CADTH Health Technology Review

Intraocular Lenses for Infants With Aphakia

PROSPERO Registration Number: CRD42021231143

Systematic Review

Authors

Clinical Effectiveness and Safety

Charlotte Wells led the systematic review; screened and selected articles; extracted, tabulated, critically appraised, and interpreted data; drafted the report; revised the report based on reviewers’ feedback; and provided final approval of the version of the report submitted for publication.

Daphne Hui supported the lead author of the review by screening and selecting studies, extracting and double-checking information, critically appraising and interpreting data, providing support in writing, reviewing the report until completion, and providing final approval of the version of the report submitted for publication.

Kwakye Peprah led the development and writing of the review protocol, participated in study selection based on the protocol-determined inclusion criteria, independently performed data extraction from assigned included studies, and checked data extracted by other reviewers for integrity and completeness.

Dr. Asim Ali contributed to the development of the review protocol and the analysis and interpretation of the study results, critically reviewed the draft report and provided feedback, and provided final approval of the version of the report submitted for publication.

Patient Engagement

Tamara Rader led family caregiver engagement activities and wrote the summary of those activities included in the report. She also reviewed the protocol and approved the Patients’ Experiences GRIPP2 Short Form Reporting Checklist table reporting family caregiver involvement in the report.

Research Information Services

Melissa Walter designed and executed the database search strategies, completed grey literature searches, maintained search alerts, prepared the search methods and appendix, and provided final approval of the version of the report submitted for publication.

David Kaunelis peer-reviewed the search strategies and approved the final version of the report submitted for publication.

Contributors

The authors would like to acknowledge Elizabeth Carson and Dr. Joanne Kim for providing project oversight and coordination and methodological support throughout the planning, conduct, and reporting of this review. They would also like to acknowledge Dr. Laura Weeks for providing project oversight and reviewing the draft protocol and draft report, Dave Marchand for his contribution to the protocol development, Dr. Brit Cooper-Jones for knowledge mobilization activities for broad public understanding of this review, and Pierre Martinelli for project management support. Finally, the authors would like to thank the 2 family members of patients with lived experience of aphakia and IOL implantation who shared their experiences with the project team members and provided their feedback on the draft protocol and draft report. Their perspectives and feedback were carefully considered by CADTH in developing this report.

Reviewers

The following individuals kindly provided comments on a draft version of the review protocol and this report.

External Reviewers

Dr. Carlos Eduardo Solarte, MD, MPH (Epi)

Assistant Professor of Ophthalmology

University of Alberta

Edmonton, Alberta

Dr. Rosanne Superstein, MD, FRCSC

Associate Professor of Ophthalmology

Université de Montréal

McGill University

Montreal, Quebec

Conflicts of Interest

There are no conflicts of interest to declare relevant to this report.

Protocol Amendments

Key Messages

• This systematic review examined intraocular lens implantation in patients aged 12 months or younger at the time of surgery compared with patients aged 12 months or younger with aphakia treated with contact lenses or glasses. It also examined intraocular lens implantation in patients aged 12 months or younger at the time of surgery (i.e., infants) compared with patients older than 12 months up to 12 years of age at the time of surgery (i.e., children).

• In total, 18 studies (3 randomized controlled trials and 15 nonrandomized studies) were identified that answered the clinical questions relevant to this review. No relevant studies were identified to inform the cost-effectiveness questions.

• Visual outcomes (i.e., visual acuity) did not seem to differ between patients aged 12 months or younger at the time of surgery who received intraocular lens implantation and in patients with aphakia treated with contact lenses or glasses. Parenting stress was higher in parents of infants who received intraocular lens implantation at 3 months after surgery compared with parents of infants who were treated with contact lenses; however, this difference was not maintained at 1 year after surgery.

• In 1 study that examined intraocular lens implantation at different ages, age did not appear to be a significant prognostic factor in poor visual outcomes (i.e., visual acuity defined as > 0.5 logMAR).

• Regarding safety, infants who underwent intraocular lens implantation experienced more frequent occurrences of complications, such as visual axis opacification, compared with infants with aphakia treated with contact lenses or glasses; therefore, more reoperations to remove the opacification were required. Many infants with aphakia who did not receive intraocular lens implantation eventually required the surgery when they got older.

• There were limited statistical comparisons available for safety outcomes for intraocular lens implantation in infants at different ages. Overall, the incidence in adverse events was similar between infants and children, except for the number of additional surgeries. In the identified literature, younger patients received more additional surgeries than older patients.

• The risk of bias in the included studies was high. There were many methodological concerns, including selection bias, reporting issues, statistical issues, and study designs with high risk of bias, such as retrospective cohort studies.

• Family input regarding patients’ and caregivers’ experiences included reports of stress related to the use of contact lenses and stress about outcomes of the cataract removal and/or intraocular lens implantation and the effect on the child, and emphasized timely treatment to ensure optimal development of the child.

Abstract

Background: Noncongenital aphakia (i.e., a lack of a natural lens within the eye) is primarily caused by either lens removal following surgical extraction of a cataract (i.e., clouding of the natural lens) or trauma of the eye causing natural lens displacement. Cataract surgery is the leading cause of noncongenital aphakia, including aphakia in pediatric patients. This systematic review focused on noncongenital aphakia in pediatric patients, specifically in patients aged 12 months of age or younger. Treatment options for visual correction of aphakia include insertion of an intraocular lens into the eye or the use of contact lenses or glasses.

Objectives: The aims of this systematic review were to compare the clinical effectiveness and safety of intraocular lens implantation versus contact lenses or glasses in infants aged 12 months or younger and to compare the clinical effectiveness and safety of intraocular lens implantation in infants aged 12 months or younger versus intraocular lens implantation in children older than 12 months up to 12 years of age. This review also aimed to explore the cost-effectiveness data for these comparisons.

Methods: An initial comprehensive literature search of English-language articles published between January 1, 2010, and January 21, 2021, was performed by an information specialist in multiple databases, with regular search alerts conducted to update the database literature searches until the report was finalized (i.e., up to November 1, 2021). Grey literature was also searched. Two reviewers independently screened titles, abstracts, and full-text articles for relevance. Two reviewers also independently reviewed relevant articles for data extraction and performed risk of bias assessments. Study selection and risk of bias assessments were conducted with the DistillerSR software. CADTH also engaged 2 family caregivers (i.e., mothers) with lived experiences of caring for young children with aphakia to provide family perspectives.

Results: In total, 18 studies (3 randomized controlled trials and 15 nonrandomized studies) were identified that answered the clinical questions of this review. No relevant cost-effectiveness studies were identified. Regarding clinical effectiveness, there did not appear to be a benefit in visual acuity with intraocular lens implantation compared with aphakia correction with contact lenses and glasses in infants. Regarding safety, infants with intraocular lenses implanted had significantly more additional surgeries because of a greater occurrence of visual axis opacification impeding vision (i.e., clouding of the eye that can obstruct vision, thus requiring surgical removal of the opacity). However, in longer-term follow-ups, many infants who did not receive a primary intraocular lens implantation (i.e., intraocular lens implantation in the same surgery as the cataract removal) underwent additional surgery later in life to implant a lens (i.e., secondary intraocular lens implantation or intraocular lens implantation during a separate surgery from the cataract removal). The results for glaucoma were mixed. There was a trend for patients who had intraocular lens implantation at a younger age (≤ 12 months) to experience more complications as a result of the surgery than patients who had intraocular lens implantation at an older age (> 12 months and up to 12 years of age). Overall, the body of evidence was of low quality, and there were many limitations with regards to the heterogeneity of studies (i.e., studies were not similar to one another) and study designs with high risk of bias.

Conclusion: Implanting intraocular lenses in patients aged 12 months or younger does not appear to confer significant visual or safety benefits compared with implantation later in life or with aphakic correction using contact lenses or glasses.

Introduction and Rationale

Aphakia is a condition in which the eye does not have a lens — the flexible structure that enables light to focus on the retina. Congenital aphakia is rare, caused by a genetic defect, and generally associated with other eye disorders such as absence of the iris and microphthalmia (i.e., 1 or both eyes are abnormally small).^1,2 However, noncongenital aphakia is primarily caused by lens removal following surgical extraction of a cataract or trauma causing lens displacement.³ Connective tissue disorders, such as Marfan syndrome, are also associated with early onset of cataracts in pediatric patients.^4,5 A cataract is the clouding of the lens; cataract surgery involves the removal of the cloudy lens to manage cataract-related visual impairment.^6,7 Cataract surgery is the leading cause of noncongenital aphakia, including aphakia in pediatric patients.^3,8 This systematic review (SR) focuses on noncongenital aphakia in pediatric patients.

Aphakia is corrected with glasses or contact lenses (CLs), in which case the patient still has aphakia, or with an artificial, intraocular lens (IOL) implantation to replace the natural lens, in which case the patient now has pseudophakia. Glasses for aphakia require a strong prescription, which causes optical and visual field distortion, and are thick and heavy, making a well-fitting pair that stays on a young child’s face difficult to find.^6,9 CLs provide better optical quality than glasses and allow for easier power adjustments required for rapidly changing eyes of pediatric patients.⁷ However, they can be costly, be easily lost, cause irritation and infection in the eyes, and be inconvenient and difficult to insert, remove, and keep clean.^9-11 These factors may lead to poor adherence with long-term use resulting in suboptimal visual outcomes.^7,9 An IOL is a tiny, artificial lens made of silicone, acrylic, or other plastic¹² that is permanently fixated in the eye; therefore, it cannot produce the sensations that the patient can feel with CLs. Additionally, IOLs do not require cleaning like glasses or reusable CLs (i.e., not single-use CLs).¹³ The IOL may be implanted immediately after lens removal (i.e., primary implantation) or after a postponement (i.e., secondary implantation) during which aphakia is corrected using glasses or CLs.¹⁴ An IOL offers an alternative to avoid the potential for visual distortion associated with glasses and the inconvenience and risk of nonadherence associated with CLs.¹⁰ IOL implantation is meant to occur once and provide a permanent solution to aphakia; however, IOL implantation in pediatric patients poses a risk for large refractive errors because the IOL power is fixed.¹⁵ Refractive errors may arise due to the rapidly changing axial length of the growing eye (i.e., distance between the front and back of the eye), which changes power requirements over time.¹⁵ As a result, it is difficult to correctly estimate the required IOL power to achieve a minimal prescription as an adult.¹⁵

Management of childhood cataracts and associated aphakia is time-sensitive and costly because it requires care from multiple health care professionals in various specialties, community health workers, and caregivers over many years. Caregivers of patients experience considerable costs and burden associated with travel and accommodations required for clinical appointments, time off work, assistance with care for other personal obligations (e.g., childcare), and anticipated and unanticipated need for or replacement of CLs or glasses. Based on inflation-adjusted US Medicaid data that considered the mean cost of cataract surgery and all additional surgeries, examinations, and supplies, the 5-year cost of cataract surgery and optical correction in an infant with a unilateral congenital cataract was US$35,293 with IOL versus US$33,452 with CLs.¹⁶ Financial burdens are more pronounced for those with limitations to their vision coverage or those without private insurance. Additionally, complexities with treating unilateral cataracts, including amblyopia and the need to patch the eye, add complications to the management of the condition.

Glasses and CLs for aphakia have generally been used in all age populations; however, the appropriate age for IOL implantation is unclear. For instance, Vasavada and Vasavada (2017) reported a general acceptance of IOL implantation in patients aged 2 years or older.¹⁷ Alternatively, a meta-analysis (MA) by Chen et al. (2020) found that in patients younger than 2 years, those who had primary IOL implantation following cataract extraction achieved better visual outcomes than those wearing CLs and without a higher risk of complications.¹⁰ In 2019, the American Academy of Ophthalmology did not recommend IOL implantation in patients aged 6 months or younger due to a higher risk of visual axis opacities compared with patients who wear CLs.¹⁵ It is generally thought that IOL implantation in young children is associated with a high rate of postoperative complications, such as visual axis opacities, glaucoma, and inflammatory events.^15,18,19 Visual axis opacification (VAO) refers to the growth of epithelial cells across the implanted lens in patients with pseudophakia or in the gap where the lens would have been in patients left with aphakia.²⁰ VAO can lead to amblyopia and requires surgical removal when it impedes vision.²¹ Glaucoma in pediatric patients is typically diagnosed through a sustained increase in intraocular pressure (e.g., > 21 mm Hg) confirmed with 2 to 3 measurements plus 1 or more of the following: optic disc cupping greater than or equal to 0.3, asymmetry greater than or equal to 0.2, or progression; corneal changes; and progressive myopic shift.²² If left untreated, glaucoma can lead to irreversible vision loss.²³ Therefore, determining the optimal timing for IOL implantation is favourable to maximize visual acuity (VA) outcomes, minimize complications, and balance health care resource use.

Overall, there is a need to determine if IOL implantation can be safely and effectively used to correct aphakia in infants up to 12 months of age and its cost-effectiveness, relative to conventional treatment (e.g., CLs or glasses). There is also a need to compare the clinical effectiveness, safety, and cost-effectiveness of IOL implantation between infants and children (i.e., up to 12 years of age).

Objectives

This SR aimed to evaluate the clinical effectiveness, safety, and cost-effectiveness of IOL implantation versus conventional treatment (i.e., glasses or CLs) in infants with noncongenital aphakia. This SR also aimed to assess the clinical effectiveness, safety, and cost-effectiveness of IOL implantation in infants aged 12 months or younger at the time of surgery versus children who older than 12 months up to 12 years of age at the time of surgery.

Research Questions

This SR addressed the following research questions:

1. What is the comparative clinical effectiveness of intraocular lens implantation versus conventional treatment in infants with noncongenital aphakia?

2. What is the safety of intraocular lens implantation in infants with noncongenital aphakia?

3. What is the comparative clinical effectiveness of intraocular lens implantation in infants of up to 12 months of age versus intraocular lens implantation after 12 months of age for pediatric patients with noncongenital aphakia?

4. What is the comparative safety of intraocular lens implantation in infants of up to 12 months of age versus intraocular lens implantation after 12 months of age for pediatric patients with noncongenital aphakia?

5. What is the cost-effectiveness of intraocular lens implantation compared with conventional treatment in infants with noncongenital aphakia?

6. What is the cost-effectiveness of intraocular lens implantation in infants of up to 12 months of age compared with IOL implantation after 12 months of age for pediatric patients with noncongenital aphakia?

Methods

To inform the conduct of this SR, a preliminary scoping review of the existing literature — including health technology assessments (HTAs) and SRs — was conducted. A protocol was written a priori, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P)²⁴ for guidance on clarity, transparency, and completeness, and was followed throughout the study process. The protocol was prospectively registered in the international repository, PROSPERO (registration number: CRD42021231143).²⁵ Any deviations from the protocol are disclosed in this final report (Table 1) and updates were made to the PROSPERO submission accordingly.

Study Design

Research questions 1, 2, 3, and 4 were intended for the review of clinical evidence. The topic of this review did not have a broad scope, and the preliminary scoping review did not identify any high-quality SRs that comprehensively addressed these research questions. Thus, it did not appear that an overview of SRs or an update of existing SRs was an appropriate review method for this SR. Therefore, a de novo SR of all identified relevant primary studies was conducted. This approach permitted an evaluation of the various population, intervention, comparator, and outcome elements in a manner suitable to address the research questions.

For research questions 5 and 6, if relevant cost-effectiveness studies of IOL implantation for aphakia were identified through a systematic literature search, these would have been summarized and critically appraised.

Literature Search Methods

The literature search was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.²⁶ The complete search strategy is presented in Appendix 1.

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946‒) via Ovid, Embase (1974‒) via Ovid, and the Cochrane Central Register of Controlled Trials (CENTRAL) via Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were intraocular lenses and juvenile/congenital cataracts or aphakia. Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was limited to English-language articles published between January 1, 2010, and January 21, 2021. When possible, retrieval was limited to the human population. Conference abstracts were excluded from the search results.

The initial search was completed on January 21, 2021. Regular alerts updated the database literature searches until the report was finalized (i.e., up to November 1, 2021). The clinical trials registries search was updated on November 2, 2021, before the completion of the stakeholder feedback period (i.e., between October 25 and November 8, 2021).

Grey literature (i.e., literature that is not commercially published) was identified by searching sources listed in relevant sections of the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist,²⁷ which includes the websites of regulatory agencies, HTA agencies, clinical guideline repositories, SR repositories, patient-related groups, and professional associations. Google was used to search for additional internet-based materials. These searches were supplemented by reviewing bibliographies of key papers and through contacts with experts and industry, as appropriate. The grey literature search was updated on November 2, 2021, before the completion of the stakeholder feedback period (i.e., between October 25 and November 8, 2021). See Appendix 1 for more information on the grey literature search strategy.

Selection and Eligibility Criteria

Table 2 provides the study eligibility criteria for the research questions. The eligibility criteria were informed by the preliminary scoping review of the existing literature and by clinical expert input.

Studies were included if they met the eligibility criteria outlined in Table 2 and were published in English. Publications in other languages were not included given the evidence suggesting that excluding non-English-language publications from evidence synthesis generally does not change conclusions.^30,31 If multiple publications were identified for the same study, they were all included and cited. However, only unique data were extracted without duplication and discussed as a single study.

The population of interest was pediatric patients with noncongenital aphakia. Studies with mixed populations that included patients who did not meet the age eligibility criteria of a specific research question were considered for inclusion if they reported separate results for the eligible patients or if the eligible patients constituted 95% or more of the entire study population. The 95% threshold was chosen because it is consistent with the convention of setting the alpha at 0.05 (e.g., similar to the P = 0.05 threshold and 95% confidence interval [CI]). The decision to include or exclude a study that reported age as mean ± standard deviation would have been made by estimating the 95% predictive interval using the t-statistic or z-statistic. Studies with mixed populations that did not report on the age of the included participants in a manner that allows for the assessment of the 95% or greater rule (e.g., a range without breakdowns or a mean without a standard deviation that can be used with the t-statistic or z-statistic to determine the 95% predictive interval) would have been excluded. However, no such situation regarding the use of the 95% rule was encountered. Based on clinical expert input, it was recognized that congenital aphakia requires different treatment but that it is rare. Therefore, studies or findings were excluded if they were specifically on congenital aphakia or if they were a mix of congenital and noncongenital aphakia. Studies or findings that did not specify the type of aphakia included were eligible for inclusion.

The intervention of interest was implanted foldable IOLs. Therefore, studies or findings that focused exclusively on nonfoldable IOLs or included both foldable and nonfoldable IOLs were considered out of scope. IOL implantation for the management of pediatric cataracts became routine practice in many countries more than 10 years ago,²⁹ and according to clinical expert input, improvements in surgical instruments over the last decade allow for smaller surgical incisions for foldable IOLs that reduce adverse events related to cataract surgeries. Therefore, on the assumption that foldable IOLs were widely implemented in many countries by 2010, studies or findings that did not report whether foldable or nonfoldable IOLs were implanted were considered for inclusion since our search was limited to 2010 onward.

Articles were excluded if they did not meet the selection criteria outlined in Table 2, if they were duplicate publications, or if they were published before 2010. If a study investigated experimental IOLs not available for usual clinical practice, it would not have been eligible for inclusion. However, no such situation occurred. Single-arm studies, eligible for 1 of the safety questions, were excluded if there was no measurement of the outcome before the cataract removal surgery (i.e., no baseline measurement) or if the specific outcome was not appropriate for a before-and-after analysis (e.g., intraocular complications).

Study Selection

Two reviewers independently selected potentially relevant citations by screening all titles and abstracts identified through the literature searches, using the eligibility criteria presented in Table 2. The study selection was conducted using the SR management software DistillerSR (Evidence Partners, Ottawa, Canada). If at least 1 reviewer considered any titles or abstracts potentially relevant during the first-level (level 1) screening, the full-text articles of the citations were retrieved for a second-level (level 2) screening to confirm their eligibility. The same 2 reviewers independently conducted the level 2 screening, examining all full-text articles for inclusion in the review. Consensus between the 2 reviewers was required for the inclusion of each article. Disagreements between the reviewers were resolved through discussion or by involving a third reviewer, if needed.

A list of studies selected for inclusion in the review was posted to the CADTH website for 10 business days to allow stakeholder review and feedback. All additional potentially relevant studies identified through stakeholder feedback were reviewed following the previously described process. In addition, publications meeting the selection criteria for the review that were identified via literature search alerts before the completion of the stakeholder feedback period for the draft report were incorporated into the analysis. Relevant studies identified after the stakeholder feedback period would have been described in the discussion, focusing on comparing their results with those obtained from the synthesis of earlier reports included in the review; however, no additional relevant studies were identified after stakeholder feedback.

The study selection process is presented in a PRISMA³² flow diagram (Appendix 2). Lists of the included and excluded studies are provided in this final report with the reasons for exclusion (Appendix 10 and Appendix 11).

Data Extraction

One reviewer performed data extraction directly into tables created in Microsoft Word, and a second reviewer independently checked the extracted data for accuracy and completeness to ensure that all relevant data from each included study were extracted. Disagreements were resolved through discussion until consensus was reached or through adjudication by a third reviewer, if necessary. The following data were extracted:

• study characteristics (e.g., first author’s name, publication year, the country where the study was conducted, funding sources)

• study methodology (e.g., study design and objectives, inclusion and exclusion criteria, recruitment method, setting)

• population details (e.g., number of participants, age, sex, gender, unilateral or bilateral cataracts, baseline characteristics)

• intervention details (e.g., information about the IOL implanted, such as the type of IOL [e.g., foldable or nonfoldable], material, the year of surgery)

• comparator details (e.g., aphakic glasses, aphakic contact lenses)

• outcome details (e.g., measurement method, unit of measurement, length of follow-up), results, and conclusions for the overall findings and for subgroups of interest.

For economic evaluation studies, examples of additional data that were planned for extraction included the type of analysis, time horizon, perspective, modelling approach, and main assumptions, as well as the sources of clinical, cost, and utility data used in analysis. However, no relevant economic evaluations were identified, therefore this was not performed.

Data on relevant outcomes were extracted for any duration of follow-up reported in the included studies. All unadjusted and adjusted measures of treatment effects — such as risk ratios, odds ratios, or risk differences for dichotomous outcomes and mean differences or standardized mean differences for continuous outcomes — and any results of statistical manipulations performed or statistical tests reported on those measures were reported.

Critical Appraisal of Individual Studies

Two reviewers independently conducted risk of bias assessments of the eligible studies and compared them, resolving any disagreements and reaching consensus through discussion or by involving a third reviewer, if needed. The risk of bias in randomized controlled trials (RCTs) was evaluated using the methods described in the revised Cochrane Risk of Bias Tool for Randomized Trials (RoB 2).³³ The RoB 2 assessment tool is structured into 5 domains to evaluate biases arising from the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. Signalling questions in each domain helps the user make domain-level judgments about the risk of bias by answering “yes,” “probably yes,” “probably no,” “no,” and “no information.” A judgment of low risk of bias, high risk of bias, or some concerns was assigned for each domain. The overall risk of bias of each trial was rated and designated as low risk of bias, some concerns, or high risk of bias based on the domain-level determinations.³³ A rationale is provided for decisions about the risk of bias for both the domain-level and overall assessments.

The risk of bias in nonrandomized studies was assessed using the Risk of Bias Assessment Tool for Non-Randomized Studies (RoBANS).^34,35 RoBANS contains 8 domains that evaluate the risk of biases in a study due to the possibility of target group comparisons, target group selection, confounder, exposure measurement, blinding of assessors, outcomes assessment, incomplete outcomes data, and selective outcomes reporting.^34,35 The tool was selected for its reliability, validity, and user-friendly design. A judgment of low risk of bias, high risk of bias, or unclear risk of bias was assigned for each domain using the criteria provided in the instrument.³⁴ The overall risk of bias for each study was classified as low, some, or high based on the domain-level judgments about the risk of bias, following the RoB 2 guidance³³ because RoBANS does not provide a specific approach for making study-level judgments. A rationale is provided for decisions about the risk of bias for both the domain-level and overall assessments.

For sources of bias that may differ across outcomes within a single primary study (i.e., bias due to deviations from missing outcomes data and measurement of the outcomes in RCTs; outcomes assessment and incomplete outcomes data in nonrandomized studies), the risk of bias was assessed for individual outcomes within individual studies.

In evaluating the risk of bias in the included studies, the critical appraisal tools were considered as guides and additional insight beyond the instruments’ signalling items was applied when necessary. The results of the risk of bias assessments were reported by describing each study’s strengths and limitations narratively; summary scores have not been calculated. Studies were not excluded from the review based on the results of the critical appraisal. However, the critical appraisal results and their effect on study findings were used to assess confidence in the evidence from the individual studies.

Data Analysis and Synthesis

Narrative Synthesis

Narrative syntheses were performed, summarizing relevant data in tables for each study (Appendix 3, Appendix 4, and Appendix 7) with descriptions in the main text for details and clarity. The study and patient characteristics were considered in the analysis of the clinical effectiveness and safety measures across the studies to determine the likelihood of clinical benefits or harm. The within- and between-study relationships were evaluated, and the findings about the direction and magnitude of any observed effects, trends, and deviations are summarized and discussed by research question, comparator, and outcome. If data were available, results regarding the clinical effectiveness and safety were reported separately for the comparison of IOL with aphakic glasses from CLs. Any impact of applying the 95% or greater inclusion rule for age or including studies or findings that did not specify noncongenital aphakia or foldable IOLs were examined (i.e., by summarizing the findings separately). Outcomes were reported in the measurement units used by the study authors and results were interpreted with due consideration for the differences in the instruments of assessment across the studies.

A narrative summary of the results of the critical appraisal for each included study is provided. Specifically, tables were developed to present the answers to the questions within the critical appraisal tools (Appendix 6), and a narrative description of the strengths and limitations of the included studies is provided within the main text of the report to give the reader an overview of the methodological quality of the literature. Although studies were not excluded from this review based on the critical appraisal results, the discussions and conclusions of this report emphasize the findings from higher-quality studies.

Quantitative Synthesis

The results of the included studies were examined for appropriateness for meta-analyses (i.e., if data were sufficiently homogeneous in their clinical, methodological, and statistical characteristics). Clinical, methodological, and statistical heterogeneity was assessed in consultation with clinical and methods experts, as was whether studies were sufficiently homogeneous for pooling.

MAs were considered for each outcome of interest for each research question on clinical effectiveness and safety. As the included studies were deemed too heterogeneous to combine, a quantitative pooling of results from individual studies was deemed inappropriate. Accordingly, the included studies were summarized narratively, and the reasons for not pooling are reported in Appendix 8.

Subgroup Analyses

In addition to analyzing the individual outcomes by research question for the overall population, the following subgroups were in scope:

• age (e.g., studies or findings on mixed populations versus no mixed populations based on the age eligibility criteria for each research question; 0 months up to and including 6 months versus after 6 months up to and including12 months for research questions 1, 2, and 5; 0 months up to and including 6 months, after 6 months up to and including 12 months, or after 12 months up to and including 24 months versus after 24 months up to 12 years of age for research questions 3, 4, and 6)

• eye involvement (e.g., bilateral versus unilateral)

• time of surgery (e.g., before 2010 versus 2010 and beyond to evaluate any difference in outcomes that might be attributable to advances in surgical instruments and technology, and broader uptake in foldable IOL use compared with single-unit rigid IOLs in Canada).

Any relevant data on these subgroups of interest were extracted and described in the narrative syntheses.

Reporting of Findings

This SR was prepared in consideration of relevant reporting guidelines (i.e., PRISMA-S,³⁶ PRISMA statement,³⁷ PRISMA harms,³⁸ Meta-analysis of Observational Studies in Epidemiology [MOOSE] reporting checklist,³⁹ and Synthesis Without Meta-analysis [SWiM] guideline⁴⁰) and meets the criteria outlined in A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) checklist.⁴¹

To facilitate ease of reading and consistency in terminology, the term “IOL implantation” has been used throughout the review, in place of “pseudophakia” or “pseudophakic.” As per the inclusion criteria of this SR, eligible comparators included aphakia corrected with glasses, CLs, or both; therefore, the term “aphakia” in this report refers to aphakia with vision correction using glasses or CLs. The use of glasses or CLs was specified if possible.

Patient and Family Engagement

CADTH involves patients, families, and patient groups to improve the quality and relevance of our assessments, ensuring that the affected patients and caregivers have an opportunity to provide input into the report. CADTH has adopted a Framework for Patient Engagement in Health Technology Assessment.⁴² The framework includes standards for patient involvement in individual HTAs that support and guide our activities involving patients. For this SR, the value of relevance, and the belief that patients have the knowledge, perspectives, and unique experiences that contribute to essential evidence for HTA, guided our patient engagement activities. For this SR, CADTH engaged 2 family caregivers (i.e., mothers) with lived experiences of caring for young children with aphakia.

Invitation to Participate and Consent

Through conversations with Dr. Ali, the clinical expert on this report, a CADTH Patient Engagement Officer emailed interested families with an invitation to participate. The preliminary request included the purpose and scope of this SR, the purpose of engagement, and the nature of engagement activities. After corresponding with 2 family caregivers, the Patient Engagement Officer obtained both persons’ informed consent to share their lived experiences with IOL implantation for infants with aphakia with CADTH staff.

Engagement Activities

The Patient Engagement Officer and members of the project team met via teleconference with each of the 2 family caregivers and learned of their lived experiences with their child’s aphakia, and perspectives on treatments including attending regular medical appointments, wearing glasses, using contact lenses on an infant or toddler, IOL implantation, and related procedures. The family caregivers were contacted at several time points during the assessment, including:

• before protocol finalization

• during the drafting of the initial reviews

• upon completion of the final report during the stakeholder feedback period.

Perspectives gained through the engagement process were used in several ways, including ensuring the relevance of outcomes of interest for the clinical assessment, making CADTH aware of patient-borne costs, and providing insights, background, and context to inform the discussion section. Parents or caregivers’ involvement enabled the research team to consider the evidence with an understanding of the wider real-life experiences. Participants were invited to provide feedback on the clarity of writing and comment on the relevance of the findings to Canadian patients and families.

Reporting

The reporting of the patient and family engagement activities followed the revised Guidance for Reporting Involvement of Patients and the Public (GRIPP2) Short Form reporting checklist⁴³ and included the outcomes, discussion, and reflection items, as suggested by that guidance, to outline in the final report the process of engagement and where and how participants’ contributions were used in the assessment. The Patient Engagement Officer kept track of patient engagement activities and interactions in detailed notes and communications, which were stored on a password-protected network drive which will be permanently deleted in accordance with CADTH’s document retention policy. CADTH provided reflections and critical perspectives on the participating caregivers’ involvement with the research team in this final report.

Opportunities for Stakeholder Feedback and Unpublished Data

All stakeholders were given the opportunity to provide feedback on the draft included studies list and the draft report during 2 review periods. The draft included studies list and the draft report were each posted on the CADTH website for 10 business days. Unpublished data identified as part of the feedback process would have been included if the source of data was in the public domain; however, no unpublished data were identified through the feedback process.

Results

Quantity of Research Available

A total of 1,371 citations were identified in the literature search. Following screening of titles and abstracts, 1,162 citations were excluded, and 209 potentially relevant reports from the electronic search were retrieved for full-text review. No potentially relevant publications were retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 176 publications were excluded for various reasons, and 33 publications met the inclusion criteria and were included in this report. These comprised 3 RCTs^44-61 and 15 nonrandomized studies,^62-76 relevant to research questions 1, 2, 3, and 4. No economic evaluations relevant to research questions 5 and 6 were identified. There were 16 clinical publications and 1 methods publication (which was not included in the overall count)⁷⁷ that reported on the same RCT — the Infant Aphakia Treatment Study (IATS).^44-59

Appendix 2 presents the PRISMA³² flow diagram of the study selection process. Additional references of potential interest are provided in Appendix 12. Lists of the included and excluded studies, with reasons for exclusion, are provided in Appendix 10 and Appendix 11, respectively.

Study Characteristics

Country of Origin, Year of Publication, and Sources of Funding

The RCTs were conducted in the US^44-59,77 and India.^60,61 The nonrandomized studies were conducted in the US,^63-65 Germany,⁶⁶ Ireland,^67,68 UK,⁶⁹ Latvia,⁷⁰ China,⁷¹ India,^72-74 France,⁷⁵ Brazil,⁶² and Korea.⁷⁶

There were multiple publications for the IATS, which were published in 2020,^46,50,53 2016,^55,56 2015,^52,59 2014,^45,49,58 2013,^54,57 2012,⁵¹ 2011,^47,48 and 2010.⁴⁴ The years of publication for the remaining studies were 2021,⁶² 2020,^{63,64,66,67,69,71} 2019,⁶⁵ 2018,⁶⁰ 2017,^61,72,75 2016,⁷³ 2014,^74,76 and 2010.⁶⁸

The studies were funded primarily by grants from organizations such as the National Eye Institute,^44-59,77 the American Society of Cataract and Refractive Surgery Foundation,⁶¹ Mayo Clinic,⁶³ Research to Prevent Blindness,⁶⁴ National Institute for Health Research,⁶⁹ Natural Science Foundation of China,⁷¹ Hyderabad Eye Research Foundation,⁷³ Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES-DS),⁶² and Inje University.⁷⁶

There were no funding sources for 5 studies.^{60,67,70,74,75} Funding sources were not reported in 4 studies.^65,66,68,72

Study Design, Methods, and Settings

Three studies were RCTs.^44-61,77 The 15 remaining studies were nonrandomized.^62-76 Twelve NRSs were retrospective chart reviews^{62-68,70,72,73,75,76} and 3 were prospective cohort studies.^69,71,74

All of the included studies included patients undergoing cataract removal surgery with or without IOL implantation.^44-77

For the comparison of IOL implantation versus aphakia corrected by CLs or glasses, 2 RCTs^44-59,77 and 7 NRSs^{63,65,67-69,71,74} were relevant. The IATS included patients who were 28 days of age to less than 210 days of age at the time of surgery.^44-59,77 Another RCT, Vasavada et al. (2018),⁶⁰ included infants up to 2 years of age. Among the NRSs, the Toddler Aphakia Pseudophakia Study (TAPS) reported by Bothun et al. (2020) included patients with the same age restrictions as the IATS (i.e., 28 days to less than 7 months).⁶³ Other age ranges included younger than 1 year of age,⁶⁷ younger than 2 years of age,⁶⁹ 6 months to 72 months,⁷¹ “pediatric patients” (age not specified),⁶⁵ 1 month to 8 months,⁷⁴ and 0.5 month to 12 months.⁶⁸ For the studies that included patients older than 12 months, only data on patients noted to be 12 months of age or younger at the time of surgery were extracted.

For the age comparison, 1 RCT⁶¹ and 8 NRSs^{62,64,66,70,72,73,75,76} were relevant. The RCT by Vasavada et al. (2017)⁶¹ included patients up to 4 years of age. The age restrictions included 5 months to 24 months,⁶² 1 month to 72 months,⁶⁴ 0 years to 17 years,⁶⁶ 1 month to 18 years,⁷⁰ 2 years to 12 years,⁷² 4 weeks to 24 months,⁷⁵ less than 7 years,⁷³ and 0.1 year to 9 years.⁷⁶

Thirteen studies were single-centre studies,^{60-62,65-68,70-74,76} and 4 studies were multicentre studies.^{44-59,63,64,69,77} The setting for 1 study was not described in detail.⁷⁵ The IATS was conducted at 12 clinical sites in the US,^44-59,77 and the TAPS was conducted at 10 of the 12 US IATS sites.⁶³ The IOL Under 2 study was conducted at 31 hospitals in the UK and Ireland.⁶⁹ The multicentre study by Eder et al. was conducted at 2 pediatric ophthalmology practices in the US.⁶⁴ All studies with known settings were conducted at research centres or hospitals^44-74,76,77 (including 1 tertiary ophthalmic institute⁷²).

There was overlap in the settings between some of the included studies. Vasavada et al. (2018),⁶⁰ Vasavada et al. (2017),⁶¹ and Shah et al. (2014)⁷⁴ were conducted at the same research centre in India. Additionally, Kirwan et al. (2010)⁶⁸ and Murphy et al. (2020)⁶⁷ were conducted at the same university hospital in Ireland. The publications from the TAPS⁶³ and the IATS^44-59,77 also shared 10 study sites in the US. However, the 2 publications by Vasavada et al.^60,61 and Shah et al. (2014)⁷⁴ did not include patients from the same years. The TAPS⁶³ and IATS publications^44-59,77 specifically focused on bilateral eye involvement and unilateral eye involvement, respectively; hence, there was no overlap in patient data. Although not explicitly stated, there was likely overlap between Murphy et al. (2020) and Kirwan et al. (2010) in their included patients because the years of surgery overlapped; further, it was not clear if different surgeons performed the procedures.^67,68

Patient Population

Aphakia and Comorbidities

All studies included patients with aphakia due to cataract removal or lens aspiration. No aphakia was caused by a perforating wound or ulcer, lens dislocation or subluxation, or spontaneous lens absorption. One study only included patients with a cataract due to congenital rubella,⁷⁴ whereas 1 study specifically excluded rubella-related cataract.⁷¹ One study only included patients with retinopathy of prematurity (ROP).⁷² Patients with cataracts due to trauma or general ocular traumas were excluded in 8 studies.^{44-61,63,67,70,71,73,77} Infants with persistent fetal vasculature were excluded in 5 studies^{44-60,69,71,75,77} Other ocular and chromosomal defects were excluded in 11 studies, such as microcornea,^44-62,69,77 microphthalmos,^62,67-69 Down syndrome,⁶⁰ previous ocular surgery,^44-59,63,77 and preoperative or congenital ocular hypertension or glaucoma.^{44-59,61-64,67,71,72,75,77} Four studies excluded “abnormalities,”^69,76 “other ocular or systematic anomalies,”⁷⁰ “systemic diseases,”⁶² and “other retinal pathologies or ocular comorbidity”⁷² without providing specifications or definitions of these terms.

Age at Surgery

As per the inclusion criteria, infants aged 12 months or younger at the time of surgery were eligible for inclusion for research questions 1 and 2, and infants aged 12 months or younger and children older than 12 months up to 12 years of age were eligible for research questions 3 and 4.

Two RCTs and 7 NRSs were relevant for the research questions on the treatment comparison in infants.^{44-60,63,65,67-69,71,74,77}

One RCT and 8 NRSs were relevant for the research questions on the age comparison between infants and children.^{61,62,64,66,70,72,73,75,76}

Seven studies^{44-60,63,66,69,71,75,77} reported the median age of patients in the study, and 7 studies reported the mean age of patients in the study.^{61,62,64,67,68,72,74}

The median ages at surgery (where reported) were:

• 1.8 months^44-59,77

• 2.4 months (bilateral) and 2.2 months (unilateral)⁶⁹

• 2.5 months⁶³

• 5.7 months⁷⁵

• 6.01 months⁶⁰

• 21.04 months⁶⁶

• 36 months.⁷¹

The mean ages at surgery (where reported) were:

• 3.46 months⁶⁷

• 3.8 months⁶⁸

• 3.97 months⁷⁴

• 14.80 months and 18.26 months⁶¹

• 15.06 months⁶²

• 18.9 months⁷²

• 34.68 months.⁶⁴

Neither the median nor the mean age at surgery were reported in 4 studies.^65,70,73,76

Sample Sizes

Sample sizes in the studies ranged from 28 eyes⁷² to 1,392 eyes.⁶⁵

The IATS RCT had a sample size of 114 eyes from 114 patients and did not have a high loss to follow-up over the 10 years follow-up (i.e., 3.5% attrition).^44-59,77 The RCTs by Vasavada et al. (2018)⁶⁰ and Vasavada et al. (2017)⁶¹ had sample sizes of 120 bilateral eyes and 61 unilateral eyes, respectively.

Sample sizes for the remaining NRSs were 28 eyes,⁷² 37 eyes,⁷⁴ 46 eyes,⁶⁴ 61 eyes,⁷⁵ 90 eyes,⁶⁶ 93 eyes,⁶² 131 eyes,⁷¹ 135 eyes,⁶⁷ 137 eyes,⁷⁰ 144 eyes,⁶⁸ 172 eyes,⁷⁶ 178 eyes,⁶³ 378 eyes,⁶⁹ 814 eyes,⁷³ and 1,392 eyes.⁶⁵

Sex and Gender

The numbers of female patients and male patients were generally equal (i.e., approximately between 45% to 55% female) in most studies.^{44-59,62,63,69,74,76,77} Approximately one-third of patients were female in the study by Vasavada et al. (2018),⁶⁰ and approximately 40% of patients were female in the studies by Vasavada et al. (2017),⁶¹ Lytvynchuk et al. (2020),⁶⁶ Ezisi et al. (2017),⁷² and Zhang et al. (2020).⁷¹ Sex of patients was not reported in 7 studies.^{64,65,67,68,70,73,75}

Eye Involvement

The majority of the included studies included patients with either unilateral or bilateral cataracts.^{61,62,64,66-70,72,74-76} One study included solely unilateral cataracts,^44-59,77 and 2 studies included solely bilateral cataracts.^60,63 The proportions of patients with unilateral and bilateral cataracts were not reported in 3 studies.^65,71,73

Year of Surgery

The year of surgery ranged from 1984 to 2018. There were 5 studies that included patients who received surgical intervention before 2000.^{64,65,67,68,76} These studies did not specify the type or brand and model of IOLs implanted; therefore, despite the potential that nonfoldable IOLs were implanted in some of these patients, as per this review’s protocol, these studies were included.

Interventions and Comparators

IOLs Implanted

All included studies had an intervention of IOL implantation following cataract surgery. One study analyzed outcomes after the use of a bag-in-the-lens (BIL) technique,⁶⁶ whereas the remaining studies implanted IOLs in the ciliary sulcus or capsular bag, if reported. Standard capsular bag implantation was sometimes referred to as “lens-in-the-bag” implantation. Four studies did not adequately report the location of IOL implantation.^64,67,68,70 The procedures (if reported) are detailed in Appendix 4, Table 5.

Brands and models of foldable IOLs implanted included:

• AcrySof SN60AT^44-59,74,77

• AcrySof SA60AT⁶⁰

• AcrySof MA60AC^44-61,77

• AcrySof MA30BM^62,74

• Hoya PC-60AD⁶²

• Aaris EC-3 PAL⁶²

• Morcher Type 89A, Type 89F or Type 89A Toric (BIL technique)⁶⁶

The specific brands and models of IOLs implanted were not reported in 4 studies but were noted as “foldable lenses.”^63,70,72,75 Eight studies did not specify what type of IOLs was used nor whether the IOL was foldable.^{64,65,67-69,71,73,76}

Comparison of IOL Implantation Versus Aphakia Corrected by Glasses or Contact Lenses

The comparator was aphakia with vision correction in 10 studies.^{44-60,63,65,67-69,71,73,74,77} The comparator was CLs (Silsoft or rigid gas permeable) for the IATS.^44-59,77 Vasavada et al. (2018) and Bothun et al. (2020) reported correction with CLs, glasses, or both CLs and glasses as the comparator.^60,63 The Shah et al. (2014) study used either CLs or glasses as vision correction in patients with aphakia.⁷⁴ The method of vision correction in patients with aphakia was not reported in 4 studies.^{65,67,68,71,73}

In some publications, there were comparative data between IOL implantation and aphakia, but the reported data included a combination of patients who were younger than 1 year of age and older than 1 year of age at the time of surgery. This combination resulted in a mixed population, and therefore those data were not extracted as per the protocol.^69,73

Age Group Comparison

Two studies had an objective to compare IOL implantation by age at surgery.^64,66 However, there were 8 publications that did not have a primary objective to compare age groups, but included age at surgery as a subgroup, which allowed for relevant data to be extracted.^{61,62,69,70,72,73,75,76}

Outcome Measures

Appendix 5 details the relevant outcomes extracted from each study.

Measures of Clinical Effectiveness (Research Questions 1 and 3)

Outcomes relevant to these research questions included VA^67,75 and health-related quality of life (HRQoL).⁵⁷

In IATS, VA was measured by 3 different methods at each follow-up. At 1 year of age, VA was measured using Teller acuity cards (molecular grating VA)⁴⁴; at 5 years of age, VA was measured using Amblyopia Treatment Study HOTV (monocular optotype VA)⁴⁵; and at 10 years of age, VA was measured using E-ETDRS testing protocol (monocular optotype VA).⁴⁶ In the study by Vera et al. (2017),⁷⁵ VA was measured using LEA pictures or matching and Snellen charts. In the study by Murphy et al. (2020), the method of measurement was not reported.⁶⁷

HRQoL was measured by examining caregiver stress levels with the ocular treatment index (OTI) and the parenting stress index (PSI).⁵⁷

Measures of Safety (Research Questions 2 and 4)

Outcomes relevant to the safety research questions for this SR included VAO,^{44-59,61-63,66-68,72-75,77} glaucoma,^{44-61,63,64,66-70,73-75,77} strabismus or nystagmus,^{44-59,62,67,76,77} additional surgeries,^{44-59,62-65,68,73-75,77} intraoperative complications,^{44-59,63,66,77} corneal changes,^44-59,77 inflammatory complications,^{60,61,66,74,75} posterior vitreous detachment (PVD),⁷¹ and vitreous opacities (VOs).⁷¹

The method of measurement for VAO and inflammatory complications was not reported in most cases. It is likely that these outcomes were measured during a routine examination using a slit lamp, as was reported in 1 study,⁶¹ but this was not clear. PVD and VO were measured using B-scan ultrasonography.⁷¹ Strabismus and other fixation-related issues such as nystagmus were measured using the Hirschberg Test, Krimsky Test, or Alternate Prism and Cover Test in the IATS, and eye movement recordings were analyzed by an eye movement expert.^54-56,58 The method of measuring strabismus was not reported in 2 studies.^62,67,76

The methods of measurement and definitions of glaucoma varied across the included studies (Table 7). Methods of measuring intraocular pressure in the IATS included Goldmann applanation tonometry, Tonopen, pneumotonometry, Perkins tonometer, and rebound tonometry, depending on the patient’s age and ability to tolerate and remain still for testing (i.e., need for anesthesia).^48-53 Other studies used Perkins tonometry^61,62,68,73 or Goldmann applanation tonometry.⁶⁸ Eight studies did not specify the method used to measure intraocular pressure.^{63,64,66,69,70,72,74,75}

Considerations for Meta-Analysis

No MA was performed for the identified body of evidence because the identified studies were deemed too heterogeneous to facilitate appropriate pooling of data. Appendix 8 details the considerations for MA by study design, outcome, and citation.

Critical Appraisal

A summary of the risk of bias assessments for the RCTs and NRSs can be found in Table 8 and in Table 9, respectively.

Randomized Controlled Trials

The RCTs were appraised using the Cochrane RoB 2 tool.³³ This tool requires that if any domain is rated at a high risk of bias, the overall risk of bias is also rated as high. Therefore, all 3 RCTs were rated as having an overall high risk of bias. However, the IATS was rated at a lower risk in most domains compared with the other RCTs.^44-59,77

Randomization Process

The IATS described a randomization process in detail with minor details missing.⁷⁷ There was allocation concealment and no concerns with the randomization process (i.e., baseline characteristics were similar between the 2 groups). The Vasavada et al. (2018)⁶⁰ study provided few details regarding the randomization process but reported that there was allocation concealment. Conversely, the Vasavada et al. (2017)⁶¹ study lacked reporting of the details regarding allocation concealment but reported that randomization was facilitated with computer generated random numbers.

Deviations From the Intended Interventions and Blinding

There were no major concerns regarding deviations from the intended interventions for any of the RCTs, and there were no concerns regarding deviations from the protocols by the surgeons. All patients in the study by Vasavada et al. (2017)⁶¹ received IOL implantation; therefore, it was impossible for patients to not adhere to the intervention. Patients in the study by Vasavada et al. (2018) also received IOL implantation and would have also automatically adhered to the IOL intervention; however, adherence to the CLs and glasses intervention was not reported.

Adherence to the prescribed postoperative patching regimen was explored in the IATS, and it was reported that there was no difference in adherence to patching between treatment groups.⁷⁸ Any differences in adherence to the treatment for CLs (e.g., not wearing CLs as prescribed) would likely reflect real-world adherence to the treatment. Patients in the IATS were not allowed to receive a secondary IOL implantation outside of extreme nonadherence, and the surgery had to be approved by a steering committee.⁷⁷ Notably, by the 1-year follow-up, no patients had received a secondary IOL⁴⁴; by the 5-year follow-up, 3 eyes (CL adherence failures) had received secondary IOLs.⁴⁵ These deviations were minimal and consistent with the IATS prespecified protocol.⁷⁷

Blinding of surgeons and participants was not possible for these surgical studies due to the nature of the procedures and the postoperative regimen. Despite this, the likelihood of bias arising from the lack of blinding was deemed to be minimal. It is unlikely that patients sought out or were successful in switching intervention groups because this would require removal of the IOL surgically or permission to implant a secondary IOL. Additionally, in the outcome evaluations, the impact of lack of blinding on bias was likely minimal for the participants undergoing the assessments, especially in the early follow-up stages, because they were infants or young children.

The IATS made a concerted effort to blind outcome assessors for VA by not informing the assessors of the clinical status of the patient and using external travelling examiners who were not involved in treatment. The 1-year follow-up required the use of Teller cards, in which an examiner looks directly at a patient’s eyes to determine eye fixation and movement; therefore, it is unclear how successful this blinding was because CLs leave a visible line on the eye. However, because the assessors were specifically trained and supervised to ensure standardization of examinations, the impact of lack of blinding on bias was likely minimal. Vasavada et al. (2017)⁶¹ also blinded assessors when examining patients for VAO; however, all patients in this study received IOL implantation and, for the purposes of this review, the attempt at blinding is not applicable.

Outcome Measurements and Missing Data

The IATS had very detailed definitions for every included outcome.^44-59,77 The studies by Vasavada et al. (2017)⁶¹ and Vasavada et al. (2018)⁶⁰ also had clearly defined outcomes and reported what tools were used in assessment. However, the Vasavada et al. (2018) study had a significant loss to follow-up (> 10% of patients) and did not provide reasons for this attrition rate; therefore, it is unclear if the high attrition introduced any bias into the study results.⁶⁰

Statistical Analysis and Reporting

The studies by Vasavada et al. (2017)⁶¹ and Vasavada et al. (2018)⁶⁰ did not have a priori statistical analysis plans; therefore, it was unclear if there were major deviations from intended analyses. Both publications took measurements from 1 eye from patients with bilateral cataracts, which was appropriate for conducting independent statistical tests. Namely, analyzing 2 eyes from the same individual would violate the assumption of independence for the tests. The IATS had a statistical analysis plan provided in the protocol with details (e.g., intention to treat) but did not appear to follow the plan for all reported results. For example, in determining the percentages of patients with a particular outcome, both the intention-to-treat number and the total number of patients with successful follow-up (i.e., per protocol) were used as a denominator.⁵² Despite this, the loss to follow-up in the IATS was small, especially considering the long follow-up period; therefore, this may not have affected the conclusions of the studies for most outcomes.

Some time points were not reported in the study by Vasavada et al. (2018),⁶⁰ and it was unclear what the reasons were. There was also inconsistent reporting of outcomes in the Vasavada et al. (2017)⁶¹ study and the IATS.^44-59,77 Namely, in different IATS publications reporting data of the same follow-up period, there were numerous reporting inconsistencies.^44,48,49 This limited the interpretation of the results and reliability of the findings.

Nonrandomized Studies

The NRSs were evaluated using RoBANS.^34,35 All NRSs were rated at a high^62-64,66-75 or unclear overall risk of bias^65,76 because methods, issues with selection bias, and selective outcomes were not reported or were not clearly reported.

Selection Bias and Confounding

Most studies were based on retrospective chart reviews, which may inherently carry selection biases. For example, in the studies by Shah et al. (2014)⁷⁴ and Zhang et al. (2020),⁷¹ patients were not excluded on the basis of ocular issues such as microphthalmos (e.g., small axial length), which is often contraindicated for IOLs. Since patients in those studies were not randomized to specific cohorts, and patients with microphthalmos were unlikely to have undergone IOL implantation, the aphakic group likely had a higher percentage of patients with microphthalmos. This can introduce bias because having ocular abnormalities may increase the likelihood of poorer outcomes at follow-up, making IOL implantation appear more favourable than glasses or CLs. Accordingly, it may not be appropriate to include patients who would not likely receive the intervention in standard clinical practice because it may result in differences in baseline characteristics between comparison groups, which poses a risk or concern for selection bias.

Many studies^69,71,74 specifically indicated that the decision to implant an IOL or treat aphakia with glasses or CLs was at the discretion of the surgeon as well as the parents. Other studies did not report what the decision was based on.^67,68,73 It is likely that some baseline characteristics were not equal between comparative groups. In studies with mixed ages at IOL implantation, it may be likely that there were more patients in the IOL group who were closer to 12 months of age or older at the time of surgery than in the aphakia group. This may be due to the concerns surrounding the use of general anesthesia in younger patients and IOL implantation in younger patients.^15,17 There was a trend for patients in the IOL groups to be older at the time of surgery than those in the aphakia groups (mean or median, if reported).^67-69,71,72 Notably, patients who are diagnosed with congenital cataracts at an older age (e.g., past 6 months of age) and undergo cataract surgery and IOL implantation later in life may have worse outcomes due to a potentially more severe presentation or a delayed diagnosis (e.g., because of lack of screening).⁷⁹ Therefore, patients who were older at cataract diagnosis or at the time of IOL implantation might have been different (e.g., clinically) from patients with aphakia or patients receiving surgery at an earlier age, potentially biasing results against the IOL group (compared with glasses or CLs) or later IOL implantation (in age comparisons).

No studies adequately controlled for or defined confounding factors in their analysis, except for the study by Solebo et al.⁶⁹ Many studies also did not account for the differences in treatment requirements, surgeries, and potential outcome variability between patients with bilateral and unilateral cataracts. Combining these groups of patients or not reporting the laterality of cataract for included patients limits the conclusions that can be made regarding the interventions examined.

Outcome Reporting and Blinding

Overall, definitions for outcomes were poorly reported. Therefore, the risk of bias for selective reporting of outcomes potentially assessed without standardized methodologies was unclear (e.g., inflammatory complications, adverse events, strabismus). This may be of particular concern for outcome assessments prone to subjectivity. For instance, inflammatory complications that were assessed with the presence and extent of synechiae using an operating microscope (e.g., with a slit lamp attachment) were prone to subjectivity of the examiner, and inter-rater reliability was unclear, especially when the number of examiners were not reported.^60,74 For outcomes that are more objective, the risk of bias for selective reporting was less of a concern. For instance, 8 studies^{62-64,66,69,73-75} provided a clear definition of glaucoma, although not all studies reported what method was used to determine intraocular pressure (IOP). Table 7 details the various definitions of glaucoma used in the included studies.

Eleven studies reported the results in a way that reflected the intention of the study and the methods.^{62,63,65,68-70,72-76} In other studies, there were unexpected additions and omissions of outcome data, and it is unclear if this was due to selective reporting, especially because no NRSs had published protocols that could be consulted for confirmation. Additionally, no studies discussed any missing data, or they excluded patients that did not reach a minimum follow-up.^62,63,67,68 It was unclear if any of the patients that did not reach the minimum follow-up were missing for reasons that were associated with the intervention or the outcome, or if this differed between groups.

Similar to the RCTs, it is unlikely that it was possible to blind any of the outcome assessors to the treatment by the nature of the intervention and, in the case of retrospective studies, it is unlikely that this was done. No NRSs discussed any attempts to mask the treatment. For the objective outcomes (e.g., additional surgeries and glaucoma) this was likely not an issue. Additionally, there was likely no performance bias from the participants because the participants were young children and most of the outcomes were assessed by individuals (i.e., examiners) who were not the participants.

Statistical Analysis and Reporting

The statistical approach used may not have been appropriate in all cases in which bilateral cataracts were included in the analysis. Incorrect conclusions may have resulted from studies that treated the eye as the unit of analysis and analyzed the data using both eyes from patients with bilateral cataracts (i.e., using statistical methods that assumed independence of samples). For example, the study by Lytvynchuk et al. (2020)⁶⁶ included both unilateral and bilateral cataracts in the analysis of age groups but used Fisher exact test to compare the groups, which assumed independence of samples. Koch et al. (2021) also included unilateral and bilateral cases in statistical tests that assumed independence of samples (i.e., analysis of variance [ANOVA]).⁶²

Data Analysis and Synthesis

Appendix 7 presents the main study findings regarding outcomes with relevant information from the included studies. The tables are presented by research question and then by outcome. Details on the comparators are noted where applicable; however, most studies did not adequately report the postoperative regimen after lens removal for patients with aphakia.

The IATS had multiple follow-up time points within multiple publications; therefore, the results from those publications were summarized separately from the other studies.

Eight studies did not specify the type of IOLs used in the study (i.e., whether the IOLs were foldable or nonfoldable).^{64,65,67-69,71,73,76} Generally, it appears that results from these studies with unclear IOL types did not differ from the results of studies with clearly reported foldable IOLs. In this section, the studies that specified the use of foldable IOLs were identified as such. Additionally, many studies did not adequately report the laterality of the cataracts that were examined or did not disaggregate the laterality data (i.e., combined bilateral and unilateral data). These studies are noted under “unclear laterality” and “mixed laterality,” respectively.

Clinical Effectiveness of Intraocular Lens Implantation Versus Conventional Treatment in Infants With Aphakia

Visual Acuity

Three studies (1 RCT; 2 NRSs) examined VA in patients with IOL implantation or aphakia.^44-46,63,67 All studies statistically examined the comparisons.^44-46,63,67 Table 10 and Table 11 provide the relevant data extracted from the studies.

Unilateral Cataracts

The IATS RCT on foldable IOLs reported that at the 1-year follow-up, the median logMAR grating VA was not statistically significantly different between IOL implantation and aphakia corrected with CLs.⁴⁴ At 4.5 and 10 years of follow-up, monocular optotype VA (measured using HOTV and electronic Early Treatment Diabetic Retinopathy Study, respectively) in treated eyes was also not statistically significantly different between IOLs and CLs.^45,46

Bilateral Cataracts

In the NRS by Bothun et al. (2020)⁶³ on foldable IOLs, the median VA in IOL implanted eyes and aphakic eyes treated with CLs, glasses, or both was not statistically significantly different at a maximum follow-up time of 5.8 years. When examining IOLs compared with glasses, the relationship remained numerically similar.⁶³

Mixed Laterality

In the NRS by Murphy et al. (2020),⁶⁷ treatment success was defined as a best corrected VA of 0.3 logMAR or better (i.e., ≤ 0.3 logMAR). There was a statistically significant difference in the proportion of patients achieving treatment success (77.42% versus 42.47% in the IOL implanted versus aphakia groups, respectively; P < 0.001), in favour of the IOL implanted group. However, the mean best corrected visual acuities expressed in logMAR for the IOL and aphakia groups were numerically similar (0.92 versus 0.98 in the IOL implanted versus aphakia groups, respectively; P = not reported [NR]). Therefore, it is likely that the distribution of VA scores varied between the groups; for example, there may have been more patients in the IOL group whose VA scores were just below the threshold used.

Health-Related Quality of Life

One RCT examined HRQoL in caregivers to patients with IOL implantation or aphakia.⁵⁷ Table 12 provides the relevant data extracted from the study.

Unilateral Cataracts

The IATS RCT examined HRQoL in the form of caregiving stress for parents or guardians of patients with unilateral foldable IOL implantation or CLs.⁵⁷

At 3 months after surgery, parenting stress was statistically significantly higher in parents of patients who had received an IOL implant compared with parents of patients who had received CLs measured by OTI and statistically significantly higher for caregivers measured by PSI (in total score as well as on the adaptability and demandingness subscales within the child domain).

At 1 year after surgery, it was reported that there were “no differences” between the groups in either the PSI or OTI although no P values were provided.⁵⁷

Bilateral Cataracts or Mixed Laterality

There were no relevant results for HRQoL in bilateral cataracts or for mixed laterality.

Safety of Intraocular Lens Implantation in Infants With Aphakia

Intraoperative Complications

One RCT examined intraoperative complications in patients with IOL implantation or aphakia.^44,48 Table 14 provides the relevant data extracted from the study.

Unilateral Cataracts

The IATS RCT on foldable IOLs examined intraoperative complications in patients receiving lens removal and IOL implantation compared with patients receiving lens removal and using CLs afterward.^44,48 Overall, there were more intraoperative complications in the IOL group (28% versus 11% in the IOL implanted versus CL groups, respectively; P = 0.031).⁴⁴ The outcomes examined included intraoperative iris prolapse, hyphema (i.e., pooling of blood inside the anterior chamber), iris damage, retained cortex (retained lens material), cloudy cornea, iris sphincterotomy, lens fragment in vitreous, and posterior capsule rupture. No individual outcomes were found to be statistically significantly different between the IOL and CL groups, except for iris prolapse, which occurred more frequently in the IOL group (21% versus 4% in the IOL implanted versus CL groups, respectively; P = 0.008).^44,48

Bilateral Cataracts or Mixed Laterality

There were no relevant results for intraoperative complications in bilateral cataracts or for mixed laterality.

Visual Axis Opacification

Five studies (1 RCT; 4 NRSs) examined VAO in patients with IOL implantation or aphakia.^{44,45,48-50,63,67,68,74} Table 15, Table 16, Table 17, and Table 18 provide the relevant data extracted from the studies.

Unilateral Cataracts

The IATS RCT on foldable IOLs examined lens reproliferation into the visual axis that interfered significantly with vision, but it was not specified if this reproliferation was severe enough to interfere with the visual axis.^44,45,48-50 The IATS also examined VAO (due to “lens reproliferation into visual axis, pupillary membrane, visually significant corectopia, retained cortex, capsular phimosis or excess deposits on IOL” [p. 6]⁴⁸) in patients who were younger than 49 days (n = 25) or 49 days or older (n = 32) at the time of surgery.⁴⁸ In the IATS, more events of reproliferation into the visual axis occurred in the IOL group than in the CL group (24 events⁴⁴ to 27 events⁴⁹ versus 1 event in the IOL implanted versus CL groups, respectively; P < 0.0001) at the 1-year follow-up.⁴⁴ VAO occurred in 37 patients in the IOL group (21 [84%] in < 49 days at surgery and 16 [50%] in ≥ 49 days at surgery) and in 3 patients in the CL group (3 [12%] in < 49 days at surgery and 0 in ≥ 49 days at surgery).⁴⁴

At the 5-year follow-up, lens reproliferation was numerically more common in the IOL group compared with the CL group (28 events versus 2 events), but no statistical testing results were provided.⁴⁹

At the 10-year follow-up, 1 patient in the IOL group and no patients in the CL group had lens reproliferation into the visual axis. No statistical testing results were provided.⁵⁰

Bilateral Cataracts

The NRS by Bothun et al. (2020)⁶³ on foldable IOLs reported that in bilateral cataract, 32% of IOL implanted patients and 8% of patients with aphakia developed VAO (P = 0.009) within a maximum follow-up of 5.8 years.

Mixed Laterality

The NRSs by Kirwan et al. (2010) and Murphy et al. (2020) both reported that VAO occurred more frequently in the IOL implanted group than in the aphakic group (P = 0.01 and P = 0.006, respectively).^67,68 Of note, these 2 studies may contain some of the same patients. In the NRS by Murphy et al., the relative risk of developing VAO was 0.5896 (95% CI, 0.3949 to 0.8803) in favour of aphakia.⁶⁷ Both studies had long-term follow-ups; the longest follow-up was 26 years in Kirwan et al. (2010) and 28 years in Murphy et al. (2020).^67,68

In an NRS on foldable IOLs that examined patients with rubella cataracts, 9 of 37 eyes had visual axis obscuration (VAOb) at 5 years follow-up.⁷⁴ Numerically, more eyes in the IOL group (7 eyes) had VAOb than in the aphakic group (2 eyes; spectacles or CLs).⁷⁴

Glaucoma and Ocular Hypertension

Five studies (1 RCT; 4 NRSs) examined glaucoma in patients with IOL implantation or aphakia.^{44,45,48,49,51-53,67-69,74} Table 19, Table 20, and Table 21 provide the relevant data extracted from the studies. Three studies statistically examined the comparisons,^{44,45,48,49,51-53,67,68} and 2 studies numerically examined the comparisons.^69,74

Unilateral Cataracts

The IATS RCT on foldable IOLs reported that in the first year after surgery, there was no statistically significant difference in the incidence of glaucoma or in the incidence of glaucoma and glaucoma suspect combined between patients who received an IOL and patients who were treated with CLs (9 patients versus 5 patients).⁵¹ This continued into the 5-year^45,49,52 and 10-year follow-ups.⁵³

The NRS by Solebo et al. (2020) reported that at 5 years after surgery, there was an equal or higher incidence of glaucoma in patients with aphakia compared with patients with IOL implantation for all ages at the time of surgery except for 26.1 weeks to 52 weeks of age. However, no statistical testing results were provided.⁶⁹

Bilateral Cataracts

The NRS by Solebo et al. (2020) reported that at the 5-year postsurgery follow-up, numerically there was an equal or higher incidence of glaucoma in patients with aphakia in all age groups at the time of surgery except for 8.5 weeks to 12.75 weeks of age compared with patients with IOL implantation. However, no statistical testing results were provided.⁶⁹

Mixed Laterality

The NRSs by Kirwan et al. (2010) and Murphy et al. (2020) both reported that glaucoma occurred more frequently in patients with aphakia than patients with IOL implantation (P = 0.02 and P = 0.018 in the Kirwan et al. [2010] and Murphy et al. [2020] studies, respectively).^67,68 Murphy et al. (2020)⁶⁷ conducted a subgroup analysis of patients who had had surgery before 2.5 months of age and before 6 weeks of age. No statistically significant differences in the incidence of glaucoma between patients with IOL implantation and patients with aphakia were found in patients younger than 2.5 months of age (P = 0.188) or younger than 6 weeks of age at surgery (P = 0.067).⁶⁷ A similar subgroup analysis of patients younger than 2.5 months old at time of surgery in Kirwan et al. (2010) also found no statistically significant difference in incidence of glaucoma between the 2 groups.⁶⁸

In an NRS by Shah et al. (2014) on foldable IOLs that examined patients with rubella cataracts, at 5-year follow-up, numerically more eyes in the aphakic group (56.0%) had secondary glaucoma than in the IOL group (16.67%).⁷⁴ However, the aphakic eyes had more ocular comorbidities, such as microphthalmos, microcornea, and preoperative glaucoma; thus, it may not have been appropriate to compare with the IOL group because it would be expected that the patients with aphakia had a higher likelihood of developing glaucoma.

Strabismus and Nystagmus

Two studies (1 RCT; 1 NRS) examined strabismus and nystagmus in patients with IOL implantation or aphakia.^{44,45,54-56,58,67} One study statistically examined the comparison^{44,45,54-56,58} and 1 study numerically examined the comparison.⁶⁷ Table 22, Table 23, and Table 24 provide the relevant data extracted from the studies.

Unilateral Cataracts

The IATS RCT on foldable IOLs examined strabismus in patients at 1-year follow-up and 5-year follow-up. Within the first year, there was no statistically significant difference between patients with IOL implantation and patients with aphakia treated with CLs when examining the cumulative percentage of patients who did not have strabismus at baseline but developed strabismus by follow-up.⁵⁴ Orthotropia was also not statistically significantly different between the 2 groups.⁴⁴ Similarly, at 5 years, orthotropia at distance and orthophoria at distance and at near was not statistically significantly different between patients with IOL implantation and patients with aphakia treated with CLs, and the number of patients who required strabismus surgery was not statistically significantly different.^45,55,56

Nystagmus was evaluated at 5-year follow-up. There was no statistically significant difference in fixation instabilities (nystagmus and saccadic oscillations) between patients with IOL implantation and patients with aphakia treated with CL.⁵⁸ When divided into nystagmus and saccadic oscillations alone, there was still no statistically significant differences between the 2 groups.⁵⁸

Bilateral Cataracts

There were no results for strabismus or nystagmus for bilateral cataracts alone.

Mixed Laterality

The NRS by Murphy et al. (2020) numerically compared the development of strabismus and occurrence of strabismus surgery; both were slightly higher in the IOL implantation group compared with the aphakia group (for strabismus, 67.35% versus 56.82% in the IOL implantation versus aphakia groups, respectively; for strabismus surgery, 12.24% versus 11.36% in the IOL implantation versus aphakia groups, respectively).⁶⁷

Additional Surgeries

Six studies (1 RCT; 5 NRSs) examined additional surgeries in patients with IOL implantation or aphakia.^{44-46,48-50,65,68,74} Table 25, Table 26, Table 27, and Table 28 provide the relevant data extracted from the studies.

Unilateral Cataract

The IATS RCT on foldable IOLs examined additional surgeries in unilateral cataracts. At 1-year follow-up, significantly more patients with IOL implantation required additional surgeries compared with patients with aphakia treated with CLs (63% versus 12% in the IOL implanted versus CL groups, respectively; P < 0.0001), which was due to the significantly higher numbers of pupil-related VAO surgeries in the IOL implanted versus CL groups (60% of patients versus 7% of patients required a VAO clearing surgery in the IOL implanted versus CL groups, respectively; P < 0.0001).⁴⁸ This trend was maintained at 5-year follow-up (72% versus 21%, in the IOL implanted versus aphakia groups, respectively; P < 0.001), which was also due to an increased number of VAO clearing surgeries in the IOL implantation group.⁴⁵ During the post-operative years 6 to 10, more patients in the CL group had additional surgeries compared with the first 5 years.^46,50 At this time, secondary IOL implantation was permitted, resulting in 21 procedures to implant a secondary IOL.^46,50 However, the statistical comparison for the number of surgeries was not provided between the IOL implantation and aphakia groups during this follow-up period.

Bilateral Cataracts

There were no results regarding additional surgeries in bilateral cataracts alone.

Mixed Laterality

The NRS by Kirwan et al. (2010) reported that statistically significantly fewer patients with aphakia had surgery to remove VAO compared with patients with IOL implantation (54.5% versus 28.9% in the IOL implanted versus aphakia groups, respectively; P = 0.01).⁶⁸ However, in patients younger than 2.5 months at the time of surgery, the numbers of additional VAO surgeries were comparable between the 2 groups (54.5% versus 36.1% in the IOL implanted versus aphakia groups, respectively; P = 0.15).⁶⁸

In 1 NRS by Shah et al. (2014) on foldable IOLs that examined patients with rubella cataracts, at 5-year follow-up, numerically more eyes in the IOL group (41.67%) had surgery to clear the visual axis than the aphakic group (4.0%).⁷⁴ This difference was not tested statistically.

Unclear Laterality

One NRS by Jackson et al. (2019) reported lens cortex reproliferation operations, which were numerically more common in the aphakic group compared with the IOL group; statistical testing results (if performed) were not provided.⁶⁵

Corneal Changes

One RCT examined corneal changes in patients with IOL implantation or aphakia.⁵⁹ Table 29 provides the relevant data extracted from the study.

Unilateral Cataracts

The IATS RCT on foldable IOLs examined corneal changes at 5 years of follow-up. There were statistically significant differences between the IOL and CL groups in endothelial cell density (P = 0.0012) and the coefficient of variation of cell area (P = 0.0053), favouring the CL group. The corneal thickness was also thinner among eyes with IOL implantation compared with aphakia treated with CLs.⁵⁹

Bilateral Cataracts and Mixed Laterality

There were no results regarding corneal changes in bilateral cataracts or mixed laterality.

Other Safety Outcomes

Five studies (2 RCTs; 3 NRSs) examined other safety outcomes.^{44,49,60,62,71,73,74} Table 15, Table 16, and Table 30 provide the relevant data extracted from the studies.

Unilateral Cataracts

The IATS RCT on foldable IOLs examined a variety of safety outcomes, statistically testing the comparison between IOL implantation and CLs for corectopia and pupillary membranes.^44,49 Corectopia (P = 0.004) and pupillary membranes (P < 0.0001) were statistically significantly more common in the IOL group compared with the CL group.⁴⁴

Bilateral Cataracts

In the RCT by Vasavada et al. (2018) on foldable IOLs, 2 aphakic eyes and 5 IOL-implanted eyes developed posterior synechiae. These patients had received surgery before the median age of 5.7 months at the time of the surgery.⁶⁰

Mixed Laterality

In an NRS by Shah et al. (2014) on foldable IOLs that examined patients with rubella cataracts, at 5-year follow-up, a numerically higher percentage of patients in the IOL group (83.3%) had posterior synechiae than in the aphakic group (48.0%).⁷⁴ No statistical testing result for the difference was provided.

Unclear Laterality

A NRS by Sachdeva et al. (2016) examined uveitis in patients with IOL implantation versus patients with aphakia. Uveitis was statistically significantly more common in patients with IOL implantation (9.6% versus 0.4% in the IOL implanted versus aphakia groups, respectively; P = 0.0001) after 5 years.⁷³

In an NRS by Zhang et al. (2020), PVD and VO were examined.⁷¹ In patients who had surgery between 6 months and 12 months of age, 2 patients in the IOL group and 1 patient in the aphakia group had PVD. Twice as many patients in the IOL group (n = 10) had VO compared with those in the aphakia group (n = 5) by 12 months of follow-up. No statistical testing result was provided for any of the comparisons.⁷¹

Clinical Effectiveness of Intraocular Lens Implantation by 12 Months of Age Versus After 12 Months of Age for Pediatric Patients with Aphakia

Visual Acuity

Two NRSs examined VA in patients of different ages at the time of surgery.^62,75 Table 13 provides the relevant data extracted from the studies.

Unilateral or Bilateral Cataracts

There were no results regarding VA in unilateral or bilateral cataracts alone.

Mixed Laterality

One NRS by Vera et al. (2017) on foldable IOLs examined VA in patients receiving IOL implantation at 1 year of age or younger compared with patients receiving IOL implantation at older than 1 year of age.⁷⁵ The median VA for patients younger than 6 months, between the ages of 6 months to 12 months, and between the ages of 12 months to 24 months at up to 5 years of follow-up was 0.50 logMAR, 0.85 logMAR, and 0.35 logMAR, respectively. When analyzing age as a prognostic factor for “poor visual outcome” (i.e., > 0.5 logMAR), age was not a significant predictor of the outcome. Of note, there were more patients in the younger than 6 months group (n = 33 eyes) than in the 6 months to 12 months group and the 12 months to 24 months group combined (n = 16 and 12 eyes, respectively). The authors also compared the proportion of eyes with poor VA (> 0.5 logMAR) versus eyes with good VA (≤ 0.5 logMAR) by laterality of the cataract but did not statistically test these comparisons due to lack of power.⁷⁵

Another NRS by Koch et al. (2021) on foldable IOLs compared patients aged 5 months to 9 months at the time of surgery with patients aged 19 months to 24 months at the time of surgery and found no statistically significant difference between the 2 groups for corrected distance VA.⁶²

Safety of Intraocular Lens Implantation by 12 Months of Age Versus After 12 Months of Age for Pediatric Patients With Aphakia

Intraoperative Complications

One NRS examined intraoperative complications in patients of different ages at the time of surgery.⁶⁶ Table 31 provides the relevant data extracted from the study.

Unilateral and Bilateral Cataracts

There were no results regarding intraoperative complications in unilateral or bilateral cataracts alone.

Mixed Laterality

In an NRS by Lytvynchuk et al. (2020) in patients operated on with the BIL technique, there was no statistically significant difference in the proportion of eyes experiencing vitreous prolapse, iris hemorrhage, iris prolapse, iris capture, anterior capsule rupture, posterior capture rupture, or BIL IOL dislocation between patients aged 0 months up to 3 months, 3 months up to 12 months, and 12 months up to 36 months at the time of surgery.⁶⁶

Visual Axis Opacification

Six studies (1 RCT; 5 NRSs) examined VAO in patients of different ages at the time of surgery.^{61,62,66,72,73,75} Table 32 provides the relevant data extracted from the studies.

Unilateral and Bilateral Cataracts

There were no results regarding VAO in unilateral or bilateral cataracts alone.

Mixed Laterality

In the RCT by Vasavada et al. (2017) on foldable IOLs,⁶¹ patients were not randomized by age at the time of surgery. However, in a subgroup analysis, the cumulative incidence of VAOb in patients aged 1 year or younger at the time of surgery versus patients older than 1 year up to and including 4 years of age at the time of surgery was 1 versus 0. Statistical testing results (if performed) were not provided.⁶¹

In an NRS by Lytvynchuk et al. (2020) examining BIL-implanted IOLs, there was no statistically significant difference in VAO between patients operated on at the age of 0 months up to 3 months, 3 months up to 12 months, and 12 months up to 36 months of age at the 1-year follow-up.⁶⁶ In another NRS by Ezisi et al. (2017) that examined capsular bag implantation, there were 3 cases of VAO: 2 in patients aged 12 months or younger at the time of surgery and 1 in patients who were older than 12 months at the time of surgery. Statistical testing results (if performed) were not provided. There were also some discrepancies in the publication between the text and the reported tables.⁷²

In an NRS by Vera et al. (2017) on foldable IOLs, the most common reason for VAO was lens reproliferation into the visual axis. The rate of VAO severe enough to require reintervention was 54%, 56%, and 50% in patients younger than 6 months, between 6 months and 12 months, and older than 12 months of age at IOL implantation, respectively.⁷⁵ A second NRS by Koch et al. (2021) on foldable IOLs found no statistically significant difference for VAO between patients who were operated on at 5 months to 9 months of age and those at 19 months to 24 months of age. Numerically, there was a lower incidence of VAO in patients 1 year to 2 years of age compared with patients younger than 1 year of age, but no statistical testing results were provided.⁶²

Unclear Laterality

In an NRS by Sachdeva et al. (2016), in patients younger than 1 year of age at the time of surgery compared with patients greater than 1 year of age at the time of surgery, the incidence of VAO was 7.7% versus 0.85%. Statistical testing results (if performed) were not provided.⁷³

Glaucoma and Ocular Hypertension

Nine studies (1 RCT; 8 NRSs) examined glaucoma in patients of different ages at the time of surgery.^{62,64,66,69,70,72,73,75} Table 33 provides the relevant data extracted from the studies.

Unilateral Cataract

In the NRS by Solebo et al. (2020),⁶⁹ unilateral cataracts were stratified by age at surgery: 0 weeks to 4.25 weeks, 4.3 weeks to 8.5 weeks, 8.5 weeks to 12.75 weeks, 12.8 weeks to 26 weeks, 26.1 weeks to 52 weeks, and 52.1 weeks up to 2 years. In the patients 12 months of age or younger at surgery, there were 3 cases of glaucoma; in patients older than 12 months of age at surgery, there were no cases of glaucoma.

Bilateral Cataracts

In the NRS by Solebo et al. (2020),⁶⁹ bilateral cataracts were stratified by age at surgery: 0 weeks to 4.25 weeks, 4.3 weeks to 8.5 weeks, 8.5 weeks to 12.75 weeks, 12.8 weeks to 26 weeks, 26.1 weeks to 52 weeks, and 52.1 weeks up to 2 years. In the patients 12 months of age or younger at surgery, there were 7 cases of glaucoma; in the patients older than 12 months of age at surgery, there were no cases.

Mixed Laterality

In the RCT by Vasavada et al. (2017) on foldable IOLs,⁶¹ patients were not randomized by age at surgery. However, subgroup analyses demonstrated that 2 eyes of patients aged 1 year or younger at surgery developed glaucoma. No patients older than 1 year of age at surgery developed glaucoma.

In an NRS by Lytvynchuk et al. (2020) that examined BIL-implanted IOLs, there was no statistically significant difference in the proportion of patients who developed glaucoma between patients operated on at 0 months up to 3 months, 3 months up to 12 months, and 12 months up to 36 months of age at the 1-year follow-up.⁶⁶ In another NRS by Ezisi et al. (2017), in capsular bag implantation, there was 1 case of glaucoma in patients operated on at 12 months of age or younger and no cases in patients operated on after 12 months of age. Statistical testing results (if performed) were not provided.⁷²

The NRS by Solebo et al. (2020) reported that an independent predictor of the development of glaucoma was younger age at surgery; the adjusted odds ratio for every reduction of 1 week in age at surgery was 1.1 (95% CI, 1.1 to 1.2).⁶⁹ Another NRS by Koch et al. on foldable IOLs (2021) examined glaucoma in patients who were operated on between 5 months and 24 months of age, with no cases of glaucoma occurring during an average of 70.85 months of follow-up.⁶²

In an NRS by Vera et al. (2017) on foldable IOLs, the incidence of glaucoma in IOL-implanted eyes was 21.21% in patients younger than 6 months at surgery. There were no cases of glaucoma in patients aged 6 months to 12 months or patients aged 12 months or older. Statistical testing results (if performed) were not provided.⁷⁵

The total percentage of secondary glaucoma in an NRS by Valeina et al. (2020)⁷⁰ after a maximum of 10 years of follow-up was 15.5% (7 cases). Six of these cases were in patients aged 1 month to 6 months at the time of surgery. One case was in a group of patients aged 25 months to 48 months at the time of surgery.⁷⁰

In an NRS by Eder et al. (2020), a study with potential follow-up to 18 years following surgery, of patients aged 0 months to 5 months, 6 months to 23 months, or 24 months to 72 months at the time of surgery, 30%, 25%, and 20% developed postoperative glaucoma, respectively. Only the right eye for bilateral cases was examined.⁶⁴

No patients developed glaucoma in the NRS by Koch et al.⁶²

Unclear Laterality

In an NRS by Sachdeva et al. (2016) on foldable IOLs that examined patients younger than 1 year of age at the time of surgery compared with patients older than 1 year of age at surgery, the incidence of glaucoma was 5.7% and 0.21%, respectively. Statistical testing results (if performed) were not provided.⁷³

Strabismus and Nystagmus

One NRS examined strabismus in patients of different ages at the time of surgery.⁷⁶ Table 34 provides the relevant data extracted from the study.

Unilateral Cataracts

The NRS by Lee and Kim (2014) compared patients with unilateral cataracts who were operated on at 1 year of age or younger with patients older than 1 year of age and found that 2 patients and 29 patients were orthotropic at follow-up, respectively (at least 2 years following surgery). The percentage of patients in either group who had strabismus was 60% and 25.6%, respectively, and this was not statistically significant (P = 0.113).⁷⁶

Bilateral Cataracts

The NRS by Lee and Kim (2014) compared patients with bilateral cataracts operated on at 1 year of age or younger with patients older than 1 year of age and found that 10 patients and 43 patients were orthotropic at follow-up, respectively (at least 2 years following surgery). The percentage of patients who had strabismus in each group was 37.5% and 10.4%, respectively, and was statistically significantly different between the 2 groups (P = 0.013).⁷⁶

Mixed Laterality

In the NRS by Koch et al. (2021), there was a positive correlation between age at surgery and strabismus, but this was not statistically significant.⁶²

Additional Surgeries

Three NRSs examined additional surgeries in patients of different ages at time of surgery.^62,64,73 Table 35 provides the relevant data extracted from the studies.

Unilateral and Bilateral Cataracts

There were no results regarding additional surgeries in unilateral or bilateral cataracts alone.

Mixed Laterality

Eder et al. (2020) compared the average number of surgeries in the first postoperative year in patients receiving IOLs. There was a statistically significant difference in the average number of surgeries between patients who were aged 0 months to 5 months at surgery and those aged 24 months to 72 months at surgery (1.70 versus 0.61; P = 0.005).⁶⁴

The study by Sachdeva et al. (2016) on foldable IOLs reported that the patients who received IOL surgery before 1 year of age had numerically more glaucoma surgeries than patients operated on after 1 year of age.⁷³ The NRS by Koch et al. (2021), also on foldable IOLs, found no statistically significant difference in additional surgeries between patients operated on at 5 months to 9 months of age and those at 19 months to 24 months of age.⁶²

Inflammatory Complications

Three studies (1 RCT; 2 NRSs) examined posterior synechiae,⁶¹ peripheral synechiae,⁶⁶ or postoperative inflammation.⁷⁵ Table 36 provides the relevant data extracted from the studies.

Unilateral Cataract and Bilateral Cataracts

There were no results regarding inflammatory complications in unilateral or bilateral cataracts alone.

Mixed Laterality

In the RCT by Vasavada et al. (2017) on foldable IOLs,⁶¹ patients were not randomized by age at surgery but were analyzed in age subgroups of patients aged 1 year or younger versus patients after 1 year of age up to including 4 years of age (i.e., ≤ 1 year versus > 1 to ≤ 4 years).

In an NRS by Lytvynchuk et al. (2020) examining BIL-implanted IOLs, there were 1, 1, and 0 cases of peripheral synechiae in patients operated on at 0 months up to 3 months, 3 months up to 12 months, and 12 months up to 36 months of age at 1-year follow-up, respectively.⁶⁶

In the NRS by Vera et al. (2017) on foldable IOLs, the incidence of postoperative inflammation (definition of inflammation not provided by the authors) in IOL-implanted eyes was 48%, 44%, and 17% in patients younger than 6 months, between 6 months and 12 months, and 12 months or older at surgery, respectively. These differences were not statistically tested.⁷⁵

Other Safety Outcomes

Seven studies (1 RCT; 6 NRSs) examined other safety outcomes such at IOL centration,⁶¹ postoperative cell deposits,⁶¹ retinal detachment,^62,75 endophthalmitis,⁷⁵ IOL-related complications,⁷⁵ intrapupillary membrane,⁶⁶ iris capture,⁶⁶ hyphema,⁶⁶ uveitis,^66,73 BIL IOL glistening,⁶⁶ BIL IOL luxation,⁶⁶ peripheral corneal opacification,⁶⁶ IOL capture,⁷² corectopia,⁶² IOL pigments and fibrin,⁶² and secondary cataracts.⁷⁰ Table 37 and Table 38 provide the relevant data extracted from the studies.

Unilateral and Bilateral Cataracts

There were no results regarding other safety outcomes in unilateral or bilateral cataracts alone.

Mixed Laterality

The NRS by Lytvynchuk et al. (2020) reported no statistically significant differences in intrapupillary membrane, iris capture, hyphema, uveitis, BIL IOL glistening, BIL IOL luxation, and peripheral corneal opacification in patients who received BIL surgery at 0 months up to 3 months, 3 months up to 12 months, and 12 months up to 36 months of age.⁶⁶

In the NRS by Vera et al. (2017) on foldable IOLs, retinal detachment only occurred in patients operated on at age 0 months to 6 months, and endophthalmitis occurred only in patients operated on at age 6 months to 12 months.⁷⁵ In patients aged 0 months to 12 months at the time of surgery, there were reported cases of IOL luxation in the vitreous (n = 3), recurrent fibrosis (n = 3), and decentering of the IOL (n = 2), whereas these were no reported cases in patients older than 12 months.⁷⁵ In the NRS by Vasavada et al. (2017), no cases of decentering of the IOL occurred in any of the age groups.⁶¹ No patients with foldable IOLs had retinal detachment in the study by Koch et al.⁶²

In an NRS by Ezisi et al. (2017), IOL capture was noted in 1 eye (7.7%) in patients aged 12 months or younger at the time of surgery; it was not noted in patients older than 12 months of age at the time of surgery.⁷²

Secondary cataract was reported in 11, 3, 3, 9, and 19 of the eyes that were operated on in patients aged 1 month to 6 months, 7 months to 12 months, 13 months to 24 months, 25 months to 48 months, and 49 months to 84 months, respectively (i.e., 48.3% of eyes younger than 12 months at surgery and 47% of eyes older than 12 months up to 84 months at surgery) in an NRS by Valeina et al. (2020) on foldable IOLs. Statistical testing results (if performed) were not provided.⁷⁰

Uveitis was reported in the NRS by Sahdeva et al. (2016), with a numerically higher proportion of patients who received surgery before 1 year of age compared with patients who received surgery after 1 year of age, but no statistical testing results were provided.

Cost-Effectiveness of Intraocular Lens Implantation Compared With Conventional Treatment in Infants With Aphakia

No relevant publications were identified regarding the cost-effectiveness of IOL implantation compared with aphakia in patients aged 12 months or younger at the time of surgery; therefore, no summary can be provided.

Cost-Effectiveness of Intraocular Lens Implantation by 12 Months of Age Compared With After 12 Months of Age for Pediatric Patients With Aphakia

No relevant publications were identified regarding the cost-effectiveness of IOL implantation in patients aged 12 months or younger at surgery compared with patients older than 12 months up to 12 years of age at the time of surgery; therefore, no summary can be provided.

Subgroup Analyses

Age

Three studies provided subgroup analyses on age for 0 months to 6 months, 6 months to 12 months, 12 months to 24 months, or 24 months to 12 years.^69,70,75 Eder et al. (2020) examined patients from 0 months to 5 months, 6 months to 23 months, or 24 months to 72 months of age at time of surgery. Results for patients in different age groups are detailed above (research question 2, research question 4).

Eye Involvement

Six studies focused exclusively on unilateral or bilateral cataracts or separated results by cataract laterality.^{44-60,63,67,69,76,77} Results for patients with separated laterality are detailed throughout the Data Analysis and Synthesis section.

Time of Surgery

Five studies included patients with IOLs implanted before 2010^{44-59,63,68,69,74,77} and 2 studies included patients implanted with IOLs after 2010.^61,71 Ten studies included patients with surgery dates that overlapped 2010.^{60,64-67,70,72,73,75,76}

The studies by Zhang et al. (2010)⁷¹ and Vasavada et al. (2017)⁶¹ were the only ones that exclusively included patients who had IOLs implanted from 2010 onwards. There was not enough data to examine trends in surgical outcomes before and after 2010.

Discussion

Study Limitations and Generalizability of Findings

Evidence Gaps

There were several evidentiary gaps that limited the generalizability of the conclusions of this review. For example, there were no relevant cost-effectiveness studies identified; therefore, no cost-effectiveness data were included to inform research question 5 and research question 6. Although financial burden was noted by the interviewed caregivers as a significant concern, as well as lack of equity as a major issue in receiving timely care (e.g., lack of insurance for some families or inability to access eye care in developing countries leading to delays in diagnosis and treatment), the lack of cost-effectiveness evidence limits the ability to evaluate the financial burden more broadly.

There was also no comparison of IOLs with glasses and CLs within the same study or within studies with comparable population groups; therefore, the clinical effectiveness and safety of aphakia treated with glasses alone and aphakia treated with CLs could not be separated or compared. Most studies did not specify the method of vision correction for patients with aphakia; therefore, the conclusions were also not clear regarding the comparative efficacy of IOLs versus glasses, CLs, or both.

One study (i.e., IATS RCT) reported on HRQoL by examining parenting stress⁵⁷; these findings were similar to the input gathered through the Patient and Family Engagement activities. Namely, caregivers identified stress and anxiety from learning to use CLs and the outcomes and related effects on the young child from the cataract removal and/or IOL implantation (e.g., intraoperative complications and postoperative complications such as VAO). Overall, the lack of additional evidence and lack of HRQoL outcomes from the patient perspective was notable.

Definitions of Outcomes

One of the major limitations in the included evidence that limits the ability to compare conclusions between studies is the different definitions used for outcomes in the included studies. This was most common in the definitions for glaucoma. Table 7 details the different definitions of glaucoma used in the studies. Discussion with the clinical expert engaged for the review noted that there is no well-accepted or common definition for glaucoma that could be applied consistently in the pediatric population; an accepted definition would have made the conclusions more comparable across the evidence base.⁸⁰ Other outcomes were not defined well (e.g., what constituted visually significant VAO or objective measurements of strabismus); therefore it was not possible to determine if the definition varied from study to study.

Heterogeneity of Studies

There was substantial heterogeneity across the included studies. Many studies included different outcomes, comparisons, and populations (e.g., rubella cataract or co-diagnoses such as microphthalmos and persistent fetal vasculature), as well as having different study designs, follow-up times, age at IOL implantation, and years with IOL implantation. There were also different proportions of patients with bilateral versus unilateral cataracts, which may have different etiologies and different responses to surgical intervention. This made it inappropriate to combine the studies for MAs and difficult to draw general conclusions regarding the effectiveness and safety of the interventions. Additionally, many studies combined unilateral and bilateral data or were not clear about the laterality of the cataracts, making it difficult to compare across these studies. Furthermore, some studies did not report if foldable IOLs were implanted, which suggests that some studies may have included patients implanted with nonfoldable IOLs. Overall, this heterogeneity did not allow for an appropriate meta-analysis of the data, which means that the included studies were narratively synthesized and, in most cases, needed to be examined in relative isolation from one another.

Quality of Evidence

The quality of the relevant evidence for this report was low. There was 1 relevant RCT that was methodologically higher in quality among certain domains but was still assessed to have an overall high risk of bias according to the Cochrane RoB 2 tool.^44-59,77 The remaining studies were very low quality due to the retrospective nature of the designs and potential introduction of selection bias. Additionally, there was uncertainty in the results because, for many comparisons and outcomes, there was only 1 study that provided relevant evidence. This limited the generalizability of the conclusions for the comparisons and prevented the conduct of any meta-analysis or narrative synthesis of those outcomes.

Directions for Future Research

Future research should consist of high-quality RCTs comparing patients of different age groups and different treatments. These studies should include comparable groups at baseline (e.g., excluding patients that would only receive 1 of the treatment options under standard clinical practice) and clearly separate patients with bilateral and unilateral cataracts. Additionally, future research examining the cost-effectiveness of treatment options for patients with aphakia could assist with appropriate and equitable decision-making.

Conclusions and Implications for Decision- or Policy-Making

Overall, there were 18 relevant studies identified.^44-77 Findings indicate that IOL implantation in patients aged 12 months or younger is no more effective for the outcome of VA than implantation of IOLs in patients older than 12 months and up to 12 years or treating them with glasses or CLs.^{44-46,62,63,67} Findings from a pivotal long-term RCT (i.e., IATS) that compared IOLs and CLs in patients younger than 1 year of age at the time of surgery were generally consistent with the limited findings from NRSs in both unilateral and bilateral cataracts. Age was not found to be a significant predictor of visual outcomes in 2 NRSs.^62,75

Findings from the IATS RCT indicated that caregiver stress is an important factor in the decision to implant IOLs at an early age, but caregiving stress levels as measured by the OTI and PSI did not differ when the patient was 1 year of age.⁵⁷ Interviews conducted by CADTH with 2 mothers with lived experiences suggested that stress from the financial burden of treatment (i.e., cost of CLs), stress of learning how to adequately provide visual treatment, and the stress of a child undergoing surgery (i.e., IOL implantation later in life) were major aspects of the experiences.

Safety outcomes were consistent with what is clinically expected. Patients who underwent IOL surgery at a younger age experienced more occurrences of VAO and therefore had a larger number of reoperations to remove the opacification. Other safety outcomes more common in the patients with IOL implantation compared with patients with aphakia, including corectopia, uveitis, pupillary membranes, and corneal changes. In glaucoma, there were mixed results comparing patients with IOL implantation versus patients with aphakia. This is inconsistent with previous clinical acceptance that IOLs may be protective against glaucoma for young children.⁵² The results for glaucoma that were compared between different age groups at the time of surgery were also mixed, but many comparisons were not statistically tested.

The evidence base was of low quality, with all studies rated to have a high or unclear risk of bias. Most commonly, the risk of selection bias was high, and the reporting for most studies was lacking, inaccurate, or inconsistent. Many studies included patients with different lateralities of the cataract (i.e., unilateral and bilateral), often combining their data into 1 outcome measure despite the different needs and outcomes for patients with different cataract lateralities. Additionally, the majority of the studies were nonrandomized,^62-76 many of which were retrospective in design, which allowed the physicians and caregivers to opt for IOL implantation (or to treat aphakia with glasses or CLs) outside of a trial context. Finally, there were concerns with the choice of statistical analysis in some of the included studies. Namely, statistical tests that require an assumption of independence of samples were used on samples that may not be considered independent (i.e., bilateral cataract).

There were no relevant cost-effectiveness studies identified. This is a limitation of the evidence base and, therefore, of this review. Parents indicated that the costs associated with treatment and the lack of equity were concerns for families of children with aphakia; therefore, the lack of evidence and analysis on the cost-effectiveness of IOL implantation is notable. Other limitations include the substantial heterogeneity of the studies, which did not allow for any MAs and led to limited narrative syntheses, and the variety of definitions used for outcomes across the included studies.

Overall, the evidence is relatively consistent with clinical experience, according to clinical expert input. However, because there are many limitations to the evidence base, additional good quality RCTs and further explorations into the cost-effectiveness of treatments for aphakia in the pediatric population are needed.

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Appendix 1: Literature Search Methods

Note that this appendix has not been copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases

• MEDLINE All (1946-present)

• Embase (1974-present)

• Cochrane Central Register of Controlled Trials (CCTR)

• Note: Subject headings and search fields have been customized for each database. Duplicates between databases were removed in Ovid.

Date of search: January 21, 2021

Alerts: Monthly search updates until project completion

Search filters applied: No filters were applied to limit the retrieval by study type.

Limits

• Publication date limit: 2010-present

• Humans

• Language limit: English-language

• Conference abstracts: excluded

Table 3: Syntax Guide

Multi-Database Strategy

1. exp aphakia/

2. aphaki*.ti,ab,kf,kw.

3. ((absence or absent) adj3 lens*).ti,ab,kf,kw.

4. 1 or 2 or 3

5. exp Cataract Extraction/

6. exp Cataract/

7. cataract*.ti,ab,kf,kw.

8. 5 or 6 or 7

9. 4 or 8

10. Lens Implantation, Intraocular/

11. exp Lenses, Intraocular/

12. ((intraocular or intra ocular or artificial* or implant* or prosthe*) adj3 (lens or lenses)).ti,ab,kf,kw.

13. (pseudophaki* adj3 lens*).ti,ab,kf,kw.

14. (IOL or IOLs or acrysof* or enVista* or (Alcon* adj (MA60* or SA60*)) or (Artisan* adj Aphakia*)).ti,ab,kf,kw.

15. 10 or 11 or 12 or 13 or 14

16. "Congenital, Hereditary, and Neonatal Diseases and Abnormalities"/ or Congenital abnormalities/ or exp Child/ or exp Infant/ or exp Pediatrics/ or Pediatricians/ or Hospitals, Pediatric/ or Child Health/

17. (child or children or childhood or infant* or infancy or baby or babies or newborn* or new born* or neonat* or neo nat* or preemie or preemies or months old or months of age or toddler* or paediatric* or pediatric* or girl or girls or boy or boys or kid or kids or preschool* or pre school* or schoolage* or school age* or preteen* or pre teen* or ((1 year or one year or 2 year or two year or 2 years or two years) adj2 (age or aged or old or olds)) or congenital* or juvenile*).ti,ab,kf,kw,jw.

18. 16 or 17

19. 9 and 15 and 18

20. Cataract/cn

21. ((genetic or developmental) adj2 cataract*).ti,ab,kf,kw.

22. 20 or 21

23. 15 and 22

24. 19 or 23

25. limit 24 to english language

26. 25 use medall

27. 24 use cctr

28. 26 or 27

29. aphakia/

30. aphaki*.ti,ab,kw,dq.

31. ((absence or absent) adj3 lens*).ti,ab,kw,dq.

32. 29 or 30 or 31

33. exp cataract extraction/

34. exp cataract/

35. cataract*.ti,ab,kw,dq.

36. 33 or 34 or 35

37. 32 or 36

38. exp lens implant/

39. lens implantation/

40. ((intraocular or intra ocular or artificial* or implant* or prosthe*) adj3 (lens or lenses)).ti,ab,kw,dv,dq.

41. (pseudophaki* adj3 lens*).ti,ab,kw,dv,dq.

42. (IOL or IOLs or acrysof* or enVista* or (Alcon* adj (MA60* or SA60*)) or (Artisan* adj Aphakia*)).ti,ab,kw,dv,dq.

43. 38 or 39 or 40 or 41 or 42

44. newborn disease/ or congenital disorder/ or congenital malformation/ or exp Child/ or pediatric patient/ or Pediatrics/ or exp pediatric surgery/ or pediatric surgeon/ or pediatric ward/ or pediatrician/ or pediatric hospital/ or child health/ or child health care/

45. (child or children or childhood or infant* or infancy or baby or babies or newborn* or new born* or neonat* or neo nat* or preemie or preemies or months old or months of age or toddler* or paediatric* or pediatric* or girl or girls or boy or boys or kid or kids or preschool* or pre school* or schoolage* or school age* or preteen* or pre teen* or ((1 year or one year or 2 year or two years or 2 years or two years) adj2 (age or aged or old or olds)) or congenital* or juvenile*).ti,ab,kw,jx,dq.

46. 44 or 45

47. 37 and 43 and 46

48. exp congenital cataract/

49. cataract/cn

50. ((genetic or developmental) adj2 cataract*).ti,ab,kw,dq.

51. 48 or 49 or 50

52. 43 and 51

53. 47 or 52

54. 53 not conference abstract.pt.

55. limit 54 to english language

56. 55 use oemezd

57. 28 or 56

58. exp animals/

59. exp animal experimentation/ or exp animal experiment/

60. exp models animal/

61. nonhuman/

62. exp vertebrate/ or exp vertebrates/

63. or/58-62

64. exp humans/

65. exp human experimentation/ or exp human experiment/

66. or/64-65

67. 63 not 66

68. 57 not 67

69. limit 68 to yr ="2010 -Current"

70. remove duplicates from 69

Clinical Trials Registries

ClinicalTrials.gov

Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.

[Search -- aphakia, intraocular lens AND (juvenile OR congenital OR pediatric OR paediatric OR infant OR children OR neonatal)]

WHO ICTRP

International Clinical Trials Registry Platform, produced by WHO. Targeted search used to capture registered clinical trials.

[Children Limit. Search terms -- intraocular lens AND cataract, intra ocular lens AND cataract, intraocular lens AND aphakia, intra ocular lens AND aphakia]

Health Canada’s Clinical Trials Database

Produced by Health Canada. Targeted search used to capture registered clinical trials.

[Search terms -- intraocular, intra ocular, aphakia, cataract, cataracts, iols]

EU Clinical Trials Register

European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.

[Search terms -- aphakia, pseudophakic, intraocular AND children/juvenile/pediatric/pediatric/congenital/neonatal, “intraocular lens,” “intraocular lenses,” “intra ocular lens,” “intra ocular lenses”]

Grey Literature

Search dates: January 22, 2021 – February 4, 2021

Keywords: aphakia, “intraocular lens,” “intraocular lenses,” “intra ocular lens,” “intra ocular lenses,” pseudophakic, acrysof, alcon, envista, (juvenile OR congenital OR neonatal OR paediatric OR pediatric OR child OR children OR infant OR infants OR infancy) AND cataract*

Limits: Publication years: 2010-present

Updated: Search updated on November 2, 2021, before the completion of stakeholder feedback period

Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool for Searching Health-Related Grey Literature were searched:

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Advisories and Warnings

• Clinical Trials Registries

• Databases (free)

• Health Statistics

• Internet Search

• Open Access Journals

The complete search archive of sites consulted for this report is available on request.

Appendix 2: Study Selection

Note that this appendix has not been copy-edited.

Figure 1: PRISMA Flow Diagram

Table 7: Definitions of Glaucoma in Included Studies

IATS = Infant Aphakia Treatment Study; IOP = intraocular pressure; mm Hg = millimetres of mercury; NRS = nonrandomized study; NR = not reported; p. = page; RCT = randomized controlled trial; TAPS = Toddler Aphakia and Pseudophakia Study.

^aThe study⁶⁹ reports the definition with a “less than” symbol. It is unclear if this is a typo.