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Autism Risk in Very Preterm InfantsNew Answers, More Questions

Infants born 2 SDabove the general population. However, Allison et al12 found

63% of children with ASD had Q-CHAT scores >60, andthis very preterm group item distributions were closer tothe reference group than to the ASD group. Further, socialand communication indicators considered core symptomsof ASD were not reported as consistently.

An important contribution of this study is the detailed in-formation about specific behaviors common in older chil-dren diagnosed with ASD who were vs were not observed

in this very preterm sample. Very preterm parents reportedmore perseveration with objects and vocalizations, as wellas some, but not frequent, difficulty with eye contact, adapt-

ing to routine changes, and sensitivity to noise. The latter be-haviors are common in very preterm infants, and may reflecthypersensitivity to intense or multisensory input that isparticularly well assessed on parent reports from experiencesin the family environment. Importantly, some Q-CHATitems reported more frequently may indicate delayed, not

necessarily impaired behaviors, whether or not ASD is diag-nosed later. For example, less empathy and pretend playreflect cognitive milestones in representational thought pro-

cesses that emerge during the late-infancy to preschoolperiod. Delayed expressive language and oral-motor coordi-

nation result in fewer words and poor articulation, respec-tively. Hypertonic lower extremities can result in toe

walking in very preterm infants and others with environmen-tally limited opportunities for locomotion and gross motorexploration. These and other ASD risk data comprise a

J.H. is funded in part by the Eunice Kennedy ShriverNational Institute of ChildHealth and Human Development, the National Institutes of Health (R01HD072267).The authors declare no conflicts of interest.

0022-3476/$ - see front matter. Copyright 2014 Mosby Inc.

All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.09.054

ASD Autism spectrum disorders

Q-CHAT Quantitative Checklist for Autism in Toddlers

See related articles, p 20

and p 26

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http://dx.doi.org/10.1016/j.jpeds.2013.09.054http://dx.doi.org/10.1016/j.jpeds.2013.09.054

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complex set of clinical and developmental information to beconsidered in differential diagnosis,where even gold stan-dard measures of ASD symptoms14 may yield false positive

results if considered in isolation. The authors are clear aboutthis, as the complex presentation of very preterm infantschallenges ASD-specific risk screening.15

What this study illustrates in great detail is that there aredelays and worrisome aspects of these very preterm toddlersQ-CHAT profiles, with implications for policy and practice

to address immediate needs. The study identified delaysand behaviors that interfere with adaptive exploration andsocial engagement, but which are fortunately amenable tospecific interventions.15 Whether or not these are harbingersof a later ASD diagnosis, they indicate problems in current

functioning and starting points for targeted interventions.If these scores do predict later ASD, the findings suggest

that the phenotypic expression of ASD in very pretermcompared with full term toddlers may differ, requiringdifferent treatment strategies to address unique needs.

In terms of next steps for future research, we propose some

design and measurement considerations to facilitate distin-guishing problematic behavioral outcomes from thosespecific to ASD, and for deciding how best to treat very pre-term toddlers. For designs to determine ASD-specific precur-sors in existing samples, it would be useful to re-examine theitem level behavioral data (eg, latent profiles) in at least

6 groups of children: full term infants and very preterm in-fants with and without major impairments who do and donot later receive an ASD diagnosis. This would determine ifgroup differences in patterns of ASD-predictive behaviorsexist, and would identify the most salient set of ASD-specific precursors, those associated with other problems,

and behavioral profiles indicative of resilience despite earlyrisk.

Expanding measurement procedures to detect ASD riskduring infancy could more sensitively predict a future ASDdiagnosis, and prescriptively identify intervention targets.

Combining multiple measures6,5 with longitudinal assess-ment16 may improve predictive precision. Valuable additionsto early screening in infants and toddlers that predicted ASDinclude easily administered measures of eye-tracking toquantify attention to faces vs geometric shapes,17 and assess-ing acoustic features of vocalizations.18 Ultimately, careful

differential diagnosis apprised by ASD-specific measures is

needed to improve prediction from screens.The usefulness of a more integrated study ofbrain circuitry

was suggested earlier by Msall inThe Journal.19 Of additionalvalue would be the inclusion of standardized diagnosticcriteria applied to very preterm newborns now routine

cranial ultrasonograms, often accompanied by magneticresonance imaging. A recent secondary analysis20 found ven-tricular enlargement predicted ASD at 16 and 21 years of age,and Limperopoulos et al21 found cerebellar injury onneonatal cranial ultrasonograms and magnetic resonance im-

aging predicted an ASD-positive screen. Later imaging alsoshows value. In very preterm newborns with cerebellar dam-

age, magnetic resonance imaging-based measures of lower

prefrontal volume at age 3 years was associated with moreproblemsreported on the Modified Checklist for Autism inToddlers.22 Also, scans during sleep in infants and toddlers

revealed patterns of aberrant inter-hemispheric communica-tion that distinguish infants later diagnosed with ASD fromthosewith a language delay, and those who developed typi-cally.23 Taken together, routine and follow-up neuroimagingappears valuable for distinguishing ASD precursors fromother risks.

Future studies would benefit from an examination of amore comprehensive set of neonatal and environmental var-iables in order to identify potential moderatorsand media-tors of risk for ASD and other disorders.24 Reliablymeasured prenatal and neonatal complications associated

with systemic inflammation that alters brain develop-ment25,26 include, but are not limited to, maternal infec-

tions, hypertension, chemical exposures (environmental,illicit, and prescribed), diabetes, nutrition, and psychologicalstress, as well as neonatal infections, oxygen therapies, med-ications, and brain abnormalities. In addition, family social

risks27 and early intervention28,29 are environmental charac-teristics that mediate perinatal threats and influence out-comes.

Understanding the mediators of the associations amongprenatal precursors of very preterm birth, brain injury, andASD risk requires a multifaceted approach. This poses a

developmental question that requires longitudinal measure-ment, design, and model testing procedures to preciselyaddress what we now know to be candidate predictor setsfor early ASD risk detection and potential amelioration.Examining perinatal conditions and biomarkers of inflam-mation with developmental changes in brain structure and

function, in addition to behavioral screens and observations,could identify underlying mechanisms involved in these bio-behavioral pathways. More fully characterizing the very pre-term ASD mechanism using procedures to detect the directand indirect influences of individual and cumulative risk fac-

tors (eg, structural equation modeling) would provide keyinformation to potentially interrupt problematic pathwayswith earlier and more specific interventions.

Ultimately, it is of value to meticulously examine ASD riskand the worrisome behavior patterns shown here. Identifyingperinatal and neonatal predictors of ASD traits and other

behavior problems and using prescriptive assessments

throughout infancy and early childhood would enable tar-geted interventions to be implemented at each stage. Theseage-by-age and issue-by-issue interventions can achieve fargreater success, and eliminate far more anguish for childrenand families, than waiting for a definitive diagnosis, andwatching what appears worrisome become disordered. To

the credit of our global community, we have the knowledgeand systems in place to provide what is needed in the contextof care for very preterm infants. Although funding may belimited, ASD risk assessments add only minimally to what

has become routine in both primary and follow-up careand research. Future studies should continue to examine

the mechanisms involved and the practices and policies

Vol. 164, No. 1 January 2014

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needed to address both ASD-like and ASD-specific featuresobserved in the most vulnerable premature infants. n

Julie A. Hofheimer, PhDDivision of Neonatal-Perinatal Medicine

Department of PediatricsUniversity of North Carolina at Chapel Hill

Chapel Hill, North Carolina

Stephen J. Sheinkopf, PhDDepartment of Psychiatry and Human Behavior

Warren Alpert Medical School of Brown Universityand Women & Infants Hospital of Rhode Island

Providence, Rhode Island

Lisa T. Eyler, PhDDepartment of Psychiatry and Autism Center

University of California at San DiegoMental Illness, Research, Education, and Clinical Center

VA San Diego Healthcare System

San Diego, California

Reprint requests: Julie A. Hofheimer, PhD, Associate Professor of Pediatrics,

Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Universityof

North Carolinaat ChapelHill, 101ManningDrive, Suite4051,CB# 7596, Chapel

Hill 27599-7596, NC. E-mail:julie_hofheimer@med.unc.edu

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