Screening positivo para autismo em
ex-pré-termos : Prevalência e risco
(Positive Screening for Autism in Ex-preterm Infants:
Prevalence and Risk)
Catherine Limperopoulos, PhDa,b, Haim Bassan, MDb, Nancy R. Sullivan, PhDc, Janet S.
Soul, MDb, Richard L. Robertson, Jr, MDd, Marianne Moore, BA, RNb, Steven A. Ringer,
MD, PhDe, Joseph J. Volpe, MDb and Adré J. du Plessis, MBChB, MPHb
a Department of Neurology and Neurosurgery, School of Physical and Occupational Therapy, and
Department of Pediatrics, McGill University, Montreal, Quebec, Canada
b Fetal-Neonatal Neurology Research Program, Department of Neurology
c Developmental Medicine Center
d Department of Radiology, Children's Hospital Boston and Harvard Medical School, Boston,
Massachusetts
e Department of Neonatology, Brigham and Women's Hospital and Harvard Medical School, Boston,
Massachusetts
Pediatrics 2008;121;758-765 (April 2008)
Apresentação:Juliana Sobral Coutinho
Paulo Henrique G. Pereira
Coordenação: Paulo R. Margotto
www.paulomargotto.com.br
14/4/2008
Introdução
• Avanços
no
tratamento
intensivo
de
neonatologia aumentaram a sobrevivência de
pré-termos, no entanto houve redução da
morbidade neurológica e do desenvolvimento a
longo prazo.
• 50% de ex-pré-termos apresentam dificuldades
na função executiva, atenção e comportamento.
• Baixo peso e idade gestacional são fatores de
risco perinatais.
• A prevalência dos distúrbios do expectro do
autismo ainda não foi sistematicamente
explorada na população dos pré-termos.
Objetivo
Aplicar testes de rastreamento para
características autísticas em crianças
com história de muito baixo peso ao
nascer e identificar fatores de risco
associados ao resultado positivo do
rastreamento.
Metodologia
• Coorte de recém-nascidos fazia parte de
um estudo prospectivo sobre função
cerebrovascular numa série consecutiva
de pré-termos menores de 1500g
• Foram excluídos aqueles com disgenesia
cerebral,
síndromes
dismórficas
e
cromossomopatias
• Total: 91 RN.
Metodologia
• Modified Checklist for Autism in Toddler (MCHAT) foi aplicado nos RN entre as idades de
18 a 24 meses ajustados pela prematuridade.
• A informação psicométrica do M-CHAT
demonstra altas especificidade e sensibilidade.
• Child Behavior Checklist (CBCL) foi aplicada
para avaliar problemas comportamentais e
emocionais.
• Vineland Adaptive Behavior Scale (VARS) foi
aplicada para avaliar as funções adaptativas:
comunicação, socialização, motricidade
Metodologia
• Amostra caracterizada quanto aos aspectos demográficos, prénatais, intra-parto, pós-parto imediato, resultado a curto prazo.
• Dentre tais variáveis, foram identificados como possíveis variáveis
preditoras de positividade no rastreio de autismo
–
–
–
–
–
–
–
–
–
–
–
Idade materna
Temperatura materna
Hemorragia intra ou ante-parto
Parto prematuro
Infecção da placenta
Idade gestacional
Peso ao nascer
Sexo
Pontuação no SNAP II
Duração da necessidade de oxigênio
Ressonância Magnética alterada
Realizada Análise da Regressão Logística Multivariada para
identificar o modelo predictivo final
Resultados
• Idade gestacional variou
de 23 a 30 semanas
• Peso
1490g
variou de 460 a
Resultados
• Correlação altamente positiva entre pontuação anormal no M-
CHAT com problemas de introspecção do CBCL
• Correlação positiva entre dificuldades de socialização e de
habilidades de comunicação com resultado positivo do MCHAT.
Resultados
Resultados
Análise da Regressão Logística Univariada
Resultados
Análise da Regressão Logística Multivariada
Discussão
• Elevada prevalência de características
autísticas nos pré-termos extremos
sobreviventes.
• Correlação positiva entre resultado
positivo do M-CHAT e introspecção e
problemas de socialização e déficits de
comunicação.
• Primeira descrição desse fenômeno em
prematuros extremos
Discussão
• Estudos
populacionais
identificaram
prematuridade, baixo peso e necessidade
de tratamento intensivo neonatal como
fatores de risco perinatais para espectro
autista.
• Tais fatores atuariam independentemente
ou interagiriam com a predisposição
genética por interferir em pontos críticos
do desenvolvimento.
Discussão
• Corioamnionite e sexo masculino são fatores já
identificados como fatores associados a autismo
• Limitações:
– M-CHAT é um instrumento de rastreio, não fecha o
diagnóstico
– Como foi aplicado aos 18 meses, as alterações
podem ser transitórias ou podem emergir a partir
dessa idade.
– Ausência de dados socioeconômicos, já que estes
podem justificar atraso do desenvolvimento.
– Amostra altamente selecionada.
Conclusão
Os resultados desse estudo sugerem que o
rastreamento precoce para sinais de
autismo são justificados em uma população
de prematuros extremos seguido por um
teste definitivo para autismo naqueles com
teste inicial positivo.
•
•
•
•
•
•
ABSTRACT
OBJECTIVE. The survival of very low birth weight infants has increased markedly in recent
years. Unfortunately, the prevalence of significant and lifelong motor, cognitive, and
behavioral dysfunction has remained a major problem confronting these children. The
objective of this study was to perform screening tests for early autistic features in children
with a history of very low birth weight and to identify risk factors associated with a positive
screening result.
METHODS. We studied 91 ex-preterm infants 1500 g at birth. Infants underwent
conventional MRI studies at preterm and/or term-adjusted age. We collected pertinent
demographic, prenatal, intrapartum, acute postnatal, and short-term outcome data for all
infants. Follow-up assessments were performed at a mean age of 21.9 ± 4.7 months, using
the Modified Checklist for Autism in Toddlers, the Vineland Adaptive Behavior Scale, and the
Child Behavior Checklist.
RESULTS. Twenty-six percent of ex-preterm infants had a positive result on the autism
screening tool. Abnormal scores correlated highly with internalizing behavioral problems on
the Child Behavior Checklist and socialization and communication deficits on the Vineland
Scales. Lower birth weight, gestational age, male gender, chorioamnionitis, acute intrapartum
hemorrhage, illness severity on admission, and abnormal MRI studies were significantly
associated with an abnormal autism screening score.
CONCLUSIONS. Early autistic behaviors seem to be an underrecognized feature of very low
birth weight infants. The results from this study suggest that early screening for signs of
autism may be warranted in this high-risk population followed by definitive autism testing in
those with positive screening results.
Key Words: autism • prematurity • MRI • risk factors • outcome
Abbreviations: VLBW—very low birth weight • M-CHAT—Modified Checklist for Autism in
Toddlers • CBCL—Child Behavior Checklist • VABS—Vineland Adaptive Behavior Scale •
SNAP-II—Score of Neonatal Acute Physiology II • PVL—periventricular leukomalacia •
PVHI—periventricular hemorrhagic infarction
Referências do artigo:
•
•
•
•
•
•
•
•
•
•
Msall ME. The limits of viability and the uncertainty of neuroprotection: challenges in optimizing
outcomes in extreme prematurity. Pediatrics. 2007;119 (1):158 –160[Free Full Text]
Tommiska V, Heinonen K, Lehtonen L, et al. No improvement in outcome of nationwide
extremely low birth weight infant populations between 1996–1997 and 1999–2000. Pediatrics.
2007;119 (1):29 –36[Abstract/Free Full Text]
Ment LR, Allan WC, Makuch RW, Vohr B. Grade 3 to 4 intraventricular hemorrhage and Bayley
scores predict outcome. Pediatrics. 2005;116 (6):1597 –1598; author reply 1598[Free Full Text]
Rushing S, Ment LR. Preterm birth: a cost benefit analysis. Semin Perinatol. 2004;28 (6):444 –
450[CrossRef][ISI][Medline]
Saigal S. Follow-up of very low birthweight babies to adolescence. Semin Neonatol. 2000;5
(2):107 –118[CrossRef][Medline]
Hack M, Flannery DJ, Schluchter M, Cartar L, Borawski E, Klein N. Outcomes in young
adulthood for very-low-birth-weight infants. N Engl J Med. 2002;346 (3):149 –
157[Abstract/Free Full Text]
Dahl LB, Kaaresen PI, Tunby J, Handegard BH, Kvernmo S, Ronning JA. Emotional,
behavioral, social, and academic outcomes in adolescents born with very low birth weight.
Pediatrics. 2006;118 (2). Available at: www.pediatrics.org/cgi/content/full/118/2/e449
Pharoah PO, Stevenson CJ, West CR. General Certificate of Secondary Education
performance in very low birthweight infants. Arch Dis Child. 2003;88 (4):295 –
298[Abstract/Free Full Text]
Anderson PJ, Doyle LW. Executive functioning in school-aged children who were born very
preterm or with extremely low birth weight in the 1990s. Pediatrics. 2004;114 (1):50 –
57[Abstract/Free Full Text]
Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand KJ. Cognitive and behavioral outcomes
of school-aged children who were born preterm: a meta-analysis. JAMA. 2002;288 (6):728 –
737[Abstract/Free Full Text]
•
•
•
•
•
•
•
•
•
•
•
Harvey JM, O'Callaghan MJ, Mohay H. Executive function of children with extremely low birthweight: a case
control study. Dev Med Child Neurol. 1999;41 (5):292 –297[CrossRef][ISI][Medline]
Msall ME, Tremont MR. Measuring functional outcomes after prematurity: developmental impact of very low
birth weight and extremely low birth weight status on childhood disability. Ment Retard Dev Disabil Res Rev.
2002;8 (4):258 –272[CrossRef][ISI][Medline]
Msall ME. Supporting vulnerable preschool children: connecting the dots before kindergarten. Pediatrics.
2004;114 (4):1086[Free Full Text]
Sigurdsson E, Van Os J, Fombonne E. Are impaired childhood motor skills a risk factor for adolescent
anxiety? Results from the 1958 U.K. birth cohort and the National Child Development Study. Am J Psychiatry.
2002;159 (6):1044 –1046
Pine D, Shaffer D, Schonfeld IS. Persistent emotional disorder in children with neurological soft signs. J Am
Acad Child Adolesc Psychiatry. 1993;32 (6):1229 –1236[ISI][Medline]
Buka SL, Fan AP. Association of prenatal and perinatal complications with subsequent bipolar disorder and
schizophrenia. Schizophr Res. 1999;39 (2):113 –119; discussion 160–161[CrossRef][ISI][Medline]
Wahlbeck K, Osmond C, Forsen T, Barker DJ, Eriksson JG. Associations between childhood living
circumstances and schizophrenia: a population-based cohort study. Acta Psychiatr Scand. 2001;104 (5):356 –
360[CrossRef][ISI][Medline]
Jones PB, Rantakallio P, Hartikainen AL, Isohanni M, Sipila P. Schizophrenia as a long-term outcome of
pregnancy, delivery, and perinatal complications: a 28-year follow-up of the 1966 north Finland general
population birth cohort. Am J Psychiatry. 1998;155 (3):355 –364[Abstract/Free Full Text]
Botting N, Powls A, Cooke RW, Marlow N. Attention deficit hyperactivity disorders and other psychiatric
outcomes in very low birthweight children at 12 years. J Child Psychol Psychiatry. 1997;38 (8):931 –
941[ISI][Medline]
Whitaker AH, Van Rossem R, Feldman JF, et al. Psychiatric outcomes in low-birth-weight children at age 6
years: relation to neonatal cranial ultrasound abnormalities. Arch Gen Psychiatry. 1997;54 (9):847 –
856[Abstract]
Saigal S, Pinelli J, Hoult L, Kim MM, Boyle M. Psychopathology and social competencies of adolescents who
were extremely low birth weight. Pediatrics. 2003;111 (5 pt 1):969 –975[Abstract/Free Full Text]
•
•
•
•
•
•
•
•
•
•
•
McCormick MC, Brooks-Gunn J, Workman-Daniels K, Turner J, Peckham GJ. The
health and developmental status of very low-birth-weight children at school age.
JAMA. 1992;267 (16):2204 –2208[Abstract]
Breslau N, Johnson EO, Lucia VC. Academic achievement of low birthweight children
at age 11: the role of cognitive abilities at school entry. J Abnorm Child Psychol.
2001;29 (4):273 –279[CrossRef][ISI][Medline]
Nadeau L, Boivin M, Tessier R, Lefebvre F, Robaey P. Mediators of behavioral
problems in 7-year-old children born after 24 to 28 weeks of gestation. J Dev Behav
Pediatr. 2001;22 (1):1 –10[ISI][Medline]
Weisglas-Kuperus N, Koot HM, Baerts W, Fetter WP, Sauer PJ. Behaviour problems
of very low-birthweight children. Dev Med Child Neurol. 1993;35 (5):406 –
416[ISI][Medline]
Hoy EA, Sykes DH, Bill JM, Halliday HL, McClure BG, Reid MM. The social
competence of very-low-birthweight children: teacher, peer, and self-perceptions. J
Abnorm Child Psychol. 1992;20 (2):123 –150[CrossRef][ISI][Medline]
Kuehn BM. CDC: autism spectrum disorders common. JAMA. 2007;297
(9):940[Free Full Text]
Leslie DL, Martin A. Health care expenditures associated with autism spectrum
disorders. Arch Pediatr Adolesc Med. 2007;161 (4):350 –355[Abstract/Free Full Text]
Fombonne E. Autism and newborn encephalopathy. Dev Med Child Neurol. 2006;48
(2):84[CrossRef][ISI][Medline]
Robins DL, Dumont-Mathieu TM. Early screening for autism spectrum disorders:
update on the modified checklist for autism in toddlers and other measures. Dev
Behav Pediatr. 2006;27 (2 Suppl):S111 –S119[CrossRef][ISI][Medline]
Soul JS, Hammer PE, Tsuji M, et al. Fluctuating pressure-passivity is common in the
cerebral circulation of sick premature infants. Pediatr Res. 2007;61 (4):467 –
473[CrossRef][ISI][Medline]
Limperopoulos C, Bassan H, Kalish L, et al. Current definitions of hypotension do not
predict abnormal cranial ultrasound in preterm infants. Pediatrics. 2007;120 (5):966 –
977[Abstract/Free Full Text]
•
•
•
•
•
•
•
•
•
•
•
Robins DL, Fein D, Barton ML, Green JA. The Modified Checklist for Autism in Toddlers: an initial
study investigating the early detection of autism and pervasive developmental disorders. J Autism
Dev Disord. 2001;31 (2):131 –144[CrossRef][ISI][Medline]
Wong V, Hui LH, Lee WC, et al. A modified screening tool for autism (Checklist for Autism in
Toddlers [CHAT-23]) for Chinese children. Pediatrics. 2004;114 (2). Available at:
www.pediatrics.org/cgi/content/full/114/2/e166
Rescorla LA. Assessment of young children using the Achenbach System of Empirically Based
Assessment (ASEBA). Ment Retard Dev Disabil Res Rev. 2005;11 (3):226 –
237[CrossRef][ISI][Medline]
Achenbach TM, Rescorla L. Manual for the Child Behavior Checklist. Preschool Forms and
Profiles. Burlington, VT: University of Vermont Department of Psychiatry; 2000
Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Interview Edition) Survey
Form Manual: A Revision of the Vineland Social Maturity Scale. Circle Pines, MN: American
Guidance Service; 1984
Richardson DK, Corcoran JD, Escobar GJ, Lee SK. SNAP-II and SNAPPE-II: simplified newborn
illness severity and mortality risk scores. J Pediatr. 2001;138 (1):92 –100[CrossRef][ISI][Medline]
Hultman CM, Sparen P, Cnattingius S. Perinatal risk factors for infantile autism. Epidemiology.
2002;13 (4):417 –423[CrossRef][ISI][Medline]
Badawi N, Dixon G, Felix JF, et al. Autism following a history of newborn encephalopathy: more
than a coincidence? Dev Med Child Neurol. 2006;48 (2):85 –89[CrossRef][ISI][Medline]
Fombonne E. The epidemiology of autism: a review. Psychol Med. 1999;29 (4):769 –
786[CrossRef][ISI][Medline]
Bolton PF, Murphy M, Macdonald H, Whitlock B, Pickles A, Rutter M. Obstetric complications in
autism: consequences or causes of the condition? J Am Acad Child Adolesc Psychiatry. 1997;36
(2):272 –281[CrossRef][ISI][Medline]
Maimburg RD, Vaeth M. Perinatal risk factors and infantile autism. Acta Psychiatr Scand.
2006;114 (4):257 –264[CrossRef][ISI][Medline]
•
•
•
•
•
•
•
•
•
•
•
Brimacombe M, Ming X, Lamendola M. Prenatal and birth complications in autism. Matern Child
Health J. 2007;11 (1):73 –79[CrossRef][ISI][Medline]
Matsuishi T, Yamashita Y, Ohtani Y, et al. Brief report: incidence of and risk factors for autistic
disorder in neonatal intensive care unit survivors. J Autism Dev Disord. 1999;29 (2):161 –
166[CrossRef][ISI][Medline]
Juul-Dam N, Townsend J, Courchesne E. Prenatal, perinatal, and neonatal factors in autism,
pervasive developmental disorder-not otherwise specified, and the general population. Pediatrics.
2001;107 (4). Available at: www.pediatrics.org/cgi/content/full/107/4/e63
Courchesne E, Karns CM, Davis HR, et al. Unusual brain growth patterns in early life in patients
with autistic disorder: an MRI study. Neurology. 2001;57 (2):245 –254[Abstract/Free Full Text]
Sparks BF, Friedman SD, Shaw DW, et al. Brain structural abnormalities in young children with
autism spectrum disorder. Neurology. 2002;59 (2):184 –192[Abstract/Free Full Text]
Levitt JG, Blanton RE, Smalley S, et al. Cortical sulcal maps in autism. Cereb Cortex. 2003;13
(7):728 –735[Abstract/Free Full Text]
Carper RA, Moses P, Tigue ZD, Courchesne E. Cerebral lobes in autism: early hyperplasia and
abnormal age effects. Neuroimage. 2002;16 (4):1038 –1051[CrossRef][ISI][Medline]
Kates WR, Burnette CP, Eliez S, et al. Neuroanatomic variation in monozygotic twin pairs
discordant for the narrow phenotype for autism. Am J Psychiatry. 2004;161 (3):539 –
546[Abstract/Free Full Text]
Herbert MR, Ziegler DA, Deutsch CK, et al. Dissociations of cerebral cortex, subcortical and
cerebral white matter volumes in autistic boys. Brain. 2003;126 (Pt 5):1182 –
1192[Abstract/Free Full Text]
Rippon G, Brock J, Brown C, Boucher J. Disordered connectivity in the autistic brain: challenges
for the "new psychophysiology. " Int J Psychophysiol. 2007;63 (2):164 –
172[CrossRef][ISI][Medline]
Courchesne E, Redcay E, Morgan JT, Kennedy DP. Autism at the beginning: microstructural and
growth abnormalities underlying the cognitive and behavioral phenotype of autism. Dev
Psychopathol. 2005;17 (3):577 –597[ISI][Medline]
•
•
•
•
•
•
•
•
•
Courchesne E. Brainstem, cerebellar and limbic neuroanatomical abnormalities in
autism. Curr Opin Neurobiol. 1997;7 (2):269 –278[CrossRef][ISI][Medline]
Courchesne E. Brain development in autism: early overgrowth followed by premature
arrest of growth. Ment Retard Dev Disabil Res Rev. 2004;10 (2):106 –
111[CrossRef][ISI][Medline]
Hashimoto T, Tayama M, Murakawa K, et al. Development of the brainstem and
cerebellum in autistic patients. J Autism Dev Disord. 1995;25 (1):1 –
18[CrossRef][ISI][Medline]
Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism: a
review and future directions. Int J Dev Neurosci. 2005;23 (2–3):183 –
187[CrossRef][ISI][Medline]
Limperopoulos C, Bassan H, Gauvreau K, et al. Does cerebellar injury in premature
infants contribute to the high prevalence of long-term cognitive, learning, and
behavioral disability in survivors? Pediatrics. 2007;120 (3):584 –
593[Abstract/Free Full Text]
Limperopoulos C, Soul JS, Gauvreau K, et al. Late gestation cerebellar growth is
rapid and impeded by premature birth. Pediatrics. 2005;115 (3):688 –
695[Abstract/Free Full Text]
Ventola P, Kleinman J, Pandey J, et al. Differentiating between autism spectrum
disorders and other developmental disabilities in children who failed a screening
instrument for ASD. J Autism Dev Disord. 2007;37 (3):425 –
436[CrossRef][ISI][Medline]
Trillingsgaard A, Ulsted Sorensen E, Nemec G, Jorgensen M. What distinguishes
autism spectrum disorders from other developmental disorders before the age of four
years? Eur Child Adolesc Psychiatry. 2005;14 (2):65 –72[CrossRef][ISI][Medline]
Lord C. Follow-up of two-year-olds referred for possible autism. J Child Psychol
Psychiatry. 1995;36 (8):1365 –1382[ISI][Medline
• Lord C, Rutter M, Le Couteur A. Autism Diagnostic InterviewRevised: a revised version of a diagnostic interview for caregivers of
individuals with possible pervasive developmental disorders. J
Autism Dev Disord. 1994;24 (5):659 –685[CrossRef][ISI][Medline]
• Lord C, Risi S, Lambrecht L, et al. The autism diagnostic
observation schedule-generic: a standard measure of social and
communication deficits associated with the spectrum of autism. J
Autism Dev Disord. 2000;30 (3):205 –223[CrossRef][ISI][Medline]
• American Psychiatric Association. Diagnostic criteria for 299.00
autistic disorder. In: Diagnostic and Statistical Manual of Mental
Disorders. 4th ed, Text Revision (DSM-IV-TR). American Psychiatric
Association; 2000
• Committee on Educational Interventions for Children with Autism,
National Research Council. Educating Children With Autism.
Washington, DC: National Academy Press; 2001
• Bryson SE, Rogers SJ, Fombonne E. Autism spectrum disorders:
early detection, intervention, education, and psychopharmacological
management. Can J Psychiatry. 2003;48 (8):506 –516[Medline]
Obrigado!!!
Ddo Paulo Henrique, Dra. Juliana e Dr. Paulo R. Margotto
14/4/2008