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
http://pediatrics.aappublications.org/content/early/2014/04/22/peds.2013-3995
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
by guest on May 8, 2014pediatrics.aappublications.orgDownloaded from by guest on May 8, 2014pediatrics.aappublications.orgDownloaded from
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.
872 MCELHANON et al by guest on May 8, 2014pediatrics.aappublications.orgDownloaded from
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
REVIEW ARTICLE
PEDIATRICS Volume 133, Number 5, May 2014 873 by guest on May 8, 2014pediatrics.aappublications.orgDownloaded from
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.
874 MCELHANON et al by guest on May 8, 2014pediatrics.aappublications.orgDownloaded from
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.
REVIEW ARTICLE
PEDIATRICS Volume 133, Number 5, May 2014 875 by guest on May 8, 2014pediatrics.aappublications.orgDownloaded from
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.
876 MCELHANON et al by guest on May 8, 2014pediatrics.aappublications.orgDownloaded from
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.
REVIEW ARTICLE
PEDIATRICS Volume 133, Number 5, May 2014 877 by guest on May 8, 2014pediatrics.aappublications.orgDownloaded from
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.
878 MCELHANON et al by guest on May 8, 2014pediatrics.aappublications.orgDownloaded from
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
PEDIATRICS Volume 133, Number 5, May 2014 879 by guest on May 8, 2014pediatrics.aappublications.orgDownloaded from
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.
880 MCELHANON et al by guest on May 8, 2014pediatrics.aappublications.orgDownloaded from
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.
REFERENCES
1. American Psychiatric Association. Di-agnostic and Statistical Manual of MentalDisorders. 5th ed. Washington, DC: Ameri-can Psychiatric Publishing; 2013
2. Centers for Disease Control and Prevention.Prevalence of autism spectrum disorders:autism and developmental disabilities moni-toring network, 14 sites, United States, 2008.MMWR Surveill Summ. 2012;61(SS03):1–19.Available at: www.cdc.gov/ncbddd/autism/documents/ADDM-2012-Community-Report.pdf
3. Croen LA, Najjar DV, Ray GT, Lotspeich L,Bernal P. A comparison of health care uti-lization and costs of children with andwithout autism spectrum disorders ina large group-model health plan. Pediat-rics. 2006;118(4). Available at: www.pediat-rics.org/cgi/content/full/118/4/e1203
4. Fletcher PC, Markoulakis R, Bryden PJ. Thecosts of caring for a child with an autismspectrum disorder. Issues Compr PediatrNurs. 2012;35(1):45–69
5. Buie T, Campbell DB, Fuchs GJ III, et al.Evaluation, diagnosis, and treatment ofgastrointestinal disorders in individualswith ASDs: a consensus report. Pediatrics.2010;125(suppl 1):S1–S18
6. RETRACTED: Wakefield AJ, Murch SH, AnthonyA, et al. Ileal-lymphoid-nodular hyperplasia,non-specific colitis, and pervasive develop-mental disorder in children. Lancet. 1998;351(9103):637–641
7. Retraction—Ileal-lymphoid-nodular hyper-plasia, non-specific colitis, and pervasivedevelopmental disorder in children. Lancet.2010;375(9713):445
8. Hornig M, Briese T, Buie T, et al. Lack ofassociation between measles virus vaccineand autism with enteropathy: a case–con-trol study. PLoS ONE. 2008;3(9):e3140
9. Lau NM, Green PH, Taylor AK, et al. Markersof celiac disease and gluten sensitivity inchildren with autism. PLoS ONE. 2013;8(6):e66155
10. Williams BL, Hornig M, Buie T, et al. Im-paired carbohydrate digestion and trans-port and mucosal dysbiosis in theintestines of children with autism andgastrointestinal disturbances. PLoS ONE.2011;6(9):e24585 doi:10.1371/journal.pone.0024585
11. Campbell DB, Li C, Sutcliffe JS, Persico AM,Levitt P. Genetic evidence implicating mul-tiple genes in the MET receptor tyrosinekinase pathway in autism spectrum disor-der. Autism Res. 2008;1(3):159–168
12. Sharp WG, Berry RC, McCracken C, et al.Feeding problems and nutrient intake inchildren with autism spectrum disorders:a meta-analysis and comprehensive reviewof the literature. J Autism Dev Disord. 2013;43(9):2159–2173
13. Ledford JR, Gast DL. Feeding problems inchildren with autism spectrum disorders:a review. Focus Autism Other Dev Disabl.2006;21(3):153–166
REVIEW ARTICLE
PEDIATRICS Volume 133, Number 5, May 2014 881 by guest on May 8, 2014pediatrics.aappublications.orgDownloaded from
14. Hediger ML, England LJ, Molloy CA, Yu KF,Manning-Courtney P, Mills JL. Reducedbone cortical thickness in boys with autismor autism spectrum disorder. J Autism DevDisord. 2008;38(5):848–856
15. Egan AM, Dreyer ML, Odar CC, Beckwith M,Garrison CB. Obesity in young children withautism spectrum disorders: prevalenceand associated factors. Child Obes. 2013;doi:10.1089/chi.2012.0028
16. Erickson CA, Stigler KA, Corkins MR, PoseyDJ, Fitzgerald JF, McDougle CJ. Gastroin-testinal factors in autistic disorder: a criti-cal review. J Autism Dev Disord. 2005;35(6):713–727
17. Gorrindo P, Williams KC, Lee EB, Walker LS,McGrew SG, Levitt P. Gastrointestinal dys-function in autism: parental report, clinicalevaluation, and associated factors. AutismRes. 2012;5(2):101–108
18. Adams JB, Johansen LJ, Powell LD, Quig D,Rubin RA. Gastrointestinal flora and gas-trointestinal status in children with autism:comparisons to typical children and cor-relation with autism severity. BMC Gastro-enterol. 2011;11:22 doi:10.1186/1471-230X-11-22
19. Schopler ER, Reichlet RJ, Renner BR. TheChildhood Autism Rating Scale. Los Angeles,CA: Western Psychological Services; 1988
20. Lord C, Rutter M, Le Couteur A. Autism Di-agnostic Interview–Revised: a revised ver-sion of a diagnostic interview for caregiversof individuals with possible pervasive de-velopmental disorders. J Autism Dev Disord.1994;24(5):659–685
21. Lord C, Risi S, Lambrecht L, et al. The Au-tism Diagnostic Observation Schedule–Ge-neric: a standard measure of social andcommunication deficits associated with thespectrum of autism. J Autism Dev Disord.2000;30(3):205–223
22. Campbell JM. Efficacy of behavioral inter-ventions for reducing problem behavior inpersons with autism: a quantitative syn-thesis of single-subject research. Res DevDisabil. 2003;24(2):120–138
23. Parracho HM, Bingham MO, Gibson GR,McCartney AL. Differences between the gutmicroflora of children with autistic spec-trum disorders and that of healthy children.J Med Microbiol. 2005;54(pt 10):987–991
24. Wang L, Angley MT, Gerber JP, et al. Is uri-nary indolyl-3-acryloylglycine a biomarkerfor autism with gastrointestinal symptoms?Biomarkers. 2009;14(8):596–603
25. Fu R, Gartlehner G, Grant M, et al. Con-ducting quantitative synthesis when com-paring medical interventions: AHRQ and theEffective Health Care Program. J Clin Epi-demiol. 2011;64(11):1187–1197
26. Higgins J. Cochrane Handbook for System-atic Reviews of Interventions. Available at:www.cochrane.org/resources/handbook/.Accessed July 16, 2013
27. Borenstein M, Hedges L, Higgins J, RothsteinH. Comprehensive Meta-Analysis. 2nd ed.Englewood, NJ: Biostat; 2005
28. Hunter JE, Schmidt FL. Methods of Meta-Analysis: Correcting Error and Bias in Re-search Findings. 2nd ed. Thousand Oaks,CA: Sage; 2004
29. Cohen J. Statistical Power Analysis for theBehavioral Sciences. 2nd ed. Mahwah, NJ:Lawrence Erlbaum Associates; 1988
30. Egger M, Davey Smith G, Schneider M,Minder C. Bias in meta-analysis detected bya simple, graphical test. BMJ. 1997;315(7109):629–634 [Clin Res Ed]
31. Becker BJ. Failsafe N or file-drawer num-ber. In: Rothstein HP, Sutton AJ, BorensteinM, eds. Publication Bias in Meta-Analysis:Prevention, Assessment and Adjustments.Chichester, West Sussex, England: JohnWiley & Sons; 2005:111–125
32. Duval S, Tweedie R. Trim and fill: a simplefunnel-plot-based method of testing andadjusting for publication bias in meta-analysis. Biometrics. 2000;56(2):455–463
33. Black C, Kaye JA, Jick H. Relation of child-hood gastrointestinal disorders to autism:nested case–control study using data fromthe UK General Practice Research Data-base. BMJ. 2002;325(7361):419–421
34. Sandhu B, Steer C, Golding J, Emond A. Theearly stool patterns of young children withautistic spectrum disorder. Arch Dis Child.2009;94(7):497–500
35. Schieve LA, Gonzalez V, Boulet SL, et al. Con-current medical conditions and health careuse and needs among children with learningand behavioral developmental disabilities,National Health Interview Survey, 2006–2010.Res Dev Disabil. 2012;33(2):467–476
36. Wang L, Christophersen CT, Sorich MJ, GerberJP, Angley MT, Conlon MA. Elevated fecal shortchain fatty acid and ammonia concentrationsin children with autism spectrum disorder.Dig Dis Sci. 2012;57(8):2096–2102
37. Ibrahim SH, Voigt RG, Katusic SK, Weaver AL,Barbaresi WJ. Incidence of gastrointestinalsymptoms in children with autism: a pop-ulation-based study. Pediatrics. 2009;124(2):680–686
38. Mouridsen SE, Rich B, Isager T. A longitudinalstudy of gastrointestinal diseases in individu-als diagnosed with infantile autism as children.Child Care Health Dev. 2010;36(3):437–443
39. Niehus R, Lord C. Early medical history ofchildren with autism spectrum disorders. JDev Behav Pediatr. 2006;27(2 suppl):S120–S127
40. Horvath K, Perman JA. Autism and gastro-intestinal symptoms. Curr GastroenterolRep. 2002;4(3):251–258
41. Valicenti-McDermott M, McVicar K, Rapin I,Wershil BK, Cohen H, Shinnar S. Frequencyof gastrointestinal symptoms in childrenwith autistic spectrum disorders and as-sociation with family history of autoim-mune disease. J Dev Behav Pediatr. 2006;27(2 suppl):S128–S136
42. Smith RA, Farnworth H, Wright B, Allgar V.Are there more bowel symptoms in childrenwith autism compared to normal childrenand children with other developmental andneurological disorders? A case controlstudy. Autism. 2009;13(4):343–355
43. Gondalia SV, Palombo EA, Knowles SR, CoxSB, Meyer D, Austin DW. Molecular charac-terisation of gastrointestinal microbiota ofchildren with autism (with and withoutgastrointestinal dysfunction) and theirneurotypical siblings. Autism Res. 2012;5(6):419–427
44. Maenner MJ, Arneson CL, Levy SE, Kirby RS,Nicholas JS, Durkin MS. Brief report: as-sociation between behavioral features andgastrointestinal problems among childrenwith autism spectrum disorder. J AutismDev Disord. 2012;42(7):1520–1525
45. Furuta GT, Williams K, Kooros K, et al.Management of constipation in childrenand adolescents with autism spectrumdisorders. Pediatrics. 2012;130(suppl 2):S98–S105 doi:10.1542/peds.2012-0900H
46. Pashankar DS. Childhood constipation:evaluation and management. Clin ColonRectal Surg. 2005;18(2):120–127
47. Whiteley P. Developmental, behavioural andsomatic factors in pervasive developmentaldisorders: preliminary analysis. Child CareHealth Dev. 2004;30(1):5–11
48. D’Cruz AM, Ragozzino ME, Mosconi MW,Shrestha S, Cook EH, Sweeney JA. Reducedbehavioral flexibility in autism spectrumdisorders. Neuropsychology. 2013;27(2):152–160 doi:10.1037/a0031721
49. Peeters B, Noens I, Philips EM, Kuppens S,Benninga MA. Autism spectrum disordersin children with functional defecation dis-orders. J Pediatr. 2013;163(3):873–878
50. Eswaran S, Muir J, Chey WD. Fiber andfunctional gastrointestinal disorders. Am JGastroenterol. 2013;108(5):718–727
51. Kazek B, Huzarska M, Grzybowska-ChlebowczykU, et al. Platelet and intestinal 5-HT2A re-ceptor mRNA in autistic spectrum disorders:results of a pilot study. Acta Neurobiol Exp(Warsz). 2010;70(2):232–238
52. Al-Ayadhi LY. Gluten sensitivity in autisticchildren in Central Saudi Arabia. Neuro-sciences (Riyadh). 2006;11(1):11–14
882 MCELHANON et al by guest on May 8, 2014pediatrics.aappublications.orgDownloaded from
53. US Department of Health and Human Services(USDHHS). Guidance for industry. Patient-reportedoutcome measures: use in medical productdevelopment to support labeling claims. 2009Available at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/UCM193282.pdf. Accessed January30, 2014
54. Lewis SJ, Heaton KW. Stool form scale asa useful guide to intestinal transit time.Scand J Gastroenterol. 1997;32(9):920–924
55. Mulle JG, Sharp WG, Cubells JF. The gutmicrobiome: a new frontier in autism re-search. Curr Psychiatry Rep. 2013;15(2):337
56. Al-Farsi YM, Al-Sharbati MM, Waly MI, et al.Effect of suboptimal breast-feeding on oc-currence of autism: a case–control study.Nutrition. 2012;28(7–8):e27–e32
57. Schultz ST, Klonoff-Cohen HS, Wingard DL,et al. Breastfeeding, infant formula supple-mentation, and autistic disorder: the resultsof a parent survey. Int Breastfeed J. 2006;1:16
58. Le Huërou-Luron I, Blat S, Boudry G. Breast-v. formula-feeding: impacts on the digestivetract and immediate and long-term healtheffects. Nutr Res Rev. 2010;23(1):23–36
59. Martín R, Heilig GH, Zoetendal EG, Smidt H,Rodríguez JM. Diversity of the Lactobacillus
group in breast milk and vagina of healthywomen and potential role in the coloniza-tion of the infant gut. J Appl Microbiol.2007;103(6):2638–2644
60. Critchfield JW, van Hemert S, Ash M,Mulder L, Ashwood P. The potential role ofprobiotics in the management of child-hood autism spectrum disorders. Gastro-enterol Res Pract. 2011;2011:161358. doi:10.1155/2011/161358
61. Elder JH, Shankar M, Shuster J, TheriaqueD, Burns S, Sherrill L. The gluten-free,casein-free diet in autism: results of a pre-liminary double blind clinical trial. J AutismDev Disord. 2006;36(3):413–420
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
REVIEW ARTICLE
PEDIATRICS Volume 133, Number 5, May 2014 883 by guest on May 8, 2014pediatrics.aappublications.orgDownloaded from
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
ServicesUpdated Information &
/peds.2013-3995http://pediatrics.aappublications.org/content/early/2014/04/22including high resolution figures, can be found at:
Permissions & Licensing
tmlhttp://pediatrics.aappublications.org/site/misc/Permissions.xhtables) or in its entirety can be found online at: Information about reproducing this article in parts (figures,
Reprints http://pediatrics.aappublications.org/site/misc/reprints.xhtml
Information about ordering reprints can be found online:
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elkpublication, it has been published continuously since 1948. PEDIATRICS is owned, published, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
by guest on May 8, 2014pediatrics.aappublications.orgDownloaded from
Top Related