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  • Clinical Research Article
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Impact of fetal inflammatory response on brain MRI abnormalities in extremely preterm infants

Pediatric Research (2025)Cite this article

Abstract

Background and objective

Neonates with fetal inflammatory response (FIR) are at increased risk of early-onset sepsis and death. We aimed to determine whether FIR and its severity are associated with brain abnormalities on MRI at term-equivalent age in extremely preterm infants.

Methods

A prospective cohort study of extremely preterm infants born between 2018 to 2021 with MRI scans completed at term equivalent age. Brain injury was assessed using the Kidokoro scoring, with MRIs independently scored by two blinded readers and adjudicated by a third. FIR severity was classified per the Amsterdam Placental Workshop Group Consensus Statement.

Results

Among 141 infants, FIR was present in 59 (42%), with 46 (78%) having severe FIR ( ≥ stage 2). FIR was significantly associated with abnormal Kidokoro scores (P < 0.01), specifically white matter (P < 0.01) and cerebellar abnormalities (P = 0.01), but not cortical or deep gray matter abnormalities. Increasing FIR severity correlated with worse Kidokoro scores in both white and gray matter (P < 0.01). Other placental lesions showed no significant association. Inter-rater reliability was high (intraclass correlation coefficient >0.7).

Conclusion

This study is the first to link FIR severity to MRI brain abnormalities in extremely preterm infants, highlighting FIR as a risk factor for brain injury and delayed maturation.

Impact

  • Fetal Inflammatory Response (FIR) is associated with white matter and cerebellar injury by term-equivalent gestational age (TEA).

  • There is significant relationship between severity and progression of FIR and brain abnormalities by TEA.

  • This is the first study demonstrating the impact of progression and severity of FIR on abnormalities on MRI brain at term-equivalent gestational age.

  • These observations provide additional insight into understanding the impact of intrauterine exposure to inflammation on the brain injury in extremely preterm infants.

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Fig. 1: Representative brain MR images of regional injury.

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Data availability

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

References

  1. Purisch, S. E. & Gyamfi-Bannerman, C. Epidemiology of preterm birth. Semin Perinatol. 41, 387–391 (2017).

    Article  PubMed  Google Scholar 

  2. Morgan, A. S., Mendonca, M., Thiele, N. & David, A. L. Management and outcomes of extreme preterm birth. BMJ 376, e055924 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hillier, S. L., Krohn, M. A., Kiviat, N. B., Watts, D. H. & Eschenbach, D. A. Microbiologic causes and neonatal outcomes associated with chorioamnion infection. Am. J. Obstet. Gynecol. 165, 955–961 (1991).

    Article  CAS  PubMed  Google Scholar 

  4. Stinson, L. F. & Payne, M. S. Infection-mediated preterm birth: Bacterial origins and avenues for intervention. Aust. N. Z. J. Obstet. Gynaecol. 59, 781–790 (2019).

    Article  PubMed  Google Scholar 

  5. Klein, L. L. & Gibbs, R. S. Infection and preterm birth. Obstet. Gynecol. Clin. North Am. 32, 397–410 (2005).

    Article  PubMed  Google Scholar 

  6. Romero, R. et al. A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am. J. Obstet. Gynecol. 179, 186–193 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Jung, E. et al. The fetal inflammatory response syndrome: the origins of a concept, pathophysiology, diagnosis, and obstetrical implications. Semin Fetal Neonatal Med. 25, 101146 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Salas, A. A. et al. Histological characteristics of the fetal inflammatory response associated with neurodevelopmental impairment and death in extremely preterm infants. J. Pediatr. 163, 652–657.e651-652 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  9. Patra, A., Huang, H., Bauer, J. A. & Giannone, P. J. Neurological consequences of systemic inflammation in the premature neonate. Neural Regen. Res. 12, 890–896 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Malaeb, S. & Dammann, O. Fetal inflammatory response and brain injury in the preterm newborn. J. Child Neurol. 24, 1119–1126 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Parikh, N. A. Advanced neuroimaging and its role in predicting neurodevelopmental outcomes in very preterm infants. Semin Perinatol. 40, 530–541 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hintz, S. R. et al. Neuroimaging and neurodevelopmental outcome in extremely preterm infants. Pediatrics 135, e32–e42 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  13. He, 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 8, e85475 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kline, J. E. et al. Early cortical maturation predicts neurodevelopment in very preterm infants. Arch. Dis. Child Fetal Neonatal Ed. 105, 460–465 (2020).

    Article  PubMed  Google Scholar 

  15. Van’t Hooft, J. et al. Predicting developmental outcomes in premature infants by term equivalent MRI: systematic review and meta-analysis. Syst. Rev. 4, 71 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  16. 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).

    Article  CAS  PubMed  Google Scholar 

  17. Bhutta, A. T., Cleves, M. A., Casey, P. H., Cradock, M. M. & Anand, K. J. Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis. JAMA 288, 728–737 (2002).

    Article  PubMed  Google Scholar 

  18. Anderson, P. J., Cheong, J. L. & Thompson, D. K. The predictive validity of neonatal MRI for neurodevelopmental outcome in very preterm children. Semin Perinatol. 39, 147–158 (2015).

    Article  PubMed  Google Scholar 

  19. Chau, V. et al. Abnormal brain maturation in preterm neonates associated with adverse developmental outcomes. Neurology 81, 2082–2089 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  20. He, L. et al. Early prediction of cognitive deficits in very preterm infants using functional connectome data in an artificial neural network framework. Neuroimage Clin. 18, 290–297 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kidokoro, H., Neil, J. J. & Inder, T. E. New MR imaging assessment tool to define brain abnormalities in very preterm infants at term. AJNR Am. J. Neuroradiol. 34, 2208–2214 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Anderson, P. J. et al. Associations of Newborn Brain Magnetic Resonance Imaging with Long-Term Neurodevelopmental Impairments in Very Preterm Children. J. Pediatr. 187, 58–65.e51 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Thompson, D. K. et al. Tracking regional brain growth up to age 13 in children born term and very preterm. Nat. Commun. 11, 696 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Logan, J. W. 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).

    Article  CAS  PubMed  Google Scholar 

  25. Jain, V. G. 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. 227, 623.e621–623.e613 (2022).

    Article  Google Scholar 

  26. Khong, T. Y. et al. Sampling and Definitions of Placental Lesions: Amsterdam Placental Workshop Group Consensus Statement. Arch. Pathol. Lab Med 140, 698–713 (2016).

    Article  PubMed  Google Scholar 

  27. Ibrahim, J., Mir, I. & Chalak, L. Brain imaging in preterm infants <32 weeks gestation: a clinical review and algorithm for the use of cranial ultrasound and qualitative brain MRI. Pediatr. Res 84, 799–806 (2018).

    Article  CAS  PubMed  Google Scholar 

  28. Greer, L. G. et al. An immunologic basis for placental insufficiency in fetal growth restriction. Am. J. Perinatol. 29, 533–538 (2012).

    PubMed  Google Scholar 

  29. Mir, I. N. et al. Placental pathology is associated with severity of neonatal encephalopathy and adverse developmental outcomes following hypothermia. Am. J. Obstet. Gynecol. 213, 849.e841–847 (2015).

    Article  Google Scholar 

  30. Redline, R. W., Heller, D., Keating, S. & Kingdom, J. Placental diagnostic criteria and clinical correlation-a workshop report. Placenta 26, S114–S117 (2005).

    Article  PubMed  Google Scholar 

  31. Alayli, Y. et al. Neurodevelopmental outcomes in extremely preterm infants with placental pathologic evidence of fetal inflammatroy response. Pediatr Res https://doi.org/10.1038/s41390-024-03391-1 (2024).

  32. Para, R. et al. The Distinct Immune Nature of the Fetal Inflammatory Response Syndrome Type I and Type II. Immunohorizons 5, 735–751 (2021).

    Article  CAS  PubMed  Google Scholar 

  33. Lee, J. et al. Characterization of the fetal blood transcriptome and proteome in maternal anti-fetal rejection: evidence of a distinct and novel type of human fetal systemic inflammatory response. Am. J. Reprod. Immunol. 70, 265–284 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Olsen, I. E., Groveman, S. A., Lawson, M. L., Clark, R. H. & Zemel, B. S. New intrauterine growth curves based on United States data. Pediatrics 125, e214–e224 (2010).

    Article  PubMed  Google Scholar 

  35. Olsen, I. E. et al. BMI curves for preterm infants. Pediatrics 135, e572–e581 (2015).

    Article  PubMed  Google Scholar 

  36. Rezaie, P. & Dean, A. Periventricular leukomalacia, inflammation and white matter lesions within the developing nervous system. Neuropathology 22, 106–132 (2002).

    Article  PubMed  Google Scholar 

  37. Murphy, D. J., Sellers, S., MacKenzie, I. Z., Yudkin, P. L. & Johnson, A. M. Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 346, 1449–1454 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Yoon, B. H. et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy. Am. J. Obstet. Gynecol. 177, 19–26 (1997).

    Article  CAS  PubMed  Google Scholar 

  39. Grether, J. K. & Nelson, K. B. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 278, 207–211 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Wu, Y. W. et al. Chorioamnionitis and cerebral palsy in term and near-term infants. JAMA 290, 2677–2684 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Polam, S., Koons, A., Anwar, M., Shen-Schwarz, S. & Hegyi, T. Effect of chorioamnionitis on neurodevelopmental outcome in preterm infants. Arch. Pediatr. Adolesc. Med. 159, 1032–1035 (2005).

    Article  PubMed  Google Scholar 

  42. Soraisham, A. S., Trevenen, C., Wood, S., Singhal, N. & Sauve, R. Histological chorioamnionitis and neurodevelopmental outcome in preterm infants. J. Perinatol. 33, 70–75 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Shi, Z. et al. Chorioamnionitis in the Development of Cerebral Palsy: A Meta-analysis and Systematic Review. Pediatrics 139 https://doi.org/10.1542/peds.2016-3781 (2017).

  44. Elimian, A. et al. Histologic chorioamnionitis, antenatal steroids, and perinatal outcomes. Obstet. Gynecol. 96, 333–336 (2000).

    CAS  PubMed  Google Scholar 

  45. Been, J. V., Degraeuwe, P. L., Kramer, B. W. & Zimmermann, L. J. Antenatal steroids and neonatal outcome after chorioamnionitis: a meta-analysis. BJOG 118, 113–122 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Xing, L. et al. Is chorioamnionitis associated with neurodevelopmental outcomes in preterm infants? A systematic review and meta-analysis following PRISMA. Med. (Baltim.) 98, e18229 (2019).

    Article  Google Scholar 

  47. Maisonneuve, E., Ancel, P. Y., Foix-L’Helias, L., Marret, S. & Kayem, G. Impact of clinical and/or histological chorioamnionitis on neurodevelopmental outcomes in preterm infants: A literature review. J. Gynecol. Obstet. Hum. Reprod. 46, 307–316 (2017).

    Article  CAS  PubMed  Google Scholar 

  48. Nosaka, R. et al. Intrauterine exposure to chorioamnionitis and neuroanatomical alterations at term-equivalent age in preterm infants. Arch. Gynecol. Obstet. 309, 1909–1918 (2024).

    Article  PubMed  Google Scholar 

  49. Kim, C. J. et al. Umbilical arteritis and phlebitis mark different stages of the fetal inflammatory response. Am. J. Obstet. Gynecol. 185, 496–500 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Hecht, J. L. et al. Relationship Between Neonatal Blood Protein Concentrations and Placenta Histologic Characteristics in Extremely Low GA Newborns. Pediatr. Res. 69, 68–73 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Oh, J. W., Park, C. W., Moon, K. C., Park, J. S. & Jun, J. K. Fetal inflammatory response is positively correlated with the progress of inflammation in chorionic plate. Placenta 97, 6–17 (2020).

    Article  CAS  PubMed  Google Scholar 

  52. Tang, Q., Zhang, L., Li, H. & Shao, Y. The fetal inflammation response syndrome and adverse neonatal outcomes: a meta-analysis. J. Matern Fetal Neonatal Med 34, 3902–3914 (2021).

    Article  PubMed  Google Scholar 

  53. Burd, I., Balakrishnan, B. & Kannan, S. Models of fetal brain injury, intrauterine inflammation, and preterm birth. Am. J. Reprod. Immunol. 67, 287–294 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Kuypers, E. et al. White matter injury following fetal inflammatory response syndrome induced by chorioamnionitis and fetal sepsis: lessons from experimental ovine models. Early Hum. Dev. 88, 931–936 (2012).

    Article  PubMed  Google Scholar 

  55. Yap, V. & Perlman, J. M. Mechanisms of brain injury in newborn infants associated with the fetal inflammatory response syndrome. Semin Fetal Neonatal Med. 25, 101110 (2020).

    Article  PubMed  Google Scholar 

  56. Oh, K. J. et al. The combined exposure to intra-amniotic inflammation and neonatal respiratory distress syndrome increases the risk of intraventricular hemorrhage in preterm neonates. J. Perinat. Med. 46, 9–20 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yanni, D. et al. Both antenatal and postnatal inflammation contribute information about the risk of brain damage in extremely preterm newborns. Pediatr. Res. 82, 691–696 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  58. van Tilborg, E. et al. Combined fetal inflammation and postnatal hypoxia causes myelin deficits and autism-like behavior in a rat model of diffuse white matter injury. Glia 66, 78–93 (2018).

    Article  PubMed  Google Scholar 

  59. Marin-Padilla, M. Developmental neuropathology and impact of perinatal brain damage. II: white matter lesions of the neocortex. J. Neuropathol. Exp. Neurol. 56, 219–235 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. Van Essen, D. C. A tension-based theory of morphogenesis and compact wiring in the central nervous system. Nature 385, 313–318 (1997).

    Article  PubMed  Google Scholar 

  61. Duan, J. et al. Histological chorioamnionitis and pathological stages on very preterm infant outcomes. Histopathology 84, 1024–1037 (2024).

    Article  PubMed  Google Scholar 

  62. Han, V. X., Patel, S., Jones, H. F. & Dale, R. C. Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. Nat. Rev. Neurol. 17, 564–579 (2021).

    Article  PubMed  Google Scholar 

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Acknowledgements

We wish to thank several people who participated in data collection: Patti J Burchfield, RN, and Pollieanna M Sepulveda, RN. This work was supported by Children’s Clinical Research Advisory Council (CCRAC) grant awarded to Dr. Imran N. Mir.

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Authors and Affiliations

  1. Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Imran N. Mir, Rachel Leon & Lina Chalak

  2. Department of Pediatric Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Michelle Machie

  3. Division of Pediatric Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Rebekah Clarke

  4. Parkland Health and Hospital System, Dallas, TX, USA

    L. Steven Brown

  5. Department of Radiology and Imaging, Keck School of Medicine of USC, Los Angeles, CA, USA

    Jessica L. Wisnowski

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  1. Imran N. Mir
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  2. Michelle Machie
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  3. Rebekah Clarke
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  4. L. Steven Brown
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  5. Rachel Leon
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  6. Jessica L. Wisnowski
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  7. Lina Chalak
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Contributions

Imran N. Mir wrote the first version of the manuscript. Steven Brown performed statistical analyses. All authors participated in the study design, data collection, data interpretation, and revision and approval of the final version of the manuscript.

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Correspondence to Imran N. Mir.

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The authors declare no competing interests.

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The Institutional Review Board of University of Texas Southwestern Medical Center and Parkland Health approved the study and waived the need for individual consent.

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Mir, I.N., Machie, M., Clarke, R. et al. Impact of fetal inflammatory response on brain MRI abnormalities in extremely preterm infants. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04230-7

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