Umbilical cord blood stem cells transplantation as an adjunctive treatment strategy for liver cirrhosis in Chinese population: a meta-analysis of effectiveness and safety

Figures & data

Figure 1 Flow diagram of the selection process.

Table 1 Clinical information from the eligible trials in the meta-analysis

Included studies	Nation	Stage of LC	No of patients Con/Exp	Age (years)		Causes of LC
				Con	Exp
Li et al (2013)^Citation26	People’s Republic of China	Child–Pugh C	48/61	ND	ND	HBV
Li and Zhang (2016)^Citation27	People’s Republic of China	Child–Pugh A–C	21/29	19.2±5.3 (mean)	18.5±6.9 (mean)	HDC
Tan et al (2012)^Citation28	People’s Republic of China	Child–Pugh A–C	20/22	ND	56 (mean)	ND
Wang et al (2012)^Citation29	People’s Republic of China	Child–Pugh B–C	31/30	50±20 (mean)	48±22 (mean)	HBV (43), HCV (13) and alcohol (5)
Wang et al (2014)^Citation30	People’s Republic of China	Child–Pugh B–C	20/30	52 (median)	53 (median)	HBV (35), HCV (5), alcohol (6) and BC (4)
Zhang et al (2015)^Citation31	People’s Republic of China	Child–Pugh A–C	23/25	56.1±9.5 (mean)	55.6±10.7 (mean)	HBV
Zhou et al (2013)^Citation32	People’s Republic of China	Child–Pugh B–C	26/30	42.8±5.1 (mean)	44.1±3.9 (mean)	HBV
Zhou et al (2016)^Citation33	People’s Republic of China	Child–Pugh B–C	30/30	46±25 (mean)	45±26 (mean)	PBC
Zhou et al (2017)^Citation34	People’s Republic of China	Child–Pugh B–C	40/40	ND	ND	Alcohol
Zhu and Han (2014)^Citation35	People’s Republic of China	Child–Pugh B–C	30/30	55.2±14.1 (mean)	54.3±12.4 (mean)	PC (49) and alcohol (11)

Notes: Con, control group (RST alone group); Exp, experimental group (RST plus USCs therapy).

Abbreviations: LC, liver cirrhosis; ND, non-determined; HBV, hepatitis B virus; HDC, hepatolenticular degeneration cirrhosis; HCV, hepatitis C virus; PBC, primary biliary cirrhosis; BC, biliary cirrhosis; PC, post-hepatitic cirrhosis; RST, routine supportive treatment; USCs, umbilical cord blood stem cells.

Table 2 Information of USCs therapy

Included studies	Therapeutic regimen		Administration route	Cell dose	Parameter types
	Exp group	Con group
Li et al (2013)^Citation26	Con Reg + USCs	RST	1×10^9	1×10^9	TBIL, ALT, PT and QoL
Li and Zhang (2016)^Citation27	Con Reg + USCs	RST	1.6–7.3×10^7	1.6–7.3×10^7	TBIL, ALB, ALT, AST and PT
Tan et al (2012)^Citation28	Con Reg + USCs	RST	3.3×10^8 to 8.7×10^9	3.3×10^8 to 8.7×10^9	TBIL, ALB, ALT and PT
Wang et al (2012)^Citation29	Con Reg + USCs	RST	1–5×10^7	1–5×10^7	TBIL, ALB, ALT, AST and PTA
Wang et al (2014)^Citation30	Con Reg + USCs	RST	1.6–7.3×10^9	1.6–7.3×10^9	TBIL, ALB, ALT, AST and PTA
Zhang et al (2015)^Citation31	Con Reg + USCs	RST	0.2–2×10^7	0.2–2×10^7	TBIL, ALT, AST and PT
Zhou et al (2013)^Citation32	Con Reg + USCs	RST	>2×10^9	>2×10^9	TBIL, ALB, ALT, AST, PT and QoL
Zhou et al (2016)^Citation33	Con Reg + USCs	RST	1–5×10^7	1–5×10^7	TBIL, ALB, ALT, AST and PTA
Zhou et al (2017)^Citation34	Con Reg + USCs	RST	1–5×10^7	1–5×10^7	TBIL, ALB, ALT, AST and PTA
Zhu and Han (2014)^Citation35	Con Reg + USCs	RST	1.7–7.5×10^7	1.7–7.5×10^7	TBIL, ALB, ALT, PT and QoL

Notes: Con, control group (RST alone group); Exp, experimental group (RST plus USCs therapy).

Abbreviations: Con Reg, Control group regimen; USCs, umbilical cord blood stem cells; RST, routine supportive treatment; TBIL, total bilirubin; ALT, alanine aminotransferase; PT, prothrombin time; QoL, quality of life; ALB, albumin; AST, aspartate aminotransferase; PTA, prothrombin activity.

Figure 2 (A) Risk of bias summary: review of authors’ judgments about each risk of bias item for the included studies. (B) Risk of bias graph: review of authors’ judgments about each risk of bias item presented as percentages across all the included studies. Each color represents a different level of bias: red for high risk, green for low risk and yellow for unclear risk of bias.

Figure 3 Forest plot of the comparison of TBIL (A), ALB (B), ALT (C), AST (D), PT (E) and PTA (F) in pre- and post-therapy.

Note: The random-effects meta-analysis model (inverse variance method) was used.
Abbreviations: IV, inverse variance method; TBIL, total bilirubin; ALB, albumin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PT, prothrombin time; PTA, prothrombin activity.

Figure 4 Forest plot of the comparison of QoL including fatigue (A), appetite (B), abdominal distension (C), ascitic fluid (D) and edema (E) between the experimental and control groups.

Notes: Control group, RST alone group; experimental group, RST plus USCs therapy.
Abbreviations: M–H, Mantel–Haenszel method; QoL, quality of life; USCs, umbilical cord blood stem cells; RST, routine supportive treatment.

Table 3 Information of adverse events during the USCs therapy

Included studies	Adverse events (number)
Li et al (2013)^Citation26	No obvious adverse reactions; excitement (12)
Li and Zhang (2016)^Citation27	Fever (1)
Tan et al (2012)^Citation28	No obvious adverse reactions
Wang et al (2012)^Citation29	No obvious adverse reactions
Wang et al (2014)^Citation30	No obvious adverse reactions
Zhang et al (2015)^Citation31	No obvious adverse reactions
Zhou et al (2013)^Citation32	No obvious adverse reactions; low-grade fever (3)
Zhou et al (2016)^Citation33	No obvious adverse reactions
Zhou et al (2017)^Citation34	No obvious adverse reactions
Zhu and Han (2014)^Citation35	Low-grade fever (1); tension, pain (1)

Abbreviation: USCs, umbilical cord blood stem cells.

Figure 5 Funnel plot of percentage of TBIL (A), ALB (B), ALT (C) and PT (D) in pre- and post-therapy.

Note: Bias analyses were conducted for parameters discussed in >6 papers.
Abbreviations: TBIL, total bilirubin; ALB, albumin; ALT, alanine aminotransferase; PT, prothrombin time.

Table 4 Subgroup analyses of TBIL, ALB, ALT and PT in pre- and post-therapy

Parameters	Time point (after therapy)	Factors at study level	Pre-therapy	Post-therapy	Analysis method	Heterogeneity		OR	95% CI	P-value
			No of patients	No of patients		I^2 (%)	P-value
TBIL	4th week	CN>1×10^8	113	113	Random	0	0.49	−9.91	−12.95 to −6.86	<0.00001
		CN<1×10^8	84	84	Random	95	<0.00001	−20.56	−53.73 to 12.61	0.22
		Hepatic artery	82	82	Random	0	0.68	−8.05	−13.22 to −2.88	0.002
		Intravenous	115	115	Random	97	<0.00001	−18.77	−42.39 to 4.85	0.12
	8th week	CN>1×10^8	91	91	Random	0	0.33	−28.17	−31.50 to −24.84	<0.00001
		CN<1×10^8	130	130	Random	49	0.12	−12.14	−18.01 to −6.26	<0.0001
ALB	4th week	CN>1×10^8	113	113	Random	0	0.92	5.59	4.44 to 6.75	<0.00001
		CN<1×10^8	59	59	Random	93	<0.0001	4.12	−2.35 to 10.58	0.21
		Hepatic artery	82	82	Random	73	0.02	3.57	0.02 to 7.11	0.05
		Intravenous	90	90	Random	41	0.19	6.55	5.08 to 8.02	<0.00001
	8th week	CN>1×10^8	91	91	Random	58	0.12	6.20	4.14 to 8.26	<0.00001
		CN<1×10^8	130	130	Random	71	0.02	6.37	3.10 to 9.64	0.0001
ALT	4th week	CN>1×10^8	113	113	Random	97	<0.00001	−84.81	−122.71 to −46.90	<0.0001
		CN<1×10^8	84	84	Random	96	<0.00001	−41.59	−88.74 to 5.56	0.08
		Hepatic artery	82	82	Random	97	<0.00001	−85.80	−142.84 to −28.76	0.003
		Intravenous	115	115	Random	98	<0.00001	−45.52	−89.67 to −1.37	0.04
	8th week	CN>1×10^8	91	91	Random	99	<0.00001	−57.36	−101.95 to −12.77	0.01
		CN<1×10^8	130	130	Random	96	<0.00001	−29.02	−49.72 to −8.33	0.006
PT	4th week	CN>1×10^8	113	113	Random	87	0.0003	−3.81	−6.82 to −0.80	0.01
		CN<1×10^8	59	59	Random	35	0.22	−2.28	−3.91 to −0.65	0.006
		Hepatic artery	82	82	Random	80	0.007	−3.88	−6.75 to −1.00	0.008
		Intravenous	90	90	Random	55	0.13	−2.12	−3.79 to −0.44	0.01

Note: Subgroup analyses were conducted in parameters discussed in >6 papers.

Abbreviations: CN, cell number; TBIL, total bilirubin; ALB, albumin; ALT, alanine aminotransferase; PT, prothrombin time; OR, odds ratio.

Figure S1 Forest plot of the comparison of TBIL (A), ALB (B), ALT (C), AST (D), PT (E) and PTA (F) between the experimental and control groups.

Notes: Control group, RST alone group; experimental group, RST plus USCs therapy.

Abbreviations: IV, inverse variance method; TBIL, total bilirubin; ALB, albumin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PT, prothrombin time; PTA, prothrombin activity; USCs, umbilical cord blood stem cells; RST, routine supportive treatment.

Figure S2 Funnel plot of percentage of total bilirubin (TBIL, A), albumin (ALB, B), alanine aminotransferase (ALT, C) and prothrombin time (PT, D) between the experimental and control groups.

Notes: Subgroup analyses were conducted in parameters discussed in >6 papers. Control group, routine supportive therapy alone group; experimental group, RST plus umbilical cord blood stem cell therapy.

Table S1 Subgroup analyses of TBIL, ALB, ALT and PT between the experimental and control groups

Parameters	Time point (after therapy)	Factors at study level	Exp group	Con group	Analysis method	Heterogeneity		OR	95% CI	P-value
			No of patients	No of patients		I^2 (%)	P-value
TBIL	4th week	CN>1×10^8	113	94	Random	57	0.10	−1.66	−7.24 to 3.93	0.56
		CN<1×10^8	84	74	Random	22	0.28	−0.47	−6.73 to 5.79	0.88
		Hepatic artery	82	76	Random	0	0.64	1.05	−4.09 to 6.19	0.69
		Intravenous	115	92	Random	57	0.10	−2.35	−7.70 to 3.01	0.39
	8th week	CN>1×10^8	91	74	Random	96	<0.00001	−8.46	−23.45 to 6.53	0.27
		CN<1×10^8	130	131	Random	52	0.10	−3.56	−8.84 to 1.71	0.19
ALB	4th week	CN>1×10^8	113	94	Random	63	0.07	5.70	3.62 to 7.78	<0.00001
		CN<1×10^8	59	51	Random	86	0.008	2.57	−2.03 to 7.17	0.27
		Hepatic artery	82	76	Random	89	0.0001	3.60	−1.95 to 9.16	0.20
		Intravenous	90	69	Random	0	1.00	4.80	3.78 to 5.82	<0.00001
	8th week	CN>1×10^8	91	74	Random	0	0.83	5.04	3.71 to 6.38	<0.00001
		CN<1×10^8	130	131	Random	80	0.002	6.56	2.65 to 10.48	0.001
ALT	4th week	CN>1×10^8	113	94	Random	30	0.24	−11.45	−17.68 to −5.22	0.0003
		CN<1×10^8	84	74	Random	59	0.09	3.08	−6.63 to 12.79	0.53
		Hepatic artery	82	76	Random	91	<0.0001	−7.01	−26.09 to 12.06	0.47
		Intravenous	115	92	Random	4	0.35	−4.27	−9.67 to 1.13	0.12
	8th week	CN>1×10^8	91	74	Random	65	0.09	−8.66	−15.32 to −2.00	0.01
		CN<1×10^8	130	131	Random	8	0.36	−0.20	−3.88 to 3.48	0.91
PT	4th week	CN>1×10^8	113	94	Random	82	0.004	−1.00	−3.14 to 1.14	0.36
		CN<1×10^8	59	51	Random	0	0.89	−1.26	−2.55 to 0.03	0.06
		Hepatic artery	82	76	Random	0	0.61	−1.68	−2.65 to −0.71	0.0007
		Intravenous	90	69	Random	53	0.15	−0.15	−1.78 to 1.48	0.86

Notes: Subgroup analyses were conducted in parameters discussed in >6 papers. Control group, RST alone group; experimental group, RST plus USCs therapy.

Abbreviations: Exp, experimental; Con, control; TBIL, total bilirubin; ALB, albumin; ALT, alanine aminotransferase; PT, prothrombin time; OR, odds ratio; RST, routine supportive therapy; USCs, umbilical cord blood stem cells.

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