The Journal of Pediatrics
Volume 156, Issue 4 , Pages 519-521, April 2010

Central Nervous System Connectivity after Extreme Prematurity: Understanding Autistic Spectrum Disorder

  • Michael E. Msall, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Michael E. Msall, MD, University of Chicago Child Development Center, 5801 S Ellis Ave, Chicago, IL 60637.

University of Chicago, Child Development Center, Chicago, Illinois

Article Outline

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

 

See related article, p 525

Two major challenges confront pediatricians for early childhood neurodevelopmental disability. First, there is increased survival of extremely preterm (EP; ≤28 weeks gestation) and very preterm (VP; 28-31 weeks gestation) infants.1 These survivors continue to have disproportionately high rates of cerebral palsy, visual disability, and sensorineural hearing loss compared with their late preterm and term peers. However, advances in developmental biology, obstetrics, and neonatology have resulted in >75% of EP and >85% of VP infants being free of these neurosensory disabilities.2

Second, there is increased recognition of a spectrum of communicative, social, and behavioral problems that are described as classical autistic spectrum disorders (ASD).3 These disorders include autism, Asperger's disorder, and pervasive developmental disorder (PDD) and have an estimated prevalence exceeding 1 in 100 children.4 Autistic spectrum disorders have both known and unknown genetic, prenatal, and postnatal causal pathways, and it has been recently suggested that EP and VP survivors can be vulnerable to ASD more so than their full term peers.5, 6, 7, 8, 9, 10 Pilot studies at age 2 years by Limperopolous et al in survivors <30 weeks gestation and by Kuban on behalf of the ELGAN Network in survivors <28 weeks gestation have demonstrated a 21% to 26% prevalence of positive screening results on the Modified Checklist for Autism in Toddlers (M-CHAT), compared with <5% in term children.11, 12 The M-CHAT is one of several validated instruments currently available to medical and educational professionals for detecting a high-risk group of children requiring a multidisciplinary assessment for confirmative diagnosis of autism.13 Major policy statements from such diverse groups such as Autism Speaks (www.autismspeaks.org), the Centers for Disease Control and Prevention (www.firstsigns.org), and the Committee of Children with Disability of the American Academy of Pediatrics have recommended heightened awareness and more systematic use of valid screening tools that are followed by comprehensive assessments linked to comprehensive developmental interventions and family supports.14, 15

The key question in light of the two challenges stated above is how the risks of early childhood screenings and developmental delays caused by preterm births translate to confirmed diagnosis of autism, PDD, and Asperger disorder in the elementary school years. It is in this respect that the study by Johnson et al involving the prospectively followed EPI-CURE cohort in this issue of The Journal is a major contribution to our understanding of the vulnerability of extremely preterm survivors to autism and related cognitive disorders.16

Who participated in this study? The EPI-CURE cohort involved all infants admitted to neonatal intensive care units throughout the United Kingdom and Ireland who were 20 to 25 weeks gestation and born between March and December 1995. A total of 843 infants of <26 weeks gestation were admitted to neonatal intensive care units, and 308 infants with gestational ages of 23 to 25 weeks were alive at 30 and 72 months.17 A total of 219 survivors (71%) were comprehensively assessed at 11 years of age. Of these survivors, 213 had been followed at 2.5 years and 202 had been examined at 6 years. Term classmates in mainstream education chosen by sex and nearest birthdate were also recruited at age 6 years. Because some of the term children went on to different schools, additional mainstream education term control subjects were again recruited at age 11 years.

How were the children assessed? The Social Communication Questionnaire (SCQ), a 31- item battery with subscales of social interaction, communication, and repetitive behaviors was used to assess core features of ASD. This tool has robust both psychometric properties and area under the receiver operator characteristic curve >0.90 for autism versus non- autism and autism versus intellectual disability (IQ <70) with standardized assessments.18 A structured interview using the Development and Well Being Assessment (DAWBA) was conducted. DAWBA uses questionnaires, interviews, and rating techniques designed to generate International 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 information about psychiatric symptoms and resultant impact. When definite symptoms are identified with the structured questions, interviewers use open-ended questions and supplementary prompts so that the parent describes the child's behavioral strengths and challenges in their own words. These descriptions are transcribed verbatim by the interviewers, but are not rated by them. In addition, teachers complete a brief questionnaire covering social, emotional, and attentional symptoms and any resultant impact on school performance. A computer program that predicts likely diagnoses brings the different sorts of information together. These computer-generated summary sheets are then reviewed by an experienced clinician who decides whether to accept or change the computer diagnosis (or lack of diagnosis) in light of their review of all available information. The scoring algorithm for the DAWBA maps to criteria for autism and pervasive developmental disorders in DSM IV and ICD-10.19

An important strength of this study is that 89% of assessments occurred at school. Special education supports and teacher ratings were obtained as were cognitive abilities and academic achievement by certified assessors masked to neonatal status. Differential loss to follow-up was well documented and can be interpreted to indicate that the estimates for positive SCQ screen results and DAWBA assessment results were conservative. The children lost to follow-up were disproportionately of minority race and had previously demonstrated cognitive disability.

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

What was found by using the DAWBA to determine whether the child met DSM-IV/ICD 10 criteria for an ASD diagnoses? On the DAWBA, 1 in 12 EP survivors met diagnostic criteria for ASD (6.5% autism, 1.5% pervasive developmental disorder, not otherwise specified), compared with 2.6 per 1000 in community samples in the United Kingdom.20 No classmate of these extremely premature children in mainstream education met diagnostic criteria for an ASD. Thus, both autism and ASD are substantially increased in these survivors born at 23, 24, and 25 weeks gestation. Again, male sex was a major predictor at neonatal discharge. At 2.5 years, children with substantial neurodevelopmental disability (severe cerebral palsy, Bayley Mental Development Index <70, blindness, or sensorineural hearing loss) were at highest risk of ASD diagnosis. These antecedents are similar to what Kuban found in the Extremely Low Gestational Age Newborn network 2009.12 In addition, children with aggressive behaviors on the Child Behavior Checklist were also at the highest risk for an ASD. This latter group reflects the more intense and challenging behaviors that too often are incorrectly attributed to misbehavior without fully assessing the child's communicative and developmental competencies. When the children were 6 years old, social interactions with peers, attentional difficulties, and hyperactivity were significantly associated with an ASD diagnoses. At age 11 years, none of the 56 children with IQ >85 had an ASD. However, >1 in 6 children with moderate or severe cognitive disability (IQ <70) had an ASD. Thus, cognitive disability increases the chance that a former EP survivor will meet criteria for an ASD.

What are the implications? This important study demonstrates that there are much higher rates of both ASD and cognitive disability at age 11 years in children who survive the limits of viability in the current era of neonatology. This vulnerability demonstrates that the initial M-CHAT screening findings in US studies are real and not just a phase that will be outgrown in time.

What does this mean for our life sustaining interventions for extremely premature infants, especially those of 23 to 25 weeks gestation? Our current interventions are not fully protecting the brain circuitry underlying communicative, social, and adaptive behavioral competencies. The suggestions of a protective effect of breastfeeding can be viewed as both promoting more biologically available nutrition and providing the tactile, thermal, and social experiences that may optimize resiliency. However, this is very simplistic. In reality, we do not fully understand the mechanisms or the interventions required to protect the development of complex dynamic circuitry that is involved in ASD.

What follow-up research is needed? The United States is very much in need of a comprehensive strategy to fully screen and assess large numbers of extremely low birth weight/EP and very low birth weight/VP survivors and late preterm infants from diverse geographic regions. . This cannot be done without more comprehensive and systematic methods for evaluating these children beyond the age of 2 years by increasing formal collaborations between pediatric primary care, early intervention, neonatal intensive care unit follow-up, and multidisciplinary centers of excellence. Until have a better understanding of the pathways underlying brain connectivity and higher cortical function after extreme prematurity, we should not assume that our ventilatory, nutrition, handling, and stress reduction strategies have been fully tested across sex, genotype, and neurocircuitry vulnerability. We need to explicitly increase our use of biomarkers and functional neuroimaging to examine risk and resiliency for vulnerable central nervous system structures that underlie communicative, social, and cognitive processes. By systematically examining cohorts of these infants throughout childhood, we may develop a combined prenatal, perinatal, and postnatal neuroprotection strategy.

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 The authors received support in part by the Grant Healthcare Foundation “Passport to Developmental Health” and LEND grant (T73MC).

PII: S0022-3476(09)01292-X

doi:10.1016/j.jpeds.2009.12.035

Refers to article:

  • Autism Spectrum Disorders in Extremely Preterm Children , 08 January 2010

    Samantha Johnson, Chris Hollis, Puja Kochhar, Enid Hennessy, Dieter Wolke, Neil Marlow
    The Journal of Pediatrics April 2010 (Vol. 156, Issue 4, Pages 525-531.e2)

The Journal of Pediatrics
Volume 156, Issue 4 , Pages 519-521, April 2010

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