T

Central Nervous System Connec

tivity after Extreme Prematurity:Understanding Autistic Spectrum Disorder

wo major challenges confront pediatricians for earlychildhood neurodevelopmental disability. First, thereis increased survival of extremely preterm (EP; #28

weeks gestation) and very preterm (VP; 28-31 weeks gesta-tion) infants.1 These survivors continue to have dispropor-

See related article, p 525

tionately high rates of cerebral palsy,visual disability, and sensorineural hearing loss compared with their late preterm and term peers. How-ever, advances in developmental biology, obstetrics, and neo-natology have resulted in >75% of EP and >85% of VPinfants being free of these neurosensory disabilities.2

Second, there is increased recognition of a spectrum of com-municative, social, and behavioral problems that are describedas classical autistic spectrum disorders (ASD).3 These disor-ders include autism, Asperger’s disorder, and pervasive devel-opmental disorder (PDD) and have an estimated prevalenceexceeding 1 in 100 children.4 Autistic spectrum disordershave both known and unknown genetic, prenatal, and postna-tal causal pathways, and it has been recently suggested that EPand VP survivors can be vulnerable to ASD more so than theirfull term peers.5-10 Pilot studies at age 2 years by Limperopo-lous et al in survivors <30 weeks gestation and by Kuban onbehalf of the ELGAN Network in survivors <28 weeks gesta-tion have demonstrated a 21% to 26% prevalence of positivescreening results on the Modified Checklist for Autism in Tod-dlers (M-CHAT), compared with <5% in term children.11,12

The M-CHAT is one of several validated instruments currentlyavailable to medical and educational professionals for detect-ing a high-risk group of children requiring a multidisciplinaryassessment for confirmative diagnosis of autism.13 Major pol-icy statements from such diverse groups such as Autism Speaks(www.autismspeaks.org), the Centers for Disease Control andPrevention (www.firstsigns.org), and the Committee of Chil-dren with Disability of the American Academy of Pediatricshave recommended heightened awareness and more system-atic use of valid screening tools that are followed by compre-hensive assessments linked to comprehensive developmentalinterventions and family supports.14,15

ASD Autistic spectrum disorders

DAWBA Development and Well Being Assessment

DSM-IV Diagnostic and Statistical Manual of Mental Disorders,

Fourth Edition

EP Extremely preterm

ICD-10 International Statistical Classification of Diseases,

10th revision

MCHAT Modified Checklist for Autism in Toddlers

PDD Pervasive developmental disorder

SCQ Social Communication Questionnaire

VP Very preterm

The key question in light of the two challenges stated aboveis how the risks of early childhood screenings and develop-mental delays caused by preterm births translate to confirmeddiagnosis of autism, PDD, and Asperger disorder in the ele-mentary school years. It is in this respect that the study by

The authors receito Developmenta

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All rights reserved. 1

Johnson et al involving the prospectively fol-lowed EPI-CURE cohort in this issue of The

Journal is a major contribution to our understanding of thevulnerability of extremely preterm survivors to autism and re-lated cognitive disorders.16

Who participated in this study? The EPI-CURE cohortinvolved all infants admitted to neonatal intensive care unitsthroughout the United Kingdom and Ireland who were 20 to25 weeks gestation and born between March and December1995. A total of 843 infants of <26 weeks gestation were ad-mitted to neonatal intensive care units, and 308 infants withgestational ages of 23 to 25 weeks were alive at 30 and 72months.17 A total of 219 survivors (71%) were comprehen-sively assessed at 11 years of age. Of these survivors, 213had been followed at 2.5 years and 202 had been examinedat 6 years. Term classmates in mainstream education chosenby sex and nearest birthdate were also recruited at age 6 years.Because some of the term children went on to differentschools, additional mainstream education term control sub-jects were again recruited at age 11 years.

How were the children assessed? The Social Communica-tion Questionnaire (SCQ), a 31- item battery with subscalesof social interaction, communication, and repetitive behav-iors was used to assess core features of ASD. This tool hasrobust both psychometric properties and area under the re-ceiver operator characteristic curve >0.90 for autism versusnon- autism and autism versus intellectual disability (IQ<70) with standardized assessments.18 A structured interviewusing the Development and Well Being Assessment(DAWBA) was conducted. DAWBA uses questionnaires, in-terviews, and rating techniques designed to generate Interna-tional Statistical Classification of Diseases, 10th revision (ICD-10) and Diagnostic and Statistics Manual of Mental Disorders,Revised Fourth Edition (DSM-IV) psychiatric diagnoses for 5-to 16-year-old children.19 Caregivers provide informationabout psychiatric symptoms and resultant impact. When def-inite symptoms are identified with the structured questions,interviewers use open-ended questions and supplementaryprompts so that the parent describes the child’s behavioralstrengths and challenges in their own words. These

ved support in part by the Grant Healthcare Foundation ‘‘Passportl Health’’ and LEND grant (T73MC).

ont matter. Copyright ª 2010 Mosby Inc.

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THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 156, No. 4

descriptions are transcribed verbatim by the interviewers, butare not rated by them. In addition, teachers complete a briefquestionnaire covering social, emotional, and attentionalsymptoms and any resultant impact on school performance.A computer program that predicts likely diagnoses brings thedifferent sorts of information together. These computer-gen-erated summary sheets are then reviewed by an experiencedclinician who decides whether to accept or change the com-puter diagnosis (or lack of diagnosis) in light of their reviewof all available information. The scoring algorithm for theDAWBA maps to criteria for autism and pervasive develop-mental disorders in DSM IV and ICD-10.19

An important strength of this study is that 89% of assess-ments occurred at school. Special education supports andteacher ratings were obtained as were cognitive abilities andacademic achievement by certified assessors masked to neo-natal status. Differential loss to follow-up was well docu-mented and can be interpreted to indicate that theestimates for positive SCQ screen results and DAWBA assess-ment results were conservative. The children lost to follow-up were disproportionately of minority race and hadpreviously demonstrated cognitive disability.

What was found by using the SCQ as a screener at age 11years? One in 6 EP survivors had positive screen results com-pared with 1 in 33 term infants. Thus, the high rates of positivescreens with the M-CHAT at 2 years of age are confirmed inmiddle elementary school years with the SCQ. The childrenat highest risk at neonatal discharge were male, <25 weeks ges-tation, delivered in breech position, and had an abnormal ce-rebral ultrasound scanning result. Children who werebreastfed as infants were less likely to be screened positivefor ASD compared to those who were not.

What was found by using the DAWBA to determinewhether the child met DSM-IV/ICD 10 criteria for an ASDdiagnoses? On the DAWBA, 1 in 12 EP survivors met diagnos-tic criteria for ASD (6.5% autism, 1.5% pervasive develop-mental disorder, not otherwise specified), compared with2.6 per 1000 in community samples in the United Kingdom.20

No classmate of these extremely premature children in main-stream education met diagnostic criteria for an ASD. Thus,both autism and ASD are substantially increased in these sur-vivors born at 23, 24, and 25 weeks gestation. Again, male sexwas a major predictor at neonatal discharge. At 2.5 years, chil-dren with substantial neurodevelopmental disability (severecerebral palsy, Bayley Mental Development Index <70, blind-ness, or sensorineural hearing loss) were at highest risk of ASDdiagnosis. These antecedents are similar to what Kuban foundin the Extremely Low Gestational Age Newborn network2009.12 In addition, children with aggressive behaviors onthe Child Behavior Checklist were also at the highest riskfor an ASD. This latter group reflects the more intense andchallenging behaviors that too often are incorrectly attributedto misbehavior without fully assessing the child’s communi-cative and developmental competencies. When the childrenwere 6 years old, social interactions with peers, attentional dif-ficulties, and hyperactivity were significantly associated withan ASD diagnoses. At age 11 years, none of the 56 children

520

with IQ >85 had an ASD. However, >1 in 6 children withmoderate or severe cognitive disability (IQ <70) had anASD. Thus, cognitive disability increases the chance that a for-mer EP survivor will meet criteria for an ASD.

What are the implications? This important study demon-strates that there are much higher rates of both ASD and cog-nitive disability at age 11 years in children who survive thelimits of viability in the current era of neonatology. Thisvulnerability demonstrates that the initial M-CHAT screen-ing findings in US studies are real and not just a phase thatwill be outgrown in time.

What does this mean for our life sustaining interven-tions for extremely premature infants, especially those of23 to 25 weeks gestation? Our current interventions arenot fully protecting the brain circuitry underlying communi-cative, social, and adaptive behavioral competencies. Thesuggestions of a protective effect of breastfeeding can beviewed as both promoting more biologically available nutri-tion and providing the tactile, thermal, and social experiencesthat may optimize resiliency. However, this is very simplistic.In reality, we do not fully understand the mechanisms or theinterventions required to protect the development of com-plex dynamic circuitry that is involved in ASD.

What follow-up research is needed? The United States isvery much in need of a comprehensive strategy to fully screenand assess large numbers of extremely low birth weight/EPand very low birth weight/VP survivors and late preterm infantsfrom diverse geographic regions. . This cannot be done withoutmore comprehensive and systematic methods for evaluatingthese children beyond the age of 2 years by increasing formalcollaborations between pediatric primary care, early interven-tion, neonatal intensive care unit follow-up, and multidisciplin-ary centers of excellence. Until have a better understanding ofthe pathways underlying brain connectivity and higher corticalfunction after extreme prematurity, we should not assume thatour ventilatory, nutrition, handling, and stress reduction strat-egies have been fully tested across sex, genotype, and neurocir-cuitry vulnerability. We need to explicitly increase our use ofbiomarkers and functional neuroimaging to examine risk andresiliency for vulnerable central nervous system structuresthat underlie communicative, social, and cognitive processes.By systematically examining cohorts of these infants through-out childhood, we may develop a combined prenatal, perinatal,and postnatal neuroprotection strategy. n

Michael E. Msall, MDUniversity of Chicago

Child Development CenterChicago, Illinois

Reprint requests: Michael E. Msall, MD, University of Chicago Child

Development Center, 5801 S Ellis Ave, Chicago, IL 60637. E-mail: mmsall@

peds.bsd.uchicago.edu.

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Leviton A. Positive screening on the Modified Checklist for Autism in

Toddlers (M-CHAT) in extremely low gestational age newborns. J Pe-

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BPD Bronchopulmonary dysplasia

VEGF Vascular endothelial growth factor

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Children With Disabilities. Identification and evaluation of children

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15. National Research Council, Committee on Educational Interventions

for Children with Autism. In: Lord C, McGee JP, editors. Educating

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16. Johnson S, Hollis C, Kochhar P, Hennessy E, Wolke D, Marlow N. Au-

tism spectrum disorders in extremly preterm children. J Pediatr

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17. Marlow N, Wolke D, Bracewell MA, Samara M, EPICure Study Group.

Neurologic and developmental disability at six years of age after ex-

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If Your Placenta Doesn’t Have It, Chances Are Your Lungs Don’t Have ItEither: The ‘‘Vascular Hypothesis’’ of Bronchopulmonary Dysplasia Starts

In Utero

reterm birth is a major health care problem, affectingapproximately12% of all births and accounting for>85% of all perinatal complications and death.1 Bron-

chopulmonary dysplasia (BPD), the chronic lung disease thatfollows ventilator and oxygen therapy for acute respiratory

icle, p 532

failure after premature birth, remains 1 ofthe main complications because it lacks ef- fective treatments.2 With improved perinatal care, preterminfants in whom BPD develops now are far more immatureand have antenatal and postnatal histories that differ fromthose of preterm infants in earlier eras. Disorders leading tovery preterm delivery today may be separated in 2 groups:those associated with intrauterine inflammation (preterm la-bor, preterm membrane rupture, and cervical insufficiency)and abnormal placentation (pre-eclampsia and fetal growthrestriction).3 In 2009, preterm infants at risk of BPD werethose born before 28 weeks gestation (or 500-1000 g birthweight). At the late canalicular stage of lung development,just when the airways become juxtaposed to the lung vascu-lature and when gas-exchange becomes possible.4 BPD haslong-term respiratory and neurodevelopmental conse-

quences that reach beyond childhood and result in increasedhealth care costs.2 Selected yet concerning reports are emerg-ing of arrested alveolar growth in older children,5 or early on-set emphysema6 and pulmonary hypertension7 in youngadults who had BPD. Thus, perinatal lung injury disrupts

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the normal sequence of lung development,resulting in the histological pattern of alveo-

lar simplification (larger, but fewer, alveoli with decreasedseptation) and muscular extension into peripheral arteries,medial hypertrophy, and loss of small arteries and decreasedcapillary density, the central hallmarks of the ‘‘new BPD.’’8

Therefore, understanding how alveoli and the underlyingcapillary network develop and how these mechanisms aredisrupted are critical for developing therapies for BPD andimproving outcomes of extreme prematurity.

Recent observations have challenged old notions that thedevelopment of the blood vessels in the lung passively followsthat of the airways. Rather, increasing evidence suggest thatlung blood vessels actively promote normal alveolar growthduring development and contribute to the maintenance ofalveolar structures throughout postnatal life.9 A working hy-pothesis is that disruption of angiogenesis during lung

ont matter. Copyright ª 2010 Mosby Inc.

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