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Adverse effects of perinatal illness severity on neurodevelopment are partially mediated by early brain abnormalities in infants born very preterm



We sought to determine the mediating effects of magnetic resonance imaging (MRI) biomarkers at term gestation on the relationship between perinatal illness severity and neurodevelopment.


The Clinical Risk Index for Babies—second edition (CRIB-II) was correlated with indices of brain maturation or injury and neurodevelopment at 2-year follow-up in infants born less than 32 weeks gestation. Using a counterfactual mediation analysis, associations between CRIB-II, MRI biomarkers, and neurodevelopment were confirmed, followed by an assessment of the mediating effects of MRI biomarkers on the relationship between CRIB-II and neurodevelopment.


CRIB-II correlated significantly with neurodevelopment and MRI biomarkers of brain injury or cortical maturation. Two MRI biomarkers, cortical surface area and global injury score, were associated with neurodevelopmental scores at follow-up and included in mediation analyses.


Biomarkers of cortical maturation or brain injury at term-equivalent age mediated a substantial portion of the risks conveyed by perinatal illness severity on neurodevelopmental outcomes at 2 years corrected age.

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Fig. 1: Mediation analysis.


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The authors would like to express our gratitude to the families who participated in the study and the clinical and administrative staff in the High-risk Follow-up Clinic at Nationwide Children’s Hospital


This study was supported, in part, by the National Institute of Neurological Disorders and Stroke, United States (NIH Grants R01-NS094200 and R01-096037).

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Authors and Affiliations



JWL wrote the manuscript. JWL and NAP conceived and designed the study, performed intermediate analyses, and reviewed statistical findings. MK reviewed statistical methods, participated in intermediate analyses, and reviewed the manuscript. JT performed statistical analyses. NAP, JK and LH participated in MRI analytics that resulted in formation of the dataset. MS conducted analyses related to the global injury score, including validation metrics. JWL, NAP, MK, OF, JK, MS, and LH reviewed the manuscript and approved the final draft.

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Correspondence to J. W. Logan.

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Logan, J.W., Tan, J., Skalak, M. et al. Adverse effects of perinatal illness severity on neurodevelopment are partially mediated by early brain abnormalities in infants born very preterm. J Perinatol 41, 519–527 (2021).

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