Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Early surgery in very preterm infants is associated with brain abnormalities on term MRI: a propensity score analysis

Journal of Perinatology volume 43, pages 877–883 (2023)Cite this article

Subjects

Abstract

Objective

To investigate the association between exposure to surgery under general anesthesia and brain abnormalities and neurodevelopmental outcomes in very preterm infants.

Study design

This prospective observational study includes 392 infants born at or below 32 weeks' gestational age. Participants completed brain MRI at term-equivalent age and Bayley-III assessment at 2 years corrected age. We evaluated the independent effects of surgery on brain MRI abnormalities and neurodevelopmental outcomes after propensity score matching.

Results

All infants completed brain MRI, and 341 (87%) completed neurodevelopmental testing. Forty-five received surgery. Surgery was associated with worse MRI abnormalities (p < 0.0001) but with none of the developmental outcomes after propensity score matching. The global brain abnormality score was associated with the Bayley Cognitive (p = 0.005) and Motor (p = 0.028) composite scores.

Conclusions

Very preterm infants exposed to surgery under general anesthesia were at higher risk of brain abnormalities on MRI at term.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Pierrat V, Marchand-Martin L, Marret S, Arnaud C, Benhammou V, Cambonie G, et al. Neurodevelopmental outcomes at age 5 among children born preterm: EPIPAGE-2 cohort study. BMJ. 2021;373:n741.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Pascal A, Govaert P, Oostra A, Naulaers G, Ortibus E, Van den Broeck C. Neurodevelopmental outcome in very preterm and very-low-birthweight infants born over the past decade: a meta-analytic review. Dev Med Child Neurol. 2018;60:342–55.

    Article  PubMed  Google Scholar 

  3. Spittle A, Orton J, Anderson PJ, Boyd R, Doyle LW. Early developmental intervention programmes provided post hospital discharge to prevent motor and cognitive impairment in preterm infants. Cochrane Database Syst Rev. 2015;2015:CD005495.

    PubMed  PubMed Central  Google Scholar 

  4. Linsell L, Malouf R, Morris J, Kurinczuk JJ, Marlow N. Risk factor models for neurodevelopmental outcomes in children born very preterm or with very low birth weight: a systematic review of methodology and reporting. Am J Epidemiol. 2017;185:601–12.

    Article  PubMed  Google Scholar 

  5. Back SA, Miller SP. Brain injury in premature neonates: a primary cerebral dysmaturation disorder? Ann Neurol. 2014;75:469–86.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Pironkova RP, Giamelli J, Seiden H, Parnell VA, Gruber D, Sison CP, et al. Brain injury with systemic inflammation in newborns with congenital heart disease undergoing heart surgery. Exp Ther Med. 2017;14:228–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Steinhorn R, McPherson C, Anderson PJ, Neil J, Doyle LW, Inder T. Neonatal morphine exposure in very preterm infants-cerebral development and outcomes. J Pediatr. 2015;166:1200–7.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Duerden EG, Guo T, Dodbiba L, Chakravarty MM, Chau V, Poskitt KJ, et al. Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants. Ann Neurol. 2016;79:548–59.

    Article  CAS  PubMed  Google Scholar 

  9. Duerden EG, Grunau RE, Guo T, Foong J, Pearson A, Au-Young S, et al. Early procedural pain is associated with regionally-specific alterations in thalamic development in preterm neonates. J Neurosci. 2018;38:878–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Matei A, Montalva L, Goodbaum A, Lauriti G, Zani A. Neurodevelopmental impairment in necrotising enterocolitis survivors: systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2020;105:432–9.

    Article  PubMed  Google Scholar 

  11. Ene D, Der G, Fletcher-Watson S, O'Carroll S, MacKenzie G, Higgins M, et al. Associations of socioeconomic deprivation and preterm birth with speech, language, and communication concerns among children aged 27 to 30 months. JAMA Netw Open. 2019;2:e1911027.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Van't Hooft J, van der Lee JH, Opmeer BC, Aarnoudse-Moens CS, Leenders AG, Mol BW, et al. Predicting developmental outcomes in premature infants by term equivalent MRI: systematic review and meta-analysis. Syst Rev. 2015;4:71.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Filan PM, Hunt RW, Anderson PJ, Doyle LW, Inder TE. Neurologic outcomes in very preterm infants undergoing surgery. J Pediatr. 2012;160:409–14.

    Article  PubMed  Google Scholar 

  14. Walsh BH, Paul RA, Inder TE, Shimony JS, Smyser CD, Rogers CE. Surgery requiring general anesthesia in preterm infants is associated with altered brain volumes at term equivalent age and neurodevelopmental impairment. Pediatr Res. 2021;89:1200–7.

    Article  CAS  PubMed  Google Scholar 

  15. Parikh NA, Sharma P, He L, Li H, Altaye M, Priyanka Illapani VS, et al. Perinatal risk and protective factors in the development of diffuse white matter abnormality on term-equivalent age magnetic resonance imaging in infants born very preterm. J Pediatr. 2021;233:58–65.e53.

    Article  PubMed  Google Scholar 

  16. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978;92:529–34.

    Article  CAS  PubMed  Google Scholar 

  17. Jensen EA, Dysart K, Gantz MG, McDonald S, Bamat NA, Keszler M, et al. The diagnosis of bronchopulmonary dysplasia in very preterm infants. An evidence-based approach. Am J Respir Crit Care Med. 2019;200:751–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Parry G, Tucker J, Tarnow-Mordi W, UK Neonatal Staffing Study Collaborative Group. CRIB II: an update of the clinical risk index for babies score. Lancet. 2003;361:1789–91.

    Article  PubMed  Google Scholar 

  19. Roberts G, Howard K, Spittle AJ, Brown NC, Anderson PJ, Doyle LW. Rates of early intervention services in very preterm children with developmental disabilities at age 2 years. J Paediatr Child Health. 2008;44:276–80.

    Article  PubMed  Google Scholar 

  20. 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  PubMed  Google Scholar 

  21. 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  PubMed  Google Scholar 

  22. 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  PubMed  Google Scholar 

  23. Tamm L, Patel M, Peugh J, Kline-Fath BM, Parikh NA. Cincinnati Infant Neurodevelopment Early Prediction Study G. Early brain abnormalities in infants born very preterm predict under-reactive temperament. Early Hum Dev. 2020;144:104985.

    Article  PubMed  PubMed Central  Google Scholar 

  24. 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  PubMed  PubMed Central  Google Scholar 

  25. 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  PubMed  Google Scholar 

  26. 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  PubMed  Google Scholar 

  27. Jain VG, Kline JE, He L, Kline-Fath BM, Altaye M, Muglia LJ, et al. Acute histologic chorioamnionitis independently and directly increases the risk for brain abnormalities seen on magnetic resonance imaging in very preterm infants. Am J Obstet Gynecol. 2022;227:623.e1–13.

  28. Bayley N. Bayley scales of infant and toddler development, third edition: Technical manual. San Antonio, TX: Harcourt Assessment, Inc.; 2006.

  29. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41–55.

    Article  Google Scholar 

  30. Hansen BB, Klopfer SO. Optimal full matching and related designs via network flows. J Comput Graph Stat. 2006;15:609–27.

    Article  Google Scholar 

  31. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009;28:3083–107.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ramaswamy VV, Bandyopadhyay T, Nanda D, Bandiya P, Ahmed J, Garg A, et al. Assessment of postnatal corticosteroids for the prevention of bronchopulmonary dysplasia in preterm neonates: a systematic review and network meta-analysis. JAMA Pediatr. 2021;175:e206826.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Moran MM, Gunn-Charlton JK, Walsh JM, Cheong JLY, Anderson PJ, Doyle LW, et al. Associations of neonatal noncardiac surgery with brain structure and neurodevelopment: a prospective case-control study. J Pediatr. 2019;212:93–101.e2.

    Article  PubMed  Google Scholar 

  34. Stolwijk LJ, Keunen K, de Vries LS, Groenendaal F, van der Zee DC, van Herwaarden MYA, et al. Neonatal surgery for noncardiac congenital anomalies: neonates at risk of brain injury. J Pediatr. 2017;182:335–341.e1.

    Article  PubMed  Google Scholar 

  35. Morriss FH Jr, Saha S, Bell EF, Colaizy TT, Stoll BJ, Hintz SR, et al. Surgery and neurodevelopmental outcome of very low-birth-weight infants. JAMA Pediatr. 2014;168:746–54.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Gano D, Andersen SK, Glass HC, Rogers EE, Glidden DV, Barkovich AJ, et al. Impaired cognitive performance in premature newborns with two or more surgeries prior to term-equivalent age. Pediatr Res. 2015;78:323–9.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Jansen L, van Steenis A, van den Berg-Huysmans AA, Wiggers-de Bruine ST, Rijken M, de Vries LS, et al. Associations between neonatal magnetic resonance imaging and short- and long-term neurodevelopmental outcomes in a longitudinal cohort of very preterm children. J Pediatr. 2021;234:46–53.e2.

    Article  PubMed  Google Scholar 

  38. 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  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We sincerely thank the parents of infants that participated in our study and the Cincinnati Infant Neurodevelopment Early Prediction Study (CINEPS) Investigators. We also greatly appreciate the support of our NICU fellows, nurses, and staff, and most importantly, all the study families that made this research possible.

Funding

Supported by the National Institutes of Health from the National Institute of Neurological Disorders and Stroke (R01-NS094200, R01-NS096037, and R01-EB029944) to NAP and from the National Center for Advancing Translational Sciences (2UL1TR001425-05A1) to KK.

Author information

Authors and Affiliations

  1. Neurodevelopmental Disorders Prevention Center, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA

    Katsuaki Kojima, Beth M. Kline-Fath, Shipra Jain & Nehal A. Parikh

  2. Department of Pediatrics, University of Cincinnati College of Medicine, 3230 Eden Avenue, Cincinnati, OH, 45267, USA

    Katsuaki Kojima, Shelley Ehrlich, Shipra Jain & Nehal A. Parikh

  3. Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA

    Chunyan Liu & Shelley Ehrlich

  4. Department of Radiology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA

    Beth M. Kline-Fath

Authors
  1. Katsuaki Kojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chunyan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shelley Ehrlich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Beth M. Kline-Fath
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shipra Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nehal A. Parikh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KK analyzed and interpreted data and cowrote the article. CL and SE analyzed and interpreted data and were involved in critical revisions. BMKF and SJ collected data and were involved in critical revisions. NAP designed the study, analyzed, and interpreted data, and cowrote the article.

Corresponding author

Correspondence to Nehal A. Parikh.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kojima, K., Liu, C., Ehrlich, S. et al. Early surgery in very preterm infants is associated with brain abnormalities on term MRI: a propensity score analysis. J Perinatol 43, 877–883 (2023). https://doi.org/10.1038/s41372-023-01645-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41372-023-01645-0

Search

Advanced search

Quick links