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  • Clinical Research Article
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Interaction of hydrocortisone and illness severity on head growth in cohort of ELBW infants

Pediatric Research volume 94, pages 1958–1965 (2023)Cite this article

Abstract

Background

Extremely low birth weight (ELBW) infants comprise a fragile population at risk for neurodevelopmental disabilities (NDD). Systemic steroids were previously associated with NDD, but more recent studies suggest hydrocortisone (HCT) may improve survival without increasing NDD. However, the effects of HCT on head growth adjusted for illness severity during NICU hospitalization are unknown. Thus, we hypothesize that HCT will protect head growth, accounting for illness severity using a modified neonatal Sequential Organ Failure Assessment (M-nSOFA) score.

Methods

We conducted a retrospective study that included infants born at 23–29 weeks gestational age (GA) and < 1000 g. Our study included 73 infants, 41% of whom received HCT.

Results

We found negative correlations between growth parameters and age, similar between HCT and control patients. HCT-exposed infants had lower GA but similar normalized birth weights; HCT-exposed infants also had higher illness severity and longer lengths of hospital stay. We found an interaction between HCT exposure and illness severity on head growth, such that infants exposed to HCT had better head growth compared to those not exposed to HCT when adjusted for illness severity.

Conclusion

These findings emphasize the importance of considering patient illness severity and suggest that HCT use may offer additional benefits not previously considered.

Impact

  • This is the first study to assess the relationship between head growth and illness severity in extremely preterm infants with extremely low birth weights during their initial NICU hospitalization.

  • Infants exposed to hydrocortisone (HCT) were overall more ill than those not exposed, yet HCT exposed infants had better preserved head growth relative to illness severity.

  • Better understanding of the effects of HCT exposure on this vulnerable population will help guide more informed decisions on the relative risks and benefits for HCT use.

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Fig. 1: Methodology for participant inclusion and data processing.
Fig. 2: Head ultrasound measurements correlate with OFC measurements.
Fig. 3: Growth parameters by age for all patients.
Fig. 4: HCT exposed patients had higher illness severity and lengths of stay.
Fig. 5: Growth parameters as function of illness severity for (left) all patients and (right) groups split by HCT exposure.

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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. Volpe, J. J. Brain injury in premature infants: A complex amalgam of destructive and developmental disturbances. Lancet Neurol. 8, 15 (2009).

    Article  Google Scholar 

  2. Montagna, A. & Nosarti, C. Socio-emotional development following very preterm birth: Pathways to psychopathology. Front. Psychol. 7, 80 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Delobel-Ayoub, M. et al. Behavioral problems and cognitive performance at 5 years of age after very preterm birth: The EPIPAGE study. PEDIATRICS 123, 1485–1492 (2009).

    Article  PubMed  Google Scholar 

  4. Joseph, R. M. et al. Neurocognitive and Academic outcomes at age 10 years of extremely preterm newborns. Pediatrics 137, e20154343 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  5. 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 

  6. Keunen, K. et al. Brain tissue volumes in preterm infants: prematurity, perinatal risk factors and neurodevelopmental outcome: A systematic review. J. Matern. Fetal Neonatal Med. 25, 89–100 (2012).

    Article  PubMed  Google Scholar 

  7. Yates, N., Gunn, A. J., Bennet, L., Dhillon, S. K. & Davidson, J. O. Preventing brain injury in the preterm infant—current controversies and potential therapies. Int. J. Mol. Sci. 22, 1671 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ibrahim, H., Sinha, I. P. & Subhedar, N. V. Corticosteroids for treating hypotension in preterm infants. Cochrane Database Syst. Rev. 2011, CD003662 (2011).

    PubMed  PubMed Central  Google Scholar 

  9. Doyle, L. W., Ehrenkranz, R. A. & Halliday, H. L. Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD001145.pub3. (2014).

  10. Halliday, H. L. Update on postnatal steroids. Neonatology 111, 415–422 (2017).

    Article  PubMed  Google Scholar 

  11. Barrington, K. J. The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr. 1, 1 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yeh, T. F. et al. Outcomes at School Age after Postnatal Dexamethasone Therapy for Lung Disease of Prematurity. N. Engl. J. Med. 350, 1304–1313 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Parikh, N. A. et al. Postnatal dexamethasone therapy and cerebral tissue volumes in extremely low birth weight infants. Pediatrics 119, 265–272 (2007).

    Article  PubMed  Google Scholar 

  14. Cummings, J. J., Pramanik, A. K., & COMMITTEE ON FETUS AND NEWBORN. Postnatal Corticosteroids to Prevent or Treat Chronic Lung Disease Following Preterm Birth. Pediatrics e2022057530. https://doi.org/10.1542/peds.2022-057530. (2022).

  15. Baud, O. et al. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): A double-blind, placebo-controlled, multicentre, randomised trial. Lancet 387, 1827–1836 (2016).

    Article  CAS  PubMed  Google Scholar 

  16. Onland, W. et al. Effect of hydrocortisone therapy initiated 7 to 14 days after birth on mortality or bronchopulmonary dysplasia among very preterm infants receiving mechanical ventilation: A randomized clinical trial. JAMA 321, 354 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Watterberg, K. L. et al. Hydrocortisone to improve survival without bronchopulmonary dysplasia. N. Engl. J. Med. 386, 1121–1131 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Parikh, N. A., Kennedy, K. A., Lasky, R. E., McDavid, G. E. & Tyson, J. E. Pilot randomized trial of hydrocortisone in ventilator-dependent extremely preterm infants: effects on regional brain volumes. J. Pediatr. 162, 685–690.e1 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. Aziz, K. B. et al. Maximum vasoactive-inotropic score and mortality in extremely premature, extremely low birth weight infants. J. Perinatol. https://doi.org/10.1038/s41372-021-01030-9 (2021).

  20. Lavilla, O. C. et al. Hourly kinetics of critical organ dysfunction in extremely preterm infants. Am. J. Respir. Crit. Care Med. 205, 75–87 (2022).

    Article  PubMed  Google Scholar 

  21. Cheong, J. L. Y. et al. Head growth in preterm infants: correlation with magnetic resonance imaging and neurodevelopmental outcome. PEDIATRICS 121, e1534–e1540 (2008).

    Article  PubMed  Google Scholar 

  22. Raghuram, K. et al. Head growth trajectory and neurodevelopmental outcomes in preterm neonates. Pediatrics 140, e20170216 (2017).

    Article  PubMed  Google Scholar 

  23. Fenton, T. R. & Kim, J. H. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr. 13, 59 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Parry, G., Tucker, J. & Tarnow-Mordi, W. CRIB II: an update of the clinical risk index for babies score. Lancet 361, 1789–1791 (2003).

    Article  PubMed  Google Scholar 

  25. Aziz, K. B., Schles, E. M., Makker, K. & Wynn, J. L. Frequency of acute kidney injury and association with mortality among extremely preterm infants. JAMA Netw. Open 5, e2246327 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Fleiss, N. et al. Evaluation of the neonatal sequential organ failure assessment and mortality risk in preterm infants with late-onset infection. JAMA Netw. Open 4, e2036518 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wynn, J. L. & Polin, R. A. A neonatal sequential organ failure assessment score predicts mortality to late-onset sepsis in preterm very low birth weight infants. Pediatr. Res. 88, 85–90 (2020).

    Article  PubMed  Google Scholar 

  28. Dorner, R. A., Burton, V. J., Allen, M. C., Robinson, S. & Soares, B. P. Preterm neuroimaging and neurodevelopmental outcome: A focus on intraventricular hemorrhage, post-hemorrhagic hydrocephalus, and associated brain injury. J. Perinatol. 38, 1431–1443 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bakdash, J. Z. & Marusich, L. R. Repeated Measures Correlation. Front. Psychol. 8, (2017). https://doi.org/10.3389/fpsyg.2017.00456.

  30. Papile, L. A., Burstein, J., Burstein, R. & Koffler, H. Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1500 gm. J. Pediatr. 92, 529–534 (1978).

    Article  CAS  PubMed  Google Scholar 

  31. Morris, I. P., Goel, N. & Chakraborty, M. Efficacy and safety of systemic hydrocortisone for the prevention of bronchopulmonary dysplasia in preterm infants: A systematic review and meta-analysis. Eur. J. Pediatr. 178, 1171–1184 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Williams, E. E., Dassios, T., Mann, M. & Greenough, A. The effect of postnatal corticosteroids on growth parameters in infants with bronchopulmonary dysplasia. J. Perinat. Med. 49, 1141–1144 (2021).

    Article  CAS  PubMed  Google Scholar 

  33. Spanswick, S. C., Epp, J. R. & Sutherland, R. J. Time-course of hippocampal granule cell degeneration and changes in adult neurogenesis after adrenalectomy in rats. Neuroscience 190, 166–176 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Gould, E., Woolley, C. S. & McEwen, B. S. Short-term glucocorticoid manipulations affect neuronal morphology and survival in the adult dentate gyrus. Neuroscience 37, 367–375 (1990).

    Article  CAS  PubMed  Google Scholar 

  35. Numakawa, T. et al. Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-gamma signaling for glutamate release via a glutamate transporter. Proc. Natl Acad. Sci. USA 106, 647–652 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jeanneteau, F., Garabedian, M. J. & Chao, M. V. Activation of Trk neurotrophin receptors by glucocorticoids provides a neuroprotective effect. Proc. Natl Acad. Sci. USA 105, 4862–4867 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bellavance, M.-A. & Rivest, S. The neuroendocrine control of the innate immune system in health and brain diseases. Immunol. Rev. 248, 36–55 (2012).

    Article  PubMed  Google Scholar 

  38. Liston, C. & Gan, W.-B. Glucocorticoids are critical regulators of dendritic spine development and plasticity in vivo. Proc. Natl Acad. Sci. 108, 16074–16079 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liston, C. et al. Circadian glucocorticoid oscillations promote learning-dependent synapse formation and maintenance. Nat. Neurosci. 16, 698–705 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Aucott, S. W., Donohue, P. K. & Northington, F. J. Increased morbidity in severe early intrauterine growth restriction. J. Perinatol. J. Calif. Perinat. Assoc. 24, 435–440 (2004).

    Google Scholar 

  41. Ullian, M. E. The role of corticosteroids in the regulation of vascular tone. Cardiovasc. Res. 41, 55–64 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Lösel, R. & Wehling, M. Nongenomic actions of steroid hormones. Nat. Rev. Mol. Cell Biol. 4, 46–55 (2003).

    Article  PubMed  Google Scholar 

  43. Puia-Dumitrescu, M. et al. Dexamethasone, Prednisolone, and Methylprednisolone Use and 2-Year Neurodevelopmental Outcomes in Extremely Preterm Infants. JAMA Netw. Open 5, e221947 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the families of the participants and the staff at Johns Hopkins Hospital and laboratory for their willingness to participate in this study.

Funding

Supported by National Institutes of Health RO1HD086058 (A.E., F.J.N.); R01 HD110091 (F.J.N., A.D.E., K.Z., R.C-V.); RO1HD070996, AG061643, and NS109029, HD074593-07 (F.J.N.); KO8NS096115 (R.C-V.), and the Thomas Wilson Foundation (R.-V.).

Author information

Author notes

  1. These authors contributed equally: Haiwen Chen, Khyzer B. Aziz.

Authors and Affiliations

  1. Division of Pediatric Neurology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Haiwen Chen & Carl E. Stafstrom

  2. Division of Neonatology – Neuroscience Intensive Care Nursery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Khyzer B. Aziz, Harisa Spahic, Sarah Miller, Alison Kilborn, Frances J. Northington, Carl E. Stafstrom & Raul Chavez-Valdez

  3. Division of Pediatric Neuroradiology, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Melike Guryildirim

  4. Division of Neonatology, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, USA

    Austin Sellers & Sandra Brooks

  5. Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Allen D. Everett

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Contributions

H.C., K.B.A., R.C-V. conceived and designed the study, analyzed the data, and drafted the article. H.C., K.B.A, H.S., S.M., A.S., S.B., A.D.E., F.J.N and R.C-V. contributed to acquisition of the data. M.G. and A.K. performed the HUS measurements. H.C., K.B.A., A.S., S.B., A.D.E., C.E.S., and R.C-V. provided critical revisions. All authors provided final approval of the version to be published.

Corresponding author

Correspondence to Raul Chavez-Valdez.

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The authors declare no competing interests.

Ethical approval

The study received institutional review board approval (JHH IRB 00026068), and signed parental informed consent was obtained for each participant within the infant’s first 30 days of life and prior to NICU discharge.

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Chen, H., Aziz, K.B., Spahic, H. et al. Interaction of hydrocortisone and illness severity on head growth in cohort of ELBW infants. Pediatr Res 94, 1958–1965 (2023). https://doi.org/10.1038/s41390-023-02689-w

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