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

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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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References

  1. Buhrer C, Metze B, Obladen MCRIB. CRIB-II, birth weight or gestational age to assess mortality risk in very low birth weight infants? Acta Paediatr. 2008;97:899–903.

    Article  Google Scholar 

  2. Ezz-Eldin ZM, Hamid TA, Youssef MR, Nabil Hel D. Clinical Risk Index for Babies (CRIB II) scoring system in prediction of mortality in premature babies. J Clin Diagn Res. 2015;9:SC08–11.

    PubMed  PubMed Central  Google Scholar 

  3. Gagliardi L, Cavazza A, Brunelli A, Battaglioli M, Merazzi D, Tandoi F, et al. Assessing mortality risk in very low birthweight infants: a comparison of CRIB, CRIB-II, and SNAPPE-II. Arch Dis Child Fetal Neonatal Ed. 2004;89:F419–22.

    Article  CAS  Google Scholar 

  4. Horsch S, Hallberg B, Leifsdottir K, Skiold B, Nagy Z, Mosskin M, et al. Brain abnormalities in extremely low gestational age infants: a Swedish population based MRI study. Acta Paediatr. 2007;96:979–84.

    Article  Google Scholar 

  5. Kaukola T, Kapellou O, Laroche S, Counsell SJ, Dyet LE, Allsop JM, et al. Severity of perinatal illness and cerebral cortical growth in preterm infants. Acta Paediatr. 2009;98:990–5.

    Article  Google Scholar 

  6. Lodha A, Sauve R, Chen S, Tang S, Christianson H. Clinical Risk Index for Babies score for the prediction of neurodevelopmental outcomes at 3 years of age in infants of very low birthweight. Dev Med Child Neurol. 2009;51:895–900.

    Article  Google Scholar 

  7. Hintz SR, Barnes PD, Bulas D, Slovis TL, Finer NN, Wrage LA, et al. Neuroimaging and neurodevelopmental outcome in extremely preterm infants. Pediatrics. 2015;135:e32–42.

    Article  Google Scholar 

  8. He L, Parikh NA. 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:e85475.

    Article  Google Scholar 

  9. Kline JE, Illapani VSP, He L, Altaye M, Logan JW, Parikh NA. Early cortical maturation predicts neurodevelopment in very preterm infants. Arch Dis Child Fetal Neonatal Ed. 2019;105:460–5.

    Article  Google Scholar 

  10. Inder TE, Anderson NJ, Spencer C, Wells S, Volpe JJ. White matter injury in the premature infant: a comparison between serial cranial sonographic and MR findings at term. Am J Neuroradiol. 2003;24:805–9.

    PubMed  Google Scholar 

  11. Laptook AR, O’Shea TM, Shankaran S, Bhaskar B, Network NN. Adverse neurodevelopmental outcomes among extremely low birth weight infants with a normal head ultrasound: prevalence and antecedents. Pediatrics. 2005;115:673–80.

    Article  Google Scholar 

  12. Parikh NA. Advanced neuroimaging and its role in predicting neurodevelopmental outcomes in very preterm infants. Semin Perinatol. 2016;40:530–41.

    Article  Google Scholar 

  13. VanderWeele TJ. Mediation analysis: a practitioner’s guide. Annu Rev Public Health. 2016;37:17–32.

    Article  Google Scholar 

  14. Tyson JE, Parikh NA, Langer J, Green C, Higgins RD, National Institute of Child H. et al. Intensive care for extreme prematurity-moving beyond gestational age. N Engl J Med. 2008;358:1672–81.

    Article  CAS  Google Scholar 

  15. Donovan EF, Tyson JE, Ehrenkranz RA, Verter J, Wright LL, Korones SB, et al. Inaccuracy of Ballard scores before 28 weeks’ gestation. National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr. 1999;135:147–52.

    Article  CAS  Google Scholar 

  16. Kidokoro H, Neil JJ, Inder TE. New MR imaging assessment tool to define brain abnormalities in very preterm infants at term. Am J Neuroradiol. 2013;34:2208–14.

    Article  CAS  Google Scholar 

  17. Makropoulos A, Robinson EC, Schuh A, Wright R, Fitzgibbon S, Bozek J, et al. The developing human connectome project: a minimal processing pipeline for neonatal cortical surface reconstruction. Neuroimage. 2018;173:88–112.

    Article  Google Scholar 

  18. Gousias IS, Rueckert D, Heckemann RA, Dyet LE, Boardman JP, Edwards AD, et al. Automatic segmentation of brain MRIs of 2-year-olds into 83 regions of interest. Neuroimage. 2008;40:672–84.

    Article  Google Scholar 

  19. Bayley N. Nayley scales of infant and toddler development—third edition. San Antonio, TX: Harcourt; 2006.

  20. Maitre NL, Burton VJ, Duncan AF, Iyer S, Ostrander B, Winter S, et al. Network implementation of guideline for early detection decreases age at cerebral palsy diagnosis. Pediatrics. 2020;145:e20192126.

    Article  Google Scholar 

  21. Novak I, Morgan C, Adde L, Blackman J, Boyd RN, Brunstrom-Hernandez J, et al. Early, accurate diagnosis and early intervention in cerebral palsy: advances in diagnosis and treatment. JAMA Pediatr. 2017;171:897–907.

    Article  Google Scholar 

  22. Parikh NA. Are structural magnetic resonance imaging and general movements assessment sufficient for early, accurate diagnosis of cerebral palsy? JAMA Pediatr. 2018;172:198–9.

    Article  Google Scholar 

  23. Greenwood S, Abdel-Latif ME, Bajuk B, Lui K. Can the early condition at admission of a high-risk infant aid in the prediction of mortality and poor neurodevelopmental outcome? A population study in Australia. J Paediatr Child Health. 2012;48:588–95.

    Article  Google Scholar 

  24. Brouwer MJ, Kersbergen KJ, van Kooij BJM, Benders M, van Haastert IC, Koopman-Esseboom C, et al. Preterm brain injury on term-equivalent age MRI in relation to perinatal factors and neurodevelopmental outcome at two years. PLoS ONE. 2017;12:e0177128.

    Article  Google Scholar 

  25. George JM, Fiori S, Fripp J, Pannek K, Bursle J, Moldrich RX, et al. Validation of an MRI brain injury and growth scoring system in very preterm infants scanned at 29- to 35-week postmenstrual age. Am J Neuroradiol. 2017;38:1435–42.

    Article  CAS  Google Scholar 

  26. Synnes A, Luu TM, Moddemann D, Church P, Lee D, Vincer M, et al. Determinants of developmental outcomes in a very preterm Canadian cohort. Arch Dis Child Fetal Neonatal Ed. 2017;102:F235–F4.

    Article  Google Scholar 

  27. Dammann O, Naples M, Bednarek F, Shah B, Kuban KC, O’Shea TM, et al. SNAP-II and SNAPPE-II and the risk of structural and functional brain disorders in extremely low gestational age newborns: the ELGAN study. Neonatology. 2010;97:71–82.

    Article  Google Scholar 

  28. Ford RM, Neulinger K, O’Callaghan M, Mohay H, Gray P, Shum D. Executive function in 7-9-year-old children born extremely preterm or with extremely low birth weight: effects of biomedical history, age at assessment, and socioeconomic status. Arch Clin Neuropsychol. 2011;26:632–44.

    Article  Google Scholar 

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Acknowledgements

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

Funding

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

Contributions

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.

Corresponding author

Correspondence to J. W. Logan.

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The authors declare that they have no conflict of interest.

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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). https://doi.org/10.1038/s41372-020-00854-1

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