Gastrointestinal Symptoms in Autism Spectrum Disorder: A ...pluk.org/centraldirectory/Autism/Pediatrics-2014-McElhanon-peds.2013-3995.pdfGastrointestinal Symptoms in Autism Spectrum

DOI: 10.1542/peds.2013-3995; originally published online April 28, 2014;Pediatrics

Barbara O. McElhanon, Courtney McCracken, Saul Karpen and William G. SharpGastrointestinal Symptoms in Autism Spectrum Disorder: A Meta-analysis

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located on the World Wide Web at: The online version of this article, along with updated information and services, is

of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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Gastrointestinal Symptoms in Autism SpectrumDisorder: A Meta-analysis

abstractBACKGROUND: In pediatric settings, parents often raise concernsabout possible gastrointestinal (GI) symptoms in autism spectrum dis-order (ASD), yet the specificity of these concerns are not well studied.

OBJECTIVE: To conduct a meta-analysis of research investigating GIsymptoms among children with ASD.

METHODS: We searched Medline, PsycINFO, and PubMed databases(1980–2012) in peer-reviewed journals. Analysis involved studieswith a comparison group presenting quantitative data on GIsymptoms using combinations of terms for ASD and GI indicators.The systematic search yielded 15 studies. We calculated effect sizesand 95% confidence intervals (CIs) using a random-effects model.

RESULTS: Children with ASD experience significantly more general GIsymptoms than comparison groups, with a standardized mean differ-ence of 0.82 (0.24) and a corresponding odds ratio (OR) of 4.42 (95% CI,1.90–10.28). Analysis also indicated higher rates of diarrhea (OR, 3.63;95% CI, 1.82–7.23), constipation (OR, 3.86; 95% CI, 2.23–6.71), andabdominal pain (OR, 2.45; 95% CI, 1.19–5.07).

CONCLUSIONS: Results indicate greater prevalence of GI symptomsamong children with ASD compared with control children. Identifiedstudies involved high methodological variability and lack of compre-hensive data prohibited analysis of GI pathophysiologies (eg, gastro-esophageal reflux) typically associated with organic etiologies,limiting conclusions about the underpinnings of the observed associ-ation. Future research must address critical questions about thecauses and long-term impact of GI symptoms in ASD. Such analyseswill require more systematic research and clinical activities,including improved diagnostic screening, standardized assessment,and exploration of potential moderators (eg, dietary restrictions).Pediatrics 2014;133:872–883

AUTHORS: Barbara O. McElhanon, MD,a CourtneyMcCracken, PhD,a Saul Karpen, MD, PhD,a and William G.Sharp, PhDa,b

aDepartment of Pediatrics, Emory University School of Medicine,Atlanta, Georgia; and bMarcus Autism Center, Atlanta, Georgia

KEY WORDSautism spectrum disorder, constipation, digestive disorders, GI

ABBREVIATIONSADI-R—Autism Diagnostic Interview–RevisedADOS—Autism Diagnostic Observation ScheduleASD—autism spectrum disorderCARS—Childhood Autism Rating ScaleCI—confidence intervalDD—developmental delayES—effect sizeGI—gastrointestinalMMR—measles-mumps-rubellaOR—odds ratioSB—siblingSMD—standardized mean differenceTD—typically developing

Dr McElhanon participated in the study conception, design,identification of studies, study selection, data collection, dataextraction, data analysis, data interpretation, and drafting andrevision of the article; Dr McCracken participated in dataanalysis, data interpretation, and drafting and revision of thearticle; Dr Karpen participated in the study conception, datainterpretation, and critical revision of the article for importantintellectual content; Dr Sharp participated in the studyconception, design, identification of studies, study selection,data collection, data extraction, data analysis, datainterpretation, and drafting and revision of the article; and allauthors approved the final manuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2013-3995

doi:10.1542/peds.2013-3995

Accepted for publication Feb 12, 2014

Address correspondence to William G. Sharp, PhD, PediatricFeeding Disorders Program, The Marcus Autism Center, 1920Briarcliff Road, Atlanta, GA 30329. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: Dr Sharp is a member of theNutricia Advisory Board on GI Concerns in Children With ASD.The other authors have indicated they have no potential conflictsof interest to disclose.

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Autism spectrum disorder (ASD) is aneurodevelopmental condition that un-folds in the first few years of life andinvolves severe impairments in socialinteraction and communication, withconcomitant restriction in interests andextreme attachment to routine or to re-petitive or perseverative behaviors.1

Estimates of ASD in pediatric populationshave climbed dramatically over the pastdecade, with ∼1 in every 88 childrencurrently meeting diagnostic criteria inthe United States.2 High prevalencecombined with greater health carecosts3 and caregiver burden4 associatedwith ASD intensifies the need to identifythe etiology of ASD and develop inter-ventions to remediate core and comor-bid symptoms. Gastrointestinal (GI)dysfunction is frequently cited amongchildren with ASD, and many causal andtherapeutic hypotheses of ASD involvethe GI system.5 This includes the idea thatthere is a specific GI pathology associ-ated with ASD, triggered by abnormalimmune function or elevated intestinalpermeability. A great amount of contro-versy has surrounded this topic sincepublication and public awareness in1998 naming a new pathologic entity,“autistic enterocolitis,”6 as responsiblefor developmental regression in 12 chil-dren after administration of themeasles-mumps-rubella (MMR) vaccine. Ultimately,this research was retracted7 for severalreasons, including questionable re-search practices, as found by the Gen-eral Medical Counsel of the UnitedKingdom. An association between theMMR vaccine and ASD has not beensupported in subsequent research8;however, questions remain about thestatus of GI system function in ASD. Ad-ditional theories have posited that chil-dren with ASD are at greater risk forgluten sensitivity,9 lactase deficien-cies,10 and gene variants.11 Although thepresence of a unique GI pathophysiologyspecific to ASDs has yet to be identified,5

elevated risk for GI symptoms in thispopulation remains a critical issue in

pediatric settings, because this pop-ulation is significantly more likely to useGI agents and experience hospitaliza-tions related to GI disturbance com-pared with peers.3

Concern about possible GI dysfunctionin ASD is intensified by high rates offeedingconcernsandconsequentmedicalsequelae in ASD. Children with ASD havea fivefold elevated risk of developing afeeding problem compared with peers.12

Severe food selectivity (ie, eating onlya narrow variety of foods) is the mostcommon feeding concern documentedamong children with ASD, predominantlyin the form of strong preferences forstarches, snack foods, and processedfoods and a bias against fruits, vegeta-bles, and proteins.13 However, feedingconcerns in ASD are often overlookedin relation to other areas of clinical con-cern, probably because selective eatingpatterns do not necessarily associategreater risk for compromised growth (eg,failure to thrive, declining growth velocity)that trigger clinical attention in pediatricsettings.12,13 Evidence suggests that atyp-ical patterns of intake in ASD place thispopulation at risk for long-term nutri-tional or medical complications not cap-tured by broad anthropometrics oranalysis of overall energy intake, in-cluding vitamin and mineral deficien-cies12 and compromised bone growth.14

Indeed, closer examination of nutrientintake in the ASD population indicatessignificant specific deficits (lower intakeof calcium and protein) and a highernumber of nutritional deficits overallamong children with ASD.12 Food selec-tivity in ASD may also explain emergingevidence of a higher incidence of obe-sity,15 based on dietary patterns involvingexcessive consumption of processedsnacks and calorie-dense foods. Etiologi-cal factors contributing to the pattern andprevalence of atypical intake in ASD re-main elusive, but may involve pathophys-iological processes in the GI tract.Although organic factors leading to

difficult or painful eating, such as gas-troesophageal reflux, gastroenteritis,and food allergies, often precipitate orplay a role in the development ofchronic feeding concerns in other pe-diatric populations,12 research has yetto identify a clear GI link to account forthe emergence, maintenance, and to-pography of feeding problems associ-ated with ASD.

Research focusing on GI dysfunctionand feeding concerns in ASD was re-cently raised to priority status by theNational Institutes of Health InteragencyAutism Coordinating Committee (http://iacc.hhs.gov/), which cited that in a net-work of 14 academic health centersthroughout the United States, feedingand GI problems were reported in 50%of patients participating in treatmentprotocols. Moreover, a recent consen-sus report concluded that the availableevidence suggests the likelihood ofgreater prevalence of GI symptoms anddisorders in ASD while also noting thatdefinitive conclusions and evidence-based recommendations regarding GIdysfunction in ASD were not possiblebecause of the absence of high-qualityclinical research data.5 This conclusionwas based on a qualitative review of theliterature involving a pool of 11 studies.Identified studies had wide methodo-logical variability, with less than half ofthe studies including a comparisongroup and with data collection consist-ing primarily of parent reports, chartreviews, or study-specific questionnaires.This article has been cited 26 timesin peer-reviewed publications (as ofApril 2013) and is probably a primaryresource for pediatricians in ap-proaching these issues, emphasizingthe need for additional research in thisarea to guide clinical and research ac-tivities. Recent growth in the researchliterature, combined with the availabil-ity of quantitative procedures for syn-thesizing outcome data, present theopportunity for an updated analysis of

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the extant literature. The current reviewsought to survey the medical literatureto identify studies using empirical meth-ods to investigate GI diagnoses, signs,and symptoms among children with ASDand to summarize the evidence on thebasis of both descriptive and meta-analytic procedures.

METHODS

Search Strategy and StudySelection

Following the guidelines outlined by thePreferred Reporting Items for System-atic Reviews and Meta-Analyses state-ment, we searched Medline, PsycINFO,and PubMed databases (January 1980and September 2012) and conductedancestral and online searches in English-language journals foreligiblestudies. Thesearch parameters (Table 1) includedcombinations of keywords regarding thetarget population (eg, “autism,” “autisticdisorder”) paired systematically with GIindicators (eg, “digestion,” “gastritis”).

We cross-checked search results andremoved overlapping citations. Refer-ences from relevant articles and pre-vious reviews in this area5,16 were alsosearched for possible studies.

To be included in the meta-analysis,studies also had to meet the followingcriteria: the sample involved a pediatricpopulation (birth to18 years ofage)withASD; the study used a non-ASD com-parison group without identified neu-robehavioral delays to analyze GIproblems (ie, typically developing peersor siblings); and the study presenteddataonGI symptomseitherdescriptively(eg, frequencies, percentages) or sta-tistically (eg, P values, t scores). To avoida known sampling bias, we excludedstudies involving an ASD sample madeup exclusively of children with knownGI diagnoses17 or comparison groupsmade up exclusively of children withoutstomach or gut issues.18

Variables Coded, Data Extraction,and Reliability

Twoauthors (B.O.M.,W.G.S.) screenedallarticles identified during the literaturesearch and coded eligible studies byusing a standardized checklist system(available on request). Data extractedduring this process included descrip-tive information: study descriptors (eg,data collection, recruitment setting),participant demographic variables (ie,sample size, age, gender), compositionof the comparison groups, ASD diag-nostic procedures, GI assessment tools,and summary of findings. When it wasreported, we coded the source of the ASDdiagnosis, with possible categories in-cluding parent report, community pro-vider using diagnostic criteria (eg,psychologist; pediatrician), chart reviewof diagnostic status, ASD rating scale (eg,Childhood Autism Rating Scale [CARS],19

Autism Diagnostic Interview–Revised[ADI-R]20), and Autism Diagnostic Obser-vation Schedule (ADOS21). We also recordedwhether a standardized measure of

cognitive status or IQ was presented.Possible GI assessment tools includedchart review, caregiver questionnaire,parent interview, physician evaluation,any relevant blood tests, stool studies,skin allergy tests, or endoscopy. Possi-ble GI symptoms and diagnoses extrac-ted included the range of terms listed inTable 1, with space provided to code forother medical concerns presented inarticles (eg, feeding concerns).

The double-entered data allowed for kcoefficients (for categorical variables)and intraclass correlations (for in-terval and continuous variables) to becalculated on all extracted information.The mean k agreement for categoricaldata was 82% (range: 52%–100%). Theoverall intraclass correlation for in-terval and continuous data was 0.97(range: 0.62–1). Coder agreementexceeded the 80% standard widelyadopted and recommended duringquantitative synthesis of research.22

Statistical Analysis

To calculate the effect size (ES), we usedmeans (SDs) or frequencies (percen-tages), or if necessary, we estimated theES from test statistics (eg, x2, t tests).When summary statistics were notpresented in an article, we attempted tocontact the primary author via e-mail.The primary goal of the meta-analysiswas to determine the overall differencein GI symptoms between children withand without ASD. For each GI concern,we calculated a separate ES estimateacross studies. For studies involvingmultiple comparison groups (eg, ASDversus typically developing [TD] or sib-ling [SB]), we pooled the comparisongroups, producing an overall effect sizecomparing children with and withoutASD. This was the case in only 2 stud-ies.23,24 Our exclusion criteria also ex-cluded subgroups of childrenwith othermedical concerns or developmentaldelays (DDs), although descriptive in-formation (eg, age range, sample size)

TABLE 1 ASD and GI Key Words Used inDatabase Search

ASD Search TermsAsperger’sAutismAutism spectrum disorderAutisticPervasive developmental disorderPDD-NOS

GI Search TermsAbdominal pain/abdomenCeliacColitisConstipationDiarrheaDigestionDigestive disorders/systemDisaccharidaseEndoscopy/colonoscopyEsophagitis/oesophagitisGastroenterologyGastritisGastrointestinalGluten(s)Gastroesophageal refluxIntestines/intestinalVomiting

PDD-NOS, pervasive developmental disorder not otherwisespecified.



regarding DD samples is presented inTable 3 for reference. We did not conductan analysis of potential moderators (eg,age, gender, diagnostic status) given thesmall number of available studies andthe lack of descriptive data presented inthe articles. Finally, for a variable to beincluded in the analysis, we required atleast 6 studies presenting data on a GIsymptom, in line with recommendedstandards for systematic reviews.25,26

We entered and analyzed data usingComprehensive Meta-Analysis 2.27 Weconverted all ESs to standardized meandifference (SMDs) using a random-effects model.28 A positive SMD (SMD. 0) indicated more GI-related con-cerns in children with ASD than in thecomparison group. We evaluated SMDmagnitude using conventional stand-ards (0.2 = small, 0.5 = medium, 0.9 =large).29 To aid in clinical interpretationof outcomes, we also calculated thecorresponding odds ratio (OR) with 95%CIs, with values reflecting the odds ofa child with ASD having a GI symptomcompared with a child without ASD.

To assess heterogeneity within sub-groups and between studies, we calcu-latedESsandassociated95%CIs foreachsubgroup. In addition, we used the Q testto formally determine whether hetero-geneity was present. To assess the ro-bustness of our results, we conducteda sensitivity analysis to determine howsensitive the combined estimate was toany 1 study by repeatedly calculating theoverall ES with 1 study omitted per it-eration and compared the results withthe overall study effect. We analyzed thethreat of possible publication bias to thevalidity of the obtained outcomes usingthe funnel plot,30 failsafe N,31 and thetrim and fill.32 The failsafe N methoddetermines the number of additional“negative” studies (eg studies showingno difference between ASD and non-ASDgroups) needed to reduce the overalltest to nonsignificance. A small numberof negative studies indicate possible

publication bias. The trim and fillmethod is a nonparametric method thatfirst estimates the number of “missingstudies” in a meta-analysis and thendetermines what effect they would haveon the outcome had they been presentall along. If the added studies signifi-cantly change the test result, then pub-lication bias is possible.

RESULTS

Characteristics of Studies andParticipants

The search yielded 15 articles out ofa pool of 961 possible studies. Figure 1presents aflowdiagramof the screeningand identification process. All articleswere published since 2000, with 5 (33%)since 2010. Only 4 of the 11 studies (36%)identified by Buie et al5 met inclusioncriteria, resulting in 11 unique articles(73%) in the review. Table 2 providesa summary of methods by study. Re-search designs included prospectivestudies (53%), as well as studies miningexisting databases33–36 or medicalcharts.37–39 In terms of confirming di-agnostic status, 3 studies (20%) usedeither the ADI-R or ADOS; 3 (20%) usedthe CARS. Six (40%) relied exclusively onchart review or clinical provider, 1 study(7%) involved parent report, and theremaining 2 studies (13%) did not iden-tify the source of ASD diagnosis.

Assessment of GI status involved eithercaregiver report (73%) ormedical chartreview (27%). Diarrhea was the mostcommon symptom assessed, followedby general GI concerns. This latter cat-egory primarily involved denoting thepercentage of children experiencing$1GI clinical element based on a compositeof possible symptoms23,33,36–41; 3 stud-ies broadly asked caregivers whetherthere were concerns about their child’sbowels,42 whether their child experi-enced chronic or ongoing GI problems,23

or whether their child had a history ofGI dysfunction.43 Nine studies (60%) in-cluded information outside the core

symptoms captured by our coding sheet,such as recurrent fever,39 feeding ordietary concerns,37,41,42 or behavioralconcerns (eg, sleep, sudden aggressivebehavior)40 or simply included a broadcategory of “other GI problems.”36

Thepoolofstudies involvedatotalsampleof 2215 children with ASD (Table 3). Allstudies reported information on age (ie,mean, SD, range). Two studies37,38 in-volved a longitudinal design assessingthe incidence of GI symptoms at fixedtime periods; both also presented anoverall composite of symptoms, whichwas used for the current analysis. Eightstudies (53%) reported matching orstatistical equivalence for age acrossgroups; 4 (27%) noted equivalence in theproportion of boys to girls.

Overall Measure of ES

Four variables (ie, general GI concerns,diarrhea, constipation, abdominal pain)met the6-studythreshold for inclusion inthe analysis. Table 4 presents ES esti-mates calculated by using randomeffects models. Overall test for hetero-geneity of study ESs was statisticallysignificant for all 4 outcome measures,indicating that the random effectsmodel was appropriate. Analysis in-dicated higher levels of GI symptoms inall 4 areas among children with ASDwhen compared with children withoutASD. OR estimates for reports of generalGI symptoms ranged from 0.39 to 48.25(Fig 2), with an overall OR of 4.42, sug-gesting that the odds of GI symptoms inchildren with ASD are 4 times moreprevalent than for children without ASD.The corresponding SMD was large andstatistically significant (P , .001). ORestimates for diarrhea ranged from0.60to 19.80 (Fig 3), with an overall OR of3.63, suggesting a greater than three-fold increase in the prevalence of di-arrhea in children with ASD. A similartrend was detected for constipation,with OR estimates ranging from 0.86 to32.87 (Fig 4) and an overall OR of 3.86.

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The corresponding SMD for both varia-bles was large and statistically signifi-cant (P, .001). Finally, OR estimates forabdominal pain ranged from 0.93 to 7.91(Fig 5), with an overall OR of 2.45. Thecorresponding SMD represented a me-dium and statistically significant (P ,.05) effect size.

Sensitivity Analysis, PublicationBias, and Reliability of Results

Sensitivity analysis involved visual in-spection of CIs for the overall ES aftereachstudywasremovedoneata time.Nostudy significantly altered the overallmean ES estimates for each of the GIvariables included in the analysis. Visualinspection of the funnel plots indicatedno potential publication bias for theoutcomes general GI concerns andabdominal pain. The funnel plots forconstipation and diarrhea suggestedpotential publication bias. However, forboth of these outcomes, the failsafe Nanalysis indicated that there would needto be at least 140 and 230 published

studies, respectively, with nonsignifi-cant findings related to each of theoutcomes to change the current ES tononsignificant. Additionally, Duval andTweedie’s trim and fill method sug-gested only imputing 2 missing studiesfor the outcomes constipation and di-arrhea. Imputing the 2 studies did notsignificantly change the ES or the con-clusion. The failsafe N was 282 for gen-eral GI concerns and 25 for abdominalpain. This evidence lends credence tothe robustness of our findings.

DISCUSSION

This meta-analysis represents the firstrigorous evaluation of evidence re-garding GI symptoms in children withASD, quantifying the past 32 years ofresearch by using standardized datacollection, strict inclusion criteria, andmultiple statistical tools to ensure themost accurate assessment of currentknowledge on this topic, and it involveda total of 15 studies on 2215 childrenwith ASD. The results indicate greater

risk of general GI symptoms amongchildren with ASD than in those withoutASD, indicating that this populationmaybe more prone to specific symptomsof abdominal pain, constipation, anddiarrhea. By conventional standards,findings reflect a large ES, correspond-ing to a greater than threefold elevatedriskofgeneralGI concerns, constipation,and diarrhea between childrenwith andwithout ASD and a “medium” effect sizecorresponding with a greater thantwofold elevated risk of abdominal pain.This pattern of results corroboratesprevious anecdotal reports and de-scriptive studies suggesting greater GIcomplaints in ASD while emphasizingthe need for more evidence-based datato support best standards of care.

At a minimum, these results reinforceexpert consensus5 that parents andhealth care providers should be edu-cated about possible GI symptoms andpathophysiology in children with ASD,and children suspected of having pos-sible GI disorders should be screenedaccordingly. In addition, the magnitudeof the observed association combinedwith difficulties identifying and study-ing GI dysfunction in ASD warrants theadoption of a lower referral thresholdby practitioners for evaluation and treat-ment by a gastroenterologist if anunderlying problem is suspected. Chil-dren with ASD often present with limitedverbal communication, and as a result,their symptom presentation may be un-usual comparedwith that of their peers.5

For example, the emergence or exacer-bation of problem behaviors, such asaggression, self-injury, sleep distur-bance, or irritability, without clear envi-ronmental influence (ie, antecedents orconsequences), may be the only indi-cation of an underlying GI problem.44

Unfortunately, lack of evidence in thisarea has prevented the developmentof evidenced-based guidelines tohelp physicians navigate the diagnosticand early intervention process.45 This

FIGURE 1Flow diagram of included and excluded studies.



TABLE2

Descriptionof

ExperimentalCharacteristicsandAssessmentMethods

byStudy

Study

Al-

Ayadhi52

Black

etal33

Gondalia

etal43

Horvath&

Perm

an40

Ibrahim

etal37

Kazek

etal51

Mouridsen

etal38

Niehus

&Lord

39Parracho

etal23

Sandhu

etal34

Schieve

etal35

Smith

etal42

Valicenti-

McDermott

etal41

Wang

etal36

Wang

etal24

N%ofTotal

Studies

(15Total)

Datacollection

Prospective

X—

XX

—X

——

X—

—X

X—

X8

53Existingdataset

orretrospective

chartreview

—X

——

X—

XX

—X

X—

—X

—7

46

Recruitm

entsetting

Community

wide

—X

XX

X—

——

XX

X—

—X

—8

53Diagnosticclinicor

developm

entalcenter

——

——

——

—X

——

—X

X—

X4

27

Hospitalormedical

center

X—

——

—X

X—

——

——

——

—3

20

ASDdiagnosticindicatora

Parent

report

——

——

——

——

——

X—

——

—1

7Clinicalprovider

ordiagnosticcriteria

X—

XX

——

——

——

—X

X—

X6

40

CARS

——

X—

——

——

——

——

X—

X3

20ADOS

——

——

——

—X

——

—X

—X

—3

20ADI-R

——

——

——

—X

——

—X

—X

—3

20Chartreview

—X

——

X—

X—

—X

——

——

—4

27Notspecified

——

——

—X

——

X—

——

——

—2

13GIdiagnostictools

Questionnaire

X—

XX

—X

——

XX

XX

XX

X11

73Chartreview

—X

——

X—

XX

——

——

——

—4

27GIsymptom

sassessed

a

GeneralGIconcerns

—X

XX

X—

X—

X—

—X

XX

X10

67Diarrhea

XX

XX

XX

—X

—X

XX

XX

—12

80Constipation

X—

XX

XX

—X

——

—X

XX

—9

60Abdominalpain

X—

XX

XX

——

——

—X

XX

—8

53Food

allergies

——

XX

——

——

——

X—

X—

—4

27Stoolconcerns

——

XX

——

—X

——

—X

——

—4

27Reflux/GER

——

—X

X—

——

——

——

XX

—4

27Vomiting

X—

——

——

—X

——

—X

X—

—4

27Inflam

matorybowel

disease

—X

——

——

X—

——

——

—X

—3

20

Flatulence

orgas

——

XX

——

——

——

—X

——

—3

20Bloating

——

—X

——

——

——

—X

——

—2

13Food

intolerance

—X

——

——

——

——

——

—X

—2

13Burpingor

belching

——

—X

——

——

——

——

——

—1

7Other

—X

—X

XX

—X

——

—X

XX

—9

60Cognitive

functioning

oradaptivelevel

——

——

——

XX

——

——

—X

—3

20

X,studycharacteristicor

variablereported

instudy;—,study

characteristicor

variablenotreported

instudy.

aSubheadingsmay

notaddup

to100%

becausemultiplegroups

wereused

inastudy.

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TABLE3

Descriptionof

Participants

Study

Al-

Ayadhi

52Black

etal33

Gondalia

etal43

Horvath&

Perm

an40

Ibrahim

etal37

Kazek

etal51

Mouridsen

etal38

Niehus

&Lord

39

Parracho

etal23

Sandhu

etal34

Schieve

etal35

Smith

etal42

Valicenti-

McDermott

etal41

Wang

etal36

Wang

etal24

Total

Sample

N

%ofTotal

Studies(15

Total)

ASDgroup

Sample

size

3396

51412

121

51118

7558

78375

5150

589

572215

—

Age(m

o)X

XX

XXa

XXa

XX

XaX

XX

XX

15100

Mean

88.8

50.8

—78

—97

—140.5

84—

—116.4

91.2

99.6

82.7

1067

SD6

——

43.2

——

——

45—

—44.4

43.2

—47.7

640

Range

——

24–144

——

36–

156

——

36–192

—36–204

——

12–

216

—5

33

Gender

XX

X—

XX

XX

X—

X—

XX

X12

80Male (%)

30(91%

)84

(88%

)42

(82%

)—

92(76%

)39

(76%

)85

(72%

)61

(81%

)48

(83%

)—

292(77.9)

—37

(74)

459

(78)

48(84)

1280

Female

(%)

3(9%)

12(13%

)9(18%

)—

29(24%

)12

(24%

)33

(28%

)14

(29%

)10

(17%

)—

83(22.1)

—13

(26)

130

(22)

9(16)

——

Comparison

group

Sample

size

33b ,c

449

5343

b242b

,c28

336b

,c24

b22

(TD:10;

SB:12)

12905

36013(TD:

35775;

DD:238)

147b

,c

(TD:

112;DD

:35)

100b

,c(TD:

50;DD:50)

163

106(TD:

56b ;SB:50)

50664

—

Subtype

TDX

X—

—X

XX

XX

XX

XX

—X

1280

DD—

——

——

——

——

—X

XX

——

320

SB—

—X

X—

——

—X

——

——

XX

533

Age(m

o)—

XX

—Xa

X—

XX

XaX

XX

XX

1280

Mean

—49.8

——

—93

—113

TD:72;

SB:72

——

TD:120;

DD:151

TD:90;

DD:94.8

106.8

TD:102;SB:

104

853

SD—

——

——

——

—TD:35;

SB:26

——

TD:38.4;

DD:42

TD:43.2;

DD:48

—TD:47.6;SB:

63.9

427

Range

——

24–144

——

36–

144

——

TD:36–144;

SB:24–

112

—36–204

——

12–

216

—5

33

Gender

—X

X—

XX

—X

X—

X—

XX

X10

67Male (%)

—394(88%

)19

(36%

)—

184(76%

)20

(71%

)—

12(50%

)TD:6

(60%

);SB:7

(58.3%

)

—TD:17.458

(48.8);DD:

138(58.1)

—TD:37(74);

DD:37(74)

75 (46)

TD:28(50);

SB:28(56)

——

Female

(%)

—55

(12%

)34

(64%

)—

58(24%

)8

(29%

)—

12(50%

)TD:4

(40%

);SB:5

(41.7%

)

—TD:18317

(51.2);DD:

100(41.9)

—TD:13(26);

DD:13(26)

88 (54)

TD:28(50);

SB:22(44)

——

aLongitudinalstudy.

bReported

matched

forage.

cReported

matched

forgender.



includes how to best identify possiblesubsets of children most at risk andhow to modify clinical practice withconsideration to the unique combina-tion of behavioral, neurologic, or medi-cal issues in ASD. For example, the

guidelines on managing constipation inASD are the same as those for assess-ment and treatment of all constipatedchildren published by the North Ameri-can Society of Pediatric Gastroenterology,Hepatology, and Nutrition, with added

notes regarding possible modificationsbased on characteristics of the diagnosis.Modifications mainly underscore theneed for greater flexibility when workingwith children with ASD given commonobstacles, such as rejecting medicines“because of the flavor.”45

Findings regarding greater GI symp-toms in ASD should be considered in thecontext of several limitations. The poolof studies included in the current re-view was small, and only 4 out of 15possible GI problems met the 6-studythreshold for inclusion in the meta-analysis. Insufficient data were avail-able todeterminewhetherGI symptomsoften linked with an organic pathology,such as gastroesophageal reflux, gas-troenteritis, food allergies, and in-flammatory bowel disease, are morecommon among children with ASD.Questions also remain about the rela-tive contribution of behavioral factors,such as toileting and feeding problems,to the observed association betweendiarrhea, constipation, and abdominalpain in ASD. Estimates suggest that∼95% of childhood constipation maybe functional, without an underlyingphysiologic cause,46 and many childrenwith ASD present with nonorganic toi-leting problems that may precipitate orplay a role in the development of con-stipation, including absent or delayedacquisition of bowel training47 andhigher rates of problem behaviors re-lated to changes in toileting routine.48

Fecal retention in ASD may also occursecondary to difficulty with sensorystimuli, sensory processing, and motorproblems, leading to altered gastroin-testinal motility and defecation physiol-ogy.49 It is also possible that elevatedrates of constipation may be related tothe ubiquity of food selectivity in thispopulation, as the dietary patterns oftenassociated with ASD involve high intakeof processed food and lack fiber-containing fruits and vegetables, whichprovide a natural laxative effect and

TABLE 4 ESs, 95% Confidence Limits, and Within-Group Tests for Heterogeneity for StudiesIncluded in the Meta-analysis for GI Symptoms

GI Symptom Number of Contributing Studies Random Effects Model

SMD (SE) Odds Ratio 95%ConfidenceLimits

P

Lower Upper

General GI concerns 10 0.91 (0.23) 5.25 2.34 11.75 ,.0001Diarrhea 12 0.71 (0.19) 3.63 1.82 7.23 ,.0001Constipation 9 0.75 (0.16) 3.86 2.23 6.71 ,.0001Abdominal pain 8 0.49 (0.20) 2.45 1.19 5.07 .016

FIGURE 2Forest plot of general GI concerns with 95% CIs. aOR outside of range.

FIGURE 3Forest plot of diarrhea with 95% CIs.

REVIEW ARTICLE



decrease intestinal transit time.50 Thus,the interweaving in children with ASD ofbehavior, diet, alterations in feedingchoices, perceived improvements ordecrements in function by parents andcaregivers with alterations in diet, allpoint toward an important and clinicallyrelevant role for broad-based, longitu-dinal, unbiased studies of feeding pat-terns, GI symptoms, and behavior.

Close appraisal of the available literaturealso indicates the need for greatermethodological rigor. The summarizedresearch was based largely on parentreport andmedical chart reviews, and nostudies included confirmation of GI prob-lemsbyathird-partycareprovidersuchasa physician. Definitions of GI symptomsalso varied among included studies. Forexample, descriptions of diarrhea rangedfrom simply diarrhea24,33,40,43,51 to persis-

tent diarrhea,42 chronic diarrhea,39,52

frequent diarrhea/colitis,35 and a his-tory of diarrhea.34 One study focusedon stool frequency and consistency,41

defined as.4weeks involving painlesspassage of $3 large unformed stoolsper day, and another provided specificdefinitions of GI symptoms that wouldlead to this diagnosis (ie, enteritis, co-litis, gastroenteritis, or loose stool).37

Studies using chart review or existingdatabases often had unique opera-tional definitions, which could affectdetection or prevalence estimates. In thefuture, prospective controlled population-based studies with a physician evalua-tion and established definitions shouldbe pursued to increase standardizationand minimize measurement discrep-ancies across studies. Thiswill probablynecessitate a standardized measure

focusing on GI issues among childrenwith ASD, because no instruments existto guide clinical and research activities.Ideally, this instrument would be de-veloped using the methods describedin the Food and Drug AdministrationGuidance53 to serve as an endpoint forrandomized clinical trials and compar-ative effectiveness studies while in-creasing early detection to support beststandards of care. In addition, the use ofa toileting diary focusing on stools perday paired with characterization by thedescriptive and visual Bristol StoolScale54 could provide a more detailed,standardized examination of possible GIsymptoms, such as diarrhea and con-stipation. In the absence of reliable andvalid assessment, it is difficult to com-pare the severity of GI symptoms acrosssamples and to develop and evaluateeffective interventions. It will also beimperative to better characterize sam-ples using diagnostic measures, suchas ADOS21 and ADI,20 that have beenstandards of best practice in researchfor more than a decade. Only 40% ofidentified studies used a standardizedassessment to confirm ASD status, whichreflects the limitations of our knowl-edge of GI symptoms and disorders inASD.

The breadth of inquiry should also beexpanded to consider possible devia-tions in the establishment and main-tenance of the gut microbiome in ASD

FIGURE 4Forest plot of constipation with 95% CIs. aOR outside of range.

FIGURE 5Forest plot of abdominal pain with 95% CIs.



and the relative contribution of earlyfeeding practices to overall gut healthand acceptance of new feeding tastesandtextures.Studiesof fecalDNAextractshave found certain bacterial clustersoverrepresentedinchildrenwithASDandgastrointestinal complaints comparedwith children with similar GI complaintsbut typical neurobehavioral development(see Mulle et al55 for review). Provisionalevidence also suggests that childrenwith ASD are at greater risk for sub-optimal breastfeeding, including lateinitiation and shorter duration of exclu-sive breastfeeding.56,57 In addition topromoting optimal nutrition, breast milkassists in the development of the gas-trointestinal tract, pancreas and endo-crine system, and related mucosaldefenses,58 and it is therefore possiblethat suboptimal breastfeeding may re-sult in atypical colonization of the gutmicrobiome in ASD.59 In turn, changes inthe gut microbiome may help explainanecdotal reports of improvement inbehavioral functioning in response todietary changes if such changes serve

a probiotic function and improve symp-toms of irritable bowel syndrome (eg,bloating, abdominal pain, flatulence)among certain children with ASD.60 Suchreports help propagate interest in theuse of dietary manipulation (eg, gluten-and casein-free diets) as an ASD-focusedtreatment.55 Dietary interventions, in-cluding the gluten- and casein-free diets,nutritional supplements, enzymes, andantimicrobial agents, have not beensubstantiated by empirical investiga-tion,61 presenting a clear need to in-vestigate how possible deviations in theGI tract in ASD relate to current dietaryrecommendations being promoted andimplemented in the ASD community.

It is clear that greater clinical and re-search scrutiny is needed to increaseawarenesson this topicand thussupportdevelopment of the best standards ofcare. Previous controversy surroundingthe MMR vaccine and proposed causallink between ASD and infection of the GItract probably deterred investigatorsfrom dedicating resources to examineGI functioning in this population while

fostering uncertainty in the ASD com-munityregardingthevalidityof this lineofinquiry. Based on the available data, thismeta-analysis indicates agreater risk forgeneral GI concerns, constipation, di-arrhea, and abdominal pain in ASD;however, conclusions about the natureandetiology of the observedassociationsare tentative at best. In addition, data onthe prevalence of other GI symptoms (eg,gastroesophageal reflux, food allergies)typically associated with organic pa-thology are insufficient. As a result, themost logical conclusions remain thatrates of other GI pathophysiology in ASDare similar to those observed in thegeneral population, and there is no evi-dencesuggestingauniqueGIpathology inASD.5 Additional research is needed toelucidate the etiology, prevalence, to-pography, and remediation of GI prob-lems in ASD, with consideration of thepotential interwoven contributions offactors such as immune abnormalities,mucosal barrier dysfunction, gastroin-testinal motility, feeding and toiletingconcerns, and the gut microbiome.

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ROUNDER IS BETTER: Last week as I write this, we had yet another ice storm.While friends kept remindingme that the stormwas not as bad as the one in 1998,we still had almost an inch of ice on our roof, porch, deck, and trees. Because thetemperature then dropped precipitously, the ice persisted for days. The housegroaned and creaked, and I was incredibly worried that the roof would notsurvive. Fortunately, the house did survive unscathed, but at least one neighbor ofmine never even worried about damage for a minute. He is the only person in thearea to live in a domed house.As reported on CNBC (Real Estate: December 29, 2013), dome homes are incrediblystrong. The shape allows the home to be self-supporting and strong enough towithstand severe tornadoes, hurricanes, and earthquakes. Domes made ofconcrete can withstand the impact of debris from other buildings or flying,uprooted trees. An additional benefit is that the roof almost never blows off.Advocates liken dome homes to an egg: the curvature makes them quite strongand the most disaster proof home that can be built. Movies can be viewed on theweb showing a domed home surviving a tornado while the conventional homes inthe immediate vicinity are obliterated. So, if severe weather has become muchmore common and domed homes seem to survive them better, why aren’t morebuilt? It isn’t because of the cost. While they may be slightly more expensive tobuild, their energy efficiency more than makes up for that quite quickly. Thebiggest issue is that people do not like the looks of them and cannot imaginethemselves living in a domed home. Even residents of areas hard hit by tornadoestend to scoff at the notion of domed homes, preferring to rebuild their classicvision of an American home. As for my wife and me, we do not live in an areaparticularly prone to natural disasters. However, if we get too many more icestorms, I may have to reconsider our house design.

Noted by WVR, MD

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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf




DOI: 10.1542/peds.2013-3995; originally published online April 28, 2014;Pediatrics

Barbara O. McElhanon, Courtney McCracken, Saul Karpen and William G. SharpGastrointestinal Symptoms in Autism Spectrum Disorder: A Meta-analysis

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