Autism Risk in Very Preterm InfantsNew Answers, More Questions

I
nfants born <30 weeks postmenstrual age experience poten-
tially devastating brain injuries associated with immaturity,
hypoxic insults, and inammatory exposures. These very
preterm infants evidence high rates of neurosensory, motor,
cognitive, language, social, and behavioral impairments that
persist through adulthood.
1
In addition,
recent studies found 25% of very preterm in-
fants screened positive for Autism Spectrum
Disorders (ASD) at 24 months adjusted gestational age.
2,3
Very pretermtoddlers withcerebral palsy andneurosensoryim-
pairments hadan8- to10-foldincrease in ASD-positive screens
compared with full term toddlers
4,5
; however, using multiple
screens in those without impairment found rates comparable
with the general population.
6
In light of the interrelated development and measurement
of cognitive, language, motor, and social functioning, recent
efforts have focused on identifying early indicators of ASD-
specic traits in very preterm infants that may eventually
be found to be precursors of an ASD diagnosis. In general,
ASD risk indicators in toddlers include problems with
communication, social reciprocity, sensory hypersensitivity,
and repetitive movements. Early screens focus on identifying
behaviors considered to be the toddler equivalent of behav-
iors observed in older children diagnosed with ASD. Actual
ASD precursor behaviors may be somewhat different in
very preterm infants, however, as the highest ASD risk rates
have been found in those with motor, cognitive,
7
and
language decits, and risk increased with the number
6
and
severity of other impairments.
3
Behaviors included in putative ASD screens may eventually
be found to be precursors of a later ASD diagnosis. However,
their presence at 12-36 months may also be due to delays and
idiosyncrasies associated with immaturity, neonatal illnesses,
and inammatory conditions (eg, infections, oxygen thera-
pies). These prematurity-related complications are known to
alter the maturation and development of the central nervous
system at critical periods,
8
with resulting compromise in
neurodevelopmental functioning.
9
As Lipkin
10
noted, ndings
fromlarge network studies demonstrate the interrelatedness of
behaviors that reect coexisting language, cognitive, motor,
neurosensory, and behavioral decits. It is those interrelation-
ships that pose a major methodological challenge for
ASD-specic screening in very preterm infants.
In this issue of The Journal, Wong et al
11
present important
ndings that address some of the above challenges. They
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
who had no cerebral palsy or severe neurosensory impairment,
and assessed ASD risk symptoms on the Quantitative Check-
list for Autism in Toddlers (Q-CHAT).
12
Higher Q-CHAT
scores indicate more frequently observed problems with social
relatedness, restricted, repetitive, and stereotyped behaviors,
communication, and sensory abnormalities.
Analyses compared very preterm infants
Q-CHAT scores with the validation sample,
and regression analyses examined the contributions of demo-
graphic and neonatal characteristics to Q-CHAT and Bayley
language scores.
13
More problematic Q-CHAT scores were observed in non-
white infants, those living in more deprived areas, and in in-
fants with lower expressive language scores. No interactions
were signicant, and the main effects likely reect more mi-
nority children living in less advantaged locations. Compared
with the reference sample, the very preterm group had higher
total Q-CHAT scores, and a worrisome 16% scored >2 SD
above the general population. However, Allison et al
12
found
63% of children with ASD had Q-CHAT scores >60, and
this very preterm group item distributions were closer to
the reference group than to the ASD group. Further, social
and communication indicators considered core symptoms
of ASD were not reported as consistently.
An important contribution of this study is the detailed in-
formation about specic behaviors common in older chil-
dren diagnosed with ASD who were vs were not observed
in this very preterm sample. Very preterm parents reported
more perseveration with objects and vocalizations, as well
as some, but not frequent, difculty with eye contact, adapt-
ing to routine changes, and sensitivity to noise. The latter be-
haviors are common in very preterm infants, and may reect
hypersensitivity to intense or multisensory input that is
particularly well assessed on parent reports from experiences
in the family environment. Importantly, some Q-CHAT
items reported more frequently may indicate delayed, not
necessarily impaired behaviors, whether or not ASD is diag-
nosed later. For example, less empathy and pretend play
reect cognitive milestones in representational thought pro-
cesses that emerge during the late-infancy to preschool
period. 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 motor
exploration. These and other ASD risk data comprise a
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 conicts 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
6
complex set of clinical and developmental information to be
considered in differential diagnosis, where even gold stan-
dard measures of ASD symptoms
14
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-specic 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 proles, with implications for policy and practice
to address immediate needs. The study identied delays
and behaviors that interfere with adaptive exploration and
social engagement, but which are fortunately amenable to
specic 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 ndings 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 distin-
guishing problematic behavioral outcomes from those
specic to ASD, and for deciding how best to treat very pre-
term toddlers. For designs to determine ASD-specic precur-
sors in existing samples, it would be useful to re-examine the
item level behavioral data (eg, latent proles) in at least
6 groups of children: full term infants and very preterm in-
fants 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 ASD-
specic precursors, those associated with other problems,
and behavioral proles 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 measures
6,5
with longitudinal assess-
ment
16
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 assess-
ing acoustic features of vocalizations.
18
Ultimately, careful
differential diagnosis apprised by ASD-specic 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 analysis
20
found ven-
tricular enlargement predicted ASD at 16 and 21 years of age,
and Limperopoulos et al
21
found cerebellar injury on
neonatal cranial ultrasonograms and magnetic resonance im-
aging predicted an ASD-positive screen. Later imaging also
shows 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 more
problems reported on the Modied Checklist for Autism in
Toddlers.
22
Also, scans during sleep in infants and toddlers
revealed patterns of aberrant inter-hemispheric communica-
tion that distinguish infants later diagnosed with ASD from
those with a language delay, and those who developed typi-
cally.
23
Taken together, routine and follow-up neuroimaging
appears valuable for distinguishing ASD precursors from
other risks.
Future studies would benet from an examination of a
more comprehensive set of neonatal and environmental var-
iables in order to identify potential moderators and media-
tors of risk for ASD and other disorders.
24
Reliably
measured prenatal and neonatal complications associated
with systemic inammation that alters brain develop-
ment
25,26
include, but are not limited to, maternal infec-
tions, hypertension, chemical exposures (environmental,
illicit, and prescribed), diabetes, nutrition, and psychological
stress, as well as neonatal infections, oxygen therapies, med-
ications, and brain abnormalities. In addition, family social
risks
27
and early intervention
28,29
are environmental charac-
teristics that mediate perinatal threats and inuence out-
comes.
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 measure-
ment, 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 inam-
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 direct
and indirect inuences of individual and cumulative risk fac-
tors (eg, structural equation modeling) would provide key
information to potentially interrupt problematic pathways
with earlier and more specic 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 tar-
geted 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 denitive 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
Vol. 164, No. 1 January 2014
7
needed to address both ASD-like and ASD-specic 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: julie_hofheimer@med.unc.edu
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