active leisure exploration of the environment. disruption.432 Biological reasons for or organized sports, have repetitive Clinicians need to be aware of disrupted sleep that are not unique to

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 29 children with ASD may include challenges, behavioral strategies are were at risk for traffic-related injury restless leg syndrome, which may be successful when consistently and almost one-third were reported associated with low iron stores,433 implemented.440 to have had near-drowning episodes. and coexisting neurologic or Data from a national survey revealed No medication is currently approved behavioral diagnoses, such as that elopement attempts in the past by the US Food and Drug epilepsy, anxiety, ADHD, or mood year were reported by approximately Administration for the treatment of disorders. The most common cause one-third of parents whose children insomnia in children with or without of both delayed sleep onset and night had ASD with or without intellectual ASD. Any medication elected should wakings are learned behaviors. As disability.449 Wandering may persist be started at a low dose and with other children, the evaluation of into adulthood. monitored for adverse effects.427 the child with ASD with delayed Sleep onset may be aided by In the survey by Anderson et al,447 sleep onset, night wakings, and/or treatment with melatonin441,442 at parents reported that the most early-morning wakings should doses from 1 to 6 mg443 and may be common perceived reasons for include a history of comorbid maintained with long-acting elopement were enjoyment of medical conditions that might melatonin.442 Adverse effects are running, attempts to get to a desired disrupt sleep, such as uncommon but may include location (such as a park), pursuit of gastroesophageal reflux, seizures, nightmares. a-adrenergic agents (eg, an intense interest (eg, water), and asthma, allergies, eczema, or clonidine) and antihistamines (eg, escape from situations or sensory enuresis. Snoring might suggest diphenhydramine) are often events that made them anxious. obstructive sleep apnea and would prescribed to help with sleep onset or Because the risk for elopement prompt referral for additional to address night-waking in children, increases with the severity of ASD assessment. Children who play video but the literature provides little and with co-occurring intellectual games or engage in other screen time support for their use.444,445 disabilities, many of the individuals at close to bedtime have later bedtimes Disordered sleep is associated with greatest risk have limited language and may have more difficulty falling challenging daytime behaviors in and cannot tell first responders their asleep.434,435 Restless sleep and children with ASD446; addressing one names, addresses, or phone numbers night wakings would suggest a need may help with the other. if they get lost. Police may interpret for laboratory evaluation for ferritin aggression caused by fear as and other indicators of iron Wandering combative behavior. sufficiency to determine if low iron stores might be present.428 An Accidents, including drowning, are Prevention is the most important environmental history of the a major cause of morbidity and intervention for elopement. Parents household may help to determine if mortality in children and youth with participating in a large national household noise, parental work developmental disabilities, including survey of children with special health hours, or other factors may affect ASD.447,448 Children and youth with care needs reported primarily using sleep. The bedtime routine and ASD may have decreased awareness physical and electronic barriers to try response to night-waking should be of social convention and community to prevent elopement, especially in reviewed to determine the rules as well as impulsivity and children who also had intellectual behavioral approaches to consider. perseverative interests that draw disabilities.447,449 Information on them to potential dangers, such as prevention and management of Empirical support exists for the bodies of water and busy roads. wandering is available for parents effectiveness of parent education and Wandering off (also called and clinicians (http:// behavioral interventions for children elopement) places them at risk for nationalautismassociation.org/big- with ASD and sleep injury. Wandering, if present, should red-safety-box/). Consistent, – disturbances.425,436 440 Behavioral be included in the problem list as adequate adult supervision is intervention includes parents a coexisting diagnosis in patients with important in all environments: school, establishing bedtime routines and ASD. In an online study, 1218 families home, and community settings. making clear their expectation that of children with ASD were questioned Families note that increased the child sleeps in his or her own bed. about elopement.447 Nearly half of supervision needs result in increased This may be difficult to establish for children with ASD between the ages family stress. Families may need to children with ASD, who may not of 4 and 10 years had tried to elope. consider deadbolts, fencing, and appreciate the social conventions Almost half of those children were alarm systems for safety as well as around sleep time and may have missing long enough for their parents personal GPS devices and repetitive rituals and comorbid to contact the police. Of those identification bracelets or other anxiety or ADHD. Despite these children, approximately two-thirds identification. Local law enforcement

Downloaded from www.aappublications.org/news by guest on October 1, 2021 30 FROM THE AMERICAN ACADEMY OF PEDIATRICS agencies may support GPS tracking. literature base.451 Later loss of motor home and school functioning is often Alerting neighbors and local law skills in adolescence should prompt assessed as part of school testing by enforcement officials as well as evaluation by a neurologist for using parent and teacher securing pools in the neighborhood underlying reasons. Regression in questionnaires, such as the Behavior and creating a family emergency plan language or social interest is reported Assessment System for Children, are suggested. If impulsivity and in approximately one-quarter of Third Edition, Parent Rating motor hyperactivity contribute to children later diagnosed with ASD. It Scales,79,462 or the Child Behavior elopement, examining the utility of is recognized most commonly Checklist.82,463,464 medication as part of an overall plan between 18 and 24 months of age. With change in behavioral symptoms, may be considered. Similarly, Regression later in childhood physical sources of discomfort and addressing sleep issues becomes requires evaluation. behavioral intervention should be important if the child is at risk for considered.465 If behavioral wandering at night. Teaching safety Co-occurring Behavioral Health interventions are insufficient to skills and appropriate community Conditions address the challenges or are behaviors is critical to prevention. All Co-occurring behavioral symptoms unavailable at the time, medication children with ASD, no matter their include hyperactivity or inattention, might be considered (see Table 10 for level of cognitive skills, are at risk for aggression, outbursts, and self- guidance on prescribing medication). wandering.449 injurious behaviors. Although these behaviors are not core features of ADHD Motor Disorders ASD, they commonly interfere with functioning in school, at home, and in Changes in DSM-5 criteria have There is increasing appreciation that the community and contribute provided flexibility to diagnose other individuals with ASD may have substantially to the challenges faced DSM-5 disorders in addition to ASD, developmental coordination disorder by families.293,294,381,452–457 which can help guide treatment. and other neurologic problems. Tic Psychiatric conditions (such as ADHD, Approximately half of children and disorders occur with an increased anxiety, OCD, mood disorders, youth with ASD also may fulfill frequency in children with ASD.450 conduct disorders, or others) are diagnostic criteria for ADHD.459 Distinguishing complex tics from identified in 70% to 90% of children Pediatricians should keep in mind stereotyped movements may be and youth with ASD.458,459 Behavioral that some children who are later challenging. challenges have a significant effect on diagnosed with ASD may have been Catatonia was added as a possible health and quality of life for children initially identified as having ADHD.69 coexisting condition to ASD in the and adolescents with ASD and their Symptoms of ADHD may further DSM-5. Slow initiation of movement families.460 Patients with ASD, like compromise social skills function in and reported deterioration in motor other children and adolescents, children with ASD because of performance have been treated with should be regularly screened for inattention to social cues and lorazepam, electroconvulsive therapy, behavioral and/or emotional impulsivity. Standard rating scales and behavioral interventions, but the conditions, as recommended by the used to assess symptoms of ADHD therapies do not have a strong AAP.461 The effect of behavior on have not yet been validated for

TABLE 10 Considerations Surrounding Medication Use No current medication corrects core social and communication symptoms of ASD Accurate diagnosis of coexisting psychiatric conditions guide therapy Medication is used to help manage • Coexisting behavioral health disorders (eg, ADHD, mood disorders, or anxiety disorders) • Associated problem behaviors or symptoms causing significant impairment and distress o Examples include the following: aggression, self-injurious behavior, sleep disturbance, mood lability, anxiety, hyperactivity, impulsivity, inattention Medication should only be considered after • Careful accounting of when the behavior started and what seems to exacerbate it • A functional behavioral assessment should guide development of a treatment plan in the school setting o Consider whether the behavior serves as communication of distress or refusal • Consider referral to a behavior therapist outside of school to assess the reasons for the behavior, provide the family with strategies, and collaborate in care • Careful history and physical to look for medical factors that may cause or exacerbate challenging behaviors (eg, gastroesophageal reflux and acute sources of pain, such as otitis media, dental injury, fracture, and others)34,380,391,485,579 Consider medication after treatable medical conditions and behavioral factors assessed and intervention does not address the symptoms of concern Include the family and patient in shared decision making that considers their goals and values543

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 31 individuals with ASD. However, they and generalized anxiety disorder as if anxiety is exacerbated by are useful in determining the clinical well as unspecified anxiety disorder. uncertainty or associated with impact of symptoms for an individual As many as 40% to 66% of school- sensory under- and overreactivity.377 patient and in monitoring treatment. aged children and adults with ASD Nonpharmacologic approaches, such It is important, however, to consider are reported to also have anxiety as neurofeedback and digitally the differential diagnosis of disorders.458,459 Anxiety disorders delivered approaches to self- inattention and hyperactivity in the are most commonly identified in regulation, are being evaluated for context of the language impairment children with ASD and typical their therapeutic potential. and perseverative focus that often cognitive and language abilities.468,469 Medications used for anxiety in the accompanies ASD. Children with Symptoms may be present in early general population may be delayed language may appear more childhood and manifest as behavioral considered as part of an overall inattentive. If they are expected to challenges, such as overreactivity. treatment plan for children and youth perform activities (including Biological predisposition to both ASD with ASD (see Table 11 for schoolwork) that they are not able to and anxiety may be attributable to psychopharmacotherapy of children understand or accomplish, a child common genetic factors and/or with ASD and anxiety). with ASD may engage in behaviors to altered neurophysiologic responses to escape, which can be interpreted as stress.470 Mood Disorders inattention and hyperactivity. Patients Depressive disorders are more Core symptoms of ASD decrease the with ASD may be focused on their common among children and adults ability of individuals with ASD to perseverative interests and may be with ASD than in the general predict the actions or interpret the internally distracted, as opposed to population. Reported rates of beliefs of others, which may lead to distracted by the environment. coexisting depression in adults and a constant state of heightened worry. Evaluation of the symptom of children are highly variable, ranging Repetitive behaviors may, in part, inattention or impulsivity includes from 12% to 33%.458,476,477 serve to instill predictability, so assessing language and educational Symptoms of depression are more anxiety may lead to increased abilities. Appropriate educational likely to lead to dual mental health stereotyped behaviors or modifications and use of language for and developmental disability perseverative thoughts. Evaluation of instruction that the student can diagnoses in adolescents and adults anxiety requires consideration of the understand are critical for successful with ASD than in children. The language demands of the intervention. Behavioral strategies coexistence of mood disorders and environment, academic expectations, should address reinforcement of on- ASD may be associated with genetic social demands, and underlying fears task behaviors, breaking down tasks and neurobiological factors as well as or phobias. Youth with ASD may lack into units that can be completed environmental factors related to sufficient language or insight to successfully, breaks for activity (often chronic stress and difficulty with describe their symptoms. Getting included in sensory activities), and understanding social situations. Both information from multiple sources adult supervision appropriate for the elevated and depressed mood may and looking at the behavioral demands. The same medications that present as behavioral symptoms in manifestations related to context will are used for symptoms of ADHD in youth with ASD. Changes in affect, help to correctly identify anxiety in children without ASD are used in participation, sleep habits, and eating patients with ASD.471 similar doses for children with may be symptoms of an underlying ASD.466 Routine monitoring is Strong evidence from RCTs supports mood disorder. Attempted suicide is important because children with ASD the use of cognitive behavioral reported to occur more frequently in may be at greater risk for adverse therapy for anxiety symptoms in people with ASD than in the general effects467 (Table 11). The evaluation school-aged children with ASD, population. Risk factors include peer of a child for a possible co-occurring especially those with typical-range victimization, behavioral problems, diagnosis of ADHD also should intelligence.295,298,472–475 Anxiety minority race or ethnicity, male sex, include consideration of a co- may be associated with reported GI lower socioeconomic status, and occurring diagnosis of anxiety.464,466 and sensory symptoms.389 Some lower level of education.478 The AAP individuals find that sensory recommends screening for Anxiety Disorders redirection or sensory activities used depression in patients older than The DSM-5 classification system in the context of a behavioral 12 years. Until ASD-specific measures separates anxiety disorders into program are helpful to diminish are developed, the same approaches separation anxiety disorder, selective feelings of anxiety. Other individuals used for all other adolescents at mutism, specific phobia, social may find symptom relief with the increased risk for depression should phobia, panic disorder, agoraphobia, introduction of routine and structure be considered.479

Downloaded from www.aappublications.org/news by guest on October 1, 2021 32 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 11 Psychotropic Medication Options for Common Target Symptoms Target Symptoms Medication Class (Examples) Comments Hyperactivity Psychostimulants (methylphenidate, dexmethylphenidate, With other coexisting symptoms, medication may not appear Impulsivity mixed amphetamine salts, lisdexamfetamine, as effective Inattention dextroamphetamine)466,580–587 May be more sensitive to adverse effects Distractibility SNRIs (atomoxetine)588–590 Steps: a-2 adrenergic agonists (clonidine, guanfacine)591–594 • Behavioral approaches implemented Atypical (second generation) antipsychotics (aripiprazole, • Problems persist, trial of medication management risperidone)595–598 • Start with a low-dose stimulant (eg, methylphenidate or mixed dextroamphetamine salts) and increase as needed and tolerated May be most effective in children without comorbid intellectual disability Targets symptoms of impulsivity and hyperactivity • If there are adverse effects or if not effective: Consider atomoxetine, especially if also with social anxiety Consider a-2 agonists (eg, short- or long-acting guanfacine, clonidine) Other medications (less evidence): atypical antipsychotic medications may decrease hyperactivity; their primary use is for irritability and aggression Adverse effects: Psychostimulants: appetite suppression and insomnia; also irritability, depressive symptoms, and social withdrawal; it does not appear to worsen repetitive behavior or oppositional behavior Guanfacine, clonidine: drowsiness, fatigue and irritability; may also include appetite suppression, nausea, sleep disturbance, and decreased blood pressure and heart rate; rebound if not weaned Irritability and severe disruptive Atypical (second generation) antipsychotics (aripiprazole, Medication most effective if combined with behavioral behavior risperidone)595–608 strategies addressing identified environmental causes for • Vocal and motoric outbursts of the behavior and developing more appropriate responses anger, frustration, and distress for the child • Acts of aggression, self-injury, DB/PCs strong support for 2 second-generation atypical property destruction antipsychotic medications (risperidone and aripiprazole) • Behaviors referred to by for reducing irritability, stereotyped or repetitive caregivers as “agitation,” movements, self-injury, and hyperactivity “tantrums,”“meltdowns,” or • Risperidone and aripiprazole are currently the only “rages” medications with FDA-approved labeling specificto irritability in ASD Adverse effects and monitoring: • Common adverse effects include wt gain and dyslipidemia • Monitoring: periodic assessment for extrapyramidal symptoms; measurement of wt, height, and BMI; and laboratory monitoring of glucose and lipid levels • Metformin might be a useful treatment to help control wt gain.609 Other agents in this class, such as olanzapine and quetiapine, may have utility on the basis of their adverse effect profiles but do not have current FDA package insert indication for use in children with ASD a-2 adrenergic agonists (clonidine, guanfacine)591,610 Small studies documenting beneficial effects on irritability; need larger trials; may have better adverse effect profiles than atypical antipsychotics SSRIs (fluvoxamine, citalopram)611,612 Few studies focused on irritability and/or aggression; some reporting improvement in irritability; insufficient evidence to advise practice

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 33 TABLE 11 Continued Target Symptoms Medication Class (Examples) Comments Anticonvulsant mood stabilizers (valproic acid and Small studies suggestive of improvement in irritability; need divalproex sodium)613–618 larger studies; a limited number of placebo-controlled studies either do not support or are inconclusive regarding anticonvulsant medication as a treatment of irritability in patients with ASD Serotonin-norepinephrine reuptake inhibitor Effect size of improvement associated with venlafaxine was (venlafaxine)619 small, and irritability was not the primary outcome measured Repetitive behavior Atypical (second generation) antipsychotics (aripiprazole, Multiple DB/PCs documenting improvement in repetitive • Stereotyped motor mannerisms risperidone)595–598,620 behavior; short-term treatment • Compulsions Common adverse effects include increased appetite, fatigue, • Behavioral rigidity, insistence on drowsiness, dizziness, and drooling sameness More effective for targets of tantrums, aggression, and SIB Anticonvulsants (valproic acid and divalproex Modest improvement has been reported with divalproex sodium)613,621,622 sodium treatment May have improvement with topiramate as a second agent with risperidone Most antiseizure drugs have potential for sedation, cognitive adverse events SSRI (fluoxetine, fluvoxamine)480,509,611,612,623–627 Studies to date have not revealed effectiveness of SSRI medications for repetitive behaviors related to ASD, although they may diminish anxiety SSRIs may be effective for reducing symptoms of OCD and of anxiety when included in a comprehensive approach to treatment Need comprehensive behavioral approaches to minimize repetitive behaviors Anxiety, depression SSRIs469,628 Anxiety relief has been reported in trials of citalopram and buspirone, with fluvoxamine revealing some effect in female patients with ASD; documented utility in children and youth without ASD a-adrenergic (clonidine, guanfacine) Hyperactivation is an adverse effect of SSRIs in children and youth with ASD that may result in stopping the medication The anxiety disorders most amenable to treatment are generalized anxiety disorder, separation anxiety disorder, and social phobias Atypical (second generation) antipsychotics469,620 If a mood dysregulation disorder is identified, treatment with a mood stabilizer and/or a second-generation antipsychotic is recommended, although an SSRI may be used to treat comorbid anxiety, OCD, or depression; behavioral activation with hypomanic or manic switches has been reported First-line treatment is a program of cognitive behavioral therapy to reduce symptoms472–475 Few studies have examined the specific effects for these symptoms; clinicians may consider use of these agents; although SSRIs, SNRIs, and/or buspirone may be effective for the treatment of anxiety in children with ASD, they have not been rigorously evaluated for this purpose507,626,627,629,630 Medications to consider include sertraline, fluoxetine, citalopram, or escitalopram for symptoms of anxiety and a-2 agonists (eg, guanfacine and clonidine and b-blockers such as propranolol), which may be useful for anxiety- related physiologic symptoms and behavioral dysregulation, and a short-acting benzodiazepine, such as lorazepam, could be considered for event related anxiety DB/PC, double-blind placebo-controlled trial; FDA, US Food and Drug Administration; SIB, self-injurious behavior; SNRI, selective norepinephrine reuptake inhibitor. Adapted from Riddle MA. Pediatric Psychopharmacology for Primary Care. 1st ed. Elk Grove Village, IL: American Academy of Pediatrics; 2016.

Downloaded from www.aappublications.org/news by guest on October 1, 2021 34 FROM THE AMERICAN ACADEMY OF PEDIATRICS As in children and youth with typical performed to reduce anxiety. Unlike Table 11 for medication development, assessment of the stereotypic behaviors of ASD, management). depression and other mood disorders compulsions usually follow an must include family history, history of obsession, diminish anxiety, and are Disruptive Behavior Disorders: environmental stressors, the potential not desired by the individual or Aggression, Self-Injurious Behavior, and for toxic ingestions, and evaluation perceived as pleasurable.482 Under Tantrums for comorbid conditions. the DSM-5, OCD-related disorders Disruptive behaviors, such as Interventions for depression include include hoarding disorder, excoriation aggression, self-injury, and tantrums, supportive therapy, cognitive (skin-picking) disorder, may complicate home and community behavioral therapy, and medication, if trichotillomania, substance- or management of individuals with ASD. indicated, as coordinated medication-induced obsessive- Behavioral outbursts may occur in interventions (see Table 11 for compulsive and related disorder, and response to stressful events in the medication use). Antidepressant use obsessive-compulsive and related environment, in reaction to a medical in people with ASD has not been disorder due to another medical condition, as functional demonstrated to address aggression condition. The perseverations communication, or as a symptom and has inconsistent effect on associated with ASD may be supporting diagnosis of a co- anxiety.480 Medication qualitatively different and less occurring mental health disorder.485 recommendations are based on data sophisticated than the repetitive and Functional behavioral analysis and from the general pediatric population intrusive thoughts and actions implementation of behavioral and expert consensus.469 associated with OCD.483 Repetitive strategies can be an important initial behaviors in general may help an step in management.486 A proposed The DSM-5 criteria for bipolar illness individual with ASD regain a sense of pathway for the primary care setting include changes in activity, energy, predictability. Anxiety, phobias, and/ for management of irritability that and mood. It may be difficult to make or depression may coexist with OCD leads to disruptive behaviors in youth a diagnosis in people with ASD with in youth with ASD. with ASD is proposed by McGuire limited language. The co-occurrence et al.485 Disruptive behaviors may of bipolar illness and ASD in Behavioral approaches are serve as communication to escape individuals with typical intelligence recommended as the first line of from a demand or an undesired ranges from 6% to 21%.481 Lifetime treatment of symptoms of OCD, situation. If successful, they may diagnosis of bipolar illness in adults depending on the language and become part of a behavioral pattern. with ASD is reported to be 9%.458 cognitive level of the patient. New onset of severe behaviors Cognitive behavioral therapy, requires consideration of potential OCD-Related Disorders including exposure and response medical reasons (see Table 12). Although restricted and repetitive prevention with or without a selective Pharmacologic treatment should be behaviors are symptoms of ASD, serotonin reuptake inhibiter, has considered if no medical etiology is some individuals with ASD may also been demonstrated to be the most identified and if the behavior is have coexisting OCD. Obsessions are effective treatment for youth with associated with irritability, is not recurrent, unwanted, and persistent OCD who do not have ASD. Cognitive responsive to available behavioral thoughts, images, or urges that cause behavioral therapy may be less interventions, or is related to a co- distress. Compulsions are repetitive effective, with fewer remissions, in occurring diagnosable behavioral behaviors or thoughts with rigid rules youth who also have ASD484 (see health disorder, such as anxiety, mood

TABLE 12 Common Presentations of Self-Injurious Behavior and the Medical Conditions to Consider If New Onset Type of Self-Injury Potential Associated Conditions Potential Associated Injury Head banging Headache, toothache, sinus infection, ear infection Detached retina, abrasions, contusions Head hitting or slapping Headache, toothache, sinus infection, ear infection Fracture of bones in hand, detached retina, abrasions, contusions Eye poking Vision loss, eye pain Eye abrasion Gum or tooth digging or Dental pain, gingivitis Gum injury, tooth autoextraction, tooth fracture banging Scratching and skin Allergy, eczema, drug reaction, skin infection or Infection, scarring picking infestation (eg, fleas, scabies) Finger and toenail biting Pain Infection, nail removal, ingrown nails, paronychia or picking Kicking or stomping Restless leg syndrome, leg pain Bruises, fractures Rumination Gastroesophageal reflux, eosinophilic esophagitis Esophageal ulceration and bleeding, dental damage, nutritional compromise, precancerous lesions of esophagus

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 35 disorders, thought disorders, and/ hyperactivity, impulsivity, repetitive behavior or coexisting psychiatric or ADHD. behavior, and more challenges with diagnoses.476,497–501 Prescription of social interaction.491 There is an medication also appears to be It has been reported that between 8% association of self-injury with specific affected by demographic factors, such and 68% of children with ASD genetic disorders that are not as race, ethnicity, and demonstrate aggressive behavior, associated with ASD, such as the geography.497,498,502 Reported depending on how stringent the severe self-biting of Lesch-Nyhan polypharmacy rates range from 12% definition is.454 Aggressive behaviors syndrome. Self-injurious behavior is in a registry cohort recruited from were reported on the Child Behavior associated with genetic disorders that diagnostic clinics499 to 29% to 35% Checklist for one-quarter of children are also associated with ASD, such as in large studies of Medicaid claims attending an ASD clinic, with similar Cornelia de Lange syndrome, fragile X data.476,493 rates from 2 to 16 years of age. syndrome, and Smith-Magenis Aggression was associated with syndrome.492 In the case of Medication may be helpful to address hyperactivity, lower cognitive skills, aggressive, self-injurious, and co-occurring symptoms or disorders. sleep problems, and internalizing disruptive behaviors, the primary Clinicians should carefully weigh behaviors such as anxiety. There was fi care provider needs to assess the potential risks and bene ts before no association with sex. Researchers safety of the child and family in an prescribing medication for behavior of other studies have observed ongoing fashion. Referral to and use psychotropic medications as increased rates of physical aggression community services and for part of a comprehensive treatment in children with ASD who have lower behavioral intervention should take approach. The prescribing clinician adaptive skills and frequent repetitive place if behaviors are unsafe or if the should understand the indications behavior.487 Management of co- patient is not responding to the and contraindications, dosing, occurring sleep problems and treatment plan. potential adverse effects, drug-drug hyperactivity may be helpful in interactions, and monitoring 488 a treatment plan that includes Psychopharmacologic Approaches to requirements of the medications they behavioral intervention to address Management prescribe.6 Table 10 provides aggression and targeted The use of medications to treat guidance for principles of prescribing pharmacotherapy.487 behavioral and psychiatric symptoms medication, and Table 11 lists Self-injurious behaviors are reported in children and youth with ASD has pharmaceutical options for common in 40% to 50% of individuals with increased significantly since the behavioral-symptom clusters. Psycho- ASD at some point across the publication of the 2007 AAP clinical pharmacogenomic testing for genetic lifespan489 and may occur more reports.493,494 With a shortage of variants that increase the likelihood frequently in people with ASD who specialists, more medication of adverse effects is an emerging area also have aggressive behaviors and management, including prescription for precision medicine. Prescribers sleep problems.490 Self-injurious of atypical antipsychotic medications, should consider CYP2D6 and behaviors in individuals with ASD is taking place in the primary care CYP2C19 metabolizer status in may be repetitive and self- setting.495,496 Large national studies making medication decisions for stimulatory (such as scratching, pica, of insurance claim data from selective serotonin reuptake or rumination). Head banging and Medicaid and commercial insurers inhibitors (SSRIs), for example, despite limited data at present to self-hitting may occur as part of reveal rates of psychopharmacology 503,504 a tantrum. Like aggression and other prescription for patients with ASD to guide practice. The limited data disruptive behaviors, self-injurious be 56% to 65%.476,493,497 One or on the utility of psycho- behaviors may serve as more psychotropic medications are pharmacogenomic testing at the time communication to escape from prescribed for 1% of children with of this publication limits insurance demands or situations that the ASD younger than 3 years, for 10% to coverage for many patients. individual does not want to be in. The 11% of children aged 3 to 5 years, for Recommendations for testing are expected to rapidly change with type of self-injurious behavior may 38% to 46% of children aged 6 to 503–505 change if the intervention of 11 years, and for 64% to 67% of ongoing research. prevention or blocking is not adolescents aged 12 to associated with addressing the 17 years.498,499 Psychotropic Areas of Psychopharmacologic underlying reason for the behavior. medication use increases with Research Persistence of self-injurious increased age, lower range of As the neurobiology of ASDs are behaviors in individuals with ASD is cognitive skills and/or presence of better understood, novel associated with more limited intellectual disability, and higher psychopharmacologic agents might cognitive and language abilities, prevalence levels of challenging be developed that will better manage

Downloaded from www.aappublications.org/news by guest on October 1, 2021 36 FROM THE AMERICAN ACADEMY OF PEDIATRICS co-occurring symptoms and/or the past decade, an increasing disease.523,524 The double-blind address core deficits. Some number of interventions based on clinical trials to date have not potentially important lines of theories of causation of ASD that are, demonstrated a treatment effect with research involve medications that as yet, unproven have been examined diet.524,525 Whether a subgroup of modulate metabolism of excitatory in clinical trials. Appropriately children with GI symptoms might neurotransmitters (such as glutamate designed trials have provided benefit from these or other dietary and g-aminobutiric acid), block evidence to support some interventions requires additional acetylcholinesterase and/or nicotinic interventions, such as the dietary study. Children may be adequately acid receptors, and act as hormones supplement melatonin, and have nourished on a casein-free diet with that naturally promote social disproven others, such as secretin.518 calcium and vitamin D affiliation (such as oxytocin and Many interventions, although still supplementation. Nutritional vasopressin). Drug trials involve widely used, remain unproven. counseling is recommended if a trial newly formulated agents as well as of this diet is elected.406 It may be repurposing exiting medications used Complementary therapies are often that improvement in unrelated – for other purposes.506 509 attractive to families because they are conditions may influence behavioral purported to correct putative symptoms (eg, removal of dairy Better understanding of the biological causes of behavioral products may decrease irritability neurobiology responsible for the symptoms and may be discussed with attributable to lactose intolerance). symptoms of ASD will allow for the an optimism about outcome that is fi identi cation of targeted often not conveyed with the Dietary supplements are often given psychopharmacologic interventions. recommendation for conventional to children who are selective eaters The use of psycho- therapies. Between 28% and 74% of by their families to compensate for pharmacogenomics to identify which children with ASD are given at least 1, a limited diet.406 However, many patients might genetically be at and usually more than 1, children with ASD are given vitamins fi 519–521 greater likelihood of bene torat complementary therapy. and minerals to treat proposed increased risk for adverse effects Although use of novel therapies is biochemical abnormalities that have fi from speci c medications is an common among children with a range been proposed to be unique to ASD. 510 important area of research. of developmental disabilities, children Popular dietary supplements include with ASD who are irritable or 526,527 528 vitamin D, vitamin B12, Integrative, Complementary, and overactive or who are reported to 529 vitamin B6 with magnesium, Alternative Therapies have food allergies may be more omega-3 fatty acids,530 and likely to be given additional multivitamin preparations. The Despite the advances in 522 understanding the neurobiology of therapies. literature to date is controversial with ASD, many unanswered questions Complementary, alternative, and respect to vitamin supplementation remain about why ASD occurs and integrative therapies used for ASD as a treatment of symptoms of ASD, how best to treat it. Families often can be grouped into 3 general areas: and at this time, no conclusive consider nutritional interventions (1) natural products (including herbs, evidence exists that people with ASD and nonmedical therapies without vitamins and minerals, and require different nutrient intake than fi a scienti c evidence base to address probiotics), (2) mind and body that recommended in the Dietary the symptoms that conventional practices (including yoga, Reference Intakes (https://www.ncbi. interventions cannot rapidly address, chiropractic, massage, acupuncture, nlm.nih.gov/books/NBK225472/). or there is limited access to progressive relaxation, and guided The long-term risks of high-dose conventional services in their supplementation have not been imagery), and (3) other therapies 531 community. Primary care providers (including traditional medicine and studied. Although maternal folic are often asked about nonstandard naturopathy).517 acid status may provide biologically interventions that are used in plausible risk for ASD, there is no integrative practice or are promoted Dietary interventions used to treat evidence that supplementing with B on the Internet, in the popular press, symptoms of ASD are perceived by vitamins has therapeutic benefitat by other families, and by many families as beneficial because this time, whether a child carries celebrities.511–516 The National they are natural and without adverse common variants in the MTHFR Center for Complementary and effects. Dietary elimination of gluten- gene.532,533 Of dietary supplements in Integrative Health maintains a Web and casein-containing foods is often common use, melatonin has been site in which current information on implemented in an attempt to demonstrated to be a safe and novel therapies in popular use for ameliorate core symptoms of ASD, effective intervention for sleep in people with ASD is reviewed.517 In not on the basis of allergy or celiac children with ASD.428

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 37 Nonbiological interventions used for and national agenda for ASD has with special health care needs (such symptoms of ASD are popular and emerged and has shaped approaches as Family Voices and Parent2Parent), have also been increasingly studied. to community services as well as autism-specific national support There has been conflicting evidence research planning.543 Provision of organizations (such as Autism Speaks regarding the effect of music patient- and family-centered care and the Autism Society), and local therapy,534 yoga,535,536 massage,537 requires the clinician to educate the organizations are effective in helping and equine-assisted therapy538,539 on family about the child’s health and families obtain information and feel the symptoms of ASD in children, but engage in respectful dialogue. supported. Clinicians should evidence does not support these Resources to support the clinician in familiarize themselves with national therapies for treatment of the core talking to families about the diagnosis and local sources of support and deficits of ASD at this time. Evidence include a toolkit developed by the information so that families can be to date does not support the use of Autism Speaks Autism Treatment given Web sites or phone numbers at auditory integration training, in Network (https://www. the time of diagnosis and again as which an individual listens to altered autismspeaks.org/tool-kit/atnair-p- indicated. State-specific information sounds through headphones in an guide-providing-feedback-families- on services and Maternal and Child effort to change auditory or other affected-autism). Health Bureau–supported programs processing.540 Existing studies are are found online (https://mchb.hrsa. insufficient at this time to support Impact of ASD on the Family gov/maternal-child-health- dance therapy, drama therapy, and The impact of having a child with ASD initiatives/autism). It is important chiropractic therapy.541 on other family members and on for providers to advocate for society is considerable. Parents of instructional material in other Medical interventions used for children with ASD report more languages as well as be nonstandard purposes also are stress544,545 and increased costs546 knowledgeable of other resources in sometimes prescribed for symptoms than do parents who do not have their communities that can provide of ASD. Clinical trials do not support a child with ASD. More than half of services or support to the culturally the use of antifungal agents, families report that a parent needs to diverse groups they serve. immunotherapy, or hyperbaric cut back on work or stop working oxygen treatment, and concern for Comorbid conditions, such as because of the care needs of the safety, in addition to lack of intellectual disability and/or child.547 The largest societal costs supporting data, cautions against psychiatric disorders, add to the associated with ASD are special chelation therapy for children with impact of ASD on family functioning education, residential care, and lost ASD.516 and access to care.551 Although days of caregiver work.4 Peer support families of older children and youth As with any intervention, families for families of children with ASD is typically report fewer interactions electing a novel therapy should work associated with less parental stress, with professionals, the stress on the with their therapeutic team to less negative mood, and more positive parent related to the ASD diagnosis identify target symptoms they hope perceptions.548 Parents who persists.552 Primary care providers to address and develop a monitoring understand more about their child’s should speak with families about the system to track change. Interventions ASD can advocate for more intensive stresses associated with ASD and the should be implemented in a stepwise and appropriate services.549 Best health of other family members and fashion so that proper attribution of practice includes giving families make appropriate referrals, either for effect is possible and confounding contact information for a family supportive counseling for the factors can be identified. It is support group at the time of caregivers or agencies that can important that the medical home diagnosis. This support may be a local address behavioral and respite needs provider and family collaborate to group that provides face-to-face of the child or to address unmet select and monitor safe and effective interaction and community activities health needs in family members. interventions.542 or an online community.550 Many families may not have the time or The effect on siblings also needs to be inclination at the time of diagnosis to considered in the context of both SECTION 6: WORKING WITH FAMILIES communicate with other families anticipatory guidance and primary Families play a key role in effective affected by ASD but may find the care. Most siblings of children with treatment for children with ASD. support useful later when they are ASD do not report having a sibling Recognition that individuals who are facing the transitions of preschool, with a disability to be a negative affected and their families are adolescence, or adulthood. National experience; however, they, too, are at partners with the professionals in all support groups that address a wider risk for increased stress and aspects of planning a personal, local, community of children and youth subsequent emotional problems.553

Downloaded from www.aappublications.org/news by guest on October 1, 2021 38 FROM THE AMERICAN ACADEMY OF PEDIATRICS Siblings may have precocious time and resources for specialized youth with ASD understand their involvement in the care of the child care.555,557 Parents of children and diagnosis within the context of their with ASD, and some resent the youth with ASD would like better developmental level can help them amount of attention and resources access to specialty care and report understand their symptoms and the child with ASD requires or the greater unmet medical and behavioral participate in decision-making.562 family’s inability to participate in health care needs558 and a higher activities in which they see their financial burden for care compared Transition to Adulthood peers engaging. Proactively teaching with parents of children without Planning for children with ASD to siblings about ASD and providing ASD.559 understand and participate in their them with peer support may be Increasing family awareness and own health care should begin early in helpful (Autism Speaks Sibling tool understanding of the medical home adolescence, with adaptation for kit: http://www.autismspeaks.org/ can promote partnership of the developmental abilities. The AAP sites/default/files/a_siblings_guide_ parents and primary care provider in clinical report “Supporting the Health to_autism.pdf). Many areas have planning and coordinating the child’s Care Transition From Adolescence to groups to provide education and care and advocating for their needs. Adulthood in the Medical Home” support to siblings. It appears that National survey data reveal that provides guidance on the steps positive parental attitudes and family-centered and coordinated care necessary to address health care a supportive family setting are through a medical home results in transitions for all patients with associated with better sibling fewer unmet needs,558 including chronic conditions.563 Got Transition adjustment as well. The pediatrician dental needs.560 Organizations, such recommends 6 core elements that should monitor the well-being and as Family Voices and Family-to- need to be addressed for health care need for behavioral health supports Family Health Information Centers, transition without disruption in care, of siblings as well as parents. can provide information and support including (1) a transition policy for Medical Home as well as resources for guiding the practice, (2) tracking and families in developing care notebooks monitoring transition, (3) assessing In the AAP’s medical home model, for their child. Through their ongoing transition readiness for youth and/or primary care is envisioned as relationship, providers can help family, (4) actively planning the accessible, continuous, children understand their own details of transition, (5) transfer of comprehensive, family centered, diagnosis at their developmental care, and (6) transition coordinated, compassionate, and level. Clinicians can remind their completion.564 The pediatric health culturally sensitive for all children patients with ASD of their strengths, care provider is also in a position to and youth, including those with such as focus, memory, visual-spatial advise the family about teaching their special health care needs. Children problem-solving, and others, as well adolescent with ASD about with ASD represent a population that as their personal accomplishments in sexuality.565 Planning for wellness has had difficulty accessing building skills and mastering barriers requires considering young adult comprehensive coordinated services. to achieve goals. Recognition of opportunities for exercise and leisure The chronic care model provides the achievement of milestones, whether it activities. Planning for medical structure for clinicians to collaborate is toilet training or college graduation, transition for all aspects of health with patients and their families.554 should be acknowledged. care should start around ages 12 to Parents of children with ASD perceive 14 years. Educational transition starts care to be less comprehensive, less Shared decision-making promotes at the school level at age 14 years and well coordinated, and less family a collaborative process for planning should involve the student as much as centered than they desire and report care through dialogue among the possible. that they are less satisfied with their individual who is affected, caregivers, care compared with parents of and clinicians. It can be particularly As a child approaches legal children with other special health useful when the evidence for an adulthood, the family may need to care needs.555 Parents also perceive intervention is either controversial or consider guardianship, either full their providers as less well informed if there is not a uniformly accepted guardianship in cases in which an regarding treatments for ASD, approach.561 Shared decision-making adult child cannot make health, especially complementary, requires clarity of the question to be financial, or other decisions because alternative, and integrative therapies, answered, the options to be of cognitive impairment; limited than they would like them to be. understood, and the family context guardianship in cases in which an Pediatricians report that they lack the and beliefs to be respected. It is often individual can participate in decision- knowledge to provide this support to a process rather than a single making; or conservatorship in cases patients with ASD556 as well as the conversation. Helping children and in which the oversight extends only to

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 39 financial decision-making. Many should initiate discussions with The social services and home- and young adults with ASD will be parents regarding their plans for community-based waiver services capable of independent decision- where their child with ASD will available to families whose children making and should be prepared for progress to postsecondary school have developmental disabilities, transition to adulthood like other education and/or employment and including ASD, differ from state to teenagers. The young adult with ASD their plans for where their child will state.568 The clinician should be may be eligible for Supplemental live in adulthood early in adolescence familiar with the requirements for Security Income (SSI) benefits. SSI is so the family can plan appropriately programs in their state that might a federal program that provides funds with community agencies. lead to a Medicaid waiver (medical for the care of individuals with assistance as a secondary insurance developmental disabilities who will Families should work with their for children with special health care not be able to support themselves child’s school throughout adolescence needs), service coordination, respite independently. Because of the strict to target the skills their child will care, and other financial or behavioral guidelines regarding cognitive and need to master to be successful in supports afforded a family when adaptive delays, some adults with young adult programs, the workforce, a child has special health care needs. ASD may not be eligible for SSI even if or postsecondary education. Goals for The clinician may need to complete their disability is a barrier to increasing skills may include a form to verify the diagnosis and employment. Families may wish to academic, social, communication, needs for eligibility. Of note, some meet with a counselor who can advise leisure, and self-care goals. Families children with ASD who have typical them on financial planning, with need information to be as proactive cognitive abilities may not qualify for attention to the needs of an adult as possible in planning for health, many special education and social child with developmental disability. academic, job, and residential needs service supports. However, later on, at in young adulthood. Additional the time of transition to adulthood, if Students with disabilities who plan to research is needed to develop and they experience difficulty with continue their education need to be evaluate evidence-based and effective employment and daily-living skills, advised of the transitioning process interventions for this age group.314 they may qualify for support services. into postsecondary education. The pediatric health care provider Students with disabilities are should provide anticipatory guidance protected under IDEA (1990; to the family in the context of ongoing SECTION 7: RESEARCH AND SERVICE amended 1997 and 2004); Section health supervision and communicate NEEDS 504 of the Rehabilitation Act of 1973; with identified adult providers for More than $1.5 billion of private and the Americans with Disabilities Act smooth health care transition.567 public research funding was devoted (1990); and the ADA Amendments to ASD between 2008 and 2010.569 Act of 2008. Some colleges may The passage of the Combating Autism provide accommodations to students State Programs, Supports, and Laws Act of 2006 (Public Law 109–416) with developmental disabilities with State laws related to education, social and its reauthorization in 2014 as the proper documentation of their needs, service, and insurance for individuals Autism Collaboration, Accountability, including recent academic testing. with ASD vary significantly. Although Research, Education and Support Act College students with ASD may the federal government mandates (CARES) Act (Public Law 113–157) benefit from continued supports early intervention for children at risk continued a trend in funding to around social skills development, for developmental delay and a free address the intervention needs of medication monitoring, and and appropriate education for individuals diagnosed with ASD. mentoring on living independently.566 students aged 3 to 21 years who have Before this time, research funding Although resources are still specific educationally handicapping was largely focused on the genetics insufficient, attention is growing for conditions, the implementation of and neurobiology of the disorder. the need to provide social skills educational services varies by state However, this changed with the training for youth with ASD with and and locality. The law states that convening of the National Institutes without intellectual disabilities to services need to be appropriate, not of Health Interagency Autism enter the workforce in competitive necessarily optimal. No legal mandate Coordinating Committee in 2006. The employment as well as job skill for adult services exists, although the committee was assembled to provide development. There are insufficient agencies that provide residential guidance to the agencies funding group-home and supported services, service coordination, job autism services, and the research community–living arrangements for training, and adult day services agenda was expanded on the basis of adults with ASD to meet the demands typically are funded through the the contributions of stakeholders, in most communities. The clinician states. including families, individuals

Downloaded from www.aappublications.org/news by guest on October 1, 2021 40 FROM THE AMERICAN ACADEMY OF PEDIATRICS affected, and federal agencies. The Research in all of these areas is postsecondary work or schooling, committee’s 2009 strategic plan, critical to move forward with early residential supports, and activities updated in 2017,570 identified 7 areas diagnosis, effective treatment, and to maintain a healthy lifestyle. for research funding: (1) early evidence-based interventions at • Informed individuals and families: detection, (2) underlying biology, (3) each age. The pediatrician can educate youth genetic and environmental risk with ASD and their families about factors, (4) treatments and the evidence for interventions, PEDIATRIC RECOMMENDATIONS interventions, (5) services and refer families for possible implementation science, (6) lifespan To provide appropriate care to all participation in clinical research services and supports, and (7) children and families affected by ASD, when appropriate, refer families to epidemiological surveillance and health, education, and public health support organizations, and infrastructure.571 The committee systems need to collaborate and build prepare families to navigate recommended that multiple levels of integrated and adequately funded and transitions. inquiry be pursued simultaneously to staffed systems. • Informed pediatric providers: To inform evidence-based clinical care. • Early identification and best serve patients and families These levels include the following: treatment: Pediatric providers affected by ASD, the clinician caring • basic and translational science in should use screening and for children and youth with ASD the areas of genetics and surveillance to provide accurate should be familiar with issues fi epigenetics, neurobiology, and and early identi cation, cost- related to diagnosis, coexisting psychopharmacology to effective and timely diagnosis, medical and behavioral conditions, understand typical and atypical prompt implementation of and the impact of ASD on the family brain development and function to evidence-based interventions, and to provide a medical home for these develop ASD-specific behavioral elimination of disparities to patients. Actively addressing and pharmacologic therapies; access to care for children with capacity building to care for ASD. Clinicians should respond children and youth with ASD additional research is needed to appropriately to family or clinical requires initiatives directed at identify and understand ASD risk concerns and results of screening provider education and practice factors that might be mitigated to to avoid delays in diagnosis and quality improvement and public reduce ASD-related disability; treatment. health, educational, and social • research into the underlying • Collaboration of systems of care: programs to support families in neurobiology of sensory symptoms Children with ASD should be their journey from diagnosis to and restricted interests and provided evidence-based services service provision to transition to repetitive behaviors to inform to address social, academic, and adult care. development of targeted behavioral needs at home and interventions; school; access to appropriate • LEAD AUTHORS clinical trials to test focused pediatric and mental health care; interventions based on the Susan L. Hyman, MD, FAAP respite services; and leisure Susan E. Levy, MD, MPH, FAAP underlying biological processes activities. Scott M. Myers, MD, FAAP involved with ASD to determine if • Planning for adolescence and they are appropriate for transition to adult systems of care: community application; CONTRIBUTORS Communities should build services • Paul H. Lipkin, MD, FAAP epidemiological surveillance to to promote social skills appropriate Michelle M. Macias, MD, FAAP gather data important for planning for work and postsecondary for current and future needs, education, access to appropriate including screening, diagnosis, and medical and behavioral health EDITOR lifespan health and mental health services, job skills development, Anne B. Rodgers services; and and community leisure • health services research to provide opportunities. Pediatricians need to COUNCIL ON CHILDREN WITH DISABILITIES guidance for comprehensive, engage with families and youth to EXECUTIVE COMMITTEE, 2019–2020 accessible, and culturally plan a transition to adult medical appropriate medical, educational, and behavioral health care. The Dennis Z. Kuo, MD, MHS, FAAP, Chairperson Susan Apkon, MD, FAAP and behavioral care for children, medical home provider should Lynn F. Davidson, MD, FAAP youth, adults, and families affected support the family and youth in Kathryn A. Ellerbeck, MD, FAAP by ASD. advocating for appropriate Jessica E.A. Foster, MD, MPH, FAAP

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 41 Susan L. Hyman, MD, FAAP Marshalyn Yeargin-Allsopp, MD, FAAP – PAST SECTION ON DEVELOPMENTAL AND Garey H. Noritz, MD, FAAP Centers for Disease Control and Prevention BEHAVIORAL PEDIATRICS EXECUTIVE Mary O’Connor Leppert, MD, FAAP COMMITTEE MEMBERS Barbara S. Saunders, DO, FAAP Christopher Stille, MD, MPH, FAAP STAFF Nerissa S. Bauer, MD, MPH, FAAP Edward Goldson, MD, FAAP Larry Yin, MD, MSPH, FAAP Alexandra Kuznetsov, RD akuznetsov@ Michelle M. Macias, MD, FAAP aap.org Laura Joan McGuinn, MD, FAAP PAST COUNCIL ON CHILDREN WITH DISABILITIES EXECUTIVE COMMITTEE SECTION ON DEVELOPMENTAL AND MEMBERS BEHAVIORAL PEDIATRICS EXECUTIVE LIAISONS Timothy Brei, MD, FAAP COMMITTEE, 2018–2019 Marilyn Augustyn, MD, FAAP – Society for Beth Ellen Davis, MD, MPH, FAAP Carol C. Weitzman, MD, FAAP, Chairperson Developmental and Behavioral Pediatrics Susan E. Levy, MD, MPH, FAAP David Omer Childers Jr, MD, FAAP Beth Ellen Davis, MD, MPH, FAAP – Council Paul H. Lipkin, MD, FAAP Jack M. Levine, MD, FAAP on Children With Disabilities Scott M. Myers, MD, FAAP Myriam Peralta-Carcelen, MD, MPH, FAAP Alice Meng, MD – Section on Pediatric Kenneth Norwood Jr, MD, FAAP, Immediate Jennifer K. Poon, MD, FAAP Trainees Past Chairperson Peter J. Smith, MD, MA, FAAP Pamela C. High, MD, MS, FAAP – Former Nathan Jon Blum, MD, FAAP, Immediate Past liaison, Society for Developmental and Chairperson LIAISONS Behavioral Pediatrics John Ichiro Takayama, MD, MPH, FAAP, Cara Coleman, MPH, JD – Family Voices Website Editor Marie Mann, MD, MPH, FAAP – Maternal and Rebecca Baum, MD, FAAP, Section Member, Child Health Bureau Committee on Psychosocial Aspects of Child STAFF Edwin Simpser, MD, FAAP – Section on and Family Health Home Care Robert G. Voigt, MD, FAAP, Newsletter Editor Carolyn McCarty, PhD Peter J. Smith, MD, MA, FAAP – Section on Carolyn Bridgemohan, MD, FAAP, Program [email protected] Developmental and Behavioral Pediatrics Chairperson Linda Paul, MPH [email protected]

ABBREVIATIONS DSM-5: Diagnostic and Statistical NDBI: naturalistic developmental AAC: augmentative and alternative Manual of Mental Disorders, behavioral intervention communication Fifth Edition OCD: obsessive-compulsive AAP: American Academy of DSM-IV: Diagnostic and Statistical disorder Pediatrics Manual of Mental Disorders, PDD: pervasive developmental ABA: applied behavior analysis Fourth Edition disorder ADDM: Autism and Developmental DSM-IV-TR: Diagnostic and Statistical PDD-NOS: pervasive developmental Disabilities Monitoring Manual of Mental disorder not otherwise fi ADHD: attention-deficit/ Disorders, Fourth Edition, speci ed hyperactivity disorder Text Revision RCT: randomized controlled trial ADI-R: Autism Diagnostic ESDM: Early Start Denver Model SCQ: Social Communication Inventory-Revised GI: gastrointestinal Questionnaire ADOS-2: Autism Diagnostic IDEA: Individuals with Disabilities SRS: Social Responsiveness Scale Observation Schedule, Education Improvement Act SSI: Supplemental Security Income Second Edition of 2004 SSRI: selective serotonin reuptake ASD: autism spectrum disorder IEP: Individualized Education inhibitor CARS-2: Childhood Autism Rating Program STAT: Screening Tool for Autism in Scale, Second Edition LEAP: Learning Experiences and Toddlers and Young Children CDC: Centers for Disease Control Alternative Programs for TEACCH: Treatment and Education and Prevention Preschoolers and their Parents of Autistic and Related fi CMA: chromosomal microarray M-CHAT: Modi ed Checklist for Communication- CNV: copy number variant Autism in Toddlers Handicapped Children fi CTM: comprehensive treatment model M-CHAT-R/F: Modi ed Checklist for USPSTF: US Preventive Services DSM: Diagnostic and Statistical Autism in Toddlers, Task Force Manual of Mental Disorders Revised with WES: whole-exome sequencing Follow-Up (Questions)

Downloaded from www.aappublications.org/news by guest on October 1, 2021 42 FROM THE AMERICAN ACADEMY OF PEDIATRICS PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2020 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: MeMix LLC is a company that makes an application (for phones). Dr Levy is on the advisory board for the application’s development. This application is being developed to assist in nutritional and dietary management of children with autism. Dr Levy has not received any money yet from this company. This application is the focus of a National Institutes of Health R21 grant, for which Dr Levy is funded for ∼2% of her salary. Once it is studied and marketed (if appropriate), Dr Levy will (possibly in the future) earn some money. Her years of relationship with the company are 2015 to the present. Dr Hyman has a relationship with Roche. Dr Hyman is the site principal investigator of a clinical trial of a novel agent being tested to promote social function in patients with autism. The University of Rochester (Dr Hyman’s institution) was 1 of .40 sites and had 2 study participants in 2018. University of Rochester will be leaving the trial in 2019 (withdrawal submitted) because of staffing, and that reimbursement for staff time does not cover the cost of participation. Funding was for the staff to complete the assessments required for the clinical trial. Dr Hyman got no personal reimbursement from the company; the funding was for staff time for recruitment and assessment and clinical research center support for the trial. COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-3448.

REFERENCES 1. American Psychiatric Association. disorder diagnosis: a critical review. J Intellect Disabil Res. 2014;58(12): Diagnostic and Statistical Manual of Autism. 2014;18(5):583–597 1121–1130 Mental Disorders (DSM-5), 5th ed. 8. Kim YS, Fombonne E, Koh YJ, Kim SJ, 13. Xu G, Strathearn L, Liu B, Bao W. Washington, DC: American Psychiatric Cheon KA, Leventhal BL. A comparison Prevalence of autism spectrum Association; 2013 of DSM-IV pervasive developmental disorder among US children and 2. Baio J, Wiggins L, Christensen DL, et al. disorder and DSM-5 autism spectrum adolescents, 2014-2016 [published Prevalence of autism spectrum disorder prevalence in an correction appears in JAMA. 2018; disorder among children aged 8 years epidemiologic sample. J Am Acad 319(5):505]. JAMA. 2018;319(1):81–82 - autism and developmental Child Adolesc Psychiatry. 2014;53(5): 14. Developmental Disabilities Monitoring – disabilities monitoring network, 11 500 508 Network Surveillance Year 2010 sites, United States, 2014. MMWR 9. Council on Children With Disabilities; Principal Investigators; Centers for – Surveill Summ. 2018;67(6):1 23 Section on Developmental Behavioral Disease Control and Prevention (CDC). 3. Leigh JP, Du J. Brief report: forecasting Pediatrics; Bright Futures Steering Prevalence of autism spectrum the economic burden of autism in Committee; Medical Home Initiatives disorder among children aged 8 years - 2015 and 2025 in the United States. for Children With Special Needs autism and developmental disabilities J Autism Dev Disord. 2015;45(12): Project Advisory Committee. monitoring network, 11 sites, United 4135–4139 Identifying infants and young children States, 2010. MMWR Surveill Summ. with developmental disorders in the 2014;63(2):1–21 4. Buescher AV, Cidav Z, Knapp M, medical home: an algorithm for 15. Christensen DL, Baio J, Van Naarden Mandell DS. Costs of autism spectrum developmental surveillance and disorders in the United Kingdom and Braun K, et al; Centers for Disease screening [published correction Control and Prevention (CDC). the United States. JAMA Pediatr. 2014; Pediatrics appears in . 2006;118(4): Prevalence and characteristics of 168(8):721–728 – 1808 1809]. Pediatrics. 2006;118(1): autism spectrum disorder among – 5. Johnson CP, Myers SM; American 405 420 children aged 8 years–autism and Academy of Pediatrics Council on 10. King M, Bearman P. Diagnostic change developmental disabilities monitoring Children With Disabilities. and the increased prevalence of network, 11 sites, United States, 2012 Identification and evaluation of autism. Int J Epidemiol. 2009;38(5): [published correction appears in children with autism spectrum 1224–1234 MMWR Morb Mortal Wkly Rep. 2016; disorders. Pediatrics. 2007;120(5): 11. Baxter AJ, Brugha TS, Erskine HE, 65(15):404]. MMWR Surveill Summ. 1183–1215 – Scheurer RW, Vos T, Scott JG. The 2016;65(3):1 23 6. Myers SM, Johnson CP; American epidemiology and global burden of 16. Sheldrick RC, Maye MP, Carter AS. Age Academy of Pediatrics Council on autism spectrum disorders. Psychol at first identification of autism Children With Disabilities. Med. 2015;45(3):601–613 spectrum disorder: an analysis of two Management of children with autism 12. Tomlinson M, Yasamy MT, Emerson E, US surveys. J Am Acad Child Adolesc spectrum disorders. Pediatrics. 2007; – Officer A, Richler D, Saxena S. Setting Psychiatry. 2017;56(4):313 320 120(5):1162–1182 global research priorities for 17. Christensen DL, Bilder DA, Zahorodny W, 7. Daniels AM, Mandell DS. Explaining developmental disabilities, including et al. Prevalence and characteristics of differences in age at autism spectrum intellectual disabilities and autism. autism spectrum disorder among 4-

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 43 year-old children in the Autism and 27. Wiggins LD, Rice CE, Barger B, et al. 37. Ozonoff S, Young GS, Landa R, et al. Developmental Disabilities Monitoring DSM-5 criteria for autism spectrum Diagnostic stability in young children at Network. J Dev Behav Pediatr. 2016; disorder maximizes diagnostic risk for autism spectrum disorder: 37(1):1–8 sensitivity and specificity in preschool a baby siblings research consortium children. Soc Psychiatry Psychiatr study. J Child Psychol Psychiatry. 2015; 18. Barbaresi WJ. The meaning of Epidemiol. 2019;54(6):693–701 56(9):988–998 “regression” in children with autism spectrum disorder: why does it matter? 28. Mazurek MO, Lu F, Macklin EA, Handen 38. Jashar DT, Brennan LA, Barton ML, Fein J Dev Behav Pediatr. 2016;37(6):506–507 BL. Factors associated with DSM-5 D. Cognitive and adaptive skills in severity level ratings for autism toddlers who meet criteria for autism 19. Bradley CC, Boan AD, Cohen AP, Charles spectrum disorder. Autism. 2019;23(2): in DSM-IV but not DSM-5. J Autism Dev JM, Carpenter LA. Reported history of 468–476 Disord. 2016;46(12):3667–3677 developmental regression and restricted, repetitive behaviors in 29. Hus V, Lord C. The autism diagnostic 39. Guthrie W, Swineford LB, Nottke C, children with autism spectrum observation schedule, module 4: Wetherby AM. Early diagnosis of autism disorders. J Dev Behav Pediatr. 2016; revised algorithm and standardized spectrum disorder: stability and 37(6):451–456 severity scores. J Autism Dev Disord. change in clinical diagnosis and 2014;44(8):1996–2012 symptom presentation. J Child Psychol 20. Tammimies K. Genetic mechanisms of Psychiatry. 2013;54(5):582–590 regression in autism spectrum 30. Shumway S, Farmer C, Thurm A, Joseph disorder. Neurosci Biobehav Rev. 2019; L, Black D, Golden C. The ADOS 40. Bennett TA, Szatmari P, Georgiades K, 102:208–220 calibrated severity score: relationship et al; Pathways in ASD Study Team. to phenotypic variables and stability Language impairment and early social 21. Huerta M, Bishop SL, Duncan A, Hus V, over time. Autism Res. 2012;5(4): competence in preschoolers with Lord C. Application of DSM-5 criteria for 267–276 autism spectrum disorders: autism spectrum disorder to three a comparison of DSM-5 profiles. samples of children with DSM-IV 31. Kanne SM, Mazurek MO, Sikora D, et al. J Autism Dev Disord. 2014;44(11): diagnoses of pervasive developmental The Autism Impact Measure (AIM): 2797–2808 disorders. Am J Psychiatry. 2012; initial development of a new tool for 169(10):1056–1064 treatment outcome measurement. 41. Anderson DK, Liang JW, Lord C. J Autism Dev Disord. 2014;44(1): Predicting young adult outcome among 22. Lord C, Petkova E, Hus V, et al. A 168–179 more and less cognitively able multisite study of the clinical diagnosis individuals with autism spectrum of different autism spectrum disorders. 32. Mandy W, Wang A, Lee I, Skuse D. disorders. J Child Psychol Psychiatry. Arch Gen Psychiatry. 2012;69(3): Evaluating social (pragmatic) 2014;55(5):485–494 306–313 communication disorder. J Child Psychol Psychiatry. 2017;58(10): 42. Wiggins LD, Baio J, Schieve L, Lee LC, 23. Mandy WP, Charman T, Skuse DH. 1166–1175 Nicholas J, Rice CE. Retention of autism Testing the construct validity of spectrum diagnoses by community proposed criteria for DSM-5 autism 33. World Health Organization. professionals: findings from the autism spectrum disorder. J Am Acad Child International classification of diseases and developmental disabilities Adolesc Psychiatry. 2012;51(1):41–50 for mortality and morbidity statistics monitoring network, 2000 and 2006. (11th Revision). Geneva, Switzerland: – 24. Mazurek MO, Lu F, Symecko H, et al. A J Dev Behav Pediatr. 2012;33(5):387 395 World Health Organization; 2018. prospective study of the concordance Available at: https://icd.who.int/ 43. Zwaigenbaum L, Bauman ML, Fein D, of DSM-IV and DSM-5 diagnostic criteria browse11/l-m/en. Accessed December et al. Early screening of autism for autism spectrum disorder. J Autism 1, 2019 spectrum disorder: recommendations Dev Disord. 2017;47(9):2783–2794 for practice and research. Pediatrics. 34. Coury D. Medical treatment of autism 2015;136(suppl 1):S41–S59 25. Maenner MJ, Rice CE, Arneson CL, et al. spectrum disorders. Curr Opin Neurol. Potential impact of DSM-5 criteria on 2010;23(2):131–136 44. Gotham K, Pickles A, Lord C. Trajectories autism spectrum disorder prevalence of autism severity in children using estimates. JAMA Psychiatry. 2014;71(3): 35. Tager-Flusberg H, Kasari C. Minimally standardized ADOS scores. Pediatrics. 292–300 verbal school-aged children with 2012;130(5). Available at: www. autism spectrum disorder: the pediatrics.org/cgi/content/full/130/5/ 26. Wiggins L, Christensen D, Van Naarden neglected end of the spectrum. Autism e1278 Braun K, Martin L, Baio J. Comparison Res. 2013;6(6):468–478 of autism spectrum disorder 45. Pugliese CE, Anthony L, Strang JF, surveillance status based on two 36. Kim SH, Macari SL, Koller J, Chawarska Dudley K, Wallace GL, Kenworthy L. different diagnostic schemes: findings K. Examining the phenotypic Increasing adaptive behavior skill from the Metropolitan Atlanta heterogeneity of early autism spectrum deficits from childhood to adolescence Developmental Disabilities Surveillance disorder: subtypes and short-term in autism spectrum disorder: role of Program, 2012. PLoS One. 2018;13(11): outcomes. J Child Psychol Psychiatry. executive function. J Autism Dev Disord. e0208079 2016;57(1):93–102 2015;45(6):1579–1587

Downloaded from www.aappublications.org/news by guest on October 1, 2021 44 FROM THE AMERICAN ACADEMY OF PEDIATRICS 46. Magiati I, Tay XW, Howlin P. Cognitive, surveys/Pages/Periodic-Survey-List-of- autism. J Clin Child Adolesc Psychol. language, social and behavioural Surveys-and-Summary-of-Findings.aspx. 2008;37(1):8–38 outcomes in adults with autism Accessed December 16, 2018 65. Zwaigenbaum L, Bryson SE, Brian J, spectrum disorders: a systematic 55. Pinto-Martin JA, Young LM, Mandell DS, et al. Stability of diagnostic assessment review of longitudinal follow-up studies Poghosyan L, Giarelli E, Levy SE. for autism spectrum disorder between in adulthood. Clin Psychol Rev. 2014; Screening strategies for autism 18 and 36 months in a high-risk cohort. 34(1):73–86 spectrum disorders in pediatric Autism Res. 2016;9(7):790–800 47. Renty JO, Roeyers H. Quality of life in primary care. J Dev Behav Pediatr. 66. Barger B, Rice C, Wolf R, Roach A. Better high-functioning adults with autism – 2008;29(5):345 350 together: developmental screening and spectrum disorder: the predictive value monitoring best identify children who of disability and support 56. Norris M, Lecavalier L. Screening need early intervention. Disabil Health characteristics. Autism. 2006;10(5): accuracy of level 2 autism spectrum J. 2018;11(3):420–426 511–524 disorder rating scales. A review of selected instruments. Autism. 2010; 67. Chesnut SR, Wei T, Barnard-Brak L, 48. Zwaigenbaum L, Bauman ML, Choueiri 14(4):263–284 Richman DM. A meta-analysis of the R, et al. Early intervention for children social communication questionnaire: with autism spectrum disorder under 57. Zwaigenbaum L, Bauman ML, Stone WL, screening for autism spectrum 3 years of age: recommendations for et al. Early identification of autism disorder. Autism. 2017;21(8):920–928 practice and research. Pediatrics. 2015; spectrum disorder: recommendations 136(suppl 1):S60–S81 for practice and research. Pediatrics. 68. Schwenck C, Freitag CM. Differentiation 2015;136(suppl 1):S10–S40 between attention-deficit/hyperactivity 49. Lipkin PH, Macias MM; American disorder and autism spectrum disorder Academy of Pediatrics, Council on 58. Rotholz DA, Kinsman AM, Lacy KK, by the social communication Children With Disabilities, Section on Charles J. Improving early identification questionnaire. Atten Defic Hyperact Developmental and Behavioral and intervention for children at risk for Disord. 2014;6(3):221–229 Pediatrics. Promoting optimal autism spectrum disorder. Pediatrics. development: identifying infants and 2017;139(2):e20161061 69. Miodovnik A, Harstad E, Sideridis G, Huntington N. Timing of the diagnosis of young children with developmental 59. Wetherby AM, Brosnan-Maddox S, Peace attention-deficit/hyperactivity disorder disorders through developmental V, Newton L. Validation of the Infant- and autism spectrum disorder. surveillance and screening. Pediatrics. Toddler Checklist as a broadband Pediatrics. 2015;136(4). Available at: 2020;145(1):e20193449 screener for autism spectrum www.pediatrics.org/cgi/content/full/ 50. Gabrielsen TP, Farley M, Speer L, disorders from 9 to 24 months of age. 136/4/e830 Villalobos M, Baker CN, Miller J. Autism. 2008;12(5):487–511 Identifying autism in a brief 70. Ratto AB, Kenworthy L, Yerys BE, et al. 60. Herlihy LE, Brooks B, Dumont-Mathieu T, observation. Pediatrics. 2015;135(2). What about the girls? Sex-based et al. Standardized screening facilitates Available at: www.pediatrics.org/cgi/ differences in autistic traits and timely diagnosis of autism spectrum content/full/135/2/e330 adaptive skills. J Autism Dev Disord. disorders in a diverse sample of low- 2018;48(5):1698–1711 51. Robins DL, Casagrande K, Barton M, risk toddlers. J Dev Behav Pediatr. 2014; Chen CM, Dumont-Mathieu T, Fein D. 35(2):85–92 71. Scarpa A, Reyes NM, Patriquin MA, et al. Validation of the modified checklist for The modified checklist for autism in autism in toddlers, revised with follow- 61. Zuckerman KE, Mattox K, Donelan K, toddlers: reliability in a diverse rural up (M-CHAT-R/F). Pediatrics. 2014; Batbayar O, Baghaee A, Bethell C. American sample. J Autism Dev Disord. fi 133(1):37–45 Pediatrician identi cation of Latino 2013;43(10):2269–2279 children at risk for autism spectrum 52. Centers for Disease Control and disorder. Pediatrics. 2013;132(3): 72. Burkett K, Morris E, Manning-Courtney Prevention. Screening and diagnosis of 445–453 P, Anthony J, Shambley-Ebron D. African autism spectrum disorder. Available at: American families on autism diagnosis https://www.cdc.gov/ncbddd/autism/ 62. Sheldrick RC, Perrin EC. Evidence-based and treatment: the influence of culture. screening.html. Accessed December 1, milestones for surveillance of cognitive, J Autism Dev Disord. 2015;45(10): 2019 language, and motor development. 3244–3254 Acad Pediatr. 2013;13(6):577–586 53. Autism Speaks. Learn the signs. 73. Zuckerman KE, Lindly OJ, Reyes NM, Available at: https://www.autismspeaks. 63. Siu AL, Bibbins-Domingo K, Grossman et al. Disparities in diagnosis and org/what-autism/from-first-concern-to- DC, et al; US Preventive Services Task treatment of autism in Latino and non- action/get-child-screened. Accessed Force (USPSTF). Screening for autism Latino white families. Pediatrics. 2017; December 1, 2019 spectrum disorder in young children: 139(5):e20163010 US Preventive Services Task Force 54. American Academy of Pediatrics. 74. Daniels AM, Halladay AK, Shih A, Elder recommendation statement. JAMA. Periodic survey: cross-survey results LM, Dawson G. Approaches to 2016;315(7):691–696 and findings. 2018. Available at: https:// enhancing the early detection of autism www.aap.org/en-us/professional- 64. Rogers SJ, Vismara LA. Evidence-based spectrum disorders: a systematic resources/Research/pediatrician- comprehensive treatments for early review of the literature. J Am Acad

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 45 Child Adolesc Psychiatry. 2014;53(2): 84. Lord C, Rutter M, Le Couteur A. Autism functional outcome. J Autism Dev 141–152 Diagnostic Interview-Revised: a revised Disord. 2011;41(8):1007–1018 version of a diagnostic interview for 75. Jones RM, Lord C. Diagnosing autism in 94. Liss M, Harel B, Fein D, et al. Predictors caregivers of individuals with possible neurobiological research studies. and correlates of adaptive functioning pervasive developmental disorders. Behav Brain Res. 2013;251:113–124 in children with developmental J Autism Dev Disord. 1994;24(5): disorders. J Autism Dev Disord. 2001; 76. Volkmar F, Siegel M, Woodbury-Smith M, – 659 685 31(2):219–230 King B, McCracken J, State M; American 85. Aldridge FJ, Gibbs VM, Schmidhofer K, Academy of Child and Adolescent 95. Kenworthy L, Case L, Harms MB, Martin Williams M. Investigating the clinical Psychiatry (AACAP) Committee on A, Wallace GL. Adaptive behavior ratings usefulness of the Social Quality Issues (CQI). Practice parameter correlate with symptomatology and IQ Responsiveness Scale (SRS) in for the assessment and treatment of among individuals with high- a tertiary level, autism spectrum children and adolescents with autism functioning autism spectrum disorders. disorder specific assessment clinic. spectrum disorder. J Am Acad Child J Autism Dev Disord. 2010;40(4): J Autism Dev Disord. 2012;42(2): Adolesc Psychiatry. 2014;53(2):237–257 416–423 294–300 77. Corsello C, Hus V, Pickles A, et al. 96. Dewey D, Cantell M, Crawford SG. Motor 86. Dawkins T, Meyer AT, Van Bourgondien Between a ROC and a hard place: and gestural performance in children ME. The relationship between the decision making and making decisions with autism spectrum disorders, Childhood Autism Rating Scale: Second about using the SCQ. J Child Psychol developmental coordination disorder, Edition and clinical diagnosis utilizing Psychiatry. 2007;48(9):932–940 and/or attention deficit hyperactivity the DSM-IV-TR and the DSM-5. J Autism disorder. J Int Neuropsychol Soc. 2007; 78. Constantino JN, Davis SA, Todd RD, et al. – Dev Disord. 2016;46(10):3361 3368 13(2):246–256 Validation of a brief quantitative 87. Lord C, Luyster R, Gotham K, Guthrie W. measure of autistic traits: comparison 97. Bhat AN, Galloway JC, Landa RJ. Autism Diagnostic Observation of the social responsiveness scale with Relationship between early motor delay Schedule, Second Edition (ADOS-2) the autism diagnostic interview-revised. and later communication delay in Manual (Part II): Toddler Module. J Autism Dev Disord. 2003;33(4): infants at risk for autism. Infant Behav Torrance, CA: Western Psychological 427–433 Dev. 2012;35(4):838–846 Services; 2012 79. Bradstreet LE, Juechter JI, Kamphaus 98. Provost B, Lopez BR, Heimerl S. A 88. Lord C, Rutter M, DiLavore PC, Risi S, RW, Kerns CM, Robins DL. Using the comparison of motor delays in young Gotham K, Bishop SL. Autism Diagnostic BASC-2 parent rating scales to screen children: autism spectrum disorder, Observation Schedule, Second Edition for autism spectrum disorder in developmental delay, and (ADOS-2) Manual (Part 1): Modules 1-4. toddlers and preschool-aged children. developmental concerns. J Autism Dev Torrance, CA: Western Psychological J Abnorm Child Psychol. 2017;45(2): Disord. 2007;37(2):321–328 Services; 2012 359–370 99. Beers AN, McBoyle M, Kakande E, Dar 89. Chlebowski C, Green JA, Barton ML, Fein 80. Leekam SR, Libby SJ, Wing L, Gould J, Santos RC, Kozak FK. Autism and D. Using the childhood autism rating Taylor C. The Diagnostic Interview for peripheral hearing loss: a systematic scale to diagnose autism spectrum Social and Communication Disorders: review. Int J Pediatr Otorhinolaryngol. disorders. J Autism Dev Disord. 2010; algorithms for ICD-10 childhood autism 2014;78(1):96–101 40(7):787–799 and Wing and Gould autistic spectrum 100. Bennetto L, Keith JM, Allen PD, Luebke disorder. J Child Psychol Psychiatry. 90. Reszka SS, Boyd BA, McBee M, Hume KA, AE. Children with autism spectrum 2002;43(3):327–342 Odom SL. Brief report: concurrent disorder have reduced otoacoustic validity of autism symptom severity 81. Wing L, Leekam SR, Libby SJ, Gould J, emissions at the 1 kHz mid-frequency measures. J Autism Dev Disord. 2014; – Larcombe M. The Diagnostic Interview region. Autism Res. 2017;10(2):337 345 44(2):466–470 for Social and Communication 101. Dawes P, Bishop D. Auditory processing Disorders: background, inter-rater 91. Bryson SE, Bradley EA, Thompson A, disorder in relation to developmental reliability and clinical use. J Child Wainwright A. Prevalence of autism disorders of language, communication Psychol Psychiatry. 2002;43(3):307–325 among adolescents with intellectual and attention: a review and critique. Int disabilities. Can J Psychiatry. 2008; 82. Havdahl KA, von Tetzchner S, Huerta M, J Lang Commun Disord. 2009;44(4): 53(7):449–459 – Lord C, Bishop SL. Utility of the Child 440 465 Behavior Checklist as a screener for 92. O’Hare A, Bremner L. Management of 102. Anketell PM, Saunders KJ, Gallagher autism spectrum disorder. Autism Res. developmental speech and language SM, Bailey C, Little JA. Brief report: 2016;9(1):33–42 disorders: part 1. Arch Dis Child. 2016; vision in children with autism spectrum 101(3):272–277 83. Kim SH, Lord C. New autism diagnostic disorder: what should clinicians interview-revised algorithms for 93. Kanne SM, Gerber AJ, Quirmbach LM, expect? J Autism Dev Disord. 2015;45(9): – toddlers and young preschoolers from Sparrow SS, Cicchetti DV, Saulnier CA. 3041 3047 12 to 47 months of age. J Autism Dev The role of adaptive behavior in autism 103. Rogers SJ, Hepburn S, Wehner E. Parent Disord. 2012;42(1):82–93 spectrum disorders: implications for reports of sensory symptoms in

Downloaded from www.aappublications.org/news by guest on October 1, 2021 46 FROM THE AMERICAN ACADEMY OF PEDIATRICS toddlers with autism and those with 112. Amiet C, Couchon E, Carr K, Carayol J, functioning autism spectrum disorder. other developmental disorders. Cohen D. Are there cultural differences Mutat Res. 2016;784–785:46–52 in parental interest in early diagnosis J Autism Dev Disord. 2003;33(6): 123. Fernandez BA, Scherer SW. Syndromic – and genetic risk assessment for autism 631 642 autism spectrum disorders: moving spectrum disorder? Front Pediatr. 2014; 104. McCormick C, Hepburn S, Young GS, from a clinically defined to 2:32 Rogers SJ. Sensory symptoms in a molecularly defined approach. children with autism spectrum 113. Srivastava S, Cohen JS, Vernon H, et al. Dialogues Clin Neurosci. 2017;19(4): disorder, other developmental Clinical whole exome sequencing in 353–371 disorders and typical development: child neurology practice. Ann Neurol. 124. Carter MT, Scherer SW. Autism – a longitudinal study. Autism. 2016;20(5): 2014;76(4):473 483 spectrum disorder in the genetics – 572 579 114. Iglesias A, Anyane-Yeboa K, Wynn J, et al. clinic: a review. Clin Genet. 2013;83(5): – 105. Lane AEAE, Molloy CA, Bishop SL. The usefulness of whole-exome 399 407 Classification of children with autism sequencing in routine clinical practice. 125. Persico AM, Napolioni V. Autism – spectrum disorder by sensory subtype: Genet Med. 2014;16(12):922 931 genetics. Behav Brain Res. 2013;251: a case for sensory-based phenotypes. 115. Lingen M, Albers L, Borchers M, et al. 95–112 Autism Res. 2014;7(3):322–333 Obtaining a genetic diagnosis in a child 126. Schönewolf-Greulich B, Bisgaard AM, 106. Ausderau KK, Furlong M, Sideris J, et al. with disability: impact on parental Møller RS, et al. Clinician’s guide to Sensory subtypes in children with quality of life. Clin Genet. 2016;89(2): genes associated with Rett-like – autism spectrum disorder: latent 258 266 phenotypes-investigation of a Danish profile transition analysis using 116. Riggs ER, Wain KE, Riethmaier D, et al. cohort and review of the literature. Clin a national survey of sensory features. Chromosomal microarray impacts Genet. 2019;95(2):221–230 J Child Psychol Psychiatry. 2014;55(8): clinical management. Clin Genet. 2014; 127. McBride KL, Varga EA, Pastore MT, et al. – 935 944 85(2):147–153 Confirmation study of PTEN mutations 107. Miller DT, Adam MP, Aradhya S, et al. 117. ACMG Board of Directors. Clinical utility among individuals with autism or Consensus statement: chromosomal of genetic and genomic services: developmental delays/mental microarray is a first-tier clinical a position statement of the American retardation and macrocephaly. Autism – diagnostic test for individuals with College of Medical Genetics and Res. 2010;3(3):137 141 developmental disabilities or congenital Genomics. Genet Med. 2015;17(6): 128. Battaglia A, Doccini V, Bernardini L, anomalies. Am J Hum Genet. 2010;86(5): 505–507 et al. Confirmation of chromosomal 749–764 fi 118. Reiff M, Giarelli E, Bernhardt BA, et al. microarray as a rst-tier clinical diagnostic test for individuals with 108. Manning M, Hudgins L; Professional Parents’ perceptions of the usefulness developmental delay, intellectual Practice and Guidelines Committee. of chromosomal microarray analysis disability, autism spectrum disorders Array-based technology and for children with autism spectrum and dysmorphic features. Eur recommendations for utilization in disorders. J Autism Dev Disord. 2015; J Paediatr Neurol. 2013;17(6):589–599 medical genetics practice for detection 45(10):3262–3275 of chromosomal abnormalities. Genet 119. Mandy W, Lai MC. Annual research 129. Bremer A, Giacobini M, Nordenskjöld M, – Med. 2010;12(11):742 745 review: the role of the environment in et al. Screening for copy number the developmental psychopathology of alterations in loci associated with 109. Schaefer GB, Mendelsohn NJ; autism spectrum disorders by two- Professional Practice and Guidelines autism spectrum condition. J Child Psychol Psychiatry. 2016;57(3):271–292 color multiplex ligation-dependent Committee. Clinical genetics evaluation probe amplification. Am J Med Genet B in identifying the etiology of autism 120. Myers S, Challman C; American Neuropsychiatr Genet. 2010;153B(1): spectrum disorders: 2013 guideline Academy of Pediatrics. Autism 280–285 revisions. Genet Med. 2013;15(5): Spectrum Disorders. In: Developmental 130. Eriksson MA, Liedén A, Westerlund J, 399–407 and Behavioral Pediatrics. Itasca, IL: et al. Rare copy number variants are American Academy of Pediatrics; 2018: 110. Muhle RA, Reed HE, Vo LC, et al. Clinical common in young children with autism 407–475 diagnostic genetic testing for spectrum disorder. Acta Paediatr. 2015; individuals with developmental 121. Tammimies K, Marshall CR, Walker S, 104(6):610–618 disorders. J Am Acad Child Adolesc et al. Molecular diagnostic yield of 131. Ho KS, Wassman ER, Baxter AL, et al. Psychiatry. 2017;56(11):910–913 chromosomal microarray analysis and Chromosomal microarray analysis of whole-exome sequencing in children 111. Sun F, Oristaglio J, Levy SE, et al. Genetic consecutive individuals with autism with autism spectrum disorder. JAMA. Testing for Developmental Disabilities, spectrum disorders using an ultra-high 2015;314(9):895–903 Intellectual Disability, and Autism resolution chromosomal microarray Spectrum Disorder. Rockville, MD: 122. Alvarez-Mora MI, Calvo Escalona R, Puig optimized for neurodevelopmental Agency for Healthcare Research and Navarro O, et al. Comprehensive disorders. Int J Mol Sci. 2016;17(12): Quality (US); 2015 molecular testing in patients with high E2070

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 47 132. McGrew SG, Peters BR, Crittendon JA, recurrently mutated genes in autism disorders among siblings of probands Veenstra-Vanderweele J. Diagnostic spectrum disorders. Science. 2012; with autism spectrum disorders. JAMA yield of chromosomal microarray 338(6114):1619–1622 Psychiatry. 2016;73(6):622–629 analysis in an autism primary care 143. Lee BK, McGrath JJ. Advancing parental 153. Sandin S, Lichtenstein P, Kuja-Halkola R, practice: which guidelines to age and autism: multifactorial Larsson H, Hultman CM, Reichenberg A. implement? J Autism Dev Disord. 2012; pathways. Trends Mol Med. 2015;21(2): The familial risk of autism. JAMA. 2014; – 42(8):1582 1591 118–125 311(17):1770–1777 133. Rosenfeld JA, Ballif BC, Torchia BS, et al. 144. Retterer K, Juusola J, Cho MT, et al. 154. Werling DM, Geschwind DH. Recurrence Copy number variations associated Clinical application of whole-exome rates provide evidence for sex- with autism spectrum disorders sequencing across clinical indications. differential, familial genetic liability for contribute to a spectrum of Genet Med. 2016;18(7):696–704 autism spectrum disorders in multiplex neurodevelopmental disorders. Genet families and twins. Mol Autism. 2015;6: Med. 2010;12(11):694–702 145. Yang Y, Muzny DM, Xia F, et al. Molecular findings among patients referred for 27 134. Schaefer GB, Starr L, Pickering D, Skar clinical whole-exome sequencing. JAMA. 155. Constantino JN, Zhang Y, Frazier T, G, Dehaai K, Sanger WG. Array 2014;312(18):1870–1879 Abbacchi AM, Law P. Sibling recurrence comparative genomic hybridization and the genetic epidemiology of autism. findings in a cohort referred for an 146. Srivastava S, Love-Nichols JA, Dies KA, et al; NDD Exome Scoping Review Work Am J Psychiatry. 2010;167(11): autism evaluation. J Child Neurol. 2010; 1349–1356 25(12):1498–1503 Group. Meta-analysis and multidisciplinary consensus statement: 156. Lindgren KA, Folstein SE, Tomblin JB, 135. Shen Y, Dies KA, Holm IA, et al; Autism exome sequencing is a first-tier clinical Tager-Flusberg H. Language and Consortium Clinical Genetics/DNA diagnostic test for individuals with reading abilities of children with Diagnostics Collaboration. Clinical neurodevelopmental disorders autism spectrum disorders and genetic testing for patients with autism [published online ahead of print June specific language impairment and their spectrum disorders. Pediatrics. 2010; 11, 2019]. Genet Med. 2019;21(11): first-degree relatives. Autism Res. 2009; 125(4). Available at: www.pediatrics. 2413–2421 2(1):22–38 org/cgi/content/full/125/4/e727 147. Glusman G, Severson A, Dhankani V, 157. Erbetta A, Bulgheroni S, Contarino VE, 136. Roesser J. Diagnostic yield of genetic et al. Identification of copy number et al. Low-functioning autism and testing in children diagnosed with variants in whole-genome data using nonsyndromic intellectual disability: autism spectrum disorders at reference coverage profiles. Front magnetic resonance imaging (MRI) a regional referral center. Clin Pediatr Genet. 2015;6:45 findings. J Child Neurol. 2015;30(12): (Phila). 2011;50(9):834–843 – 148. Jiang YH, Wang Y, Xiu X, Choy KW, 1658 1663 137. Tassone F, Choudhary NS, Tassone F, Pursley AN, Cheung SW. Genetic 158. Vasa RA, Ranta M, Huisman TA, Pinto PS, fi et al. Identi cation of expanded alleles diagnosis of autism spectrum Tillman RM, Mostofsky SH. Normal rates of the FMR1 gene in the CHildhood disorders: the opportunity and of neuroradiological findings in Autism Risks from Genes and challenge in the genomics era. Crit Rev children with high functioning autism. Environment (CHARGE) study. J Autism Clin Lab Sci. 2014;51(5):249–262 J Autism Dev Disord. 2012;42(8): Dev Disord. 2013;43(3):530–539 – 149. Jiang YH, Yuen RK, Jin X, et al. Detection 1662 1670 138. Iossifov I, Ronemus M, Levy D, et al. De of clinically relevant genetic variants in 159. Cooper AS, Friedlaender E, Levy SE, novo gene disruptions in children on autism spectrum disorder by whole- et al. The implications of brain MRI in the autistic spectrum. Neuron. 2012; genome sequencing. Am J Hum Genet. autism spectrum disorder. J Child – 74(2):285 299 2013;93(2):249–263 Neurol. 2016;31(14):1611–1616 ’ 139. Krumm N, O Roak BJ, Shendure J, 150. Retterer K, Scuffins J, Schmidt D, et al. 160. Monterrey JC, Philips J, Cleveland S, Eichler EE. A de novo convergence of Assessing copy number from exome et al. Incidental brain MRI findings in an autism genetics and molecular sequencing and exome array CGH autism twin study. Autism Res. 2017; neuroscience. Trends Neurosci. 2014; based on CNV spectrum in a large 10(1):113–120 37(2):95–105 clinical cohort. Genet Med. 2015;17(8): 161. Filipek PA, Accardo PJ, Ashwal S, et al. – 140. Krumm N, Turner TN, Baker C, et al. 623 629 Practice parameter: screening and Excess of rare, inherited truncating 151. Ozonoff S, Young GS, Carter A, et al. diagnosis of autism: report of the mutations in autism. Nat Genet. 2015; Recurrence risk for autism spectrum Quality Standards Subcommittee of the – 47(6):582 588 disorders: a Baby Siblings Research American Academy of Neurology and 141. Pisula E, Ziegart-Sadowska K, et al. Consortium study. Pediatrics. 2011; the Child Neurology Society. Neurology. Braoder autism phenotype in siblings of 128(3). Available at: www.pediatrics. 2000;55(4):468–479 — children with ASD a review. Int J Mol org/cgi/content/full/128/3/e488 162. Moeschler JB, Shevell M; Committee on – Sci. 2015;16(6):13217 13258 152. Jokiranta-Olkoniemi E, Cheslack-Postava Genetics. Comprehensive evaluation of 142. O’Roak BJ, Vives L, Fu W, et al. Multiplex K, Sucksdorff D, et al. Risk of the child with intellectual disability or targeted sequencing identifies psychiatric and neurodevelopmental global developmental delays.

Downloaded from www.aappublications.org/news by guest on October 1, 2021 48 FROM THE AMERICAN ACADEMY OF PEDIATRICS Pediatrics. 2014;134(3). Available at: same coin? J Child Neurol. 2015;30(14): twin studies. J Child Psychol Psychiatry. www.pediatrics.org/cgi/content/full/ 1963–1971 2016;57(5):585–595 134/3/e903 173. Jokiranta E, Sourander A, Suominen A, 184. Colvert E, Tick B, McEwen F, et al. 163. Campistol J, Díez-Juan M, Callejón L, Timonen-Soivio L, Brown AS, Sillanpää Heritability of autism spectrum et al. Inborn error metabolic screening M. Epilepsy among children and disorder in a UK population-based twin in individuals with nonsyndromic adolescents with autism spectrum sample. JAMA Psychiatry. 2015;72(5): autism spectrum disorders. Dev Med disorders: a population-based study. 415–423 – Child Neurol. 2016;58(8):842 847 J Autism Dev Disord. 2014;44(10): 185. Sandin S, Hultman CM, Kolevzon A, 2547–2557 164. Hadjixenofontos A, Schmidt MA, Gross R, MacCabe JH, Reichenberg A. Whitehead PL, et al. Evaluating 174. Woolfenden S, Sarkozy V, Ridley G, Coory Advancing maternal age is associated mitochondrial DNA variation in autism M, Williams K. A systematic review of with increasing risk for autism: spectrum disorders. Ann Hum Genet. two outcomes in autism spectrum a review and meta-analysis [published 2013;77(1):9–21 disorder - epilepsy and mortality. Dev correction appears in J Am Acad Child Med Child Neurol. 2012;54(4):306–312 Adolesc Psychiatry. 2012;51(6):660]. 165. Herman GE, Henninger N, Ratliff-Schaub J Am Acad Child Adolesc Psychiatry. K, Pastore M, Fitzgerald S, McBride KL. 175. Yasuhara A. Correlation between EEG 2012;51(5):477–486.e1 Genetic testing in autism: how much is abnormalities and symptoms of autism 186. Sandin S, Schendel D, Magnusson P, enough? Genet Med. 2007;9(5):268–274 spectrum disorder (ASD). Brain Dev. et al. Autism risk associated with 2010;32(10):791–798 166. Schiff M, Benoist JF, Aïssaoui S, et al. parental age and with increasing Should metabolic diseases be 176. Kagan-Kushnir T, Roberts SW, Snead OC difference in age between the parents. systematically screened in III. Screening electroencephalograms in Mol Psychiatry. 2016;21(5):693–700 nonsyndromic autism spectrum autism spectrum disorders: evidence- 187. Hultman CM, Sandin S, Levine SZ, disorders? [published correction based guideline. J Child Neurol. 2005; Lichtenstein P, Reichenberg A. appears in PLoS One. 2011;6(8)]. PLoS 20(3):197–206 One. 2011;6(7):e21932 Advancing paternal age and risk of 177. Tick B, Bolton P, Happé F, Rutter M, autism: new evidence from 167. Shevell M, Ashwal S, Donley D, et al; Rijsdijk F. Heritability of autism a population-based study and a meta- Quality Standards Subcommittee of the spectrum disorders: a meta-analysis of analysis of epidemiological studies. Mol American Academy of Neurology; twin studies. J Child Psychol Psychiatry. Psychiatry. 2011;16(12):1203–1212 Practice Committee of the Child 2016;57(5):585–595 188. Kong A, Frigge ML, Masson G, et al. Rate Neurology Society. Practice parameter: of de novo mutations and the evaluation of the child with global 178. Nordenbæk C, Jørgensen M, Kyvik KO, importance of father’s age to disease developmental delay: report of the Bilenberg N. A Danish population-based risk. Nature. 2012;488(7412):471–475 Quality Standards Subcommittee of the twin study on autism spectrum American Academy of Neurology and disorders. Eur Child Adolesc Psychiatry. 189. Bourgeron T. From the genetic the Practice Committee of the Child 2014;23(1):35–43 architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurology Society. Neurology. 2003; 179. Charman T, Young GS, Brian J, et al. – Neurosci. 2015;16(9):551–563 60(3):367 380 Non-ASD outcomes at 36 months in 168. Zecavati N, Spence SJ. Neurometabolic siblings at familial risk for autism 190. de la Torre-Ubieta L, Won H, Stein JL, disorders and dysfunction in autism spectrum disorder (ASD): a baby Geschwind DH. Advancing the spectrum disorders. Curr Neurol siblings research consortium (BSRC) understanding of autism disease Neurosci Rep. 2009;9(2):129–136 study. Autism Res. 2017;10(1):169–178 mechanisms through genetics. Nat Med. 2016;22(4):345–361 169. Council on Environmental Health. 180. Bailey A, Le Couteur A, Gottesman I, Prevention of childhood lead toxicity et al. Autism as a strongly genetic 191. De Rubeis S, Buxbaum JD. Genetics and [published correction appears in disorder: evidence from a British twin genomics of autism spectrum disorder: Pediatrics. 2017;140(2):e20171490]. study. Psychol Med. 1995;25(1):63–77 embracing complexity. Hum Mol Genet. 2015;24(R1):R24–R31 Pediatrics. 2016;138(1):e20161493 181. Robinson EB, Neale BM, Hyman SE. 170. El Achkar CM, Spence SJ. Clinical Genetic research in autism spectrum 192. Sanders SJ, He X, Willsey AJ, et al; characteristics of children and young disorders. Curr Opin Pediatr. 2015; Autism Sequencing Consortium. adults with co-occurring autism 27(6):685–691 Insights into autism spectrum disorder spectrum disorder and epilepsy. genomic architecture and biology from 182. Bourgeron T. Current knowledge on the Neuron Epilepsy Behav. 2015;47:183–190 71 risk loci. . 2015;87(6): genetics of autism and propositions for 1215–1233 171. Ghacibeh GA, Fields C. Interictal future research. C R Biol. 2016;339(7–8): 193. Lee H, Deignan JL, Dorrani N, et al. epileptiform activity and autism. 300–307 Clinical exome sequencing for genetic Epilepsy Behav. 2015;47:158–162 183. Tick B, Bolton P, Happé F, Rutter M, identification of rare Mendelian 172. Jeste SS, Tuchman R. Autism spectrum Rijsdijk F. Heritability of autism disorders. JAMA. 2014;312(18): disorder and epilepsy: two sides of the spectrum disorders: a meta‐analysis of 1880–1887

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 49 194. Liu X, Takumi T. Genomic and genetic Hallmayer JF. Autism genetics: psychiatry. Am J Psychiatry. 2011; aspects of autism spectrum disorder. opportunities and challenges for 168(10):1041–1049 Biochem Biophys Res Commun. 2014; clinical translation. Nat Rev Genet. 2017; 214. Kalkbrenner AE, Schmidt RJ, Penlesky 452(2):244–253 18(6):362–376 AC. Environmental chemical exposures 195. Rossi M, El-Khechen D, Black MH, 204. Waltereit R, Banaschewski T, Meyer- and autism spectrum disorders: Farwell Hagman KD, Tang S, Powis Z. Lindenberg A, Poustka L. Interaction of a review of the epidemiological Outcomes of diagnostic exome neurodevelopmental pathways and evidence. Curr Probl Pediatr Adolesc sequencing in patients with diagnosed synaptic plasticity in mental Health Care. 2014;44(10):277–318 or suspected autism spectrum retardation, autism spectrum disorder 215. Becerra TA, Wilhelm M, Olsen J, disorders. Pediatr Neurol. 2017;70: and schizophrenia: implications for Cockburn M, Ritz B. Ambient air 34–43.e2 psychiatry. World J Biol Psychiatry. pollution and autism in Los Angeles 2014;15(7):507–516 196. Brandler WM, Sebat J. From de novo county, California. Environ Health mutations to personalized therapeutic 205. Gardener H, Spiegelman D, Buka SL. Perspect. 2013;121(3):380–386 interventions in autism. Annu Rev Med. Perinatal and neonatal risk factors for 216. Volk HE, Lurmann F, Penfold B, Hertz- 2015;66:487–507 autism: a comprehensive meta-analysis. Picciotto I, McConnell R. Traffic-related Pediatrics. 2011;128(2):344–355 197. Coe BP, Girirajan S, Eichler EE. The air pollution, particulate matter, and genetic variability and commonality of 206. Christensen J, Grønborg TK, Sørensen autism. JAMA Psychiatry. 2013;70(1): neurodevelopmental disease. Am J Med MJ, et al. Prenatal valproate exposure 71–77 Genet C Semin Med Genet. 2012;160C(2): and risk of autism spectrum disorders 217. Mazina V, Gerdts J, Trinh S, et al. 118–129 and childhood autism. JAMA. 2013; 309(16):1696–1703 Epigenetics of autism-related 198. Gonzalez-Mantilla AJ, Moreno-De-Luca A, impairment: copy number variation and Ledbetter DH, Martin CL. A cross- 207. Bromley RL, Mawer G, Clayton-Smith J, maternal infection. J Dev Behav Pediatr. disorder method to identify novel Baker GA; Liverpool and Manchester 2015;36(2):61–67 candidate genes for developmental Neurodevelopment Group. Autism 218. Braunschweig D, Van de Water J. brain disorders. JAMA Psychiatry. 2016; spectrum disorders following in utero – exposure to antiepileptic drugs. Maternal autoantibodies in autism. 73(3):275 283 – Neurology. 2008;71(23):1923–1924 Arch Neurol. 2012;69(6):693 699 199. Li J, Cai T, Jiang Y, et al. Genes with de 219. Brimberg L, Sadiq A, Gregersen PK, novo mutations are shared by four 208. Dodds L, Fell DB, Shea S, Armson BA, Diamond B. Brain-reactive IgG neuropsychiatric disorders discovered Allen AC, Bryson S. The role of prenatal, correlates with autoimmunity in from NPdenovo database [published obstetric and neonatal factors in the mothers of a child with an autism correction appears in Mol Psychiatry. development of autism. J Autism Dev spectrum disorder. Mol Psychiatry. 2016;21(2):298]. Mol Psychiatry. 2016; Disord. 2011;41(7):891–902 2013;18(11):1171–1177 21(2):290–297 209. Wu S, Wu F, Ding Y, Hou J, Bi J, Zhang Z. 220. Bauman MD, Iosif AM, Ashwood P, et al. 200. Moreno-De-Luca A, Myers SM, Challman Advanced parental age and autism risk Maternal antibodies from mothers of TD, Moreno-De-Luca D, Evans DW, in children: a systematic review and children with autism alter brain growth Ledbetter DH. Developmental brain meta-analysis. Acta Psychiatr Scand. and social behavior development in the dysfunction: revival and expansion of 2017;135(1):29–41 rhesus monkey. Transl Psychiatry. 2013; old concepts based on new genetic 210. Pinto-Martin JA, Levy SE, Feldman JF, 3:e278 evidence [published correction appears Lorenz JM, Paneth N, Whitaker AH. in Lancet Neurol. 2013;12(5):423]. Prevalence of autism spectrum 221. Anderson GM. Autism biomarkers: Lancet Neurol. 2013;12(4):406–414 disorder in adolescents born weighing challenges, pitfalls and possibilities. , J Autism Dev Disord. 2015;45(4): 201. Mullin AP, Gokhale A, Moreno-De-Luca A, 2000 grams. Pediatrics. 2011;128(5): – 1103–1113 Sanyal S, Waddington JL, Faundez V. 883 891 Neurodevelopmental disorders: 211. Lampi KM, Lehtonen L, Tran PL, et al. 222. McDougle CJ, Landino SM, Vahabzadeh mechanisms and boundary definitions Risk of autism spectrum disorders in A, et al. Toward an immune-mediated from genomes, interactomes and low birth weight and small for subtype of autism spectrum disorder. proteomes. Transl Psychiatry. 2013;3: gestational age infants. J Pediatr. 2012; Brain Res. 2015;1617:72–92 e329 – 161(5):830 836 223. Isles AR. Neural and behavioral 202. Pescosolido MF, Gamsiz ED, Nagpal S, 212. Guinchat V, Thorsen P, Laurent C, Cans epigenetics; what it is, and what is Morrow EM. Distribution of disease- C, Bodeau N, Cohen D. Pre-, peri- and hype. Genes Brain Behav. 2015;14(1): associated copy number variants neonatal risk factors for autism. Acta 64–72 across distinct disorders of cognitive Obstet Gynecol Scand. 2012;91(3): 224. Tordjman S, Somogyi E, Coulon N, et al. development. J Am Acad Child Adolesc – 287 300 Gene 3 Environment interactions in Psychiatry. 2013;52(4):414–430.e14 213. Duncan LE, Keller MC. A critical review autism spectrum disorders: role of 203. Vorstman JAS, Parr JR, Moreno-De-Luca of the first 10 years of candidate gene- epigenetic mechanisms. Front D, Anney RJL, Nurnberger JI Jr., by-environment interaction research in Psychiatry. 2014;5:53

Downloaded from www.aappublications.org/news by guest on October 1, 2021 50 FROM THE AMERICAN ACADEMY OF PEDIATRICS 225. Bohacek J, Mansuy IM. Molecular 236. Schechter R, Grether JK. Continuing a systematic review of current insights into transgenerational non- increases in autism reported to epidemiological evidence. Arch Pediatr genetic inheritance of acquired California’s developmental services Adolesc Med. 2003;157(7):628–634 behaviours. Nat Rev Genet. 2015;16(11): system: mercury in retrograde. Arch 247. Clarke CE, Weberling McKeever B, 641–652 Gen Psychiatry. 2008;65(1):19–24 Holton A, Dixon GN. The influence of 226. Ladd-Acosta C, Hansen KD, Briem E, 237. Baird G, Pickles A, Simonoff E, et al. weight-of-evidence messages on Fallin MD, Kaufmann WE, Feinberg AP. Measles vaccination and antibody (vaccine) attitudes: a sequential Common DNA methylation alterations in response in autism spectrum mediation model. J Health Commun. multiple brain regions in autism. Mol disorders. Arch Dis Child. 2008;93(10): 2015;20(11):1302–1309 Psychiatry. 2014;19(8):862–871 832–837 248. Nyhan B, Reifler J, Richey S, Freed GL. 227. Loke YJ, Hannan AJ, Craig JM. The role 238. Fombonne E, Zakarian R, Bennett A, Effective messages in vaccine of epigenetic change in autism Meng L, McLean-Heywood D. Pervasive promotion: a randomized trial. spectrum disorders. Front Neurol. 2015; developmental disorders in Montreal, Pediatrics. 2014;133(4). Available at: 6:107 Quebec, Canada: prevalence and links www.pediatrics.org/cgi/content/full/ 228. Wong CC, Meaburn EL, Ronald A, et al. with immunizations. Pediatrics. 2006; 133/4/e835 118(1). Available at: www.pediatrics. Methylomic analysis of monozygotic 249. Casanova MF. The neuropathology of org/cgi/content/full/118/1/e139 twins discordant for autism spectrum autism. In: Volkmar FR, Rogers SJ, Paul disorder and related behavioural traits. 239. Institute of Medicine Immunization R, Pelphrey KA, eds. Handbook of Autism Mol Psychiatry. 2014;19(4):495–503 Safety Review Committee. Immunization and Pervasive Developmental 229. Jain A, Marshall J, Buikema A, Bancroft Safety Review: Vaccines and Autism. Disorders, 4th ed, Vol 1. Hoboken, NJ: T, Kelly JP, Newschaffer CJ. Autism Washington, DC: National Academies Wiley & Sons; 2014:346–531 Press; 2004 occurrence by MMR vaccine status 250. Chen JA, Peñagarikano O, Belgard TG, among US children with older siblings 240. Jefferson T, Price D, Demicheli V, Bianco Swarup V, Geschwind DH. The emerging with and without autism. JAMA. 2015; E; European Research Program for picture of autism spectrum disorder: 313(15):1534–1540 Improved Vaccine Safety Surveillance genetics and pathology. Annu Rev 230. Uno Y, Uchiyama T, Kurosawa M, Aleksic (EUSAFEVAC) Project. Unintended events Pathol. 2015;10:111–144 following immunization with MMR: B, Ozaki N. Early exposure to the 251. Wegiel J, Kuchna I, Nowicki K, et al. The combined measles-mumps-rubella a systematic review. Vaccine. 2003; 21(25–26):3954–3960 neuropathology of autism: defects of vaccine and thimerosal-containing neurogenesis and neuronal migration, vaccines and risk of autism spectrum 241. Klein KC, Diehl EB. Relationship between and dysplastic changes. Acta disorder. Vaccine. 2015;33(21): MMR vaccine and autism. Ann Neuropathol. 2010;119(6):755–770 2511–2516 Pharmacother. 2004;38(7–8):1297–1300 252. Stoner R, Chow ML, Boyle MP, et al. 231. Taylor LE, Swerdfeger AL, Eslick GD. 242. Mutter J, Naumann J, Schneider R, Patches of disorganization in the Vaccines are not associated with Walach H, Haley B. Mercury and autism: neocortex of children with autism. autism: an evidence-based meta- accelerating evidence? Neuro N Engl J Med. 2014;370(13):1209–1219 analysis of case-control and cohort Endocrinol Lett. 2005;26(5):439–446 studies. Vaccine. 2014;32(29):3623–3629 253. Walsh P, Elsabbagh M, Bolton P, Singh I. 243. Kimmel SR, Burns IT, Wolfe RM, In search of biomarkers for autism: 232. Maglione MA, Das L, Raaen L, et al. Zimmerman RK. Addressing scientific, social and ethical challenges. fi Safety of vaccines used for routine immunization barriers, bene ts, and Nat Rev Neurosci. 2011;12(10):603–612 immunization of U.S. children: risks. J Fam Pract. 2007;56(suppl 2): a systematic review. Pediatrics. 2014; S61–S69 254. Goldani AAS, Downs SR, Widjaja F, – Lawton B, Hendren RL. Biomarkers in 134(2):325 337 244. Parker SK, Schwartz B, Todd J, autism. Front Psychiatry. 2014;5:100 233. DeStefano F, Price CS, Weintraub ES. Pickering LK. Thimerosal-containing Increasing exposure to antibody- vaccines and autistic spectrum 255. Ruggeri B, Sarkans U, Schumann G, stimulating proteins and disorder: a critical review of published Persico AM. Biomarkers in autism polysaccharides in vaccines is not original data [published correction spectrum disorder: the old and the associated with risk of autism. appears in Pediatrics. 2005;115(1):200]. new. Psychopharmacology (Berl). 2014; J Pediatr. 2013;163(2):561–567 Pediatrics. 2004;114(3):793–804 231(6):1201–1216 234. Demicheli V, Rivetti A, Debalini MG, Di 245. Ortqvist Å, Blennow M, Carlsson RM, 256. Hazlett HC, Gu H, Munsell BC, et al; IBIS Pietrantonj C. Vaccines for measles, et al. Vaccination of children–a Network. Early brain development in mumps and rubella in children. systematic review. Acta Paediatr. 2010; infants at high risk for autism Cochrane Database Syst Rev. 2012;(2): 99(461):1–192 spectrum disorder. Nature. 2017; 542(7641):348–351 CD004407 246. Wilson K, Mills E, Ross C, McGowan J, 235. Gerber JS, Offit PA. Vaccines and Jadad A. Association of autistic 257. Courchesne E, Campbell K, Solso S. autism: a tale of shifting hypotheses. spectrum disorder and the measles, Brain growth across the life span in Clin Infect Dis. 2009;48(4):456–461 mumps, and rubella vaccine: autism: age-specific changes in

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 51 anatomical pathology. Brain Res. 2011; 268. Schultz RT, Grelotti DJ, Klin A, et al. The analytical review. J Autism Dev Disord. 1380:138–145 role of the fusiform face area in social 2009;39(3):495–510 cognition: implications for the 258. Sacco R, Gabriele S, Persico AM. Head 279. Jeste SS, Frohlich J, Loo SK. pathobiology of autism. Philos Trans R circumference and brain size in autism Electrophysiological biomarkers of Soc Lond B Biol Sci. 2003;358(1430): spectrum disorder: a systematic review diagnosis and outcome in 415–427 and meta-analysis. Psychiatry Res. neurodevelopmental disorders. Curr 2015;234(2):239–251 269. Nordahl CW, Scholz R, Yang X, et al. Opin Neurol. 2015;28(2):110–116 Increased rate of amygdala growth in 280. Marco EJ, Hinkley LB, Hill SS, Nagarajan 259. Elder LM, Dawson G, Toth K, Fein D, children aged 2 to 4 years with autism SS. Sensory processing in autism: Munson J. Head circumference as an spectrum disorders: a longitudinal a review of neurophysiologic findings. early predictor of autism symptoms in study. Arch Gen Psychiatry. 2012;69(1): Pediatr Res. 2011;69(5, pt 2):48R–54R younger siblings of children with 53–61 autism spectrum disorder. J Autism 281. Massand E, Bowler DM, Mottron L, 270. Blackmon K. Structural MRI biomarkers Dev Disord. 2008;38(6):1104–1111 Hosein A, Jemel B. ERP correlates of of shared pathogenesis in autism recognition memory in autism 260. Dawson G, Munson J, Webb SJ, Nalty T, spectrum disorder and epilepsy. spectrum disorder. J Autism Dev Abbott R, Toth K. Rate of head growth Epilepsy Behav. 2015;47:172–182 Disord. 2013;43(9):2038–2047 decelerates and symptoms worsen in 271. Chen R, Jiao Y, Herskovits EH. Structural 282. Di Giorgio E, Frasnelli E, Salva OR, et al. the second year of life in autism. Biol MRI in autism spectrum disorder. – ifference in visual social Psychiatry. 2007;61(4):458 464 Pediatr Res. 2011;69(5, pt 2):63R–68R predispositions between newborns at 261. Zwaigenbaum L, Young GS, Stone WL, 272. Nickl-Jockschat T, Habel U, Michel TM, low- and high-risk for autism. Sci Rep. et al. Early head growth in infants at et al. Brain structure anomalies in 2016;6:29860 risk of autism: a baby siblings research autism spectrum disorder–a meta- 283. Constantino J, Kennon-McGill S, consortium study. J Am Acad Child analysis of VBM studies using anatomic Weichselbaum C, et al. Infant viewing of Adolesc Psychiatry. 2014;53(10): likelihood estimation. Hum Brain Mapp. social scenes is under genetic control 1053–1062 2012;33(6):1470–1489 and atypical in autism. Nature. 2017; 262. Chaste P, Klei L, Sanders SJ, et al. 273. Wolff JJ, Gu H, Gerig G, et al; IBIS 547(7663):340–344 Adjusting head circumference for Network. Differences in white matter 284. Simion F, Di Giorgio E. Face perception covariates in autism: clinical correlates fiber tract development present from 6 and processing in early infancy: inborn of a highly heritable continuous trait. to 24 months in infants with autism. Am predispositions and developmental Biol Psychiatry. 2013;74(8):576–584 J Psychiatry. 2012;169(6):589–600 changes. Front Psychol. 2015;6:969 274. Philip RC, Dauvermann MR, Whalley HC, 263. Chawarska K, Campbell D, Chen L, Shic 285. Jones W, Klin A. Attention to eyes is Baynham K, Lawrie SM, Stanfield AC. A F, Klin A, Chang J. Early generalized present but in decline in 2–6-month-old systematic review and meta-analysis of overgrowth in boys with autism. Arch infants later diagnosed with autism. – the fMRI investigation of autism Gen Psychiatry. 2011;68(10):1021 1031 Nature. 2013;504(7480):427–431 spectrum disorders. Neurosci Biobehav 264. Gray KM, Taffe J, Sweeney DJ, Forster S, Rev. 2012;36(2):901–942 286. Walker CK, Anderson KW, Milano KM, Tonge BJ. Could head circumference be et al. Trophoblast inclusions are 275. Mahajan R, Mostofsky SH. used to screen for autism in young significantly increased in the placentas Neuroimaging endophenotypes in males with developmental delay? of children in families at risk for autism spectrum disorder. CNS Spectr. J Paediatr Child Health. 2012;48(4): autism. Biol Psychiatry. 2013;74(3): 2015;20(4):412–426 329–334 204–211 276. Cerliani L, Mennes M, Thomas RM, Di 265. Raznahan A, Wallace GL, Antezana L, 287. Anderson GM, Jacobs-Stannard A, Martino A, Thioux M, Keysers C. et al. Compared to what? Early brain Chawarska K, Volkmar FR, Kliman HJ. Increased functional connectivity overgrowth in autism and the perils of Placental trophoblast inclusions in between subcortical and cortical autism spectrum disorder. Biol population norms. Biol Psychiatry. 2013; resting-state networks in autism – Psychiatry. 2007;61(4):487–491 74(8):563 575 spectrum disorder. JAMA Psychiatry. 266. Schumann CM, Bloss CS, Barnes CC, 2015;72(8):767–777 288. Voineagu I, Yoo HJ. Current progress and challenges in the search for autism et al. Longitudinal magnetic resonance 277. Doyle-Thomas KA, Lee W, Foster NE, et al; biomarkers. Dis Markers. 2013;35(1): imaging study of cortical development NeuroDevNet ASD Imaging Group. 55–65 through early childhood in autism. Atypical functional brain connectivity J Neurosci. 2010;30(12):4419–4427 during rest in autism spectrum 289. Anderson GM, Stahl SS. Two proposed 267. Shen MD, Nordahl CW, Young GS, et al. disorders. Ann Neurol. 2015;77(5): early biomarker tests of ASD: more – Early brain enlargement and elevated 866 876 harm than good. J Autism Dev Disord. 2014;44(4):988–989 extra-axial fluid in infants who develop 278. Jeste SS, Nelson CA III. Event related autism spectrum disorder. Brain. 2013; potentials in the understanding of 290. Jordan BR, Tsai DF. Whole-genome 136(pt 9):2825–2835 autism spectrum disorders: an association studies for multigenic

Downloaded from www.aappublications.org/news by guest on October 1, 2021 52 FROM THE AMERICAN ACADEMY OF PEDIATRICS diseases: ethical dilemmas arising spectrum disorders. Pediatrics. 2011; 311. Lovaas OI, Smith T. A comprehensive from commercialization–the case of 127(5). Available at: www.pediatrics. behavioral theory of autistic children: genetic testing for autism. J Med Ethics. org/cgi/content/full/127/5/e1303 paradigm for research and treatment. – 2010;36(7):440 444 301. McPheeters ML, Warren Z, Sathe N, J Behav Ther Exp Psychiatry. 1989;20(1): – 291. Hernandez LM, Rudie JD, Green SA, et al. A systematic review of medical 17 29 Bookheimer S, Dapretto M. Neural treatments for children with autism 312. Smith T, Eikeseth S. O. Ivar lovaas: signatures of autism spectrum spectrum disorders. Pediatrics. 2011; pioneer of applied behavior analysis disorders: insights into brain network 127(5). Available at: www.pediatrics. and intervention for children with dynamics. Neuropsychopharmacology. org/cgi/content/full/127/5/e1312 autism. J Autism Dev Disord. 2011;41(3): – – 2015;40(1):171 189 302. National Autism Center. Findings and 375 378 292. Ameis SH, Kassee C, Corbett-Dick P, Conclusions: National Standards 313. Leaf JB, Leaf JA, Milne C, et al. An et al. ystemic review and guide to Project, Phase 2. Randolph, MA: evaluation of a behaviorally based management of core and psychiatric National Autism Center at May Institute; social skills group for individuals symptoms in youth with autism. Acta 2015 diagnosed with autism spectrum – Psychiatr Scand. 2018;138(5):379 400 303. Odom SL, Boyd BA, Hall LJ, Hume K. disorder. J Autism Dev Disord. 2017; – 293. Mannion A, Leader G. Comorbidity in Evaluation of comprehensive treatment 47(2):243 259 autism spectrum disorder: a literature models for individuals with autism 314. Lounds Taylor J, Dove D, Veenstra- review. Res Autism Spectr Disord. 2013; spectrum disorders. J Autism Dev VanderWeele J, et al. Interventions for 7(12):1595–1616 Disord. 2010;40(4):425–436 Adolescents and Young Adults With 294. Lyra L, Rizzo LE, Sunahara CS, et al. 304. Schreibman L, Stahmer AC. A Autism Spectrum Disorders. Rockville, What do Cochrane systematic reviews randomized trial comparison of the MD: Agency for Healthcare Research say about interventions for autism effects of verbal and pictorial and Quality; 2012 spectrum disorders? Sao Paulo Med J. naturalistic communication strategies 315. Linstead E, Dixon DR, French R, et al. 2017;135(2):192–201 on spoken language for young children Intensity and learning outcomes in the 295. Wong C, Odom SL, Hume KA, et al. with autism. J Autism Dev Disord. 2014; treatment of children with autism – Evidence-based practices for children, 44(5):1244 1251 spectrum disorder. Behav Modif. 2017; – youth, and young adults with autism 305. Murza KA, Schwartz JB, Hahs-Vaughn 41(2):229 252 spectrum disorder: a comprehensive DL, Nye C. Joint attention interventions 316. Orinstein AJ, Helt M, Troyb E, et al. review. J Autism Dev Disord. 2015;45(7): for children with autism spectrum Intervention for optimal outcome in 1951–1966 disorder: a systematic review and children and adolescents with a history 296. Schreibman L, Dawson G, Stahmer AC, meta-analysis. Int J Lang Commun of autism. J Dev Behav Pediatr. 2014; – – et al. Naturalistic developmental Disord. 2016;51(3):236 251 35(4):247 256 behavioral interventions: empirically 306. Houtrow A, Murphy N; Council on 317. Granpeesheh D, Tarbox J, Dixon DR. validated treatments for autism Children With Disabilities. Prescribing Applied behavior analytic interventions spectrum disorder. J Autism Dev physical, occupational, and speech for children with autism: a description Disord. 2015;45(8):2411–2428 therapy services for children with and review of treatment research. Ann – 297. Smith T, Iadarola S. Evidence base disabilities. Pediatrics. 2019;143(4): Clin Psychiatry. 2009;21(3):162 173 update for autism spectrum disorder. e20190285 318. Landry SH, Smith KE, Swank PR, Miller- J Clin Child Adolesc Psychol. 2015;44(6): 307. Maglione MA, Gans D, Das L, Timbie J, Loncar CL. Early maternal and child 897–922 Kasari C; Technical Expert Panel; HRSA influences on children’s later – 298. Weitlauf AS, McPheeters ML, Peters B, Autism Intervention Research independent cognitive and social et al. Therapies for Children With Behavioral (AIR-B) Network. Nonmedical functioning. Child Dev. 2000;71(2): – Autism Spectrum Disorder: Behavioral interventions for children with ASD: 358 375 Interventions Update. Rockville, MD: recommended guidelines and further 319. Tamis-LeMonda CS, Bornstein MH, Agency for Healthcare Research and research needs. Pediatrics. 2012; Baumwell L. Maternal responsiveness – Quality; 2014 130(suppl 2):S169 S178 and children’s achievement of language 299. Wang L, Mandell DS, Lawer L, Cidav Z, 308. Stahmer AC. Effective strategies by any milestones. Child Dev. 2001;72(3): – – Leslie DL. Healthcare service use and other name. Autism. 2014;18(3):211 212 748 767 costs for autism spectrum disorder: 309. Roane HS, Fisher WW, Carr JE. Applied 320. Siller M, Sigman M. The behaviors of a comparison between Medicaid and behavior analysis as treatment for parents of children with autism predict private insurance. J Autism Dev Disord. autism spectrum disorder. J Pediatr. the subsequent development of their 2013;43(5):1057–1064 2016;175:27–32 children’s communication. J Autism Dev – 300. Warren Z, McPheeters ML, Sathe N, 310. Baer DM, Wolf MM, Risley TR. Some Disord. 2002;32(2):77 89 Foss-Feig JH, Glasser A, Veenstra- current dimensions of applied behavior 321. Green J, Charman T, McConachie H, Vanderweele J. A systematic review of analysis. J Appl Behav Anal. 1968;1(1): et al; PACT Consortium. Parent-mediated early intensive intervention for autism 91–97 communication-focused treatment in

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 53 children with autism (PACT): 331. Bearss K, Johnson C, Smith T, et al. 340. Scahill L, Bearss K, Lecavalier L, et al. a randomised controlled trial. Lancet. Effect of parent training vs parent Effect of parent training on adaptive 2010;375(9732):2152–2160 education on behavioral problems in behavior in children with autism children with autism spectrum spectrum disorder and disruptive 322. Kasari C, Gulsrud AC, Wong C, Kwon S, disorder: a randomized clinical trial. behavior: results of a randomized trial. Locke J. Randomized controlled JAMA. 2015;313(15):1524–1533 J Am Acad Child Adolesc Psychiatry. caregiver mediated joint engagement 2016;55(7):602–609.e3 intervention for toddlers with autism. 332. Bearss K, Burrell TL, Stewart L, Scahill J Autism Dev Disord. 2010;40(9): L. Parent training in autism spectrum 341. Bearss K, Lecavalier L, Minshawi N, 1045–1056 disorder: what’s in a name? [published et al. Toward an exportable parent correction appears in Clin Child Fam training program for disruptive 323. Solomon R, Van Egeren LA, Mahoney G, Psychol Rev. 2015;18(2):183]. Clin Child behaviors in autism spectrum Quon Huber MS, Zimmerman P. PLAY – Fam Psychol Rev. 2015;18(2):170 182 disorders. Neuropsychiatry (London). Project Home Consultation intervention 2013;3(2):169–180 program for young children with 333. Wainer AL, Ingersoll BR. Increasing access to an ASD imitation intervention autism spectrum disorders: 342. Grahame V, Brett D, Dixon L, et al. via a telehealth parent training a randomized controlled trial. J Dev Managing repetitive behaviours in program. J Autism Dev Disord. 2015; Behav Pediatr. 2014;35(8):475–485 young children with autism spectrum 45(12):3877–3890 324. Gutstein SE. Empowering families disorder (ASD): pilot randomised 334. Ingersoll B, Berger NI. Parent through relationship development controlled trial of a new parent group engagement with a telehealth-based intervention: an important part of the intervention. J Autism Dev Disord. 2015; parent-mediated intervention program – biopsychosocial management of autism 45(10):3168 3182 for children with autism spectrum spectrum disorders. Ann Clin disorders: predictors of program use 343. Wetherby AM, Guthrie W, Woods J, et al. Psychiatry. 2009;21(3):174–182 and parent outcomes [published Parent-implemented social intervention 325. Estes A, Munson J, Rogers SJ, Greenson correction appears in J Med Internet for toddlers with autism: an RCT. – J, Winter J, Dawson G. Long-term Res. 2015;17(11):e239]. J Med Internet Pediatrics. 2014;134(6):1084 1093 outcomes of early intervention in 6- Res. 2015;17(10):e227 344. Boyd BA, Hume K, McBee MT, et al. year-old children with autism spectrum 335. Ingersoll B, Wainer AL, Berger NI, Comparative efficacy of LEAP, TEACCH disorder. J Am Acad Child Adolesc Pickard KE, Bonter N. Comparison of and non-model-specific special Psychiatry. 2015;54(7):580–587 a self-directed and therapist-assisted education programs for preschoolers 326. Rogers SJ, Estes A, Lord C, et al. Effects telehealth parent-mediated intervention with autism spectrum disorders. of a brief Early Start Denver model for children with ASD: a pilot RCT. J Autism Dev Disord. 2014;44(2): (ESDM)-based parent intervention on J Autism Dev Disord. 2016;46(7): 366–380 2275–2284 toddlers at risk for autism spectrum 345. Strain PS, Bovey EH II. Randomized, disorders: a randomized controlled 336. Turner-Brown L, Hume K, Boyd BA, Kainz controlled trial of the LEAP model of trial. J Am Acad Child Adolesc K. Preliminary efficacy of family early intervention for young children – Psychiatry. 2012;51(10):1052 1065 implemented TEACCH for toddlers: with autism spectrum disorders. Topics effects on parents and their toddlers 327. Dawson G, Jones EJ, Merkle K, et al. Early Child Spec Educ. 2011;31(3): with autism spectrum disorder. Early behavioral intervention is 133–154 J Autism Dev Disord. 2019;49(7): associated with normalized brain 2685–2698 346. Strain PS, Hoyson M. The need for activity in young children with autism. longitudinal, intensive social skill 337. Lindgren S, Wacker D, Suess A, et al. J Am Acad Child Adolesc Psychiatry. intervention: LEAP follow-up outcomes – Telehealth and autism: treating 2012;51(11):1150 1159 for children with autism. Topics Early challenging behavior at lower cost. Child Spec Educ. 2000;20(2):116–122 328. Ingersoll BR, Wainer AL. Pilot study of Pediatrics. 2016;137(suppl 2): a school-based parent training S167–S175 347. Virues-Ortega J, Julio FM, Pastor- program for preschoolers with ASD. Barriuso R. The TEACCH program for Autism. 2013;17(4):434–448 338. Kasari C, Gulsrud A, Paparella T, Hellemann G, Berry K. Randomized children and adults with autism: 329. Oono IP, Honey EJ, McConachie H. comparative efficacy study of parent- a meta-analysis of intervention studies. Parent-mediated early intervention for mediated interventions for toddlers Clin Psychol Rev. 2013;33(8):940–953 young children with autism spectrum with autism. J Consult Clin Psychol. 348. Lipkin PH, Okamoto J; Council on disorders (ASD). Cochrane Database – 2015;83(3):554 563 Children with Disabilities; Council on Syst Rev. 2013;(4):CD009774 339. Harrop C. Evidence-based, parent- School Health. The Individuals With 330. Beaudoin AJ, Sébire G, Couture M. mediated interventions for young Disabilities Education Act (IDEA) for Parent training interventions for children with autism spectrum children with special educational toddlers with autism spectrum disorder: the case of restricted and needs. Pediatrics. 2015;136(6). Available disorder. Autism Res Treat. 2014;2014: repetitive behaviors. Autism. 2015;19(6): at: www.pediatrics.org/cgi/content/full/ 839890 662–672 136/6/e1650

Downloaded from www.aappublications.org/news by guest on October 1, 2021 54 FROM THE AMERICAN ACADEMY OF PEDIATRICS 349. US Department of Education. Protecting 359. Laugeson EA, Gantman A, Kapp SK, future research directions. Augment students with disabilities. Available at: Orenski K, Ellingsen R. A randomized Altern Commun. 2015;31(3):203–214 https://www2.ed.gov/about/offices/list/ controlled trial to improve social skills 369. American Academy of Pediatrics ocr/504faq.html. Accessed December 1, in young adults with autism spectrum Committee on Children with Disabilities. 2019 disorder: The UCLA PEERS(®) program. Auditory integration training and J Autism Dev Disord. 2015;45(12): 350. Ricketts J. Research review: reading facilitated communication for autism. 3978–3989 comprehension in developmental Pediatrics. 1998;102(2, pt 1):431–433 disorders of language and 360. Krasny L, Williams BJ, Provencal S, 370. Schlosser RW, Balandin S, Hemsley B, communication. J Child Psychol Ozonoff S. Social skills interventions for Iacono T, Probst P, von Tetzchner S. Psychiatry. 2011;52(11):1111–1123 the autism spectrum: essential Facilitated communication and ingredients and a model curriculum. 351. Kasari C, Rotheram-Fuller E, Locke J, authorship: a systematic review. Child Adolesc Clin North Am. 2003;12(1): Gulsrud A. Making the connection: Augment Altern Commun. 2014;30(4): 107–122 randomized controlled trial of social 359–368 skills at school for children with autism 361. Green VA, Pituch KA, Itchon J, Choi A, 371. Adams C, Lockton E, Freed J, et al. The spectrum disorders. J Child Psychol O’Reilly M, Sigafoos J. Internet survey of Social Communication Intervention Psychiatry. 2012;53(4):431–439 treatments used by parents of children Project: a randomized controlled trial of with autism. Res Dev Disabil. 2006; 352. Kretzmann M, Shih W, Kasari C. the effectiveness of speech and 27(1):70–84 Improving peer engagement of children language therapy for school-age with autism on the school playground: 362. DeThorne LS, Johnson CJ, Walder L, children who have pragmatic and a randomized controlled trial. Behav Mahurin-Smith J. When “Simon says” social communication problems with or Ther. 2015;46(1):20–28 doesn’t work: alternatives to imitation without autism spectrum disorder. Int for facilitating early speech J Lang Commun Disord. 2012;47(3): 353. Foster EM, Pearson E. Is inclusivity an development. Am J Speech Lang Pathol. 233–244 indicator of quality of care for children 2009;18(2):133–145 with autism in special education? 372. Lloyd M, MacDonald M, Lord C. Motor Pediatrics. 2012;130(suppl 2): 363. Anderson DK, Lord C, Risi S, et al. skills of toddlers with autism spectrum S179–S185 Patterns of growth in verbal abilities disorders. Autism. 2013;17(2):133–146 among children with autism spectrum 354. Otero TL, Schatz RB, Merrill AC, Bellini S. 373. Ament K, Mejia A, Buhlman R, et al. disorder. J Consult Clin Psychol. 2007; Social skills training for youth with Evidence for specificity of motor 75(4):594–604 autism spectrum disorders: a follow-up. impairments in catching and balance in Child Adolesc Psychiatr Clin N Am. 2015; 364. Wodka EL, Mathy P, Kalb L. Predictors of children with autism. J Autism Dev 24(1):99–115 phrase and fluent speech in children Disord. 2015;45(3):742–751 with autism and severe language delay. 355. Whalon KJ, Conroy MA, Martinez JR, 374. Bilaver LA, Cushing LS, Cutler AT. Pediatrics. 2013;131(4). Available at: Werch BL. School-based peer-related Prevalence and correlates of www.pediatrics.org/cgi/content/full/ social competence interventions for educational intervention utilization 131/4/e1128 children with autism spectrum among children with autism spectrum disorder: a meta-analysis and 365. Schlosser RW, Wendt O. Effects of disorder. J Autism Dev Disord. 2016; descriptive review of single case augmentative and alternative 46(2):561–571 research design studies. J Autism Dev communication intervention on speech 375. Srinivasan SM, Pescatello LS, Bhat AN. Disord. 2015;45(6):1513–1531 production in children with autism: Current perspectives on physical a systematic review. Am J Speech Lang 356. Reichow B, Steiner AM, Volkmar F. activity and exercise recommendations Pathol. 2008;17(3):212–230 Cochrane review: social skills groups for children and adolescents with for people aged 6 to 21 with autism 366. Ganz JB, Mason RA, Goodwyn FD, Boles autism spectrum disorders. Phys Ther. spectrum disorders (ASD). Evid Based MB, Heath AK, Davis JL. Interaction of 2014;94(6):875–889 Child Health. 2013;8(2):266–315 participant characteristics and type of 376. Zimmer M, Desch L; Section on AAC with individuals with ASD: a meta- 357. Reichow B, Volkmar FR. Social skills Complementary and Integrative analysis. Am J Intellect Dev Disabil. interventions for individuals with Medicine; Council on Children with 2014;119(6):516–535 autism: evaluation for evidence-based Disabilities; American Academy of practices within a best evidence 367. Knight V, Sartini E, Spriggs AD. Pediatrics. Sensory integration synthesis framework. J Autism Dev Evaluating visual activity schedules as therapies for children with Disord. 2010;40(2):149–166 evidence-based practice for individuals developmental and behavioral with autism spectrum disorders. disorders. Pediatrics. 2012;129(6): 358. Laugeson EA, Ellingsen R, Sanderson J, J Autism Dev Disord. 2015;45(1): 1186–1189 Tucci L, Bates S. The ABC’s of teaching 157–178 social skills to adolescents with autism 377. Wigham S, Rodgers J, South M, spectrum disorder in the classroom: 368. Ganz JB. AAC interventions for McConachie H, Freeston M. The the UCLA PEERS (®) Program. J Autism individuals with autism spectrum interplay between sensory processing Dev Disord. 2014;44(9):2244–2256 disorders: state of the science and abnormalities, intolerance of

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 55 uncertainty, anxiety and restricted and 388. Bresnahan M, Hornig M, Schultz AF, disorders: a meta-analysis and repetitive behaviours in autism et al. Association of maternal report of comprehensive review of the literature. spectrum disorder. J Autism Dev infant and toddler gastrointestinal J Autism Dev Disord. 2013;43(9): Disord. 2015;45(4):943–952 symptoms with autism: evidence from 2159–2173 a prospective birth cohort. JAMA 378. Barton EE, Reichow B, Schnitz A, Smith 398. Bandini LG, Anderson SE, Curtin C, et al. Psychiatry. 2015;72(5):466–474 IC, Sherlock D. A systematic review of Food selectivity in children with autism sensory-based treatments for children 389. Mazurek MO, Vasa RA, Kalb LG, et al. spectrum disorders and typically with disabilities. Res Dev Disabil. 2015; Anxiety, sensory over-responsivity, and developing children. J Pediatr. 2010; 37:64–80 gastrointestinal problems in children 157(2):259–264 with autism spectrum disorders. 379. Case-Smith J, Weaver LL, Fristad MA. A 399. Hubbard KL, Anderson SE, Curtin C, J Abnorm Child Psychol. 2013;41(1): systematic review of sensory Must A, Bandini LG. A comparison of 165–176 processing interventions for children food refusal related to characteristics with autism spectrum disorders. 390. Buie T, Fuchs GJ III, Furuta GT, et al. of food in children with autism Autism. 2015;19(2):133–148 Recommendations for evaluation and spectrum disorder and typically treatment of common gastrointestinal developing children. J Acad Nutr Diet. 380. Bauman ML. Medical comorbidities in problems in children with ASDs. 2014;114(12):1981–1987 autism: challenges to diagnosis and Pediatrics. 2010;125(suppl 1):S19–S29 treatment. Neurotherapeutics. 2010; 400. Emond A, Emmett P, Steer C, Golding J. 7(3):320–327 391. Maenner MJ, Arneson CL, Levy SE, Kirby Feeding symptoms, dietary patterns, RS, Nicholas JS, Durkin MS. Brief and growth in young children with 381. Joshi G, Petty C, Wozniak J, et al. The report: association between behavioral autism spectrum disorders. Pediatrics. heavy burden of psychiatric features and gastrointestinal problems 2010;126(2). Available at: www. comorbidity in youth with autism among children with autism spectrum pediatrics.org/cgi/content/full/126/2/ spectrum disorders: a large disorder. J Autism Dev Disord. 2012; e337 comparative study of a psychiatrically 42(7):1520–1525 referred population. J Autism Dev 401. Johnson CR, Turner K, Stewart PA, et al. Disord. 2010;40(11):1361–1370 392. McElhanon BO, McCracken C, Karpen S, Relationships between feeding Sharp WG. Gastrointestinal symptoms problems, behavioral characteristics 382. Viscidi EW, Triche EW, Pescosolido MF, in autism spectrum disorder: a meta- and nutritional quality in children with et al. Clinical characteristics of children analysis. Pediatrics. 2014;133(5): ASD. J Autism Dev Disord. 2014;44(9): with autism spectrum disorder and co- 872–883 2175–2184 occurring epilepsy. PLoS One. 2013;8(7): e67797 393. Santocchi E, Guiducci L, Fulceri F, et al. 402. Hyman SL, Stewart PA, Schmidt B, et al. Gut to brain interaction in autism Nutrient intake from food in children 383. van Eeghen AM, Pulsifer MB, Merker VL, spectrum disorders: a randomized with autism. Pediatrics. 2012;130(suppl et al. Understanding relationships controlled trial on the role of probiotics 2):S145–S153 between autism, intelligence, and on clinical, biochemical and epilepsy: a cross-disorder approach. neurophysiological parameters. BMC 403. Keown K, Bothwell J, Jain S. Nutritional Dev Med Child Neurol. 2013;55(2): Psychiatry. 2016;16:183 implications of selective eating in 146–153 a child with autism spectrum disorder. 394. Son JS, Zheng LJ, Rowehl LM, et al. BMJ Case Rep. 2014;2014: 384. Sansa G, Carlson C, Doyle W, et al. Comparison of fecal microbiota in bcr2013202581 Medically refractory epilepsy in autism. children with autism spectrum Epilepsia. 2011;52(6):1071–1075 disorders and neurotypical siblings in 404. Ma NS, Thompson C, Weston S. Brief report: scurvy as a manifestation of 385. Ibrahim SH, Voigt RG, Katusic SK, the Simons simplex collection. PLoS food selectivity in children with autism. Weaver AL, Barbaresi WJ. Incidence of One. 2015;10(10):e0137725 J Autism Dev Disord. 2016;46(4): gastrointestinal symptoms in children 395. Levy SE, Souders MC, Ittenbach RF, 1464–1470 with autism: a population-based study. Giarelli E, Mulberg AE, Pinto-Martin JA. Pediatrics. 2009;124(2):680–686 Relationship of dietary intake to 405. Chiu M, Watson S. Xerophthalmia and vitamin A deficiency in an autistic child 386. Chaidez V, Hansen RL, Hertz-Picciotto I. gastrointestinal symptoms in children with a restricted diet. BMJ Case Rep. Gastrointestinal problems in children with autistic spectrum disorders. Biol – 2015;2015:bcr2015209413 with autism, developmental delays or Psychiatry. 2007;61(4):492 497 typical development. J Autism Dev 396. Hollway JA, Aman MG, Butter E. 406. Stewart PA, Hyman SL, Schmidt BL, et al. Disord. 2014;44(5):1117–1127 Correlates and risk markers for sleep Dietary supplementation in children disturbance in participants of the with autism spectrum disorders: 387. Buie T, Campbell DB, Fuchs GJ III, et al. Autism Treatment Network. J Autism common, insufficient, and excessive. Evaluation, diagnosis, and treatment of Dev Disord. 2013;43(12):2830–2843 J Acad Nutr Diet. 2015;115(8):1237–1248 gastrointestinal disorders in individuals with ASDs: a consensus 397. Sharp WG, Berry RC, McCracken C, et al. 407. Bailey RL, Fulgoni VL III, Keast DR, report. Pediatrics. 2010;125(suppl 1): Feeding problems and nutrient intake Lentino CV, Dwyer JT. Do dietary S1–S18 in children with autism spectrum supplements improve micronutrient

Downloaded from www.aappublications.org/news by guest on October 1, 2021 56 FROM THE AMERICAN ACADEMY OF PEDIATRICS sufficiency in children and adolescents? 417. Fields V. Prevalence of pica in preschool 428. Malow BA, Byars K, Johnson K, et al; J Pediatr. 2012;161(5):837–842 children with and without autism Sleep Committee of the Autism spectrum disorder, study to explore Treatment Network. A practice pathway 408. Marshall J, Ware R, Ziviani J, Hill RJ, — for the identification, evaluation, and Dodrill P. Efficacy of interventions to early development United States – management of insomnia in children improve feeding difficulties in children 2008 2016. In: Proceedings from the and adolescents with autism spectrum with autism spectrum disorders: Epidemic Intelligence Service – disorders. Pediatrics. 2012;130(suppl a systematic review and meta-analysis. Conference; April 29 May 2, 2019; 2):S106–S124 Child Care Health Dev. 2015;41(2): Atlanta, GA 278–302 418. Mohanty PH, Gabel M. Agitation and 429. Humphreys JS, Gringras P, Blair PS, et al. Sleep patterns in children with 409. Sharp WG, Jaquess DL, Morton JF, decreased oral intake in an adolescent autistic spectrum disorders: Herzinger CV. Pediatric feeding with autism. Pediatr Ann. 2012;41(6): a prospective cohort study. Arch Dis disorders: a quantitative synthesis of 1–3 Child. 2014;99(2):114–118 treatment outcomes. Clin Child Fam 419. Barton JC, Barton JC, Bertoli LF. Pica – 430. Goldman SE, Richdale AL, Clemons T, Psychol Rev. 2010;13(4):348 365 associated with iron deficiency or Malow BA. Parental sleep concerns in 410. de Vinck-Baroody O, Shui A, Macklin EA, depletion: clinical and laboratory autism spectrum disorders: variations Hyman SL, Leventhal JM, Weitzman C. correlates in 262 non-pregnant adult from childhood to adolescence. Overweight and obesity in a sample of outpatients. BMC Blood Disord. 2010;10: J Autism Dev Disord. 2012;42(4): children with autism spectrum 9 531–538 disorder. Acad Pediatr. 2015;15(4): 420. Miano S, Ferri R. Epidemiology and 396–404 431. Veatch OJ, Pendergast JS, Allen MJ, management of insomnia in children et al. Genetic variation in melatonin 411. Broder-Fingert S, Brazauskas K, with autistic spectrum disorders. pathway enzymes in children with Lindgren K, Iannuzzi D, Van Cleave J. – Paediatr Drugs. 2010;12(2):75 84 autism spectrum disorder and Prevalence of overweight and obesity in comorbid sleep onset delay. J Autism a large clinical sample of children with 421. Cortesi F, Giannotti F, Ivanenko A, Dev Disord. 2015;45(1):100–110 autism. Acad Pediatr. 2014;14(4): Johnson K. Sleep in children with 408–414 autistic spectrum disorder. Sleep Med. 432. Williams SR, Zies D, Mullegama SV, 2010;11(7):659–664 Grotewiel MS, Elsea SH. Smith-Magenis 412. Zuckerman KE, Hill AP, Guion K, Voltolina syndrome results in disruption of L, Fombonne E. Overweight and obesity: 422. Cohen S, Conduit R, Lockley SW, Rajaratnam SM, Cornish KM. The CLOCK gene transcription and reveals prevalence and correlates in a large an integral role for RAI1 in the relationship between sleep and clinical sample of children with autism maintenance of circadian rhythmicity. behavior in autism spectrum disorder spectrum disorder. J Autism Dev Am J Hum Genet. 2012;90(6):941–949 Disord. 2014;44(7):1708–1719 (ASD): a review. J Neurodev Disord. 2014;6(1):44 433. Dosman C, Witmans M, Zwaigenbaum L. 413. Phillips KL, Schieve LA, Visser S, et al. Iron’s role in paediatric restless legs Prevalence and impact of unhealthy 423. Fadini CC, Lamônica DA, Fett-Conte AC, syndrome - a review. Paediatr Child fl weight in a national sample of US et al. In uence of sleep disorders on Health. 2012;17(4):193–197 adolescents with autism and other the behavior of individuals with autism learning and behavioral disabilities. spectrum disorder. Front Hum 434. Engelhardt CR, Mazurek MO, Sohl K. Matern Child Health J. 2014;18(8): Neurosci. 2015;9:347 Media use and sleep among boys with 1964–1975 autism spectrum disorder, ADHD, or 424. Veatch OJ, Maxwell-Horn AC, Malow BA. typical development. Pediatrics. 2013; 414. Hinckson EA, Dickinson A, Water T, Sleep in autism spectrum disorders. 132(6):1081–1089 Sands M, Penman L. Physical activity, Curr Sleep Med Rep. 2015;1(2):131–140 dietary habits and overall health in 435. Foley LS, Maddison R, Jiang Y, Marsh S, overweight and obese children and 425. Blackmer AB, Feinstein JA. Management Olds T, Ridley K. Presleep activities and youth with intellectual disability or of sleep disorders in children with time of sleep onset in children. – autism. Res Dev Disabil. 2013;34(4): neurodevelopmental disorders: Pediatrics. 2013;131(2):276 282 1170–1178 a review. Pharmacotherapy. 2016;36(1): 436. Weiskop S, Richdale A, Matthews J. 84–98 415. Du RY, Yiu CKY, King NM. Oral health Behavioural treatment to reduce sleep behaviours of preschool children with 426. Mazurek MO, Sohl K. Sleep and problems in children with autism or autism spectrum disorders and their behavioral problems in children with fragile X syndrome. Dev Med Child – barriers to dental care. J Autism Dev autism spectrum disorder. J Autism Neurol. 2005;47(2):94 104 Disord. 2019;49(2):453–459 Dev Disord. 2016;46(6):1906–1915 437. Reed HE, McGrew SG, Artibee K, et al. 416. Call NA, Simmons CA, Mevers JE, Alvarez 427. Malow BA, Katz T, Reynolds AM, et al. Parent-based sleep education JP. Clinical outcomes of behavioral Sleep difficulties and medications in workshops in autism. J Child Neurol. – treatments for pica in children with children with autism spectrum 2009;24(8):936 945 developmental disabilities. J Autism Dev disorders: a registry study. Pediatrics. 438. Johnson CR, Turner KS, Foldes E, Brooks Disord. 2015;45(7):2105–2114 2016;137(suppl 2):S98–S104 MM, Kronk R, Wiggs L. Behavioral

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 57 parent training to address sleep 448. Guan J, Li G. Injury mortality in 458. Buck TR, Viskochil J, Farley M, et al. disturbances in young children with individuals with autism. Am J Public Psychiatric comorbidity and medication autism spectrum disorder: a pilot trial. Health. 2017;107(5):791–793 use in adults with autism spectrum Sleep Med. 2013;14(10):995–1004 disorder. J Autism Dev Disord. 2014; 449. Rice CE, Zablotsky B, Avila RM, et al. 44(12):3063–3071 439. Vriend JL, Corkum PV, Moon EC, Smith Reported wandering behavior among IM. Behavioral interventions for sleep children with autism spectrum 459. Salazar F, Baird G, Chandler S, et al. Co- problems in children with autism disorder and/or intellectual disability. occurring psychiatric disorders in spectrum disorders: current findings J Pediatr. 2016;174:232–239.e2 preschool and elementary school-aged and future directions. J Pediatr Psychol. 450. Canitano R, Vivanti G. Tics and Tourette children with autism spectrum 2011;36(9):1017–1029 syndrome in autism spectrum disorder. J Autism Dev Disord. 2015; – 440. Malow BA, Adkins KW, Reynolds A, et al. disorders. Autism. 2007;11(1):19–28 45(8):2283 2294 Parent-based sleep education for 451. DeJong H, Bunton P, Hare DJ. A 460. Kuhlthau KA, McDonnell E, Coury DL, children with autism spectrum systematic review of interventions used Payakachat N, Macklin E. Associations disorders. J Autism Dev Disord. 2014; to treat catatonic symptoms in people of quality of life with health-related 44(1):216–228 with autistic spectrum disorders. characteristics among children with – 441. Tordjman S, Najjar I, Bellissant E, et al. J Autism Dev Disord. 2014;44(9): autism. Autism. 2018;22(7):804 813 Advances in the research of melatonin 2127–2136 461. Weitzman C, Wegner L; Section on in autism spectrum disorders: 452. Gurney JG, McPheeters ML, Davis MM. Developmental and Behavioral literature review and new perspectives. Parental report of health conditions Pediatrics; Committee on Psychosocial Int J Mol Sci. 2013;14(10):20508–20542 and health care use among children Aspects of Child and Family Health; 442. Cortesi F, Giannotti F, Sebastiani T, with and without autism: National Council on Early Childhood; Society for Panunzi S, Valente D. Controlled-release Survey of Children’s Health. Arch Developmental and Behavioral melatonin, singly and combined with Pediatr Adolesc Med. 2006;160(8): Pediatrics; American Academy of cognitive behavioural therapy, for 825–830 Pediatrics. Promoting optimal persistent insomnia in children with development: screening for behavioral 453. Simonoff E, Jones CR, Baird G, Pickles A, autism spectrum disorders: and emotional problems. Pediatrics. Happé F, Charman T. The persistence a randomized placebo-controlled trial. 2015;135(2):384–395 and stability of psychiatric problems in J Sleep Res. 2012;21(6):700–709 adolescents with autism spectrum 462. Volker MA, Lopata C, Smerbeck AM, 443. Malow B, Adkins KW, McGrew SG, et al. disorders. J Child Psychol Psychiatry. et al. BASC-2 PRS profiles for students Melatonin for sleep in children with 2013;54(2):186–194 with high-functioning autism spectrum autism: a controlled trial examining disorders. J Autism Dev Disord. 2010; 454. Hill AP, Zuckerman KE, Hagen AD, et al. dose, tolerability, and outcomes. 40(2):188–199 Aggressive behavior problems in J Autism Dev Disord. 2012;42(8): children with autism spectrum 463. Ooi YP, Rescorla L, Ang RP, Woo B, Fung 1729–1737; author reply 1738 disorders: prevalence and correlates in DS. Identification of autism spectrum 444. Merenstein D, Diener-West M, Halbower a large clinical sample. Res Autism disorders using the Child Behavior AC, Krist A, Rubin HR. The trial of infant Spectr Disord. 2014;8(9):1121–1133 Checklist in Singapore. J Autism Dev response to diphenhydramine: the Disord. 2011;41(9):1147–1156 455. Orinstein A, Tyson KE, Suh J, et al. TIRED study–a randomized, controlled, Psychiatric symptoms in youth with 464. Rosen TE, Mazefsky CA, Vasa RA, Lerner patient-oriented trial. Arch Pediatr a history of autism and optimal MD, et al. Co-occuring psychiatric Adolesc Med. 2006;160(7):707–712 outcome. J Autism Dev Disord. 2015; conditions in autism spectrum 445. Fiks AG, Mayne SL, Song L, et al. 45(11):3703–3714 disorder. Int Rev Psychiatry. 2018;30(1): Changing patterns of alpha agonist 40–61 456. Gotham K, Brunwasser SM, Lord C. medication use in children and Depressive and anxiety symptom 465. American Academy of Pediatrics. Caring adolescents 2009-2011. J Child Adolesc trajectories from school age through for Children With Autism Spectrum Psychopharmacol. 2015;25(4):362–367 young adulthood in samples with Disorder: A Practical Resource Toolkit 446. Sikora DM, Johnson K, Clemons T, Katz autism spectrum disorder and for Clinicians, 3rd edition. Available at: T. The relationship between sleep developmental delay. J Am Acad Child https://toolkits.solutions.aap.org/ problems and daytime behavior in Adolesc Psychiatry. 2015;54(5): autism/home. Accessed December 1, children of different ages with autism 369–376.e3 2019 spectrum disorders. Pediatrics. 2012; 457. Verheij C, Louwerse A, van der Ende J, 466. Mahajan R, Bernal MP, Panzer R, et al; 130(suppl 2):S83–S90 et al. The stability of comorbid Autism Speaks Autism Treatment 447. Anderson C, Law JK, Daniels A, et al. psychiatric disorders: a 7 year follow Network Psychopharmacology Occurrence and family impact of up of children with pervasive Committee. Clinical practice pathways elopement in children with autism developmental disorder-not otherwise for evaluation and medication choice spectrum disorders. Pediatrics. 2012; specified. J Autism Dev Disord. 2015; for attention-deficit/hyperactivity 130(5):870–877 45(12):3939–3948 disorder symptoms in autism spectrum

Downloaded from www.aappublications.org/news by guest on October 1, 2021 58 FROM THE AMERICAN ACADEMY OF PEDIATRICS disorders. Pediatrics. 2012;130(suppl in youth with high-functioning autism Pediatrics. 2016;137(suppl 2): 2):S125–S138 spectrum disorders. Child Psychiatry S136–S148 Hum Dev. 2015;46(4):533–547 467. Doyle CA, McDougle CJ. Pharmacologic 486. Doehring P, Reichow B, Palka T, Phillips treatments for the behavioral 476. Spencer D, Marshall J, Post B, et al. C, Hagopian L. Behavioral approaches symptoms associated with autism Psychotropic medication use and to managing severe problem behaviors spectrum disorders across the polypharmacy in children with autism in children with autism spectrum and lifespan. Dialogues Clin Neurosci. 2012; spectrum disorders. Pediatrics. 2013; related developmental disorders: 14(3):263–279 132(5):833–840 a descriptive analysis. Child Adolesc Psychiatr Clin N Am. 2014;23(1):25–40 468. Sukhodolsky DG, Scahill L, Gadow KD, 477. De-la-Iglesia M, Olivar JS. Risk factors et al. Parent-rated anxiety symptoms in for depression in children and 487. Fitzpatrick SE, Srivorakiat L, Wink LK, children with pervasive developmental adolescents with high functioning Pedapati EV, Erickson CA. Aggression in disorders: frequency and association autism spectrum disorders. autism spectrum disorder: with core autism symptoms and ScientificWorldJournal. 2015;2015: presentation and treatment options. cognitive functioning. J Abnorm Child 127853 Neuropsychiatr Dis Treat. 2016;12: – – Psychol. 2008;36(1):117 128 478. Segers M, Rawana J. What do we know 1525 1538 469. Vasa RA, Mazurek MO, Mahajan R, et al. about suicidality in autism spectrum 488. Chen C, Shen YD, Xun GL, et al. Assessment and treatment of anxiety in disorders? A systematic review. Autism Aggressive behaviors and treatable risk youth with autism spectrum disorders. Res. 2014;7(4):507–521 factors of preschool children with Pediatrics. 2016;137(suppl 2): 479. Zuckerbrot RA, Cheung A, Jensen PS, autism spectrum disorder. Autism Res. – S115–S123 Stein REK, Laraque D; GLAD-PC Steering 2017;10(6):1155 1162 470. Bitsika V, Sharpley CF, Andronicos NM, Group. Guidelines for Adolescent 489. Richards C, Davies L, Oliver C. Agnew LL. Hypothalamus-pituitary- Depression in Primary Care (GLAD-PC): Predictors of self-injurious behavior adrenal axis daily fluctuation, anxiety part I. Practice preparation, and self-restraint in autism spectrum and age interact to predict cortisol identification, assessment, and initial disorder: towards a hypothesis of concentrations in boys with an autism management. Pediatrics. 2018;141(3): impaired behavioral control. J Autism spectrum disorder. Physiol Behav. 2015; e20174081 Dev Disord. 2017;47(3):701–713 138:200–207 480. Williams K, Brignell A, Randall M, Silove 490. Soke GN, Rosenberg SA, Rosenberg CR, 471. Kerns CM, Maddox BB, Kendall PC, et al. N, Hazell P. Selective serotonin reuptake Vasa RA, Lee LC, DiGuiseppi C. Self- Brief measures of anxiety in non- inhibitors (SSRIs) for autism spectrum injurious behaviors in children with treatment-seeking youth with autism disorders (ASD). Cochrane Database autism spectrum disorder enrolled in spectrum disorder. Autism. 2015;19(8): Syst Rev. 2013;(8):CD004677 the Study to Explore Early Development. – 969–979 481. Vannucchi G, Masi G, Toni C, Dell’Osso L, Autism. 2018;22(5):625 635 472. Kreslins A, Robertson AE, Melville C. The Erfurth A, Perugi G. Bipolar disorder in 491. Richards C, Moss J, Nelson L, Oliver C. effectiveness of psychosocial adults with Asperger’s syndrome: Persistence of self-injurious behaviour interventions for anxiety in children a systematic review. J Affect Disord. in autism spectrum disorder over and adolescents with autism spectrum 2014;168:151–160 3 years: a prospective cohort study of disorder: a systematic review and 482. Krebs G, Heyman I. Obsessive- risk markers. J Neurodev Disord. 2016; meta-analysis. Child Adolesc Psychiatry compulsive disorder in children and 8:21 Ment Health. 2015;9:22 adolescents. Arch Dis Child. 2015; 492. Powis L, Oliver C. The prevalence of – 473. Lickel A, MacLean WE Jr., Blakeley-Smith 100(5):495 499 aggression in genetic syndromes: A, Hepburn S. Assessment of the 483. Zandt F, Prior M, Kyrios M. Repetitive a review. Res Dev Disabil. 2014;35(5): – prerequisite skills for cognitive behaviour in children with high 1051 1071 behavioral therapy in children with and functioning autism and obsessive 493. Schubart JR, Camacho F, Leslie D. without autism spectrum disorders. compulsive disorder. J Autism Dev Psychotropic medication trends among J Autism Dev Disord. 2012;42(6): Disord. 2007;37(2):251–259 children and adolescents with autism 992–1000 484. Murray K, Jassi A, Mataix-Cols D, spectrum disorder in the Medicaid – 474. Sukhodolsky DG, Bloch MH, Panza KE, Barrow F, Krebs G. Outcomes of program. Autism. 2014;18(6):631 637 Reichow B. Cognitive-behavioral therapy cognitive behaviour therapy for 494. Jobski K, Höfer J, Hoffmann F, for anxiety in children with high- obsessive-compulsive disorder in young Bachmann C. Use of psychotropic drugs functioning autism: a meta-analysis. people with and without autism in patients with autism spectrum Pediatrics. 2013;132(5). Available at: spectrum disorders: A case controlled disorders: a systematic review. Acta www.pediatrics.org/cgi/content/full/ study. Psychiatry Res. 2015;228(1):8–13 Psychiatr Scand. 2017;135(1):8–28 132/5/e1341 485. McGuire K, Fung LK, Hagopian L, et al. 495. Rettew DC, Greenblatt J, Kamon J, et al. 475. Ung D, Selles R, Small BJ, Storch EA. A Irritability and problem behavior in Antipsychotic medication prescribing in systematic review and meta-analysis of autism spectrum disorder: a practice children enrolled in Medicaid. cognitive-behavioral therapy for anxiety pathway for pediatric primary care. Pediatrics. 2015;135(4):658–665

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 59 496. Riddle MA. Pediatric 505. Hess GP, Fonseca E, Scott R, Fagerness complementary and alternative Psychopharmacology for Primary Care, J. Pharmacogenomic and medicine to treat and manage the 1st ed. Elk Grove Village, IL: American pharmacogenetic-guided therapy as symptoms of autism in children: Academy of Pediatrics; 2016 a tool in precision medicine: current a survey of parents in a community 497. Mandell DS, Morales KH, Marcus SC, state and factors impacting acceptance population. J Altern Complement Med. – Stahmer AC, Doshi J, Polsky DE. by stakeholders. Genet Res. 2015;97:e13 2016;22(1):25 32 Psychotropic medication use among 506. Farmer C, Thurm A, Grant P. 516. Levy SE, Hyman SL. Complementary and Medicaid-enrolled children with autism Pharmacotherapy for the core alternative medicine treatments for spectrum disorders. Pediatrics. 2008; symptoms in autistic disorder: current children with autism spectrum 121(3). Available at: www.pediatrics. status of the research. Drugs. 2013; disorders. Child Adolesc Psychiatr Clin org/cgi/content/full/121/3/e441 73(4):303–314 NAm. 2015;24(1):117–143 498. Rosenberg RE, Mandell DS, Farmer JE, 507. Politte LC, Henry CA, McDougle CJ. 517. National Center for Complementary and Law JK, Marvin AR, Law PA. Psychopharmacological interventions Integrative Health. Autism. 2017. Psychotropic medication use among in autism spectrum disorder. Harv Rev Available at: https://nccih.nih.gov/ children with autism spectrum Psychiatry. 2014;22(2):76–92 health/autism. Accessed November 12, disorders enrolled in a national 508. Baribeau DA, Anagnostou E. An update 2017 registry, 2007-2008. J Autism Dev on medication management of Disord. 2010;40(3):342–351 518. Levy SE. Repeated doses of porcine behavioral disorders in autism. Curr secretin did not improve symptoms, 499. Coury DL, Anagnostou E, Manning- Psychiatry Rep. 2014;16(3):437 language, or cognitive functioning in Courtney P, et al. Use of psychotropic 509. Accordino RE, Kidd C, Politte LC, Henry children with autism or autism medication in children and adolescents CA, McDougle CJ. spectrum disorder. Evid Based Ment with autism spectrum disorders. Psychopharmacological interventions Health. 2002;5(1):22 Pediatrics. 2012;130(suppl 2):S69–S76 in autism spectrum disorder. Expert 519. Perrin JM, Coury DL, Hyman SL, Cole L, 500. Mire SS, Nowell KP, Kubiszyn T, Goin- – Opin Pharmacother. 2016;17(7):937 952 Reynolds AM, Clemons T. Kochel RP. Psychotropic medication use 510. Brown JT, Eum S, Cook EH, Bishop JR. Complementary and alternative among children with autism spectrum Pharmacogenomics of autism medicine use in a large pediatric disorders within the Simons Simplex spectrum disorder. autism sample. Pediatrics. 2012; Collection: are core features of autism Pharmacogenomics. 2017;18(4): 130(suppl 2):S77–S82 spectrum disorder related? Autism. 403–414 2014;18(8):933–942 520. Akins RS, Krakowiak P, Angkustsiri K, 511. Nath D. Complementary and alternative 501. Witwer A, Lecavalier L. Treatment Hertz-Picciotto I, Hansen RL. Utilization medicine in the school-age child with incidence and patterns in children and patterns of conventional and autism. J Pediatr Health Care. 2017; adolescents with autism spectrum complementary/alternative treatments 31(3):393–397 disorders. J Child Adolesc in children with autism spectrum Psychopharmacol. 2005;15(4):671–681 512. Lindly OJ, Thorburn S, Heisler K, Reyes disorders and developmental NM, Zuckerman KE. Parents’ use of disabilities in a population-based study. 502. Frazier TW, Shattuck PT, Narendorf SC, – complementary health approaches for J Dev Behav Pediatr. 2014;35(1):1 10 Cooper BP, Wagner M, Spitznagel EL. young children with autism spectrum Prevalence and correlates of 521. Hanson E, Kalish LA, Bunce E, et al. Use disorder. J Autism Dev Disord. 2018; psychotropic medication use in of complementary and alternative 48(5):1803–1818 adolescents with an autism spectrum medicine among children diagnosed disorder with and without caregiver- 513. Höfer J, Hoffmann F, Bachmann C. Use with autism spectrum disorder. reported attention-deficit/hyperactivity of complementary and alternative J Autism Dev Disord. 2007;37(4): disorder. J Child Adolesc medicine in children and adolescents 628–636 Psychopharmacol. 2011;21(6):571–579 with autism spectrum disorder: 522. Valicenti-McDermott M, Burrows B, a systematic review. Autism. 2017;21(4): 503. Bousman CA, Hopwood M. Commercial Bernstein L, et al. Use of 387–402 pharmacogenetic-based decision- complementary and alternative support tools in psychiatry. Lancet 514. Green RR, Santoro N, Allshouse AA, Neal- medicine in children with autism and Psychiatry. 2016;3(6):585–590 Perry G, Derby C. Prevalence of other developmental disabilities: associations with ethnicity, child 504. Hicks JK, Bishop JR, Sangkuhl K, et al; complementary and alternative comorbid symptoms, and parental Clinical Pharmacogenetics medicine and herbal remedy use in stress. J Child Neurol. 2014;29(3): Implementation Consortium. Clinical Hispanic and non-Hispanic white 360–367 Pharmacogenetics Implementation women: results from the study of ’ Consortium (CPIC) guideline for CYP2D6 womens health across the nation. 523. Marí-Bauset S, Zazpe I, Mari-Sanchis A, and CYP2C19 genotypes and dosing of J Altern Complement Med. 2017;23(10): Llopis-González A, Morales-Suárez- – selective serotonin reuptake inhibitors. 805 811 Varela M. Evidence of the gluten-free Clin Pharmacol Ther. 2015;98(2): 515. Hopf KP, Madren E, Santianni KA. Use and casein-free diet in autism 127–134 and perceived effectiveness of spectrum disorders: a systematic

Downloaded from www.aappublications.org/news by guest on October 1, 2021 60 FROM THE AMERICAN ACADEMY OF PEDIATRICS review. J Child Neurol. 2014;29(12): with autism spectrum disorde. disorders. Brain Dev. 2013;35(2): 1718–1727 Cochrane Database Syst Rev. 2014;6: 133–138 CD004381 524. Dosman C, Adams D, Wudel B, Vogels L, 545. Hayes SA, Watson SL. The impact of Turner J, Vohra S. Complementary, 535. Koenig KP, Buckley-Reen A, Garg S. parenting stress: a meta-analysis of holistic, and integrative medicine: Efficacy of the Get Ready to Learn yoga studies comparing the experience of autism spectrum disorder and gluten- program among children with autism parenting stress in parents of children and casein-free diet. Pediatr Rev. 2013; spectrum disorders: a pretest-posttest with and without autism spectrum 34(10):e36–e41 control group design. Am J Occup Ther. disorder. J Autism Dev Disord. 2013; 2012;66(5):538–546 43(3):629–642 525. Hyman SL, Stewart PA, Foley J, et al. The gluten-free/casein-free diet: a double- 536. Hourston S, Atchley R. Autism and mind- 546. Horlin C, Falkmer M, Parsons R, blind challenge trial in children with body therapies: a systematic review. Albrecht MA, Falkmer T. The cost of autism. J Autism Dev Disord. 2016;46(1): J Altern Complement Med. 2017;23(5): autism spectrum disorders. PLoS One. 205–220 331–339 2014;9(9):e106552 526. Jia F, Wang B, Shan L, Xu Z, Staal WG, Du 537. Wan Yunus F, Liu KP, Bissett M, Penkala 547. Child and Adolescent Health L. Core symptoms of autism improved S. Sensory-based intervention for Measurement Initiative. National profile after vitamin D supplementation. children with behavioral problems: of children with special health care Pediatrics. 2015;135(1). Available at: a systematic review. J Autism Dev needs and autism spectrum disorders: www.pediatrics.org/cgi/content/full/ Disord. 2015;45(11):3565–3579 key findings from the 2009/10 NS- 135/1/e196 538. Borgi M, Loliva D, Cerino S, et al. CSHCN & 2011/12 NSCH. 2013. Available at: https://www.childhealthdata.org/ 527. Saad K, Abdel-Rahman AA, Elserogy YM, Effectiveness of a standardized equine- assisted therapy program for children docs/drc/asd-data-brief_7-30-13.pdf. et al. Vitamin D status in autism Accessed December 1, 2019 spectrum disorders and the efficacy of with autism spectrum disorder. vitamin D supplementation in autistic J Autism Dev Disord. 2016;46(1):1–9 548. Clifford T, Minnes P. Who participates in children. Nutr Neurosci. 2016;19(8): 539. Hoagwood KE, Acri M, Morrissey M, support groups for parents of children 346–351 Peth-Pierce R. Animal-assisted with autism spectrum disorders? The role of beliefs and coping style. 528. Bertoglio K, Jill James S, Deprey L, therapies for youth with or at risk for mental health problems: a systematic J Autism Dev Disord. 2013;43(1): Brule N, Hendren RL. Pilot study of the 179–187 effect of methyl B12 treatment on review. Appl Dev Sci. 2017;21(1):1–13 behavioral and biomarker measures in 540. Sinha Y, Silove N, Hayen A, Williams K. 549. Siller M, Reyes N, Hotez E, Hutman T, children with autism. J Altern Auditory integration training and other Sigman M. Longitudinal change in the Complement Med. 2010;16(5):555–560 sound therapies for autism spectrum use of services in autism spectrum disorder: understanding the role of 529. Nye C, Brice A. Combined vitamin B6- disorders (ASD). Cochrane Database Syst Rev. 2011;(12):CD003681 child characteristics, family magnesium treatment in autism demographics, and parent cognitions. spectrum disorder. Cochrane Database 541. Brondino N, Fusar-Poli L, Rocchetti M, Autism. 2014;18(4):433–446 Syst Rev. 2005;(4):CD003497 Provenzani U, Barale F, Politi P. 550. Mohd Roffeei SH, Abdullah N, Basar SK. 530. Mankad D, Dupuis A, Smile S, et al. A Complementary and alternative therapies for autism spectrum Seeking social support on Facebook for randomized, placebo controlled trial of children with autism spectrum omega-3 fatty acids in the treatment of disorder. Evid Based Complement Alternat Med. 2015;2015:258589 disorders (ASDs). Int J Med Inform. young children with autism. Mol 2015;84(5):375–385 Autism. 2015;6:18 542. Committee on Children With Disabilities. Counseling families who choose 551. Zablotsky B, Kalb LG, Freedman B, Vasa 531. Valerie T. Discretionary fortification–a complementary and alternative R, Stuart EA. Health care experiences public health perspective. Nutrients. fi medicine for their child with chronic and perceived nancial impact among 2014;6(10):4421–4433 illness or disability [published families of children with an autism 532. DeVilbiss EA, Gardner RM, Newschaffer correction appears in Pediatrics. 2001; spectrum disorder. Psychiatr Serv. – CJ, Lee BK. Maternal folate status as 108(2):507]. Pediatrics. 2001;107(3): 2014;65(3):395 398 a risk factor for autism spectrum 598–601 552. McStay RL, Trembath D, Dissanayake C. disorders: a review of existing 543. Levy SE, Frasso R, Colantonio S, et al. Maternal stress and family quality of evidence. Br J Nutr. 2015;114(5): Shared decision making and treatment life in response to raising a child with 663–672 decisions for young children with autism: from preschool to adolescence. – 533. Hickey SE, Curry CJ, Toriello HV. ACMG autism spectrum disorder. Acad Res Dev Disabil. 2014;35(11):3119 3130 practice guideline: lack of evidence for Pediatr. 2016;16(6):571–578 553. Green L. The well-being of siblings of MTHFR polymorphism testing. Genet 544. Estes A, Olson E, Sullivan K, et al. individuals with autism. ISRN Neurol. Med. 2013;15(2):153–156 Parenting-related stress and 2013;2013:417194 534. Geretsegger M, Elefant C, Mössler K, psychological distress in mothers of 554. Kuo DZ, Houtrow AJ; Council on Children Gold C, et al. Music therapy for people toddlers with autism spectrum With Disabilities. Recognition and

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 61 management of medical complexity. [published correction appears in 574. Stone WL, Coonrod EE, Turner LM, Pediatrics. 2016;138(6):e20163021 Pediatrics. 2019;143(2):e20183610]. Pozdol SL. Psychometric properties of Pediatrics. 2018;142(5):e20182587 the STAT for early autism screening. 555. Carbone PS, Behl DD, Azor V, Murphy J Autism Dev Disord. 2004;34(6): NA. The medical home for children with 564. Got Transition. Health care providers. 691–701 autism spectrum disorders: parent and Available at: http://www.gottransition. pediatrician perspectives. J Autism Dev org/providers/index.cfm. Accessed 575. Rowberry JJ, Macari S, Chen G, et al. Disord. 2010;40(3):317–324 December 1, 2019 Screening for autism spectrum disorders in 12-mo-old high-risk 556. Golnik A, Ireland M, Borowsky IW. 565. Autism Speaks. Puberty and siblings by parental report. J Autism Medical homes for children with adolescence resource: a guide for Dev Disord. 2015;45:221–229 autism: a physician survey. Pediatrics. parents of adolescents with autism – 2009;123(3):966 971 spectrum disorder. Available at: https:// 576. Smith NJ, Sheldrick RC, Perrin EC. An Abbreviated Screening Instrument for 557. Liptak GS, Orlando M, Yingling JT, et al. www.autismspeaks.org/sites/default/ Autism Spectrum Disorders. Infant Satisfaction with primary health care files/documents/atn/puberty_tool_kit. Ment Health J. 2012;34(2):149–155 received by families of children with pdf. Accessed December 1, 2019 developmental disabilities. J Pediatr 577. Salisbury LA, Nyce JD, Hannum CD, 566. Kuder SJ, Accardo A. What works for Health Care. 2006;20(4):245–252 Sheldrick RC, Perrin EC. Sensitivity and college students with autism spectrum specificity of 2 autism screeners among 558. Cheak-Zamora NC, Farmer JE. The disorder. J Autism Dev Disord. 2018; referred children between 16 and 48 impact of the medical home on access – 48(3):722 731 mo of age. J Dev Behav Pediatr. 2018; to care for children with autism 39(3):254–258 spectrum disorders. J Autism Dev 567. Nicolaidis C, Kripke CC, Raymaker D. Disord. 2015;45(3):636–644 Primary care for adults on the autism 578. Choueiri R, Wagner S. A new interactive spectrum. Med Clin North Am. 2014; screening test for autism spectrum 559. Kogan MD, Strickland BB, Blumberg SJ, 98(5):1169–1191 disorders in toddlers. J Pediatr. 2015; Singh GK, Perrin JM, van Dyck PC. A 167(2):460–466 national profile of the health care 568. Velott DL, Agbese E, Mandell D, et al. experiences and family impact of Medicaid 1915(c) Home- and 579. Myers SM. Management of autism autism spectrum disorder among Community-Based Services waivers for spectrum disorders in primary care. children in the United States, 2005-2006. children with autism spectrum Pediatr Ann. 2009;38(1):42–49 – Pediatrics. 2008;122(6). Available at: disorder. Autism. 2016;20(4):473 482 580. Quintana H, Birmaher B, Stedge D, et al. www.pediatrics.org/cgi/content/full/ 569. Interagency Autism Coordinating Use of methylphenidate in the 122/6/e1149 Committee. IACC strategic plan for treatment of children with autistic 560. McKinney CM, Nelson T, Scott JM, autism spectrum disorder research: disorder. J Autism Dev Disord. 1995; Heaton LJ, Vaughn MG, Lewis CW. 2013 update. 2013. Available at: https:// 25(3):283–294 Predictors of unmet dental need in iacc.hhs.gov/publications/strategic- 581. Handen BL, Johnson CR, Lubetsky M. children with autism spectrum plan/2013/. Accessed March 25, 2017 Efficacy of methylphenidate among disorder: results from a national 570. Interagency Autism Coordinating children with autism and symptoms of sample. Acad Pediatr. 2014;14(6): fi Committee. IACC strategic plan for attention-de cit hyperactivity disorder. 624–631 autism spectrum disorder: 2017 J Autism Dev Disord. 2000;30(3): – 561. Adams RC, Levy SE; Council on Children update. Available at: https://iacc.hhs. 245 255 with Disabilities. Shared decision- gov/publications/strategic-plan/2017/. 582. Research Units on Pediatric making and children with disabilities: Accessed December 1, 2019 Psychopharmacology Autism Network. pathways to consensus. Pediatrics. Randomized, controlled, crossover trial 571. Interagency Autism Coordinating 2017;139(6):e20170956 of methylphenidate in pervasive Committee. IACC strategic plan for developmental disorders with 562. Huws JC, Jones RS. Diagnosis, autism spectrum disorder research: disclosure, and having autism: an hyperactivity. Arch Gen Psychiatry. 2005; 2011 update. 2011. Available at: https:// 62(11):1266–1274 interpretative phenomenological iacc.hhs.gov/publications/strategic- analysis of the perceptions of young plan/2011/. Accessed March 25, 2017 583. Pearson DA, Santos CW, Aman MG, et al. people with autism. J Intellect Dev Effects of extended release Disabil. 2008;33(2):99–107 572. Rutter M, Bailey A, Lord C. The Social methylphenidate treatment on ratings Communication Questionnaire (SCQ) of attention-deficit/hyperactivity 563. White PH, Cooley WC; Transitions Manual. Los Angeles, CA: Western Clinical Report Authoring Group; disorder (ADHD) and associated Psychological Services; 2003 American Academy of Pediatrics; behavior in children with autism American Academy of Family 573. Stone WL, Coonrod EE, Ousley O. Brief spectrum disorders and ADHD Physicians; American College of report: screening tool for autism in symptoms. J Child Adolesc – Physicians. Supporting the health care two-year-olds (STAT): development and Psychopharmacol. 2013;23(5):337 351 transition from adolescence to preliminary data. J Autism Dev Disord. 584. Posey DJ, Aman MG, McCracken JT, adulthood in the medical home 2000;30(6):607–612 et al. Positive effects of

Downloaded from www.aappublications.org/news by guest on October 1, 2021 62 FROM THE AMERICAN ACADEMY OF PEDIATRICS methylphenidate on inattention and double-blind, placebo-controlled study 601. Aman MG, Lam KS, Van Bourgondien ME. hyperactivity in pervasive of the efficacy of transdermal clonidine Medication patterns in patients with developmental disorders: an analysis of in autism. J Clin Psychiatry. 1992;53(3): autism: temporal, regional, and secondary measures. Biol Psychiatry. 77–82 demographic influences. J Child 2007;61(4):538–544 Adolesc Psychopharmacol. 2005;15(1): 593. Handen BL, Sahl R, Hardan AY. 116–126 585. Reichow B, Volkmar FR, Bloch MH. Guanfacine in children with autism Systematic review and meta-analysis of and/or intellectual disabilities. J Dev 602. Aman M, Rettiganti M, Nagaraja HN, pharmacological treatment of the Behav Pediatr. 2008;29(4):303–308 et al. Tolerability, safety, and benefits of symptoms of attention-deficit/ risperidone in children and adolescents 594. Scahill L, McCracken JT, King BH, et al; hyperactivity disorder in children with with autism: 21-month follow-up after 8- Research Units on Pediatric pervasive developmental disorders. week placebo-controlled trial. J Child Psychopharmacology Autism Network. J Autism Dev Disord. 2013;43(10): Adolesc Psychopharmacol. 2015;25(6): Extended-release guanfacine for 2435–2441 482–493 hyperactivity in children with autism 586. Jahromi LB, Kasari CL, McCracken JT, spectrum disorder. Am J Psychiatry. 603. Research Units on Pediatric et al. Positive effects of 2015;172(12):1197–1206 Psychopharmacology Autism Network. methylphenidate on social Risperidone treatment of autistic 595. McCracken JT, McGough J, Shah B, et al; communication and self-regulation in disorder: longer-term benefits and Research Units on Pediatric children with pervasive developmental blinded discontinuation after 6 months. Psychopharmacology Autism Network. disorders and hyperactivity. J Autism Am J Psychiatry. 2005;162(7):1361–1369 Dev Disord. 2009;39(3):395–404 Risperidone in children with autism and serious behavioral problems. 604. Pandina GJ, Bossie CA, Youssef E, Zhu Y, 587. Santosh PJ, Baird G, Pityaratstian N, N Engl J Med. 2002;347(5):314–321 Dunbar F. Risperidone improves Tavare E, Gringras P. Impact of behavioral symptoms in children with 596. Shea S, Turgay A, Carroll A, et al. comorbid autism spectrum disorders autism in a randomized, double-blind, Risperidone in the treatment of on stimulant response in children with placebo-controlled trial. J Autism Dev fi disruptive behavioral symptoms in attention de cit hyperactivity disorder: Disord. 2007;37(2):367–373 a retrospective and prospective children with autistic and other effectiveness study. Child Care Health pervasive developmental disorders. 605. Marcus RN, Owen R, Manos G, et al. Dev. 2006;32(5):575–583 Pediatrics. 2004;114(5). Available at: Safety and tolerability of aripiprazole www.pediatrics.org/cgi/content/full/ for irritability in pediatric patients with 588. Arnold LE, Aman MG, Cook AM, et al. 114/5/e634 autistic disorder: a 52-week, open-label, Atomoxetine for hyperactivity in autism multicenter study. J Clin Psychiatry. spectrum disorders: placebo-controlled 597. Marcus RN, Owen R, Kamen L, et al. A 2011;72(9):1270–1276 crossover pilot trial. J Am Acad Child placebo-controlled, fixed-dose study of Adolesc Psychiatry. 2006;45(10): aripiprazole in children and 606. Kent JM, Kushner S, Ning X, et al. 1196–1205 adolescents with irritability associated Risperidone dosing in children and 589. Harfterkamp M, Buitelaar JK, Minderaa with autistic disorder. J Am Acad Child adolescents with autistic disorder: RB, van de Loo-Neus G, van der Gaag RJ, Adolesc Psychiatry. 2009;48(11): a double-blind, placebo-controlled – Hoekstra PJ. Long-term treatment with 1110 1119 study. J Autism Dev Disord. 2013;43(8): 1773–1783 atomoxetine for attention-deficit/ 598. Owen R, Sikich L, Marcus RN, et al. hyperactivity disorder symptoms in Aripiprazole in the treatment of 607. Findling RL, Mankoski R, Timko K, et al. children and adolescents with autism irritability in children and adolescents A randomized controlled trial spectrum disorder: an open-label with autistic disorder. Pediatrics. 2009; investigating the safety and efficacy of extension study. J Child Adolesc 124(6):1533–1540 aripiprazole in the long-term Psychopharmacol. 2013;23(3):194–199 maintenance treatment of pediatric 599. Arnold LE, Vitiello B, McDougle C, et al. patients with irritability associated with 590. Handen BL, Aman MG, Arnold LE, et al. Parent-defined target symptoms autistic disorder. J Clin Psychiatry. Atomoxetine, parent training, and their respond to risperidone in RUPP autism 2014;75(1):22–30 combination in children with autism study: customer approach to clinical spectrum disorder and attention- trials. J Am Acad Child Adolesc 608. Troost PW, Lahuis BE, Steenhuis MP, deficit/hyperactivity disorder. JAm Psychiatry. 2003;42(12):1443–1450 et al. Long-term effects of risperidone Acad Child Adolesc Psychiatry. 2015; in children with autism spectrum 600. Aman MG, McDougle CJ, Scahill L, et al; 54(11):905–915 disorders: a placebo discontinuation Research Units on Pediatric study. J Am Acad Child Adolesc 591. Jaselskis CA, Cook EH Jr., Fletcher KE, Psychopharmacology Autism Network. Psychiatry. 2005;44(11):1137–1144 Leventhal BL. Clonidine treatment of Medication and parent training in hyperactive and impulsive children with children with pervasive developmental 609. Anagnostou E, Aman MG, Handen BL, autistic disorder. J Clin disorders and serious behavior et al. Metformin for treatment of – Psychopharmacol. 1992;12(5):322 327 problems: results from a randomized overweight induced by atypical 592. Fankhauser MP, Karumanchi VC, clinical trial. J Am Acad Child Adolesc antipsychotic medication in young German ML, Yates A, Karumanchi SD. A Psychiatry. 2009;48(12):1143–1154 people with autism spectrum disorder:

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 1, January 2020 63 a randomized clinical trial. JAMA 616. Wasserman S, Iyengar R, Chaplin WF, global severity in adult autism Psychiatry. 2016;73(9):928–937 et al. Levetiracetam versus placebo in spectrum disorders. Am J Psychiatry. childhood and adolescent autism: 2012;169(3):292–299 610. Fung LK, Mahajan R, Nozzolillo A, et al. a double-blind placebo-controlled study. Pharmacologic treatment of severe 624. Hollander E, Phillips A, Chaplin W, et al. Int Clin Psychopharmacol. 2006;21(6): irritability and problem behaviors in A placebo controlled crossover trial of 363–367 autism: a systematic review and meta- liquid fluoxetine on repetitive behaviors analysis. Pediatrics. 2016;137(suppl 2): 617. Hirota T, Veenstra-Vanderweele J, in childhood and adolescent autism. S124–S135 Hollander E, Kishi T. Antiepileptic Neuropsychopharmacology. 2005;30(3): medications in autism spectrum 582–589 611. King BH, Hollander E, Sikich L, et al; disorder: a systematic review and STAART Psychopharmacology Network. meta-analysis. J Autism Dev Disord. 625. Ji N, Findling RL. An update on Lack of efficacy of citalopram in 2014;44(4):948–957 pharmacotherapy for autism spectrum children with autism spectrum disorder in children and adolescents. 618. Canitano R. Mood stabilizers in children disorders and high levels of repetitive Curr Opin Psychiatry. 2015;28(2):91–101 and adolescents with autism spectrum behavior: citalopram ineffective in disorders. Clin Neuropharmacol. 2015; 626. Couturier JL, Nicolson R. A children with autism. Arch Gen – retrospective assessment of citalopram – 38(5):177 182 Psychiatry. 2009;66(6):583 590 in children and adolescents with 619. Niederhofer H. Venlafaxine has modest pervasive developmental disorders. 612. McDougle CJ, Naylor ST, Cohen DJ, effects in autistic children. Therapy. J Child Adolesc Psychopharmacol. 2002; Volkmar FR, Heninger GR, Price LH. A 2004;1(1):87–90 double-blind, placebo-controlled study 12(3):243–248 620. McDougle CJ, Holmes JP, Carlson DC, of fluvoxamine in adults with autistic 627. Namerow L, Thomas P, Bostic JQ, Prince Pelton GH, Cohen DJ, Price LH. A double- disorder. Arch Gen Psychiatry. 1996; J, Monuteaux MC. Use of citalopram in blind, placebo-controlled study of 53(11):1001–1008 pervasive developmental disorders. risperidone in adults with autistic J Dev Behav Pediatr. 2003;24(2):104–108 613. Hollander E, Chaplin W, Soorya L, et al. disorder and other pervasive Divalproex sodium vs placebo for the developmental disorders. Arch Gen 628. Strawn JR, Welge JA, Wehry AM, Keeshin treatment of irritability in children and Psychiatry. 1998;55(7):633–641 B, Rynn MA. Efficacy and tolerability of adolescents with autism spectrum 621. Hollander E, Soorya L, Wasserman S, antidepressants in pediatric anxiety disorders. Neuropsychopharmacology. Esposito K, Chaplin W, Anagnostou E. disorders: a systematic review and 2010;35(4):990–998 Divalproex sodium vs. placebo in the meta-analysis. Depress Anxiety. 2015; – 614. Belsito KM, Law PA, Kirk KS, Landa RJ, treatment of repetitive behaviours in 32(3):149 157 Zimmerman AW. Lamotrigine therapy autism spectrum disorder. Int 629. Buitelaar JK, van der Gaag RJ, van der for autistic disorder: a randomized, J Neuropsychopharmacol. 2006;9(2): Hoeven J. Buspirone in the double-blind, placebo-controlled trial. 209–213 management of anxiety and irritability J Autism Dev Disord. 2001;31(2): 622. Rezaei V, Mohammadi MR, Ghanizadeh in children with pervasive 175–181 A, et al. Double-blind, placebo- developmental disorders: results of an open-label study. J Clin Psychiatry. 1998; 615. Hellings JA, Nickel EJ, Weckbaugh M, controlled trial of risperidone plus 59(2):56–59 McCarter K, Mosier M, Schroeder SR. topiramate in children with autistic The overt aggression scale for rating disorder. Prog Neuropsychopharmacol 630. Vasa RA, Carroll LM, Nozzolillo AA, et al. – aggression in outpatient youth with Biol Psychiatry. 2010;34(7):1269 1272 A systematic review of treatments for autistic disorder: preliminary findings. 623. Hollander E, Soorya L, Chaplin W, et al. A anxiety in youth with autism spectrum J Neuropsychiatry Clin Neurosci. 2005; double-blind placebo-controlled trial of disorders. J Autism Dev Disord. 2014; 17(1):29–35 fluoxetine for repetitive behaviors and 44(12):3215–3229

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Supplemental Information

SUPPLEMENTAL TABLE 14 Recurrent CNVs Most Commonly Identified in Cohorts With ASD by Using CMA Analysis CNV Region Frequencya Common Clinical Features 16p11.2 deletion 1 in 304 ASD, DD or ID, expressive language impairment, relative or absolute macrocephaly, overweight 16p11.2 duplication 1 in 396 ASD, schizophrenia, bipolar disorder, ADHD, relative or absolute microcephaly, underweight 15q11.2-q13 (BP2–BP3) duplication 1 in 494 ASD, DD or ID, epilepsy, hypotonia, ataxia, behavior problems 15q13.2-q13.3 (BP4–BP5) deletion 1 in 659 ASD, DD or ID, epilepsy, schizophrenia, cardiac defects 1q21.1 duplication 1 in 659 ASD, DD or ID, schizophrenia, ADHD, relative macrocephaly, hypertelorism 22q11.2 duplication 1 in 659 ASD, DD or ID, hypotonia, motor delay 16p13.11 deletion 1 in 791 ASD, DD or ID, epilepsy, schizophrenia, congenital anomalies 7q11.23 duplication 1 in 989 ASD, DD or ID, growth retardation, hypotonia 16p12.2 deletion 1 in 989 ASD, DD or ID, schizophrenia, epilepsy, growth retardation, cardiac defects, microcephaly, hypotonia 17q12 deletion 1 in 1978 ASD, DD or ID, schizophrenia, renal cysts, mature-onset diabetes of the young type 5 15q13.2–13.3 (BP4–BP5) duplication 1 in 1978 ASD, DD or ID, obesity BP2 breakpoint 2; BP3 breakpoint 3; BP4 breakpoint 4; BP5 breakpoint 5; DD developmental delay; ID intellectual disability. a Moreno-De-Luca D et al631; the frequency of each CNV among 3955 probands with ASD from the Autism Genetic Resource Exchange, Autism Genome Project, and Simons Foundation Autism Research Initiative Simplex Collection cohorts.

PEDIATRICS Volume 145, Number 1, January 2020 1 Downloaded from www.aappublications.org/news by guest on October 1, 2021 2 SUPPLEMENTAL TABLE 13 Selected Genetic Syndromes Associated With ASD Condition Physical Findings Gene Confirmatory Testing Importance Fragile X syndrome Long face, prominent forehead and jaw, FMR1 (CGG repeat Targeted mutation analysis (PCR and Genetic counseling (X-linked dominant large ears, joint laxity, macroorchidism expansion, abnormal Southern blot) inheritance); all mothers of individuals after puberty in boys methylation) with an FMR1 full mutation are carriers of an FMR1 premutation or full mutation; extended family counseling is necessary; premutation carriers are at risk for fragile X–associated tremor/ ataxia syndrome and FMR1-related primary ovarian insufficiency in female patients; several targeted Downloaded from pharmacologic therapies are under investigation Neurofibromatosis 1 Multiple café-au-lait macules, axillary and NF1 Clinical criteria; optimized protein Genetic counseling (autosomal dominant inguinal freckling, iris Lisch nodules, truncation testing, sequence analysis, inheritance); 50% de novo, 50% cutaneous neurofibromas and deletion or duplication analysis are inherited; associated problems available but infrequently required requiring investigation or monitoring www.aappublications.org/news (optic gliomas, other CNS tumors, peripheral nerve sheath tumors, vasculopathy, hypertension, orthopedic issues, osteopenia) PTEN hamartoma tumor syndrome (includes Marked macrocephaly, skin hamartomas, PTEN PTEN sequence analysis, deletion or Genetic counseling (autosomal dominant Cowden syndrome and pigmented macules of the glans penis duplication analysis inheritance with highly variable Bannayan-Riley-Ruvalcaba syndrome) expression); associated problems requiring investigation or monitoring (significant risk of benign and malignant tumors of the thyroid, byguest on October1,2021 breast, and endometrium as well as intestinal polyps, colorectal cancer, renal cell carcinoma, cutaneous melanoma, and cerebellar dysplastic gangliocytoma) Rett syndrome Deceleration of head growth velocity, MECP2 MECP2 sequence analysis, deletion or Genetic counseling (.99% de novo, ,1% acquired microcephaly, loss of duplication analysis germline mosaicism); associated purposeful hand use, prominent hand problems requiring investigation or stereotypies (especially hand wringing monitoring and anticipatory guidance or clasping), apraxia, hyperventilation (failure to thrive, gastroesophageal or breath-holding, seizures reflux, respiratory problems, osteopenia, sudden death); targeted pharmacologic therapy under investigation Smith-Lemli-Opitz syndrome Characteristic facial features (narrow DHCR7 7-dehydrocholesterol level (elevated); DHCR7 Genetic counseling (autosomal recessive forehead, low-set ears, ptosis, sequence analysis available inheritance); potential role for epicanthal folds, short nose, treatment with cholesterol anteverted nares), microcephaly, cleft palate, 2- to 3-toe syndactyly, postaxial polydactyly, hypospadias in male EITISVlm 4,Nme ,Jnay2020 January 1, Number 145, Volume PEDIATRICS SUPPLEMENTAL TABLE 13 Continued Condition Physical Findings Gene Confirmatory Testing Importance patients, prenatal and postnatal growth retardation Timothy syndrome Long QT interval, other ECG abnormalities CACNA1C Targeted mutation analysis, sequence Genetic counseling, autosomal dominant, (atrioventricular block, macroscopic analysis, deletion or duplication analysis usually de novo, but parental germline T-wave alternans), congenital heart mosaicism has been observed; defects, cutaneous syndactyly, low-set treatment related to long QTc ears, flat nasal bridge, thin upper lip, (b-blocker, pacemaker, implantable round facies, baldness for the first 2 y defibrillator) and avoidance of

Downloaded from of life followed by thin scalp hair, hypoglycemia dental abnormalities, frequent infections because of altered immune response, intermittent hypoglycemia Tuberous sclerosis Hypopigmented macules, angiofibromas, TSC1, TSC2 Clinical criteria; TSC1 and TSC2 sequencing Genetic counseling (autosomal dominant shagreen patches (connective tissue available inheritance); associated problems www.aappublications.org/news nevi), ungual fibromas, retinal requiring investigation or monitoring hamartomas (CNS tumors, seizures, renal angiomyolipomas or cysts, cardiac rhabdomyomas and arrhythmias); potential role for targeted pharmacologic therapy (mTOR inhibitors) CACNA1C, calcium channel, voltage-dependent, L-type, a-1c subunit; CGG, cytosine-guanine-guanine; CNS, central nervous system; DHCR7, 7-dehydrocholesterol reductase; ECG, electrocardiogram; FMR1, fragile X mental retardation 1; MECP2, methyl CpG binding protein 2; mTOR, mammalian target of rapamycin; PCR, polymerase chain reaction; PTEN, phosphatase and tensin homolog; QTc, corrected QT interval; TSC1, tuberous sclerosis 1; TSC2, tuberous sclerosis 2. Adapted with permission from Myers SM, Challman TD. Autism Spectrum Disorders. In: Voigt RG, Macias MM, Myers SM, eds. Developmental and Behavioral Pediatrics. Elk Grove Village, IL: American Academy of Pediatrics; 2011:249–291. byguest on October1,2021 RMTEAEIA CDM FPEDIATRICS OF ACADEMY AMERICAN THE FROM 3 SUPPLEMENTAL TABLE 15 Selected ASD Risk Genes Identified or Confirmed in Whole-Exome Studies Gene Gene Name Broad Functional Categorization SCN2A sodium channel, voltage-gated, type II, a subunit Synaptic functions (eg, ion channels, neurotransmitter receptors, cell adhesion GRIN2B glutamate receptor, ionotropic, N-methyl-D-aspartate 2B molecules, microtubule assembly, scaffolding proteins, actin cytoskeleton) KATNAL2 katanin p60 subunit A-like 2 ANK2 ankyrin 2, neuronal DSCAM Down syndrome cell adhesion molecule NRXN1 neurexin 1 SHANK2 SH3 and multiple ankyrin repeat domains 2 SHANK3 SH3 and multiple ankyrin repeat domains 3

PTEN phosphatase and tensin homolog Intracellular signaling, activity-dependent synaptic protein synthesis and SYNGAP1 synaptic Ras GTPase activating protein 1 degradation DYRK1A dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A POGZ pogo transposable element with ZNF domain CUL3 cullin 3

CHD2 chromodomain helicase DNA binding protein 2 Transcription regulation, chromatin remodeling CHD8 chromodomain helicase DNA binding protein 8 ADNPa activity-dependent neuroprotector homeobox ARID1B AT rich interactive domain 1B (SWI1-like) ASH1L ASH1 (absent, small, or homeotic)-like KDM5B lysine-specific demethylase 5B KMT2C lysine-specific methyltransferase 2C SETD5 SET domain containing 5 TBR1 T-box, brain, 1 Based on de novo loss of function variants and small de novo deletions (false discovery rate , 0.01). Adapted from Sanders SJ, He X, Willsey AJ, et al; Autism Sequencing Consortium. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron. 2015;87(6):1215–1233; Krumm N, O’Roak BJ, Shendure J, Eichler EE. A de novo convergence of autism genetics and molecular neuroscience. Trends Neurosci. 2014;37(2):95–105; Brandler WM, Sebat J. From de novo mutations to personalized therapeutic interventions in autism. Annu Rev Med. 2015;66:487–507; De Rubeis S, He X, Goldberg AP, et al; DDD Study; Homozygosity Mapping Collaborative for Autism; UK10K Consortium. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515(7526):209–215; Bourgeron T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurosci. 2015;16(9):551–563; and Sanders SJ, Murtha MT, Gupta AR, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012; 485(7397):237–241. a Also involved in microtubule dynamics at the synapse.

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SUPPLEMENTAL TABLE 16 Selected Metabolic Conditions That May (Rarely) Be Associated With an ASD Phenotype Disorders of amino acid metabolism Phenylketonuria (untreated) Homocystinuria Branched-chain ketoacid dehydrogenase kinase deficiency Disorders of g-aminobutyric acid metabolism Succinic semialdehyde dehydrogenase deficiency Disorders of cholesterol metabolism Smith-Lemli-Opitz syndrome (7-dehydrocholesterol reductase deficiency) Disorders associated with cerebral folate deficiency Folate receptor 1 gene mutations Dihydrofolate reductase deficiency Disorders of creatine transport or metabolism Arginine-glycine amidinotransferase deficiency Guanidinoacetate methyltransferase deficiency X-linked creatine transporter deficits Disorders of carnitine biosynthesis 6-N-trimethyllysine dioxygenase deficiency Disorders of purine and pyrimidine metabolism Adenylosuccinate lyase deficiency Adenosine deaminase deficiency Cytosolic 59-nucleotidase superactivity Dihydropyrimidine dehydrogenase deficiency Phosphoribosyl pyrophosphate synthetase superactivity Lysosomal storage disorders Sanfilippo syndrome (mucopolysaccharidosis type III) Mitochondrial disorders Mitochondrial DNA mutations Nuclear DNA mutations Others Biotinidase deficiency Urea cycle defects Adapted from Schaefer GB, Mendelsohn NJ; Professional Practice and Guidelines Com- mittee. Clinical genetics evaluation in identifying the etiology of autism spectrum dis- orders: 2013 guideline revisions. Genet Med. 2013;15(5):399–407; Legido A, Jethva R, Goldenthal MJ. Mitochondrial dysfunction in autism. Semin Pediatr Neurol. 2013;20(3): 163–175; Jiang YH, Wang Y, Xiu X, Choy KW, Pursley AN, Cheung SW. Genetic diagnosis of autism spectrum disorders: the opportunity and challenge in the genomics era. Crit Rev Clin Lab Sci. 2014;51(5):249–262; and Frye RE. Metabolic and mitochondrial disorders associated with epilepsy in children with autism spectrum disorder. Epilepsy Behav. 2015; 47:147–157.

SUPPLEMENTAL REFERENCES data sets to infer pathogenicity for cohorts. Mol Psychiatry. 2013;18(10): rare copy number variants in autism 1090–1095 631 . Moreno-De-Luca D, Sanders SJ, Willsey AJ, et al. Using large clinical

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