92204 • Autism Spectrum Disorder

Table of Contents

92204 • Autism Spectrum Disorder

How to Receive Credit

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Individual State Behavioral Health Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. EPIDEMIOLOGY

3. ETIOLOGY: RESEARCH AND THEORIES

OBSTETRIC COMPLICATIONS

INFECTION

FAMILIAL/GENETIC FACTORS

VACCINATIONS

PARENTAL AGE

4. THE PATHOPHYSIOLOGY OF ASD

5. SCREENING AND DIAGNOSIS

DIAGNOSTIC CRITERIA

DIFFERENTIAL DIAGNOSIS OF ASD

6. COMORBIDITIES

SEIZURE DISORDERS

SLEEP DISORDERS/DISTURBANCE

ADHD

ANXIETY DISORDERS

MOOD DISORDERS

GASTROINTESTINAL ISSUES

7. TREATMENT

EVIDENCE-BASED RECOMMENDATIONS

CHARACTERISTICS OF EFFECTIVE INTERVENTIONS

NATURALISTIC DEVELOPMENTAL BEHAVIORAL INTERVENTIONS

PARENT-FOCUSED BEHAVIORAL MANAGEMENT PROGRAMS

NEURODIVERSITY-AFFIRMING INTERVENTIONS

EDUCATIONAL INTERVENTIONS

SPEECH-LANGUAGE INTERVENTIONS

PHARMACOTHERAPY

COMPLEMENTARY AND ALTERNATIVE MEDICINE

8. IMPACT OF ASD ON THE FAMILY

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

9. PROGNOSIS

10. CONCLUSION

11. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

92204 • Autism Spectrum Disorder

Mary Franks, MSN, APRN, FNP-C

Sharon M. Griffin, RN, PhD

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

For many years, children with autism were thought to have emotional problems or to suffer from schizophrenia. However, it is now understood that autism spectrum disorder is a neurodevelopmental disorder, characterized by specific symptoms that vary in type and severity with each individual. Over the years, the diagnosis of autism has changed dramatically, and many patients, parents, and healthcare professionals are facing an adjustment to these changes.

92204 • Autism Spectrum Disorder

Education Category. Pediatrics

Release Date. 01/01/2024

Expiration Date. 12/31/2026

How to Receive Credit

To complete this course for continuing education credit please go to http://www.netce.com/course/2722 in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

Course Overview

For many years, children with autism were thought to have emotional problems or to suffer from schizophrenia. However, it is now understood that autism spectrum disorder is a neurodevelopmental disorder, characterized by specific symptoms that vary in type and severity with each individual. Over the years, the diagnosis of autism has changed dramatically, and many patients, parents, and healthcare professionals are facing an adjustment to these changes.

Audience

This course is designed for healthcare professionals in all practice settings who may be involved in the care of patients with an autism spectrum disorder.

Accreditations & Approvals

In support of improving patient care, NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE has been approved by NBCC as an Approved Continuing Education Provider, ACEP No. 6361. Programs that do not qualify for NBCC credit are clearly identified. NetCE is solely responsible for all aspects of the programs. As a Jointly Accredited Organization, NetCE is approved to offer social work continuing education by the Association of Social Work Boards (ASWB) Approved Continuing Education (ACE) program. Organizations, not individual courses, are approved under this program. Regulatory boards are the final authority on courses accepted for continuing education credit. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 5 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 5 ANCC contact hour(s). NetCE designates this continuing education activity for 1 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 6 hours for Alabama nurses. NetCE designates this continuing education activity for 2 NBCC clock hour(s). Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 5 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. Social workers participating in this intermediate to advanced course will receive 5 Clinical continuing education clock hours. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. Successful completion of this CME activity, which includes participation in the activity with individual assessments of the participant and feedback to the participant, enables the participant to earn 5 MOC points in the American Board of Pediatrics' (ABP) Maintenance of Certification (MOC) program. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABP MOC credit. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 0.5 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through July 29,2025); Alabama, Provider #ABNP0353, (valid through July 29, 2025); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2025; South Carolina, Provider #50-2405; South Carolina, Provider #50-2405. West Virginia RN and APRN, Provider #50-2405.

Individual State Behavioral Health Approvals

In addition to states that accept ASWB, NetCE is approved as a provider of continuing education by the following state boards: Alabama State Board of Social Work Examiners, Provider #0515; Florida Board of Clinical Social Work, Marriage and Family Therapy and Mental Health Counseling, CE Broker Provider #50-2405; Illinois Division of Professional Regulation for Social Workers, License #159.001094; Illinois Division of Professional Regulation for Licensed Professional and Clinical Counselors, License #197.000185; Illinois Division of Professional Regulation for Marriage and Family Therapists, License #168.000190;

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

Autism spectrum disorder (ASD) has a significant impact on daily functioning and quality of life and has significant morbidity and disability associated with severe cases. However, it often goes unrecognized and is commonly underdiagnosed. The purpose of this course is to educate healthcare professionals about the epidemiology, diagnosis, and management of ASD. Additionally, this course will provide the information necessary to screen children seen in primary care for ASD in order to appropriately refer patients and their families for more expansive assessment and treatment referral as rapidly as possible in order to avoid unnecessary morbidity and mortality.

Learning Objectives

Upon completion of this course, you should be able to:

1. Review the epidemiology of autism spectrum disorder (ASD).

2. Discuss the theories of autism etiology and pathophysiology.

3. Discuss components of screening for and diagnosing autism, including the impact of comorbidities on ASD diagnosis and treatment.

4. Identify the goals of treatment for children with ASD.

5. Discuss the classes of evidence-based interventions and characteristics of effective treatments for ASD.

6. Outline the role of pharmacotherapy in the management of ASD.

7. Discuss the impact of ASD on the family.

8. Review the prognosis of individuals diagnosed with ASD.

Faculty

Sharon M. Griffin, RN, PhD, specializes in Health Education and Chronic Disease Management especially as it relates to her primary areas of study and research. She has more than 30 years of healthcare experience nationwide and is an accomplished author, presenter and consultant. She frequently lectures on the subjects of Attention Deficit/Hyperactivity Disorder (AD/HD), Obsessive-Compulsive Disorder (OCD) and related disorders. Dr. Griffin is the cofounder of the University Center for Assessment and Learning (UCAL) of Andrews University in Berrien Springs, Michigan. She enjoys writing and teaching and has been listed in Who’s Who in American Nursing, Two Thousand Notable American Women, and the eleventh edition of the World Who’s Who of Women, Cambridge, England.

Mary Franks, MSN, APRN, FNP-C, is a board-certified Family Nurse Practitioner and NetCE Nurse Planner. She works as a Nurse Division Planner for NetCE and a per diem nurse practitioner in urgent care in Central Illinois. Mary graduated with her Associate’s degree in nursing from Carl Sandburg College, her BSN from OSF Saint Francis Medical Center College of Nursing in 2013, and her MSN with a focus on nursing education from Chamberlain University in 2017. She received a second master's degree in nursing as a Family Nurse Practitioner from Chamberlain University in 2019. She is an adjunct faculty member for a local university in Central Illinois in the MSN FNP program. Her previous nursing experience includes emergency/trauma nursing, critical care nursing, surgery, pediatrics, and urgent care. As a nurse practitioner, she has practiced as a primary care provider for long-term care facilities and school-based health services. She enjoys caring for minor illnesses and injuries, prevention of disease processes, health, and wellness. In her spare time, she stays busy with her two children and husband, coaching baseball, staying active with her own personal fitness journey, and cooking. She is a member of the American Association of Nurse Practitioners and the Illinois Society of Advanced Practice Nursing, for which she is a member of the bylaws committee.

Faculty Disclosure

Contributing faculty, Sharon M. Griffin, RN, PhD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Contributing faculty, Mary Franks, MSN, APRN, FNP-C, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John V. Jurica, MD, MPH

Sharon Cannon, RN, EdD, ANEF

Alice Yick Flanagan, PhD, MSW

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

For several decades after the first description of autism in 1911, children with autism were thought to have emotional problems or to suffer from a type of schizophrenia. In 1938, the Austrian pediatrician Hans Asperger identified a similar syndrome, with social or emotional impairment as the core feature, that he termed "autistic psychopathy," and in 1944, he published a comprehensive study on the topic [1]. Asperger's observations did not become widely known until 1981, and the syndrome was not included in medical diagnostic manuals until 1994 [1].

Autism spectrum disorder (ASD) is now understood to be a neurodevelopmental disorder that affects communication and behavior. Although ASD can be diagnosed at any age, it is classified as a developmental disorder because symptoms generally appear in the first two to three years of life [2]. ASD is identified as a "spectrum" disorder because it is characterized by wide variation in the type and severity of symptoms that each individual experiences [3]. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR), people with ASD have difficulty with communication and interpersonal interactions, restricted interests and repetitive behaviors, and symptoms or behaviors that interfere with the individual's ability to function properly at school, at work, and in all other areas of life [2,4].

The independent diagnoses of autistic disorder, atypical autism, Asperger disorder, childhood autism, childhood disintegrative disorder, early infantile autism, high-functioning autism, Kanner autism, and pervasive developmental disorder not otherwise specified have been in common use for some time; however, these subtypes have largely been abandoned in favor of a diagnosis that reflects the current understanding of autism. Individuals with one of these previously established diagnoses, and any new cases, will now generally be given a diagnosis of ASD [4]. The goal of the spectrum diagnosis is to make a diagnosis of ASD less subjective and more specific, in order to correctly exclude those who do not have ASD while correctly identifying and including those who do while eliminating the previous strict age requirement (prior to 3 years of age) [5]. The DSM-5-TR also separates the behavioral criteria from medical conditions that may underlie the cause for the behavioral symptoms of ASD.

There has been debate about whether the new diagnostic criteria and the rediagnosis of patients using the new criteria will create gaps in treatment or problems with insurance coverage, but the unreliability of the older criteria necessitated a change. Studies have shown that most patients (91%) with a previously diagnosed pervasive developmental disorder are subsequently diagnosed with ASD [6].

2. EPIDEMIOLOGY

Autism is the most common neurodevelopmental disorder in the United States. Estimates of the prevalence of ASD suggest that as many as 400,000 individuals in the United States have ASD or a related condition [7]. In the United States, ASD prevalence is 1 in 36 children at 8 years of age and is 3.8 times more common among boys than girls, with male-to-female prevalence ratios was 3.8 [8]. Prevalence estimates among White children (24.3) was lower than prevalence among Black, Hispanic, or Asian/Pacific Islander children (29.3, 31.6, and 33.4, respectively). ASD prevalence among children of two or more races was 22.9, which was not different than among White children but was lower than prevalence among Asian/Pacific Islander, Black, and Hispanic children [8]. In addition, Black children have less access to services than White children with ASD. The overall median age at earliest known ASD diagnosis (49 months of age) is similar by sex and by racial and ethnic groups [8]. Reported rates of ASD have been rising in many countries for more than two decades. Based on a review of epidemiologic studies, the global prevalence of ASD is estimated to be 7.6 cases per 1,000 population [9].

In 2015, the direct and indirect costs of caring for children and adults with ASD in the United States were estimated to be $268 billion, more than the cost of stroke and hypertension combined [10]. Lost productivity for caregivers of an individual with ASD averages $18,720 per year [11]. One study found that ASD is associated with approximately $3.6 million in lifetime social costs that could be mitigated by identifying known modifiable risk factors [12].

3. ETIOLOGY: RESEARCH AND THEORIES

Like ASD itself, the theories of autism are diverse and often overlapping. It was once believed that poor parenting caused autism. The terms "refrigerator mother" or "refrigerator parents" were used to describe emotionally frigid parents who were thought to be too distant, cold, and uncaring to allow the child to bond properly. This view has been referred to as the psychogenic theory of autism; however, it remains unsupported by the scientific and medical communities.

The final common pathway theory proposes that the causes of autism all share the characteristic of damage in regions of the brain responsible for the development of normal communication, social functioning, and play [13]. Contemporary researchers have coined the term connectivity theory to describe atypical communication between regions of the brain [14]. The connectivity referenced is generally functional connectivity, or the degree to which synchronized activity occurs between brain regions. By examining connectivity patterns while participants rest in a brain scanner, researchers report that autism is sometimes characterized by underconnectivity between distant brain regions, sometimes by overconnectivity between neighboring ones, and sometimes by differences in connectivity within certain brain networks [14].

The signaling imbalance theory of autism suggests that the condition arises from a hyperexcitable brain [15]. Balanced brain signaling occurs when glutamate and gamma-amino butyric acid (GABA) operate in sync, allowing brain cells to be active in some circumstances and muted in others. Brain hyperactivity may contribute to the repetitive behaviors and motor difficulties characteristic of autism and also might contribute to social dysfunction, although this connection is less direct [15].

The predictive coding theory (also called predictive processing or the Bayesian brain) holds that brains generate a model of the world that predicts what one sees, hears, touches, smells, and tastes [16]. According to this theory, brains of persons with autism either do not form accurate predictions or sensory input is overridden by the internal predictive models. Predictive coding may account for the social, sensory, and other difficulties of autism [16].

The biologic theory of autism holds that various medical conditions, including gene mutations and/or infections or environmental exposures in genetically predisposed individuals, cause ASD [3]. Studies of have found that certain medical conditions occur with greater frequency in children with ASD than in children without autism. When autism occurs in conjunction with a medical condition that is capable of damaging the nervous system, the medical condition is typically assigned as the cause of autism. Medical conditions that are commonly identified with autism include [17,18,19,20]:

- Fragile X syndrome

- Tuberous sclerosis complex (TSC)

- Congenital rubella

- Herpes encephalitis

- Abnormalities of carbohydrate metabolism

- Moebius syndrome

- Leber congenital amaurosis (an eye disorder)

While the definitive causes of ASD remain unknown, research has focused on obstetric complications, infection, genetics, vaccinations, and parental age [7].

OBSTETRIC COMPLICATIONS

Research suggests that adverse events during the prenatal and perinatal periods and during delivery may place infants at increased risk of ASD. Some of the factors associated with increased ASD risk include hypertension or diabetes in the mother, maternal prepregnancy obesity, threatened abortion, gestational age ≤36 weeks, spontaneous labor, induced labor, pre-eclampsia, and fetal distress [21,22].

The authors of one study compared the frequency of prenatal/perinatal factors among 323 children with ASD, 257 of their unaffected siblings, and 1,504 typically developing controls, and investigated the effects of the factors on the severity of autistic symptoms. Results indicated that the children with ASD and their unaffected siblings had more prenatal/perinatal events than did the typically developing controls, with higher numbers of events in the children with ASD than in their unaffected siblings. Additionally, the events were associated with greater stereotyped behaviors, social-emotional problems, socio-communication deficits, and overall ASD severity. Six prenatal/perinatal events (pre-eclampsia, polyhydramnios, oligoamnios, placenta previa, umbilical cord knot, and gestational diabetes) were associated with the severity of autistic symptoms, particularly stereotyped behaviors and socio-communication deficits [23].

The authors of another study sought to estimate the prevalence of ASD in 899 children, 10 years of age, who were born extremely preterm (23 to 27 weeks gestational age) between 2002 and 2004 [24]. The children were first evaluated with the Autism Diagnostic Interview-Revised (ADI-R). Those who met the ADI-R criteria were then assessed with the Autism Diagnostic Observation Schedule-2 (ADOS-2). A positive ADOS-2 score was the criterion for ASD. Twenty-six participants were not assessed for ASD because of severe sensory or motor impairment. Sixty-one children in the remaining sample met the criteria for ASD, resulting in an overall prevalence of 7.1%. ASD risk decreased with increasing gestational age, from 15.0% at 23 to 24 weeks, to 6.5% at 25 to 26 weeks, to 3.4% 27 weeks [24].

Several studies of one of the largest population-based datasets (nearly 6 million live births) found that children conceived using artificial reproductive technology (ART) were twice as likely to be diagnosed with autism [25]. The exact association is unclear, although the higher likelihood of adverse pregnancy and delivery outcomes with ART are suspect (e.g., twin birth, low birth weight, prematurity). Findings from the Study to Explore Early Development (SEED), a population-based case-control study, found that among 1,538 mother-child pairs, ASD was associated with any female infertility diagnosis and several specific diagnoses (e.g., blocked tubes, endometriosis, uterine-factor infertility, polycystic ovarian syndrome), with associations limited to and much stronger among second or later births. The findings were not explained by sociodemographic factors or multiple or preterm birth, and ASD was not associated with ART or non-ART infertility treatments [26].

Although a number of birth and pregnancy complications have been associated with autism, alone they are unlikely to cause the condition. It is more likely that they either operate in combination with other factors or are indications of existing abnormalities [13,27].

INFECTION

Infections that damage the brain during fetal development or childhood and that have been associated with autism include [17,18,28,29,30,31,32,33,34]:

- Rubella: The rubella virus may damage the fetal brain and result in severe birth defects known as the congenital rubella syndrome (CRS) when infection occurs early in pregnancy. Rubella infection and CRS are now rare in the United States due to widespread vaccination. However, studies have found that rubella vaccines do not elicit a strong immune response in many women and that, even in strong responders, subclinical reinfection is possible, as vaccine-induced immunity is significantly less protective than natural immunity. Epidemiologic studies have found no association between rubella vaccination and autism. Some evidence suggests that altered vitamin A metabolism, which precipitates rubella infection, causes CRS through maternal liver dysfunction and exposure of the fetus to excessive vitamin A, which is a known teratogen.

- Cytomegalovirus (CMV): CMV infection may result in mental handicap/disability/deficit and, more rarely, autism. However, many newborn children who have been exposed to CMV have no apparent problems. While maternal CMV seropositivity is associated with more severe ASD symptoms in children, a direct role for the virus has yet to be determined.

- Herpes encephalitis: The herpes virus can sometimes infect an infant's brain, leading to encephalitis. Occasionally, children who develop herpes encephalitis display an autistic-like condition; however, a definitive role of HSV on the onset of ASD has yet to be determined.

Findings from a 2019 study indicate that fetal exposure to maternal infection that requires hospitalization increases the child's risk for ASD and depression later in life [35]. A population-based cohort study of nearly 1.8 million Swedish children born between 1973 and 2014 were observed for up to 41 years. In the cohort, exposure to maternal infection in pregnancy significantly increased the child's risk for ASD and depression. Estimates for ASD and depression were similar following a severe maternal infection. The hazard ratio following a urinary tract infection was 1.89 for ASD and 1.30 for depression [35].

Maternal infection and fever during pregnancy were evaluated using data from the SEED study of children 2 to 5 years of age born between 2003 and 2006 in the United States. The study explored a possible association between maternal infection and fever during pregnancy and risk of ASD and other developmental disorders (DDs) [36]. The study included three groups of children: 606 with ASD, 856 with a DD, and 796 from the general population, randomly sampled from state birth records. Telephone interviews with the mother as well as maternal prenatal and labor/delivery medical records provided information about infection and fever during pregnancy. ASD and DD status were determined by an in-person standardized developmental assessment of the child at 3 to 5 years of age. After adjustment for covariates, maternal infection anytime during pregnancy was not associated with ASD or DDs. However, second trimester infection accompanied by fever elevated the risk for ASD approximately twofold, suggesting that the inflammatory response to the infectious agent may be relevant [36].

FAMILIAL/GENETIC FACTORS

Evidence Based Practice Recommendation

The American College of Medical Genetics and Genomics recommends a genetic consultation be offered to all persons/families with autism spectrum disorders. Evaluations should be considered for any individual along the entire autism spectrum.

https://www.acmg.net/PDFLibrary/Austism-Spectrum-Genetics-Evaluation.pdf

Last Accessed: December 15, 2023

Level of Evidence: Expert Opinion/Consensus Statement

Autism occurs more frequently in some families than in others. Published estimates of sibling recurrence for ASD range from 6.9% to 19.5% [37,38]. Six hundred sixty-four infants with an older biological sibling with ASD were followed from early in life to 36 months of age, when they were classified as either having or not having ASD, after receiving a clinical diagnosis from an expert clinician. In this study, 18.7% of the infants developed ASD, with infant gender and having more than one older affected sibling being significant predictors of ASD outcome. Male infants had a threefold increased risk of ASD, and infants with more than one older affected sibling had a twofold increased risk of ASD [39]. Additionally, in some families of children with autism, researchers have identified parents who may have undiagnosed ASD [17,40]. This is not surprising given that ASD and related subclinical traits show familial clustering, which supports the role of genetic factors in the architecture of ASD [41,42,43,44,45]. Researchers have identified dozens of copy number variant loci and ASD-relevant genes and loci, many of which overlap those associated with other neurodevelopmental disorders [46,47].

Studies of twins have demonstrated a moderate genetic heritability for ASD and a substantial shared twin environmental component [48]. In studies of twins in which at least one of the twins has a disability, researchers have found that the rate of both identical twins having autism is significantly higher than the rate in nonidentical twins. Studies have also indicated that identical twins have a concordance rate for ASD between 36% and 95%. The rate for nonidentical twins is 0% to 31% [17,49,50].

VACCINATIONS

In the early 1990s, the number of autistic diagnoses was steadily rising. Some believed this to be an epidemic, which pointed to a toxin or other environmental factor as the cause of autism. This perceived epidemic coincided with a change in the childhood vaccine schedule. Some parents of children with autism, along with certain grassroots organizations and researchers, turned their focus to vaccines. They believed that a link existed between autism and vaccines, specifically the preservative, thimerosal.

Thimerosal is 49.6% ethyl mercury, a known neurotoxin [51]. It has been used safely since the 1930s to prevent the contamination of vaccines [52,53]. By 1999, thimerosal was used in more than 30 vaccines in the United States. Although the amount of thimerosal used in each vaccine was less than the amount considered toxic by the Environmental Protection Agency (EPA), when the amounts from all of the required vaccinations for infants were added together, the sum exceeded the safe level [54]. An early study by the Centers for Disease Control and Prevention (CDC) suggested a possible connection between the amount of thimerosal given and certain neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD), speech and language delays, and tics. However, further review led many to feel that this study was flawed [52].

In 1999, the American Academy of Pediatrics (AAP) and the U.S. Public Health Service recommended removing thimerosal from vaccines due to the cumulative exposure risk [55]. However, this was mainly done as a precautionary measure to reduce the population's heavy metal exposure wherever possible, not in response to a known effect. By 2001, all vaccines that were routinely recommended for children in the United States had available alternatives without thimerosal [53].

The Institute of Medicine (IOM) convened several committees to examine the evidence and determine if there was a causal relationship between autism and thimerosal [56,57]. The eighth and final report, published in 2004 by the IOM Immunization Safety Review Committee, concluded that the evidence favored rejection of a causal relationship between thimerosal-containing vaccines and autism [58]. A study of the prevalence of autism in California children, conducted from 1995 to 2007, found that autism rates had continued to increase after thimerosal was eliminated from most childhood vaccines. These results supported the IOM conclusion that thimerosal is not a primary cause of autism [59]. However, some researchers, using the same government data, discovered an overall decrease in neurodevelopmental disorder diagnoses following the removal of thimerosal from vaccines [60]. A 2013 study conducted by the CDC looked at the number of antigens from vaccines during the first two years of life and found that the total amount of antigen from vaccines received was the same between children with ASD and those without ASD [61].

PARENTAL AGE

Advanced paternal age has been suggested as a risk factor for autism, but the evidence for such an association remains mixed [62]. One meta-analysis examined the association while controlling for documented autism risk factors (e.g., family history, perinatal conditions, infant characteristics, demographic variables) [63]. Multiple study methods were adopted, including a birth cohort and a family analysis of siblings discordant for autism. The meta-analysis also included population-based epidemiologic studies. In the birth cohort, autism risk increased with increasing paternal age. The offspring of men 50 years of age and older were 2.2 times more likely to have autism than the offspring of men 20 years of age and younger. The family analysis of discordant siblings showed that affected siblings had older paternal age, after adjusting for maternal age and parity [63].

4. THE PATHOPHYSIOLOGY OF ASD

Neuroimaging studies of patients with ASD reveal abnormal cellular configurations in several regions of the brain, including the frontal and temporal lobes and the cerebellum. Enlargements of the amygdala and the hippocampus are common in childhood. Magnetic resonance imaging (MRI) studies have provided evidence for differences in neuroanatomy and connectivity, specifically reduced or atypical connectivity in frontal brain regions and thinning of the corpus callosum in both children and adults with ASD. Some of the regional differences correlate significantly with the severity of specific autistic symptoms. Similarly, region-specific differences in concentrations of gray matter have been found [7].

Observed reductions in brain GABA (a naturally occurring amino acid and neurotransmitter) are believed to contribute to the sensorimotor and behavioral anomalies manifest in ASD [7,64,65]. Glutathione, the brain's primary antioxidant, makes its impact through the process of oxidative stress, which in turn may play a role in the pathogenesis and pathophysiology of ASD [66]. A 2022 study aimed at replicating previous findings of impaired glutamate metabolism in ASD found that adults with ASD exhibit elevated levels of GABA in the left dorsolateral prefrontal cortex. Concentrations of GABA were quantified in the anterior cingulate cortex and dorsolateral prefrontal cortex of 43 adults with ASD and 43 neurotypical controls by magnetic resonance spectroscopy. The ASD group showed increased absolute GABA concentrations and elevated GABA/creatine ratios in the left dorsolateral prefrontal cortex compared to the controls [67].

Children with ASD have discreet reductions in plasma levels of cysteine, glutathione, and methionine; reductions in the ratio of the enzymes S-adenosyl-L-methionine (SAMe) to S-adenosyl-L-homocystein (central to the regulation of many biologic processes); and reductions in the ratio of reduced to oxidized glutathione (an antioxidant capable of preventing damage to cellular components) [68]. Reduced concentrations of N-acetylaspartate (NAA) (a metabolite generally abundant in the central nervous system) have been associated with cognitive dysfunction, diminished neuronal activity, and reduced cellular oxidative metabolism. Reduced NAA has been found to diminish neuronal metabolism in boys with ASD in contrast to age-matched controls [65,69]. Metabolic anomalies (e.g., elevated blood serotonin, reduced serum biotinidase), impaired mitochondrial function, and neural inflammation also have been identified in some people with ASD [68,70].

5. SCREENING AND DIAGNOSIS

The DSM-5-TR divides the characteristics of ASD into two core domains: social communication/social interaction and restricted/repetitive patterns of behavior [4]. Delays in or absence of the development of spoken language is common in autism. In some instances, language begins to develop appropriately and then seems to stop suddenly. Approximately 25% of children with ASD will have a regression in language or social skills, typically between 18 and 24 months of age [71,72].

Other features of ASD include [7]:

- Developmental regression (13% to 48% of children with ASD have apparently normal development until 15 to 30 months of age, when they lose verbal/nonverbal communication skills)

- The absence of protodeclarative pointing (e.g., using the index finger to indicate an item of interest to another person)

- Unusual responses to environmental stimuli (e.g., screaming at certain sounds)

- The absence of typical responses to pain and physical injury

- The absence of symbolic (make-believe) play

- Vulnerability to infections and febrile illnesses

Developmental screening can be done by a number of healthcare professionals. Those who screen should be uniquely positioned to identify symptoms of ASD early in childhood, support the family through the processes of diagnosis and intervention, and promote the child's developmental health. ASD can sometimes be detected as early as 18 months of age, and by 2 years of age, diagnosis by an experienced professional is considered very reliable. Early diagnosis is critical to providing timely treatment [73].

The AAP recommends that all children be screened for developmental delays and disabilities during regular well-child visits at 9, 18, and 30 months of age, with additional screening as needed for children at high risk for developmental problems due to preterm birth or low birth weight. Additionally, all children should be screened specifically for ASD with a standardized tool at 18 and 24 months of age, with ongoing developmental surveillance [10,74]. Developmental surveillance for ASD includes asking caregivers about any concerns they have about their child's development or behavior, informal observation, and monitoring of symptoms in the context of routine health supervision [10].

The American Academy of Child and Adolescent Psychiatry recommends that the developmental assessment of young children (including infants) and the psychiatric assessment of all children should routinely include questions about ASD symptomology [75]. Guidelines developed by the American Academy of Neurology (AAN) and the Child Neurology Society also recommend that developmental surveillance be performed (using recommended screening tools) at all well-child visits, beginning at infancy and continuing through school-age, and that the evaluations be repeated any time concerns about the child's developmental progress are raised (i.e., not meeting developmental milestones) [76]. (The AAN guideline was retired in 2021.) Developmental screening tools recommended by the AAP include the Ages and Stages Questionnaire, the BRIGANCE Early Childhood Screens, the Child Development Inventories, and the Parents' Evaluations of Developmental Status [75,76]. The U.S. Department of Health and Human Services has provided a compendium of developmental screening tools for young children [77].

After considering the parent's assessment and clinical observations, the provider should assess a positive or negative screen for developmental delays. If specific behaviors are exhibited by the child (Table 1), immediate evaluation for autism should be performed using one of the validated screening instruments [10,78]. If the screening is positive for ASD, a standard psychiatric assessment should follow, including interviews with the child and family, a review of past records, and a full history [10,78].

Table 1: BEHAVIORAL CUES INDICATING THE NEED FOR REFERRAL TO A SPECIALIST

Behavior

Age

No babbling, pointing, or other gestures

By 12 months of age

No single words

By 16 months of age

No two-word, spontaneous (nonecholalic) phrases

By 24 months of age

Any lack of developmentally appropriate language or social skills

At any age

Source: [10,78]

A medical assessment also is necessary and typically includes a physical examination, a hearing screen, and genetic testing [10,78]. Psychologic tests, a communication assessment, and occupational/physical therapy evaluations also may be warranted [10].

The provider should discuss the importance of these assessments with the family, assist them in navigating through the process, and connect them with community and other resources. Families with low income or language barriers may require additional attention to take the next steps [10].

DIAGNOSTIC CRITERIA

To fulfill diagnostic criteria for ASD using the DSM-5-TR, all three symptoms of social communication and interaction must be present, in addition to two of the four symptoms related to restrictive and repetitive behaviors (Table 2) [4,10].

Table 2: DSM-5-TR CRITERIA FOR ASD AND EXAMPLES

Domains

Criteria: Deficits

Examplesa

Persistent deficits in social communication, social interaction across multiple contexts, as manifested by criteria in this domain (currently or by history, must have all three symptoms in this domain)

Social-emotional reciprocity

Abnormal social approach and failure of normal back-and-forth conversation

Reduced sharing of interests, emotions, or affect

Failure to initiate or respond to social interactions

Nonverbal communicative behaviors used for social interaction

Poorly integrated verbal, nonverbal communication

Abnormalities in eye contact and body language or deficits in understanding and use of gestures

Total lack of facial expressions and nonverbal communication

Developing, maintaining, understanding relationships

Difficulties adjusting behavior to suit various social contexts

Difficulties sharing imaginative play or making friends; absence of interest in peers

Restricted, repetitive patterns of behavior, interests, or activities, as manifested by at least two of the following, currently or by history

Stereotyped or repetitive motor movements, use of objects, or speech

Simple motor stereotypies, lining up toys or flipping objects

Echolalia

Idiosyncratic phrases

Insistence on sameness, inflexible adherence to routines, or ritualized patterns of verbal or nonverbal behavior

Extreme distress at small changes

Difficulties with transitions

Rigid thinking patterns

Greeting rituals

A need to take same route or eat the same food every day

Highly restricted, fixated interests that are abnormal in intensity or focus

Strong attachment to or preoccupation with unusual objects

Excessively circumscribed or perseverative interest

Hyper- or hyporeactivity to sensory input or unusual interests in sensory aspects of the environment

Apparent indifference to pain/temperature

Adverse response to specific sounds or textures

Excessive smelling or touching of objects

Visual fascination with lights or movement

aSymptoms must be present in 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 and are not better explained by intellectual disability or global developmental delay.

Source: [4,10]

The DSM-5-TR also introduced an approach to severity rating that reflects the impairment of the ASD symptoms and resulting needs of the individual (Table 3) [4,10]. Although attempts have been made to capture severity of core symptoms and allow for measurement of improvement with interventions, no single adequate measure has been established to date [79,80,81,82,83].

Table 3: ASD SYMPTOMS BY LEVEL OF SEVERITY

Severity Level

Social Affective

Restrictive/Repetitive Behaviors

Level 3 (requiring very substantial support)

Severe deficits in verbal and nonverbal social communication skills cause severe impairments in functioning, very limited initiation of social interactions, and minimal response to social overtures from others.

Inflexibility of behavior, extreme difficulty coping with change, or other restricted/repetitive behaviors markedly interfere with functioning in all spheres.

Great distress/difficulty changing focus or action.

Level 2 (requiring substantial support)

Marked deficits in verbal and nonverbal social communication skills; social impairments apparent even with supports in place; limited initiation of social interactions; and reduced or abnormal responses to social overtures from others.

Inflexibility of behavior, difficulty coping with change, or other restricted/repetitive behaviors appear frequently enough to be obvious to the casual observer and interfere with functioning in a variety of contexts.

Distress and/or difficulty changing focus or action.

Level 1 (requiring support)

Without supports in place, deficits in social communication cause noticeable impairments. Difficulty initiating social interactions, and clear examples of atypical or unsuccessful response to social overtures of others. May appear to have decreased interest in social interactions.

Inflexibility of behavior causes significant interference with functioning in one or more contexts.

Difficulty switching between activities.

Problems of organization and planning hamper independence.

Source: [4]

DIFFERENTIAL DIAGNOSIS OF ASD

Symptoms consistent with a diagnosis of ASD overlap significantly with a wide range of psychiatric and medical conditions. Accurate diagnosis of ASD is made difficult by the many differential diagnoses that should be considered in an individual presenting with the cognitive and behavioral symptoms of ASD [84]. Children with intellectual disability may have autistic features but not meet the criteria for ASD. Additionally, children with ASD may or may not have intellectual disability. It is important, therefore, that alternative diagnoses (Table 4) be firmly ruled out before an individual is diagnosed with autism [4,13,84,85,86,87]. Signs of neglect or abuse, sensory problems, and speech/language disorder should be closely examined [10,84].

Table 4: EXAMPLES OF SYNDROMES/DISORDERS ASSOCIATED WITH ASD

Condition

Characteristics

Fragile X syndrome

Intellectual disability, macrocephaly, large ears, large testicles, hypotonia, joint hyperextensibility

Tuberous sclerosis

Hypopigmented macules, CNS hamartomas, seizures, intellectual disability

Angelman syndrome

Global developmental delay, hypotonia, wide-based ataxic gait, seizures, progressive spasticity

Rett syndrome (primarily in girls)

Apparently typical development for first 5 months of life and normal head circumference at birth. Deceleration of head growth from 5 to 48 months, resulting in microcephaly. Loss of previously acquired hand skills, with onset of hand-wringing stereotypes. Seizures often develop.

Tourette syndrome

Tics seen in Tourette syndrome may appear similar to motor stereotypes associated with ASD. Children with Tourette syndrome usually lack social/communication impairments seen with ASD; however, social isolation may be a factor due to embarrassment or peer avoidance.

Landau-Kleffner syndrome

Loss of language comprehension and verbal expression. Child often appears to have acquired deafness; some children develop serious behavioral dysfunction, including hyperactivity, temper outbursts, or withdrawn behaviors, but rarely as severe as those seen with ASD.

Obsessive compulsive disorder (OCD)

The obsessive thoughts and repetitive actions seen in OCD can appear similar to the ritualistic behaviors and motor stereotypes seen in ASD.

Attention deficit-hyperactivity disorder (ADHD)

Children with ADHD may have impairments in social skills and may have difficulty sustaining conversation due to inattention. Likewise. children with ASD often have problems with hyperactivity, impulsivity, and inattention.

Cornelia de Lange syndrome

Growth delays, intellectual disability, and/or developmental delays and behavioral problems. Children also may have hearing impairment and abnormal speech development.

Prader-Willi syndrome (PWS)

All individuals with PWS have some cognitive impairment that ranges from low normal intelligence with learning disabilities to mild-to-moderate intellectual disability. Behavioral problems are common and can include temper tantrums, obsessive/compulsive behavior, and skin picking. Motor milestones and language development are often delayed.

Oppositional defiant disorder (ODD)

Behavior problems seen in children with ODD are usually intentional, whereas children with ASD are more likely to display behavior problems (e.g., tantrums) for no apparent reason.

Source: [4,13,84,85,86,87]

6. COMORBIDITIES

Many children and adults with ASD have comorbid health conditions. One retrospective study examined the comorbidity burden of ASD in more than 14,000 children and young adults across three general hospitals and one pediatric hospital [88]. Patients with autism had higher than expected rates of all of the medical conditions studied (e.g., eczema, allergies, gastrointestinal problems, seizures, asthma) compared with general patient populations of health centers [88]. Additional studies from the United States, Europe, and Asia confirmed the high prevalence of medical comorbidities among children and young adults with ASD [89,90,91,92]. Medical comorbidities such as epilepsy, gastrointestinal conditions, and respiratory disorders are associated with a mortality rate that is 3 to 10 times higher among patients with ASD than in the general population [93,94].

A consensus report published by the AAP states that, "care providers should be aware that problem behavior in patients with ASD may be the primary or sole symptom of the underlying medical condition" [95]. Further, "behaviors in the ASD population are often physical in origin, identifiable through investigation, and treatable or manageable through appropriate medical care" [96]. The AAP also encourages clinicians to listen to parents, because they generally give accurate and quality information [97]. However, like the clinicians who are working with communicatively impaired patients with ASD, parents or caregivers also may face communication barriers with the child. Furthermore, parents may be unaware of the possible implications of the symptoms, especially if they have been previously told that behaviors are simply autistic. Nearly one-third of adults with high-functioning autism report that they do not receive appropriate medical care for physical health problems [97].

Autism is increasingly recognized as a whole-body disorder, with the core characteristics commonly attributed to ASD now being attributed to manifestations of a systemic and complex disease process [96]. Study results are challenging the belief that ASD is static, lifelong, and unchangeable, with many results providing evidence that significant improvement is possible following intensive, individualized intervention [98,99,100,101]. It is now established that "specific medical problems are associated with the severity of the condition and that successfully addressing these comorbidities often leads to significant improvement in overall functioning" [96].

Managing comorbid illness in the patient with ASD is challenging on many levels (e.g., communication deficits, processing pain or tenderness, lack of history), but can be improved with knowledge about the symptoms (Table 5) that manifest in the patient who presents with comorbid health issues [96].

Table 5: SYMPTOMS OF COMORBID HEALTH ISSUES

Behaviors that May Indicate Underlying Illness

Sudden behavior change; change to appetite, dietary preferences

Loss of previously acquired skills

Irritability, low mood, tantrums, oppositional behavior; aggression

Heightened anxiety; avoidance behaviors

New repetitive movements

Hypersensitive to sensory input (e.g., sensitive to light, specific sounds)

Teeth grinding

Facial grimacing

Vocal moaning, groaning, sighing, whining

Common Sources of Paina/Discomfort

Headache, earache, toothache

Sore throat

Reflux, esophagitis, gastritis, colitis

Soft or hard stool constipation (underlying cause is relevant)

Small intestinal bacterial overgrowth

Musculoskeletal injury or disease

Seizure disorder (including subclinical crisis)

Allergy disorder

aPain can be acute or chronic, progressive or static.

Source: [95,96,102]

SEIZURE DISORDERS

The prevalence of seizure disorders is high in people with ASD, and their co-occurrence with ASD contributes to an elevated mortality risk [103]. One meta-analysis of 19 studies found a pooled ASD prevalence of 6.3% in epilepsy. When divided by type, the risks of ASD for general epilepsy, infantile spasms, and focal seizures were 4.7%, 19.9% and 41.9%, respectively [103]. Individuals with epilepsy 18 years of age and younger were found to have a risk of ASD that was 13.2 times greater than that of individuals 18 years of age and older. Individuals with co-occurring intellectual disability had a risk for ASD that was 4.9 times higher than those without intellectual disability. Primary risk factors for epilepsy in patients with ASD include the presence of intellectual disability, female sex, age, and symptomatic etiology of epilepsy [103].

SLEEP DISORDERS/DISTURBANCE

Approximately two-thirds of children with ASD have chronic insomnia [104]. Sleep disturbances can contribute to the psychosocial burden of ASD and exacerbate symptoms such as inattention or irritability [105]. Anxiety and sensory over-responsivity alone are independently associated with a variety of sleep problems (e.g., bedtime resistance, sleep-onset delay, sleep anxiety, night waking), making children with ASD and one or both of these co-occurring conditions particularly predisposed to sleep disturbances [106]. Children's sleep habits and the sensory-processing patterns of avoidance, sensitivity, seeking, and registration were assessed in a cross-sectional study of 231 primary school students 7 to 12 years of age [107]. Each of the sensory-processing patterns was found to have a negative relationship with sleep habits, with a significant difference between children who had more challenges with sleep maintenance compared with those with normal sleep patterns [107].

ADHD

Approximately one-half of children and adolescents with ASD also may fulfill the diagnostic criteria for ADHD [95]. This co-occurrence presents a greater deficit in inhibitory control, attention, and working memory. In social cognition, the clinical features of ADHD increase the difficulties in cases of ASD [108,109].

ANXIETY DISORDERS

An estimated 40% to 66% of school-aged children and adults with ASD are reported to also have an anxiety disorder [110,111]. This includes separation anxiety disorder, selective mutism, specific phobia, social phobia, panic disorder, agoraphobia, generalized anxiety disorder, and unspecified anxiety disorder. Symptoms may be present in early childhood and manifest in behaviors such as over-reactivity. Genetic factors and/or altered neurophysiologic responses to stress may predispose some to this comorbidity [95].

MOOD DISORDERS

Depressive disorders are more common among children and adults with ASD than in the general population, with reported rates ranging from 12% to 33% [110,112]. The coexistence of a mood disorder with ASD may again be attributed to genetic factors and/or an altered neurophysiologic stress response. Chronic stress and difficulty understanding social situations may also be contributing factors to this comorbidity [95].

GASTROINTESTINAL ISSUES

Gastrointestinal issues are common in patients with ASD and may be related to problem behaviors, sensory over-responsivity, dysregulated sleep, anxiety, and irritability [90,113,114,115]. Children with autism have been found to be twice as likely as children with a learning disability or other developmental delay to have frequent diarrhea and/or colitis during the past year and also were seven times more likely to have experienced these gastrointestinal problems than typical controls [116].

7. TREATMENT

The goals of treatment for children with ASD are to minimize core deficits; maximize functional independence; and eliminate, minimize, or prevent problem behaviors that may be interfering with the child's functional skills [10]. Intensive, individualized interventions are the most effective treatments for ASD. Early identification increases the likelihood of a favorable outcome; therefore, patients should be referred for specialized diagnostic and therapeutic interventions as soon as signs or symptoms of ASD appear [117,118].

The intervention chosen will vary according to the child's age, strengths, and weaknesses. Other factors affecting the intervention chosen include its type and intensity, setting and/or mode of delivery (e.g., school or home, professional or trained parent), and specific target(s) of the intervention [119,120]. It is important for clinicians to have an understanding of available interventions and of the evidence base so that they can effectively communicate with families, educators, therapists, and other service providers about the rationale for treatment recommendations.

When circumstances dictate that families must wait for a formal diagnosis of autism, detailed assessments of the child's skills and difficulties across multiple domains can inform general approaches to management based on the child's individual profile. Even simple assessments can help place observed behaviors within a developmental framework that can serve as a baseline for determining interventions and monitoring subsequent progress [121].

EVIDENCE-BASED RECOMMENDATIONS

The goal of evidence-based intervention and support is to alleviate distress, improve adaptation, and promote well-being. Support for people with autism varies from individual to individual and within the same individual over the lifespan. Support should be collaborative, with individuals with autism, families, and service providers assuming a shared decision-making approach that maximizes the individual's potential, minimizes barriers, and optimizes the person-environment fit [121,122].

Legal mandates in education law in the United States, which include the Individuals with Disabilities Education Improvement Act of 2004 (IDEA), the No Child Left Behind Act of 2001, and its successor, the Every Student Succeeds Act of 2015, require the use of practices that are evidence-based or supported by scientifically based research [10]. The National Autism Center initiated the National Standards Project (NSP), which set the goal of establishing evidence-based standards for educational and behavioral interventions for children with ASD. Phase 1 of the NSP, released in 2009, examined and quantified the level of research that supports interventions targeting core characteristics of ASD in children and young adults younger than 22 years of age. Phase 2 of the NSP, released in 2015, provided an updated systematic review of the literature on interventions for this population. Phase 3 will provide updated information about interventions that have been shown to be effective. This phase of the project was scheduled for release in 2021, but it had not been released as of 2023 [123].

The increased prevalence of ASD has increased the demand for effective treatment options, and intervention science is providing evidence about which practices are effective [124]. A report published in 2013 describes two broad classes of evidence-based interventions: comprehensive treatment models (CTMs) and focused interventions [10,124]. CTMs consist of a set of practices designed to achieve a broad learning or developmental impact on the core characteristics of ASD [124]. Examples of CTMs include Treatment and Education of Autistic and Related Communication-Handicapped Children (TEACCH) and the Early Start Denver Model (ESDM) [124,125,126,127]. As of 2023, an estimated 30 CTM programs are operating in the United States [124].

The TEACCH program gathers, creates, and disseminates information about community-based services, training programs, and the latest research to individuals with ASD and their families. The program also provides clinical services (e.g., referrals, diagnostic evaluations) as well as parent support groups and individual counseling for higher-functioning clients. TEACCH conducts national and international training for teachers and other professionals and conducts research on psychologic, educational, and biomedical studies related to autism [126]. Trained ESDM therapists provide in-home training for infants and toddlers that involves their parents and families, with an emphasis on boosting the child's developmental domains of social-emotional, cognitive, and language abilities [127].

Focused interventions are designed to address a single or limited range of skills (e.g., increasing social communication, learning a specific task) that may be delivered over a short period of time. Examples of focused interventions include discrete trial teaching (DTT) and prompting [10,124]. DTT was one of the earliest forms of applied behavior analysis (ABA). DTT was an extremely structured process, undertaken as many as 40 hours per week, that broke down desired skills and behaviors into small, discrete components, rewarding successful completion, and, in some cases, punishing unwanted behavior. DTT has since evolved [128]. Prompting procedures include any help (e.g., gestures, verbal clues) given to learners that assist them in using a specific skill. Prompting procedures often are used in conjunction with other evidence-based practices, such as DTT. Although interventions based on ABA approaches have been extensively used in educational and other settings for individuals with autism, many current interventions based on ABA approaches have shifted from repetitive DTT-type training to more natural, child-initiated, developmentally appropriate strategies and tasks [121,129].

CHARACTERISTICS OF EFFECTIVE INTERVENTIONS

There is considerable regional variation in the availability of interventions for the management of ASD as well as significant overlap in the methods used. According to the AAP, the common characteristics of effective and empirically supported interventions include [10]:

- Individualized skills assessment that includes measurable goals and objectives

- Instruction provided by properly trained individuals in a low student-to-teacher ratio that addresses core symptoms and the child's individualized goals, interests, and preferences

- Collaboration among multiple providers

- An environment that is structured, predictable, organized to prevent distraction, and that promotes opportunities for the child to initiate communication and interact with peers

- Functional behavioral analysis and improvement plan based on an IDEA mandate

- Child's progress is systematically monitored and instructional strategies adjusted as needed

- Family provides ongoing input and receives education and support

- Transition planning (e.g., from school to adulthood)

NATURALISTIC DEVELOPMENTAL BEHAVIORAL INTERVENTIONS

As stated, many interventions have shifted away from ABA-based approaches toward more natural, child-initiated, developmentally appropriate strategies and tasks [121]. Naturalistic developmental behavioral intervention (NDBI) is an emerging class of interventions for young children with ASD. One meta-analysis of outcomes using NDBIs found small but significant positive effects for expressive language, reduction in ASD symptoms, and play skills. Larger effects were found for social engagement and overall cognitive development [130]. A second meta-analysis examined the quality of evidence supporting NDBIs and investigated whether effects varied as a function of specific features of the intervention [131]. A total of 27 studies were extracted from a comprehensive meta-analysis of nonpharmacologic intervention studies for children 0 to 8 years of age with ASD. The authors found that increases in language, social communication, play skills, and cognition were largest for skills directly targeted by the intervention [131]. One NDBI intervention titled JASPER (joint attention, symbolic play, engagement, and regulation intervention) was examined in a 2021 systematic literature review [132]. Of the 19 articles included in the review, most found that children with ASD who received the JASPER intervention showed significantly greater improvements in at least one outcome related to child joint attention, joint engagement, play, and language skills compared to children who did not receive the intervention [132].

PARENT-FOCUSED BEHAVIORAL MANAGEMENT PROGRAMS

The time requirements and financial cost of many home- or clinic-based interventions often are beyond the means of families of children with ASD and can leave parents exhausted by the demands [7]. To meet the needs of these families, psychoeducation groups for parents of newly diagnosed children are now routinely offered by many child and adolescent clinics [121]. These clinics aim to educate parents about ASD by teaching them how to enhance their child's social and communication skills and how to manage some of the challenging behaviors (e.g., temper tantrums, fears and phobias, sleep problems). These programs are typically group-based and occur over a few weeks' time. They have been found to increase parental competence and well-being and improve adaptive behavior of the child with ASD [133,134].

NEURODIVERSITY-AFFIRMING INTERVENTIONS

Neurodiversity is broadly defined as an approach to learning and disability that suggests that diverse neurologic conditions appear as a result of normal variations in the human genome; that these variations should be recognized and respected as any other human variation; and that individuals with these variations are not in need of fixing, but rather should be recognized and respected as a social category on par with gender, ethnicity, sexual orientation, or disability status [135]. Neurodiversity challenges the assumption that ASD is a disease or disorder that needs to be eradicated, prevented, treated, or cured [136]. Self-advocating individuals with autism argue that in "highly social and unpredictable environments some of their differences may manifest as disabilities, while in more autism-friendly environments the disabilities can be minimized, allowing other differences to manifest as talents" [136].

While the neurodiversity movement has introduced a new era for autism research, therapists and researchers who support neurodiversity-affirming clinical interventions for ASD face significant challenges [137,138,139]. In light of neurodiversity developments, one researcher proposed recasting autism as emergent and transactional, which he describes as a model of the autism phenotype [139]. This model describes a trajectory that starts with the individual brain differences underlying neurodiversity. Next, a behavioral phenotype emerges over the first few years of life (or later) from a developmental transaction between these individual brain differences and the child's experience in the world. Evidence for this model comes from replicated intervention trials in which changing key aspects of the early social transactional environment around the neurodivergent child results in consequent alterations to the emerging dimensions of the autism phenotype [139].

EDUCATIONAL INTERVENTIONS

Intensive, individual special education provided by an educator familiar with instructing children with ASD is central to the treatment of ASD [7]. School-aged children with ASD should be enrolled in an appropriate educational program that provides support and promotes language, academic, adaptive, and social skills development. Federal law entitles all students with disabilities to a free and appropriate public education (FAPE) and mandates that these students be placed in the least restrictive environment that allows them to progress toward achieving their goals. These goals must be developed and measured within the framework of an individualized education program (IEP), which is a blueprint for the student's school year. The IEP includes academic and behavioral goals, interventions, modifications, supports, and hands-on learning opportunities that help the student transition from the school years to adulthood. Parents, teachers, and other individuals who work with the student with autism all participate in developing the IEP [140].

Some students with ASD are educated in inclusive classrooms with supports; others benefit from a disorder-specific approach [124]. Classroom-based models include TEACCH and the Learning Experiences and Alternative Programs for Preschoolers and Their Parents (LEAP). LEAP blends behavioral strategies with special and general education teaching techniques to improve social interaction [141]. One randomized controlled trial found that LEAP was associated with improvement in socialization, cognition, language, and challenging behavior. The LEAP model also was found to be superior to a treatment-as-usual method [142,143,144]. One emphasis of the TEACCH model is the use of visual cues to enhance comprehension and encourage spontaneous communication among children with limited verbal skills [121]. TEACCH was associated with more reported improvement in ASD severity for students who had greater cognitive delays. A comparison of the LEAP and TEACCH models found that their common features may be responsible for the improvements seen in all students [142].

Barriers to the child with ASD receiving appropriate educational interventions include regional variation in availability and types of therapy; long wait times for service; less-than-desired intensity of the program (e.g., may not include all components the family desires); and lack of insurance coverage [10]. In some instances, pediatricians and parents may require legal assistance to influence a local board of education to provide appropriate funding for children with ASD [7].

SPEECH-LANGUAGE INTERVENTIONS

Evidence Based Practice Recommendation

According to the Scottish Intercollegiate Guidelines Network, interventions to support communicative understanding and expression in individuals with autism (e.g., the Picture Exchange Communication System) should be considered.

https://www.sign.ac.uk/assets/sign145.pdf

Last Accessed: December 15, 2023

Strength of Recommendation: Strong

Delays in speech onset may be complicated by general developmental delays or by coexisting speech disorders. Up to 30% of children with ASD never acquire verbal speech [145]. Speech-language therapy is the most commonly identified intervention provided for children with ASD [10]. Strategies used include reinforcement of speech sounds and communicative acts, imitation of the child's sounds, and exaggerated imitation and slowed tempo. Augmentative and alternative communication (AAC) is used when there is a deficit in spontaneous speech and includes strategies such as the Picture Exchange Communication System (PECS) and speech-generating devices [146,147]. AAC methods teach the individual to communicate independently [10].

PECS was developed in 1985 and first implemented with preschool students diagnosed with autism. The primary goal of PECS is to teach functional communication. It consists of six phases and begins by teaching the individual with autism to communicate with another person by giving that person a picture of a desired item in exchange for the item. It starts with the exchange of simple icons but quickly builds to sentence structure where the child is taught to comment in response to questions [148]. Speech-generating devices and programs that use AAC on digital tablets are increasingly in use. The devices provide acoustic feedback to the child and are relatively inexpensive and portable [10].

Despite being used extensively in schools and other setting for children with ASD, there is no strong evidence for the effects of any particular model of speech-language therapy, and the specific strategies involved very widely from one service to another. The main goal is to enhance understanding and communication by whatever means are most appropriate for the individual, rather than concentrating solely on the production of speech [121].

PHARMACOTHERAPY

Data from Medicaid and commercial insurers indicate that 56% to 65% of patients with ASD are prescribed psychotropic medications [149,150,151]. One or more medications are prescribed for 1% of children 3 years of age and younger; 10% of children 3 to 5 years of age; 38% to 46% of children 6 to 11 years of age; and 64% to 67% of adolescents 12 to 17 years of age [152,153]. Increased use of medications is attributed to a lower level of cognitive skills and/or intellectual disability, disruptive behavior, or a co-existing diagnosis. A better understanding of the neurobiology of ASD will allow for identification of targeted interventions to better manage co-occurring symptoms and/or address core deficits [10]. As of yet, there is no drug that clearly leads to improvements in the basic symptoms of autism. Drugs are generally prescribed to treat associated behavioral issues and comorbid disorders [7]. Considerations for medication use in treatment of ASD are summarized in Table 6[10,121].

Table 6: CONSIDERATIONS FOR MEDICATION USE IN ASD

Obtain an accurate diagnosis of coexisting psychiatric conditions to guide therapy.

Use medication to manage coexisting behavioral health disorders (e.g., ADHD) and associated problem behaviors/symptoms that cause significant impairment and distress (e.g., aggression, sleep disturbance, anxiety, inattention).

Consider medication use only after:

- Accounting for when behavior began and what exacerbates it.

- Obtaining functional behavioral assessment (i.e., determining if behavior is a communication of distress or a refusal).

- Referral to behavior therapist has been considered.

- Obtaining thorough history/physical exam.

- Assessing and intervening as needed for treatable medical conditions/behavioral factors when intervention does not address symptoms of concern.

Source: [10]

Medication should be used with caution, particularly because obtaining an accurate diagnosis of ASD is challenging. For example, the classical symptoms of depression may present differently in ASD, while anxiety may initially manifest as an increase in behavioral problems [121]. Additionally, few trials of drugs for people with ASD have been conducted; these individuals often are excluded from clinical trials [121]. Given these challenges and the often unpredictable response to drugs by people with ASD, it is important that medications are prescribed on an individualized and experimental basis, with careful attention to adverse effects and a weighing of benefits against the risk of adverse effects [121]. Practice guidelines from the AAP stress the importance of having a quantifiable means of assessing treatment efficacy when medications are prescribed [154].

First-Generation (Typical) Antipsychotics

Antipsychotics such as haloperidol, chlorpromazine, and thioridazine are frequently used in the treatment of adults with psychiatric disorders. They also are sometimes used to provide temporary relief from agitation, aggression, insomnia, stereotypies (i.e., repetitive behaviors), or other behavioral symptoms associated with ASD [155]. Antipsychotics also are used to help correct maladaptive behavior or as a temporary adjunct to other forms of treatment [13]. Unwanted side effects include dystonia, akinesia, akathisia, cognitive slowing, weight gain, and rarely irreversible neurologic problems, especially if used over a long period of time. Many of these side effects are reversed when the drug is stopped [2,155,156,157].

Second-Generation (Atypical) Antipsychotics

The atypical antipsychotic risperidone has been approved since 1993 for the short-term treatment of adults with schizophrenia and since 2003 for the short-term treatment of adults with acute manic or mixed episodes associated with extreme mood swings. In 2006, the U.S. Food and Drug Administration (FDA) approved the agent for the symptomatic treatment of agitation and irritability in children and adolescents with autism. The approval was the first for the use of a drug to treat behaviors associated with autism in children [158]. The effectiveness of risperidone in ameliorating irritable behavior in children with autism was established in two 8-week, placebo-controlled trials in 156 patients 5 to 16 years of age. These children achieved significantly improved behavioral symptom scores compared with controls [158,159,160]. The most common side effects of risperidone include increased appetite, weight gain, and sedation, with weight gain being the most significant [2,157,159,160]. Aripiprazole, another atypical antipsychotic, also is FDA approved for the treatment of irritability associated with autism [157,161]. In preliminary studies, the atypical antipsychotics olanzapine and ziprasidone have been shown to have similar beneficial effects, but their use in ASD is off-label [157,162,163,164,165]. Although they are effective in controlling behavioral symptoms, olanzapine and ziprasidone are associated with significant adverse effects, including abdominal pain, seizures, and excessive weight gain (olanzapine only) [157,161,162].

All atypical antipsychotics are associated with a high incidence of cardiometabolic side effects, such as age-inappropriate weight gain, hypertension, lipid and glucose abnormalities, and obesity [166]. These are particularly problematic during childhood, as they are strong predictors of adult obesity, metabolic syndrome, and cardiovascular morbidity and malignancy. The risk versus benefit of antipsychotic therapy should be thoroughly assessed when considering long-term use, and the agents should initially be prescribed in low doses and titrated slowly [161].

Anticonvulsants

The rate of seizures among people with ASD in community-based populations has been reported to range from 7% to 23%, with rates as high as 46% reported in clinically ascertained samples [167]. Although anticonvulsants cannot always eliminate seizures, they may reduce the number of seizures that occur. The smallest amount of medication that is effective should be used. Anticonvulsants commonly used are carbamazepine, lamotrigine, topiramate, and valproic acid [157].

Stimulants

Stimulants such as methylphenidate are sometimes used to address symptoms of hyperactivity, impulsivity, disinhibition, and inattention; however, they may not be as effective in the presence of coexisting symptoms [10,161,168,169]. Treatment with stimulants has been associated with sudden death in children and adolescents with pre-existing structural cardiac abnormalities, and sudden death, stroke, and myocardial infarction have been reported in young adults [157]. Prior to initiating treatment with a stimulant, assess the patient's medical and family history of sudden death or ventricular arrhythmia and conduct a physical exam to assess for cardiac disease [157].

Antidepressants

The use of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and other antidepressants have been studied for use in children and adolescents with ASD, with mixed results, and controversy persists about whether these agents should be used in these populations. For example, a 2013 Cochrane review concluded that there is no benefit, and emerging evidence of harm, with SSRIs in the treatment of ASD [170]. One meta-review assessed the effects of antidepressants for the acute treatment of ASD and found that, compared with placebo, while selected antidepressants can be effective, statistically significant differences do not always translate into clinically significant results. Additionally, there is little information about the tolerability of antidepressants in ASD, as well as little data on suicidal ideation/behavior [171]. Children with ASD are at risk of developing a serotonin syndrome when treated with serotonergic agents. Therefore, children who are treated with these agents should be evaluated at baseline before beginning treatment and then regularly evaluated for symptoms of a serotonin syndrome [7].

Other Medications

Medications that have shown some promise in improving the core symptoms of ASD include donepezil hydrochloride, levocarnitine (l-carnitine), and bumetanide [172,173,174]. Medications that have shown mixed results include amantadine and arbaclofen [175,176].

A Report on the Hormone Secretin

Secretin is a polypeptide neurotransmitter involved in digestion. As a diagnostic agent, it may be given during an endoscopy to assess digestive function [157]. Anecdotal reports of the success of secretin have prompted a growing number of parents to seek out medical professionals willing to try the hormone on their child. However, secretin has not been approved by the FDA to treat autism, nor is it recommended by the National Institutes of Health (NIH) [177]. A meta-analysis of 14 years of data reported by the Cochrane Collaboration found no evidence that intravenous secretin, either in single or multiple doses, had any effect on function, behavior, core features, or quality of life for patients with autism [178]. Researchers concluded that the hormone should not be recommended or administered as part of the treatment plan.

COMPLEMENTARY AND ALTERNATIVE MEDICINE

Surveys of parents of children with ASD indicate that up to 95% use complementary and alternative medicine (CAM) therapies for their child's general health or to improve symptoms of ASD or associated symptoms (e.g., irritability, hyperactivity, gastrointestinal problems, sleep disturbances) [179]. In the United States, most parents report concerns regarding conventional medication safety (84%) and side effects (83%) as the main reasons for choosing CAM therapies [180]. The specific CAM therapies parents use include biologically based therapies (e.g., herbs, foods, vitamins) (54%), mind-body interventions (e.g., meditation) (30%), manipulative or body-based methods (e.g., massage) (25%), energy therapies (e.g., Reiki or electromagnetic fields) (8%), and alternative medical systems, such as homeopathy (1%) [181]. CAM therapies for which some positive research evidence exists are summarized in Table 7[180,182].

Table 7: CAM THERAPIES FOR TREATMENT OF ASD

Treatment

Purpose

Improvement(s)

Adverse Effects

Melatonin

Sleep

Sleep duration, overall sleep

Minimal to none

B6/magnesium

Correct deficiency

Social interaction, communication, repetitive behavior (in some but not all randomized controlled trials)

Neuropathy, diarrhea (at doses >200–300g)

B12

Correct deficiency

Some functioning and behavior

None reported

Multivitamin/mineral

Nutritional deficit associated with ASD

Sleep, GI, functioning, hyperactivity, self-injury; parent-rated irritability scores

None reported

Folic acid

Genetic abnormality

Receptive, expressive language

None reported

Omega-3

Correct deficiency

Stereotypy, hyperactivity, inappropriate speech

None reported

Probiotics/GI medication

Remove toxins; improve immune function

Improvement in core symptoms of autism (e.g., eye contact)

None reported

Iron supplements

Correct deficiency

Restless sleep

None reported

Herbal remedies

Improve core symptoms

Problem solving, attention, planning

None reported

Chelation

Remove toxic heavy metals

None

Renal/hepatic toxicity, fatigue, diarrhea

L-Carnosine

Neuroprotective

Receptive/expressive language

Hyperactivity, excitability

Ascorbic acid (90 mg/kg)

Correct redox balance

None

Can interfere with B12 absorption

Cyproheptadine

High 5-HT levels

ASD symptoms

None reported

Immune therapies

Deficiencies

Some ASD symptoms

None reported

Massage

Improve attachment; decrease overarousal

ASD symptoms, sleep, social relatedness, anxiety, disruptive behavior, sensory impairment

Not examined

Acupuncture

Unblocking energy flow

Attention, receptive language, self-care, communication, motor skills, social isolation

Few, mild

Possible infection, bleeding

Exercise

Decrease hyperactive, repetitive behavior

Self-stimming and academic scores

Not examined

Music therapy

Improve communication, engagement

Imitating signs/words, eye-contact, turn-taking, joint attention

Not examined

Animal-assisted therapy

Improve attachment

Playful mood, focus, language use, social awareness

Not examined

Neurofeedback

EEG changes

Attention, speech/language, sociability, sensory cognitive awareness

Not examined

Source: [180,182]

CAM therapies that improve physiologic abnormalities, such as oxidative stress and inflammation, hold promise for improving symptoms of ASD [179,183,184]. However, more research is necessary.

8. IMPACT OF ASD ON THE FAMILY

The impact of having a child with ASD is considerable. Parents report more stress and a greater financial burden than parents who do not have a child with ASD [185,186,187]. Parents also may be at increased risk of depression and anxiety [185]. Government data indicate that 57.1% of parents of children with ASD either cut back or stop working; 29.9% spend 11 or more hours per week providing care; 33.5% pay more than $1,000 annually in out-of-pocket medical expenditures; 43.0% report that the child's condition causes financial problems; and 30.6% of family members avoided changing jobs in order to maintain health insurance for their child [188]. Data derived from the National Health Interview Survey indicate that, after adjusting for child demographic characteristics and non-ASD-associated illnesses, ASD is associated with $3,020 higher healthcare costs and $14,061 higher aggregate non-healthcare costs, including $8,610 higher school costs [189].

Best practices include providing families with contact information for a family support group at the time of diagnosis [10]. Peer support for families of children with ASD has been shown to lessen parental stress, decrease negative mood, and increase positive perceptions [190]. This support may be a local group that provides face-to-face interaction and community activities, or it may be an online community. One study of peer support exchanged via social media found that parents received both informational and emotional support, including discussing and addressing the challenges and difficulties of caring for and raising a child with ASD as well as receiving information about improving children's social lives and self-care routines [191]. Families who do not reach out for support at the time of diagnosis may find the support useful later when they are faced with the transitions from preschool to adolescence to adulthood [10]. National support groups (Resources) and local organizations also are effective in helping families obtain information and feel supported. Clinicians should familiarize themselves with these resources. Additionally, they should advocate for instructional material in English and other languages to support a culturally diverse practice [10].

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because family education is such a vital aspect of the management of ASD, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for understanding. When there is an obvious disconnect in the communication process between the practitioner and patient or patient's family due to a lack of proficiency in the English language, an interpreter is required.

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between patients, patient's families, and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter.

9. PROGNOSIS

While it is difficult to project the prognosis and trajectory of development for the child with ASD, most (more than 80%) who are diagnosed with ASD after a comprehensive evaluation at 3 years of age or younger retain their diagnosis [192,193]. If the child has average or above-average cognitive abilities, recognition and diagnosis of ASD can be more difficult.

An estimated 9% of children who are diagnosed with ASD in early childhood may not meet the diagnostic criteria for ASD by young adulthood [10]. In these instances, the child is more likely to have a history of higher cognitive skills at 2 years of age, to have participated in earlier intervention services, and to have a demonstrated decrease in repetitive behaviors over time [194]. The prognosis for children with ASD in various subgroups (e.g., girls, racial/ethnic subgroups) requires further study [10].

A change in diagnosis (e.g., from ASD to ADHD) is more likely in the child who was diagnosed with ASD before 30 months of age. An improvement in ASD severity rating is more likely to occur in children with significant increases in tested verbal IQ; however, executive function difficulties are associated with poorer adaptive outcomes, independent of the child's IQ [195,196]. High-functioning adults with ASD report a quality of life that is associated more with the presence and support of family and community than with management of their ASD-related symptoms [10]. As discussed, researchers are increasingly recognizing how co-occurring medical conditions can help identify the phenotypic differences within populations affected by ASD, which can influence prognosis and the choice of interventions [10].

10. CONCLUSION

ASD is the most common neurologic disorder in the United States; however, it often goes unrecognized and is commonly underdiagnosed. Developmental screening can be done by a number of healthcare professionals, but primary care providers are uniquely positioned to identify symptoms of ASD early in childhood. Early diagnosis is critical to identifying comorbid conditions and providing timely, appropriate treatment. Intensive, individualized interventions are the most effective treatments for ASD. They should be based on the child's age, strengths, and weaknesses and should include input from the family and collaboration among the interprofessional team.

Peer support for families of children with ASD has been shown to lessen parental stress, decrease negative mood, and increase positive perceptions. Support maybe a local group, an online community, or a national support group. Clinicians should familiarize themselves with these resources and should advocate for instructional material in English and other languages to support a culturally diverse practice.

11. RESOURCES

Association for Behavioral Analysis International

https://www.abainternational.org

Association for Science in Autism Treatment

https://asatonline.org

Autism National Committee (AutCom)

https://www.autcom.org

Autism Research Institute

https://www.autism.org

Autism Society

https://www.autism-society.org

Centers for Disease Control and Prevention

Learn the Signs. Act Early.

https://www.cdc.gov/ncbddd/actearly

Eunice Kennedy Shriver National Institute of Child Health and Human Development

https://www.nichd.nih.gov

Family Voices

https://familyvoices.org

Global Autism Project

https://www.globalautismproject.org

Indiana Institute on Disability and Community

https://www.iidc.indiana.edu

Kennedy Krieger Institute: Interactive Autism Network

https://iancommunity.org

Health Resources and Services Administration

https://mchb.hrsa.gov/programs-impact/autism

National Center on Birth Defects and Developmental Disabilities

https://www.cdc.gov/ncbddd

National Institute of Mental Health

https://www.nimh.nih.gov

National Institute of Neurological Disorders and Stroke

Autism Spectrum Disorder Information Page

https://www.ninds.nih.gov/Disorders/All-Disorders/Autism-Spectrum-Disorder-Information-Page

National Institute on Deafness and Other Communication Disorders

https://www.nidcd.nih.gov

Organization for Autism Research

https://researchautism.org

Parent to Parent USA

https://www.p2pusa.org

Works Cited

1. Iannelli V. A History and Timeline and the History of Autism. Available at https://www.verywellhealth.com/autism-timeline-2633213#citation-8. Last accessed November 30, 2023.

2. National Institute of Mental Health. Autism Spectrum Disorder. Available at https://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-asd/index.shtml. Last accessed November 30, 2023.

3. National Institute of Child Health and Human Development. Autism Spectrum Disorder (ASD). Available at https://www.nichd.nih.gov/health/topics/autism. Last accessed November 30, 2023.

4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Text revision. Washington, DC: American Psychiatric Association; 2022.

5. MedPage Today. Gever J. Autism Criteria Critics Blasted by DSM-5 Leader. Available at https://www.medpagetoday.com/meetingcoverage/apa/32578. Last accessed November 30, 2023.

6. Huerta M, Bishop SL, Duncan A, Hus V, Lord C. Application of DSM-5 criteria for autism spectrum disorder to three samples of children with DSM-IV diagnoses of pervasive developmental disorders. Am J Psychiatry. 2012;169(10):1056-1064.

7. Brasic JR. Autism Spectrum Disorder. Available at https://emedicine.medscape.com/article/912781-overview#a1. Last accessed November 30, 2023.

8. Maenner MJ, Warren Z, Williams AR, et al. Prevalence and characteristics of ausitm spectrum disorder among children aged 8 years – Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2020. MMWR Surveill Summ. 2023;72(2):1-14.

9. Baxter AJ, Brugha TS, Erskine HE, Scheurer RW, Vos T, Scott JG. The epidemiology and global burden of autism spectrum disorders. Psychol Med. 2015;45(3):601-613.

10. Hyman SL, Levy SE, Myers SM, and Council on Children with Disabilities, Section on Developmental and Behavioral Pediatrics. Identification, evaluation, and management of children with autism spectrum disorder. Pediatrics. 2020;145(1):e20193447.

11. Centers for Disease Control and Prevention. What is Autism Spectrum Disorder? Available at https://www.cdc.gov/ncbddd/autism/facts.html. Last accessed November 30, 2023.

12. Cakir J, Frye RE, Walker SJ. The lifetime social cost of autism: 1990–2029. Res Autism Spec Disord. 2020;72:101502.

13. Baron-Cohen S, Bolton P. Autism: The Facts. New York, NY: Oxford University Press; 1993.

14. Spectrum. Theories of Autism. Zamzow R. The Connectivity Theory of Autism, Explained. Available at https://www.spectrumnews.org/news/connectivity-theory-autism-explained/. Last accessed November 30, 2023.

15. Spectrum. Theories of Autism. Deweerdt S. The Signaling Imbalance Theory of Autism, Explained. Available at https://www.spectrumnews.org/news/signaling-imbalance-theory-autism-explained/. Last accessed November 30, 2023.

16. Spectrum. Theories of Autism. Musser G. The Predictive Coding Theory of Autism, Explained. Available at https://www.spectrumnews.org/news/predictive-coding-theory-autism-explained/. Last accessed November 30, 2023.

17. Centers for Disease Control and Prevention. Data and Statistics on Autism Spectrum Disorder. Available at https://www.cdc.gov/ncbddd/autism/data.html. Last accessed November 30, 2023.

18. Hutton J. Does rubella cause autism: a 2015 reappraisal? Front Hum Neurosci. 2016;10:25.

19. Yamashita Y, Fujimoto C, Nakajima E, Isagai T, Matsuishi T. Possible association between congenital cytomegalovirus infection and autistic disorder. J Autism Dev Disord. 2003;33(4):455-459.

20. Weiss LA. Autism genetics: emerging data from genome-wide copy-number and single nucleotide polymorphism scans. Expert Rev Mol Diagn.2009;9(8):795-803.

21. Wang C, Geng H, Liu W, Zhang G. Prenatal, perinatal, and postnatal factors associated with autism: a meta-analysis. Medicine (Baltimore). 2017;96(18):e6696.

22. Varcin KJ, Newnham JP, Whitehouse AJO. Maternal pre-pregnancy weight and autistic-like traits among offspring in the general population. Autism Res. 2019;12(1):80-88.

23. Chien YL, Chou MC, Chou WJ, et al. Prenatal and perinatal risk factors and the clinical implications on autism spectrum disorder. Autism. 2019;23(3):783-791.

24. Joseph RM, O'Shea TM, Allred EN, et al. Prevalence and associated features of autism spectrum disorder in extremely low gestational age newborns at age 10 years. Autism Res. 2017;10(2):224-232.

25. Centers for Disease Control and Prevention. Key Findings: The Association Between Assisted Reproductive Technology And Autism Spectrum Disorder. Available at https://www.cdc.gov/ncbddd/autism/features/artandasd.html. Last accessed November 30, 2023.

26. Schieve LA, Drews-Botsch C, Harris S, et al. Maternal and paternal infertility disorders and treatments and autism spectrum disorder: findings from the Study to Explore Early Development. J Autism Dev Disord. 2017;47(12):3994-4005.

27. Glasson EJ, Bower C, Petterson B, de Klerk N, Chaney G, Hallmayer JF. Perinatal factors and the development of autism: a population study. Arch Gen Psychiatry. 2004;61(6):618-627.

28. DeStefano F, Chen RT. Autism and measles-mumps-rubella vaccination: controversy laid to rest? CNS Drugs. 2001;15(11):831-837.

29. Miller E. Measles-mumps-rubella vaccine and the development of autism. Semin Pediatr Infect Dis. 2003;14(3):199-206.

30. Lintas C, Altieri L, Lombardi F, Sacco R, Persico AM. Association of autism with polyomavirus infection in postmortem brains.J Neurovirol. 2010;16(2):141-149.

31. Nordin J, Anderson R, Anderson R, et al. Immunizations. Bloomington, MN: Institute for Clinical Systems Improvement; 2012.

32. Mawson AR, Croft AM. Rubella virus infection, the congenital rubella syndrome, and the link to autism. Int J Environ Res Public Health. 2019;16(19):3543.

33. Slawinski BL, Talge N, Ingersoll B, et al. Maternal CMV seropositivity and autism symptoms in children. Am J Reprod Immunol. 2018;79(5):e12840.

34. Zappulo E, Riccio MP, Binda S, et al. Prevalence of HSV1/2 congenital infection assessed through genome detection on dried blood spot in individuals with autism spectrum disorders. In Vivo. 2018;32(5):1255-1258.

35. al-Haddad BJS, Jacobsson B, Chabra S, et al. Long-term risk of neuropsychiatric disease after exposure to infection in utero. JAMA Psychiatry. 2019;76(6):594-602.

36. Croen LA, Qian Y, Ashwood P, et al. Infection and fever in pregnancy and autism spectrum disorders: findings from the study to explore early development. Autism Res. 2019;12(10):1551-1561.

37. Ozonoff S, Young GS, Carter A, et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011;128(3):e488-e495.

38. Messinger DS, Young GS, Webb SJ, et al. Early sex differences are not autism-specific: a Baby Siblings Research Consortium (BSRC) study. Mol Autism. 2015;6:32.

39. Ozonoff S, Young GS, Carter A, et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011;128(3):e488-e495.

40. Cohen S. Targeting Autism: What We Know, Don't Know, and Can Do to Help Young Children with Autism Spectrum Disorders. 3rd ed. Berkeley, CA: University of California Press, Ltd.; 2006.

41. Colvert E, Tick B, McEwen F, et al. Heritability of autism spectrum disorder in a UK population-based twin sample. JAMA Psychiatry. 2015;72(5):415-423.

42. Bai D, Yip BHK, Windham GC, et al. Association of genetic and environmental factors with autism in a 5-country cohort. JAMA Psychiatry. 2019;76(10:1035-1043.

43. Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. The familial risk of autism. JAMA. 2014;311(17):1770-1777.

44. Yuen RK, Thiruvahindrapuram B, Merico D, et al. Whole-genome sequencing of quartet families with autism spectrum disorder.Nat Med. 2015;21(2):185-191.

45. Leppa VM, Kravitz SN, Martin CL, et al. Rare inherited and denovo CNVs reveal complex contributions to ASD risk in multiplex families. Am J Hum Genet. 2016;99(3):540-554.

46. Yuen RKC, Merico D, Bookman M, et al. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat Neurosci. 2017;20(4):602-611.

47. Tammimies K, Marshall CR, Walker S, et al. Molecular diagnostic yield of chromosomal microarray analysis and whole-exome sequencing in children with autism spectrum disorder. JAMA. 2015;314(9):895-903.

48. Hallmayer J, Cleveland S, Torres A, et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011;68(11):1095-1102.

49. Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics. 2004;113(5):e472-e486.

50. Sadakata T, Washida M, Iwayama Y, et al. Autistic-like phenotypes in CADPS2-knockout mice and aberrant CADPS2 splicing in autistic patients. J Clin Invest. 2007;117(4):931-943.

51. Geier DA, Geier MR. Early downward trends in neurodevelopmental disorders following removal of thimerosal-containing vaccines.J Am Phys Surg. 2006;11(1):8-13.

52. Orenstein WA, Paulson JA, Brady MT, Cooper LZ, Seib K. Global vaccination recommendations and thimerosal. Pediatrics. 2013;131(1):149-151.

53. Centers for Disease Control and Prevention. Thimerosal FAQs. Available at https://www.cdc.gov/vaccinesafety/concerns/thimerosal/faqs.html. Last accessed November 30, 2023.

54. Geier MR, Geier DA. Neurodevelopmental disorders after thimerosal-containing vaccines: a brief communication. Exp Biol Med. 2003;228(6):660-664.

55. American Academy of Pediatrics, United States Public Health Service. Joint statement of the American Academy of Pediatrics (AAP) and the United States Public Health Service (USPHS). Pediatrics. 1999;104(3 Pt 1):568-569.

56. Stratton K, Gable A, McCormick MC, Institute of Medicine (US) Immunization Safety Review Committee. Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders. Washington, DC: National Academies Press; 2001.

57. National Academy of Sciences. MMR Vaccine and Thimerosal-Containing Vaccines Are Not Associated with Autism, IOM Report Says. Available at https://www.nationalacademies.org/news/2004/05/mmr-vaccine-and-thimerosal-containing-vaccines-are-not-associated-with-autism-iom-report-says. Last accessed November 30, 2023.

58. Institute of Medicine Immunization Safety Review Committee. Immunization Safety Review: Vaccines and Autism. Washington, DC: National Academies Press; 2004.

59. Schechter R, Grether JK. Continuing increases in autism reported to California's development services system: mercury in retrograde. Arch Gen Psychiatry. 2008;65(1):19-24.

60. Geier DA, Geier MR. An assessment of downward trends in neurodevelopmental disorders in the United States following removal of thimerosal from childhood vaccines. Med Sci Monit. 2006;12(6):CR231-CR239.

61. DeStefano F, Price CS, Weintraub ES. Increasing exposure to antibody-stimulating proteins and polysaccharides in vaccines is not associated with risk of autism. J Pediatrics. 2013;163:561-567.

62. Kaltsas A, Moustakli E, Zikopoulos A, et al. Impact of advanced paternal age on fertility and risks of genetic disorders in offspring. Genes (Basel). 2023;14(2):486.

63. Hultman CM, Sandin S, Levine SZ, Lichtenstein P, Reichenberg A. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol Psychiatry. 2011;16(12):1203-1212.

64. Puts NAJ, Wodka EL, Harris AD, et al. Reduced GABA and altered somatosensory function in children with autism spectrum disorder. Autism Res. 2017;10(4):608-619.

65. Hwang BJ, Mohamed MA, Brašić JR. Molecular imaging of autism spectrum disorder. Int Rev Psychiatry. 2017;29(6):530-554.

66. Endres D, Tebartz van Elst L, Meyer SA, et al. Glutathione metabolism in the prefrontal brain of adults with high-functioning autism spectrum disorder: an MRS study. Mol Autism. 2017;8:10.

67. Maier S, Duppers AL, Runge K, et al. Increased prefrontal GABA concentrations in adults with autism spectrum disorders. Autism Res. 2022;15(7):1222-1236.

68. Giulivi C, Zhang JR, Omanska-Klusek A, et al. Mitochondrial dysfunction in autism. JAMA. 2010;304(21):2389-2396.

69. Hardan AY, Fung LK, Frazier T, et al. A proton spectroscopy study of white matter in children with autism. Prog Neuropsychopharmacol Biol Psychiatry. 2016;66:48-53.

70. Saghazadeh A, Ataeinia B, Keynejad K, Abdolalizadeh A, Hirbod-Mobarakeh A, Rezaei N. Anti-inflammatory cytokines in autism spectrum disorders: a systematic review and meta-analysis. Cytokine. 2019;123:154740.

71. Barbaresi WJ. The meaning of "regression" in children with autism spectrum disorder: why does it matter? J Dev Behav Pediatr. 2016;37(6):506-507.

72. Bradley CC, Boan AD, Cohen AP, Charles JM, Carpenter LA. Reported history of developmental regression and restricted, repetitive behaviors in children with autism spectrum disorders. J Dev Behav Pediatr. 2016;37(6):451-456.

73. Centers for Disease Control and Prevention. Autism Spectrum Disorder. Screening and Diagnosis of Autism Spectrum Disorder for Healthcare Providers. Available at https://www.cdc.gov/ncbddd/autism/hcp-screening.html#1. Last accessed November 30, 2023.

74. Coury D, Wolfe A, Lipkin PH, et al. Screening of Young Children for Autism Spectrum Disorders: Results from a National Survey of Pediatricians. Available at https://www.aap.org/en/research/pas-abstracts/screening-of-young-children-for-autism-spectrum-disorders-results-from-a-national-survey-of-pediatricians/. Last accessed November 30, 2023.

75. Volkmar F, Siegel M, Woodbury-SmithM, et al. Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2014;53(2):237-257.

76. American Academy of Neurology. Screening and Diagnosis of Autism. Available at https://www.aan.com/Guidelines/home/GuidelineDetail/33. Last accessed November 30, 2023.

77. U.S. Department of Health and Human Services. Birth to 5: Watch Me Thrive! A Compendium of Screening Measures For Young Children. Available at https://www.acf.hhs.gov/sites/default/files/documents/ecd/screening_compendium_march2014.pdf. Last accessed November 30, 2023.

78. Lipkin PH, Macias MM, and Council on Children with Disabilities, Section on Developmental and Behavioral Pediatrics. Pediatrics. 2020;145(1):e20193449.

79. Hus V, Lord C. The autism diagnostic observation schedule, module 4: revised algorithm and standardized severity scores. J Autism Dev Disord. 2014;44(8):1996-2012.

80. Shumway S, Farmer C, Thurm A, Joseph L, Black D, Golden C. The ADOS calibrated severity score: relationship to phenotypic variables and stability over time. Autism Res. 2012;5(4):267-276.

81. Silkey M, Duran-Pacheco G, Johnson M, et al. The Autism Impact Measure (AIM): meaningful change thresholds and core symptom changes over one year from an online survey in the U.S. J Autism Dev Disord. 2023;53:3422-3434.

82. Wiggins LD, Barger B, Moody E, Soke G, Pandey J, Levy S. Brief report: the ADOS calibrated severity score best measures autism diagnostic symptom severity in pre-school children. J Autism Dev Disord. 2019;49(7):2999-3006.

83. Ridout S, Eldevik S. Measures used to assess treatment outcomes in children with autism receiving early and intensive behavioral interventions: a review. Rev J Autism Dev Disord. 2023.

84. Green IW, Kidd CL, Accordino RE. Differential diagnosis of autism spectrum disorder across the lifespan. In: McDougle C (ed). Autism Spectrum Disorder. New York, NY: Oxford University Press; 2015.

85. Autism Society. Differential Diagnosis. Available at https://autismsociety.org/screening-diagnosis/. Last accessed November 30, 2023.

86. National Organization for Rare Disorders. Rare Disease Database. Available at https://rarediseases.org/rare-diseases/. Last accessed November 30, 2023.

87. Macferran K, Major N, Fussel J. High P. Differential and etiologic diagnosis of autism spectrum disorder. Developed for the Autism Case Training: A Developmental-Behavioral Pediatrics Curriculum; 2011.

88. Kohane IS, McMurry A, Weber G, et al. The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS One. 2012;7(4):e33224.

89. Isaksen J, Bryn V, Diseth TH, et al. Children with autism spectrum disorders – the importance of medical investigations. Eur J Paediatr Neurol. 2013;17(1):68-76.

90. Mazurek MO, Vasa RA, Kalb LG, et al. Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders. J Abnorm Child Psychol. 2013;41(1):165-176.

91. Memari A, Ziaee V, Mirfazeli F, Kordi R. Investigation of autism comorbidities and associations in a school-based community sample.J Child Adolesc Psychiatr Nurs. 2012;25(2):84-90.

92. Kose S, Erermis S, Ozturk O, et al. Health related quality of life in children with autism spectrum disorders: the clinical and demographic related factors in Turkey. Res Autism Spectrum Disord. 2013;7(2):213-220.

93. Bilder D, Botts EL, Smith KR, et al. Excess mortality and causes of death in autism spectrum disorders: a follow up of the 980s Utah/UCLA autism epidemiologic study. J Autism Dev Disord. 2013;43(5):1196-1204.

94. Woolfenden S, Sarkozy V, Ridley G, Coory M, Williams K. A systematic review of two outcomes in autism spectrum disorder—epilepsy and mortality. Dev Med Child Neurol. 2012;54(4):306-312.

95. Buie T, Campbell DB, Fuchs GJ III, et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics. 2010;125(Suppl 1):S1-S18.

96. Treating Autism, Autism Treatment Trust. Medical Comorbidities in Autism Spectrum Disorders: A Primer for Health Care Professionals and Policy Makers. Available at https://nationalautismassociation.org/pdf/MedicalComorbiditiesinASD2013.pdf. Last accessed November 30, 2023.

97. Nicolaidis C, Raymaker D, McDonald K, et al. Comparison of healthcare experiences in autistic and non-autistic adults: a cross-sectional online survey facilitated by an academic-community partnership. J Gen Intern Med. 2013;28(6):761-769.

98. Barger BD, Campbell JM, McDonough JD. Prevalence and onset of regression within autism spectrum disorders: a meta-analytic review. J Autism Dev Disord. 2013;43(4):817-828.

99. Ekinci O, Arman AR, Melek I, Bez Y, Berkem M. The phenomenology of autistic regression: subtypes and associated factors. Eur Child Adolesc Psychiatry. 2012;21(1):23-29.

100. Fein D, Barton M, Eigsti IM, et al. Optimal outcome in individuals with a history of autism. J Child Psychol Psychiatry. 2013;54(2):195-205.

101. Pellicano E. Do autistic symptoms persist across time? Evidence of substantial change in symptomatology over a 3-year period in cognitively able children with autism. Am J Intellect Dev Disabil. 2012;117(2):156-166.

102. Munoz-Yunta JA, Ortiz T, Palau-Baduell M, et al. Magnetoencephalographic pattern of epileptiform activity in children with early-onset autism spectrum disorders. Clin Neurophysiol. 2008;119(3):626-634.

103. Strasser L, Downes M, Kung J, Cross JH, De Haan M. Prevalence and risk factors for autism spectrum disorder in epilepsy: a systematic review and meta-analysis. Dev Med Child Neurol. 2018;60(1):19-29.

104. Souders MC, Zavodny S, Eriksen W, et al. Sleep in children with autism spectrum disorder. Curr Psychiatry Rep. 2017;19(6):34.

105. Cortese S, Wang F, Angriman M, Masi G, Bruni O. Sleep disorders in children and adolescents with autism spectrum disorder: diagnosis, epidemiology, and management. CNS Drugs. 2020;34(4):415-423.

106. Mazurek MO, Petroski GF. Sleep problems in children with autism spectrum disorder: examining the contributions of sensory over-responsivity and anxiety. Sleep Med. 2015;16(2):270-279.

107. Rajaei S, Kalantari M, Azari ZP, Tabatabaee SM, Dunn W. Sensory processing patterns and sleep quality in primary school children. Iran J Child Neurol. 2020;14(3):57-68.

108. Berenguer-Forner C, Miranda-Casas A, Pastor-Cerezuela G, Rosello-Miranda R. Comorbidity of autism spectrum disorder and attention deficit with hyperactivity. A review study. Rev Neurol. 2015;60(Suppl 1)S37-S43.

109. Elwin M, Elvin T, Larsson JO. Symptoms and level of functioning related to comorbidity in children and adolescents with ADHD: a cross-sectional registry study. Child Adolesc Psychiatry Ment Health. 2020;14:30.

110. Buck TR, Viskochil J, Farley M, et al. Psychiatric comorbidity and medication use in adults with autism spectrum disorder. J Autism Dev Disord. 2014;44(12):3063-3071.

111. Salazar F, Baird G, Chandler S, et al. Cooccurring psychiatric disorders in preschool and elementary school-aged children with autism spectrum disorder. J Autism Dev Disord. 2015;45(8):2283-2294.

112. De-la-Iglesia M, Olivar JS. Risk factors for depression in children and adolescents with high functioning autism spectrum disorders. Scientific World J. 2015:127853.

113. Heijtz RD, Wang S, Anuar F, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A. 2011;108(7):3047-3052.

114. Schurman JV, Friesen CA, Dai H, Danda CE, Hyman PE, Cocjin JT. Sleep problems and functional disability in children with functional gastrointestinal disorders: an examination of the potential mediating effects of physical and emotional symptoms. BMC Gastroenterol. 2012;12(1):142.

115. Chandler S, Carcani-Rathwell I, Charman T, et al. Parent-reported gastro-intestinal symptoms in children with autism spectrum disorders. J Autism Dev Disord. 2013;43(12):2737-2747.

116. Schieve LA, Gonzalez V, Boulet SL, et al. Concurrent medical conditions and health care use and needs among children with learning and behavioral developmental disabilities, National Health Interview Survey, 2006–2010. Res Dev Disabil. 2012;33(2):467-476.

117. French L, Kennedy EMM. Annual research review: early intervention for infants and young children with, or at-risk of, autism spectrum disorder: a systematic review. J Child Psychol Psychiatry. 2018;59(4):444-456.

118. Zwaigenbaum L, Penner M. Autism spectrum disorder: advances in diagnosis and evaluation. BMJ. 2018;361:k1674.

119. Zwaigenbaum L, Bauman ML, Choueiri R, et al. Early intervention for children with autism spectrum disorder under 3 years of age: recommendations for practice and research. Pediatrics. 2015; 136(Suppl 1):S60-S81.

120. Smith T, Iadarola S. Evidence base update for autism spectrum disorder. J Clin Child Adolesc Psychol. 2015;44(6):897-922.

121. Fuentes J, Hervas A, Howlin P, and ESCAP ASD Working Party. ESCAP practice guidance for autism: a summary of evidence-based recommendations for diagnosis and treatment. Eur Child Adolesc Psychiatry. 2021;30(6):961-984.

122. Lai MC, Anagnostou E, Wiznitzer M, Allison C, Baron-Cohen S. Evidence-based support for autistic people across the lifespan: maximising potential, minimising barries, and optimising the perso-environment fit. Lancet Neurol. 2020;19(5):434-451.

123. National Autism Center at May Institute. National Standards Project. Available at https://nationalautismcenter.org/national-standards/. Last accessed November 30, 2023.

124. Wong C, Odom SL, Hume K, et al. Evidence-Based Practices for Children, Youth, and Young Adults with Autism Spectrum Disorder. Chapel Hill, NC: Frank Porter Graham Child Development Institute; 2013.

125. Odom SL, Boyd BA, Hall LJ, Hume K. Evaluation of comprehensive treatment models for individuals with autism spectrum disorders. J Autism Dev Disord. 2010;40(4):425-436.

126. UNC School of Medicine. TEACCH Autism Program. Available at https://teacch.com/. Last accessed November 30, 2023.

127. Early Start Denver Model. Available at https://www.esdm.co/. Last accessed November 30, 2023.

128. Child Mind Institute. What is Applied Behavior Analysis? Available at https://childmind.org/article/what-is-applied-behavior-analysis/. Last accessed November 30, 2023.

129. Lord C, Brugha TS, Charman T, et al. Autism spectrum disorder. Nat Rev Dis Primers. 2020;6(1):5.

130. Tiede G, Walton KM. Meta-analysis of naturaistic developmental behavioral interventions for young children with autism spectrum disorder. Autism. 2019;23(8):2080-2095.

131. Crank JE, Sandbank M, Dunham K, et al. Understanding the effects of naturalistic developmental behavioral interventions: a project AIM meta-analysis. Autism Res. 2021;14(4):817-834.

132. Waddington H, Reynolds JE, Macaskill E, Curtis S, Taylor LJ, Whitehouse AJ. The effects of JASPER intervention for children with autism spectrum disorder: a systematic review. Autism. 2021;25(8):2370-2385.

133. Tonge B, Brereton A, Kiomall M, Mackinnon A, Rinehart NJ. A randomised group comparison controlled trial of 'preschoolers with autism': a parent education and skills training intervention for young children with autistic disorder. Autism. 2014;18(2):166-177.

134. Cheng WM, Smith TB, Butler M, Taylor TM, Clayton D. Effects of parent-implemented interventions on outcomes of children with autism: a meta-analysis. J Autism Dev Disord. 2023;53(11):4147-4163.

135. Devita-Raeburn E. The Controversy Over Autism's Most Common Therapy. Available at https://www.spectrumnews.org/features/deep-dive/controversy-autisms-common-therapy/. Last accessed November 30, 2023.

136. Baron-Cohen S. The Concept of Neurodiversity is Dividing the Autism Community. Available at https://blogs.scientificamerican.com/observations/the-concept-of-neurodiversity-is-dividing-the-autism-community/. Last accessed November 30, 2023.

137. Pantazakos T, Vanaken GJ. Addressing the autism mental health crisis; the potential of phenomenology in neurodiversity-affirming clinical practices. Front Psychol. 2023;14:1225152.

138. Chapman R, Botha M. Neurodivergence-informed therapy. Dev Med Child Neurol. 2023;65(3):310-317.

139. Green J. Debate: neurodiversity, autism and healthcare. Child Adolesc Ment Health. 2023;28(3):438-442.

140. Organization for Autism Research. Individualized Education Programs (IEPs). Available at https://researchautism.org/educators/teachers-corner/#ieps. Last accessed November 30, 2023.

141. Association for Science in Autism Treatment. LEAP Model. Available at https://asatonline.org/for-parents/learn-more-about-specific-treatments/leap-model/. Last accessed November 30, 2023.

142. Boyd BA, Hume K, McBee MT, et al. Comparative efficacy of LEAP, TEACCH and non-model-specific special education programs for preschoolers with autism spectrum disorders. J Autism Dev Disord. 2014;44(2):366-380.

143. Strain PS, Bovey EH II. Randomized, controlled trial of the LEAP model of early intervention for young children with autism spectrum disorders. Topics Early Child Spec Educ. 2011;31(3):133-154.

144. Strain PS, Hoyson M. The need for longitudinal, intensive social skill intervention: LEAP follow-up outcomes for children with autism. Topics Early Child Spec Educ. 2000;20(2):116-122.

145. Anderson DK, Lord C, Risi S, et al. Patterns of growth in verbal abilities among children with autism spectrum disorder. J Consult Clin Psychol. 2007;75(4):594-604.

146. Schlosser RW, Wendt O. Effects of augmentative and alternative communication intervention on speech production in children with autism: a systematic review. Am J Speech Lang Pathol. 2008;17(3):212-230.

147. Ganz JB, Mason RA, Goodwyn FD, Boles MB, Heath AK, Davis JL. Interaction of participant characteristics and type of AAC with individuals with ASD: a meta-analysis. Am J Intellect Dev Disabil. 2014;119(6):516-535.

148. National Autism Resources. The Picture Exchange Communication System. Available at https://nationalautismresources.com/the-picture-exchange-communication-system-pecs/. Last accessed November 30, 2023.

149. Spencer D, Marshall J, Post B, et al. Psychotropic medication use and polypharmacy in children with autism spectrum disorders. Pediatrics. 2013;132(5):833-840.

150. Schubart JR, Camacho F, Leslie D. Psychotropic medication trends among children and adolescents with autism spectrum disorder in the Medicaid program. Autism. 2014;18(6):631-637.

151. Mandell DS, Morales KH, Marcus SC, Stahmer AC, Doshi J, Polsky DE. Psychotropic medication use among Medicaid-enrolled children with autism spectrum disorders. Pediatrics. 2008;121(3).

152. Rosenberg RE, Mandell DS, Farmer JE, Law JK, Marvin AR, Law PA. Psychotropic medication use among children with autism spectrum disorders enrolled in a national registry, 2007–2008. J Autism Dev Disord. 2010;40(3):342-351.

153. Coury DL, Anagnostou E, ManningCourtney P, et al. Use of psychotropic medication in children and adolescents with autism spectrum disorders. Pediatrics. 2012;130(Suppl 2):S69-S76.

154. Myers SM, Johnson CP, the Council on Children With Disabilities. Pediatrics. 2007;5:1162-1182.

155. Malone RP, Waheed A. The role of antipsychotics in the management of behavioural symptoms in children and adolescents with autism. Drugs. 2009;69(5):535-548.

156. Swinson RP, Antony MM, Rachman S, Richter MA (eds). Obsessive-Compulsive Disorder Theory, Research, and Treatment. New York, NY: The Guilford Press; 1998.

157. LexiComp Online. Available at https://online.lexi.com. Last accessed November 30, 2023.

158. U.S. Food and Drug Administration. FDA Approves the First Drug to Treat Irritability Associated with Autism, Risperdal. Available at https://wayback.archive-it.org/7993/20170113132901/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108759.htm. Last accessed November 30, 2023.

159. Jesner OS, Aref-Adib M, Coren E. Risperidone for autism spectrum disorder. Cochrane Database Syst Rev. 2007;(1):CD005040.

160. McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med. 2002;347:314-321.

161. DeFilippis M, Wagner KD. Treatment of autism spectrum disorder in children and adolescents. Psychopharmacol Bull. 2016;46(2):18-41.

162. Stachnik JM, Nunn-Thompson C. Use of atypical antipsychotics in the treatment of autistic disorder. Ann Pharmacother. 2007;41(4):626-634.

163. Malone RP, Cater J, Sheikh RM, Choudhury MS, Delaney MA. Olanzapine versus haloperidol in children with autistic disorder: an open pilot study. J Am Acad Child Adolesc Psychiatry. 2001;40(8):887-894.

164. Barnard L, Young AH, Pearson J, Geddes J, O'Brien G. A systematic review of the use of atypical antipsychotics in autism.J Psychopharmacol. 2002;16(1):93-101.

165. McDougle CJ, Kem DL, Posey DJ. Case series: use of ziprasidone for maladaptive symptoms in youths with autism. J Am Acad Child Adolesc Psychiatry. 2002;41(8):921-927.

166. Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA. 2009;302(16):1765-1773.

167. El Achkar CM, Spence SJ. Clinical characteristics of children and young adults with co-occurring autism spectrum disorder and epilepsy. Epilepsy Behav. 2015;47:183-190.

168. Nickels K, Katusic SK, Colligan RC, Weaver AL, Voigt RG, Barbaresi WJ. Stimulant medication treatment of target behaviors in children with autism: a population-based study. J Dev Behav Pediatr. 2008;29(2):75-81.

169. Posey DJ, Aman MG, McCracken JT, et al. Positive effects of methylphenidate on inattention and hyperactivity in pervasive developmental disorders: an analysis of secondary measures. Biol Psychiatry. 2007;61(4):538-544.

170. Williams K, Brignell A, Randall M, Silove N, Hazell P. Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2013;(8):CD004677.

171. Boaden K, Tomlinson A, Cortese S, Cipriani A. Antidepressants in children and adolescents: meta-review of efficacy, tolerability and suicidality in acute treatment. Front Psychiatry. 2020;11:717.

172. Gabis LV, Ben-Hur R, Shefer S, Jokel A, Ben Shalom D. Improvement of language in children with autism with combined donepezil and choline treatment. J Molecular Neuroscience. 2019;69:224-234.

173. Malaguarnera M, Cauli O. Effects of l-carnitine in patients with autism spectrum disorders: review of clinical studies. Molecules. 2019;24(23):4262.

174. Feng JY, Li HH, Wang B, Shan L, Jia FY. Successive clinical application of vitamin D and bumetanide in children with autism spectrum disorder: a case report. Medicine (Baltimore). 2020;99(2):e18661.

175. Hafizi S, Tabatabaei D, Lai MC. Review of clinical studies targeting inflammatory pathways for individuals with autism. Front Psychiatry. 2019;10:849.

176. Veenstra-VanderWeele J, Cook EH, King BH, et al. Arbaclofen in children and adolescents with autism spectrum disorder: a randomized, controlled, phase 2 trial. Neuropsychopharmacology. 2017;42(7):1390-1398.

177. National Institutes of Health. The Use of Secretin to Treat Autism. Available at https://www.nichd.nih.gov/newsroom/releases/secretin. Last accessed November 30, 2023.

178. Williams KJ, Wray JJ, Wheeler DM. Intravenous secretin for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2012;(4):CD003495.

179. Bent S, Hendren RL. Complementary and alternative treatments for autism part 1: evidence-supported treatments. AMA J Ethics. 2015;17(4):369-374.

180. Lofthouse N, Hendren R, Hurt E, Arnold LE, Butter E. A review of complementary and alternative treatments for autism spectrum disorders. Autism Res Treat. 2012;(8):870391.

181. Hanson E, Kalish LA, Bunce E, et al. Use of complementary and alternative medicine among children diagnosed with autism spectrum disorder. J Autism Dev Disorders. 2007;37(4):628-636.

182. Brondino N, Fusar-Poli L, Rocchetti M, Provenzani U, Barale F, Politi P. Complementary and alternative therapies for autism spectrum disorder. Evid Based Complement Alternat Med. 2015:258589.

183. Manivasagam T, Arunadevi S, Essa MM, et al. Role of oxidative stress and antioxidants in autism. Adv Neurobiol. 2020;24:193-206.

184. Pan X, Wu X, Yan D, Peng C, Rao C, Yan H. Acrylamide-induced oxidative stress and inflammatory response are alleviated by N-acetylcysteine in PC12 cells: involvement of the crosstalk between Nrf2 and NF-ĸB pathways regulated by MAPKs. Toxicol Lett. 2018;288:55-64.

185. Estes A, Olson E, Sullivan K, et al. Parenting-related stress and psychological distress in mothers of toddlers with autism spectrum disorders. Brain Dev. 2013;35(2):133-138.

186. Hayes SA, Watson SL. The impact of parenting stress: a meta-analysis of studies comparing the experience of parenting stress in parents of children with and without autism spectrum disorder. J Autism Dev Disord. 2013;43(3):629-642.

187. Horlin C, Falkmer M, Parsons R, Albrecht MA, Falkmer T. The cost of autism spectrum disorders. PLoS One. 2014;9(9):e106552.

188. Child and Adolescent Health Measurement Initiative, 2013. National Profile of Children with Special Health Care Needs and Autism Spectrum Disorders: Key Findings from the 2009/10 NS-CSHCN and 2011/12 NSCH. U.S. Department of Health and Human Services, Health Resources and Services Administration: 2013.

189. Lavelle TA, Weinstein MC, Newhouse JP, Munir K, Kuhlthau KA, Prosser LA. Econimic burden of childhood autism spectrum disorders. Pediatrics. 2014;13393):e520-e529.

190. Clifford T, Minnes P. Who participates in support groups for parents of children with autism spectrum disorders? The role of beliefs and coping style. J Autism Dev Disord. 2013;43(1):179-187.

191. Mohd Roffeei SH, Abdullah N, Basar SK. Seeking social support on Facebook for children with autism spectrum disorders (ASDs).Int J Med Inform. 2015;84(5):375-385.

192. Kim SH, Macari SL, Koller J, Chawarska K. Examining the phenotypic heterogeneity of early autism spectrum disorder: subtypes and short-term outcomes. J Child Psychol Psychiatry. 2016;57(1):93-102.

193. Ozonoff S, Young GS, Landa R, et al. Diagnostic stability in young children at risk for autism spectrum disorder: a baby siblings research consortium study. J Child Psychol Psychiatry. 2015; 56(9):988-998.

194. Anderson DK, Liang JW, Lord C. Predicting young adult outcome among more and less cognitively able individuals with autism spectrum disorders. J Child Psychol Psychiatry. 2014;55(5):485-494.

195. Gotham K, Pickles A, Lord C. Trajectories of autism severity in children using standardized ADOS scores. Pediatrics. 2012;130(5).

196. Pugliese CE, Anthony L, Strang JF, Dudley K, Wallace GL, Kenworthy L. Increasing adaptive behavior skill deficits from childhood to adolescence in autism spectrum disorder: role of executive function. J Autism Dev Disord. 2015;45(6):1579-1587.

Evidence-Based Practice Recommendations Citations

1. Schaefer GB, Mendelsohn NJ, Professional Practice and Guidelines Committee. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15(5):399-407. Available at https://www.acmg.net/PDFLibrary/Austism-Spectrum-Genetics-Evaluation.pdf. Last accessed December 15, 2023.

2. Scottish Intercollegiate Guidelines Network. Assessment, Diagnosis and Clinical Interventions for Children and Young People with Autism Spectrum Disorders: A National Clinical Guideline. Edinburgh: Scottish Intercollegiate Guidelines Network; 2016. Available at https://www.sign.ac.uk/assets/sign145.pdf. Last accessed December 15, 2023.