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• W3119480304 abstract "See related article, p 58In this volume of The Journal of Pediatrics, Parikh et al report on white matter changes in the brains of a large cohort of very preterm infants (<32 weeks of gestation) who underwent magnetic resonance imaging (MRI) at term equivalent age (39-45 weeks’ postmenstrual age).1Parikh NA Perinatal risk and protective factors in the development of diffuse white matter abnormality on term-equivalent age MRI in infants born very preterm.J Pediatr. 2021; 233: 58-65Abstract Full Text Full Text PDF Scopus (8) Google Scholar This research team has developed a method for objectively quantifying the MRI finding of diffuse excessive high signal intensity (DEHSI), and analyzed this measure, which they now refer to as diffuse white matter abnormality (DWMA), in relation to multiple perinatal factors. Factors found to be associated with increased DWMA were pneumothorax, severe bronchopulmonary dysplasia, severe retinopathy of prematurity, and male sex; associated with decreased DWMA were postnatal treatment with dexamethasone, duration of treatment with caffeine, and exclusive human milk diet at discharge. If some of these associations are valid and indicative of causal relationships, and if the putative association between DWMA and neurodevelopmental outcome is valid and causal, the study by Parikh et al could have important implications for clinical care of very preterm infants.1Parikh NA Perinatal risk and protective factors in the development of diffuse white matter abnormality on term-equivalent age MRI in infants born very preterm.J Pediatr. 2021; 233: 58-65Abstract Full Text Full Text PDF Scopus (8) Google Scholar See related article, p 58 The authors are to be commended for moving toward quantitative, rather than qualitative, MRI assessment, a direction in which other researchers have also been moving.2Pagnozzi A.M. Dowson N. Doecke J. Fiori S. Bradley A.P. Boyd R.N. et al.Identifying relevant biomarkers of brain injury from structural MRI: validation using automated approaches in children with unilateral cerebral palsy.PLoS One. 2017; 12: e0181605Crossref PubMed Scopus (4) Google Scholar,3O'Muircheartaigh J. Robinson E.C. Pietsch M. Wolfers T. Aljabar P. Grande L.C. et al.Modelling brain development to detect white matter injury in term and preterm born neonates.Brain. 2020; 143: 467-479Crossref PubMed Scopus (22) Google Scholar Additional strengths of this study include scanning infants from 5 medical centers on the same scanner with the same protocol, as well as adjustment for age at the time of scanning in order to account for the large regional white matter changes that influence T2 scans between 39 and 45 weeks. The clinical usefulness of their approach will depend on linking quantitative MRI technology to the clinical interface, making automated tools to measure abnormalities on infant brain scans available and easy for clinicians to use. The early diagnosis of such brain abnormalities might open opportunities for earlier intervention to preserve neurologic function, leading to better long-term outcomes. The potential limitations of the neuroimaging data include the normalization of the DWMA volume by whole white matter volume, which is quite large in comparison; an alternative approach would have been to normalize by the white matter volume only within the slices used to quantify the DWMA. Nonetheless, the researchers report similar conclusions were obtained irrespective of whether data were normalized or not. Parikh et al used a signal cutoff for white matter of more than 1.8 SD above the mean intensity for both gray and white matter, despite having a segmentation method that separates the gray and white matter. It would be interesting to know whether a specific white matter cutoff might demonstrate greater usefulness for identifying DWMA. As Parikh et al acknowledge, there is limited evidence that DEHSI on neonatal MRI is associated with long-term neurodevelopmental outcomes, but most existing studies are based on qualitative assessment of DEHSI, rather than quantitative assessment.4He L. Parikh N.A. Atlas-guided quantification of white matter signal abnormalities on term-equivalent age MRI in very preterm infants: findings predict language and cognitive development at two years of age.PLoS One. 2013; 8: e85475Crossref PubMed Scopus (22) Google Scholar,5He L. Parikh N.A. Automated detection of white matter signal abnormality using T2 relaxometry: application to brain segmentation on term MRI in very preterm infants.Neuroimage. 2013; 64: 328-340Crossref PubMed Scopus (27) Google Scholar Using the novel method developed by Parikh et al, the quantity of DEHSI has been associated with Bayley cognitive and language scores at age 2.6Parikh N.A. He L. Bonfante-Mejia E. Hochhauser L. Wilder P.E. Burson K. et al.Automatically quantified diffuse excessive high signal intensity on MRI predicts cognitive development in preterm infants.Pediatr Neurol. 2013; 49: 424-430Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar,7Parikh N.A. He L. Priyanka Illapani V.S. Altaye M. Folger A.T. Yeates K.O. Objectively diagnosed diffuse white matter abnormality at term is an independent predictor of cognitive and language outcomes in infants born very preterm.J Pediatr. 2020; 220: 56-63Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar In this regard, it would be interesting to compare the reliability of DWMA estimated quantitatively with the reliability of DEHSI reported qualitatively. Of note, the method of quantifying DEHSI used in this report is different from the fully automated method described previously by Parikh et al, in that some manual procedures (eg, selecting slices of interest and removing gray matter/white matter border voxels that were incorrectly detected) were required, which could introduce inter-rater variation.4He L. Parikh N.A. Atlas-guided quantification of white matter signal abnormalities on term-equivalent age MRI in very preterm infants: findings predict language and cognitive development at two years of age.PLoS One. 2013; 8: e85475Crossref PubMed Scopus (22) Google Scholar It would be interesting to see if different brain regions of signal abnormality were more or less associated with the clinical factors. In a previous study by the authors, the centrum semiovale signal abnormality was most closely correlated with Bayley scores.4He L. Parikh N.A. Atlas-guided quantification of white matter signal abnormalities on term-equivalent age MRI in very preterm infants: findings predict language and cognitive development at two years of age.PLoS One. 2013; 8: e85475Crossref PubMed Scopus (22) Google Scholar Other investigators have related the anatomical location of white matter high signal intensity with the 18-month outcomes.8Guo T. Duerden E.G. Adams E. Chau V. Branson H.M. Chakravarty M.M. et al.Quantitative assessment of white matter injury in preterm neonates: association with outcomes.Neurology. 2017; 88: 614-622Crossref PubMed Scopus (81) Google Scholar The current study extends, and reports similar findings to, prior investigations of antecedents of white matter abnormality in extremely preterm neonates.9Parikh N.A. He L. Li H. Priyanka Illapani V.S. Klebanoff M.A. Antecedents of objectively diagnosed diffuse white matter abnormality in very preterm infants.Pediatr Neurol. 2020; 106: 56-62Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar,10Parikh N.A. Lasky R.E. Kennedy K.A. McDavid G. Tyson J.E. Perinatal factors and regional brain volume abnormalities at term in a cohort of extremely low birth weight infants.PLoS One. 2013; 8: e62804Crossref PubMed Scopus (45) Google Scholar The association with male sex is consistent with the higher frequency among male infants of both neonatal morbidities, as well as neurodevelopmental impairments.11Stevenson D.K. Verter J. Fanaroff A.A. Oh W. Ehrenkranz R.A. Shankaran S. et al.Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage.Arch Dis Child Fetal Neonatal Ed. 2000; 83: F182-F185Crossref PubMed Google Scholar,12Kuban K.C. Joseph R.M. O'Shea T.M. Allred E.N. Heeren T. Douglass L. et al.Extremely Low Gestational Age Newborn StudyGirls and boys born before 28 weeks gestation: risks of cognitive, behavioral, and neurologic outcomes at age 10 years.J Pediatr. 2016; 173: 69-75.e61Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Currently, there are no known therapies to ameliorate these sex differences. We can think of no plausible biological mechanism by which severe retinopathy of prematurity could disrupt white matter development, although these 2 conditions might share pathogenetic mechanisms. With regard to pneumothorax and severe bronchopulmonary dysplasia, efforts to decrease both are important aspects of neonatal clinical care and ongoing research. The other 3 factors associated with DWMA are of particular interest because these therapies are used frequently to treat neonates born extremely preterm. Caffeine has been shown within a multicenter randomized trial to influence white matter microstructure at term equivalent age in a direction consistent with increased maturity, but not at 11 years.13Doyle L.W. Cheong J. Hunt R.W. Lee K.J. Thompson D.K. Davis P.G. et al.Caffeine and brain development in very preterm infants.Ann Neurol. 2010; 68: 734-742Crossref PubMed Scopus (66) Google Scholar,14Kelly C.E. Ooi W.L. Yang J.Y. Chen J. Adamson C. Lee K.J. et al.Caffeine for apnea of prematurity and brain development at 11 years of age.Ann Clin Transl Neurol. 2018; 5: 1112-1127Crossref PubMed Scopus (9) Google Scholar Hence, the observational data from Parikh et al are consistent with more rigorous data obtained from a randomized trial. Caffeine also improves neurodevelopmental outcomes in early childhood, and motor outcomes later in childhood.15Schmidt B. Roberts R. Davis P. Doyle L. Barrington K. Ohlsson A. et al.Long-term effects of caffeine therapy for apnea of prematurity.N Engl J Med. 2007; 357: 1893-1902Crossref PubMed Scopus (636) Google Scholar, 16Doyle L.W. Halliday H.L. Ehrenkranz R.A. Davis P.G. Sinclair J.C. An update on the impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk of bronchopulmonary dysplasia.J Pediatr. 2014; 165: 1258-1260Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 17Schmidt B. Roberts R.S. Anderson P.J. Asztalos E.V. Costantini L. Davis P.G. et al.Academic performance, motor function, and behavior 11 years after neonatal caffeine citrate therapy for apnea of prematurity: an 11-year follow-up of the CAP randomized clinical trial.JAMA Pediatr. 2017; 171: 564-572Crossref PubMed Scopus (109) Google Scholar, 18Doyle L.W. Schmidt B. Anderson P.J. Davis P.G. Moddemann D. Grunau R.E. et al.Reduction in developmental coordination disorder with neonatal caffeine therapy.J Pediatr. 2014; 165 (356-9.e352)Abstract Full Text Full Text PDF Scopus (52) Google Scholar Here quality improvement practices to ensure infants receive caffeine optimally would be worthwhile. Corticosteroids are another therapy Parikh et al identified as associated with reduced DWMA. On the one hand corticosteroids decrease bronchopulmonary dysplasia, but they potentially cause long-term harm, particularly cerebral palsy.19Doyle L.W. Cheong J.L. Ehrenkranz R.A. Halliday H.L. Late (>7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.Cochrane Database Syst Rev. 2017; 10: CD001145PubMed Google Scholar,20Doyle L.W. Cheong J.L. Ehrenkranz R.A. Halliday H.L. Early (<8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.Cochrane Database Syst Rev. 2017; 10: CD001146PubMed Google Scholar Clinicians need to balance these risks and benefits, as acknowledged by Parikh et al. Human milk feeding has the potential for both direct salutary effects on brain development (attributable to unique components that are not present in infant formula) as well an indirect benefit owing to a lesser risk of necrotizing enterocolitis. More definitive information about the neurodevelopmental benefit of human milk feeding is likely to come from a large clinical trial (ClinicalTrials.gov Identifier: NCT01534481), the results of which might be available soon. Finally, it must be remembered that the ideal evidence base for neonatal therapeutics is not determined by brain MRI findings at term equivalent age, but by clinically relevant longer term neurodevelopmental outcomes. Perinatal Risk and Protective Factors in the Development of Diffuse White Matter Abnormality on Term-Equivalent Age Magnetic Resonance Imaging in Infants Born Very PretermThe Journal of PediatricsVol. 233PreviewTo identify perinatal clinical diseases and treatments that are associated with the development of objectively diagnosed diffuse white matter abnormality (DWMA) on structural magnetic resonance imaging (MRI) at term-equivalent age in infants born very preterm. Full-Text PDF CorrigendumThe Journal of PediatricsVol. 242PreviewAfter manuscript acceptance and publication online, The Journal of Pediatrics was notified of several errors in the Editorial “Magnetic Resonance Biomarkers in Very Preterm Infants: Relationships to Perinatal Factors” by O’Shea, Thompson, and Doyle (J Pediatr 2021, in press, https://doi.org/10.1016/j.jpeds.2020.12.081 ). Following editorial communication with the authors, the authors made revisions to the Editorial. The final version of the article has since been updated. Full-Text PDF" @default.
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• W3119480304 title "Magnetic Resonance Biomarkers in Very Preterm Infants: Relationships to Perinatal Factors" @default.
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