Meta-Analysis of Cord Blood for Cerebral Palsy

Megan Finch-Edmondson, PhD, lead author

Introduction to cerebral palsy:

Cerebral palsy is an umbrella term that describes a group of disorders affecting a person’s movement and posture. Cerebral palsy is a life-long condition that arises from injury to the brain during development, usually before, during or shortly after birth. Cerebral palsy is a highly variable condition. Symptoms may include difficulties in walking, balance and motor control, eating, swallowing, speech or coordination of eye movements. Cerebral palsy can vary in the way it affects an individual’s movement (type), the part of the body affected (topography) and by how severe the symptoms are (severity), which can be measured using the Gross Motor Function Classification System (GMFCS). In addition, people with cerebral palsy may also experience other impairments or co-occurring conditions such as epilepsy, behaviour disorders, or vision or hearing impairments.

What treatments exist?

Numerous interventions exist that help people with cerebral palsy to develop and maintain their functional skills as well as reduce the symptoms of cerebral palsy. These include various rehabilitative and medical interventions such as physical, occupational, and speech therapies, as well as botox injections, oral or intrathecal baclofen and even surgery to manage muscle stiffness and contractures¹. Currently there are no available treatments that directly target the underlying brain injury to improve function and quality of life.

Why cell therapies?

There is significant interest in investigating cell therapies such as umbilical cord blood as a treatment for cerebral palsy. This is because umbilical cord blood contains a variety of stem and progenitor cells that have been shown to be beneficial following a brain injury in laboratory research. These benefits include reducing inflammation and cell death, and promoting repair following a brain injury, mainly via release of cellular factors (“trophic mechanisms”). This may help to reduce the size or severity of an injury, and/or improve the connections within the brain².

Cord blood for cerebral palsy:

The earliest reported infusions of umbilical cord blood for cerebral palsy date back nearly 20 years. This was included in a paper published by Sun et al. in 2010 in which 140 children with cerebral palsy received autologous (their own) umbilical cord blood from March 2004 to December 2009³. Since then, numerous studies have been published, with a 2021 review finding nearly 800 individuals with cerebral palsy had been treated with umbilical cord blood across all phases of clinical studies, including six medium/large randomised placebo-controlled trials⁴. A 2016 systematic review concluded that cord blood treatment is safe and more effective than rehabilitation alone in improving gross motor function⁵, however cord blood is not approved for the treatment of cerebral palsy by any regulatory agency in the world.

Challenges with the research evidence to date:

Some uncertainty exists as to whether cord blood is truly effective for treating cerebral palsy. This may be partly due to the variability between the studies completed so far. This variability comes from the inclusion of participants of all ages, types of cerebral palsy and severity, as well as differences in the way the cord blood cells have been given, large variation in cell number (dose), how long after the treatment the participants were followed up, and which tests were used to check for changes. All of these factors and more may influence to the effectiveness of cord blood for treating cerebral palsy.

A challenge with clinical trials is that small samples in individual studies can lead to a lack of ‘power’ to conclusively answer questions about whether a treatment works, as well as explore different sub-groups within the data. It is only once a field reaches a certain level of maturity, with enough data available that this becomes possible.

A research solution:

Now, with several large randomised controlled trials published, researchers from the Cerebral Palsy Alliance Research Institute felt that it was the right time to conduct an Individual Participant Data Meta-Analysis (IPDMA) to do just this. An IPDMA is a specific type of systematic review that obtains the original research data for each trial participant directly from the researchers responsible for each study. These data can then be combined and re-analysed centrally to ask additional questions of the data.

What did the researchers find?

For this IPDMA, researchers had enough data to analyse the effects of cord blood treatment on gross motor function. Therefore, the questions the team most wanted to answer were: 1) what is the overall effect of cord blood treatment for improving gross motor function in individuals with cerebral palsy, and 2) what effect does cord blood cell dose have on this improvement? The preliminary findings of this IPDMA study were presented at the 2023 Cord Blood Connect conference in Miami⁶.

Promisingly, this preliminary IPDMA study suggested that umbilical cord blood treatment in children with cerebral palsy improved gross motor skills more than controls, and that higher cell dose is likely beneficial, with data presented for the 6-month follow up timepoint.

The team is currently performing more analyses including looking at additional time points, in addition to looking at several factors that might reveal treatment-responders. This study represents an incredible international collaboration between many of the research teams working in this area. Findings from this study may help inform future trials and ensure that cord blood is applied in a way to deliver the best possible outcomes for children with cerebral palsy. Stay tuned for the full results expected next year.

Study collaborators include:

• Cerebral Palsy Alliance Research Institute, The University of Sydney, Sydney, Australia: Megan Finch-Edmondson, Madison CB Paton, Annabel Webb, Remy K Blatch-Williams, Alexandra R Griffin
• Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran: Mahmoudreza Ashrafi
• McGovern Medical School, The University of Texas Health Science Center, Houston, USA: Charles S Cox, Jr, Steven Kosmach
• Murdoch Children's Research Institute, The Royal Children's Hospital Melbourne, The University of Melbourne, Melbourne, Australia: Kylie Crompton
• CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea: MinYoung Kim
• The Marcus Center for Cellular Cures, Duke University School of Medicine, Durham, USA: Joanne Kurtzberg, Jessica Sun
• Royan Stem Cell Technology, Tehran, Iran: Masoumeh Nouri, Morteza Zarrabi
• Faculty of Medicine and Health, The University of Sydney, Sydney, Australia: Iona Novak

References

1. Novak I, Morgan C, Fahey M, Finch-Edmondson M, Galea C, Hines A, et al. State of the Evidence Traffic Lights 2019: Systematic Review of Interventions for Preventing and Treating Children with Cerebral Palsy. Current Neurology and Neuroscience Reports. 2020;20(2):3.
2. Nguyen T, Purcell E, Smith MJ, Penny TR, Paton MCB, Zhou L, et al. Umbilical Cord Blood-Derived Cell Therapy for Perinatal Brain Injury: A Systematic Review & Meta-Analysis of Preclinical Studies. International Journal of Molecular Sciences. 2023;24(5):4351.
3. Sun J, Allison J, McLaughlin C, Sledge L, Waters-Pick B, Wease S, et al. Differences in quality between privately and publicly banked umbilical cord blood units: a pilot study of autologous cord blood infusion in children with acquired neurologic disorders. Transfusion. 2010;50(9):1980-7.
4. Paton MCB, Finch-Edmondson M, Fahey MC, London J, Badawi N, Novak I. Fifteen years of human research using stem cells for cerebral palsy: A review of the research landscape. J Paediatr Child Health. 2021;57(2):295-6.
5. Novak I, Walker K, Hunt RW, Wallace EM, Fahey M, Badawi N. Concise Review: Stem Cell Interventions for People With Cerebral Palsy: Systematic Review With Meta-Analysis. Stem Cells Translational Medicine. 2016;5(8):1014-25.
6. Finch-Edmondson M, Paton M, Webb A, Ashrafi M, Blatch-Williams R, Cox J, Charles, et al. Abstract 5 Umbilical Cord Blood Treatment to Improve Gross Motor Function in Individuals with Cerebral Palsy: Results from an Individual Participant Data Meta-Analysis. Stem Cells Translational Medicine. 2023;12(Supplement_1):S6-S.