The items of this meta-analysis were reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) (Additional file 2).
Article selection process
Approximately, 2078 articles were identified after the initial search. 1898 irrelevant articles were eliminated through browsing titles and abstracts, and 118 articles were excluded due to unexpected outcomes and interventions. Finally, 62 clinical trials, including 2 trials from the reference list, were taken into the analysis even if the elimination of 2 systematic reviews (Figure 1).
Baseline of included studies
The data were purified from studies performed over the past 11 years. Only 2 studies were prospective and the rest were randomized controlled trials (RCTs) ranging from study phrase 1/2 to study phrase 3. Asia was ranked first in the NO. of studies, and then North America and Europe. The MSC used in these studies were mainly isolated from bone marrow, adipose and umbilical cord. The injection dose ranged from 4×107 to 1.2 ×109 cells. The follow-up day was from 6 months to 2 years.
Pooled analysis of all studies
Totally, 62 clinical trials, containing populations with different characteristics, were included into analysis (Figure 2A). We discovered that MSC administration would not induce major side events, such as vascular disorders (1.17, 95% CI: 0.52-2.62, p=0.70), urticaria/dermatitis (0.93, 95% CI: 0.93-1.07, p=0.70), central nervous system disorders (1.13, 95% CI: 0.61-2.12, p=0.69), diarrhea (0.90, 95% CI: 0.49-1.63, p=0.73), death (0.99, 95% CI: 0.66-1.49, p=0.96), infection (1.03, 95% CI: 0.70-1.53, p=0.87). However, our analysis demonstrated that transient fever (3.65, 95% CI: 2.05-6.49) will occur within 48 hours if people receive MSC administration. Meanwhile, MSC injections also potentially caused administration site conditions (1.98. 95% CI: 1.01-3.87, p<0.01). Populations trended to benefit from receiving MSC therapy as they were like to have a lower rate of arrhythmia (0.62, 95% CI: 0.36-1.07, p=0.05).
As for minor side events, MSC presumably caused sleeplessness (5.90, 95% Ci: 1.04-33.47, p=0.05), constipation (2.45, 94% CI:1.01- 5.97, p=0.05), and fatigue (2.99, 1.06-8.44, p=0.05). Other minor side events, including, anemia (1.25, 95% CI: 0.39-4.07, p=0.71), metabolism and nutrition disorders (0.69, 95% CI: 0.20-2.43, p=0.56), nausea (2.00, 95% CI: 0.81-4.93, p=0.13), seizure (2.27, 94% CI: 0.79-6.56, p=0.13), vomiting (1.87,95% CI: 0.22-7.94, p=0.40), were non-significantly intimate to MSC treatment (Figure 2B).
Subgroup analysis of all studies
Subsequently, we dissected potential factors, including administration (method), age, methodology (analysis) of the article, cell type, population (disease), gender proportion, location, study phrase and publication date (year), influencing the major side events (Figure 3A). We identified that the non-significance of death, infection and diarrhea, which were not treatment-related side events of MSC therapy, were not altered in the slightest by any of the analyzed factors. MSC therapy was demonstrated to reduce the incidence of arrhythmia in the population with the age <60 years (p<0.01), PP analysis (p=0.01) and beyond 5 years (p<0.01). Despite the non-significant central nervous system disorders (head and dizziness) proved by pooled analysis, AD-MSC (p<0.01), placenta MSC (p<0.01) and uc-MSC (p<0.01) were more easily to cause headache and dizziness. Meanwhile, a population with degenerative joint diseases (p<0.01) and digestive diseases (p<0.01) could have headache and dizziness symptoms while receiving MSC implantation. Urticaria significantly occurred when the data were analyzed by PP analysis exclusively (p<0.01). As for vascular disorders, Asian people more easily had vascular disorders (p<0.01) after MSC treatment. Administration site conditions preferred to occur in populations with the age < 60 years (p=0.02), heart related diseases (p=0.01), the male proportion >60% (p=0.08), in study phrase 1/2 (p=0.01), and within 5 years (p=0.05). Even though transient fever was conspicuously associated with MSC treatment, populations with the age > 60 years (p=0.86), the male proportion < 60% (p=0.7), receiving local implantation (p=0.76), in North America (p=0.82) and study phrase 1 (p=0.15), had a lower risk of transient fever over the period MSC of therapy.
In terms of the minor side events, only five side events, including anemia, constipation, metabolism and nutrition disorders and nausea, were analyzed (Figure 3B). Similarly, the interactions between the 9 predicted factors and seldomly reported side events were dissected. Contrary to pooled analysis, neither constipation nor fatigue was a significant side event in these subgroup analyses. Similar to pooled analysis, both metabolism and nutrition disorders and nausea were non-impacted by these factors and were non-significant side events. Interestingly, we found that populations with the age < 60 years trended to have transient anemia (p=0.07) post-MSC treatment.
Pooled analysis of high-quality studies
After the elimination of low-quality articles (Kim 2018; Koh 2012; Lee 2017; Lin 2012; Oh 2018; Shi 2012; Sponer 2018; Wang 2006; Wang 2014; Wang 2016; Xie 2007; Zeng 2015; Xiao 2012; Skyler 2015), only seven major side events and one minor side event left (Figure 4). We merely found a close relationship between transient fever (3.08, 95% CI: 1.67-1.48, p=0.01) and MSC administration. Other side events, such as metabolism and nutrition disorders (0.49, 95% CI: 0.11-2.10, p=0.33), infection (1.05, 95% CI: 0.59-1.61, p=0.83), death (0.99, 95% CI: 0.66-1.48, p=0.96), arrhythmia (0.58, 95% CI: 0.33-1.03, p=0.06), central nervous system disorders (0.96, 95% CI: 0.49-1.88, p=0.91), vascular disorders (0.85, 95% CI: 0.30-2.45, p=0.77), and administration site conditions (2.15, 95% CI: 0.98-4.73, p=0.06) were not significantly impacted by MSC administration.
Subgroup analysis of high-quality studies
We examined whether the potential factors significantly influenced the terminal outcomes (7 major side events) reported by high-quality studies (Figure 5). MSC administration would not directly lead to death, death, central nervous disorders (headache and dizziness), or vascular disorders. Populations with the age <60 years (p<0.01), receiving BMSC injection (p=0.04), in study phrase 3 (p=0.04), and beyond 5 years (p<0.01) seemed to have a lower incidence of arrhythmia and benefit from MSC administration. When it came to transient fever, MSC administration would not trigger fever in populations with the age > 60 years (p=0.86), the male proportion <60% (p=0.70), from Europe (p=0.82), in study phrase 2 (p=0.15), beyond 5 years (p=0.11), and receiving local implantation (p=0.76).
Leave-one meta-analysis was performed for administration site conditions, arrhythmia, death, dermatitis, diarrhea, transient fever, infection, central nervous system disorders, and vascular disorders, and fatigue, metabolism and nutrition disorders, anemia, constipation, and nausea from all studies (Additional file 3-16), and for administration site conditions, arrhythmia, death, transient fever, infection, central nervous system disorders, and vascular disorders from high-quality studies (Additional file 17-23 ).
Publication bias and article quality
We assessed the article quality by using the Cochrane Collaboration’s tool for assessing the risk of bias (Figure 6). We concluded that most studies’ design was suitable and high quality. Only 14 studies were considered as low quality because they had more than two entries marked as high risk and less than four entries evaluated as low risk. There was performance bias, selection bias, detection bias, and attrition bias potentially lowering the integral quality of included studies. Furtherly, we tested the publication bias for administration site conditions, arrhythmia, death, dermatitis, diarrhea, transient fever, infection, central nervous system disorders, and vascular disorders (Additional file 24-32) from all studies. Publication bias for administration site conditions, arrythmia, death, fever, infection, central nervous system disorders, and vascular disorders (Additional file 33-39) from high-quality studies were conducted as well.