Conjunctival autograft for pterygium.

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Cochrane Database Syst Rev. Author manuscript; available in PMC 2017 February 11. Published in final edited form as: Cochrane Database Syst Rev. ; 2: CD011349. doi:10.1002/14651858.CD011349.pub2.

Conjunctival autograft for pterygium Elizabeth Clearfield1, Valliammai Muthappan2, Xue Wang1, and Irene C Kuo2 1Department

of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA 2Department

of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

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Abstract Background—A pterygium is a fleshy, wing-shaped growth from the conjunctiva, crossing over the limbus onto the cornea. Prevalence ranges widely around the world. Evidence suggests that ultraviolet light is a major contributor in the formation of pterygia. Pterygia impair vision, limit eye movements, and can cause eye irritation, foreign body sensation, and dryness. In some susceptible patients, the pterygium can grow over the entire corneal surface, blocking the visual axis.

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Surgery is the only effective treatment for pterygium, though recurrences are common. With simple excision techniques (that is, excising the pterygium and leaving bare sclera), the risk of recurrence has been reported to be upwards of 80%. Pterygium excision combined with a tissue graft has a lower risk of recurrence. In conjunctival autograft surgery, conjunctival tissue from another part of the person’s eye along with limbal tissue is resected in one piece and used to cover the area from which the pterygium was excised. Another type of tissue graft surgery for pterygium

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Contact address: Irene C Kuo, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland, 21287, USA. [email protected]. CONTRIBUTIONS OF AUTHORS Conceiving the review: ICK, VM, XW, CEVG Designing the review: ICK, VM, XW Drafting the protocol: ICK, VM, XW Co-ordinating the review: EC Undertaking electronic and manual searches: CEVG Screening search results: ICK, EC Organizing retrieved papers against inclusion criteria: EC Appraising methodological quality of papers: ICK, VM, EC Abstracting data from papers: ICK, VM, EC, CEVG Data management of the review: EC Entering data into RevMan: EC Analyzing and presenting results: ICK, EC Interpreting results: ICK, EC Writing the review: ICK, EC DECLARATIONS OF INTEREST EC: No conflict of interest or financial interest. VM: No conflict of interest or financial interest. XW: No conflict of interest or financial interest. ICK: No conflict of interest or financial interest. DIFFERENCES BETWEEN PROTOCOL AND REVIEW To meet Cochrane standards, we modified our methods to include an assessment of the certainty of the evidence using the GRADE classification. These assessments are presented in the Summary of Findings table.

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is amniotic membrane graft, whereby a piece of donor amniotic membrane is fixed to the remaining limbus and bare sclera area after the pterygium has been excised. Objectives—The objective of this review was to assess the safety and effectiveness of conjunctival autograft (with or without adjunctive therapy) compared with amniotic membrane graft (with or without adjunctive therapy) for pterygium. We also planned to determine whether use of MMC yielded better surgical results and to assess the direct and indirect comparative costs of these procedures.

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Search methods—We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 10, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other NonIndexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), PubMed (1948 to November 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to November 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched 21 November 2014), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/ search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 23 November 2015. Selection criteria—We included in this review randomized controlled trials that had compared conjunctival autograft surgery (with or without adjunctive therapy) with amniotic membrane graft surgery (with or without adjunctive therapy) in people with primary or recurrent pterygium.

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Data collection and analysis—Two review authors independently screened search results and assessed full-text reports from among the potentially eligible trials. Two review authors independently extracted data from the included trials and assessed the trial characteristics and risk of bias. The primary outcome was the risk of recurrence of pterygium at 3 months and 6 months after surgery. We combined results from individual studies in meta-analyses using random-effects models. Risk of recurrence of pterygium was reported using risk ratios to compare conjunctival autograft with amniotic membrane transplant. Main results—We identified 20 studies that had analyzed a total of 1947 eyes of 1866 participants (individual studies ranged from 8 to 346 participants who were randomized). The studies were conducted in eight different countries: one in Brazil, three in China, three in Cuba, one in Egypt, two in Iran, two in Thailand, seven in Turkey, and one in Venezuela. Overall risk of bias was unclear, as many studies did not provide information on randomization methods or masking to prevent performance and detection bias.

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The risk ratio for recurrence of pterygium using conjunctival autograft versus amniotic membrane transplant was 0.87 (95% confidence interval (CI) 0.43 to 1.77) and 0.53 (95% CI 0.33 to 0.85) at 3 months and 6 months, respectively. These estimates include participants with primary and recurrent pterygia. We performed a subgroup analysis to compare participants with primary pterygia with participants with recurrent pterygia. For participants with primary pterygia, the risk ratio was 0.92 (95% CI 0.37 to 2.30) and 0.58 (95% CI 0.27 to 1.27) at 3 months and 6 months, respectively. We were only able to estimate the recurrence of pterygia at 6 months for participants with recurrent pterygia, and the risk ratio comparing conjunctival autograft with amniotic membrane transplant was 0.45 (95% CI 0.21 to 0.99). One included study was a doctoral thesis

Cochrane Database Syst Rev. Author manuscript; available in PMC 2017 February 11.

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and did not use allocation concealment. When this study was excluded in a sensitivity analysis, the risk ratio for pterygium recurrence at 6 months’ follow-up was 0.43 (95% CI 0.30 to 0.62) for participants with primary and recurrent pterygium. One of the secondary outcomes, the proportion of participants with clinical improvement, was analyzed in only one study. This study reported clinical outcome as the risk of non-recurrence, which was seen in 93.8% of participants in the conjunctival limbal autograft group and 93.3% in the amniotic membrane transplant group at 3 months after surgery. We did not analyze data on the need for repeat surgery, vision-related quality of life, and direct and indirect costs of surgery due to an insufficient number of studies reporting these outcomes.

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Thirteen studies reported adverse events associated with conjunctival autograft surgery and amniotic membrane transplant surgery. Adverse events that occurred in more than one study were granuloma and pyogenic granuloma and increased intraocular pressure. None of the included studies reported that participants had developed induced astigmatism. Authors’ conclusions—In association with pterygium excision, conjunctival autograft is associated with a lower risk of recurrence at six months’ after surgery than amniotic membrane transplant. Participants with recurrent pterygia in particular have a lower risk of recurrence when they receive conjunctival autograft surgery compared with amniotic membrane transplant. There are few studies comparing the two techniques with respect to visual acuity outcomes, and we identified no studies that reported on vision-related quality of life or direct or indirect costs. Comparison of these two procedures in such outcome measures bears further investigation. There were an insufficient number of studies that used adjunctive mitomycin C to estimate the effects on pterygium recurrence following conjunctival autograft or amniotic membrane transplant. Medical Subject Headings (MeSH)

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*Autografts;

Amnion [transplantation]; Conjunctiva [*transplantation]; Pterygium [*surgery]; Randomized Controlled Trials as Topic; Recurrence; Time Factors

MeSH check words Humans

PLAIN LANGUAGE SUMMARY Tissue graft surgery to treat a wing-shaped growth (pterygium) in the eye

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Review question—We reviewed the evidence to see which surgery used to treat pterygium (a growth in the eye) is better and safer? We wanted to known which surgery was better at preventing the pterygium from growing back. Background—A pterygium is a wing-shaped growth in the outer layer of an eye from the corner of the eye and crosses the border between the white of the eye and the iris (the colored part of the eye). Its cause is believed to be exposure to ultraviolet light from the sun. The growth is more common in men and older people. If the pterygium is large enough, seeing can be difficult. It also can make the patient feel that their eye is irritated, dry, or has


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something in it. It also can cause cosmetic concerns. In some people, the pterygium grows to cover the entire front of the eye and makes it hard to see. Surgery is required to treat this growth. Even after surgery, it can grow back. When the doctor removes only the growth and leaves the spot underneath exposed, the growth returns in about 80% of patients. A new surgery technique removes the growth and then covers the spot with tissue. This surgery is called a tissue graft. When a tissue graft is used to cover the bare spot, the pterygium does not regrow in as many eyes as when the spot is left bare. There are two types of tissue graft surgery: conjunctival autograft surgery (CAG) and amniotic membrane transplant (AMT). The purpose of this review was to compare recurrence of pterygium after these two types of tissue graft.

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In CAG, tissue from another part of the patient’s eye is removed and then placed over the bare spot that was left where the pterygium was removed. In AMT, tissue from a baby’s placenta after childbirth is used to cover this bare spot. The surgeon gets this tissue from a tissue bank. Study characteristics—We considered the type of pterygium surgery to be better if it the pterygium returned in a smaller proportion of people at three and six months after the surgery. We searched online databases of published medical articles to find studies that had assigned participants to one of the two surgeries. We included in our review only the studies in which the participants were assigned randomly to their surgery, so that they had an equal chance of being assigned to either one. Study participants could have this growth for the first time (primary pterygium) or could need another surgery because their growth had returned previous surgery. The evidence is current to November 2015.

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Key results—We found 20 studies that compared the two surgeries in a total of 1947 eyes. We combined information from the studies to determine which surgery was better. Six months after surgery, the pterygium returned only one third to over half as often in people who had CAG surgery than in people who had AMT surgery. This difference could not be explained by chance alone. The studies we found did not answer all of our questions. We still want to know the effects of the surgeries on clarity of vision, quality of vision, quality of life and costs. More research studies are needed that answer these questions.

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Quality of the evidence—The overall quality of the evidence in favor of CAG is low to moderate because of issues in the conduct of the studies and results were sometimes not similar across studies. Future published research may have an impact on the conclusions provided in this review.


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SUMMARY OF FINDINGS FOR THE MAIN COMPARISON [Explanation] Conjunctival autograft com pared to amniotic membrane transplant for pterygium Patient or population: people with primary or recurrent pterygium Intervention: conjunctival autograft Comparison: amniotic membrane transplant Outcomes

Anticipated absolute effects* (95% CI) Risk with amniotic membrane transplant

Risk with conjunctival autograft

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Relative effect (95% CI)

No. of eyes (studies)

Quality of the evidence (GRADE)

RR 0.87 (0.43 to 1.77)

538 (6 RCTs)

⊕○○○ VERY LOW 1,2,3

RR 0.53 (0.33 to 0.85)

1021 (10 RCTs)

⊕⊕⊕○ MODERATE1

Comment

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Recurrence of pterygium follow-up: 3 months

Study population

Recurrence of pterygium follow-up: 6 months

Study population

Clinical improvement (nonrecurrence risk) follow-up: 3 months

See comment

One study reported the risk of nonrecurrence as 93.8% for participants in the conjunctival limbal autograft group and 93.3% in the amniotic membrane transplant group at 3 months after surgery

Need for repeat surgery

See comment

2 studies reported the need for repeat surgery but did not provide time points. In 1 study, 1 participant in the amniotic membrane transplant group developed suture lysis, and amniotic membrane revision was perform ed. In the other study, 1 participant in each surgical group had surgery again

Mean change in visual acuity

See comment

No study reported mean change. 1 study reported the logMAR at baseline and postoperatively, and there was no difference

89 per 1000

189 per 1000

77 per 1000 (38 to 158)

100 per 1000 (62 to 161)


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Conjunctival autograft com pared to amniotic membrane transplant for pterygium Patient or population: people with primary or recurrent pterygium Intervention: conjunctival autograft Comparison: amniotic membrane transplant Outcomes

Anticipated absolute effects* (95% CI) Risk with amniotic membrane transplant

Risk with conjunctival autograft

Relative effect (95% CI)

No. of eyes (studies)

Quality of the evidence (GRADE)

Comment

(mean difference 0.00, 95% CI −0.66 to 0.66)

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Quality of life

None of the included studies reported on quality of life measures after the 2 surgeries

Direct and indirect costs

None of the included studies reported on direct or indirect costs after the 2 surgeries

*

The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio

GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect

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1

Allocation concealment unclear in every study and evidence of possible attrition bias. 2 Estim ate is not precise, ranging from 0.43 to 1.77. 3 Individual study results are inconsistent.

BACKGROUND Description of the condition

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A pterygium is a fleshy, wing-shaped growth from the conjunctiva, crossing over the limbus onto the cornea. The tissue is fibrovascular and can occur over the nasal or temporal cornea. It can be a bilateral process and asymmetric with one eye affected by a larger pterygium than the other. In addition, two pterygia can affect a single eye, one nasally and the other temporally. The pterygium consists of collagen tissue that is hyperplastic and denatured, marked by elastotic degeneration (degeneration of collagen fibers). It often is preceded by a growth of the conjunctiva without extension onto the cornea, known as a pingueculum. It is believed that ultraviolet light is a major contributor in the formation of pterygia, though the finding that a high prevalence of pterygium exists outside inhabitants of equatorial regions strongly suggests that reflected, scattered light is also critical (Droutsas 2010). A study in Japan found a high prevalence of pterygium in welders, despite the wearing of eye protection with ultraviolet light filtration (Karai 1984). Both individual susceptibility and


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environmental exposure appear to be risk factors responsible for the occurrence of pterygium.

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Pterygium is twice as common in men as in women, except in Aruba, where it is equally common between the sexes (Singh 2005). It is more prevalent in older age groups, but the incidence is higher in younger individuals. It is uncommon in people younger than 20 years of age and among people who wear glasses (Singh 2005). The incidence increases greatly in people between 20 and 40 years of age (Hill 1989). The prevalence is 23% in Aruba, 18% in Puerto Rico, 5% to 15% in Texas, Florida, California, Arizona, and New Mexico, and drops to 2% or less in areas more than 40 degrees from the equator (Raj 2010). A recent metaanalysis of 20 studies, mostly from Asia, estimated the prevalence of pterygium to be 10.2% (95% confidence interval (CI) 6.3% to 16.1%) (Liu 2013). The pooled prevalence among men was higher than among women (14.5% versus 13.6%), and the proportion of participants with unilateral cases of pterygium was higher than those with bilateral cases of pterygium (8% versus 6.2%; no P value or CI reported). A greater prevalence of pterygium was associated with increasing geographical latitude and age. Risk factors for pterygium include male gender (odds ratio 2.32, 95% CI 1.66 to 3.23) and outdoor activity (odds ratio 1.76, 95% CI 1.55 to 2.00) (Liu 2013).

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Pterygia can impair vision through altered tear film, induced astigmatism, photophobia, epiphora, and binocular diplopia due to contraction of the Tenon’s capsule, which limits eye movements. Pterygia can cause symptoms such as eye irritation, foreign body sensation, and dryness. In mild climates, it is unusual for a pterygium to grow over the visual axis, but patients are often concerned about the cosmetic appearance of their eye. In potentially susceptible individuals, the pterygium can grow across the entire corneal surface, impairing vision. Description of the intervention Surgery is the only effective treatment for pterygia, and many techniques have been described. No technique prevents recurrences, which are often associated with more ocular morbidity than the primary occurrence. The most common techniques in use include bare sclera excision, first described in 1948 (D’Ombrain 1948), and tissue grafting. These surgeries may be combined with adjunctive radiation or chemotherapy agents such as mitomycin C (MMC) (Kirwan 2003). The risk of recurrence after simple excision is reported to be as high as 88% in certain populations (Chen 1995). Graft tissue use is believed to have been first described in 1876, in which a mucous membrane was used to cover the defect left by pterygium surgery (Klein 1876).

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In this review, we focused on two types of tissue grafting procedures: conjunctival autograft versus amniotic membrane graft. Conjunctival limbal autograft (hereafter referred to as “conjunctival autograft”) involves removing limbal tissue and adjacent conjunctiva in one piece from another part of the person’s eye and using the tissue to cover the area from which the pterygium was excised. Careful attention is paid to aligning the limbal tissue of the autograft to the limbal area over which the pterygium used to lie and which is denuded in the process of removing the pterygium. Conjunctival autograft has been the most popular method of pterygium surgery since it was re-introduced in the 1980s (Kenyon 1985). A Cochrane Database Syst Rev. Author manuscript; available in PMC 2017 February 11.

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similar method was described at a meeting in 1965 (Barraquer 1965). The size of the autograft tissue is determined by the size of the pterygium tissue that is excised. The orientation of the autograft tissue is such that the limbal side of the transplant is fixed to the limbal area from where the pterygium was excised. The method has been modified over time to include adjunctive use of MMC (an alkylating agent that crosslinks DNA and thus inhibits mitosis) or use of tissue adhesive instead of sutures to attach the conjunctival autograft to the underlying tissue. Though the technique is significantly more lengthy and difficult compared to simple excision, it has the benefit of reducing the recurrence risk to 5% to 15% (Chen 1995).

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Amniotic membrane graft, fixed either with sutures or tissue adhesive, is a relatively new technique used increasingly in recent years. A piece of amniotic membrane from a tissue bank or other organization is centered over the area from which the pterygium was removed then sutured or “glued” over the bare scleral area. The tissue can be cryopreserved, dehydrated, and sterilized; if dehydrated, it is re-hydrated, then cut to the proper size and sutured in such a way to cover the bare sclera left after excision of the pterygium (Prabhasawat 1997; Shimazaki 1998). Possible reasons for the effectiveness of amniotic membrane graft in pterygium surgery include inhibition of pathological neovascularization (Hao 2000; Kim 1995; Kobayashi 1999), scar formation (Tseng 1999), and inflammation (Bultmann 1999; Solomon 1999). How the intervention might work Pterygium pathogenesis can be conceptualized as occurring in two stages:

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1.

initial and progressive disruption of the limbal corneal-conjunctival epithelial barrier; and

2.

progressive active “conjunctivalization” of the cornea by tissue characterized by extensive cellular proliferation, inflammation, connective tissue remodeling, and angiogenesis (Coroneo 1999).

The corneal limbal stem cells are usually abnormal in pterygia (Kwok 1994), such that the limbal corneal-conjunctival epithelial barrier is disrupted, and the cornea assumes conjunctival characteristics in a process marked by extensive cellular proliferation, inflammation, connective tissue remodeling, and angiogenesis. A healthy limbus acts as a barrier to conjunctival overgrowth (Coroneo 1999). Inclusion of healthy tissue from grafting may reduce pterygium recurrence both physically and physiologically. It is unlikely that moving a limited area of limbus stem cells to another site would damage the ocular surface.

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Why it is important to do this review Conjunctival autograft may be the most common surgical technique for pterygium, but it is not universally accepted that it is the technique with the lowest risk of recurrence. Unlike newer methods, it does not require tissue allograft (tissue from another person). Amniotic membrane transplantation is an alternative, but it is more expensive and utilizes more resources. It is unclear how conjunctival autograft outcomes compare with those of amniotic membrane grafts. Moreover, it is unclear whether these procedures yield better results when combined with MMC. The parameters surrounding use of MMC, a potent antimetabolite Cochrane Database Syst Rev. Author manuscript; available in PMC 2017 February 11.

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that alkylates and crosslinks DNA, must be carefully identified and evaluated, as complications such as corneoscleral melt, necrosis, and perforation have been reported with MMC.

OBJECTIVES The objective of this review was to assess the safety and effectiveness of conjunctival autograft (with or without adjunctive therapy) compared with amniotic membrane graft (with or without adjunctive therapy) for pterygium. We also planned to determine whether use of MMC yielded better surgical results and to assess the direct and indirect comparative costs of these procedures.

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Criteria for considering studies for this review Types of studies—We included only randomized controlled trials (RCTs) in this review. Types of participants—We included studies of participants with primary or recurrent pterygium. We used no restrictions with respect to age, gender, co morbidities, or use of adjunctive therapy. Types of interventions—We included studies in which conjunctival autograft was compared with amniotic membrane transplantation. We included studies in which intraoperative or postoperative MMC was used in both treatment arms. Types of outcome measures

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Primary outcomes: The primary outcome for comparison of the treatments was the recurrence of pterygium, as defined by the included studies, between three and six months’ follow-up. Recurrence is commonly defined as a recurrent pterygium greater than 1 mm in size anterior to the limbus; in different studies, the definition varied. We used and recorded the definition from each individual study. Secondary outcomes: We considered the following secondary outcomes for comparison of the treatments for this review, assessed at six months and at one year.

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1.

The proportion of participants with clinical improvement as defined in the included studies. Clinical improvement typically is defined as 1) lack of recurrence and 2) resolution of pre-operative symblepharon, binocular diplopia, hyperemia, or vascularization or improvement of ocular motility (involvement of ocular motility is rare and would be lumped with binocular diplopia).

2.

The proportion of participants requiring repeat surgery for pterygium.

3.

Mean change in best corrected and uncorrected visual acuity from baseline to a follow-up time point, as reported by individual studies.


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4.

Vision-related quality of life as assessed by a validated questionnaire, such as the National Eye Institute Visual Functioning Questionnaire (NEI VFQ).

5.

The direct and indirect costs of the interventions.

Adverse outcomes: We compared the proportion of participants experiencing adverse outcomes such as new diplopia, induced astigmatism, and other complications as reported from the included studies. Search methods for identification of studies

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Electronic searches—We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 10, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), PubMed (1948 to November 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to November 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched 25 November 2013), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 23 November 2015. See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3, PubMed (Appendix 4), LILACS (Appendix 5), mRCT (Appendix 6), ClinicalTrials.gov (Appendix 7), and the ICTRP (Appendix 8).

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Searching other resources—We searched reference lists of included studies to identify any additional eligible studies. We also used the Science Citation Index Expanded database to identify additional studies that may have cited trials included in this review. We did not handsearch conference proceedings or journals specifically for this review; many conference abstracts have been handsearched by Cochrane and included in CENTRAL. Data collection and analysis

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Selection of studies—Two review authors independently reviewed titles and abstracts resulting from the literature searches against the eligibility criteria for this review. Each review author classified each record as “definitely relevant,” “possibly relevant,”’ or “definitely not relevant.” We resolved any disagreements through discussion. After reaching a consensus, we retrieved full-text reports for all records that both review authors classified as “definitely relevant” or “possibly relevant.” The two review authors independently reassessed each full-text report for inclusion of the study described therein. We contacted the investigators of studies in which eligibility was uncertain for further information, as required, after examining the full-text reports. We resolved any disagreements through discussion. We documented the reasons for exclusion of studies after review of full-text reports by both review authors. For reports written in languages not read by the review


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authors, we used Google Translate or consulted with a translator, or both to assess studies for eligibility.

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Data extraction and management—Two review authors, using data extraction forms developed by the Cochrane Eyes and Vision Group, independently extracted characteristics of each eligible study including the setting, methods, participants, interventions, comparisons, and outcomes. One review author entered data into The Cochrane Collaboration’s statistical software, Review Manager (RevMan 2014), and a second review author verified the entered data. We resolved any disagreements after data abstraction or data entry through discussion. We contacted study investigators to request unreported information. If after two weeks we did not receive a response, we proceeded with available information in the published reports. Data from included studies written in languages other than English were abstracted by at least one native reader and confirmed using Google Translate by a review author. Assessment of risk of bias in included studies—Two review authors independently assessed the included studies for potential sources of bias according to the guidelines in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We evaluated the following risk of bias domains: random sequence generation and allocation concealment (selection bias), masking of participants and personnel (performance bias), masking of outcome assessors (detection bias), missing data and intention-to-treat analysis (attrition bias), selective outcome reporting (reporting bias), and other potential sources of bias. We assessed each study for each bias parameter as either “low risk,” “high risk,” or “unclear risk” (insufficient information to permit judgment of low or high risk of bias).

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We resolved disagreements through discussion. Whenever the methods were unclearly reported or additional information was required to assess the risk of bias, we contacted study investigators. If the investigators did not respond within two weeks, we assessed the risk of bias based on the descriptions as reported in the published reports. Measures of treatment effect—We calculated summary risk ratios with 95% confidence intervals for dichotomous outcomes. These included proportion of participants who had post-surgery recurrence of pterygium, had clinical improvement, who required repeat surgery, and had adverse outcomes. For risk of recurrence of pterygium, we planned to include summary reported data by estimating the hazard ratio if possible. We planned to assess normality of continuous outcomes and calculate mean differences and 95% confidence intervals for vision-related quality of life data and costs of interventions.

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Unit of analysis issues—The unit of analysis was the eye for all outcomes, with the exception of vision-related quality of life, where the unit of analysis was the person. We planned to attempt to extract or request from the investigators of within-person trials the data needed to account for the design. If we were unable to retrieve these data, we planned to incorporate statistical techniques to approximate a paired analysis as outlined in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). Whenever two eyes of a participant were enrolled in studies included in this review, we Cochrane Database Syst Rev. Author manuscript; available in PMC 2017 February 11.

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reported whether or not appropriate statistical techniques were employed to account for within-person correlation. Dealing with missing data—We contacted study investigators to provide more information on desired data that had not been reported such as standard deviations. If we received no response within two weeks, we used the data as reported in the published reports. We did not impute data for the purposes of this review.

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Assessment of heterogeneity—We assessed clinical and methodological heterogeneity by examining variations in participant characteristics, inclusion/exclusion criteria, and methods of assessments of primary and secondary outcomes. We calculated the I2 statistic (%) to determine the proportion of variation in outcomes due to heterogeneity, with a value above 50% suggesting substantial statistical heterogeneity. We also examined the result of the Chi2 test for heterogeneity and the degree of overlap in confidence intervals of included studies. Poor overlap also could suggest the presence of heterogeneity. Assessment of reporting biases—To assess for selective outcome reporting, we compared the outcomes prespecified in protocols and the outcomes in the published report(s) from included studies. To assess potential publication bias, we planned to examine the symmetry of a funnel plot when 10 or more studies were included in meta-analysis. We examined study characteristics or other factors that could contribute to asymmetry of the funnel plot.

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Data synthesis—We performed meta-analysis when clinical and methodological heterogeneity was minimal. We combined the results of included trials in a meta-analysis using a random-effects model, unless fewer than three studies were included, in which case we used a fixed-effect model. If the I2 statistic suggested substantial heterogeneity (greater than 50%) and the direction of treatment effects were inconsistent across studies, we did not combine results in a meta-analysis and instead presented a narrative summary.

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Subgroup analysis and investigation of heterogeneity—Whenever sufficient data were available, we conducted subgroup analyses by stratifying participants based on whether they had primary pterygia or recurrent pterygia at study entry. As the characteristics of primary and recurrent pterygia are different, the surgeon may choose a different surgical approach for treating recurrent pterygia. Recurrent pterygia may be more difficult to remove because the eye already has scarring from the primary pterygium and its surgical removal. Eyes that are subject to recurrent pterygia may have a predisposition, either biological or environmental, for exuberant tissue response to the causative factors of pterygium. We also had planned to consider a subgroup analysis by comparing trials that enrolled only unilateral cases and those that enrolled bilateral cases, but only two of the included studies reported on the percentage of enrolled participants with bilateral pterygia versus unilateral pterygium, and only one eye was designated the study and was assigned randomly to an intervention group in both these trials (Besharati 2008; Luanratanakorn 2006). Another potential source of heterogeneity among the studies is the type of fixation used for the tissue graft (sutures or glue) and the use of the MMC as an adjuvant to the tissue graft surgery. It is possible that the


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fixation and use of MMC could have an effect on the recurrence of pterygium. We plan to evaluate this as more information becomes available. Sensitivity analysis—We performed sensitivity analyses to determine the impact of excluding a study with lower methodological quality due to incomplete outcome data. We also planned to consider sensitivity analyses excluding studies funded by industry and those that were unpublished at the time of this review, however these were not necessary as we did not identify any industry-funded or unpublished trials eligible for this review.

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‘Summary of findings’ table—The results of our analyses are summarized in the Summary of findings for the main comparison. The main outcomes presented are recurrence of pterygium at 3 months, recurrence of pterygium at 6 months, clinical improvement, need for repeat surgery, ean change in visual acuity, quality of life and direct and indirect costs. We used GRADE to assess the quality of the evidence (Guyatt 2011). With this approach, we took into account five factors that could affect our confidence in the study results: study limitations, consistency of effect, imprecision, indirectness, and publication bias.

RESULTS Description of studies

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Results of the search—The original electronic searches conducted 23 November 2015 yielded 1841 records, of which we screened 1236 after removing duplicates (Figure 1). Of these, 35 appeared potentially relevant, and we obtained and screened the full-text reports. After further analysis, we excluded 12 reports of 12 studies, and included 22 reports of 20 randomized controlled trials (RCTs) that compared the surgeries of interest in this review. Additionally, one trial register record was listed under Studies awaiting classification. Our searches of other sources did not identify any potentially eligible trials. Included studies—We included 20 RCTs in this review (1947 eyes of 1866 participants), published as 22 reports. All of the studies except for one were parallel-group RCTs (Perry 2000). Perry 2000 was a within-person RCT, in which each participant had bilateral pterygium, and one eye was randomly assigned to surgery with conjunctival autograft and the other eye was assigned to surgery with amniotic membrane transplant.

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Types of participants: We included studies that enrolled participants with primary or recurrent pterygium. Eleven studies restricted enrollment to primary pterygium alone (Chen 2012; Fernández García 2012; Keklikci 2007; Kheirkhah 2011; Küçükerdönmez 2007; Liang 2012; Ozer 2009; Paes 2010; Pérez Parra 2008; Tananuvat 2004; Toker 2016), five studies restricted enrollment to recurrent pterygium alone (Aragonés Cruz 2008; Chen 2009; Katircioglu 2014; Salman 2011; Stangogiannis-Druya 2004), and three studies included participants with either primary or recurrent pterygium (Besharati 2008; Küçükerdönmez 2007a; Luanratanakorn 2006). Two of the three studies that included participants with both types of pterygium reported outcomes separately by pterygium status (Küçükerdönmez 2007a; Luanratanakorn 2006), and one presented combined results only (Besharati 2008). In one included study, it was unclear whether enrolled participants had primary or recurrent pterygia or both, because participants were reported only as having symptomatic pterygium Cochrane Database Syst Rev. Author manuscript; available in PMC 2017 February 11.

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(Perry 2000). The studies were conducted in eight different countries: one in Brazil, three in China, three in Cuba, one in Egypt, two in Iran, two in Thailand, seven in Turkey, and one in Venezuela.

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Types of interventions: The studies analyzed a total of 1947 eyes of 1866 participants. Eight hundred fifty-eight eyes received conjunctival autograft surgery and 887 eyes received amniotic membrane transplant surgery. Some studies had a third intervention group that we did not include in our meta-analyses (Chen 2009; Keklikci 2007; Ozer 2009; Salman 2011). Among these third arm intervention groups were 42 participants who received a combination of the two surgeries we assessed (conjunctival autograft plus amniotic membrane transplant) (Chen 2009), 52 participants who were treated with topical mitomycin C over the excision location in lieu of a conjunctival autograft or amniotic membrane transplant (Keklikci 2007 and Salman 2011), and 48 participants who received surgery using the bare sclera technique (pterygia removed and no further treatment) (Ozer 2009). Types of outcomes: Recurrence of pterygium was the primary outcome in 19 of 20 included studies. Küçükerdönmez 2007 reported on recurrence of pterygium only as a note in their results; the primary outcome of interest in this study was graft vascularization.

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Excluded studies—We excluded 12 studies from the review after assessment of full-text reports. We have reported the excluded studies and reasons for exclusion in the Characteristics of excluded studies table. We excluded two studies because they were not RCTs (Liu 2014; Yan 2010). We excluded four studies because it was unclear whether participants were randomized to the type of surgery they received (Katircioglu 2007; Kim 2008; Ozkurt 2009; Paris 2008). We attempted to contact the authors of these four studies to ask whether their participants were randomized, but received no response, so we chose to exclude them. Two excluded studies had no conjunctival autograft treatment group (Li 2014; Zhang 2014), another was a laboratory study of proteins found in tear films after various surgeries for pterygium (Nava-Castaneda 2007), and three used a technique that involved a conjunctival flap in addition to a conjunctival autograft, which is an alternative surgical method not analyzed in this review (Lin 2009; Pei 2011; Xia 2008). Risk of bias in included studies

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No trial was distinguished by having a low risk of bias across all criteria. The overwhelming majority of trials (17 of 20) were marked by having an unclear risk of bias or high risk of bias in five or more of the seven parameters we assessed for bias, categorized into selection, performance, detection, attrition, and reporting biases. The most common assessment was unclear risk of bias, meaning the authors did not describe any or all of the following: methods of selection of participants, allocation of participants to treatment arms, masking of surgical arm from participants and outcome observers, how data attrition was handled, or funding source(s). Attrition bias (incomplete outcome data) was the bias for which the largest number of trials were at highest risk. Figure 2 and Figure 3 show a summary of the risk of bias judgments made by the review authors.


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Allocation—Overall, the majority of included trials were judged to have an unclear risk of selection bias. All trials were reported as randomized, but 16 out of 20 trials did not describe the methods of random sequence generation, and were therefore rated as at unclear risk of bias (Aragonés Cruz 2008; Besharati 2008; Chen 2009; Chen 2012; Fernández García 2012; Katircioglu 2014; Keklikci 2007; Kheirkhah 2011; Liang 2012; Luanratanakorn 2006; Ozer 2009; Pérez Parra 2008; Perry 2000; Salman 2011; Stangogiannis-Druya 2004; Tananuvat 2004). None of the included trials reported their method of allocation concealment before randomization; we therefore judged each as having unclear risk of this type of selection bias. We judged three studies (two by the same authors) to have a low risk of selection bias as they reported using a random number generator to allocate participants to their surgical group (Küçükerdönmez 2007; Küçükerdönmez 2007a; Toker 2016). Another study that was a published doctoral thesis also reported that the authors used a random number scheme (Paes 2010). In communication with the author, he stated the randomization scheme such that participants were given a number from a random number table by the secretary in the order they arrived. If the sum of digits was an even number, the participants were put into one group; if the sum of digits was an odd number, participants were put into the other group. We judged this technique to be a randomization without allocation concealment and later removed this trial in a sensitivity analysis to see if the study with a lack of allocation concealment had a large effect on our conclusions.


Masking (performance bias and detection bias)—Sixteen studies did not report on whether or not they masked participants and outcomes assessors and were judged to have unclear risk of bias (Aragonés Cruz 2008; Besharati 2008; Chen 2009; Chen 2012; Fernández García 2012; Katircioglu 2014; Keklikci 2007; Kheirkhah 2011; Liang 2012; Ozer 2009; Paes 2010; Pérez Parra 2008; Perry 2000; Salman 2011; Stangogiannis-Druya 2004; Tananuvat 2004). However, due to the nature of the surgical procedures and the different appearance of the eye in the early postoperative period, both performance and detection biases were inherent to these studies. Surgeons performing the surgery would be able to differentiate between amniotic membrane transplant and conjunctival autograft. For postoperative visits, trained observers (if not a surgeon) could differentiate between amniotic membrane transplant and conjunctival autograft. We judged two studies by the same author as low risk because they reported that both participants and outcomes assessors were masked (Küçükerdönmez 2007; Küçükerdönmez 2007a), and though we feel it was realistic to mask participants, we suspect that efforts at masking outcomes assessors were undermined by the ease with which a trained observer would be able to see whether a conjunctival autograft or amniotic membrane transplant was done, based simply on the fact that the site from which conjunctival autograft was harvested will be visible in the first few weeks to months after surgery. However, we judged these two studies to be at low risk of bias because they attempted to prevent performance and detection bias. One study reported that it was designed as a single-blind randomized controlled trial, and stated that only outcomes assessor (and not participants or surgeons) were masked (Luanratanakorn 2006). This study was judged as having a high risk of performance bias but a low risk of detection bias. We judged another study, Toker 2016, to have high risk of bias for detection bias after communication with the author revealed that the doctors who did the postoperative examinations were not masked. Though we do believe that since the authors of this trial did


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not did not attempt to mask the outcomes assessors, this results in a high risk of bias, we also think that masking at this stage is not truly possible, and we are unsure if the knowledge of type of procedure received would affect an assessor’s ability to determine whether recurrence, our primary outcome, had occurred.

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Incomplete outcome data—We judged eight of the included studies to have low risk of attrition bias because they reported that there was no loss to follow-up (Chen 2009; Chen 2012; Küçükerdönmez 2007; Küçükerdönmez 2007a; Liang 2012; Ozer 2009; Pérez Parra 2008; Salman 2011). In four studies, there was no mention of loss to follow-up or missing data, and it was not clear from the tables whether all participants completed the study; we judged these studies to have unclear risk of attrition bias (Aragonés Cruz 2008; Fernández García 2012; Perry 2000; Stangogiannis-Druya 2004). One study, an abstract reporting a clinical trial that was not linked to a full publication, lacked information about trial methods; another reported that five participants were lost to follow-up, but still included data from those participants in the analysis (Perry 2000 and Aragonés Cruz 2008, respectively). We judged eight included studies to have a high risk of attrition bias because they reported that participants were lost to follow-up and that these participants’ data were excluded from the analysis (Besharati 2008; Katircioglu 2014; Keklikci 2007; Kheirkhah 2011; Luanratanakorn 2006; Paes 2010; Tananuvat 2004; Toker 2016). This judgment was made because the participants may have been lost to follow-up due to a complication of the surgery to which they were assigned. It is possible that a participant was lost to follow-up because of pterygium recurrence (our primary outcome) and chose to have another surgery outside the trial.

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Selective reporting—We judged the majority of the RCTs included in this review to be at unclear for risk of reporting bias, as they did not have a protocol available to compare anticipated outcomes to reported outcomes. Two studies reported that they presented a protocol to the human subjects research or ethics committees at their respective institutions, however the authors did not provide a reference or a way to access the protocol and the studies were thus judged to have unclear risk of reporting bias ( Luanratanakorn 2006 and Paes 2010). Additionally, we judged four studies as having a high risk of reporting bias either because the authors reported that they collected data on an outcome that was not reported, or the authors stated that participants were seen at several time points but only the “final” results were reported, not data for each time point (Aragonés Cruz 2008; Besharati 2008; Katircioglu 2014; Tananuvat 2004).

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Other potential sources of bias—We judged five studies to have low risk of other biases (Katircioglu 2014; Kheirkhah 2011; Küçükerdönmez 2007; Küçükerdönmez 2007a; Luanratanakorn 2006). In these studies, the funding sources were clearly reported and did not pose a conflict of interest, and there were no concerns about the methodology used during the study. We judged eight studies to have unclear risk of bias, mainly due to not reporting funding, though two were due to questions about the design of the study (Aragonés Cruz 2008; Besharati 2008; Chen 2009; Chen 2012; Keklikci 2007; Ozer 2009; Paes 2010; Perry 2000). We considered no studies to have had high risk of bias due to funding or conflicts of interest, but judged four as high risk because both eyes of some participants


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were randomized, but the analysis did not take into consideration the non-independence of eyes (Liang 2012; Pérez Parra 2008; Salman 2011; Tananuvat 2004), and judged two as high risk for unclear study design and a lack of detail about the type of analysis done (Fernández García 2012; Stangogiannis-Druya 2004). Effects of interventions See: Summary of findings for the main comparison Summary of findings for conjunctival autograft compared to amniotic membrane transplant

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Recurrence of pterygium—Of the 20 studies, 13 specified the times from surgery to recurrences. The primary outcome of this review was recurrence between three and six months. As some studies reported data at exactly three months and six months, and others reported data monthly, we have included any report of recurrence between two months and four months in our “three month” section and any report of recurrence between five months and seven months in our “six month” section. Six studies reported recurrence at three months after surgery (Besharati 2008; Keklikci 2007; Kheirkhah 2011; Paes 2010; Tananuvat 2004; Toker 2016), and 10 studies reported recurrence at six months after surgery (Besharati 2008; Fernández García 2012; Kheirkhah 2011; Küçükerdönmez 2007a; Luanratanakorn 2006; Paes 2010; Salman 2011; Stangogiannis-Druya 2004; Tananuvat 2004; Toker 2016). One study reported recurrence only at 12 months after surgery (Liang 2012), and one reported recurrence only at 24 months after surgery (Chen 2012). As these time points were not one of our specified outcomes, we did not present these data individually.

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Recurrence at three months after surgery: Recurrence of pterygium at three months after surgery ranged from 0% to 16.7% in the conjunctival autograft groups and 4.76% to 26.9% in the amniotic membrane transplant groups. These groups included participants with both primary and recurrent pterygia. In a meta-analysis of data from the six studies reporting this outcome, the risk of recurrence was statistically equivalent between the two groups (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.43 to 1.77). Therefore, we are uncertain as to which surgery resulted in a lower risk of recurrence at three months (Figure 4, Analysis 1.1). We graded the quality of the evidence for this outcome as very low due to imprecision in the estimate, inconsistencies among the individual study results and a lack of allocation concealment in the included studies. A grade of very low means the true effect may be substantially different from the estimate of effect.

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In a subgroup analysis, we separated from the group four studies that included only participants with primary pterygium. In this subgroup, there was also no statistically significant difference between risk of recurrence of pterygium between participants treated with conjunctival autograft and participants treated with amniotic membrane transplant. The risk ratio was 0.92, but the 95% confidence interval crossed the null value (0.37 to 2.30) (Figure 4, Analysis 1.1). Findings from the two analyses support no difference in recurrence after 3 months.


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Recurrence at six months after surgery: Recurrence of pterygium at six months after surgery ranged from 3.33% to 16.7% in the conjunctival autograft groups and 2.6% to 42.3% in the amniotic membrane transplant groups. Though there was some statistical heterogeneity among the studies that included participants with primary pterygia (I2 = 60%), we elected to perform a meta-analysis because we did not judge the methodological heterogeneity to be too great to combine the data. The statistical heterogeneity was attributable to one larger study that included 228 participants and reported that the risk of recurrence of pterygium was higher in the conjunctival autograft group compared to the amniotic membrane transplant group (RR 2.32, 95% CI 1.02 to 5.15). The nine other studies included in this meta-analysis favored the conjunctival autograft group, reporting a lower risk of recurrence with this surgery compared to the amniotic membrane transplant group. However, it should be noted that only two of these were statistically significantly in favor of the conjunctival autograft surgery. Our meta-analysis favored the conjunctival autograft group, finding that this group had a 47% lower risk of recurrence compared with the amniotic membrane transplant group (RR 0.53, 95% CI 0.33 to 0.85) (Figure 5, Analysis 1.2). We graded the quality of evidence for this outcome as moderate due to concerns about allocation concealment and evidence of possible attrition bias.

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For this outcome, we performed a subgroup analysis on data for participants with primary pterygium and participants with recurrent pterygium. In the analysis of participants with primary pterygium, there was also no difference in recurrence of pterygium at six months between the conjunctival autograft group and the amniotic membrane transplant group (RR 0.58, 95% CI 0.27 to 1.27) (Figure 5, Analysis 1.2). However, for participants who had recurrent pterygium, there was a 55% reduction in risk of recurrence for participants who received conjunctival autograft surgery compared with participants who received amniotic membrane transplant surgery (RR 0.45, 95% CI 0.21 to 0.99) (Figure 5, Analysis 1.2). Thus, participants with recurrent pterygia who received conjunctival autograft had recurrence of pterygium six months after surgery less often than did participants who received AMT for their recurrent pterygia. Studies reporting recurrence overall or recurrence at non-specific time points: Seven studies reported on recurrence over the course of follow-up but did not assess recurrence at specific time points (Aragonés Cruz 2008; Chen 2009; Katircioglu 2014; Küçükerdönmez 2007; Ozer 2009; Pérez Parra 2008; Perry 2000). These studies reported the mean follow-up time for each arm and the number of participants with recurrence during the study. We have summarized these results below.

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Aragonés Cruz 2008 reported an overall risk of recurrence of 2 out of 28 (7.1%) participants in the limbal conjunctival autograft group compared with 3 out of 28 participants (10.7%) in the amniotic membrane transplant group, representing a non-statistically significant difference in risk of recurrence between the two study arms (RR 0.67, 95% CI 0.12 to 3.69).

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Chen 2009 analyzed pterygium recurrence between 12 and 24 months after surgery. The risks of recurrence were similar in the two surgeries: 9 out of 40 (22.5% of participants) in the limbal conjunctival autograft


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group versus 10 out of 45 (22.2%) in the amniotic membrane transplant group. These risks of recurrence were not statistically significantly different (RR 1.01, 95% CI 0.46 to 2.24).

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Katircioglu 2014 summarized recurrence of pterygium at time of last follow-up, which was 27.2 ± 20.8 months (range 12 to 94 months) overall. The mean follow-up time was 25.9 ± 24.4 months in the conjunctival autograft group and 28.8 ± 15.7 months in the amniotic membrane transplant group. Recurrence was defined as fibrovascular tissue growth onto the cornea, as described by Prabhasawat 1997. Four out of 30 participants (13.4%) in the conjunctival autograft group had recurrence of pterygium, and 2 out of 25 participants (8%) in the amniotic membrane transplant group had recurrence of pterygium, a difference that was not statistically significant (RR 1.67, 95% CI 0.33 to 8.36).

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Küçükerdönmez 2007 had a mean follow-up of 13.66 ± 5.23 months in the limbal conjunctival autograft group (range 6 to 24 months) and 14.40 ± 3.25 in the amniotic membrane transplant group (range 6 to 26 months). They reported that “during the study” no pterygium recurrence was observed in either group.

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Ozer 2009 reported recurrence “during the study period.” Average followup for participants who received conjunctival limbal autograft was 69.91 ± 12.41 months (range 59 to 82), and among this group, 11 out of 63 had recurrence of pterygium (14.29%). Average follow-up time for participants in the amniotic membrane transplant group was 61.43 ± 9.83 months (range 53 to 74), and 12 of 52 had recurrence of pterygium during this time (23.08%). There was no statistically significant difference in risk of recurrence between the two groups (RR 0.76, 95% CI 0.36 to 1.57).

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Pérez Parra 2008 reported one case of recurrence in the conjunctival autograft group at five months, and this represented 2.2% recurrence in this surgical group. The authors reported three cases of recurrent pterygium in the amniotic membrane transplant group (6.6%), but they did not report the time points at which these recurrences occurred. The risk of recurrence in this study was not significantly different between the two surgical groups (RR 0.33, 95% CI 0.36 to 3.08).

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Perry 2000 reported on a group of eight participants with bilateral pterygium who randomly received conjunctival autograft in one eye and amniotic membrane transplant in the other eye. Throughout the study follow-up (mean 12.5 months, range 9 to 22 months), none of the eyes that received amniotic membrane transplant had pterygium recurrence, but two of the eyes (25%) that received conjunctival autograft had recurrence.

Sensitivity analysis: We performed a sensitivity analysis on the recurrence of pterygium outcomes in which we removed one study from the meta-analysis. Paes 2010 was a doctoral thesis rather than a peer-reviewed journal article. We had planned to perform a sensitivity


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analysis to exclude studies at high risk of bias and those that were unpublished at the time of the review, and this study met both criteria. In communication with the author, it appeared that the study was randomized, however allocation was not concealed. The author described the randomization method as assigning each participant a number when he/she arrived, then allocating participants to conjunctival autograft or amniotic membrane transplant depending on whether the sum of the digits of the random number the participant received was even or odd. In the sensitivity analysis excluding this study, the risk of recurrence of pterygium at three months’ postsurgery in the conjunctival autograft group was still not statistically different from the risk in the amniotic membrane transplant group (RR 0.62, 95% CI 0.30 to 1.27) (Table 1). In the analysis of pterygium recurrence at six months after surgery excluding the Paes 2010 study, the risk of recurrence was lower in the conjunctival autograft group compared with the amniotic membrane transplant group (RR 0.43, 95% CI 0.30 to 0.62). Participants in the conjunctival autograft group had a statistically significantly 57% lower risk of recurrence compared with the amniotic membrane transplant group (Table 1). Proportion of participants with clinical improvement—Keklikci 2007 was the only study that specifically reported on clinical improvement, citing the risk of non-recurrence as 93.8% for participants in the conjunctival limbal autograft group and 93.3% in the amniotic membrane transplant group at three months after surgery. None of the other studies reported on clinical improvement per se, and though it is easy to derive the risk of non-recurrence by taking the inverse of the risk of recurrence, non-recurrence is not necessarily equivalent to clinical improvement, so we opted against this calculation or inclusion of “clinical improvement” as thus defined. Another way to report clinical improvement would be to describe and compare the participants’ symptoms before and after surgery, but no studies did so.

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Proportion of participants requiring repeat surgery for pterygium—One study mentioned the need for repeat surgery, but the context was in reference to adverse events and not as a planned outcome (Keklikci 2007). It was noted that in the amniotic membrane graft group, suture lysis was detected in one case (3.33%) on the third day postoperatively and that amniotic membrane revision was performed. There was no information about the need for any repeat surgery in the conjunctival autograft group. Another study reported that two participants (one each from the conjunctival autograft and amniotic membrane transplant groups) had repeat surgery, but the time point during follow-up at which the surgery was required was not reported (Toker 2016).

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Mean change in visual acuity from baseline to follow-up points—No studies reported the mean change in visual acuity, but one trial described visual acuity over the study period (Katircioglu 2014). This study included only participants with recurrent pterygium. The authors compared baseline and postoperative logMAR but did not provide a specific time point at which the mean change in visual acuity was assessed. The mean baseline logMAR in participants of the conjunctival autograft group (n = 30) was 0.2 ± 1.4, and the mean baseline logMAR in the amniotic membrane transplant group (n = 25) was 0.2 ± 1.0. The mean postoperative logMAR in the conjunctival autograft group was 0.1 ± 1.3


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and in the amniotic membrane transplant group was 0.1 ± 1.2. There was no difference in the visual acuity postoperatively (mean difference 0.00, 95% CI −0.66 to 0.66). Tananuvat 2004 did not report measures of visual acuity, but the authors noted that “no eye had a loss of uncorrected visual acuity greater than 1 line at the last visit.” Quality of life measures—None of the included studies reported on quality of life measures. Direct and indirect costs—No study examined direct or indirect costs of conjunctival autografting or amniotic membrane transplant.

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Adverse events—Thirteen studies reported adverse events associated with conjunctival autograft surgery and amniotic membrane transplant surgery (Aragonés Cruz 2008; Besharati 2008; Chen 2012; Katircioglu 2014; Kheirkhah 2011; Küçükerdönmez 2007; Liang 2012; Luanratanakorn 2006; Pérez Parra 2008; Perry 2000; Salman 2011; Tananuvat 2004; Toker 2016), however only one study included incidences of two adverse events of highest interest, diplopia and induced astigmatism. Besharati 2008 reported on diplopia at three months and six months. Two participants in the amniotic membrane transplant group developed diplopia by six months versus no participants in the conjunctival autograft group, and one participant in the amniotic membrane transplant group had restriction of eye movement. It is unclear whether the participant with restriction of eye movement also had diplopia.

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Other adverse events that occurred in more than one study were granuloma and pyogenic granuloma and increased intraocular pressure. Table 2 shows a summary of all adverse events reported in the included studies. None of the included studies reported that any participants had developed induced astigmatism; only one paper analyzed change in visual acuity, describing no difference between conjunctival autograft and amniotic membrane transplant. Adverse events that were reported in multiple studies are summarized in Figure 6 (Analysis 1.3).

DISCUSSION Summary of main results

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In this review, we report outcome data from 20 randomized controlled trials that compared conjunctival autograft versus amniotic membrane transplant for the treatment of pterygium. We could include eleven studies in a meta-analysis for our primary outcome, recurrence of pterygium after the surgery, assessed at three and six months after surgery. At three months, there was no statistically significant difference in risk of recurrence between the two procedures in studies of primary pterygia or studies of both recurrent and primary pterygia. At six months, without regard to primary or recurrent nature of the pterygia, the conjunctival autograft group had a 47% lower risk of recurrence compared with the amniotic membrane transplant group. Subgroup analysis showed that at six months after surgery, there was no difference in recurrence between the two procedures performed for primary pterygia; however, there was a 55% reduction in risk of recurrence with conjunctival autograft


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compared with amniotic membrane transplant for recurrent pterygia. After removing a study that lacked allocation concealment, there was still no difference in risk of recurrence between the two surgeries at three months. The meta-analysis favored conjunctival autograft at six months for participants with primary and recurrent pterygia. Other than the graft material being different (conjunctiva vs. amniotic membrane), there are no inherent technical differences between the two types of surgery. Seven studies reported recurrence at nonspecific time points during the study. These studies showed no difference in the risk of pterygium recurrence when comparing conjunctival autograft with amniotic membrane transplant.

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Only one study reported on change in visual acuity from baseline to follow-up points; there was no difference in this outcome between conjunctival autograft and amniotic membrane transplant. Only one study reported “clinical improvement” (defined by the authors as the non-recurrence risk), and another study reported the need for repeat surgery. No studies compared participants’ symptoms before and after surgery. Non-recurrence is not equivalent to clinical improvement, because clinical improvement implies a favorable change in patients’ quality of vision or quality of life. Clinical improvement might also imply that the patient would choose to have pterygium surgery again if presented with the option.

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We found no difference in adverse events between conjunctival autograft and amniotic membrane transplant groups. However, “adverse events” often were not prespecified or described in sufficient detail. Many “adverse events” listed in study reports were nonspecific and could be expected in the typical postoperative course of most ophthalmic procedures, including pterygium surgery: “conjunctival edema,” “conjunctivitis,” “conjunctival inflammation,” “corneal scar,” punctate epithelial erosions, eyelid edema, pain. Other “adverse events” mentioned in the studies were too vague, such as “graft reaction.” Adverse events specific to the surgeries evaluated in this review are symblepharon, pyogenic granuloma, and diplopia and/or restriction of eye movement. None of the included studies evaluated the participant-reported outcome of vision-related quality of life. Additionally, none of the included studies reported on the differences in the direct or indirect costs of the interventions. Overall completeness and applicability of evidence

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All included studies evaluated recurrence of pterygium, our primary outcome; however, only eleven reported recurrence at specific time points that were useful in our meta-analysis. Though there was some statistical heterogeneity among the studies, the types of participants included and the techniques for conjunctival autograft and amniotic membrane transplant were similar. Some studies included participants with primary pterygia, others participants with recurrent pterygia, while some studies included participants with either primary or recurrent pterygia. As results from separate analyses of primary versus recurrent pterygia were similar, we believe the applicability of the evidence to the average pterygium patient to be high. The results from separate analyses of primary versus recurrent pterygium from patient populations of different latitudes and different ethnicities were similar, barring one study (Paes 2010) that had opposing results. The evidence supports that conjunctival autograft in combination with surgical excision of the pterygium confers a lower risk of Cochrane Database Syst Rev. Author manuscript; available in PMC 2017 February 11.

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pterygium recurrence than does surgical excision with amniotic membrane transplant six months after surgery.

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We took special consideration in assessing the risk of detection bias. As noted, a surgeon or trained observer could easily distinguish which surgery had been performed on an eye by noting whether there were two surgical sites (conjunctival autograft surgery) or only one surgical site (amniotic membrane transplant). Bias may be present if the same person who performed the surgery was also an outcomes assessor. It is possible that the surgeon who performed amniotic membrane transplant would want to believe that his/her surgery had a successful outcome and may not want to admit if there is recurrence. When surgeons and outcomes assessors are separate individuals, there is a lower risk of these inherent biases because recurrence is an objective outcome. Still, it is possible that even a masked observer would be able to determine which procedure was used because at three months after surgery, the area from which the conjunctiva autograft was harvested will not look normal compared with amniotic membrane transplant, where there is no part of the surgical eye from which tissue was removed. If an outcomes assessor were to see two surgical sites on the eye that were healing, he/she would be able to tell that the participant received conjunctival autograft surgery rather than amniotic membrane transplant. We cannot say whether the ability of a theoretically masked outcome observer to practically tell which of the two procedures was performed would bias their decision on recurrence, and because so many of the included studies were unclear on who observed outcomes (the surgeon versus a different assessor), the best we could do while evaluating these studies was to keep these inherent biases in mind and consider the fact that there was a risk for performance and detection bias.

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The time frame of this evidence is clinically applicable and biologically appropriate. Like other types of corneal procedures (for example corneal transplantation, laser in-situ keratomileusis, photorefractive keratectomy), extensive wound healing and remodeling occur after either type of pterygium surgery. Therefore, outcomes at six months are more clinically applicable than outcomes at three months, at which time tissue is still undergoing remodeling and outcomes are not stable. One study, Liang 2012, used conjunctival hyperemia and edema in the first few months after surgery as an outcome measure, with which we and other authors did not agree. Edema and hyperemia commonly occur after uncomplicated pterygium surgery and other types of eye surgery and are thus non-specific outcomes. They have not been shown to be associated with recurrence of pterygium.

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The relative beneficial effect of conjunctival autograft over amniotic membrane transplant in preventing further recurrence of recurrent pterygia is clinically important given that recurrent pterygia are more fibrovascular and adherent to underlying tissue than are primary pterygia. There may also be fibrotic scarring with recurrent pterygium, making it more difficult for the surgeon to resect the pterygia. No study reported whether the primary surgery in cases of recurrent pterygium was performed with conjunctival autograft or amniotic membrane transplant. The beneficial effect of conjunctival autograft is clinically significant because if the first surgery also was done with an autograft, there may not be enough tissue to harvest for a second autograft. Another advantage of conjunctival autograft over amniotic membrane transplant is that though donors of amniotic membrane are serologically tested for transmissible diseases, including hepatitis B, hepatitis C, and human


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immunodeficiency virus, there is always a risk of microbial transmission (for example prion disease) when using biological products. Few data have been reported on adverse events associated with these two procedures; moreover, there was wide variation in terms of what constituted an “adverse event” in these studies. The limited data available suggest no difference in adverse events between conjunctival autograft and amniotic membrane transplant. However, more data must be collected on well-defined and prespecified adverse events to ascertain whether a difference in adverse events exists between the two procedures.

Author Manuscript

A source of heterogeneity among our included studies was the fixation technique used by the surgeons in each study. It is possible that using sutures versus using glue to fix the tissue graft over the location of pterygium removal may have an effect on the risk of recurrence. We chose to combine studies based on recurrent versus primary pterygia and by outcome time points, but in doing so, we did not take into account the fixation technique. Estimates of the risk ratio for recurrence may have been different if we had also completed a subgroup analysis by fixation technique. The recurrence could additionally have been affected by the combination of fixation technique plus the use of adjuvant MMC. These surgical techniques should be evaluated as more information becomes available. Quality of the evidence

Author Manuscript

The quality of evidence in favor of conjunctival autograft is moderate. The majority of trials did not describe methods for randomization and allocation or for masking of participants and outcomes assessors, leading to assessments of unclear risk of bias. Seven of 10 studies had a high level of attrition bias, the most common reason being excluding the data of participants lost to follow-up. In our Summary of findings for the main comparison, we have used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria to report the level of evidence for the outcomes included in this study. For the primary outcome of recurrence at three months, we graded the quality of evidence as very low because there was a lack of description in the methods of the individual studies, the estimate was imprecise, the results of the individual studies were inconsistent (ranging from 0.4 to 0.2). We graded the primary outcome of recurrence at six months as moderate, because there was a lack of description in the methods of the studies, but this was not subject to the same imprecision or inconsistencies as seen in the data on recurrence at three months. Potential biases in the review process

Author Manuscript

This review was performed to Cochrane standards, and we attempted to avoid bias by using systematic methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). Agreements and disagreements with other studies or reviews A literature review and meta-analysis published in 2012 reported that conjunctival autograft had a lower recurrence risk compared to amniotic membrane transplant for primary pterygium treatment (Li 2012). This review included both randomized controlled trials and cohort studies and reported a hazard ratio instead of a risk ratio. They found that the


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recurrence of conjunctival autograft compared with amniotic membrane transplant was 0.30 (95% CI 0.16 to 0.59) for primary and 0.22 (95% CI 0.02 to 2.37) for recurrent pterygium.

AUTHORS’ CONCLUSIONS Implications for practice

Author Manuscript

Though there is uncertainty as to which treatment has a lower risk of recurrence at early time points (one to three months after surgery), recurrence of pterygium at three months after surgery ranged from 0% to 16.7% in the conjunctival autograft groups and 4.76% to 26.9% in the amniotic membrane transplant groups. Surgical excision of pterygium combined with conjunctival autograft has a 46% lower risk of recurrence compared with excision combined with amniotic membrane transplant six months after surgery, which is a more clinically relevant time frame than is three months after surgery. Recurrence of pterygium at six months after surgery ranged from 3.33% to 16.7% in the conjunctival autograft groups and 2.6% to 42.3% in the amniotic membrane transplant groups. Both surgical procedures appear to be safe; there was uncertainty as to which surgery was associated with fewer adverse events or a clinically significant change in visual acuity. Most “adverse events,” however, were not well-defined or specific. With excision of recurrent pterygium, conjunctival autograft is favored over amniotic membrane transplant to avoid risk of recurrence. This result may be counterintuitive, given that amniotic membrane is favored in settings of large conjunctival defects, poor availability of autologous conjunctival tissue, and recurrent pterygia associated with conjunctival scarring.

Author Manuscript

Implications for research Though we conclude that conjunctival autograft surgery for pterygium confers a lower risk of recurrence, further research is needed to determine the effects of conjunctival autograft versus amniotic membrane transplant on visual acuity, quality of vision and life, and the costs to the patient and society, if insurance is paying for the procedure and supplies. In addition to better defining “adverse events” after pterygium surgery, future studies should enroll more participants in order to provide more precise estimates of outcomes. Additional research on pterygium excision with or without the use of MMC is important. Becuase MMC may reduce the recurrence of pterygium, it would have been difficult to separate the effect of MMC from the grafting techniques we compared in this review. We suggest a systematic review comparing conjunctival autograph with or without MMC in order to elucidate the effects of this adjuvant treatment.

Author Manuscript

Acknowledgments The review authors would like to thank Claire Twose and Lori Rosman, Trials Search Co-ordinators, Cochrane Eyes and Vision Group (CEVG), for designing the search strategies. We thank Sonal Singh and Barbara Hawkins for their comments during the preparation of the review. We also acknowledge the CEVG editorial team’s support and peer reviewers for their comments on the review. SOURCES OF SUPPORT


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Author Manuscript

•

No sources of support supplied

External sources •

National Eye Institute, National Institutes of Health, USA. Elizabeth Clearfield is supported by the Cochrane Eyes and Vision Group US project Grant 1 U01 EY020522

•

National Institute for Health Research, UK.

•

Richard Wormald, Co-ordinating Editor for the Cochrane Eyes and Vision Grou (CEV), acknowledges financial support for his CEVG research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology.

•

The NIHR also funds the CEV Editorial Base in London.

Author Manuscript

The views expressed in this publication are those of the authors and not necessarily those of the NIHR, NHS, or the Department of Health.

References to studies included in this review *Indicates the major publication for the study


Aragonés Cruz 2008 {published data only}. Aragonés Cruz B, Alemañy Martorell J. Comparative study of the use of mitomycin C in recurrent pterygium [Estudio comparativo del uso de mitomicina C en el pterigium recidivante]. Revista Cubana de Oftalmología. 2008; 21(2):1–11. Besharati 2008 {published data only}. Besharati MR, Miratashi SA, Ahmadi AB. Pterygium surgery: amniotic membrane or conjunctival autograft transplantation. International Journal of Ophthalmology. 2008; 1(4):362–6. Chen 2009 {published data only}. Chen L, Mu L, Li MX. Clinical observation of three different operation methods for recurrent pterygium. International Journal of Ophthalmology. 2009; 9(11): 2211–3. Chen 2012 {published data only}. Chen LR, Yao JP, Zhu Y, Zhang YZ, Zhou Y, Gao B. Comparative analysis of surgical excision combined with limbal stem cell transplantation and amniotic membrane transplantation for the treatment of pterygium. International Eye Science. 2012; 12(10):2006–8. Fernández García 2012 {published data only}. Fernández García K, Gómez Castillo Z, Castillo Pérez A, Pérez Parra Z, Jareño Ochoa M, Perea Ruiz CA. Use of conjunctival autograft and amniotic membrane in primary pterygium surgery [Autoinjerto conjuntival y membrana amnióticaen la cirugía del pterigión primario]. Revista Cubana de Oftalmología. 2012; 25(2):212–7. Katircioglu 2014 {published data only}. Katircioglu YA, Altiparmak U, Goktas SE, Cakir B, Singar E, Ornek F. Comparison of two techniques for the treatment of recurrent pterygium: amniotic membrane vs conjunctival autograft combined with mitomycin C. Seminars in Ophthalmology. 2015; 30(5–6):321–7. [PubMed: 24506693] Keklikci 2007 {published data only}. Keklikci U, Celik Y, Cakmak SS, Unlu MK, Bilek B. Conjunctival-limbal autograft, amniotic membrane transplantation, and intraoperative mitomycin C for primary pterygium. Annals of Ophthalmology. 2007; 39(4):296–301. [PubMed: 18025649] Kheirkhah 2011 {published and unpublished data}. Kheirkhah A, Nazari R, Nikdel M, Ghassemi H, Hashemi H, Behrouz MJ. Postoperative conjunctival inflammation after pterygium surgery with amniotic membrane transplantation versus conjunctival autograft. American Journal of Ophthalmology. 2011; 152(5):733–8. [PubMed: 21742306] Küçükerdönmez 2007 {published data only}. Küçükerdönmez C, Akova YA, Altinörs DD. Vascularization is more delayed in amniotic membrane graft than conjunctival autograft after pterygium excision. American Journal of Ophthalmology. 2007; 143(2):245–9. [PubMed: 17173849]


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Author Manuscript Author Manuscript Author Manuscript Author Manuscript

Küçükerdönmez 2007a {published data only}. Küçükerdönmez C, Akova YA, Altinörs DD. Comparison of conjunctival autograft with amniotic membrane transplantation for pterygium surgery. Cornea. 2007; 26(4):407–13. [PubMed: 17457187] Küçükerdönmez C, Dursin D, Akova YA. Comparison of conjunctival autograft with amniotic membrane transplantation for pterygium surgery: surgical and cosmetic outcome. American Academy of Ophthalmology. 2004; 179 Liang 2012 {published data only}. Liang W, Li R, Deng X. Comparison of the efficacy of pterygium resection combined with conjunctival autograft versus pterygium resection combined with amniotic membrane transplantation. Eye Science. 2012; 27(2):102–5. [PubMed: 22678875] Luanratanakorn 2006 {published data only}. Luanratanakorn P, Ratanapakorn T, Suwan-Apichon O, Chuck RS. Randomised controlled study of conjunctival autograft versus amniotic membrane graft in pterygium excision. British Journal of Ophthalmology. 2006; 90(12):1476–80. [PubMed: 16837545] Ozer 2009 {published data only}. Ozer A, Yildirim N, Erol N, Yurdakul S. Long-term results of bare sclera, limbal-conjunctival autograft and amniotic membrane graft techniques in primary pterygium excisions. Ophthalmologica. 2009; 223(4):269–73. [PubMed: 19339811] Paes 2010 {published data only}. Fernandes LM, Paes JP, de Morais BBO, da Costa CMG, de Oliveira EM, Felix FS, et al. Surgical treatment of primary pterygium: comparison between techniques of autologous conjunctive transplant and transplantation of amniotic membrane. Investigative Ophthalmology and Visual Science. 2007; 48(13) ARVO E-Abstract 5296. Pereira Paes, J. Surgical Treatment of the Primary Pterygium: Comparison Between Rotation of Conjunctival Flap and Amniotic Membrane Transplant [Tratamento Cirurgico do Pterigio Primario: Comparação Entre as Tecnicas de Rotação de Retalho Conjuntival e Transplante de Membrana Amniotica] [Doctoral dissertation]. Universidade Estadual de Campinas; Faculdade de Ciências Médicas: 2010. Pérez Parra 2008 {published data only}. Pérez Parra Z, Castillo Pérez ADLC, Escalona Leyva E, López Hernández S, Márquez Villalón S. Conjunctival autograft versus amniotic membrane graft in primary pterygium surgery [Autoinjerto conjuntival versus injerto de membrana amniótica en la cirugía del pterigión primario]. Revista Cubana de Oftalmología. 2008; 21(1):0. Perry 2000 {published data only}. Perry HD, Kanellopoulos AJ, Donnenfeld ED, Doshi SJ. Comparison of amniotic membrane transplantation (AMT) to conjunctival autograft (CAT) in the surgical management of pterygia. American Academy of Ophthalmology. 2000:225. Salman 2011 {published data only}. Salman AG, Mansour DE. The recurrence of pterygium after different modalities of surgical treatment. Saudi Journal of Ophthalmology. 2011; 25(4):411–5. [PubMed: 23960956] Stangogiannis-Druya 2004 {published data only}. Stangogiannis-Druya E, Martínez M, Paz EL, Márquez K, Stangogiannis-Druya C. Amniotic membrane graft or conjunctival autograft in recurrent nasal pterygium Hospital Unversitario de Caracas January–June 2004 [Transplante de membrana amniótica o auto injerto conjuntival en pterigión nasal recidivantes Hospital universitario de Caracas enero–junio 2004]. Revista Oftalmológica Venezolana. 2004; 60(4):181– 7. Tananuvat 2004 {published data only}. Tananuvat N, Martin T. The results of amniotic membrane transplantation for primary pterygium compared with conjunctival autograft. Cornea. 2004; 23(5):458–63. [PubMed: 15220729] Toker 2016 {published data only}. Toker E, Eraslan M. Recurrence after primary pterygium excision: amniotic membrane transplantation with fibrin glue versus conjunctival autograft with fibrin glue. Current Eye Research. 2016; 41(1):1–8. [PubMed: 25849961]

References to studies excluded from this review Katircioglu 2007 {published data only}. Katircioglu YA, Altiparmak UE, Duman S. Comparison of three methods for the treatment of pterygium: amniotic membrane graft, conjunctival autograft and conjunctival autograft plus mitomycin C. Orbit. 2007; 26(1):5–13. [PubMed: 17510864] Kim 2008 {published data only}. Kim HJ, Lee SY. The comparative study of clinical results in surgically treated pterygium patients with amniotic membrane transplantation versus limbal autograft. Investigative Ophthalmology and Visual Science. 2008; 49(13) ARVO E-abstract 6031.


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Li 2014 {published data only}. Li T, Chen SX, Xia XG, Yin Z, Huang MZ, Guo PY. Pterygium conjunctive reverse transplantation combined with amniotic membrane transplantation on recurrent pterygium. International Eye Science. 2014; 14(9):1715–6. Lin 2009 {published data only}. Lin XS, Song YP. Comparison between amniotic membrane transplantation and conjunctival autograft for treating pterygium. International Journal of Ophthalmology. 2009; 9(7):1367–8. Liu 2014 {published data only}. Liu J, Wang Y, Yuan JM. Different surgical methods on the tear film stability in treating pterygium patients. International Eye Science. 2015; 15(3):558–61. Nava-Castaneda 2007 {published data only}. Nava-Castaneda A, Garnica-Hayashi L, Jaimes M, Garfias Y. Comparative study of concentration of Muc5ac and Muc2 mucins in tear film in surgical treated pterygiums with amniotic membrane transplantation vs conjunctival autograft. Investigative Ophthalmology and Visual Science. 2007; 48(13) ARVO E-Abstract 5290. Ozkurt 2009 {published data only}. Ozkurt YB, Kocams O, Comez AT, Uslu B, Dogan OK. Treatment of primary pterygium. Optometry and Vision Science. 2009; 86(10):1178–81. [PubMed: 19741559] Paris 2008 {published data only}. Paris FDS, De Farias CC, Melo GB, Dos Santos MS, Batista JLA, Comes JAP. Postoperative subconjunctival corticosteroid injection to prevent pterygium recurrence. Cornea. 2008; 27(4):406–10. [PubMed: 18434842] Pei 2011 {published data only}. Pei Y, Huang Y, Xiao F, Cheng WW, Yang J. Comparison of the effects of two kinds of surgery in pterygium. International Journal of Ophthalmology. 2011; 11(10):1835–7. Xia 2008 {published data only}. Xia ZX, Lan YQ, Wang M, Xiao JH, Guo H, Hu YK. Analysis of efficacy of three different operation modes for preventing recurrence of pterygium. International Journal of Ophthalmology. 2008; 8(8):1623–5. Yan 2010 {published data only}. Yan XY, Chen HM, Tang ZJ. The recurrent rate of different surgical procedures for pterygium after one year. International Journal of Ophthalmology. 2010; 10(7): 1423–4. Zhang 2014 {published data only}. Zhang WW, Xie P. Comparation on effect of two kinds operation in treatment of recurrent pterygium with symblepharon. International Eye Science. 2014; 14(12): 2286–8.

Author Manuscript

References to studies awaiting assessment CTRI/2015/07/005960 {unpublished data only}. CTRI/2015/07/005960. Comparative outcome of conjunctival autograft and amniotic membrane transplantation following double pterygium excision in the same eye. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=10669

Additional references

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Barraquer 1965. Barraquer, J. The Cornea World Congress. Washington: Butterworths; 1965. Bultmann 1999. Bultmann S, You L, Spandau U. Amniotic membrane down-regulates chemokine expression in human keratocytes. Investigative Ophthalmology and Visual Science. 1999; 40:S578. Chen 1995. Chen PP, Ariyasu RG, Kaza V, LaBree LD, McDonnell PJ. A randomized trial comparing mitomycin C and conjunctival autograft after excision of primary pterygium. American Journal of Ophthalmology. 1995; 120(2):151–60. [PubMed: 7639298] Coroneo 1999. Coroneo MT, Di Girolamo N, Wakefield D. The pathogenesis of pterygia. Current Opinion in Ophthalmology. 1999; 10(4):282–8. [PubMed: 10621537] D’Ombrain 1948. D’Ombrain A. The surgical treatment of pterygium. British Journal of Ophthalmology. 1948; 32(2):65–71. [PubMed: 18170420] Droutsas 2010. Droutsas K, Sekundo W. Epidemiology of pterygium. A review [Epidemiologie des pterygiums. Eine ubersicht]. Der Ophthalmologe. 2010; 107(6):511–6. [PubMed: 20393731]


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Guyatt 2011. Guyatt GH, Oxman AD, Schünemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. Journal of Clinical Epidemiology. 2011; 64(4):380–2. [PubMed: 21185693] Hao 2000. Hao Y, Ma DH, Hwang DG, Kim WS, Zhang F. Identification of antiangiogenic and antiinflammatory proteins in human amniotic membrane. Cornea. 2000; 19(3):348–52. [PubMed: 10832697] Higgins 2011a. Higgins, JPT.; Altman, DG.; Green, S., editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration; 2011. Chapter 8: Assessing risk of bias in included studies. Available from www.cochranehandbook.org Higgins 2011b. Higgins, JPT.; Deeks, JJ.; Altman, DG.; Green, S., editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration; 2011. Chapter 16: Special topics in statistics. Available from www.cochranehandbook.org Hill 1989. Hill JC, Maske R. Pathogenesis of pterygium. Eye. 1989; 3(Pt 2):218–26. [PubMed: 2695353] Karai 1984. Karai I, Horiguchi S. Pterygium in welders. British Journal of Ophthalmology. 1984; 68(5):347–9. [PubMed: 6712915] Kenyon 1985. Kenyon KR, Wagoner MD, Hettinger ME. Conjunctival autograft transplantation for advanced and recurrent pterygium. Ophthalmology. 1985; 92(11):1461–70. [PubMed: 4080320] Kim 1995. Kim JC, Tseng SC. Transplantation of preserved human amniotic membrane for surface reconstruction in severely damaged rabbit corneas. Cornea. 1995; 14(5):473–84. [PubMed: 8536460] Kirwan 2003. Kirwan JF, Constable PH, Murdoch IE, Khaw PT. Beta irradiation: new uses for an old treatment: a review. Eye. 2003; 17(2):207–15. [PubMed: 12640408] Klein 1876. Klein S. Zur operation des pterygium und zur transplantation von schleimhaut. Allgemeine Wien Medizinischen Zeitung. 1876; 21:19. Kobayashi 1999. Kobayashi, A.; Inana, G.; Meller, D. Differential gene expression by human cultured umbilical vein endothelial cells on amniotic membrane. 4th Ocular Surface and Tear Conference; Miami, FL, USA. 14 May 1999; Kwok 1994. Kwok LS, Coroneo MT. A model for pterygium formation. Cornea. 1994; 13(3):219–24. [PubMed: 8033571] Li 2012. Li M, Zhu M, Yongfu Y, Gong L, Zhao N, Robitaille MJ. Comparison of conjunctival autograft transplantation and amniotic membrane transplantation for pterygium: a meta-analysis. Cornea. 2012; 250(3):375–81. Liu 2013. Liu L, Wu J, Geng J, Yuan Z, Huang D. Geographical prevalence and risk factors for pterygium: a systematic review and meta-analysis. BMJ Open. 2013; 3(11):1–8. Prabhasawat 1997. Prabhasawat P, Barton K, Burkett G, Tseng SC. Comparison of conjunctival autografts, amniotic membrane grafts, and primary closure for pterygium excision. Ophthalmology. 1997; 104(6):974–85. [PubMed: 9186439] Raj 2010. Raj, AKS. Dissertation. Rajiv Gandhi University of Health Sciences; Karnataka, Bangalore: 2010. Clinical study to compare the incidence of recurrence after pterygium excision with bare sclera technique without intraoperative mitomycin C, with intraoperative mitomycin C application and conjunctival limbal autograft. RevMan 2014 [Computer program]. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration; 2014. Shimazaki 1998. Shimazaki J, Shinozaki N, Tsubota K. Transplantation of amniotic membrane and limbal autograft for patients with recurrent pterygium associated with symblepharon. British Journal of Ophthalmology. 1998; 82(3):235–40. [PubMed: 9602618] Singh 2005. Singh, G. Pterygium and its surgery. In: Smolin, G.; Foster, CS.; Azar, DT.; Dohlman, CH., editors. Smolin and Thoft’s The Cornea: Scientific Foundations and Clinical Practice. Lippincott Williams and Wilkins; 2005. p. 1001


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Solomon 1999. Solomon, A.; Monroy, D.; Ji, Z. Suppression of epithelial expression of IL-1-beta by the amniotic membrane. 4th Ocular Surface and Tear Conference; Miami, FL, USA. 14 May 1999; Tseng 1999. Tseng SC, Li DQ, Ma X. Suppression of transforming growth factor-beta isoforms, TGFbeta receptor type II, and myofibroblast differentiation in cultured human corneal and limbal fibroblasts by amniotic membrane matrix. Journal of Cellular Physiology. 1999; 179(3):325–35. [PubMed: 10228951]

APPENDICES Appendix 1. CENTRAL search strategy


#1

MeSH descriptor: [Pterygium] explode all trees

#2

Pterygi*

#3

Pterigi*

#4

#1 or #2 or #3

#5

(auto-graft* or autograft* or graft* or autotransplant* or transplant*)

#6

(surger* or surgic*)

#7

MeSH descriptor: [Surgical Procedures, Operative] explode all trees

#8

MeSH descriptor: [Transplantation] explode all trees

#9

Any MeSH descriptor with qualifier(s): [Surgery - SU]

#10

Any MeSH descriptor with qualifier(s): [Transplantation - TR]

#11

#5 or #6 or #7 or #8 or #9 or #10

#12

#4 and #11

Appendix 2. MEDLINE (Ovid) search strategy

Author Manuscript

1.

Randomized Controlled Trial.pt.

2.

Controlled Clinical Trial.pt.

3.

(randomized or randomised).ab,ti.

4.

placebo.ab,ti.

5.

drug therapy.fs.

6.

randomly.ab,ti.

7.

trial.ab,ti.

8.

groups.ab,ti.

9.

1 or 2 or 3 or 4 or 5 or 6 or 7 or 8

10.

exp animals/ not humans.sh.

11.

9 not 10


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12.

exp Pterygium/

13.

Pterygi*.tw.

14.

Pterigi*.tw.

15.

or/12–14

16.

exp Surgical Procedures, Operative/

17.

exp Transplantation/

18.

surgery.fs.

19.

transplantation.fs.

20.

(auto-graft* or autograft* or graft* or autotransplant* or transplant*).tw.

21.

(surger* or surgic*).tw.

22.

or/16–21

23.

11 and 15 and 22

The search filter for trials at the beginning of the MEDLINE strategy is adapted from the published paper by Glanville et al (Glanville 2006).

Appendix 3. EMBASE.com search strategy


#1

’randomized controlled trial’/exp

#2

’randomization’/exp

#3

’double blind procedure’/exp

#4

’single blind procedure’/exp

#5

random*:ab,ti

#6

#1 OR #2 OR #3 OR #4 OR #5

#7

’animal’/exp OR ’animal experiment’/exp

#8

’human’/exp

#9

#7 AND #8

#10

#7 NOT #9

#11

#6 NOT #10

#12

’clinical trial’/exp

#13

(clin* NEAR/3 trial*):ab,ti

#14

((singl* OR doubl* OR trebl* OR tripl*) NEAR/3 (blind* OR mask*)):ab,ti

#15

’placebo’/exp

#16

placebo*:ab,ti


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#17

random*:ab,ti

#18

’experimental design’/exp

#19

’crossover procedure’/exp

#20

’control group’/exp

#21

’latin square design’/exp

#22

#12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21

#23

#22 NOT #10

#24

#23 NOT #11

#25

’comparative study’/exp

#26

’evaluation’/exp

#27

’prospective study’/exp

#28

control*:ab,ti OR prospectiv*:ab,ti OR volunteer*:ab,ti

#29

#25 OR #26 OR #27 OR #28

#30

#29 NOT #10

#31

#30 NOT (#11 OR #23)

#32

#11 OR #24 OR #31

#33

’pterygium’/exp

#34

pterygi*:ab,ti

#35

pterigi*:ab,ti

#36

#33 OR #34 OR #35

#37

’surgery’/exp

#38

(auto NEXT/1 graft*):ab,ti OR autograft*:ab,ti OR graft*:ab,ti OR autotransplant*:ab,ti OR transplant*:ab,ti

#39

surger*:ab,ti OR surgic*:ab,ti

#40

’surgery’/lnk

#41

#37 OR #38 OR #39 OR #40

#42

#32 AND #36 AND #41

Appendix 4. PubMed search strategy #1

((randomized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (randomised[tiab] OR randomized[tiab]) OR (placebo[tiab]) OR (drug therapy[sh]) OR (randomly[tiab]) OR (trial[tiab]) OR (groups[tiab])) NOT (animals[mh] NOT humans[mh])


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#2

Pterygi*[tiab] NOT Medline[sb]

#3

Pterigi*[tiab] NOT Medline[sb]

#4

#2 OR #3

#5

(auto-graft*[tiab] OR autograft*[tiab] OR graft*[tiab] OR autotransplant*[tiab] OR transplant*[tiab]) NOT Medline[sb]

#6

(surger*[tiab] OR surgic*[tiab]) NOT Medline[sb]

#7

#5 OR #6

#8

#1 AND #4 AND #7

Appendix 5. LILACS search strategy Author Manuscript

(Pterygi$ OR Pterigi$ OR Pterigion OR Pterígio OR MH: C11.187.781$) AND (surger$ OR surgic$ OR “Procedimientos Quirúrgicos Operativos” OR “Procedimentos Cirúrgicos Operatórios” OR MH:E04$ OR MH:VS3.003.001.006.002$ OR Transplant$ OR Trasplant$ OR auto-graft$ OR autograft$ OR graft$ OR autotransplant$ OR transplant$ OR /SU OR /TR)

Appendix 6. meta Register of Controlled Trials search strategy pterygium or pterigium

Appendix 7. ClinicalTrials.gov search strategy pterygium

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Appendix 8. ICTRP search strategy pterygium OR pterigium

CHARACTERISTICS OF STUDIES Characteristics of included studies [ordered by study ID] Aragonés Cruz 2008

Author Manuscript

Methods

Study design: parallel-group RCT Number randomized (total and per group): Total: 57 Per group: conjunctival limbal autograft 29; amniotic membrane transplant 28 Exclusions after randomization: 1 did not receive surgery (in the limbal conjunctival autograft group) Number analyzed (total and per group): Total: 51 Per group: conjunctival limbal autograft 25; amniotic membrane transplant 26 Unit of analysis (individuals vs eyes): individual (1 eye per individual) Losses to follow-up: 5 lost to follow-up: conjunctival limbal autograft group 3; amniotic membrane transplant group 2 How was missing data handled?: not reported Reported power calculation: no Unusual study design?: none

Participants

Country: Cuba


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Age: median age - limbal conjunctival autograft 41.93 years, amniotic membrane transplant 44.81 years Gender (percent): limbal conjunctival autograft 35.7% men, 64.3% women; amniotic membrane transplant 39.3% men, 60.7% women Inclusion criteria: presenting with recurrent pterygium, older than 15, signed informed consent Exclusion criteria: younger than 15, presenting with primary pterygium of any grade Equivalence of baseline characteristics: unclear

Author Manuscript

Interventions

Intervention 1: limbal conjunctival autograft Intervention 2: amniotic membrane transplant Length of follow-up: Planned: not reported Actual: not reported

Outcomes

Primary outcome, as defined in study reports: recurrence Secondary outcomes, as defined in study reports: time without recurrence Adverse events reported: yes Intervals at which outcomes assessed: 24 hours, 72 hours, 1 week, every 15 days during the first 3 months and then monthly

Notes

Type of study: published Funding sources: not reported Disclosures of interest: not reported Study period: not reported Trial registration: none reported Reported subgroup analyses: no

Risk of bias

Author Manuscript

Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Sequence generation was not reported

Allocation concealment (selection bias)

Unclear risk

Allocation concealment was not reported

Masking of participants and personnel (performance bias)

Unclear risk

Masking of participants and personnel was not reported

Masking of outcome assessment (detection bias)

Unclear risk

Masking of outcomes assessors was not reported

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Five participants were reported to have been lost to follow-up, yet they were included in the analysis. No mention of whether loss to follow-up was due to a treatment effect

Selective reporting (reporting bias)

High risk

The authors collected data on time without recurrence, but it is not reported in the results

Other bias

Unclear risk

Design of study and data analysis is not clear. Funding sources are not reported

Besharati 2008

Author Manuscript

Methods

Study design: parallel-group RCT Number randomized (total and per group): Total: 50 eyes of 50 participants Per group: 24 eyes of 24 participants into the conjunctival autograft group; 26 eyes of 26 participants in the amniotic membrane transplantation group Exclusions after randomization: 10 eyes in total because of difficulties in participants’ follow-up Number analyzed (total and per group): Total: not reported Per group: not reported Unit of analysis: individual (1 eye per participant was enrolled) Losses to follow-up: not reported How was missing data handled?: excluded


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Reported power calculation: no Unusual study design?: none

Author Manuscript

Participants

Country: Iran Age (mean ± SD): 49.3 ± 15.5 years, range 24 to 77 years old Gender (percent): 80% men; 20% women Inclusion criteria: primary and secondary pterygium Exclusion criteria: diabetes, collagen vascular disease, dry eye, glaucoma Equivalence of baseline characteristics: no, there was a difference in the cosmetic appearance of the eyes between the two groups (considered a clinical sign of pterygium)

Interventions

Intervention 1: conjunctival autograft transplantation Intervention 2: amniotic membrane transplantation Length of follow-up: Planned: 24 months Actual: 24 months

Outcomes

Primary outcome, as defined in study reports: recurrences of 2 mm in the area of original pterygium; complications Secondary outcomes, as defined in study reports: not reported Adverse events reported: yes Intervals at which outcomes assessed: 1 week and 1, 3, 6, and 24 months

Notes

Type of study: published Funding sources: not reported Disclosures of interest: not reported Study period: April 2004 to February 2006 Trial registration: none reported Reported subgroup analyses: no

Risk of bias


Bias




Unclear risk

Method of random sequence generation was not reported


Unclear risk



Unclear risk



Unclear risk

Masking of outcome assessors was not reported


High risk

10/50 (20%) eyes were “excluded from the analysis because of difficulties in patients’ follow up”


High risk

Protocol was not available. Some outcomes are described at 1, 3, and 6 months but not at 2 years despite the fact that recurrence is described at 2 years

Other bias

Unclear risk

Funding source was not reported

Chen 2009 Methods

Study design: parallel-group RCT Number randomized (total and per group): Total: 127 eyes Per group: conjunctival autograft: 40; amniotic membrane graft: 45; amniotic membrane graft combined with conjunctival autograft: 42 Exclusions after randomization: none reported Number analyzed (total and per group): Total: 127 eyes


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Per group: conjunctival autograft: 40; amniotic membrane graft: 45; amniotic membrane graft combined with conjunctival autograft: 42 Unit of analysis (individuals vs eyes): eyes Losses to follow-up: none How was missing data handled?: N/A Reported power calculation: no Unusual study design: none

Author Manuscript

Participants

Country: China Age: not reported Gender (percent): not reported Inclusion criteria: people with recurrent pterygium, with history of 1 to 3 surgical excisions, and relapse after surgery Exclusion criteria: not reported Equivalence of baseline characteristics: yes

Interventions

Intervention 1: limbal stem cell autograft transplant Intervention 2: amniotic membrane transplant Intervention 3: combined amniotic membrane transplant and limbal stem cell autograft transplant Length of follow-up: Planned: 12 to 24 months Actual: 12 to 24 months

Outcomes

Primary outcome, as defined in study reports: recurrence Secondary outcomes, as defined in study reports: lack of recurrence, proportion of participants with clinical improvement Adverse events reported: no Intervals at which outcomes assessed: every 3 months up to 12 to 24 months

Notes

Type of study: published Funding sources: not reported Disclosures of interest: not reported Study period: March 2002 to March 2007 Trial registration: none reported Reported subgroup analyses: no

Risk of bias


Bias




Unclear risk

“… were randomly divided into three groups….” but does not describe how the sequence was generated


Unclear risk



Unclear risk



Unclear risk



Low risk

No loss to follow-up was reported


Unclear risk

A protocol was not available

Other bias

Unclear risk

Data for baseline characteristics not reported, only stated that groups were comparable, funding sources not reported

Chen 2012 Methods

Study design: parallel-group RCT Number randomized (total and per group):


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Total: 90 persons (90 eyes) Per group: limbal conjunctival transplantation 45; amniotic membrane transplant 45 Exclusions after randomization: N/A Number analyzed (total and per group): Total: 90 Per group: limbal conjunctival transplantation 45; amniotic membrane transplant 45 Unit of analysis (individuals vs eyes): individual (1 eye per participant) Losses to follow-up: none reported How was missing data handled?: not reported Reported power calculation: no Unusual study design: no

Author Manuscript

Participants

Country: China Age: limbal conjunctival transplantation 47 ± 8.5; amniotic membrane transplant 49 ± 9.5 Gender (percent): limbal conjunctival transplantation 55.6% men, 44.4% women; amniotic membrane transplant 51.1% men, 48.8% women Inclusion criteria: people with primary pterygium in 1 eye, 2 to 3 mm Exclusion criteria: not reported Equivalence of baseline characteristics: yes

Interventions

Intervention 1: limbal conjunctival transplantation Intervention 2: amniotic membrane transplant Length of follow-up: Planned: 2 years Actual: 20.6 ± 2.5 months

Outcomes

Primary outcome, as defined in study reports: recurrence Secondary outcomes, as defined in study reports: the proportion of participants with clinical improvement; healing time Adverse events reported: yes Intervals at which outcomes assessed: 2 years

Notes

Type of study: published Funding sources: not reported Disclosures of interest: not reported Study period: March 2007 to March 2010 Trial registration: none reported Reported subgroup analyses: no

Risk of bias


Bias




Unclear risk

Method of sequence generation was not reported


Unclear risk



Unclear risk



Unclear risk

Masking of outcome assessment was not reported


Low risk

There was no missing data


Unclear risk


Other bias

Unclear risk

Funding sources were not reported

Fernández García 2012 Methods

Study design: parallel-group RCT


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Author Manuscript

Number randomized (total and per group): Total: 80 Per group: conjunctival autograft 40; amniotic membrane transplant 40 Exclusions after randomization: none reported Number analyzed (total and per group): Total: 80 Per group: conjunctival autograft 40; amniotic membrane transplant 40 Unit of analysis (individuals vs eyes): individuals (1 eye per participant) Losses to follow-up: none reported How was missing data handled?: N/A Reported power calculation: no Unusual study design?: none

Author Manuscript

Participants

Country: Cuba Age: 20 to 59 years Gender (percent): overall 57.5% men, 42.5% women Inclusion criteria: people with primary pterygium between 20 and 59 years old Exclusion criteria: people with recurrent pterygium and ocular pathologies Equivalence of baseline characteristics: not reported

Interventions

Intervention 1: conjunctival autograft Intervention 2: amniotic membrane transplant Length of follow-up: Planned: 6 months Actual: 6 months

Outcomes

Primary outcome, as defined in study reports: recurrence of pterygium Secondary outcomes, as defined in study reports: none reported Adverse events reported: yes, authors report no surgical or visual complications Intervals at which outcomes assessed: 24 hours, 1 week, 1 month, 3 months, and 6 months

Notes

Type of study: published Funding sources: none reported Disclosures of interest: none reported Study period: September 2009 to September 2010 Trial registration: none reported Reported subgroup analyses: no

Risk of bias


Bias




Unclear risk

Sequence generation was not described


Unclear risk

Allocation concealment was not described


Unclear risk



Unclear risk



Unclear risk

It was not reported whether there was any missing data


Unclear risk


Other bias

High risk

Funding sources were not reported. The study design is not clear and the only outcome or data that is reported per group is the recurrence of pterygium

Katircioglu 2014


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Methods

Study design: parallel-group RCT Number randomized (total and per group): Total: 60 eyes of 55 participants Per group: 30 eyes of 30 participants in the conjunctival autograft transplantation group; 30 eyes of 25 participants in the amniotic membrane transplantation group Exclusions after randomization: none Number analyzed (total and per group): Total: 55 eyes of 55 participants Per group: 30 eyes of 30 participants in the conjunctival autograft transplantation group; 25 eyes of 25 participants in the amniotic membrane transplantation group Unit of analysis: individual Losses to follow-up: 5 eyes of 5 participants in the amniotic membrane transplantation group How was missing data handled?: excluded Reported power calculation: no Unusual study design?: participants with minimum follow-up of 12 months were included

Participants

Country: Turkey Age (mean ± SD): 57.1 ± 12.6 years, range 32 to 81 years old in total; 55.4 ± 12.9 years in the conjunctival autograft transplantation group; 59.1 ± 12.1 years in the amniotic membrane transplantation group Gender (percent): total 61.8% men, 38.1% women; conjunctival autograft transplant 60% men, 40% women; amniotic membrane transplantation 64% men, 36% women Inclusion criteria: 1) people with recurrent pterygium; 2) minimum follow-up of 12 months Exclusion criteria: presence of major eye diseases such as dry eye, cicatricial pemphigoid, and glaucoma, and vitreoretinal disease and intercurrent severe systemic disease, or any condition affecting follow-up or documentation Equivalence of baseline characteristics: yes

Interventions

Intervention 1: conjunctival autograft transplantation + MMC Intervention 2: amniotic membrane transplantation + MMC Length of follow-up: Planned: not reported Actual: overall 27.2 ± 20.8 months (range 12 to 94 months); conjunctival autograft 25. 9 ± 24.4 years; amniotic membrane transplant 28.8 ± 15.7 months

Outcomes

Primary outcome, as defined in study reports: recurrences (fibrovascular tissue growth; published rating system by Prabhasawat [Prabhasawat 1997]) Secondary outcomes, as defined in study reports: best spectacle corrected visual acuity; epithelial defect lasting more than 5 days; presence of intraoperative severe pain Adverse events reported: yes Intervals at which outcomes assessed: 1 day, 1 week, 1 month, 3 months, 6 months, and every 12 months thereafter

Notes

Type of study: published Funding sources: not reported Disclosures of interest: “The authors report no conflicts of interest.” Study period: May 2004 to July 2006 Trial registration: none reported Reported subgroup analyses: no

Risk of bias

Author Manuscript

Bias




Unclear risk



Unclear risk



Unclear risk



Unclear risk



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Author Manuscript


High risk

5 eyes were excluded due to loss to follow-up, and their data were excluded


High risk

Unclear reason for not describing outcomes at designated time points. The authors state that participants were seen at: “1, 3, 6, every 12 months” but results are only reported as being at the “final” point

Other bias

Low risk

The authors report no conflicts of interest

Keklikci 2007 Study design: parallel-group RCT Number randomized (total and per group): Total: 94 eyes of 94 participants Per group: 32 eyes of 32 participants in the conjunctival limbal autograft transplantation group; 30 eyes of 30 participants in the amniotic membrane transplantation group; 32 eyes of 32 participants in the topical MMC group (MMC applied to sclera area instead of a tissue graft) Exclusions after randomization: none Number analyzed (total and per group): Total: 94 eyes of 94 participants Per group: 32 eyes of 32 participants in the conjunctival limbal autograft transplantation group; 30 eyes of 30 participants in the amniotic membrane transplantation group; 32 eyes of 32 participants in the topical MMC group Unit of analysis (individuals vs eyes): individual Losses to follow-up: none How was missing data handled?: N/A Reported power calculation: no Unusual study design?: none

Participants

Country: Turkey Age (mean ± SD): conjunctival limbal autograft transplantation group 39.84 ± 11.69, range 15 to 55 years; amniotic membrane transplantation group 41.83 ± 13.41, range 19 to 68 years; topical MMC group 44.72 ± 11.21, range 20 to 65 years Gender (percent): conjunctival limbal autograft transplantation 46.9% men, 53.1% women; amniotic membrane transplant 53.3% men, 46.7% women; topical MMC group 56.2% men, 43.8% women Inclusion criteria: people with primary pterygium Exclusion criteria: not reported Equivalence of baseline characteristics: yes

Interventions

Intervention 1: conjunctival limbal autograft transplantation Intervention 2: amniotic membrane transplantation Intervention 3: MMC 0.2 mg/mL to the sclera area beyond the limbus, using a 2 × 2 mm sponge applied for 2 minutes Length of follow-up: Planned: 36 months Actual: conjunctival limbal autograft group 24.38 ± 7.93 (range 12 to 36 months); amniotic membrane transplant group 23.63 ± 7.30 (range 12 to 36 months); topical MMC group 23.44 ± 7.24 (range 12 to 36 months)

Outcomes

Primary outcome, as defined in study reports: recurrences (fibrovascular tissue from limbus onto cornea); complication Secondary outcomes, as defined in study reports: none Adverse events reported: yes Intervals at which outcomes assessed: 1 day, 3 days, 1 week, 1 month, 3 months, and every 3 months thereafter

Notes

Type of study: published Funding sources and disclosures of interest: “The authors have stated that they do not have a significant financial interest or other relationship with any product manufacturer or provider of services discussed in this article. The authors do not discuss the use of off-label products, which includes unlabeled, unapproved, or investigative products or devices” Study period: January 2001 to January 2003 Trial registration: none reported Reported subgroup analyses: no

Author Manuscript

Methods


Risk of bias Bias



Random sequence

Unclear risk

Method of random sequence generation was not reported; “they were randomly assigned (by UEA)


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generation (selection bias)

using an adaptive randomization procedure to receive CA combined with intraoperative MMC or AMT combined with intraoperative MMC treatment.”

Author Manuscript


Unclear risk



Unclear risk



Unclear risk



High risk

5/60 (8.3%) eyes were lost to follow-up, and they were excluded from the analysis


Unclear risk


Other bias

Unclear risk

Funding source was not reported

Kheirkhah 2011


Methods

Study design: parallel-group RCT Number randomized (total and per group): Total: 42 eyes of 42 participants Per group: 21 eyes of 21 participants each group Exclusions after randomization: 3 eyes of 3 participants (not distinguished between exclusion and lost to follow-up) Number analyzed (total and per group): Total: 39 eyes of 39 participants Per group: conjunctival autograft transplantation 20 eyes of 20 participants; amniotic membrane transplant 19 eyes of 19 participants Unit of analysis (individuals vs eyes): individual (1 eye per participant was enrolled) Losses to follow-up: 3 eyes of 3 participants (not distinguished between exclusion and lost to follow-up) How was missing data handled?: excluded Reported power calculation: no Unusual study design?: participants with less than 12-month follow-up were excluded from the analysis

Participants

Country: Iran Age (mean ± SD): overall 45.6 ± 13.9 years, range 19 to 83 years; conjunctival autograft 47.7 ± 15.7 years; amniotic membrane transplant 42.8 ± 13.2 years Gender (percent): overall 56.4% men, 43.6% women; conjunctival autograft transplantation group 60% men, 40% women; amniotic membrane transplantation 52.6% men, 47.4% women Inclusion criteria: primary nasal pterygium Exclusion criteria: not reported Equivalence of baseline characteristics: yes

Interventions

Intervention 1: conjunctival autograft transplantation Intervention 2: amniotic membrane transplantation Length of follow-up: Planned: 12 months Actual: 12 months

Outcomes

Primary outcome, as defined in study reports: recurrences; complications Secondary outcomes, as defined in study reports: not distinguished Adverse events reported: yes Intervals at which outcomes assessed: 1 day, 1 week, 2 weeks, and 1, 3, 6, 9, and 12 months

Notes

Type of study: published Funding sources: “The authors indicate no financial support or financial conflict of interest involved in conception and design of study.” Disclosures of interest: “The authors indicate no financial support or financial conflict of interest involved in conception and design of study.” Study period: not reported


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Trial registration: none reported Reported subgroup analyses: no Risk of bias

Author Manuscript

Bias




Unclear risk



Unclear risk



Unclear risk



Unclear risk



High risk

3/42 (7.1%) eyes were excluded from the analysis


Unclear risk


Other bias

Low risk

None

Küçükerdönmez 2007 Study design: parallel-group RCT Number randomized (total and per group): Total: 27 eyes of 27 participants Per group: conjunctival autograft 14 eyes of 14 participants; amniotic membrane transplant 13 eyes of 13 participants Exclusions after randomization: none Number analyzed (total and per group): Total: 27 eyes of 27 participants Per group: conjunctival autograft 14 eyes of 14 participants; amniotic membrane transplant 13 eyes of 13 participants Unit of analysis (individuals vs eyes): individual (1 eye per participant was enrolled) Losses to follow-up: none How was missing data handled?: N/A Reported power calculation: no Unusual study design?: none

Participants

Country: Turkey Age (mean ± SD): limbal conjunctival autograft 42.95 years (range 28 to 59 years); amniotic membrane transplant 44.92 years (range 32 to 65 years) Gender (percent): total 55.6% men and 44.4% women; limbal conjunctival autograft 57.1% men and 42.9% women; amniotic membrane transplant group 53.8% men and 46.2% women Inclusion criteria: primary pterygium, aged between 28 and 65 years old Exclusion criteria:

Author Manuscript

Methods

Author Manuscript

1

major systemic diseases (e.g. diabetes)

2

vascular disease (excluding hypertension)

3

serious ocular surface disease (e.g. cicatricial pemphigoid)

4

glaucoma

5

previous history of ocular surgery

Equivalence of baseline characteristics: the size of defects measured was not statistically significantly different between the 2 groups; other baseline demographics were reported but were not evaluated for statistically significant differences so we cannot judge whether these characteristic are equivalent between the two groups


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Interventions

Intervention 1: limbal conjunctival autograft transplantation Intervention 2: amniotic membrane transplantation Length of follow-up: Planned: 1 month Actual: limbal conjunctival autograft 13.66 ± 5.23 (range 6 to 24 months); amniotic membrane transplant 14.40 ± 3.25 (range 6 to 26 months)

Outcomes

Primary outcome, as defined in study reports: graft vascularization Secondary outcomes, as defined in study reports: recurrence Adverse events reported: yes Intervals at which outcomes assessed: 1 day, 7 days, 30 days, then monthly intervals

Notes

Type of study: published Funding sources: “The authors indicate no financial support or financial conflict of interest.” Disclosures of interest: “The authors indicate no financial support or financial conflict of interest.” Study period: not reported Trial registration: none reported Reported subgroup analyses: no

Risk of bias


Bias




Low risk

”Randomization was accomplished by a list created by a random-number generator“


Unclear risk



Low risk

”Patients were not informed of the surgical procedure they received. We aimed to prevent intraobserver (surgeon) bias caused by the preoperative status (for example, size, fleshiness, vascularization) of the pterygium.”


Low risk

Outcomes assessors were masked to the type of surgery


Low risk

Authors reported no missing data


Unclear risk


Other bias

Low risk

None

Küçükerdönmez 2007a

Author Manuscript

Methods

Study design: parallel-group RCT Number randomized (total and per group): Total: 78 eyes of 78 participants Per group: conjunctival autograft 40 eyes of 40 participants; amniotic membrane transplant 38 eyes of 38 participants Exclusions after randomization: none Number analyzed (total and per group): Total: 78 eyes of 78 participants Per group: conjunctival autograft 40 eyes of 40 participants; amniotic membrane transplant 38 eyes of 38 participants Unit of analysis (individuals vs eyes): individual (1 eye per participant was enrolled) Losses to follow-up: none How was missing data handled?: N/A Reported power calculation: no Unusual study design?: none

Participants

Country: Turkey Age (mean ± SD): conjunctival autograft 52.4 ± 12.40 years (range 37 to 94 years); amniotic membrane transplant 57.1 ± 9.91 years (range 40 to 73 years) Gender (percent): total 50% men and 50% women; conjunctival autograft 52.5% men and 47.5% women; amniotic membrane transplant 47.4% men and 52.6% women


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Inclusion criteria: primary or recurrent pterygium Exclusion criteria: 1

people with major systemic diseases (e.g. diabetes), vascular disease (excluding hypertension), serious ocular surface disease (e.g. cicatricial pemphigoid), and previous history of a vitreoretinal surgery

2

people using artificial teardrops for dry eyes (> 4 times a day), topical or systemic steroids, or non-steroidal anti-inflammatory agents

Equivalence of baseline characteristics: yes

Author Manuscript

Interventions

Intervention 1: conjunctival autograft transplantation Intervention 2: amniotic membrane transplantation Length of follow-up: Planned: at least 6 months Actual: conjunctival autograft 16.6 ± 3.52 (range 9 to 19 months); amniotic membrane transplant 13.4 ± 2.08 (range 10 to 16 months)

Outcomes

Primary outcome, as defined in study reports: recurrence of pterygium Secondary outcomes, as defined in study reports: none Adverse events reported: no Intervals at which outcomes assessed: 1 day, 1 week, 2 weeks, and monthly thereafter

Notes

Type of study: published Funding sources: not reported Disclosures of interest: “The authors state that they have no proprietary interest in the products named in this study.” Study period: January 2002 to September 2003 Trial registration: none reported Reported subgroup analyses: yes

Risk of bias


Bias




Low risk

“Randomization was accomplished by using a list created by a random-number generator”


Unclear risk



Low risk

Masking of personnel was not reported, though the surgeon would not be masked due to the nature of the surgery. ”Patients were randomized to either of the 2 treatment groups in a masked manner, with patients being informed neither of the surgical procedure they received nor of their pterygium grade status.”


Low risk

Outcome assessors were masked to the type of surgery


Low risk

The authors reported no missing data


Unclear risk

A protocol was unavailable

Other bias

Low risk

“The authors state that they have no proprietary interest in the products named in this study.”

Liang 2012 Methods

Study design: parallel-group RCT Number randomized (total and per group): Total: 133 eyes of 118 participants Per group: conjunctival autograft 81 eyes of 81 participants; amniotic membrane transplant 52 eyes of 52 participants Exclusions after randomization: none


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Number analyzed (total and per group): Total: 133 eyes of 118 participants Per group: conjunctival autograft 81 eyes of 81 participants; amniotic membrane transplant 52 eyes of 52 participants Unit of analysis (individuals vs eyes): eye Losses to follow-up: none How was missing data handled?: N/A Reported power calculation: no Unusual study design?: both eyes of some participants were independently assigned to 2 intervention groups without taking account non-independence of eyes

Author Manuscript

Participants

Country: China Age (mean ± SD): conjunctival autograft range 32 to 85 years old; amniotic membrane transplant group range 30 to 81 years old Gender (percent): total 38.3% men and 61.7% women; conjunctival autograft 39.5% men and 60.5% women; amniotic membrane transplant 38.5% men and 61.5% women Inclusion criteria: pterygium Exclusion criteria: no ocular surface disease or systemic illnesses Equivalence of baseline characteristics: not reported

Interventions

Intervention 1: limbal conjunctival autograft transplantation Intervention 2: amniotic membrane transplantation Length of follow-up: Planned: 12 months Actual: 12 months

Outcomes

Primary outcome, as defined in study reports: foreign body sensation or discomfort; eyelid edema and conjunctival hyperemia edema; recurrence Secondary outcomes, as defined in study reports: not distinguished Adverse events reported: no Intervals at which outcomes assessed: 1 week and 12 months

Notes

Type of study: published Funding sources: not reported Disclosures of interest: not reported Study period: July 2008 to July 2010 Trial registration: none reported Reported subgroup analyses: yes

Risk of bias


Bias




Unclear risk



Unclear risk



Unclear risk



Unclear risk



Low risk

No missing data


Unclear risk


Other bias

High risk

Both eyes of single participant were independently assigned to the 2 intervention groups without taking account non-independence of eyes; funding source not reported


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Author Manuscript

Luanratanakorn 2006 Study design: parallel-group RCT Number randomized (total and per group): Total: 346 eyes of 346 participants Per group: not reported Exclusions after randomization: 1 (died) Number analyzed (total and per group): Total: 287 eyes of 287 participants Per group: conjunctival autograft 120 eyes of 120 participants; amniotic membrane transplant 167 eyes of 167 participants Unit of analysis (individuals vs eyes): individual (1 eye per participant was enrolled) Losses to follow-up: 58 participants How was missing data handled?: excluded Reported power calculation: yes (80%) Unusual study design?: none

Participants

Country: Thailand Age (mean ± SD): conjunctival autograft 45.42 ± 11.47 years (range 19 to 72 years); amniotic membrane transplant 46.49 ± 13.63 years (range 18 to 80 years) Gender (percent): total 34.8% men and 65.2% women; limbal conjunctival autograft transplantation group 36.7% men and 63.3% women; amniotic membrane transplant 33.5% men and 66.5% women Inclusion criteria:

Author Manuscript

Methods

1

people who were diagnosed with pterygium (both primary and recurrent pterygia) at Srinagarind Hospital and met the indication for surgical treatment

2

people with pterygium who signed the informed consent to enroll in the study

Exclusion criteria: 1

people who had glaucoma in the study eye

2

people who had an intraocular pressure > 21 mmHg in the study eye

3

people who had a history of allergy to steroid eye drops

4

people enrolled in another study that might affect this study

5

people who had not co-operated during pterygium excision surgery

Author Manuscript


Author Manuscript

Interventions

Intervention 1: amniotic membrane transplantation Intervention 2: limbal conjunctival autograft transplantation Length of follow-up: Planned: 6 months Actual: 6 months

Outcomes

Primary outcome, as defined in study reports: recurrence; complications Secondary outcomes, as defined in study reports: none Adverse events reported: yes Intervals at which outcomes assessed: 6 weeks and 6 months

Notes

Type of study: published Funding sources: “This study was supported by an invitation grant from the Faculty of Medicine, Khon Kaen University.” Disclosures of interest: none Study period: 2000 to 2001 Trial registration: protocol #I44034 approved by the Medical Science Subcommittee for the protection of Human Subjects in Research of Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand Reported subgroup analyses: yes

Risk of bias Bias




Unclear risk

”The patients were randomised into two groups by a simple randomisation technique.“


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Unclear risk



High risk

Only the outcomes assessor was masked, participants and surgeons were not. “This study was designed as a single-blind randomised control trial.”


Low risk

“This study was designed as a single-blind randomised control trial”; “The results at 6 weeks and 6 months were examined by the same investigator in a blind assessment to grade the final appearance”


High risk

59/346 (17.1%) participants were lost to follow-up, and they were not included in the final analysis


Unclear risk

Authors report a protocol was written but do not provide a reference or a way to access the protocol

Other bias

Low risk

None

Ozer 2009


Methods

Study design: parallel-group RCT (for the participants in the amniotic membrane graft and limbal conjunctival autograft transplantation groups) Number randomized (total and per group): Total: 163 eyes of 163 participants Per group: limbal conjunctival autograft 63 eyes of 63 participants; amniotic membrane transplant 52 eyes of 52 participants; bare sclera 48 eyes of 48 participants Exclusions after randomization: none Number analyzed (total and per group): Total: 163 eyes of 163 participants Per group: limbal conjunctival autograft 63 eyes of 63 participants; amniotic membrane transplant 52 eyes of 52 participants; bare sclera 48 eyes of 48 participants Unit of analysis (individuals vs eyes): individual (1 eye per participant was enrolled in the study) Losses to follow-up: none How was missing data handled?: N/A Reported power calculation: no Unusual study design?: participants in the bare sclera technique group were not randomized

Participants

Country: Turkey Age (mean ± SD): limbal conjunctival autograft 49.63 ± 14.42 years; amniotic membrane transplant 47.92 ± 15.52 years; bare sclera 47.88 ± 14.21 years Gender (percent): limbal conjunctival autograft 49.2% men and 50.8% women; amniotic membrane transplant 51.9% men and 48.1% women; bare sclera technique 41.7% men and 58.3% women Inclusion criteria: people with primary pterygium between the ages of 22 and 74 years Exclusion criteria: people with recurrent pterygium Equivalence of baseline characteristics: yes; “The age and sex distribution in all of the groups showed no significant differences.”

Interventions

Intervention 1: conjunctival limbal autograft transplantation Intervention 2: amniotic membrane transplantation Intervention 3: bare sclera technique Length of follow-up: Planned: not reported Actual: conjunctival limbal autograft 69.91 ± 12.41 (range 59 to 82 months); amniotic membrane transplant 61.43 ± 9.83 (range 53 to 74 months); bare sclera technique 72.39 ± 11.03 (range 61 to 77 months)

Outcomes

Primary outcome, as defined in study reports: corneal epithelialization; recurrences; complication Secondary outcomes, as defined in study reports: not distinguished Adverse events reported: yes Intervals at which outcomes assessed: 2, 5, 7, 15, and 30 days, and every month thereafter

Notes

Type of study: published Funding sources: not reported Disclosures of interest: not reported Study period: from June 1995


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Author Manuscript

Trial registration: none reported Reported subgroup analyses: no Risk of bias


Bias




Unclear risk

Participants in the bare sclera technique group were not randomized, but participants in the groups of interest to this review were randomized. The randomization method was not reported. “The first 45 consecutive patients underwent BST because LCAT and AMGT were not previously used by the surgeons at Eskiehir Osmangazi University. Once the preliminary preparations had been completed, the randomization procedure was begun, starting with the 46th patient. We chose the patients for LCAT and AMGT randomly, rather than in consideration of certain criteria. The reason we excluded BCT from our randomization process was due to the high risk of recurrence of pterygium in cases reported not only in the literature but also in our clinic. However, 3 patients refused to undergo either LCAT or AMGT after these new techniques had been explained to them in order to obtain their informed consent. For this reason, these 3 patients were placed in the group undergoing BST. ”


Unclear risk



Unclear risk



Unclear risk



Low risk

No missing data


Unclear risk


Other bias

Unclear risk

Funding source was not reported; results in recurrence risk were different in texts and table

Paes 2010

Author Manuscript

Methods

Study design: parallel-group RCT Number randomized (total and per group): Total: not reported Per group: not reported Exclusions after randomization: participants lost to follow-up were excluded, but this number was not reported Number analyzed (total and per group): Total: 228 Per group: conjunctival autograft 102; amniotic membrane transplant 126 Unit of analysis (individuals vs eyes): individual (1 eye per participant) Losses to follow-up: number was not reported, but those lost to follow-up were not included in the report How was missing data handled?: N/A Reported power calculation: no Unusual study design?: none

Participants

Country: Brazil Age: mean age 35 years (range 20 to 53) Gender (percent): conjunctival autograft 50.98% men, 49.02% women; amniotic membrane transplant 60.31% men, 39.69% women


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Author Manuscript

Inclusion criteria: people with primary pterygium grade II (2 to 4 mm corneal invasion), aged 18 to 60 years, absence of infection in ocular surface Exclusion criteria: age younger than 18 or older than 60, primary pterygium grade I or III, recurrent pterygium, presence of ocular surface infection, loss to follow-up Equivalence of baseline characteristics: not reported

Author Manuscript

Interventions


Outcomes

Primary outcome, as defined in study reports: recurrence Secondary outcomes, as defined in study reports: satisfaction with surgery, postoperative pain Adverse events reported: no Intervals at which outcomes assessed: baseline, daily for one week, on the 15th day then 1, 6, and 12 months postoperatively

Notes

Type of study: published (doctoral thesis) Funding sources: not reported Disclosures of interest: not reported Study period: January 2001 to October 2005 Trial registration: none reported Reported subgroup analyses: yes, by gender

Risk of bias

Author Manuscript

Bias




Low risk

Authors made use of a random number table; when the sum of digits was an even number, the participants were put into 1 group, and when the sum of digits was an odd number, participants were put into the other surgical group


High risk

Allocation concealment was not performed


Unclear risk



Unclear risk



High risk

Participants who were lost to follow-up were not included in the study report, therefore it is unclear to which group they were randomized or what data were missing for them


Unclear risk

Authors report a protocol was presented to the Committee of Ethics in Research; however authors do not provide a reference or a way to access the protocol

Other bias

Unclear risk

Funding and other disclosures not provided

Perry 2000

Author Manuscript

Methods

Study design: parallel-group RCT Number randomized (total and per group): Total: 16 eyes of 8 participants Per group: conjunctival autograft 8; amniotic membrane transplant 8 Exclusions after randomization: none Number analyzed (total and per group): Total: 16 eyes of 8 participants Per group: conjunctival autograft 8; amniotic membrane transplant 8 Unit of analysis (individuals vs eyes): eyes (each participant had amniotic membrane transplant in 1 eye and conjunctival autograft in the other eye) Losses to follow-up: not reported How was missing data handled?: not reported Reported power calculation: no


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Author Manuscript

Unusual study design?: participants had bilateral symptomatic pterygium and had 1 type of surgery in each eye

Author Manuscript

Participants

Country: not reported Age: not reported Gender (percent): not reported Inclusion criteria: bilateral symptomatic pterygium Exclusion criteria: none reported Equivalence of baseline characteristics: not reported

Interventions

Intervention 1: conjunctival autograft Intervention 2: amniotic membrane transplantation Length of follow-up: Planned: not reported Actual: mean 12.5 months (range 9 to 22 months)

Outcomes

Primary outcome, as defined in study reports: visual acuity, recurrence Secondary outcomes, as defined in study reports: adverse events Adverse events reported: yes Intervals at which outcomes assessed: not reported

Notes

Type of study: published conference abstract Funding sources: not reported Disclosures of interest: not reported Study period: not reported Trial registration: none reported Reported subgroup analyses: no

Risk of bias

Author Manuscript

Bias




Unclear risk

Method of randomization not reported


Unclear risk



Unclear risk



Unclear risk



Unclear risk

It was not reported whether or not there was missing data


Unclear risk

In this abstract, it is unclear if there was selective reporting bias

Other bias

Unclear risk

Funding sources and other disclosures were not reported

Author Manuscript

Pérez Parra 2008 Methods

Study design: parallel-group RCT Number randomized (total and per group): Total: 90 eyes of 60 participants Per group: conjunctival autograft 45 eyes of 30 participants; amniotic membrane transplant 45 eyes of 30 participants Exclusions after randomization: none reported Number analyzed (total and per group): Total: 90 eyes of 60 participants Per group: conjunctival autograft 45 eyes of 30 participants; amniotic membrane transplant 45 eyes of 30 participants Unit of analysis (individuals vs eyes): eyes


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Author Manuscript

Losses to follow-up: not reported How was missing data handled?: not reported Reported power calculation: no Unusual study design?: some participants had two eyes included in the study without taking into account non-independence of eyes

Author Manuscript

Participants

Country: Cuba Age: mean 47 years (range 23 to 74) Gender (percent): 60% male, 40% female Inclusion criteria: over 20 years of age, vascular and symptomatic primary pterygium Exclusion criteria: history of ophthalmic disease, systemic disease such as diabetes mellitus, vascular diseases and collagenopathies Equivalence of baseline characteristics: not reported

Interventions


Outcomes

Primary outcome, as defined in study reports: recurrence of pterygium Secondary outcomes, as defined in study reports: none reported Adverse events reported: yes Intervals at which outcomes assessed: 24 hours, 7 days, 1, 6, 12 months

Notes

Type of study: published Funding sources: not reported Disclosures of interest: not reported Study period: January 2006 to January 2007 Trial registration: none reported Reported subgroup analyses: no

Risk of bias


Bias




Unclear risk

Sequence generation was not reported


Unclear risk



Unclear risk



Unclear risk

Masking of outcomes assessors was not re-ported


Low risk

No missing data was reported


Unclear risk

It is unclear if selective outcome reporting occurred; a protocol was not available

Other bias

High risk

Funding sources were not described; some participants had surgery in both eyes while others had surgery in only 1 eye

Salman 2011 Methods

Study design: parallel-group RCT Number randomized (total and per group): Total: 60 eyes of 48 participants Per group: conjunctival autograft 20 eyes; amniotic membrane transplant 20 eyes; topical MMC plus AMT 20 eyes Exclusions after randomization: none


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Author Manuscript

Number analyzed (total and per group): Total: 60 eyes of 48 participants Per group: conjunctival autograft 20 eyes; amniotic membrane transplant 20 eyes; topical MMC plus AMT 20 eyes Unit of analysis (individuals vs eyes): eye Losses to follow-up: none How was missing data handled?: N/A Reported power calculation: no Unusual study design?: both eyes of single participant were independently assigned to intervention groups without taking into account non-independence of eyes; participants with follow-up less than 6 months were excluded from the study Participants

Author Manuscript

Country: Egypt Age (mean ± SD): overall 45.2 ± 3.7 (range 28 to 52 years); limbal conjunctival autograft 45.2 ± 7.3 (range 30 to 50 years); amniotic membrane transplant 49.1 ± 2.3 (range 29 to 52 years); topical MMC plus AMT 39.1 ± 13.1 (range 30 to 52 years) Gender (percent): overall 80% men and 20% women; conjunctival limbal autograft 80% men and 20% women; amniotic membrane transplant 90% men and 10% women; topical MMC plus AMT group 70% men and 30% women Inclusion criteria: people with recurrent pterygium, primary pterygium excision performed 6 to 15 months before selection into study Exclusion criteria: 1

dry eye syndrome

2

wound-healing problems such as ocular cicatricial pemphigoid

3

immunocompromised patients or use of immunosuppressive drugs

4

follow-up less than 6 months postoperatively

Equivalence of baseline characteristics: not reported

Author Manuscript

Interventions

Intervention 1: conjunctival limbal autograft transplantation Intervention 2: amniotic membrane transplantation Intervention 3: MMC 0.05% for 3 min followed by amniotic membrane transplantation Length of follow-up: Planned: 2 years Actual: 2 years

Outcomes

Primary outcome, as defined in study reports: recurrences Secondary outcomes, as defined in study reports: complications: conjunctival irritation, chemosis, transient increase in intraocular pressure, conjunctival granuloma, transient superficial keratitis Adverse events reported: yes Intervals at which outcomes assessed: not reported

Notes

Type of study: published Funding sources: “Fund of Ophthalmology Department, Ain Shams University.” Disclosures of interest: “No financial interest of authors for any of used materials” Study period: not reported Trial registration: none reported Reported subgroup analyses: no

Risk of bias

Author Manuscript

Bias




Unclear risk

Method of random sequence generation was not reported. “The cases were divided randomly into three equal groups”


Unclear risk



Unclear risk



Unclear risk



Clearfield et al.

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Author Manuscript


Low risk

No loss to follow-up


Unclear risk


Other bias

High risk

Both eyes of single participant were independently assigned to intervention groups without taking into account non-independence of eyes; participants with less than 6 months’ follow-up were excluded from the study

Stangogiannis-Druya 2004


Methods

Study design: parallel-group RCT Number randomized (total and per group): Total: 60 Per group: conjunctival autograft 30, amniotic membrane transplant 30 Exclusions after randomization: not reported Number analyzed (total and per group): Total: 60 Per group: conjunctival autograft 30, amniotic membrane transplant 30 Unit of analysis (individuals vs eyes): individuals (1 eye per participant) Losses to follow-up: not reported How was missing data handled?: not reported Reported power calculation: no Unusual study design?: none

Participants

Country: Venezuela Age: not reported Gender (percent): not reported Inclusion criteria: recurrent pterygium Exclusion criteria: people under 20 years of age, people with primary pterygium, external eye diseases such as conjunctivitis, dry eye, blepharitis Equivalence of baseline characteristics: not reported

Interventions


Outcomes

Primary outcome, as defined in study reports: recurrence of pterygium Secondary outcomes, as defined in study reports: not reported Adverse events reported: yes Intervals at which outcomes assessed: 24 hours, 72 hours, 1 week, 1 month, 5 months

Notes

Type of study: published Funding sources: not reported Disclosures of interest: not reported Study period: January to June 2004 Trial registration: none reported Reported subgroup analyses: no

Risk of bias

Author Manuscript

Bias




Unclear risk

Sequence generation was not described


Unclear risk

Method of allocation concealment was not described


Unclear risk

Masking of participants and personnel was not described


Clearfield et al.

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Author Manuscript


Unclear risk

Masking of outcome assessors was not described


Unclear risk

It is unclear if there was any missing data or loss to follow-up


Unclear risk

It is unclear if there was selective reporting of outcomes; a protocol was not available

Other bias

High risk

No details about the type of analysis were provided, funding sources and disclosures were not included

Tananuvat 2004 Study design: parallel-group RCT Number randomized (total and per group): Total: 92 eyes of 83 participants Per group: not reported Exclusions after randomization: total 6 participants; conjunctival autograft 5 participants; amniotic membrane transplantation 1 participant Number analyzed (total and per group): Total: 86 eyes of 78 participants Per group: 42 eyes of 41 participants in the conjunctival autograft transplantation group; 44 eyes of 39 participants in the amniotic membrane transplantation group Unit of analysis (individuals vs eyes): eye Losses to follow up: 6 due to follow-up < 6 months How was missing data handled?: discarded Reported power calculation: no Unusual study design?: for 9 participants, both eyes of single participant were independently randomized to intervention groups without taking into account non-independence of eyes; participants with a follow-up period of less than 6 months were excluded

Participants

Country: Thailand Age (mean ± SD): conjunctival autograft 44.81 ± 8.77 years (range 21 to 59 years); amniotic membrane transplant 41.93 ± 9.0 years (range 27 to 60 years) Gender (percent): total 42.5% men and 57.5% women; conjunctival autograft 43.9% men and 56.1% women; amniotic membrane transplant 41.0% men and 59.0% women Inclusion criteria: primary pterygium; age between 20 and 60 years Exclusion criteria:

Author Manuscript

Methods

Author Manuscript

1

more than 1 head of pterygium

2

ocular infection and inflammation

3

glaucoma

4

previous ocular surgery in the study eye

5

systemic diseases such as rheumatoid arthritis or other collagen vascular diseases


Author Manuscript

Interventions

Intervention 1: conjunctival autograft transplantation Intervention 2: amniotic membrane transplantation Length of follow-up: Planned: 12 months Actual: 12.4 ± 3.1 months in the conjunctival autograft transplantation group; 14.4 ± 5.4 months in the amniotic membrane transplantation group

Outcomes

Primary outcome, as defined in study reports: recurrence risk Secondary outcomes, as defined in study reports: complication Adverse events reported: yes Intervals at which outcomes assessed: 1 day, 1 week, and 1, 3, 6, and 12 months

Notes

Type of study: published Funding sources: “Supported by the Faculty of Medicine Endowment Fund, Faculty of Medicine, Chiang Mai University.” Disclosures of interest: “The authors did not have a financial interest in any product investigated in this study.” Study period: not reported Trial registration: none reported


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Author Manuscript

Reported subgroup analyses: yes Risk of bias


Bias




Unclear risk



Unclear risk



Unclear risk



Unclear risk



High risk

6/83 (7.2%) participants were excluded because the follow-up period was less than 6 months, and they were not included in the analysis. Authors say that the exclusion of these participants may be the reason why the follow-up for the AMT group was “significantly longer” than for CA group


High risk

Except for recurrences, outcomes in results were not described beyond “clinical outcome” (Intro) or “other complications” (Materials and Methods). Three such outcomes are pyogenic granuloma (complication), high intraocular pressure, and “loss of uncorrected visual acuity of more than one line” (authors report “none”; however, unclear if some eyes lost one line of visual acuity)

Other bias

High risk

For 9 participants, both eyes of single participant were independently randomized to intervention groups without taking into account nonindependence of eyes; “Eyes, rather than people, were used as a unit for statistical analysis because there were only 9 patients who had both eyes operated on, and each eye was independently randomized to treatment”

Toker 2016

Author Manuscript

Methods

Study design: parallel-group RCT Number randomized (total and per group): Total: 82 eyes of 74 participants Per group: conjunctival autograft 43 eyes of 40 participants; amniotic membrane transplant 39 eyes of 34 participants Exclusions after randomization: not reported Number analyzed (total and per group): Total: 73 eyes of 65 participants Per group: conjunctival autograft 37 eyes of 34 participants; amniotic membrane transplant 36 eyes of 31 participants Unit of analysis (individuals vs eyes): baseline characteristics by individual; outcomes by eyes Losses to follow-up: conjunctival autograft group 6 eyes of 6 participants; amniotic membrane transplant group 3 eyes of 3 participants How was missing data handled?: excluded Reported power calculation: no Unusual study design?: the study initially randomized 74 participants total, but they only included analyses for 65 participants because they excluded outcome data for the 9 participants who did not complete the 1-year follow-up

Participants

Country: Turkey Age (mean ± SD): conjunctival autograft 52 ± 13.7; amniotic membrane transplant 49. 8 ± 14.1 Gender (percent): conjunctival autograft 52.9% male, 47.1% female; amniotic membrane transplant 51.6% male, 48.4% female


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Author Manuscript

Inclusion criteria: people with primary pterygium, cosmetically significant pterygium or clinically significant pterygium presenting with ocular irritation, inflammation, or reduced vision Exclusion criteria: < 18 years of age, other concurrent ocular or lid pathology, glaucoma, ocular hypertension, pregnancy, and known hypersensitivity to any component of fibrin glue Equivalence of baseline characteristics: yes

Author Manuscript

Interventions

Intervention 1: conjunctival autograft fixed with fibrin glue Intervention 2: amniotic membrane transplant fixed with fibrin glue Length of follow-up: Planned: 12 months Actual: 12 months

Outcomes

Primary outcome, as defined in study reports: rate of recurrence Secondary outcomes, as defined in study reports: complications Adverse events reported: yes Intervals at which outcomes assessed: 1, 7, and 14 days, 1, 2, 3, 4, 6, 8, and 10 months, 1 year

Notes

Type of study: published Funding sources: none reported Disclosures of interest: “The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper. The authors have no financial interest on any of the materials mentioned in the study.” Study period: February 2008 to January 2011 Trial registration: none reported Reported subgroup analyses: no

Risk of bias

Author Manuscript

Bias




Low risk

“Randomization was accomplished using a random number table.”


Unclear risk



Unclear risk

In communication with a study author, we learned that participants were masked to which surgery they received, but masking of personnel was not reported


High risk

In communication with a study author, we learned that the doctors who performed the postoperative examinations were not masked


High risk

9 eyes were not followed up for the full year and not discussed

Characteristics of excluded studies [ordered by study ID]

Author Manuscript

Study

Reason for exclusion

Katircioglu 2007

Unclear whether participants were randomized

Kim 2008


Li 2014

No conjunctival autograft arm, only amniotic membrane transplant alone or combined with conjunctive reverse transplantation

Lin 2009

Compared conjunctival flap technique to amniotic membrane transplant

Liu 2014

Not a randomized controlled trial

Nava-Castaneda 2007

Ex vivo study of mucins found in tear film after pterygium surgeries

Ozkurt 2009



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Author Manuscript

Study

Reason for exclusion

Paris 2008


Pei 2011

Compared corneal limbal stem cell transplant with conjunctival flap technique to amniotic membrane transplant

Xia 2008

Compared conjunctival flap technique to amniotic membrane transplant

Yan 2010

Not a randomized controlled trial

Zhang 2014

Compared corneal limbal stem cell transplant to amniotic membrane transplant

Characteristics of studies awaiting assessment [ordered by study ID] CTRI/2015/07/005960

Author Manuscript

Methods

Study design: parallel-group randomized controlled trial Target sample size: 31 participants

Participants

Country: India Inclusion criteria: people with double pterygium with operable features Exclusion criteria: children under age 18 years, previous history of trauma or chemical injury, pregnancy

Interventions

Intervention 1: conjunctival autograft Intervention 2: amniotic membrane transplant Length of follow-up: Planned: 3 years

Outcomes

Primary outcome, as defined in study reports: recurrence of pterygium nasally and temporally Secondary outcomes, as defined in study reports: recurrence based on site of replacement Intervals at which outcomes assessed: planned to 1 year

Notes

Type of study: not yet published Funding sources: reported as self funded Disclosures of interest: not reported Study period: recruitment began May 2011

Author Manuscript

DATA AND ANALYSES Comparison 1

Conjunctival autograft (CAG) versus amniotic membrane transplant (AMT) Outcome or subgroup title

No. of studies

No. of participants

Author Manuscript

Statistical method

Effect size

1 Recurrence of pterygium at 3 months

6

538

Risk Ratio (M-H, Random, 95% CI)

0.87 [0.43, 1.77]

1.1 Participants with primary pterygium

5

488


0.92 [0.37, 2.30]

1.2 Participants with primary or recurrent pterygium

1

50


0.62 [0.21, 1.85]

2 Recurrence of pterygium at 6 months

10

1021


0.53 [0.33, 0.85]

2.1 Participants with primary pterygium

7

815


0.58 [0.27, 1.27]

2.2 Participants with recurrent pterygium

3

96


0.45 [0.21, 0.99]

2.3 Participants with primary or recurrent pterygium

2

110


0.38 [0.15, 0.95]


Clearfield et al.

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Author Manuscript

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

3 Adverse events

8

3.1 Pyogenic granuloma during the study

3

141


0.33 [0.07, 1.55]

3.2 Pyogenic granuloma at 6 months

2

337


1.99 [0.67, 5.90]

3.3 Granuloma during study

3

186


0.71 [0.23, 2.18]

3.4 Increased IOP at 6 months

2

327


2.52 [0.91, 7.00]


Analysis 1.1.

Comparison 1 Conjunctival autograft (CAG) versus amniotic membrane transplant (AMT), Outcome 1 Recurrence of pterygium at 3 months.


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Author Manuscript Author Manuscript Author Manuscript Analysis 1.2.

Author Manuscript

Comparison 1 Conjunctival autograft (CAG) versus amniotic membrane transplant (AMT), Outcome 2 Recurrence of pterygium at 6 months.


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Page 60

Author Manuscript Author Manuscript Author Manuscript Analysis 1.3.

Comparison 1 Conjunctival autograft (CAG) versus amniotic membrane transplant (AMT), Outcome 3 Adverse events.

Author Manuscript Cochrane Database Syst Rev. Author manuscript; available in PMC 2017 February 11.

Clearfield et al.

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Figure 1.

Study flow diagram.

Author Manuscript Cochrane Database Syst Rev. Author manuscript; available in PMC 2017 February 11.

Clearfield et al.

Page 62

Author Manuscript Figure 2.

Author Manuscript

Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies.

Author Manuscript Author Manuscript Cochrane Database Syst Rev. Author manuscript; available in PMC 2017 February 11.

Clearfield et al.

Page 63


Figure 3.

Risk of bias summary: review authors’ judgments about each risk of bias item for each included study.


Clearfield et al.

Page 64


Figure 4.

Forest plot of comparison: 1 Conjunctival autograft (CAG) versus amniotic membrane transplant (AMT), outcome: 1.1 Recurrence of pterygium at 3 months.


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Figure 5.

Forest plot of comparison: 1 Conjunctival autograft (CAG) versus amniotic membrane transplant (AMT), outcome: 1.2 Recurrence of pterygium at 6 months.


Clearfield et al.

Page 66


Figure 6.

Forest plot of comparison: 1 Conjunctival autograft (CAG) versus amniotic membrane transplant (AMT), outcome: 1.3 Adverse events.


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Table 1

Author Manuscript

Sensitivity Analysis

Author Manuscript

Estimates Including Paes 2010 Study

Estimates Not Including Paes 2010 Study

Outcome

Number of Studies (Participants)


Number of Studies (Participants)


Recurrence of pterygium at 3 months

6 (538)

0.87 [0.43, 1.77]

5 (310)

0.62 [0.30, 1.27]

Participants with primary pterygium

5 (488)

0.92 [0.37, 2.30]

4 (260)

0.62 [0.24, 1.60]

Participants with primary or recurrent pterygium

1 (50)

0.62 [0.21, 1.85]

1 (50)

0.62 [0.21, 1.85]

Recurrence of pterygium at 6 months

10 (1,021)

0.53 [0.33, 0.85]

9 (793)

0.43 [0.30, 0.62]

Participants with primary pterygium

7 (815)

0.58 [0.27, 1.27]

6 (587)

0.43 [0.27, 0.69]

Participants with recurrent pterygium

3 (96)

0.45 [0.21, 0.99]

3 (96)

0.45 [0.21, 0.99]

Participants with primary or recurrent pterygium

2 (110)

0.38 [0.15, 0.95]

2 (110)

0.38 [0.15, 0.95]


Author Manuscript 1 (Besharati 2008) 1 (Besharati 2008) 1 (Besharati 2008)

6 months 1 month 3 months 6 months

Chemosis

Conjunctival contraction

1 (Besharati 2008) 1 (Besharati 2008) 1 (Besharati 2008) 1 (Toker 2016) 1 (Aragonés Cruz 2008)

1 month 3 months 6 months During study Overall

Graft dehiscence/suture dehiscence

Cochrane Database Syst Rev. Author manuscript; available in PMC 2017 February 11. 1 month

1 (Tananuvat 2004)

During study

Infection

2 (Luanratanakorn 2006; Salman 2011)

6 months

Increased intraocular pressure

1 (Besharati 2008)

3 (Aragonés Cruz 2008; Pérez Parra 2008; Salman 2011)

During study

Granuloma

1 (Küçükerdönmez 2007)

During study

Graft reaction

1 (Liang 2012)

12 months

Foreign body sensation or discomfort

1 (Liang 2012)

1 (Besharati 2008)

12 months

6 months

Eyelid edema and conjunctival hyperemia edema

1 (Besharati 2008)

3 months

Eye movement restriction

1 (Katircioglu 2014)

During study

1 (Besharati 2008)

6 months

Epithelial defect (lasting more than 5 days)

1 (Besharati 2008)

3 months

Diplopia

1 (Aragonés Cruz 2008)

1 (Besharati 2008)

6 months Overall

1 (Besharati 2008)

3 months

Conjunctivitis

1 (Besharati 2008)

1 month

Corneal scar

1 (Kheirkhah 2011)

During study

Conjunctival inflammation - grade 1 to 3

1 (Salman 2011)

Time point

Number of studies (reference)

Author Manuscript

Event

0 (0)

5 (11.9)

8 (6.7)

4 (4.3)

1 (7.1)

0 (0)

2 (5.4)

3 (12.5)

3 (12.5)

3 (12.5)

11 (13.6)

8 (9.9)

0 (0)

0 (0)

1 (3.3)

0 (0)

0 (0)

0 (0)

16 (66.7)

16 (66.7)

16 (66.7)

3 (15)

2 (8.5)

1 (4.2)

3 (12.5)

4 (20.0)

Conjunctival autograft, n (%)

Author Manuscript

Adverse events

1 (3.8)

4 (9.1)

5 (3.0)

6 (6.5)

0 (0)

1 (3.6)

2 (5.6)

1 (3.8)

1 (3.8)

1 (3.8)

17 (32.7)

12 (23.1)

1 (3.8)

1 (3.8)

0 (0)

2 (7.7)

1 (3.8)

1 (3.6)

16 (61.5)

16 (61.5)

16 (61.5)

16 (84.2)

5 (19.2)

3 (11.5)

4 (15.4)

2 (10.0)

Amniotic membrane transplant, n (%)

0.36 (0.02 to 8.43)

1.31 (0.38 to 4.55)

2.52 (0.91 to 7.00)

0.71 (0.23 to 2.18)

2.80 (0.12 to 63.20)

0.33 (0.01 to 7.85)

0.97 (0.14 to 6.54)

3.25 (0.36 to 29.16)

3.25 (0.36 to 29.16)

3.25 (0.36 to 29.16)

0.42 (0.21 to 0.81)

0.43 (0.19 to 0.98)

0.36 (0.02 to 8.43)

0.36 (0.02 to 8.43)

0.67 (0.20 to 2.22)

0.22 (0.01 to 4.28)

0.36 (0.02 to 8.43)

0.33 (0.01 to 7.85)

1.08 (0.72 to 1.64)

1.08 (0.72 to 1.64)

1.08 (0.72 to 1.64)

0.18 (0.06 to 0.51)

0.43 (0.09 to 2.03)

0.36 (0.04 to 3.24)

0.81 (0.20 to 3.26)

2.00 (0.41 to 9.71)

Risk ratio (95% CI)

Author Manuscript

Table 2 Clearfield et al. Page 68

Author Manuscript During study During study During study 1 month

Author Manuscript

Inflammation

Graft edema

Other defect taking > 10 days to heal

Pyogenic granuloma

1 (Chen 2012)

2 years

CI: confidence interval

Wound healing

Symblepharon


Overall

Superficial punctate keratitis

1 (Perry 2000)

During study 1 (Chen 2012)

1 (Chen 2012)

2 years

2 years

1 (Besharati 2008)

6 months


Overall

Subconjunctival hemorrhage


3 (Kheirkhah 2011; Perry 2000; Tananuvat 2004)

During study During study

2 (Besharati 2008; Luanratanakorn 2006)

6 months

Severe pain

1 (Besharati 2008)

3 months

1 (Besharati 2008)


1 (Küçükerdönmez 2007)

1 (Pérez Parra 2008)

Number of studies (reference)

3 (6.7)

1 (12.5)

1 (2.2)

0 (0)

1 (2.2)

3 (10.7)

4 (14.2)

4 (13.4)

1 (1.3)

8 (5.6)

4 (16.7)

4 (16.7)

4 (13.4)

0 (0)

2 (4.4)

Conjunctival autograft, n (%)

Author Manuscript

Time point

3 (6.7)

0 (0)

1 (2.2)

1 (3.8)

2 (4.4)

3 (10.7)

0 (0)

2 (8.0)

5 (7.0)

5 (2.6)

2 (7.7)

2 (7.7)

5 (20)

2 (15.4)

0 (0)

Amniotic membrane transplant, n (%)

1.00 (0.21 to 4.69)

3.00 (0.14 to 64.26)

1.00 (0.06 to 15.50)

0.36 (0.02 to 8.43)

0.50 (0.05 to 5.32)

1.00 (0.22 to 4.54)

9.00 (0.51 to 159.70)

1.67 (0.33 to 8.36)

0.33 (0.07 to 1.55)

1.99 (0.67 to 5.90)

2.17 (0.44 to 10.78)

2.17 (0.44 to 10.78)

2.52 (0.11 to 59.18)

0.19 (0.01 to 3.56)

5.00 (0.25 to 101.31)

Risk ratio (95% CI)

Author Manuscript

Event

Clearfield et al. Page 69


Conjunctival-Limbal Autograft for Primary and Recurrent Pterygium.

Comparison of Inferior and Superior Conjunctival Autograft for Primary Pterygium.

Conjunctival autograft in primary and recurrent pterygium: a study.

Conjunctival metaplasia after pterygium excision and limbal autograft.

[Preliminary results of the pterygium excision technic with conjunctival autograft].

Comparison of anchored conjunctival rotation flap and conjunctival autograft techniques in pterygium surgery.

Visual outcome and efficacy of conjunctival autograft, harvested from the body of pterygium in pterygium excision.

Combined conjunctival autograft and overlay amniotic membrane transplantation; a novel surgical treatment for pterygium.

Evaluation of the recurrence rate for pterygium treated with conjunctival autograft.

Erratum: combined conjunctival autograft and overlay amniotic membrane transplantation; a novel surgical treatment for pterygium: erratum.

A comparison between fibrin sealant and sutures for attaching conjunctival autograft after pterygium excision.

Sandwich fibrin glue technique for attachment of conjunctival autograft during pterygium surgery.

Twelve-Year Outcomes of Pterygium Excision with Conjunctival Autograft versus Intraoperative Mitomycin C in Double-Head Pterygium Surgery.

Comparison of efficacy of three surgical methods of conjunctival autograft fixation in the treatment of pterygium.

Sequential pterygium excision with conjunctival autograft in the management of primary double-headed pterygia.

The Use of Conjunctival Rotational Autograft in the Management of Pterygium.

Comparison between sutureless and glue free versus sutured limbal conjunctival autograft in primary pterygium surgery.

Comparison of Two Techniques for the Treatment of Recurrent Pterygium: Amniotic Membrane vs Conjunctival Autograft Combined with Mitomycin C.

Biodegradable collagen matrix (Ologen™) implant and conjunctival autograft for scleral necrosis after pterygium excision: two case reports.

Autologous blood versus fibrin glue for conjunctival autograft adherence in sutureless pterygium surgery: a randomised controlled trial.

Recurrence After Primary Pterygium Excision: Amniotic Membrane Transplantation with Fibrin Glue Versus Conjunctival Autograft with Fibrin Glue.

Sutureless, Glue-less Conjunctival Autograft versus Conjunctival Autograft with Sutures for Primary, Advanced Pterygia: An Interventional Pilot study.

Conjunctival Short-term Evolution after Pterygium Excision.

Combined conjunctival rotational autograft with 0.02% mitomycin C in primary pterygium surgery: a long-term follow-up study.