International Immunopharmacology 98 (2021) 107921

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International Immunopharmacology
journal homepage: www.elsevier.com/locate/intimp

Efficacy of bevacizumab in the treatment of pterygium: An updated

meta-analysis of randomized controlled trials
Xin Zhang a, 1, Yaping Jiang a, 1, Qiangqiang Fu b, Xiaoyan Zhang c, *, Yihui Chen a, *
a
Department of Ophthalmology, Yangpu hospital, School of Medicine, Tongji University, Shanghai 200092, China
b
Department of Scientific Research Management, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
c
Department of Ophthalmology, Huashan Hospital, Fudan University, Shanghai 200040, China

A R T I C L E I N F O A B S T R A C T

Keywords: Recurrence is the most common problem following pterygium surgery. Whether bevacizumab can prevent pte­
Pterygium rygium recurrence is controversial. To address this point, we carried out a meta-analysis of randomized
Bevacizumab controlled trials evaluating the efficacy and safety of bevacizumab in the treatment of pterygium. We searched
Recurrence
the PubMed, EMBASE, Cochrane Library, Web of Science, Chinese Biomedical Literature, China National
Meta-analysis
Knowledge Infrastructure, and Wan fang databases up to September 20, 2020 for relevant articles. We used the
Cochrane assessment tool to evaluate the methodologic quality of the included studies, and calculated the
relative risk (RR) and 95% confidence interval (CI) of the reported recurrence and complication rates. A total of
17 studies including 1124 patients with 1144 eyes were included in the meta-analysis. The combined results
showed that bevacizumab significantly reduced the recurrence rate of pterygium after surgery (RR = 0.652, 95%
CI: 0.504–0.845, Z = 3.24, P = 0.001) and was not significantly associated with the occurrence of postoperative
complications compared to control treatments (RR = 0.832, 95% CI: 0.604–1.145, Z = 1.13, P = 0.259). A
subgroup analysis showed that the rate of pterygium recurrence was significantly lower with bevacizumab than
in the control group at a dose of 2.5 mg (RR = 0.47, 95% CI: 0.24–0.91) administered by subconjunctival in­
jection (RR = 0.54, 95% CI: 0.39–0.75) after a follow-up time of ≤ 6 months (RR = 0.63, 95% CI: 0.45–0.88).
Thus, bevacizumab can reduce the risk of pterygium recurrence after surgery, and does not differ from placebo or
other drug treatments in terms of the risk of complications.

1. Introduction inflammation and fibrovascular proliferation [1,10–11]; compared to

Pterygium is a common conjunctival degenerative condition that is
characterized by palpebral fissure or bulbar conjunctiva fibrovascular
growth that invades the cornea [1–2]. Pterygium not only affects the
appearance of the cornea but also causes corneal astigmatism [3],
eventually leading to vision loss. The main treatment is surgical resec­
tion using the bare sclera, rotational conjunctival flap, or conjunctival
autograft technique [4]. However, the recurrence rate after pterygium
surgery is high [5] and varies according to the method of surgery [6–7].
To reduce the risk of recurrence, many adjuvant therapies are used with
surgery such as radiotherapy, mitomycin C, 5-fluorouracil, and anti-
vascular endothelial growth factor (VEGF) antibody [1,8–9].
The occurrence and development of pterygium is closely related to
normal conjunctiva, VEGF is overexpressed in pterygium tissue [12–14].
A number of anti-VEGF drugs such as pegaptanib, ranibizumab, and
aflibercept are used to treat eye diseases caused by abnormal angio­
genesis [15]. Bevacizumab is a humanized mouse monoclonal anti-
VEGF antibody that inhibits VEGF receptor to prevent pathologic
angiogenesis. In recent years, there have been many randomized
controlled trials (RCTs) investigating the use of bevacizumab for pte­
rygium treatment; however, there is conflicting evidence regarding its
safety and efficacy [14,16]. To address this point, in this study we car­
ried out a meta-analysis of randomized controlled trials of adjuvant
bevacizumab therapy in patients with pterygium treated by surgery.

* Corresponding authors at: Department of Ophthalmology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200092, China (Yihui Chen);
Department of Ophthalmology, Huashan Hospital, Fudan University, Shanghai 200040, China (Xiaoyan Zhang).
E-mail addresses: adele1854@gmail.com (X. Zhang), cyh80h@163.com (Y. Chen).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.intimp.2021.107921
Received 10 February 2021; Received in revised form 22 June 2021; Accepted 22 June 2021
Available online 2 July 2021
1567-5769/© 2021 Elsevier B.V. All rights reserved.
X. Zhang et al. International Immunopharmacology 98 (2021) 107921

2. Materials and methods

2.1. Search strategy

Two reviewers (Z.X. and J.Y.P.) independently searched the

PubMed, EMBASE, Cochrane Library, Web of Science, Chinese
Biomedical Literature, China National Knowledge Infrastructure, and
Wan fang databases up to September 20, 2020 for relevant publications
using the following search terms: (1) “pterygium” OR “pterygiums” OR
“pterygia”; (2) “bevacizumab” OR “avastin”; (3) “randomized controlled
trial” OR “controlled clinical trial” OR “placebo” OR “randomized” OR
“randomly” OR “trial”; and (4) species limitation: “humans”. There were
no restrictions on publication date or language.

2.2. Inclusion criteria

Articles were considered for inclusion if they met the following

criteria: (1) study design: RCTs, not limited to certain languages; (2)
subjects: patients with primary, impending recurrent pterygium or
recurrent pterygium; (3) intervention: topical bevacizumab eye drops or
subconjunctival bevacizumab injection; (4) comparison: bevacizumab
vs control treatment; and (5) outcome measure: recurrence rate and/or
complications. There were no restrictions on the dose of bevacizumab,
follow-up time, or timing of bevacizumab administration.

2.3. Data extraction and quality assessment

Two researchers (Z.X. and J.Y.P.) independently screened the liter­

ature based on the inclusion criteria. The author, publication date, type
of pterygium, route of drug administration, bevacizumab dose, follow-
up time, and outcome indicators (number of events and total number
of participants with complications and recurrence) were extracted from
each included study. The same 2 authors used the Cochrane risk-of-bias
tool to independently evaluate the quality of the studies according to the
following 7 evaluation items: random sequence generation, allocation
concealment, blinding of participants and personnel, blinding of
outcome assessment, incomplete outcome data, selective reporting, and
other types of bias. The levels of bias were low, high, or unclear risk. Any
disagreements between the 2 authors were resolved through discussion.
In the case of missing data, an attempt was made to contact the author of
the study for information.

2.4. Statistical analysis

We imported all data into Stata v14 (Stata Corp, College Station, TX,
USA) and Review Manager v5.3 (Cochrane Collaboration, Copenhagen,
Denmark), and calculated the relative risk (RR) and 95% confidence
interval (CI) of the outcome indicators (recurrence rate and complica­
tions). We calculated the I2 statistic to evaluate the heterogeneity of the
studies. The fixed effects model was used for the meta-analysis as the
heterogeneity was relatively low (I2 < 50%). We performed subgroup
analysis and used a meta-regression to address the heterogeneity among
studies. Moreover, we performed sensitivity analysis to evaluate the
stability of the results.
3. Results
3.1. Literature search and study selection
A flow diagram of the study selection process is shown in Fig. 1. The
database searches returned 134 articles. After removing 62 duplicates,
the remaining articles were filtered based on the title and abstract,
which excluded 42 irrelevant articles; thus, the full text of 30 articles
was screened. There were 12 articles that did not meet the inclusion
criteria for outcome indicators (1 study included both primary and
recurrent pterygium cases but did not report the number of each type),
Fig. 1. Flow diagram of the publication retrieval strategy.
and 1 for which the full text was not available. Ultimately, 17 RCTs were
included in our meta-analysis [17–33].
3.2. Characteristics of included studies
The 17 RCTs included in the meta-analysis had a total of 1124 pa­
tients (624 males and 500 females) with 1144 eyes. The sample size
ranged from 30 to 132 eyes; mean age ranged from 37 to 74 years;
follow-up time was between 3 and 30 months; and the total injected dose
of bevacizumab was 0.5–5 mg (Table 1). All 17 studies reported the rate
of recurrence, and 12 reported the rate of complications
[17–19,22–28,30–31].
3.3. Risk of bias in the included studies
The 17 studies included in the meta-analysis were published between
2010 and 2020. We assessed the risk of bias in the included studies using

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Table 1
Characteristics of randomized controlled trials included in the meta-analysis
Study Group No. of patients Mean age or age F Surgical Type of Bevacizumab Drug administration Follow-up, Final no. of Recurrence Complications
(eyes) range method pterygium dose route months patients

Bekibele, 2016 B 35 (35) 51.49 33 CAT Recurrent 0.5 mg Subconjunctival 18.35 26 1 0

Cont 35 (35) 27 1 0
Chen, 2012 B 17 (17) 56.6–57.9 20 CLSCA Recurrent 2.5 mg Subconjunctival, 6 17 0 0
Cont 19 (19) topical 19 5 0
Chen, 2019 B 40 (50) 53.2–53.7 46 AMT Primary 1.25 mg Subconjunctival 3 40 1 4
Cont 40 (50) 40 4 4
Hwang, 2015 B 36 (36) 73.9 37 BST Primary 2.50% Topical 6 36 15 2
Cont 96 (96) 96 25 4
Karalezli, 2014 B 42 (42) 53.04–58.82 45 LCA Primary 5 mg Topical 28.5–29.3 42 1 N/A
Cont 46 (46) 46 2 N/A
Kasetsuwan, 2015 B 12 (12) 50.7–59.3 12 BST Primary 0.05% Topical 3 12 4 N/A
Cont 10 (10) 10 9 N/A
Nuzzi, 2017 B 42 (42) 52.39–54.02 40 BST Primary 2.5 mg Subconjunctival 6 42 3 0
Cont 41 (41) 41 10 0
Ozgurhan, 2013 B 22 (22) 48.4–50.5 10 CAT Recurrent 5 mg Topical 6 22 0 2
Cont 22 (22) 22 2 1
3

Ozsutcu, 2014 B 30 (30) 40.8–43.25 39 RCF Primary 2.5 mg Subconjunctival 9 30 3 0

Cont 60 (60) 60 12 0
Razeghinejad, B 17 (17) 41.6–45.8 13 RCF Primary 1.25 mg Subconjunctival 6–10 15 2 7
2010 Cont 21 (21) 15 2 10
Shahin, 2012 B 20 (20) 58.12 17 LCA Primary 1.25 mg Subconjunctival 6 20 4 0
Cont 21 (21) 21 2 0
Shenasi, 2011 B 40 (40) 55.94–58.67 14 BST Primary 1.25 mg Subconjunctival 9 33 15 19
Cont 40 (40) 33 19 21
Singh, 2015 B 30 (30) 37.33 26 CAT Primary 1.25 mg Subconjunctival 3 30 2 5
Cont 30 (30) 30 3 4
Xu, 2013 B 40 (40) 41–44 49 CLSCA Primary 2.5 mg Subconjunctival 12 40 5 1
Cont 40 (40) 40 6 7
Yang, 2020 B 53 (53) 64.3 40 LCA Primary 1.25 mg Subconjunctival 12 53 1 N/A

International Immunopharmacology 98 (2021) 107921

Cont 48 (48) 48 4 N/A
Zhang, 2014 B 34 (34) 49.8–50.1 29 CLSCA Primary 2.5 mg Subconjunctival 6 34 0 N/A
Cont 32 (32) 32 4 N/A
Zhou, 2011 B 24 (31) 50.3 30 SPE Recurrent 1.25 mg Subconjunctival 6 24 3 N/A
Cont 28 (36) 28 10 N/A

Abbreviations: B, bevacizumab; BST, bare sclera technique; SPE, simple pterygium excision; CAT, conjunctival autograft transplantation; CLSCA, corneal limbal stem cell autograft; Cont, control; F, number of females;
LCA, limbal-conjunctival autograft transplantation; N/A, not available; RCF, rotational conjunctival flap.
X. Zhang et al.
the Cochrane evidence quality assessment tool; at least two evaluation
items of all included studies are low-risk, and more than 13 studies
contain at least 4 low-risk evaluation items (7 evaluation items). And,
we used the Egger test to analyze publication bias; the results revealed
that there was no publication bias associated with the RCTs included in
the meta-analysis (P = 0.121, Fig. 2 and Table 2).
3.4. Recurrence rate of pterygium with bevacizumab vs control treatment
In the 17 studies, there was a total of 526 eyes of 516 patients in the
bevacizumab group and 618 eyes of 608 patients in the control group.
The fixed-effects model applied to the summary results showed that the
recurrence rate was 11.4% (60/526) with bevacizumab and 19.4%
(120/618) with the control treatment. Thus, bevacizumab reduced the
rate of pterygium recurrence compared to the control (RR = 0.652, 95%
CI: 0.504–0.845, Z = 3.24, P = 0.001; I2 = 36.7%) (Fig. 3).
3.5. Complications with bevacizumab vs control treatment
There were 370 eyes of 360 patients in the bevacizumab group and
462 eyes of 452 patients in the control group. According to the fixed-
effects model, the rate of complications was 10.8% (40/370) in the
bevacizumab group and 11.0% (51/462) in the control group; the rates
in the 2 groups did not differ significantly (RR = 0.83, 95% CI:
0.60–1.15, Z = 1.13, P = 0.259; I2 = 0.0%) (Fig. 4).
3.6. Subgroup analysis and meta-regression of the effect of different
variables on pterygium recurrence
We carried out a subgroup analysis to evaluate the effect of pteryg­
ium type, surgical method, bevacizumab dose, route of administration,
and follow-up time on the rate of pterygium recurrence in patients
treated with bevacizumab vs the control (Table 3). The rate of recur­
rence of pterygium was significantly lower in patients treated with
bevacizumab than in control subjects at a bevacizumab dose of 2.5 mg
(RR = 0.47, 95% CI: 0.24–0.91) administered by subconjunctival in­
jection (RR = 0.54, 95% CI: 0.39–0.75). The recurrence rate was also
lower in the bevacizumab group than in the control group at a follow-up
time ≤ 6 months (RR = 0.63, 95% CI: 0.45–0.88), while no difference
between groups was observed for follow-up times exceeding 6 months
(RR = 0.69, 95% CI: 0.46–1.03). A meta-regression of the different
variables on pterygium recurrence showed that the type of pterygium,
the method of surgery, the duration of postoperative follow-up, and the
dose and method of injection of bevacizumab, were not a source of
heterogeneity (P greater than 0.05) (Table 4).
3.7. Sensitivity analysis of the effect of bevacizumab on recurrence of
primary pterygium
A sensitivity analysis was performed to evaluate the stability of the
results and determine which studies made the greatest contribution to
between-studies heterogeneity. Although the combined heterogeneity of
recurrence rates was acceptable, our results from the subgroup analysis
showed that the heterogeneity was mainly associated with primary
pterygium; we therefore conducted a sensitivity analysis for this subtype
and found that the sensitivity of the analysis to heterogeneity was
increased after excluding 2 studies (RR = 0.76944226, 95% CI:
0.57823575–1.0238754 [21] and RR = 0.78102463, 95% CI:
0.59194493–1.0305004 [22] compared to RR = 0.72505172, 95% CI:
0.55366215–0.94949602 for all studies combined) (Table 5).
4. Discussion
Our meta-analysis on the efficacy of bevacizumab in the treatment of
pterygium included 17 RCTs. Among them, 12 RCTs also reported
complications. The study by Hirst et al. found that 50% of pterygium
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International Immunopharmacology 98 (2021) 107921
patients have an average recurrence time of about 4 months, and 97% of
patients have recurrence within 1 year [34]. In our meta-analysis, 3
studies have a follow-up time of 3 months, while in the remaining 14
studies, the follow-up time is greater than 6 months, and the longest time
is over 2 years; therefore, the included studies have a reliable time
framework to assess recurrence. Our meta-analysis found that compared
with the control group, bevacizumab treatment can significantly reduce
the postoperative recurrence of primary or recurrent pterygium (RR =
0.652, 95% CI: 0.504–0.845, Z = 3.24, P = 0.001) without causing
obvious complications such as infection, corneal abrasion, subcon­
junctival hemorrhage, persistent epithelial defect, corneal edema, and
iritis (RR = 0.832, 95% CI: 0.604–1.145, Z = 1.13, P = 0.259) [35].
Subgroup analysis showed that in short-term follow-up (≤6 months),
subconjunctival injection of bevacizumab at a dose of 2.5 mg can
effectively reduce the recurrence rate of pterygium surgery, especially
for recurrent pterygium. To detect the source of heterogeneity, we
conducted subgroup analysis, sensitivity analysis, and meta regression.
In the results of the subgroup analysis, we found that the heterogeneity
of the primary pterygium group was significantly higher than that of the
recurrent pterygium group (I2 = 40.3% vs 0.0%). Although the hetero­
geneity of studies included in the primary pterygium group was not
significant (40.3% < 50%), we still did a sensitivity analysis. In the re­
sults of the sensitivity analysis, we found that excluding two studies
increased the sensitivity of the analysis: the study by Kasetsuwan et al.
[21] contributed heterogeneity with its small sample size (bevacizumab
group: 12 eyes; control group: 10 eyes) whereas in the study by Nuzzi
et al. [22] randomization and blinding methods were not clearly
described and some patients were lost to follow-up. Meta-regression
analysis showed that the type of pterygium, surgical method, post­
operative follow-up time, and the dose and injection method of bev­
acizumab were not associated with the source of heterogeneity.
Our meta-analysis concluded that bevacizumab was more effective in
recurrent pterygium than in primary pterygium with no significant
complications. However, the results of the meta-analysis by Hu et al.
showed that bevacizumab was not statistically significant in preventing
pterygium recurrence [36]. This is inconsistent with our findings, and
may be due to the inclusion of more RCTs in our study. In the updated
meta-analysis by Sun et al. by including more RCTs, bevacizumab was
found to reduce the recurrence rate of primary pterygium without
increasing complications, but had no significant effect on recurrent
pterygium [37]. Sun’s findings partially support our findings. Our study
showed that bevacizumab was effective for both primary and recurrent
pterygium and more effective in recurrent pterygium. Therefore, we
analyzed the reasons for the different conclusions of Sun’s study and
ours, and found that that recurrent pterygium was combined with
impending recurrent pterygium in the subgroup analysis by Sun et al.
We believed this combined analysis was inappropriate because of the
differences in outcomes and treatment of recurrent pterygium and
impending recurrent pterygium, which may have important implica­
tions for the conclusions of Sun’s study. In addition, the results of the
subgroup analysis of follow-up time by Sun et al. differed from ours, and
we considered that this mainly depended on the researchers’ grouping
criteria for follow-up time. A network meta-analysis by Zeng showed that
bevacizumab was effective in preventing primary and recurrent pte­
rygium recurrence [38]. These previous studies were more in favor of
the results of our study.
VEGF was the core molecule responsible for the development of
pterygium [39]. The VEGF family includes VEGF-a, b, c, d, f and their
tyrosine kinase receptors VEGFR-1, 2, 3, and their expression levels
reflect angiogenesis Important indicators [40]. Among them, VEGFR-2 is
the main and direct signal of angiogenesis. The study of Wang et al.
found that the expression of VEGFR-2 in pterygium tissue was higher
than that in normal conjunctival tissue, and the expression of VEGFR-2
was higher in recurrent pterygium [41]. Zeng et al. proved that
compared with primary pterygium, the mRNA expression levels of
VEGF-a and VEGF-c in recurrent pterygium were significantly up-
X. Zhang et al. International Immunopharmacology 98 (2021) 107921

Fig. 2. Risk of bias in the studies included in the meta-analysis. A. Risk of bias summary. B. Graphical representation of risk of bias. C. Results of the Egger test for the
detection of publication bias in the included studies. Green, yellow, and red represent low, unclear, and high risk of bias, respectively.

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Table 2
Risk of different types of bias in included studies
Study Random sequence Allocation Blinding of participants Blinding of outcome Incomplete Selective Other types
generation concealment and personnel assessment outcome data reporting of bias

Bekibele, 2016 Low Low Low Low High Low Unclear

Chen, 2012 Unclear Unclear Unclear Unclear Low Low High
Chen, 2019 Low Low Unclear Unclear Low Low Unclear
Hwang, 2015 Unclear Unclear Low Low Low Low Unclear
Karalezli, 2014 Low Low Low Low Low High High
Kasetsuwan, Low Low Low Low Low Low Low
2015
Nuzzi, 2017 Unclear Unclear Unclear Low Low High Unclear
Ozgurhan, 2013 Unclear Unclear Low Low Low Low Low
Ozsutcu, 2014 Low Low Low Low Low Low Unclear
Razeghinejad, Low Low Low Low High Low Low
2010
Shahin, 2012 Low Low Low Low Low Low Low
Shenasi, 2011 Unclear Unclear Low Low High Low Low
Singh, 2015 Low Low Low Low Low Low Low
Xu, 2013 Unclear Unclear Unclear Unclear Low Low High
Yang, 2020 Low Low Unclear Unclear Low Low Unclear
Zhang, 2014 Low Low Unclear Unclear Low Low Unclear
Zhou, 2011 Low Low Unclear Unclear Low Unclear High

Fig. 3. Forest plot of recurrence rates in bevacizumab-treated and control groups.

regulated [42]. In addition, high levels of VEGF-c secretion-induced
lymph angiogenesis have also been confirmed to play a vital role in the
development of pterygium [43]. Therefore, based on the results of these
studies, we believed that bevacizumab can prevent the recurrence of
pterygium by inhibiting VEGF receptor to prevent pathologic angio­
genesis, and it was more effective in recurrent pterygium. There were
certain challenges with the clinical application of bevacizumab for the
treatment of pterygium. In addition to the issues of efficacy and safety,
the standard dose of bevacizumab has not been established. In our meta-
analysis, we found that 2.5 mg of bevacizumab by subconjunctival in­
jection was most effective in reducing recurrence rates of pterygium,
which also differed from previous studies by Hu et al. and Sun et al.
This study had some limitations. First, only RCTs were included in
the meta-analysis, which may have resulted in the omission of other
types of study that met the inclusion criteria. Second, some of the
included studies did not specify the bevacizumab dose, which may have
undermined the reliability of our results. Third, the quality of some of
the included trials was low (e.g., because of unclear random assignment

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X. Zhang et al. International Immunopharmacology 98 (2021) 107921

Fig. 4. Forest plot of complications in bevacizumab-treated and control groups.

Table 3 Table 4
Subgroup analysis of the effect of different variables on the relationship between Meta-regression of the effect of different variables on the relationship between
bevacizumab treatment and pterygium recurrence after surgery bevacizumab treatment and pterygium recurrence after surgery
Variable No. of Events Total RR (95% CI) P Variable Coef. Std. t P>|t| 95% CI
trials value Err.
Lower CI Upper CI
Dose, mg limit limit
1.25 7 72 450 0.71 0.49
Type − 0.074 0.263 − 0.280 0.782 − 0.636 0.487
(0.48–1.05)
Dose, mg − 0.212 0.148 − 1.430 0.173 − 0.528 0.104
2.5 4 44 289 0.47
Injection 0.382 0.362 1.060 0.307 − 0.388 1.153
(0.24–0.91)
method
5 2 5 132 0.37
Follow-up 0.129 0.371 0.350 0.732 − 0.662 0.921
(0.06–2.37)
period,
Type of pterygium
months
Primary 13 158 959 0.73 0.07
Surgical − 0.048 0.104 − 0.460 0.649 − 0.269 0.173
(0.55–0.95)
method
Recurrent 4 22 185 0.29
(0.12–0.74) Abbreviations: Coef., coefficient; Std. Err., standard error; CI, confidence inter­
Injection method val.
Subconjunctival 13 122 858 0.54 0.97
(t is the estimated value of t, used to test statistical significance.)
(0.39–0.75)
Topical 4 58 286 0.97
(0.64–1.46) and blinding methods and loss of patient to follow-up), and these
Surgical method contributed significantly to the heterogeneity between studies. Addi­
Bare sclera technique 4 100 303 0.69 0.94
tionally, there may have been variability in the quality of included
(0.34–1.39)
Conjunctival autograft 3 9 157 0.59 studies because of differences in investigators’ definitions of study
transplantation (0.16–2,16) quality.
Corneal limbal stem cell 3 20 182 0.32
autograft (0.06–1.68) 5. Conclusion
Limbal-conjunctival 3 14 230 0.77
autograft (0.19–3.04)
transplantation The results of this meta-analysis of RCTs demonstrate that bev­
Rotational conjunctival 2 19 120 0.61 acizumab has good safety and efficacy in reducing the rate of pterygium
flap (0.23–1.66) recurrence in patients who undergo surgery for pterygium.
Follow-up period, months
≤6 10 106 636 0.63 0.73
(0.45–0.88) Funding
>6 7 74 508 0.69
(0.46–1.03) This study was supported by grants from the Scientific Research
Abbreviations: CI, confidence interval; RR, relative risk. Foundation of Shanghai Municipal Commission of Health and Family

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