To evaluate punctate white matter lesion (PWML) influence in preterm infants on the long-term neurodevelopmental outcome (NDO).
PubMed and EMBASE were searched from January 1, 2000, to May 31, 2021. Studies were included in which PWML in preterm infants on MRI around term-equivalent age (TEA) and NDO at ≥12 months were reported. Study and patient characteristics and NDO on motor, cognitive, and behavioral domains were extracted. The quality of studies was assessed using the Cochrane-approved Quality in Prognosis Studies tool.
This analysis included nine studies with a total of 1655 patients. Mean incidence of isolated PWML was 22.1%. All studies showed a relationship between PWML and motor delay. Two studies found a significant correlation between cognitive and behavioral outcomes and PWML. Number and PWML location are related to severity and impairment types.
PWML were not always separately described from generalized WMI, only studies with imaging around TEA were included, and studies were heterogenic in design and quality.
PWML is common in preterm infants and predictive of adverse NDO, in particular on motor outcomes and less on cognitive and behavioral outcomes. The type and severity of impairments are related to the number and location of PMWL.
PWML is common in preterm infants and seems predictive of adverse NDO.
DWI and SWI MRI sequences are informative because the different patterns suggest a difference in the underlying pathology.
The type and severity of impairments are related to the number and location of PMWL.
Our review can inform clinicians and parents about the NDO of preterm infants with a diagnosis of PWML.
Prospective neuroimaging case–control cohort studies are recommended.
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Fynch-Edmondson, M., Morgan, C., Hunt, R. W. & Novak, I. Emergent prophylactic, reparative and restorative brain interventions for infants born preterm with cerebral palsy. Front. Physiol. 10, 15 (2019).
Liu, Y. et al. White matter abnormalities are related to microstructural changes in preterm neonates at term-equivalent age: a diffusion tensor imaging and probabilistic tractography study. Am. J. Neuroradiol. 33, 839–845 (2012).
Pavlova, M. A. & Krageloh-Mann, I. Limitations on the developing preterm brain: impact of periventricular white matter lesions on brain connectivity and cognition. Brain 136, 998–1011 (2013).
El Ters, N. M., Vesoulis, Z. A., Liao, S. M., Smyser, C. D. & Mathur, A. M. Term-equivalent functional brain maturational measures predict neurodevelopmental outcomes in premature infants. Early Hum. Dev. 119, 68–72 (2018).
Fawke, J. Neurological outcomes following preterm birth. Semin. Fetal Neonatal Med. 12, 374–382 (2007).
Pierrat, V. et al. Neurodevelopmental outcome at 2 years for preterm children born at 22 to 34 weeks’ gestation in France in 2011: EPIPAGE-2 cohort study. BMJ 358, j3448 (2017).
Jeon, T. Y. et al. Neurodevelopmental outcomes in preterm infants: comparison of infants with and without diffuse excessive high signal intensity on MR images at near-term-equivalent age. Radiology 263, 518–526 (2012).
Kidokoro, H. et al. Brain injury and altered brain growth in preterm infants: predictors and prognosis. Pediatrics 134, e444–e453 (2014).
Hintz, S. R. et al. Preterm neuroimaging and school-age cognitive outcomes. Pediatrics 142, e20174058 (2018).
Estep, M. E. et al. Diffusion tractography and neuromotor outcome in very preterm children with white matter abnormalities. Pediatr. Res. 76, 86–92 (2014).
Iwata, S. et al. Qualitative brain MRI at term and cognitive outcomes at 9 years after very preterm birth. Pediatrics 129, e1138–e1147 (2012).
Miller, S. P. et al. Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neurodevelopmental outcome. J. Pediatr. 147, 609–616 (2015).
Back, S. A. & Miller, S. P. Brain injury in premature neonates: a primary cerebral dysmaturation disorder? Ann. Neurol. 75, 469–486 (2014).
De Vries, L. S., Benders, M. J. & Groenendaal, F. Progress in neonatal neurology with a focus on neuroimaging in the preterm infant. Neuropediatrics 46, 234–241 (2015).
Rutherford, M. A. et al. Magnetic resonance imaging of white matter diseases of prematurity. Neuroradiology 52, 505–521 (2010).
Leijser, L. M. et al. Brain imaging findings in very preterm infants throughout the neonatal period: part I. Incidences and evolution of lesions, comparison between ultrasound and MRI. Early Hum. Dev. 85, 101–119 (2009).
Leijser, L. M. et al. Comparing brain white matter on sequential cranial ultrasound and MRI in very preterm infants. Neuroradiology 50, 799–811 (2008).
Hart, A. R., Whitby, E. W., Griffiths, P. D. & Michael, F. S. Magnetic resonance imaging and developmental outcome following preterm birth: review of current evidence. Dev. Med. Child Neurol. 50, 655–663 (2008).
Inder, T. E. et al. Neuroimaging of the preterm brain: review and recommendations. J. Peadiatr. 237, 276–287 (2021).
Kersbergen, K. J. et al. Different patterns of punctate white matter lesions in serially scanned preterm infants. PLoS One 9, e108904 (2014).
Pavaine, J. et al. Diffusion tensor imaging-based assessment of white matter tracts and visual-motor outcomes in very preterm neonates. Neuroradiology 58, 301–310 (2016).
Guo, T. et al. Quantitative assessment of white matter injury in preterm neonates. Neurology 88, 614–622 (2017).
Cornette, L. G. et al. Magnetic resonance imaging of the infant brain: anatomical characteristics and clinical significance of punctate lesions. Arch. Dis. Child. Fetal Neonatal Ed. 86, 171–177 (2002).
Benders, M. J., Kersbergen, K. J. & De Vries, L. S. Neuroimaging of white matter injury, intraventricular and cerebellar hemorrhage. Clin. Perinatol. 41, 69–82 (2014).
Wagenaar, N. et al. Clinical risk factors for punctate white matter lesions on early magnetic resonance imaging in preterm newborns. J. Pediatr. 182, 34–40 (2017).
Ramenghi, L. A. et al. Magnetic resonance imaging assessment of brain maturation in preterm neonates with punctate white matter lesions. Neuroradiology 49, 161–167 (2007).
Nanba, Y. et al. Magnetic resonance imaging regional T1 abnormalities at term accurately predict motor outcome in preterm infants. Pediatrics 120, e10–e19 (2007).
Van Wezel-Meijler, G. et al. Predictive value of neonatal MRI as compared to ultrasound in premature infants with mild periventricular white matter changes. Neuropediatrics 30, 231–238 (1999).
Volpe, J. J. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol. 8, 110–124 (2009).
Parodi, A. et al. Punctate white matter lesions of preterm infants: risk factor analysis. Eur. J. Paediatr. Neurol. 23, 733–739 (2019).
Malova, M. et al. Nosological differences in the nature of punctate white matter lesions in preterm infants. Front. Neurol. 12, 657461 (2021).
Hughes, A. J., Redsell, S. A. & Glazebrook, C. Motor development interventions for preterm infants: a systematic review and meta-analysis. Pediatrics 138, e20160147 (2016).
Moher, D., Liberati, A., Tetzlaff, J. & Altman, D. G. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. Int. J. Surg. 118, 536–548 (2006).
Papile, L. A., Burstein, J., Burstein, R. & Koffler, H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weight less than 1,500 gm. J. Pediatr. 92, 529–534 (1978).
Ouzzani, M., Hammady, H., Fedorowicz, Z. & Elmagarmid, A. Rayyan—a web and mobile app for systematic reviews. Syst. Rev. 5, 210 (2016).
Higgins, J. P. T., Churchill, R., Chandler, J. & Cumpston, M. S. Assessing risk of bias in included studies. In Cochrane Handbook for Systematic Reviews of Interventions: Version 5.2.0 (eds Higgins, J. P. T. & Green, S.) (Cochrane, 2017).
Hayden, J. A., Côté, P. & Bombardier, C. Evaluation of the quality of prognosis studies in systematic reviews. Ann. Intern. Med. 144, 427–437 (2006).
Chau, V. et al. Abnormal brain maturation in preterm neonates associated with adverse developmental outcomes. Neurology 81, 2082–2089 (2013).
De Bruine, F. T. et al. Clinical implications of MR imaging findings in the white matter in very preterm infants: a 2-year follow-up study. Radiology 261, 899–906 (2011).
Martinez-Biarge, M. et al. Neurodevelopmental outcomes in preterm infants with white matter injury using a new MRI classification. Neonatology 116, 227–235 (2019).
Tusor, N. et al. Punctate white matter lesions associated with altered brain development and adverse motor outcome in preterm infants. Sci. Rep. 7, 13250 (2017).
Arberet, C. et al. Isolated neonatal MRI punctate white matter lesions in very preterm neonates and quality of life at school age. J. Neonatal Perinat. Med. 10, 257–266 (2017).
Palisano, R. J. et al. Validation of a model of gross motor function for children with cerebral palsy. Phys. Ther. 80, 974–985 (2000).
Bayley, N. Bayley Scales of Infant and Toddler Development – Third Edition. J. Psychoeduc. Assess. 25, 180–198 (2007).
Achenbach, T. M. & Ruffle, T. M. The Child Behavior Checklist and related forms for assessing behavioral/emotional problems and competencies. Pediatr. Rev. 21, 265–271 (2000).
Saigal, S. et al. Development, reliability and validity of a new measure of overall health for pre-school children. Qual. Life Res. 14, 243–257 (2005).
Young, J. M. et al. Associations of perinatal clinical and magnetic resonance imaging measures with developmental outcomes in children born very preterm. J. Pediatr. 170, 90–96 (2016).
Sie, L. T. et al. Predictive value of neonatal MRI with respect to late MRI findings and clinical outcome. A study in infants with periventricular densities on neonatal ultrasound. Neuropediatrics 36, 78–89 (2005).
De Bruïne, F. T. et al. Prognostic value of gradient echo T2* sequences for brain MR imaging in preterm infants. Pediatr. Radiol. 44, 305–312 (2014).
Dyet, L. E. et al. Natural history of brain lesions in extremely preterm infants studied with serial magnetic resonance imaging from birth and neurodevelopmental assessment. Pediatrics 118, 536–548 (2006).
Martinez-Biarge, M. et al. MRI based preterm white matter injury classification: the importance of sequential imaging in determining severity of injury. PLoS One 11, e0156245 (2016).
Kersbergen, K. J. et al. Microstructural brain development between 30 and 40 weeks corrected age in a longitudinal cohort of extremely preterm infants. Neuroimage 103, 214–224 (2014).
Hack, M. et al. 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 (2005).
Woodward, L. J., Anderson, P. J., Austin, N. C., Howard, K. & Inder, T. E. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N. Engl. J. Med. 355, 685–694 (2006).
Vesoulis, Z. A., El Ters, N. M., Herco, M., Whitehead, H. V. & Mathur, A. M. A web-based calculator for the prediction of severe neurodevelopmental impairment in preterm infants using clinical and imaging characteristics. Children (Basel) 5, 151 (2018).
Woodward, L. J., Clark, C. A. C., Bora, S. & Inder, T. E. Neonatal white matter abnormalities an important predictor of neurocognitive outcome for very preterm children. PLoS One 7, e51879 (2012).
Spittle, A. J. et al. Neonatal white matter abnormality predicts childhood motor impairment in very preterm children. Dev. Med. Child Neurol. 53, 1000–1006 (2011).
Niwa, T. et al. Punctate white matter lesions in infants: new insight using susceptibility-weighted imaging. Neuroradiology 53, 669–679 (2011).
The authors would like to thank “Eu-Brain” non-profit association for the technical support in the editing of the article.
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de Bruijn, C.A.M., Di Michele, S., Tataranno, M.L. et al. Neurodevelopmental consequences of preterm punctate white matter lesions: a systematic review. Pediatr Res 93, 1480–1490 (2023). https://doi.org/10.1038/s41390-022-02232-3