Autism Risk in Very Preterm Infants—New Answers, More Questions


nfants born 2 SD specific traits in very preterm infants that may eventually above the general population. However, Allison et al12 found be found to be precursors of an ASD diagnosis. In general, ASD risk indicators in toddlers include problems with 63% of children with ASD had Q-CHAT scores >60, and communication, social reciprocity, sensory hypersensitivity, this very preterm group item distributions were closer to and repetitive movements. Early screens focus on identifying the reference group than to the ASD group. Further, social behaviors considered to be the toddler equivalent of behavand communication indicators considered core symptoms iors observed in older children diagnosed with ASD. Actual of ASD were not reported as consistently. ASD precursor behaviors may be somewhat different in An important contribution of this study is the detailed invery preterm infants, however, as the highest ASD risk rates formation about specific behaviors common in older chilhave been found in those with motor, cognitive,7 and dren diagnosed with ASD who were vs were not observed in this very preterm sample. Very preterm parents reported language deficits, and risk increased with the number6 and more perseveration with objects and vocalizations, as well severity of other impairments.3 as some, but not frequent, difficulty with eye contact, adaptBehaviors included in putative ASD screens may eventually ing to routine changes, and sensitivity to noise. The latter bebe found to be precursors of a later ASD diagnosis. However, haviors are common in very preterm infants, and may reflect their presence at 12-36 months may also be due to delays and hypersensitivity to intense or multisensory input that is idiosyncrasies associated with immaturity, neonatal illnesses, particularly well assessed on parent reports from experiences and inflammatory conditions (eg, infections, oxygen therain the family environment. Importantly, some Q-CHAT pies). These prematurity-related complications are known to items reported more frequently may indicate delayed, not alter the maturation and development of the central nervous necessarily impaired behaviors, whether or not ASD is diagsystem at critical periods,8 with resulting compromise in nosed later. For example, less empathy and pretend play neurodevelopmental functioning.9 As Lipkin10 noted, findings reflect cognitive milestones in representational thought profrom large network studies demonstrate the interrelatedness of cesses that emerge during the late-infancy to preschool behaviors that reflect coexisting language, cognitive, motor, period. Delayed expressive language and oral-motor coordineurosensory, and behavioral deficits. It is those interrelationnation result in fewer words and poor articulation, respecships that pose a major methodological challenge for tively. Hypertonic lower extremities can result in toe ASD-specific screening in very preterm infants. walking in very preterm infants and others with environmenIn this issue of The Journal, Wong et al11 present important tally limited opportunities for locomotion and gross motor findings that address some of the above challenges. They exploration. These and other ASD risk data comprise a screened for ASD in very preterm infants born at 13 London hospitals, with follow-up at 20-28 (mean = 24) months adjusted gestational age. This report focused on 141 infants


Autism spectrum disorders Quantitative Checklist for Autism in Toddlers

J.H. is funded in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health (R01HD072267). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Mosby Inc. All rights reserved.


Vol. 164, No. 1  January 2014 complex set of clinical and developmental information to be considered in differential diagnosis, where even “gold standard” measures of ASD symptoms14 may yield false positive results if considered in isolation. The authors are clear about this, as the complex presentation of very preterm infants challenges ASD-specific risk screening.15 What this study illustrates in great detail is that there are delays and worrisome aspects of these very preterm toddlers’ Q-CHAT profiles, with implications for policy and practice to address immediate needs. The study identified delays and behaviors that interfere with adaptive exploration and social engagement, but which are fortunately amenable to specific interventions.15 Whether or not these are harbingers of 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 preterm compared with full term toddlers may differ, requiring different treatment strategies to address unique needs. In terms of next steps for future research, we propose some design and measurement considerations to facilitate distinguishing problematic behavioral outcomes from those specific to ASD, and for deciding how best to treat very preterm toddlers. For designs to determine ASD-specific precursors in existing samples, it would be useful to re-examine the item level behavioral data (eg, latent profiles) in at least 6 groups of children: full term infants and very preterm infants with and without major impairments who do and do not later receive an ASD diagnosis. This would determine if group differences in patterns of ASD-predictive behaviors exist, and would identify the most salient set of ASDspecific precursors, those associated with other problems, and behavioral profiles indicative of resilience despite early risk. Expanding measurement procedures to detect ASD risk during infancy could more sensitively predict a future ASD diagnosis, and prescriptively identify intervention targets. Combining multiple measures6,5 with longitudinal assessment16 may improve predictive precision. Valuable additions to early screening in infants and toddlers that predicted ASD include easily administered measures of eye-tracking to quantify attention to faces vs geometric shapes,17 and assessing 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 of brain circuitry was suggested earlier by Msall in The Journal.19 Of additional value would be the inclusion of standardized diagnostic criteria applied to very preterm newborns’ now routine cranial ultrasonograms, often accompanied by magnetic resonance imaging. A recent secondary analysis20 found ventricular enlargement predicted ASD at 16 and 21 years of age, and Limperopoulos et al21 found cerebellar injury on neonatal cranial ultrasonograms and magnetic resonance imaging predicted an ASD-positive screen. Later imaging also shows value. In very preterm newborns with cerebellar damage, magnetic resonance imaging-based measures of lower

prefrontal volume at age 3 years was associated with more problems reported on the Modified Checklist for Autism in Toddlers.22 Also, scans during sleep in infants and toddlers revealed patterns of aberrant inter-hemispheric communication that distinguish infants later diagnosed with ASD from those with a language delay, and those who developed typically.23 Taken together, routine and follow-up neuroimaging appears valuable for distinguishing ASD precursors from other risks. Future studies would benefit from an examination of a more comprehensive set of neonatal and environmental variables in order to identify potential moderators and mediators of risk for ASD and other disorders.24 Reliably measured prenatal and neonatal complications associated with systemic inflammation that alters brain development25,26 include, but are not limited to, maternal infections, hypertension, chemical exposures (environmental, illicit, and prescribed), diabetes, nutrition, and psychological stress, as well as neonatal infections, oxygen therapies, medications, and brain abnormalities. In addition, family social risks27 and early intervention28,29 are environmental characteristics that mediate perinatal threats and influence outcomes. Understanding the mediators of the associations among prenatal precursors of very preterm birth, brain injury, and ASD risk requires a multifaceted approach. This poses a developmental question that requires longitudinal measurement, design, and model testing procedures to precisely address what we now know to be candidate predictor sets for early ASD risk detection and potential amelioration. Examining perinatal conditions and biomarkers of inflammation with developmental changes in brain structure and function, in addition to behavioral screens and observations, could identify underlying mechanisms involved in these biobehavioral pathways. More fully characterizing the very preterm ASD mechanism using procedures to detect the direct and indirect influences of individual and cumulative risk factors (eg, structural equation modeling) would provide key information to potentially interrupt problematic pathways with earlier and more specific interventions. Ultimately, it is of value to meticulously examine ASD risk and the worrisome behavior patterns shown here. Identifying perinatal and neonatal predictors of ASD traits and other behavior problems and using prescriptive assessments throughout infancy and early childhood would enable targeted interventions to be implemented at each stage. These age-by-age and issue-by-issue interventions can achieve far greater success, and eliminate far more anguish for children and families, than waiting for a definitive diagnosis, and watching what appears worrisome become disordered. To the credit of our global community, we have the knowledge and systems in place to provide what is needed in the context of care for very preterm infants. Although funding may be limited, ASD risk assessments add only minimally to what has become routine in both primary and follow-up care and research. Future studies should continue to examine the mechanisms involved and the practices and policies 7


needed to address both ASD-like and ASD-specific features observed in the most vulnerable premature infants. n Julie A. Hofheimer, PhD Division of Neonatal-Perinatal Medicine Department of Pediatrics University of North Carolina at Chapel Hill Chapel Hill, North Carolina Stephen J. Sheinkopf, PhD Department of Psychiatry and Human Behavior Warren Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island Providence, Rhode Island Lisa T. Eyler, PhD Department of Psychiatry and Autism Center University of California at San Diego Mental 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, University of North Carolina at Chapel Hill, 101 Manning Drive, Suite 4051, CB# 7596, Chapel Hill 27599-7596, NC. E-mail: [email protected]

References 1. Stephens BE, Vohr BR. Neurodevelopmental outcome of the premature infant. Pediatr Clin North Am 2009;56:631-46. 2. Limperopoulos C, Bassan H, Sullivan NR, Soul JS, Robertson RL Jr, Moore M, et al. Positive screening for autism in ex-preterm infants: prevalence and risk factors. Pediatrics 2008;121:758-65. 3. Luyster R, Kuban K, O’Shea T, Paneth N, Allred E, Leviton A, et al. The Modified Checklist for Autism in Toddlers in extremely low gestational age newborns: individual items associated with motor, cognitive, vision, and hearing limitations. Paediatr Perinat Epidemiol 2011;25:366-76. PubMed PMID: 21649679. 4. Johnson S, Hollis C, Hennessy E, Kochhar P, Wolke D, Marlow N. Screening for autism in preterm children: diagnostic utility of the Social Communication Questionnaire. Arch Dis Childhood 2011;96:73-7. 5. Pinto-Martin JA, Levy SE, Feldman JF, Lorenz JM, Paneth N, Whitaker AH. Prevalence of autism spectrum disorder in adolescents born weighing

Autism risk in very preterm infants--new answers, more questions.

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