Stem cell treatment and cerebral palsy: Systemic review and meta-analysis

Table 1 Intervention and study population overview

		Study Population			Intervention
Ref.	Country	Sample size	Age (yr)	Patient condition	Intervention and study groups	Application route	Type of stem cells	Source	Origin	Dose
Chen et al[45], 2013	China	60	1-35	CP, GMFCS level 3 to 5	Group 1: SC + rehabilitation Group 2: Rehabilitation only	Intrathecal	Mesenchymal stem cells in vitro transformed to neural stem cell- like cells	Bone marrow	Autologous	Fixed quantity of 1-2 × 107 cells, twice
Huang et al[46], 2018	China	56	3-12	CP	Group 1: SC + rehabilitation Group 2: Placebo + rehabilitation	Intravenous	Mesenchymal stem cells	Cord blood	Allogeneic	Fixed quantity of 5 × 107 cells, 4 times
Kang et al[47], 2015	South Korea	36	0.5-20	CP, GMFCS level 1 to 5	Group 1: SC Group 2: Placebo No rehabilitation	Intravenous/intraarterial	Mononuclear cells	Cord blood	Allogeneic1	5.46 × 107 cells/kg, once
Liu et al[40], 2017	China	105	0.5-12.5	Spastic CP, GMFCS level 2 to 5	Group 1: MNC Group 2: MSC Group 3: rehabilitation	Intrathecal	Mesenchymal stromal cells and mononuclear cells	Bone marrow	Autologous	106 cells/kg, 4 times
Luan et al[44], 2012	China	91	< 0.5-3.5	CP, GMFSC level 1 to 5	Group 1: SC + rehabilitation Group 2: rehabilitation only	Intraventricular	Neural progenitor cells	Aborted healthy fetuses’ forebrains	Allogeneic	Fixed quantity of 8-10 × 106 cells, once
Min et al[39], 2013	South Korea	105	0.8-10	CP	Group 1: SC+ EPO + rehabilitation Group 2: placebo SC + EPO + rehabilitation Group 3: placebo SC+ placebo + rehabilitation	Intravenous	Mononuclear cells	Cord blood	Allogeneic1	≥ 3 × 107 cells/kg, once
Rah et al[42], 2017	South Korea	57	2-10	Non-severe CP	Group 1: G-CSF at baseline, SC 1 mo later Group 2: G-CSF at baseline, placebo 1 mo later crossover at 7 mo	Intravenous	Mobilized mononuclear cells	Peripheral blood	Autologous	5.97 × 108 cells/ kg, once
Sun et al[41], 2017	USA	63	1-6	CP of any type, GMFCS Level 2 to 4 or 1 with hemiplegia	Group 1: SC + rehabilitation Group 2: Placebo + rehabilitation	Intravenous	Mononuclear cells	Cord blood	Autologous	2 × 107 cells/kg, once

¹Administation of cyclosporine. MNC: Mononuclear cells; MSC: Mesenchymal stem cells; EPO: Erythropoietin; CP: Cerebral palsy; SC: Stem cells; GMFCS: Gross motor function classification system.

Table 2 Evaluation of the risk of bias

Ref.	Random sequence generation: Selection bias	Allocation concealment	Blinding of participants and personnel: Performance bias	Blinding of outcome assessment: Detection bias	Incomplete outcome data: Attrition bias	Selective reporting
Chen et al[45], 2013	High	High	High	Low	High	High
Huang et al[46], 2018	Unclear	Unclear	High	Low	Low	Unclear
Kang et al[47], 2015	Low	Low	Low	Low	Low	Unclear
Liu et al[40], 2017	Low	Unclear	High	Unclear	Low	Low
Luan et al[44], 2012	Unclear	Unclear	High	Unclear	High	Unclear
Min et al[39], 2013	Low	Low	Low	Low	Low	Low
Rah et al[42], 2017	Low	Low	Low	Low	High	Unclear
Sun et al[41], 2017	Low	Low	Low	Low	Low	Unclear

Table 3 Raw motor outcome data

Ref.	Follow-up assessments after intervention (mo)	Change in GMFM-88/66 after 6 mo ± SD	Change in GMFM-88/66 after 12 mo ± SD	% improvement compared to baseline after whole observation period
Chen et al[45], 2013	1, 3, 6	Numbers inaccurately indicated	-	-
Huang et al[46], 2018	3, 6, 12, 24	Control: + 2.96 ± 1.66; MSC: + 7.62 ± 2.44	Control: + 4.75 ± 1.45; MSC: + 10.27 ± 2.96	Control: 5.67%; UCB: 14.89%
Kang et al[47], 2015	1, 3, 6	Control: 3.85 ± 3.75; UCB: 7.08 ± 7.36		Control: 13.1%; UCB: 24.2%
Liu et al[40], 2017	3,6, 12	Control: + 1.85; BMMNC: + 3.1; BMMSC: + 10.45	Control: + 2.91; BMMNC: + 6.46; BMMSC: + 12.52	Control: 7.84%; BMMSC: 33.76%
Luan et al[44], 2012	1, 6, 12	Control: not indicated; NPC: + 8.86	-	-
Min et al[39], 2013	1, 3, 6	Control: + 7.8 ± 5.1; EPO only: + 9.0 ± 6,3; UCB + EPO: + 9.1 ± 6.7	-	No baseline score provided
Rah et al[42], 2017	12 mo after treatment resp. 6 mo for crossover-group	-	Transplantation at baseline: + 2.9; Transplantation after 6 mo: + 6.37	No baseline score provided
Sun et al[41], 2017	12, 24	-	Control: + 6.9 ± 5.5; UCB: + 7.5 ± 6.8 (High dose: improvement + 4.3 ± 1.5 greater than expected. Low-dose and placebo: no significant improvement beyond expectation.)	Control: 13.3%; UCB: 15.3%

BMMNC: Bone marrow mononuclear cells; BMMSC: Bone marrow mesenchymal stem cells; EPO: Erythropoietin; NPC: Neural progenitor cells; UCB: Umbilical cord blood; MSC: Mesenchymal stem cells; GMFM: Gross Motor Function Measure.

Table 4 Reported serious adverse events

Ref.	Serious adverse events in cell recipient group	Serious adverse events in control group	Allogenic cells	Application route
Chen et al[45], 2013	0/30	0/30		Intrathecal
Huang et al[46], 2018	0/27	0/27	x	Intravenous
Kang et al[47], 2015	0/18	0/18	x (+ immunosuppressant)	Intravenous/intraarterial
Liu et al[40], 2017	0/68	0/34		Intrathecal
Luan et al[44], 2012	1/45	0/49	x	Intraventricular
Min et al[39], 2013	3/36	6/70	x (+ immunosuppressant)	Intravenous
Rah et al[42], 2017	0/57	-		Intravenous
Sun et al[41], 2017	0/63	-		Intravenous
Total	4/344 (1.2%)	6/228 (2.6%)