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

Inder TE (2012) Neonatal White Matter Abnormalities an Important Predictor of Neurocognitive Outcome for Very Preterm Children. PLoS ONE 7(12): e51879. doi:10.1371/journal.pone.0051879 Neonatal White Matter Abnormalities an Important Predictor of Neurocognitive Outcome for Very Preterm Children Lianne J. Woodward 0 Caron A. C. Clark 0 Samudragupta Bora 0 Terrie E. Inder 0 Olivier Baud, H opital Robert Debre, France 0 1 Canterbury Child Development Research Group, Department of Psychology, University of Canterbury , Christchurch , New Zealand , 2 New Zealand Brain Research Institute , Christchurch , New Zealand , 3 Department of Psychology, University of Oregon , Eugene, Oregon , United States of America, 4 Departments of Pediatrics, Neurology and Radiology, Washington University School of Medicine , St Louis, Missouri , United States of America 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. - Funding: Funding for this study was provided by the following funding organizations: the New Zealand Health Research Council of New Zealand (ref no: 03/196) (URL: http://www.hrc.govt.nz/); the Neurological Foundation of New Zealand (ref no. 0227PG) (URL: http://www.neurological.org.nz/) and Canterbury Medical Research Foundation (ref. no. 05/01) (URL: http://www.cmrf.org.nz/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Central to reducing the longer-term morbidities associated with very preterm birth is the need to identify early neonatal markers of risk. Children born very preterm now represent almost 2% of all live births in the U.S. and other developed countries, [1] with follow-up studies identifying high rates of subsequent neurodevelopmental impairment. Approximately 10% of survivors develop neurosensory impairments such as cerebral palsy, blindness, and deafness. A further 40% will be affected by cognitive deficits, language problems, developmental coordination disorder, inattention, and educational underachievement. [2,3,4,5] These impairments pose major challenges, with a third of children born very preterm requiring ongoing specialist health care and up to two-thirds needing educational or psychological support during their school years. [6,7,8]. To date, efforts to identify early perinatal markers of later neurodevelopmental risk have been somewhat disappointing, with most factors correlating only modestly with outcome. One potential exception is the presence and severity of cerebral white matter abnormalities on term magnetic resonance imaging (MRI). These diffuse white matter abnormalities affect between 5070% of very preterm infants and include: white matter volume loss; ventriculomegaly; white matter signal abnormality; thinning of the corpus callosum; and delayed myelination. [9,10] White matter abnormalities have been shown to be more predictive of later neurodevelopmental impairment than gestational age and other perinatal factors. [11,12,13,14] Short-term follow-up studies suggest that prediction may be better for motor than for cognitive outcomes. [12,14] However, a recent study of 60 very preterm born children at age 9, found that moderate-to-severe white matter abnormalities on term MRI were associated with increased risks of both cognitive delay (WISC score ,85; Odds ratio, OR = 8) and cerebral palsy (OR = 10), with these associations persisting after adjustment for other clinical risk factors. [11]. However, some caution is warranted. First, with the exception of Iwata, [11] follow-up beyond 2 to 3 years is extremely rare. [15] Given the extended developmental trajectories of many cognitive skills, longer-term follow-up is essential to provide an accurate assessment of clinically important neurocognitive impairments. This need is further reinforced by findings that early measures, such as the Bayley Scales, correlate only modestly with longerterm cognitive outcome. [16,17] A second limitation of existing research has been the reliance on a single, typically global, measure of cognition making it difficult to assess whether associations are pervasive or confined to specific cognitive domains. Third, considerable variability exists with respect to the measurement of white matter abnormalities, with some studies grouping children with no and mild abnormalities [12,18] and others combining all white matter abnormalities cases. [11] These differences make comparison across studies difficult and also potentially obscure linear relationships in the data. [13,14] Fourth, there is a critical need for comparative studies to include a representative group of full-term born children. Recent difficulties with the Bayley-III norms underscore this point. [19,20] Finally and import (...truncated)