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PLOS ONE  2012 

Neonatal White Matter Abnormalities an Important Predictor of Neurocognitive Outcome for Very Preterm Children

DOI: 10.1371/journal.pone.0051879

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Background Cerebral white matter abnormalities on term MRI are a strong predictor of motor disability in children born very preterm. However, their contribution to cognitive impairment is less certain. Objective Examine relationships between the presence and severity of cerebral white matter abnormalities on neonatal MRI and a range of neurocognitive outcomes assessed at ages 4 and 6 years. Design/Methods The study sample consisted of a regionally representative cohort of 104 very preterm (≤32 weeks gestation) infants born from 1998–2000 and a comparison group of 107 full-term infants. At term equivalent, all preterm infants underwent a structural MRI scan that was analyzed qualitatively for the presence and severity of cerebral white matter abnormalities, including cysts, signal abnormalities, loss of white matter volume, ventriculomegaly, and corpus callosal thinning/myelination. At corrected ages 4 and 6 years, all children underwent a comprehensive neurodevelopmental assessment that included measures of general intellectual ability, language development, and executive functioning. Results At 4 and 6 years, very preterm children without cerebral white matter abnormalities showed no apparent neurocognitive impairments relative to their full-term peers on any of the domain specific measures of intelligence, language, and executive functioning. In contrast, children born very preterm with mild and moderate-to-severe white matter abnormalities were characterized by performance impairments across all measures and time points, with more severe cerebral abnormalities being associated with increased risks of cognitive impairment. These associations persisted after adjustment for gender, neonatal medical risk factors, and family social risk. Conclusions Findings highlight the importance of cerebral white matter connectivity for later intact cognitive functioning amongst children born very preterm. Preterm born children without cerebral white matter abnormalities on their term MRI appear to be spared many of the cognitive impairments commonly associated with preterm birth. Further follow-up will be important to assess whether this finding persists into the school years.


[1]  Heron M, Sutton PD, Xu J, Ventura SJ, Strobino DM, et al. (2010) Annual summary of vital statistics: 2007. Pediatrics 125: 4–15.
[2]  Woodward LJ, Moor S, Hood KM, Champion PR, Foster-Cohen S, et al. (2009) Very preterm children show impairments across multiple neurodevelopmental domains by age 4 years. Arch Dis Child Fetal Neonatal Ed 94: F339–344.
[3]  Litt J, Taylor HG, Klein N, Hack M (2005) Learning disabilities in children with very low birthweight: prevalence, neuropsychological correlates, and educational interventions. J Learn Disabil 38: 130–141.
[4]  Williams J, Lee KJ, Anderson PJ (2010) Prevalence of motor-skill impairment in preterm children who do not develop cerebral palsy: a systematic review. Dev Med Child Neurol 52: 232–237.
[5]  Pritchard VE, Clark CA, Liberty K, Champion PR, Wilson K, et al. (2009) Early school-based learning difficulties in children born very preterm. Early Hum Dev 85: 215–224.
[6]  Johnson S, Hennessy E, Smith R, Trikic R, Wolke D, et al. (2009) Academic attainment and special educational needs in extremely preterm children at 11 years of age: the EPICure study. Arch Dis Child Fetal Neonatal Ed 94: F283–289.
[7]  Larroque B, Ancel PY, Marchand-Martin L, Cambonie G, Fresson J, et al. (2011) Special care and school difficulties in 8-year-old very preterm children: the Epipage cohort study. PLoS One 6: e21361.
[8]  Wocadlo C, Rieger I (2006) Educational and therapeutic resource dependency at early school-age in children who were born very preterm. Early Hum Dev 82: 29–37.
[9]  Inder TE, Anderson NJ, Spencer C, Wells S, Volpe JJ (2003) White matter injury in the premature infant: a comparison between serial cranial sonographic and MR findings at term. AJNR Am J Neuroradiol 24: 805–809.
[10]  Inder TE, Wells SJ, Mogridge NB, Spencer C, Volpe JJ (2003) Defining the nature of the cerebral abnormalities in the premature infant: a qualitative magnetic resonance imaging study. J Pediatr 143: 171–179.
[11]  Iwata S, Nakamura T, Hizume E, Kihara H, Takashima S, et al. (2012) Qualitative brain MRI at term and cognitive outcomes at 9 years after very preterm birth. Pediatrics 129: e1138–1147.
[12]  Skiold B, Vollmer B, Bohm B, Hallberg B, Horsch S, et al.. (2012) Neonatal magnetic resonance imaging and outcome at age 30 months in extremely preterm infants. J Pediatr 160: 559–566 e551.
[13]  Spittle AJ, Cheong J, Doyle LW, Roberts G, Lee KJ, et al. (2011) Neonatal white matter abnormality predicts childhood motor impairment in very preterm children. Dev Med Child Neurol 53: 1000–1006.
[14]  Woodward LJ, Anderson PJ, Austin NC, Howard K, Inder TE (2006) Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med 355: 685–694.
[15]  Myers E, Ment LR (2009) Long-term outcome of preterm infants and the role of neuroimaging. Clin Perinatol 36: 773–789, vi.
[16]  Roberts G, Anderson PJ, Doyle LW (2010) The stability of the diagnosis of developmental disability between ages 2 and 8 in a geographic cohort of very preterm children born in 1997. Arch Dis Child 95: 786–790.
[17]  Hack M, Taylor HG, Drotar D, Schluchter M, Cartar L, et al. (2005) Poor predictive validity of the Bayley Scales of Infant Development for cognitive function of extremely low birth weight children at school age. Pediatrics 116: 333–341.
[18]  Miller SP, Ferriero DM, Leonard C, Piecuch R, Glidden DV, et al. (2005) Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neurodevelopmental outcome. J Pediatr 147: 609–616.
[19]  Anderson PJ, De Luca CR, Hutchinson E, Roberts G, Doyle LW (2010) Underestimation of developmental delay by the new Bayley-III Scale. Arch Pediatr Adolesc Med 164: 352–356.
[20]  Moore T, Johnson S, Haider S, Hennessy E, Marlow N (2012) Relationship between test scores using the second and third editions of the Bayley Scales in extremely preterm children. J Pediatr 160: 553–558.
[21]  Statistics New Zealand 2001 Census: Regional Summary. Available from: (accessed May 2008).
[22]  Marlow N (2004) Neurocognitive outcome after very preterm birth. Arch Dis Child Fetal Neonatal Ed 89: F224–228.
[23]  Johnson S (2007) Cognitive and behavioural outcomes following very preterm birth. Semin Fetal Neonatal Med 12: 363–373.
[24]  Wolke D, Ratschinski G, Ohrt B, Riegel K (1994) The cognitive outcome of very preterm infants may be poorer than often reported: an empirical investigation of how methodological issues make a big difference. Eur J Pediatr 153: 906–915.
[25]  Wechsler D (1989) Wechsler Preschool and Primary Scale of Intelligence-Revised. San Antonio, TX: The Psychological Corporation.
[26]  LoBello SG (1991) A short form of the Wechsler Preschool and Primary Scale of Intelligence-Revised. J Sch Psychol 29: 229–236.
[27]  Wiig EH, Secord W, Semel E (1992) Clinical Evaluation of Language Fundamentals-Preschool: examiners manual. New York: The Psychological Corporation.
[28]  Morrow CE, Vogel AL, Anthony JC, Ofir AY, Dausa AT, et al. (2004) Expressive and receptive language functioning in preschool children with prenatal cocaine exposure. J Pediatr Psychol 29: 543–554.
[29]  Mather N, Woodcock RW (2001) Woodcock-Johnson III Tests of Achievement: examiner’s manual. Itasca, IL: Riverside Publishing.
[30]  Welsh MC, Pennington BF, Groisser DB (1991) A normative-developmental study of executive function: a window on prefrontal function in children. Dev Neuropsychol 7: 131–149.
[31]  Jacques S, Zelazo PD (2001) The Flexible Item Selection Task (FIST): a measure of executive function in preschoolers. Dev Neuropsychol 20: 573–591.
[32]  Espy KA (1997) The Shape School: assessing executive function in preschool children. Dev Neuropsychol 13: 495–499.
[33]  Korkman M, Kirk U, Kemp S (1998) NEPSY: a developmental neuropsychological assessment. San Antonio: TX: The Psychological Corporation.
[34]  Wechsler D (2003) Wechsler Intelligence Scale for Children-Fourth edition (WISC-IV): administration and scoring manual. San Antonio: TX: The Psychological Corporation.
[35]  Milner B (1971) Interhemispheric differences in the localization of psychological processes in man. Br Med Bull 27: 272–277.
[36]  Hughes C, Russell J (1993) Autistic children’s difficulty with mental disengagement from an object: its implications for theories of autism. Dev Psychol 29: 498–510.
[37]  Conners CK, Staff MHS (2001) Conners’ Kiddie Continuous Performance Test (K-CPT): technical guide and software manual. North Tonawanda: NY: Multi-Health Systems.
[38]  Woodward LJ, Clark CA, Pritchard VE, Anderson PJ, Inder TE (2011) Neonatal white matter abnormalities predict global executive function impairment in children born very preterm. Dev Neuropsychol 36: 22–41.
[39]  Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand KJ (2002) Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis. JAMA 288: 728–737.
[40]  Baron IS, Rey-Casserly C (2010) Extremely preterm birth outcome: a review of four decades of cognitive research. Neuropsychol Rev 20: 430–452.
[41]  Boardman JP, Dyet LE (2007) Recent advances in imaging preterm brain injury. Minerva Pediatr 59: 349–368.
[42]  Cheong JL, Thompson DK, Wang HX, Hunt RW, Anderson PJ, et al. (2009) Abnormal white matter signal on MR imaging is related to abnormal tissue microstructure. AJNR Am J Neuroradiol 30: 623–628.
[43]  Allin MP, Kontis D, Walshe M, Wyatt J, Barker GJ, et al. (2011) White matter and cognition in adults who were born preterm. PLoS One 6: e24525.
[44]  Skranes J, Vangberg TR, Kulseng S, Indredavik MS, Evensen KA, et al. (2007) Clinical findings and white matter abnormalities seen on diffusion tensor imaging in adolescents with very low birth weight. Brain 130: 654–666.
[45]  Eikenes L, Lohaugen GC, Brubakk AM, Skranes J, Haberg AK (2011) Young adults born preterm with very low birth weight demonstrate widespread white matter alterations on brain DTI. Neuroimage 54: 1774–1785.
[46]  de Kieviet JF, Zoetebier L, van Elburg RM, Vermeulen RJ, Oosterlaan J (2012) Brain development of very preterm and very low-birthweight children in childhood and adolescence: a meta-analysis. Dev Med Child Neurol 54: 313–323.
[47]  Nosarti C, Giouroukou E, Healy E, Rifkin L, Walshe M, et al. (2008) Grey and white matter distribution in very preterm adolescents mediates neurodevelopmental outcome. Brain 131: 205–217.
[48]  Taylor HG, Filipek PA, Juranek J, Bangert B, Minich N, et al. (2011) Brain volumes in adolescents with very low birth weight: effects on brain structure and associations with neuropsychological outcomes. Dev Neuropsychol 36: 96–117.
[49]  Haynes RL, Billiards SS, Borenstein NS, Volpe JJ, Kinney HC (2008) Diffuse axonal injury in periventricular leukomalacia as determined by apoptotic marker fractin. Pediatr Res 63: 656–661.
[50]  Volpe JJ (2009) Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol 8: 110–124.
[51]  Inder TE, Huppi PS, Warfield S, Kikinis R, Zientara GP, et al. (1999) Periventricular white matter injury in the premature infant is followed by reduced cerebral cortical gray matter volume at term. Ann Neurol 46: 755–760.


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