A Systematic Review of Medical Treatments forChildren With Autism Spectrum Disorders
abstract
CONTEXT: As many as 1 in every 110 children in the United States has
an autism spectrum disorder (ASD). Many medical treatments for ASDs
have been proposed and studied, but there is currently no consensus
regarding which interventions are most effective.
OBJECTIVE: To systematically review evidence regarding medical
treatments for children aged 12 years and younger with ASDs.
METHODS: We searched the Medline, PsycInfo, and ERIC (Education
Resources Information Center) databases from 2000 to May 2010, regulatory data for approved medications, and reference lists of included
articles. Two reviewers independently assessed each study against
predetermined inclusion/exclusion criteria. Studies of secretin were
not included in this review. Two reviewers independently extracted
data regarding participant and intervention characteristics, assessment techniques, and outcomes and assigned overall quality andstrength-of-evidence ratings on the basis of predetermined criteria.
RESULTS: Evidence supports the benefit of risperidone and aripiprazole for challenging and repetitive behaviors in children with ASDs.
Evidence also supports significant adverse effects of these medications. Insufficient strength of evidence is present to evaluate the benefits or adverse effects for any other medical treatments for ASDs,
including serotonin-reuptake inhibitors and stimulant medications.
CONCLUSIONS: Although many children with ASDs are currently
treated with medical interventions, strikingly little evidence exists to
support benefit for most treatments. Risperidone and aripiprazole
have shown benefit for challenging and repetitive behaviors, but associated adverse effects limit their use to patients with severe impairment or risk of injury. Pediatrics 2011;127:e1312–e1321

AUTHORS: Melissa L. McPheeters, PhD, MPH,a,b Zachary
Warren, PhD,c,d Nila Sathe, MA, MLIS, a Jennifer L. Bruzek,
PhD,a Shanthi Krishnaswami, MBBS, MPH,a Rebecca N.
Jerome, MLIS, MPH, e and Jeremy Veenstra-VanderWeele,
MDd,f,gaVanderbilt Evidence-Based Practice Center, Institute for
Medicine and Public Health; and bDepartment of Obstetrics andGynecology, Vanderbilt University Medical Center; cDepartmentsof Psychiatry and Pediatrics; dVanderbilt Kennedy
Center/Treatment and Research Institute for Autism Spectrum
Disorders; fDepartments of Psychiatry, Pediatrics, andPharmacology, gCenter for Molecular Neuroscience; and eEskind
Biomedical Library and Department of Biomedical Informatics,
Vanderbilt University, Nashville, Tennessee

KEY WORDS
autism spectrum disorders, antipsychotics, risperidone,
aripiprazole, serotonin-reuptake inhibitors, citalopram,fluoxetine, psychostimulants
ABBREVIATIONSASD—autism spectrum disorder
SRI—serotonin-reuptake inhibitor
RCT—randomized controlled trial
RUPP—Research Units on Pediatric Psychopharmacology
ABC-C—Aberrant Behavior Checklist Community Version
ABC-C-I—ABC-C irritability/agitation/crying subscale
ABC-C-H—ABC-C hyperactivity/noncompliance subscale
ABC-C-S—ABC-C stereotypy subscale
CY-BOCS—Children’s Yale-Brown Obsessive Compulsive Scale
We acknowledge that all authors of this article meet authorshipcriteria and have made substantial contributions to conception
and design, acquisition of data, or analysis and interpretation of
data; have participated in drafting the article or revising it
critically for important intellectual content; and have given final
approval of the version to be published.
The authors of this report are responsible for its content.
Statements made in this report should not be construed as anendorsement by the Agency for Healthcare Research and Qualityor the US Department of Health and Human Services.
www.pediatrics.org/cgi/doi/10.1542/peds.2011-0427
doi:10.1542/peds.2011-0427
Accepted for publication Mar 1, 2011
Address correspondence to Jeremy Veenstra-VanderWeele, MD,
465 21st Ave S, 7158 Medical Research Building III, Nashville, TN37232. E-mail: j.vvw@vanderbilt.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2011 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: Dr Warren has received researchsupport from the Marino Autism Research Institute, Autism Speaks,
and the Simons Foundation; and Dr Veenstra-VanderWeele hasreceived research support from Autism Speaks, the American
Academy of Child and Adolescent Psychiatry,(Continued on last page)e1312

McPHEETERS et al
Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

REVIEW ARTICLESAs many as 1 in every 110 children in
the United States has an autism spectrum disorder (ASD).1 Affected children have multiple symptoms that canbe reduced into 3 broad categories: social impairment; communication impairment; and repetitive behavior.2–5
Comorbidity with other conditions iscommon, including intellectual disability, seizure disorders, hyperactivity,
and anxiety.1,2,4,5 Many treatments havebeen proposed and studied, including
behavioral, educational, medical, allied health, and complementary medicine interventions, but there is currently no global consensus regarding
which intervention strategy is most effective.6,7 Given the lifelong nature of
ASDs, most patients are exposed tomultiple interventions that address
different target symptoms.
Medical treatments are primarily directed toward comorbid symptoms,
rather than core symptoms, in children with ASDs. As part of a systematic review of therapies for children
younger than 12 with ASDs,8 we reviewed the literature on antipsychotic,
serotonin-reuptake inhibitor (SRI), andstimulant medications (Table 1). Allother medical treatments except secretin (see accompanying review9)
had insufficient evidence for an evaluation of their possible benefits in children with ASDs; information about
these and other therapies addressedin the full review8 can be found at www.
effectivehealthcare.ahrq.gov.

METHODS
Search Strategy
We searched Medline via the PubMedinterface, PsycINFO (psychology andpsychiatry literature), and ERIC (Education Resources Information Center)(educational literature) from 2000 to
May 2010 by using relevant controlled
vocabulary terms and key terms related to ASDs (eg, autistic disorder)
and therapy-related terms (eg, thera-

TABLE 1 Description of Medical and Related Interventions Addressed in the Report
Intervention
Antipsychotic medications

SRIs

Stimulants and other medications
for hyperactivity

Description
Pharmacologic agents including risperidone, aripiprazole, andhaloperidol that act primarily on the dopamine andserotonin systems; outside of ASDs, primarily used to treat
psychotic and mood disorders; within ASDs, primarily
studied for effects on challenging behaviors including
irritability, aggression, and self-injurious behavior
Pharmacologic agents including fluoxetine and citalopram
that act on the serotonin system; outside of ASDs, primarily
used to treat depression, anxiety, and obsessive-compulsive
disorder; within ASDs, studied for potential to ameliorate
repetitive and problem behaviors
Pharmacologic agents including methylphenidate,amphetamine, and dextroamphetamine that act primarilyon the dopamine system; outside of ASDs, primarily used totreat hyperactivity and inattention in patients withattention-deficit/hyperactivity disorder; within ASDs, studied
to treat hyperactivity

peutics). We also hand-searched thereference lists of all included articles
to identify additional studies, reviewed
clinical trials related to therapies for
ASDs to identify corresponding articles, and reviewed regulatory information on drugs approved for the treatment of irritability in patients with
ASDs (aripiprazole and risperidone).
Study Selection
We developed inclusion and exclusion
criteria in consultation with an expert
panel of clinicians and educators involved in ASD care. We included all
study designs and required that studies of medical interventions include
at least 30 participants with ASDs
younger than the age of 13 years. We
also required that studies be published in the year 2000 or later, after
the publication of the Diagnostic andStatistical Manual of Mental Diseases, Fourth Edition2 and the widespread implementation of goldstandard ASD assessment tools
including the Autism Diagnostic Observation System10 and the Autism
Diagnostic Interview-Revised.11
Data Extraction
Using standardized forms, 2 investigators independently extracted data
regarding study design; descriptionsof the study populations, intervention, and comparison groups; andbaseline and outcome data, as well
as data about harms or adverse effects. We also captured data on the
conduct and timing of assessments
to inform the assessment of quality.
Principal outcomes of interest included effects on core symptoms of
ASDs or common comorbid symptoms including sleep, anxiety, hyperactivity, and challenging behavior(eg, irritability/agitation).
Study-Quality Assessment
Two investigators independently assessed each study by using a qualityassessment form developed by the review team with input from experts inthe field. We evaluated the following elements with a series of yes/no questions in each domain (eg, were outcomes coded and assessed by people
blinded to the intervention status of
the participants?):● study design;● diagnostic approach;● participant

ascertainment
characterization;and● intervention description;● outcomes measurement; and● statistical analysis.

PEDIATRICS Volume 127, Number 5, May 2011
Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

e1313

TABLE 2 Domains Used to Assess Strength of
the Evidence
Risk of bias: Reflects issues in study design andconduct that could result in biased estimatesof effect
Consistency: Reflects similarity of effect sizes
seen across studies; consistency cannot be
assessed when only 1 study is available
Directness: Reflects the relationship between theintervention and the ultimate health outcomeof interest
Precision: Reflects the level of certainty aroundthe effect observed

Disagreements between assessors
were resolved through discussion toreach consensus. Overall assessmentof quality was determined by using aprespecified algorithm that is available in the full report.8
We assessed the strength of evidenceof the current research by using methods established in the Evidence-Based
Practice Centers’ methods guide for effectiveness and comparative effectiveness reviews.12 Assessments werebased on consideration of 4 domains:risk of bias; consistency in direction of
the effect; directness in measuring intended outcomes; and precision of effect (Table 2). We determined thestrength of evidence separately for
major intervention-outcome pairs byusing a prespecified approach that is
described in detail in the full review.8
Data Synthesis
Given considerable heterogeneity inthe interventions and outcome
measures used in studies that met
our inclusion criteria, we did notconduct any meta-analyses. We summarized characteristics of study
populations and interventions andused descriptive statistics to reportstudy outcomes.

RESULTS
Figure 1 outlines the flow of articles
retrieved for the review, and Table 3
summarizes the study characteristics.
Eighteen unique studies addressed thee1314

medical interventions listed above forchildren with ASDs. Of these studies, 10were randomized controlled trials (RCTs).
We located 9 studies that addressed antipsychotic medications,13–29 5 studies
that addressed SRI medications,30–34
and 4 studies that evaluated stimulant
medications.35–40 Table 4 summarizes
the study results.
Antipsychotics
Two of the 4 RCTs of risperidone
targeted challenging behavior as
the primary outcome.18,23 The firststudy13,14,16–21 was sponsored by the National Institute of Mental Health aspart of the Research Units on Pediatric
Psychopharmacology (RUPP) Autism
Network. The second study was sponsored by the manufacturer of risperidone (Risperdal [Ortho-McNeil-Janssen
Pharmaceuticals, Inc, Titusville, NJ]).22
There were 89 subjects in risperidone
arms and 91 subjects in placebo arms.
Both studies used a graduated-dosetitration design over 8 weeks; the average risperidone dose ranged from 1.5
to 1.8 mg/day, and dosing was primarily once23 or twice13,14,16–21 daily. In these2 studies, baseline ratings of challenging behavior, as measured by the
Aberrant Behavior Checklist Community
Version irritability/agitation/crying subscale (ABC-C-I), were similar between therisperidone and placebo arms. Scoreson subscales of the Aberrant Behavior
Checklist can range from 0 to 48 withhigher scores indicating greater behavioral impairment. Decreases in ABC-C-I
scores were significantly greater for
subjects in the risperidone arms in bothstudies (mean decreases: 12.1–14.9)
compared with those in the placeboarms (mean decreases: 3.6 – 6.5).
Similar improvements were seen on
the ABC-C hyperactivity/noncompliance subscale (ABC-C-H) in both trials,
which indexes both hyperactivity andchallenging behavior. Baseline ABC-C-H
ratings were similar in both treat-ment groups, with significantly
greater decreases for subjects in therisperidone arms (mean decreases:
14.8 –14.9) compared with those in
the placebo arms (mean decreases:
4.7–7.4).
Secondary outcomes in the 2 RCTs ofrisperidone included measures of repetitive behavior including the ABC-C
stereotypy subscale (ABC-C-S). Baseline ABC-C-S ratings were similar between the risperidone and placeboarms, and there were significantly
greater decreases for subjects in therisperidone arm compared with thosein the placebo arm in 1 RCT (mean decreases: 4.8 vs 1.7)18 but would nothave been significant after correction
for multiple testing in the other RCT(mean decreases: 4.3 vs 2.4).23 One
study16,18 also used the Children’s YaleBrown Obsessive Compulsive Scale(CY-BOCS) modified for pervasive development disorder to assess repetitive behavior and found no baseline
differences between the groups but asignificantly greater decrease in subjects in the risperidone arms compared with those in the placebo arms
(mean decreases: 3.9 vs 1.0). A numberof other outcomes were measured inthese studies, but none outside of challenging behavior, hyperactivity, and repetitive behavior would have yielded
statistically significant findings oncecorrected for multiple comparisons.
Two additional RCTs did not provide
specific numerical ratings on either
challenging or repetitive behavior.15,24
One of these studies was an 8-weekdrug-discontinuation RCT with risperidone and placebo arms15 after positive
response during 4 months of openlabel risperidone treatment.18 This
study indexed “relapse” by using acomposite measure of the ABC-C-I andclinician ratings15 and found significantly less “relapse” in subjects in therisperidone arm (2 of 16) compared withthose in the placebo arm (10 of 16).

McPHEETERS et al
Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

REVIEW ARTICLES

Nonduplicate articles
identified in searches

Articles excluded
n = 3406

N = 4120● Literature search: n = 3779
● Hand search/grey-literaturesearch: n = 341
Full-text articles excludedan = 531• Participants not within age range
n = 293

Full-text articles
reviewedn = 714• Not original researchn = 135• Ineligible study sizen = 406• Not relevant to key questionsn = 285• Unable to abstract data
Unique full-text
articles included inreviewn = 183 (comprising
159 uniquestudies)n = 16Full-text articles included in
the medical literaturen = 18• Antipsychotics, n = 9• SRIs, n = 5• Stimulants, n = 4

FIGURE 1
Location of studies that addressed medical interventions. a The total number of articles in the exclusion categories exceeded the number of articles excluded, because most of the articles fit into
multiple exclusion categories.

The last RCT was a 6-month study withrisperidone and placebo arms thatused a variety of general rating scales
to assess response.24 The study authors only reported median Childhood
Autism Rating Scale ratings for thoseparticipants with at least a 20% response, and more improvement wasreported for subjects in the risperidone arms (11.1) than for those in theplacebo arms (2.5).24
Reports of all the risperidone RCTs
also provided data on adverse eventsor adverse effects. All study authors
reported on weight gain,14,15,18,22–24
which was greater for subjects in therisperidone arms (mean weight gain:
2.7–2.8 kg) than for those in the placebo arms (mean weight gain: 0.8 –1.7
kg).14,18,22,23 Authors of 3 of the
RCTs14,15,18,22,23 provided data on otheradverse events in both the risperidone
and placebo arms. Somnolence ordrowsiness was the most common adverse event in 2 of these studies, occurring in 53 of 89 subjects in the risperidone arms and 9 of 91 subjects inthe placebo arms, but there was some
improvement in somnolence overtime.14,18,22,23 From both of these studies, more extrapyramidal symptoms,
including tremor, dyskinesia, and rigidity, were reported in the risperidone arm compared with the placeboarm, but these events were categorized differently between the 2 studies
and did not clearly show a statisticallysignificant difference between treatment arms.14,18,22,23
The RUPP study18 authors also reported a greater rise in prolactin levels in subjects in the risperidone arm(mean increase: 27.7 ng/mL) compared with those in the placebo arm(mean increase: 0.8 ng/mL),21 although
they did not report clinical events,

such as gynecomastia or galactorrhea, that could be related to elevated prolactin levels. The RUPP
study specifically assessed cognitive
function in a subset of subjects andfound no worsening and some evidence of improvement on risperidone that would not be statisticallysignificant after correction for multiple testing.13,18
We identified two 8-week RCTs of aripiprazole in children with ASDs,26,27 bothof which were sponsored by the manufacturer of aripiprazole (Abilify [Otsuka America Pharmaceutical, Inc., Tokyo, Japan]). The primary outcome forthese studies was challenging behavior indexed by the ABC-C-I. These studies included a total of 213 subjects inthe aripiprazole arms and 103 subjects in the placebo arms.
One study used a fixed-dose design
with 1 placebo arm and 3 arms corresponding to 5, 10, and 15 mg/day ofaripiprazole26; all subjects began at 2
mg/day with forced titration weekly
until they reached their goal dose. The
other study used a dose-titration
schedule with weekly progression
from 2 to 15 mg/day following clinicaljudgment.27 In these 2 studies, baseline
ABC-C-I ratings were similar among
the subjects in the aripiprazole andplacebo arms; there were greater decreases for subjects in the aripiprazole arms (mean decrease: 12.4 –14.4)
in comparison with those in the placebo arms (mean decrease: 5.0 – 8.4).
The trial with differing set doses ofaripiprazole revealed increasing response with increasing dose.26 Overall,
the results of the trial that used titration following clinical judgment weremore pronounced.27
Similar improvements for the ABCC-H were reported across both trials.
Baseline ratings were similar among
subjects in the aripiprazole and placebo arms; there were greater decreases for subjects in the aripipra-

PEDIATRICS Volume 127, Number 5, May 2011
Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

e1315

TABLE 3 Overview of Studies of Medical Interventions
Characteristic

Intervention
Antipsychotic medications
SRIs
Stimulants and other medications
for hyperactivity
Diagnostic approach
Clinical DSM-IV diagnosis ⫹ ADI-R
and/or ADOSOther approachesa
Treatment duration⬎1 to ⱕ3 mo⬎3 to ⱕ6 mo⬎6 to ⱕ12 mo⬎12 moStudy population
United States
EuropeOther
Total No. of participants

RCTs(N ⫽ 10), n

Prospective
Case Series(N ⫽ 3), nRetrospective
Case Series(N ⫽ 5), n

Total
Literature(N ⫽ 18), n

7
2
1

2
1
0

0
2
3

9
5
4

7

1

0

8

3

2

5

10

7
3
0
0

1
0
2
0

0
0
2
3

8
3
4
3

6
0
4
720

1
2
0
123

5
0
0
558

12
2
4
1401

The numbers shown indicate the number of unique studies with each characteristic. ADI-R indicates Autism Diagnostic
Interview-Revised; ADOS, Autism Diagnostic Observation Schedule; DSM-IV, Diagnostic and Statistical Manual of Mental
Diseases, Fourth Edition.
a Clinical DSM-IV diagnosis ⫹ other diagnostic tool or ADOS ⫹ other diagnostic tool or only clinical DSM-IV diagnosis or onlyADOS.

One 8-week RCT with 40 participants
compared the addition of cyproheptadine versus placebo to haloperidol.28
The medication doses were titrated up
from some starting point to cyproheptadine 0.05 mg/kg per day and haloperidol 0.2 mg/kg per day, but no details
were provided. The ABC-C scoresshown were markedly lower than the
total ABC-C scores obtained at baselinein other medication trials,18,23,26,27
which suggests that a subscale may
have been administered, although it is
not stated.28 The response to placebo
plus haloperidol was smaller28 than the
response found in previous haloperidol
trials.42,43 The improvement in ABC-C
score in the cyproheptadine-plushaloperidol arm was larger (mean decrease: 10.9) than the improvement in
the placebo-plus-haloperidol arm (meandecrease: 3.7).28
Serotonin-Reuptake Inhibitors

zole arms (mean decrease: 12.7–
16.3) than for those in the placeboarms (mean decrease: 2.8 –7.7).
Secondary outcomes in the 2 major
RCTs of aripiprazole included measures of repetitive behavior.41 Bothstudies included the ABC-C-S. Baseline
ratings of stereotypy were similar
among subjects in the aripiprazole andplacebo arms. Decreases in ABC-C-S
scores were greater for subjects in thearipiprazole arms (mean improvements: 4.2– 4.8) compared with thosein the placebo arms (mean improvements: 1.8 –2.0). Both studies also
used the CY-BOCS modified for pervasive development disorder41 to assess
repetitive behavior and found no baseline differences between the groups
but a greater decrease in subjects inthe aripiprazole arms compared withthose in the placebo arms (mean decreases: 2.4 –3.8 vs 0.8 –1.7). The ABC-C
inappropriate-speech subscale, whichcorresponds primarily to repetitive
speech, also revealed significant ime1316

27

provement in 1 study and a supportive trend in the other.26
The 2 aripiprazole RCTs also provided
data on adverse effects. The authorsof both studies reported on weight
gain,26,27 which was greater in subjects
in the aripiprazole arms (mean weight
gain: 1.3–2.0 kg) than in those in theplacebo arms (mean weight gain: 0.3–
0.8 kg), and a statistically significant
difference was reported from both of
the studies.26,27 Somnolence and sedation were the most common adverse
events in both of these studies (66 of
210 subjects in the aripiprazole arms;
8 of 101 subjects in the placeboarms).26,27 The authors of both studies
also reported more extrapyramidal
symptoms including tremor, dyskinesia, and rigidity (44 of 210 subjects inthe aripiprazole arms; 10 of 210 subjects in the placebo arms).26,27 Bothstudies found a statistically significant
decrease in prolactin levels in subjects
in the aripiprazole arms in contrast
with those in the placebo arms.26,27

We reviewed citalopram and escitalopram together, because escitalopram is the active component (enantiomer) of citalopram. We reviewed
fluoxetine separately. We identified a12-week RCT of citalopram32 that focused on repetitive-behavior outcomes. Subjects were begun on 2.5
mg of citalopram daily with weekly
increases up to a maximum dose of
20 mg/day.32
No significant difference among subjects in the citalopram (n ⫽ 73) andplacebo (n ⫽ 76) arms was seen inmeasures of repetitive behavior; there
were similar baseline scores on the
CY-BOCS modified for pervasive development disorder and similar improvements (mean decreases: 2.0 vs 1.9) ineach arm. The other measures of repetitive behavior, including the Repetitive Behavior Scale-Revised, also resulted in similar baseline scores andsimilar improvements in each arm
and no evidence for an effect ofcitalopram.32

McPHEETERS et al
Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

REVIEW ARTICLESTABLE 4 Summary of Results of Studies
Intervention
Antipsychotic medications
Risperidone vs placebo

Aripiprazole vs placebo

Cyproheptadine added to haloperidolvs haloperidol and placebo
SRIs
Citalopram or Escitalopram vsplaceboStudy Design/Quality

Study Results and Overall Strength of Evidence

4 RCTs/1 of good quality,13,14,16–21
3 of fair quality15,22–24
2 prospective case series25,29

Improvements in challenging and repetitive behaviors; strength of evidence for
reducing challenging and repetitive behaviors is moderate
Strength of evidence for adverse events is high on the basis of results of RCTs
and case series; common adverse effects included weight gain, sedation,and extrapyramidal effects
Improvements in challenging and repetitive behaviors; strength of evidence for
reducing challenging and repetitive behaviors is high; strength of evidence
for adverse events is high; common adverse effects included weight gain,
sedation, and extrapyramidal effects
Behavioral improvement reported but without indicating specific domains in 1
study; strength of evidence is insufficient

2 RCTs/good quality26,27

1 RCT/fair quality28

1 RCT/good quality32

1 prospective case series33

Fluoxetine vs placebo

Various SRIs (including sertraline,
citalopram, paroxetine,
fluvoxamine)
Psychostimulants

1 RCT/fair quality30

1 retrospective case series31
1 retrospective case series34

1 RCT/good quality35–37
3 retrospective case series38–40

One secondary measure in this study,
the ABC-C-I, revealed an advantage forcitalopram. The baseline ratings were
not statistically different between thecitalopram and placebo arms, butmore improvement was seen in thescores of subjects in the citalopramarm (mean decrease: 3.2) than inthose in the placebo arm (mean decrease: 0.9).32
Adverse effects in this study included amarked increase in “activation” symptoms, including increased energy, disinhibition, and decreased sleep, in
subjects in the citalopram arm in comparison with those in the placeboarm.32 Diarrhea and dry or itchy skinwere also more common in subjects inthe citalopram arm.
One prospective case series of escitalopram also met our criteria.33 This 10week study sought to identify pharmacogenetic modifiers of treatment

No significant difference between the groups on repetitive behavior in 1 study;
significant but clinically small reduction in challenging behavior in thetreatment group compared with the placebo group
Strength of evidence for effect of citalopram or escitalopram to reduce
repetitive or challenging behavior is insufficient; strength of evidence foradverse events is insufficientGreater change in repetitive behavior with fluoxetine compared with placebo;
strength of evidence for fluoxetine to decrease repetitive behavior isinsufficient
Strength of evidence for adverse events is insufficient
40 of 89 subjects were ranked as “much improved”; strength of evidence forthe effect of SRIs to reduce repetitive behavior is insufficient; strength ofevidence for adverse events is low when SRIs are considered as a class
Improvement in hyperactivity and noncompliance in 1 study; adverse events
included increases in challenging behavior and loss of appetite
Strength of evidence for effectiveness in reducing hyperactivity is insufficient;
strength of evidence around adverse events is insufficient

response in the challenging-behavior
domain as measured by the ABC-C-I.
Fifty-eight subjects underwent aforced-dose titration of escitalopramfrom 2.5 mg/day increasing weekly up
to 20 mg; most of the subjects did not
tolerate the full dose. It is unfortunatethat the data were presented in figures only; raw values could not be
inferred. It is evident, however, that
the ABC-C-I for all subjects was similar at baseline and that improvements were ⬃10 points for 3 of the 4
genotype groups.33
One randomized controlled crossover trial of fluoxetine with two
8-week treatment periods separated
by a 4-week washout period30 randomly assigned 19 subjects to fluoxetine followed by placebo and 20 toplacebo followed by fluoxetine. During each phase of the study, subjects
began the first week at 2.5 mg/day

fluoxetine or placebo, followed asclinically indicated to 0.8 mg/kg per
day for weeks 4 to 8.
Subjects in the first fluoxetine group
showed an improvement of 1.2 on the
CY-BOCS, and those in the first placebo
arm showed an improvement of 0.5.
These differences were not statistically significant when consideredalone. Subjects in the second fluoxetine arm showed an improvement of
1.2, and those in the second placebo
arm showed a worsening of 0.1. When
analyzed together with the first treatment period in a repeated-measuresdesign, the CY-BOCS score change forsubjects in the fluoxetine arms was
significantly greater than for those in
the placebo arms. No adverse eventswere significantly more frequent in the
fluoxetine group, although more subjects on fluoxetine had their dose reduced because of agitation.30

PEDIATRICS Volume 127, Number 5, May 2011
Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

e1317

Psychostimulants
The RUPP Autism Network’s doubleblind crossover trial35–37 of methylphenidate included 72 children who received a 1-day placebo followed by 2days at each of 3 (low, medium, high)test doses of methylphenidate; doses
ranged from 7.5 to 50.0 mg/day. The
subjects who tolerated methylphenidate (n ⫽ 66) moved on to a 4-week,
double-blind crossover phase. Subjects with a positive response in the
double-blind phase (n ⫽ 34) completed an 8-week open-label continuation phase at their best dose. The
primary outcome measure was hyperactivity/noncompliance as assessedby the teacher-rated ABC-C-H. Blindedclinicians also assessed participants
by using the Clinical Global Impressionof Improvement scale; this subscale
and the ABC parent- and teacher-rated
hyperactivity subscales were combined to assess response.
In the double-blind crossover phase,
all methylphenidate doses demonstrated mean effects that were statistically superior to placebo, and effectsizes favored the medium dose for parent ratings and the high dose forteacher ratings. Mean parent ratings
on the ABC-C lethargy/social withdrawal subscale significantly worsened during the high dose of methylphenidate compared with placebo.
Irritability was the most frequent reason for discontinuation (18%) of treatment. Other adverse effects reported
included appetite and sleep changes,
anxiety, depression, headache, and diarrhea.

DISCUSSION
Assessment of the Literature
Although many children with ASDs are
currently treated with medical interventions,44–46 strikingly little evidence
exists to support clear benefit for mostmedications. Nonetheless, a few medications have shown benefit for chale1318

lenging behavior as well as repetitive
behavior and hyperactivity.
Medications to address challenging
behavior have the strongest evidence
to support their use. Risperidone andaripiprazole are the 2 best-studied
medications for ASDs, and the corresponding pharmaceutical companies
have funded at least 1 RCT for each.
Each medication has at least 2 RCTs
that have revealed improvement inparent-reported measures of challenging behavior and measures of hyperactivity. Although it was not the primary target behavior addressed inthese studies, repetitive behavior also
showed improvement with both risperidone and aripiprazole. We rated thestrength of evidence for the effect onchallenging and repetitive behaviors to
be moderate for risperidone and highfor aripiprazole, which means that future research is unlikely to change ourassessment of the benefit of these antipsychotic medications.
Both medications also cause significant adverse effects including marked
weight gain, sedation, and risk of extrapyramidal symptoms. Strength ofevidence around adverse events ishigh for both risperidone and aripiprazole. When considered in aggregate,
risperidone and aripiprazole are efficacious but are associated with significant adverse effects that limit their
use to patients with severe impairment or risk of injury.
The SRI fluoxetine showed benefit for
repetitive behavior in a single crossover RCT; although this effect was
driven primarily by the second arm of
the study.30 An RCT of the SRI citalopram32 revealed no benefit for repetitive behavior but possible improvement in challenging behavior. With
only 1 good-quality RCT available andan additional RCT of fair quality, we
consider the strength of evidence forthe ability of SRI medications to reduce repetitive or challenging behavior

to be insufficient. Evidence of adverse effects with SRIs (decreased sleep and increased energy) had insufficientstrength of evidence (2 RCTs, 1 of which
was of good quality) with variability in
how the outcomes were measured. The
strength of evidence for the effect ofstimulants on hyperactivity and challenging behavior was also insufficient on
the basis of 1 good-quality RCT.
Future Directions
At present, the literature surrounding
medication for children with ASDs
lacks properly designed, appropriately
powered RCTs of a number of medical
interventions that have been inadequately studied to date. Most of the
medical interventions that are currently being applied for children with
ASDs44–46 have insufficient strength ofevidence to evaluate either their potential benefit or adverse effects.
Some of the strongest study results to
support the use of medical interventions have been funded by pharmaceutical companies or device manufacturers that profit from the treatment. The
National Institutes of Health havefunded 2 published large-scale studiesof medical interventions, but more
publicly funded studies of medications
for ASDs are warranted.
It is important to note that the marked
improvements in challenging behaviors seen with risperidone and aripiprazole support the study of other antipsychotic medications that do notcause as much weight gain or liability
to develop metabolic disorders. In addition, medications for hyperactivity
and inattention symptoms deserve further scrutiny in subjects with ASDs.
Dosing information remains inadequate in the stimulant literature and isparticularly important for balancing
positive outcomes with potential
harms. The data on SRIs are scatteredand contradictory, and there is a particular need to consider modifiers

McPHEETERS et al
Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

REVIEW ARTICLESsuch as age and pharmacogenetics.33
The largest published trial of citalopram found no effect at all on repetitive or compulsive behavior but founda possible effect on challenging behavior (ABC-C-I).32 A number of medical
treatments have been evaluated in single studies or in small sample sizes
that did not meet criteria for our review,47–51 and larger well-controlled
studies are necessary to evaluate theirpotential benefit. On the basis of available evidence, new treatments are urgently needed to treat both core symptoms and associated symptoms inpatients with ASDs.
Finally, this literature lacks comparisons of medical interventions with behavioral interventions and combinations of the 2, despite the fact thatmost children are undergoing multiple
concurrent treatments. This approachhas proven crucial in studies ofobsessive-compulsive disorder, depression, and anxiety,52–54 but only 2studies of adequate size have considered combination treatment with ris-

peridone and behavioral treatment,
and these studies lacked an arm thatconsidered behavioral treatment
alone, in addition to their lack of a placebo control.

CONCLUSIONS
A few medications have shown benefit
for challenging or repetitive behaviors, and the clearest evidence favors
risperidone and aripiprazole. Significant adverse-effect profiles, however,make it clear that although thesedrugs are efficacious, caution is warranted regarding their use in patients
without severe impairments or risk of
injury. Insufficient evidence is available to judge the potential benefit oradverse effects of all other medical interventions currently used to treat
autism.

stitute of Mental Health, the Eunice
Kennedy Shriver National Institute ofChild Health and Human Development,
the Maternal and Child Health Bureau, the National Science Foundation, and the Agency for Healthcare
Research and Quality; and Dr
Veenstra-VanderWeele has received
research support from the National
Institute of Mental Health, the Eunice
Kennedy Shriver National Institute ofChild Health and Human Development, and the Agency for Healthcare
Research and Quality.

ACKNOWLEDGMENTS
This project was supported by the
Agency for Healthcare Research andQuality (contract number: HHSA 290
2007 10065 I). Dr Warren has received
research support from the National In-

We are grateful for the contributionsof Wendy Stone, PhD, who provided
guidance and mentorship, including
insight into the development of key
questions and interpretation of thedata. Ms Allison Glasser, BA, provided extraordinary project coordination, without which we could nothave completed this review. We also
appreciate the input of the parents
who participated as we formulated
our approach.

6. National Autism Center. National Standards
Report. Randolph, MA: National Autism Center;2009. Available at: www.nationalautismcenter.
org/pdf/NAC Standards Report.pdf. Accessed
March 9, 2011

VanderWeele J. A systematic review of secretin for children with autism spectrum
disorders. Pediatrics. 2011;127(5). Available at: www.pediatrics.org/cgi/content/
full/127/5/eXXX

7. National Research Council, Committee on
Educational Interventions for Children With
Autism. Educating Children With Autism.
Washington, DC; National Academies Press;
2001. Available at: http://books.nap.edu/
catalog.php?record_id⫽10017. Accessed
March 9, 2011

10. Lord C, Risi S, Lambrecht L, et al. The Autism
Diagnostic Observation Schedule-Generic: astandard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord. 2000;
30(3):205–223

REFERENCES
1. Autism and Developmental Disabilities Monitoring Network. Prevalence of the Autism
Spectrum Disorders (ASDs) in Multiple Areasof the United States, 2004 and 2006. Atlanta,
GA: Centers for Disease Control and Prevention;2009. Available at: www.cdc.gov/ncbddd/autism/states/ADDMCommunityReport2009.
pdf. Accessed March 9, 2011
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 2000
3. Zwaigenbaum L, Bryson S, Lord C, et al. Clinical assessment and management of toddlers with suspected autism spectrum
disorder: insights from studies of high-risk
infants. Pediatrics. 2009;123(5):1383–1391
4. Myers SM, Johnson CP; American Academyof Pediatrics, Council on Children With Disabilities. Management of children with autism spectrum disorders. Pediatrics. 2007;
120(5):1162–1182
5. Myers SM. Management of autism spectrum disorders in primary care. Pediatr
Ann. 2009;38(1):42– 49

8. Warren Z, Veenstra-VanderWeele J, Stone
W, Bruzek JL, Nahmias AS, Foss-Feig JH, etal. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness
Review 26. (Prepared by the Vanderbilt
Evidence-based Practice Center underContract 290-02-HHSA-290-2007-10065-I.)
AHRQ Publication 11-EHC035-EF. Rockville,
MD: Agency for Healthcare Research andQuality; 2007Available at: www.
effectivehealthcare.ahrq.gov/reports/final.
cfm. Accessed March 2011
9. Krishnaswami S, McPheeters ML, Veenstra-

11. Lord C, Rutter M, Le Couteur A. Autism Diagnostic Interview-Revised: a revised version
of a diagnostic interview for caregivers ofindividuals with possible pervasive developmental disorders. J Autism Dev Disord.
1994;24(5):659 – 685
12. Owens DK, Lohr KN, Atkins D, et al. AHRQ series
paper 5: grading the strength of a body ofevidence when comparing medical
interventions—Agency for Healthcare Research and Quality and the effective healthcare program. J Clin Epidemiol. 2010;63(5):513–523
13. Aman MG, Hollway JA, McDougle CJ, et al.

PEDIATRICS Volume 127, Number 5, May 2011
Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017e1319

Cognitive effects of risperidone in children
with autism and irritable behavior. J Child
Adolesc Psychopharmacol. 2008;18(3):227–236
14. Aman MG, Arnold LE, McDougle CJ, et al.
Acute and long-term safety and tolerabilityof risperidone in children with autism. J
Child Adolesc Psychopharmacol. 2005;
15(6):869 – 884
15. Research Units on Pediatric Psychopharmacology Autism Network. Risperidone
treatment of autistic disorder: longer-term
benefits and blinded discontinuation after 6
months. Am J Psychiatry. 2005;162(7):1361–1369
16. McDougle CJ, Scahill L, Aman MG, et al. Risperidone for the core symptom domains ofautism: results from the study by the autism network of the research units on pediatric psychopharmacology. Am J Psychiatry. 2005;162(6):1142–1148
17. Martin A, Scahill L, Anderson GM, et al.
Weight and leptin changes amongrisperidone-treated youths with autism:
6-month prospective data. Am J Psychiatry.
2004;161(6):1125–1127
18. McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med.
2002;347(5):314 –321
19. Arnold LE, Vitiello B, McDougle C, et al.
Parent-defined target symptoms respondto risperidone in RUPP autism study: customer approach to clinical trials. J Am Acad
Child Adolesc Psychiatry. 2003;42(12):1443–1450
20. Williams SK, Scahill L, Vitiello B, et al. Risperidone and adaptive behavior in children
with autism. J Am Acad Child Adolesc Psychiatry. 2006;45(4):431– 439
21. Anderson GM, Scahill L, McCracken JT, et al.
Effects of short- and long-term risperidone
treatment on prolactin levels in children
with autism. Biol Psychiatry. 2007;61(4):545–550
22. Pandina GJ, Bossie CA, Youssef E, Zhu Y, Dunbar F. Risperidone improves behavioral
symptoms in children with autism in a randomized, double-blind, placebo-controlled
trial. J Autism Dev Disord. 2007;37(2):367–373
23. Shea S, Turgay A, Carroll A, et al. Risperidone in the treatment of disruptive behavioral symptoms in children with autistic
and other pervasive developmental disorders. Pediatrics. 2004;114(5). Available at:www.pediatrics.org/cgi/content/full/114/
5/e634
24. Nagaraj R, Singhi P, Malhi P. Risperidone inchildren with autism: randomized, placebo-

e1320

controlled, double-blind study. J Child Neurol. 2006;21(6):450 – 455
25. Masi G, Cosenza A, Mucci M, Brovedani P. A
3-year naturalistic study of 53 preschool
children with pervasive developmental disorders treated with risperidone. J Clin Psychiatry. 2003;64(9):1039 –1047
26. Marcus RN, Owen R, Kamen L, et al. A
placebo-controlled, fixed-dose study of aripiprazole in children and adolescents withirritability associated with autistic disorder. J Am Acad Child Adolesc Psychiatry.
2009;48(11):1110 –1119
27. Owen R, Sikich L, Marcus RN, et al. Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics. 2009;124(6):1533–1540
28. Akhondzadeh S, Erfani S, Mohammadi MR,
et al. Cyproheptadine in the treatment ofautistic disorder: a double-blind placebocontrolled trial. J Clin Pharm Ther. 2004;
29(2):145–150
29. Correia CT, Almeida JP, Santos PE, et al.
Pharmacogenetics of risperidone therapy
in autism: association analysis of eight candidate genes with drug efficacy and adverse
drug reactions. Pharmacogenomics J.
2010;10(5):418 – 430
30. Hollander E, Phillips A, Chaplin W, et al. A
placebo controlled crossover trial of liquid
fluoxetine on repetitive behaviors in childhood and adolescent autism. Neuropsychopharmacology. 2005;30(3):582–589
31. DeLong GR, Ritch CR, Burch S. Fluoxetine response in children with autistic spectrum
disorders: correlation with familial majoraffective disorder and intellectual achievement. Dev Med Child Neurol. 2002;44(10):652– 659
32. King BH, Hollander E, Sikich L, et al. Lack ofefficacy of citalopram in children with autism spectrum disorders and high levels ofrepetitive behavior: citalopram ineffective
in children with autism. Arch Gen Psychiatry. 2009;66(6):583–590
33. Owley T, Brune CW, Salt J, et al. A pharmacogenetic study of escitalopram in autism
spectrum disorders. Autism Res. 2010;3(1):
1–7
34. Henry CA, Steingard R, Venter J, Guptill J,
Halpern EF, Bauman M. Treatment outcome
and outcome associations in children with
pervasive developmental disorders treatedwith selective serotonin reuptake
inhibitors: a chart review. J Child Adolesc
Psychopharmacol. 2006;16(1–2):187–195
35. Research Units on Pediatric Psychopharmacology Autism Network. Randomized,
controlled, crossover trial of methylphenidate in pervasive developmental disorders

with hyperactivity. Arch Gen Psychiatry.
2005;62(11):1266 –1274
36. 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
37. Jahromi LB, Kasari CL, McCracken JT, et al.
Positive effects of methylphenidate on social communication and self-regulation inchildren with pervasive developmental disorders and hyperactivity. J Autism Dev Disord. 2009;39(3):395– 404
38. Nickels K, Katusic SK, Colligan RC, Weaver
AL, Voigt RG, Barbaresi WJ. Stimulant
medication treatment of target behaviors
in children with autism: a populationbased study. J Dev Behav Pediatr. 2008;
29(2):75– 81
39. Posey DJ, Puntney JI, Sasher TM, Kem DL,
McDougle CJ. Guanfacine treatment of hyperactivity and inattention in pervasive developmental disorders: a retrospective
analysis of 80 cases. J Child Adolesc Psychopharmacol. 2004;14(2):233–241
40. Stigler KA, Desmond LA, Posey DJ, Wiegand RE, McDougle CJ. A naturalistic retrospective analysis of psychostimulants
in pervasive developmental disorders. J
Child Adolesc Psychopharmacol. 2004;
14(1):49 –56
41. Scahill L, McDougle CJ, Williams SK, et al.
Children’s Yale-Brown Obsessive Compulsive Scale modified for pervasive developmental disorders. J Am Acad Child Adolesc Psychiatry. 2006;45(9):1114 –1123
42. Anderson LT, Campbell M, Adams P, Small
AM, Perry R, Shell J. The effects of haloperidol on discrimination learning andbehavioral symptoms in autistic children. J Autism Dev Disord. 1989;19(2):227–239
43. Anderson LT, Campbell M, Grega DM,
Perry R, Small AM, Green WH. Haloperidol
in the treatment of infantile autism: effects on learning and behavioral symptoms. Am J Psychiatry. 1984;141(10):1195–1202
44. Aman MG, Lam KS, Van Bourgondien ME.
Medication patterns in patients with
autism: temporal, regional, and demographic influences. J Child Adolesc Psychopharmacol. 2005;15(1):116 –126
45. Aman MG, Lam KS, Collier-Crespin A. Prevalence and patterns of use of psychoactive
medicines among individuals with autism in
the Autism Society of Ohio. J Autism Dev Disord. 2003;33(5):527–534
46. Esbensen AJ, Greenberg JS, Seltzer MM,

McPHEETERS et al
Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

REVIEW ARTICLES

Aman MG. A longitudinal investigation of
psychotropic and non-psychotropic medication use among adolescents andadults with autism spectrum disorders.
J Autism Dev Disord. 2009;39(9):1339 –1349
47. Amminger GP, Berger GE, Schafer MR, Klier
C, Friedrich MH, Feucht M. Omega-3 fatty acids supplementation in children with
autism: a double-blind randomized,
placebo-controlled pilot study. Biol Psychiatry. 2007;61(4):551–553
48. Arnold LE, Aman MG, Cook AM, et al. Atomoxetine for hyperactivity in autism spectrum
disorders: placebo-controlled crossover pilot trial. J Am Acad Child Adolesc Psychiatry.
2006;45(10):1196 –1205

49. Rossignol DA, Rossignol LW, Smith S, et al.
Hyperbaric treatment for children with
autism: a multicenter, randomized, doubleblind, controlled trial. BMC Pediatr. 2009;
9:21
50. Guastella AJ, Einfeld SL, Gray KM, et al.
Intranasal oxytocin improves emotion
recognition for youth with autism spectrum disorders. Biol Psychiatry. 2010;
67(7):692– 694
51. Erickson CA, Posey DJ, Stigler KA, Mullett J,
Katschke AR, McDougle CJ. A retrospective
study of memantine in children and adolescents with pervasive developmental disorders. Psychopharmacology (Berl). 2007;
191(1):141–147
52. Walkup JT, Albano AM, Piacentini J, et al.

Cognitive behavioral therapy, sertraline, ora combination in childhood anxiety. N Engl J
Med. 2008;359(26):2753–2766
53. Pediatric OCD Treatment Study (POTS)
Team. Cognitive-behavior therapy, sertraline, and their combination for children andadolescents with obsessive-compulsive
disorder: the Pediatric OCD Treatment
Study (POTS) randomized controlled trial.
JAMA. 2004;292(16):1969 –1976
54. March J, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, andtheir combination for adolescents withdepression: Treatment for Adolescents
With Depression Study (TADS) randomized controlled trial. JAMA. 2004;292(7):807– 820(Continued from first page)NARSAD, Seaside Therapeutics, Roche Pharmaceuticals, and Novartis. The other authors have indicated they have no financial relationships relevant to thisarticle to disclose.
COMPANION PAPERS: Companions to this article can be found on pages e1303 and e1322 and online at www.pediatrics.org/cgi/doi/10.1542/peds.2011-0426 andwww.pediatrics.org/cgi/doi/10.1542/peds.2011-0428.

PEDIATRICS Volume 127, Number 5, May 2011
Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

e1321

A Systematic Review of Medical Treatments for Children With Autism Spectrum
Disorders
Melissa L. McPheeters, Zachary Warren, Nila Sathe, Jennifer L. Bruzek, Shanthi
Krishnaswami, Rebecca N. Jerome and Jeremy Veenstra-VanderWeele
Pediatrics 2011;127;e1312
DOI: 10.1542/peds.2011-0427 originally published online April 4, 2011;

Updated Information &Services

including high resolution figures, can be found at:
http://pediatrics.aappublications.org/content/127/5/e1312

References

This article cites 47 articles, 3 of which you can access for free at:
http://pediatrics.aappublications.org/content/127/5/e1312.full#ref-list-1

Subspecialty Collections

This article, along with others on similar topics, appears in thefollowing collection(s):Developmental/Behavioral Pediatrics
http://classic.pediatrics.aappublications.org/cgi/collection/developme
nt:behavioral_issues_sub

Permissions & Licensing

Information about reproducing this article in parts (figures, tables) orin its entirety can be found online at:https://shop.aap.org/licensing-permissions/Reprints

Information about ordering reprints can be found online:
http://classic.pediatrics.aappublications.org/content/reprints

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by theAmerican Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN:.

Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

A Systematic Review of Medical Treatments for Children With Autism Spectrum
Disorders
Melissa L. McPheeters, Zachary Warren, Nila Sathe, Jennifer L. Bruzek, Shanthi
Krishnaswami, Rebecca N. Jerome and Jeremy Veenstra-VanderWeele
Pediatrics 2011;127;e1312
DOI: 10.1542/peds.2011-0427 originally published online April 4, 2011;

The online version of this article, along with updated information and services, islocated on the World Wide Web at:
http://pediatrics.aappublications.org/content/127/5/e1312

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by theAmerican Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN:.

Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017