Stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants

Abstract

Background: Hypoxic-ischaemic encephalopathy (HIE) is a leading cause of mortality and long-term neurological sequelae, affecting thousands of children worldwide. Current therapies to treat HIE are limited to cooling. Stem cell-based therapies offer a potential therapeutic approach to repair or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal trials.

Objectives: To determine the efficacy and safety of stem cell-based interventions for the treatment of hypoxic-ischaemic encephalopathy (HIE) in newborn infants.

Search methods: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 5), MEDLINE via PubMed (1966 to 8 June 2020), Embase (1980 to 8 June 2020), and CINAHL (1982 to 8 June 2020). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection criteria: Randomised controlled trials, quasi-randomised controlled trials and cluster trials comparing 1) stem cell-based interventions (any type) compared to control (placebo or no treatment); 2) use of mesenchymal stem/stromal cells (MSCs) of type (e.g. number of doses or passages) or source (e.g. autologous versus allogeneic, or bone marrow versus cord) versus MSCs of other type or source; 3) use of stem cell-based interventions other than MSCs of type (e.g. mononuclear cells, oligodendrocyte progenitor cells, neural stem cells, hematopoietic stem cells, and inducible pluripotent stem cells) or source (e.g. autologous versus allogeneic, or bone marrow versus cord) versus stem cell-based interventions other than MSCs of other type or source; or 4) MSCs versus stem cell-based interventions other than MSCs.

Data collection and analysis: For each of the included trials, two authors independently planned to extract data (e.g. number of participants, birth weight, gestational age, type and source of MSCs or other stem cell-based interventions) and assess the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). The primary outcomes considered in this review are all-cause neonatal mortality, major neurodevelopmental disability, death or major neurodevelopmental disability assessed at 18 to 24 months of age. We planned to use the GRADE approach to assess the quality of evidence.

Main results: Our search strategy yielded 616 references. Two review authors independently assessed all references for inclusion. We did not find any completed studies for inclusion. Fifteen RCTs are currently registered and ongoing. We describe the three studies we excluded.

Authors' conclusions: There is currently no evidence from randomised trials that assesses the benefit or harms of stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants.

Trial registration: ClinicalTrials.gov NCT02854579.

Conflict of interest statement

MB has received research funding from ALF grant (non‐profit ‐ Lund University) and Crafoord Foundation (non‐profit) for research projects not related to Cochrane.

OR: no known conflicts of interest.

AM: is supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant KL2 TR001118. AM's institution has received a grant from the Francis Family Foundation (Parker B. Francis Fellowship Award). AM also has submitted a provisional patent to the US Patent and Trademark Office that involves by‐products of stem cells ("cell‐free therapies"). This patent does not conflict with this planned systematic review, as the review is only considering different types of cell‐based interventions.

DL owns shares in Premacure AB, and has received consultancy fees from Shire Inc. The collaboration with Premacure AB and Shire Inc. is specifically related to treatment of extremely preterm infants with a protein complex aiming to decrease prevalence of severe morbidity associated with extremely preterm birth.

BT's work on stem cells is supported by the Canadian Institute for Health Research, the Canadian Stem Cell Network, the Canadian Thoracic Society, the Ottawa Hospital Research Institute and the Children's Hospital of Eastern Ontario Research Institute, and the Ontario Institute of Regenerative Medicine.

Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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