Review

. 2023 Jun;93(7):1819-1827.

doi: 10.1038/s41390-022-02295-2. Epub 2022 Oct 4.

Neuroprotective therapies in the NICU in term infants: present and future

Eleanor J Molloy^{1

2

3

4}, Mohamed El-Dib⁵, Sandra E Juul⁶, Manon Benders⁷, Fernando Gonzalez⁸, Cynthia Bearer^{9

10}, Yvonne W Wu¹¹, Nicola J Robertson^{12

13}, Tim Hurley^{14

15}, Aoife Branagan^{14

15}, C Michael Cotten¹⁶, Sidhartha Tan^{17

18

19}, Abbot Laptook²⁰, Topun Austin²¹, Khorshid Mohammad²², Elizabeth Rogers²³, Karen Luyt^{24

25}, Sonia Bonifacio²⁶, Janet S Soul²⁷, Alistair J Gunn²⁸; Newborn Brain Society Guidelines and Publications Committee

Collaborators, Affiliations

Collaborators

Newborn Brain Society Guidelines and Publications Committee:
Sonia Bonifacio, Pia Wintermark, Hany Aly, Taeun Chang, Vann Chau, Hannah Glass, Monica Lemmon, An Massaro, Courtney Wusthoff, Gabrielle deVeber, Andrea Pardo, Melisa Carrasco McCaul

Affiliations

¹ Paediatrics, Trinity College Dublin, Trinity Research in Childhood Centre (TRICC), Dublin, Ireland. Eleanor.molloy@tcd.ie.
² Children's Hospital Ireland (CHI) at Tallaght, Dublin, Ireland. Eleanor.molloy@tcd.ie.
³ Neonatology, CHI at Crumlin, Dublin, Ireland. Eleanor.molloy@tcd.ie.
⁴ Neonatology, Coombe Women's and Infants University Hospital, Dublin, Ireland. Eleanor.molloy@tcd.ie.
⁵ Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ University of Washington, Seattle, WA, USA.
⁷ Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
⁸ Department of Neurology, Division of Child Neurology, University of California San Francisco, San Francisco, CA, USA.
⁹ Division of Neonatology, Department of Pediatrics, Rainbow Babies & Children's Hospital, Cleveland, OH, USA.
¹⁰ Case Western Reserve University School of Medicine, Cleveland, OH, USA.
¹¹ Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
¹² Institute for Women's Health, University College London, London, UK.
¹³ Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
¹⁴ Paediatrics, Trinity College Dublin, Trinity Research in Childhood Centre (TRICC), Dublin, Ireland.
¹⁵ Neonatology, Coombe Women's and Infants University Hospital, Dublin, Ireland.
¹⁶ Department of Pediatrics, Duke University, Durham, NC, USA.
¹⁷ Pediatrics, Division of Neonatology, Children's Hospital of Michigan, Detroit, MI, USA.
¹⁸ Wayne State University School of Medicine, Detroit, MI, 12267, USA.
¹⁹ Pediatrics, Division of Neonatology, Central Michigan University, Mount Pleasant, MI, USA.
²⁰ Department of Pediatrics, Women and Infants Hospital, Brown University, Providence, RI, USA.
²¹ Department of Paediatrics, University of Cambridge, Cambridge, UK.
²² Section of Neonatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada.
²³ Department of Pediatrics, University of California, San Francisco Benioff Children's Hospital, San Francisco, CA, USA.
²⁴ Translational Health Sciences, University of Bristol, Bristol, UK.
²⁵ Neonatology, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.
²⁶ Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, 750 Welch Road, Suite 315, Palo Alto, CA, 94304, USA.
²⁷ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
²⁸ Departments of Physiology and Paediatrics, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.

PMID: 36195634
PMCID: PMC10070589
DOI: 10.1038/s41390-022-02295-2

Review

Neuroprotective therapies in the NICU in term infants: present and future

Eleanor J Molloy et al. Pediatr Res. 2023 Jun.

. 2023 Jun;93(7):1819-1827.

doi: 10.1038/s41390-022-02295-2. Epub 2022 Oct 4.

Authors

Collaborators

Newborn Brain Society Guidelines and Publications Committee:
Sonia Bonifacio, Pia Wintermark, Hany Aly, Taeun Chang, Vann Chau, Hannah Glass, Monica Lemmon, An Massaro, Courtney Wusthoff, Gabrielle deVeber, Andrea Pardo, Melisa Carrasco McCaul

Affiliations

¹ Paediatrics, Trinity College Dublin, Trinity Research in Childhood Centre (TRICC), Dublin, Ireland. Eleanor.molloy@tcd.ie.
² Children's Hospital Ireland (CHI) at Tallaght, Dublin, Ireland. Eleanor.molloy@tcd.ie.
³ Neonatology, CHI at Crumlin, Dublin, Ireland. Eleanor.molloy@tcd.ie.
⁴ Neonatology, Coombe Women's and Infants University Hospital, Dublin, Ireland. Eleanor.molloy@tcd.ie.
⁵ Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ University of Washington, Seattle, WA, USA.
⁷ Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
⁸ Department of Neurology, Division of Child Neurology, University of California San Francisco, San Francisco, CA, USA.
⁹ Division of Neonatology, Department of Pediatrics, Rainbow Babies & Children's Hospital, Cleveland, OH, USA.
¹⁰ Case Western Reserve University School of Medicine, Cleveland, OH, USA.
¹¹ Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
¹² Institute for Women's Health, University College London, London, UK.
¹³ Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
¹⁴ Paediatrics, Trinity College Dublin, Trinity Research in Childhood Centre (TRICC), Dublin, Ireland.
¹⁵ Neonatology, Coombe Women's and Infants University Hospital, Dublin, Ireland.
¹⁶ Department of Pediatrics, Duke University, Durham, NC, USA.
¹⁷ Pediatrics, Division of Neonatology, Children's Hospital of Michigan, Detroit, MI, USA.
¹⁸ Wayne State University School of Medicine, Detroit, MI, 12267, USA.
¹⁹ Pediatrics, Division of Neonatology, Central Michigan University, Mount Pleasant, MI, USA.
²⁰ Department of Pediatrics, Women and Infants Hospital, Brown University, Providence, RI, USA.
²¹ Department of Paediatrics, University of Cambridge, Cambridge, UK.
²² Section of Neonatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada.
²³ Department of Pediatrics, University of California, San Francisco Benioff Children's Hospital, San Francisco, CA, USA.
²⁴ Translational Health Sciences, University of Bristol, Bristol, UK.
²⁵ Neonatology, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.
²⁶ Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, 750 Welch Road, Suite 315, Palo Alto, CA, 94304, USA.
²⁷ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
²⁸ Departments of Physiology and Paediatrics, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.

PMID: 36195634
PMCID: PMC10070589
DOI: 10.1038/s41390-022-02295-2

Abstract

Outcomes of neonatal encephalopathy (NE) have improved since the widespread implementation of therapeutic hypothermia (TH) in high-resource settings. While TH for NE in term and near-term infants has proven beneficial, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. There is therefore a critical need to find additional pharmacological and non-pharmacological interventions that improve the outcomes for these children. There are many potential candidates; however, it is unclear whether these interventions have additional benefits when used with TH. Although primary and delayed (secondary) brain injury starting in the latent phase after HI are major contributors to neurodisability, the very late evolving effects of tertiary brain injury likely require different interventions targeting neurorestoration. Clinical trials of seizure management and neuroprotection bundles are needed, in addition to current trials combining erythropoietin, stem cells, and melatonin with TH. IMPACT: The widespread use of therapeutic hypothermia (TH) in the treatment of neonatal encephalopathy (NE) has reduced the associated morbidity and mortality. However, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. This review details the pathophysiology of NE along with the evidence for the use of TH and other beneficial neuroprotective strategies used in term infants. We also discuss treatment strategies undergoing evaluation at present as potential adjuvant treatments to TH in NE.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Pathophysiology, phases of injury, and therapeutic windows for present and future neuroprotective interventions in term newborns.**
Earliest phases of injury are targeted by interventions, including therapeutic hypothermia, acute neuroprotective bundles, and melatonin. Neuroplasticity bundles, erythropoietin, and stem cell therapies aim to reduce injury during the later phases. Improved seizure management offers neuroprotection throughout all stages of injury.

See this image and copyright information in PMC

References

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Neuroprotective therapies in the NICU in term infants: present and future

Collaborators

Affiliations

Neuroprotective therapies in the NICU in term infants: present and future

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

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