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  • Clinical Research Article
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Early-life exposure to analgesia and 18-month neurodevelopmental outcomes in very preterm infants

Pediatric Research volume 94, pages 738–746 (2023)Cite this article

Abstract

Background

We assessed variability of analgesic use across three tertiary neonatal intensive care units (NICUs) accounting for early-life pain, quantified as number of invasive procedures. We also determined whether analgesia exposure modifies associations between early-life pain and neurodevelopment.

Methods

Multicenter prospective study of 276 very preterm infants (born <24–32 weeks’ gestational age [GA]). Detailed data of number of invasive procedures and duration of analgesia exposure were collected in initial weeks after birth. Eighteen-month neurodevelopmental assessments were completed in 215 children with Bayley Scales for Infant Development—Third edition.

Results

Multivariable linear regressions revealed significant differences in morphine use across sites, for a given exposure to early-life pain (interaction p < 0.001). Associations between early-life pain and motor scores differed by duration of morphine exposure (interaction p = 0.01); greater early-life pain was associated with poorer motor scores in infants with no or long (>7 days) exposure, but not short exposure (≤7 days).

Conclusions

Striking cross-site differences in morphine exposure in very preterm infants are observed even when accounting for early-life pain. Negative associations between greater early-life pain and adverse motor outcomes were attenuated in infants with short morphine exposure. These findings emphasize the need for further studies of optimal analgesic approaches in preterm infants.

Impact

  • In very preterm neonates, both early-life exposure to pain and analgesia are associated with adverse neurodevelopment and altered brain maturation, with no clear guidelines for neonatal pain management in this population.

  • We found significant cross-site variability in morphine use across three tertiary neonatal intensive care units in Canada.

  • Morphine use modified associations between early-life pain and motor outcomes. In infants with no or long durations of morphine exposure, greater early-life pain was associated with lower motor scores, this relationship was attenuated in those with short morphine exposure.

  • Further trials of optimal treatment approaches with morphine in preterm infants are warranted.

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Fig. 1: Participant flowchart.
Fig. 2: Duration of exposure to fentanyl, morphine, midazolam and sucrose across study sites.
Fig. 3: Pearson correlations of early cumulative doses and durations of exposure to fentanyl, morphine, midazolam and sucrose.
Fig. 4: Days of morphine exposure by the number of invasive procedures, for each study site.
Fig. 5: Bayley-3 scores by the number early invasive procedures, separated by duration of exposure to morphine and sucrose.

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Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due to conditions of patient consent and research ethics board approvals but are available from the corresponding author on reasonable request and appropriate patient consent and data transfer agreements.

References

  1. Carbajal, R. et al. Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA 300, 60 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Grunau, R. E. et al. Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants. Pain 143, 138–146 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Vinall, J. et al. Invasive procedures in preterm children: brain and cognitive development at school age. Pediatrics 133, 412–421 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Smith, G. C. et al. Neonatal intensive care unit stress is associated with brain development in preterm infants. Ann. Neurol. 70, 541–549 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ranger, M. et al. Neonatal pain-related stress predicts cortical thickness at age 7 years in children born very preterm. PLoS ONE 8, e76702 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ranger, M. & Grunau, R. E. Early repetitive pain in preterm infants in relation to the developing brain. Pain. Manag. 4, 57–67 (2014).

    Article  PubMed  Google Scholar 

  7. Brummelte, S. et al. Procedural pain and brain development in premature newborns. Ann. Neurol. 71, 385–396 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Duerden, E. G. et al. Early procedural pain is associated with regionally-specific alterations in thalamic development in preterm neonates. J. Neurosci. 38, 878–886 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Duerden, E. G. et al. Association of early skin breaks and neonatal thalamic maturation: a modifiable risk? Neurology 95, e3420–e3427 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Puia-Dumitrescu, M. et al. Assessment of 2-year neurodevelopmental outcomes in extremely preterm infants receiving opioids and benzodiazepines. JAMA Netw. Open 4, e2115998 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Borenstein-Levin, L. et al. Narcotics and sedative use in preterm neonates. J. Pediatr. 180, 92.e1–98.e1 (2017).

    Article  Google Scholar 

  12. Carbajal, R. et al. Sedation and analgesia practices in neonatal intensive care units (Europain): results from a prospective cohort study. Lancet Respir. Med. 3, 796–812 (2015).

    Article  PubMed  Google Scholar 

  13. Lago, P. et al. Sedation and analgesia practices at italian neonatal intensive care units: results from the Europain Study. Ital. J. Pediatr. 43, 26 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Duerden, E. G. et al. Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants. Ann. Neurol. 79, 548–559 (2016).

    Article  CAS  PubMed  Google Scholar 

  15. Zwicker, J. G. et al. Smaller cerebellar growth and poorer neurodevelopmental outcomes in very preterm infants exposed to neonatal morphine. J. Pediatr. 172, 81.e2–87.e2 (2016).

    Article  Google Scholar 

  16. McPherson, C. et al. Brain injury and development in preterm infants exposed to fentanyl. Ann. Pharmacother. 49, 1291–1297 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mcpherson, C., Miller, S. P., El-Dib, M., Massaro, A. N. & Inder, T. E. The influence of pain, agitation, and their management on the immature brain. Pediatr. Res. 88, 168–175 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  18. McPherson, C. & Grunau, R. E. Pharmacologic analgesia and sedation in neonates. Clin. Perinatol. 49, 243–265 (2022).

    Article  PubMed  Google Scholar 

  19. Chau, C. M. Y. et al. Morphine biotransformation genes and neonatal clinical factors predicted behaviour problems in very preterm children at 18 months. EBioMedicine 40, 655–662 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Nunes, A. S. et al. Atypical neuromagnetic resting activity associated with thalamic volume and cognitive outcome in very preterm children. Neuroimage Clin. 27, 102275 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  21. 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 1,500gm. J. Pediatr. 92, 529–534 (1978).

    Article  CAS  PubMed  Google Scholar 

  22. Guo, T. et al. Quantitative assessment of white matter injury in preterm neonates. Neurology 88, 614–622 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Benavente-Fernandez, I. et al. Association of socioeconomic status and brain injury with neurodevelopmental outcomes of very preterm children. JAMA Netw. Open 2, e192914 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Cayam-Rand, D. et al. Predicting developmental outcomes in preterm infants: a simple white matter injury imaging rule. Neurology 93, e1231–e1240 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Keels, E. et al. Prevention and management of procedural pain in the neonate: an update. Pediatrics 137, e20154271 (2016).

    Article  Google Scholar 

  26. Ng, E., Taddio, A. & Ohlsson, A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Database Syst. Rev. 1, CD002052 (2017).

    PubMed  Google Scholar 

  27. Steinbauer, P. et al. Long-term impact of systematic pain and sedation management on cognitive, motor, and behavioral outcomes of extremely preterm infants at preschool age. Pediatr. Res. 89, 540–548 (2021).

    Article  PubMed  Google Scholar 

  28. Giordano, V. et al. Effect of increased opiate exposure on three years neurodevelopmental outcome in extremely preterm infants. Early Hum. Dev. 123, 1–5 (2018).

    Article  CAS  PubMed  Google Scholar 

  29. Steinhorn, R. et al. Neonatal morphine exposure in very preterm infants—cerebral development and outcomes. J. Pediatr. 166, 1200.e4–1207.e4 (2015).

    Article  Google Scholar 

  30. Bellu, R. et al. Opioids for newborn infants receiving mechanical ventilation. Cochrane Database Syst. Rev. 3, CD013732 (2021).

    PubMed  Google Scholar 

  31. Lammers, E. M. et al. Association of fentanyl with neurodevelopmental outcomes in very-low-birth-weight infants. Ann. Pharmacother. 48, 335–342 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Simons, S. H. P. et al. Routine morphine infusion in preterm newborns who received ventilatory support. JAMA 290, 2419 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. de Graaf, J. et al. Long-term effects of routine morphine infusion in mechanically ventilated neonates on children’s functioning: five-year follow-up of a randomized controlled trial. Pain 152, 1391–1397 (2011).

    Article  PubMed  Google Scholar 

  34. de Graaf, J. et al. Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age? Pain 154, 449–458 (2013).

    Article  PubMed  Google Scholar 

  35. Nandi, R. & Fitzgerald, M. Opioid analgesia in the newborn. Eur. J. Pain 9, 105–108 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Fitzgerald, M. & Walker, S. M. Infant pain management: a developmental neurobiological approach. Nat. Clin. Pract. Neurol. 5, 35–50 (2009).

    Article  PubMed  Google Scholar 

  37. Durrmeyer, X., Vutskits, L., Anand, K. J. S. & Rimensberger, P. C. Use of analgesic and sedative drugs in the NICU: integrating clinical trials and laboratory data. Pediatr. Res. 67, 117–127 (2010).

    Article  PubMed  Google Scholar 

  38. Ranger, M. et al. Adverse behavioral changes in adult mice following neonatal repeated exposure to pain and sucrose. Front. Psychol. 9, 2394 (2018).

    Article  PubMed  Google Scholar 

  39. Tremblay, S. et al. Repeated exposure to sucrose for procedural pain in mouse pups leads to long-term widespread brain alterations. Pain 158, 1586–1598 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank the child and families who participated in this longitudinal study. We also thank Giselle Da Rocha, Janet Rigney, Mark LePine, Steven Ufkes, Mary Beckingham, Poala Zen, and the staff in the Neonatal Follow-up Programs at BC Women’s & Children’s Hospital, the Hospital for Sick Children, and Mount Sinai Hospital for their assistance with this study.

Funding

The study was supported by the Canadian Institutes of Health Research (CIHR MOP-136966 and PJT-168894), CP Alliance (PG-016817), and Brain Canada (The Canadian Neonatal Brain Platform). S.P.M. received support from the Bloorview Children’s Hospital Chair in Paediatric Neuroscience, and now from the Hudson Family Hospital Chair in Pediatric Medicine and the James & Annabel McCreary Chair in Pediatrics. R.E.G. holds a senior scientist salary award from the BC Children’s Hospital Research Institute. T.S. is supported by CIHR Canada Graduate Scholarship – Master’s and Doctoral Awards, Ontario Ministry of Health & University of Toronto Clinician Investigator Program, and the SickKids Research Institute Clinician Scientist Training Program. M.A.M. is supported by a CIHR Postdoctoral Research Fellowship and Michael Smith for Health Research Foundation Trainee Award.

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Author notes

  1. These authors contributed equally: Ruth E. Grunau, Steven P. Miller.

Authors and Affiliations

  1. Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada

    Thiviya Selvanathan, Pearl Zaki, Stephanie H. Au-Young, Vann Chau, Linh G. Ly, Edmond Kelly & Steven P. Miller

  2. Department of Pediatrics, University of British Columbia, BC Children’s Hospital Research Institute, Vancouver, BC, Canada

    Mia A. McLean, Cecil M. Y. Chau, Anne R. Synnes, Ruth E. Grunau & Steven P. Miller

  3. Department of Pediatrics, Mount Sinai Hospital, Toronto, ON, Canada

    Edmond Kelly

  4. BC Women’s Hospital, Vancouver, BC, Canada

    Ruth E. Grunau

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  1. Thiviya Selvanathan
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Contributions

T.S., R.E.G. and S.P.M. made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and critically reviewing the manuscript for important intellectual content. C.M.Y.C., A.R.S., L.G.L., and E.K. contributed to the conception and design, acquisition of data, and critically reviewing the manuscript for important intellectual content. P.Z. contributed to acquisition of data, analysis and interpretation of data, drafting of the manuscript and critically reviewing the manuscript for important intellectual content. M.A.M., S.H.A.-Y., and C.M.Y.C. contributed to acquisition of data and critically reviewing the manuscript for important intellectual content. All authors approved the final version of the manuscript to be published.

Corresponding author

Correspondence to Steven P. Miller.

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The authors declare no competing interests.

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Written informed consent was obtained from a parent/guardian of each participant in the study.

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Selvanathan, T., Zaki, P., McLean, M.A. et al. Early-life exposure to analgesia and 18-month neurodevelopmental outcomes in very preterm infants. Pediatr Res 94, 738–746 (2023). https://doi.org/10.1038/s41390-023-02536-y

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  • DOI: https://doi.org/10.1038/s41390-023-02536-y

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