Cord Blood Treatment for Children With Cerebral Palsy: Individual Participant Data Meta-Analysis

Major Points and Findings:

To date, this paper is the most rigorous pooled analysis of umbilical cord blood (UCB) treatment for cerebral palsy. Instead of combining the averages printed in each paper, the authors obtained the raw, child-by-child data from the original trial teams in the United States, South Korea, Iran and Australia and re-analysed it in one model. With data at this level they could examine the influence of cell dose and age and identify which children respond, questions that no single trial had been able to answer.

Cord blood improved gross motor function more than control treatment, by about 1.4 points on the GMFM-66 at 6 and 12 months. The effect is modest. It was concentrated in younger children with milder cerebral palsy who received higher cell doses. In children at GMFCS levels IV and V, no significant effect was detected at any dose.

Aim:

To determine the effect of UCB on gross motor function (GMFM-66) at 1, 3, 6 and 12 months, whether cell dose changes that effect, which children respond, and how safe UCB is compared with controls.

Methods:

The authors carried out a systematic review and one-stage individual participant data meta-analysis, registered in advance (PROSPERO CRD42021259527). Databases and ClinicalTrials.gov were searched on 9 May 2024.

Any clinical study in English was eligible, controlled or not, if it gave autologous or allogeneic UCB by any route to people with cerebral palsy of any age and collected GMFM-66 scores at baseline and follow-up. Concomitant erythropoietin (EPO) was allowed.

Of 13 eligible studies, raw data came from 11 (7 controlled trials and 4 single-arm studies, one unpublished), giving 498 records from 447 children. The teams behind two small single-arm studies (26 children) did not respond.

The main analysis compared 170 children given UCB alone with 171 controls. Children who received EPO were analysed separately, and any child who received more than one UCB dose was excluded. Models were adjusted for baseline GMFM-66 and for differences between studies.

Mean age was 54.6 months (range 8 months to 18.9 years). Boys made up 60% of the children. Cerebral palsy was spastic in 90% and bilateral in 85%, and 52% were at GMFCS level IV or V.

Treatment: 84% of the cord blood was allogeneic, and 86% of that came from an unrelated donor. Only 26% of allogeneic recipients had no HLA mismatch. All studies but one infused intravenously. The exception was an Iranian trial of 72 children that gave 5 × 10⁶ mononuclear cells per kg intrathecally. The mean intravenous dose was about 56 × 10⁶ total nucleated cells (TNC) per kg, ranging from 9.7 to 210.3 × 10⁶ after imputation of missing counts. The dose analysis covered intravenous recipients only.

Of the 7 randomized trials, 4 were rated low risk of bias, 1 some concerns and 2 high risk. No sign of publication bias was found.

Results:

Compared with controls, GMFM-66 was higher after UCB by:

• 1.36 points at 6 months (95% CI 0.41 to 2.32, p = 0.005)
• 1.42 points at 12 months (95% CI 0.31 to 2.52, p = 0.012)
• No significant difference at 1 month (p = 0.97) or 3 months (p = 0.26)

Results were similar when EPO-treated children were added (1.18 and 1.23 points), when single-arm studies were removed, and when the unpublished study was removed. The authors see the delay as consistent with a treatment that works by calming inflammation and supporting repair, which therapy must then turn into skills.

Dose: The effect grew with the number of cells infused, significantly at 3 months (p below 0.001) and 12 months (p = 0.047). At 3, 6 and 12 months the average effect was close to or below zero for doses under roughly 50 × 10⁶ TNC per kg.

Severity: The effect was significantly larger at GMFCS levels I to III than at levels IV to V, at 3 months (p = 0.003), 6 months (p = 0.047) and 12 months (p below 0.001), and this held after adjusting for age. Higher doses produced larger gains in the milder group. In the GMFCS IV to V group no significant effect was detected at any dose.

After adjusting for severity, younger children responded better at 6 months (p = 0.035) and 12 months (p = 0.024). The authors summarise the best responders as children under about 5 years. Response did not differ by cause or type of cerebral palsy, and an apparent advantage for children born near term disappeared after adjusting for severity.

Unrelated allogeneic cord blood appeared to outperform autologous, but allogeneic recipients had received more than twice the dose (mean 71.3 versus 31.1 × 10⁶ TNC per kg). After adjusting for dose the difference was no longer significant. HLA mismatch made no significant difference either, though confidence intervals were wide.

Safety: Across all 13 studies there were 924 adverse events and 87 serious adverse events. Serious events occurred at a similar rate with UCB (52 events among 324 participants, 16.0%) and without (35 among 272, 12.9%). Only one serious event was judged definitely related to UCB. It was a treatable reaction to the cryoprotectant during infusion, with swelling and redness around one eye. At least five milder infusion reactions (hives, fever, cough, nausea) were also recorded.

Conclusions:

UCB is safe and improves gross motor function in some children with cerebral palsy, with larger effects at higher doses and in younger children with milder disability. Against published thresholds for a clinically important GMFM-66 change, the authors rate the gains as medium to large, particularly in the responder subgroups.

The authors list several limitations. The studies differed widely in participants, products and timing, which weakened the subgroup analyses. The rehabilitation each child received could not be accounted for, so the contribution of therapy cannot be separated from that of the cells. Cause-of-injury data were inconsistent. Some trials were at high risk of bias, and single-arm data risk mistaking normal development for treatment effect. Only gross motor function could be analysed. They call for a well-designed phase 3 trial.

Several authors declare financial interests, including royalties from cord blood companies and patents on the use of UCB in cerebral palsy. The study itself was unfunded.

Background Information:

Cord blood is thought to act through signalling. It is not expected to replace brain cells. The discussion raises two further points relevant to treatment planning. First, children with milder cerebral palsy reach about 90% of their motor potential before the age of 5, which is one reason earlier treatment may be more effective. Second, the authors propose studying doses above 150 × 10⁶ TNC per kg, although reaching them may require cord blood from several donors. They caution that repeated exposure to different donors carries a theoretical risk of immune sensitisation, that long-term monitoring (including for anti-HLA antibodies) would be needed, and that repeated dosing still has to be tested in high-quality trials.