A Systematic Review of the Cost-Effectiveness of Cleft Care in Low- and Middle-Income Countries: What is Needed?

Objective The objective of this paper is to conduct a systematic review that summarizes the cost-effectiveness of cleft lip and/or palate (CL/P) care in low- and middle-income countries (LMICs) based on existing literature. Design We searched eleven electronic databases for articles from January 1, 2000 to December 29, 2020. This study is registered in PROSPERO (CRD42020148402). Two reviewers independently conducted primary and secondary screening, and data extraction. Setting All CL/P cost-effectiveness analyses in LMIC settings. Patients, Participants In total, 2883 citations were screened. Eleven articles encompassing 1,001,675 patients from 86 LMICs were included. Main Outcome Measures We used cost-effectiveness thresholds of 1% to 51% of a country's gross domestic product per capita (GDP/capita), a conservative threshold recommended for LMICs. Quality appraisal was conducted using the Joanna Briggs Institute (JBI) checklist. Results Primary CL/P repair was cost-effective at the threshold of 51% of a country's GDP/capita across all studies. However, only 1 study met at least 70% of the JBI criteria. There is a need for context-specific cost and health outcome data for primary CL/P repair, complications, and existing multidisciplinary management in LMICs. Conclusions Existing economic evaluations suggest primary CL/P repair is cost-effective, however context-specific local data will make future cost-effectiveness analyses more relevant to local decision-makers and lead to better-informed resource allocation decisions in LMICs.


Introduction
Cleft lip and/or palate (CL/P) is the most common craniofacial congenital anomaly worldwide.Yet, CL/P is undertreated in low-and middle-income countries (LMICs).2][3][4] These experiences are exacerbated by delays in care.
Economic evaluations help clinicians and policymakers make informed decisions in resource-constrained settings. 5ost-effectiveness analyses are used to compare the value of interventions, and prioritized interventions in LMICs are those that are cost-effective and feasible. 5The objective of this paper is to conduct a systematic review that summarizes the cost-effectiveness of CL/P care in LMICs based on existing literature.This will consolidate existing decision-analyses for CL/P in LMICs and assess the methodologic quality of these analyses in how they can be used to help inform LMIC resource allocation decisions.

Methods
This systematic review is conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Figure 1).The full search strategy with key terms and protocol is registered and available on PROSPERO, number CRD42020148402 (Appendix 1).The search strategy was designed and executed by an Information Specialist (JB) with expertise in systematic reviews with additional clinical input (KC).
We searched 11 electronic databases from January 1, 2000 to December 29, 2020 using keywords and medical subject headings related to the following concepts: cleft lip, cleft palate, cost-effectiveness, and economic evaluations.The search strategy was initially developed in Ovid MEDLINE, and then adapted to the syntax and subject headings of the other databases: Global Health Cost-Effectiveness Analysis Registry, Cost-Effectiveness Analysis (CEA) Registry, Ovid EMBASE, Global Index Medicus, ScHARRHUD database, Cochrane Database of Systematic Reviews database, and the Center for Reviews and Dissemination Databases, which includes the Health Technology Assessment Database (HTA), HTA Database Canadian Repository, the NHS Economic Evaluation Database (NHS EED) and the Database of Abstracts of Reviews of Effects.Additionally, we hand-searched gray literature and bibliographies of identified publications.Finally, we searched PROSPERO for ongoing or recently completed systematic reviews.
Two reviewers (KC, GH) independently assessed the titles, abstracts, and full texts for inclusion using DistillerSR.Full economic evaluations that reported cost-benefit analyses, costeffectiveness analyses, or cost-utility analyses of primary cleft lip and/or palate repair in LMIC settings as defined by the World Bank were included. 6Only English language studies were included due to feasibility and resource constraints.We excluded studies that were not full economic evaluations, such as studies that reported only health outcomes, or costminimization, cost-consequence and cost-of-illness studies.
Two reviewers (KC and AE or GH) independently extracted data and conducted the quality appraisal using the Joanna Briggs Institute (JBI) critical appraisal tool for economic evaluations. 7These criteria are a validated international tool to evaluate evidence related to the feasibility, appropriateness, meaningfulness, and effectiveness of health care interventions. 7

Analysis
We reported costs in 2020 International Dollars (USD).Where country-specific costs were provided, these were inflated to the most recent year based on the country's consumer price index. 6r articles that provided summaries across countries and regions, we used the inflation rate for the specific region or the region with the highest volume of cleft surgeries, as appropriate.Cost-effectiveness analyses are composed of cost-utility analyses or cost-benefit analyses.Cost-utility analysis is a method of economic evaluation, where health outcomes are valued using a generic measure of health, such as Disability-Adjusted Life Years (DALYs). 8The results are reported as an Incremental Cost-Effectiveness Ratio of dollars per DALY averted.In cost-benefit analyses, health outcomes are valued in monetary terms and can be based on the Gross National Index per capita (GNI/capita) for each country. 5,9Surgeries performed in a country with a higher GNI/capita will thus report a higher economic benefit compared to surgeries performed in a country with a lower GNI/ capita.The results are reported as a ratio of costs to benefits or as a net benefit or loss, and if they were based on disability weights from the Global Burden of Disease (GBD) study then these values may be adjusted by age-weighting at 4% and discounting at 3%. 9,10[13]

Results
We screened 2883 citations and included 11 economic evaluations.5][16][17][18][19][20][21][22][23][24] Four studies considered patients from a low-income country (Table 1).There were no studies that considered multidisciplinary care.None of the included studies used a model-based economic evaluation.All studies were based on a lifetime horizon.All costs came from an NGO perspective and were reported in international USD.Eight of the 11 studies conducted a cost-utility analysis using DALYs to value health outcomes, with 6 studies conducting cost-benefit analyses.

Data Inputs
All studies used cost data from NGOs: Operation Smile (n = 3), Interplast (n = 2), Smile Train (n = 3), Smile for Children (n = 1), the Children's Surgical Center (n = 1), and Hands Across the World (n = 1).Age at surgery ranged from 142 days old to 74 years old.DALYs were derived from isolated cleft lip or isolated cleft palate disability weights produced by the GBD studies in 1990 or 2004 for ten of the 11 studies.The remaining study measured and applied disability weights based on the expertise of 5 surgeons. 24Although studies may have included patients with combined cleft lip and cleft palate, ten of the studies did not consider a disability weight for untreated cleft lip and palate, and 1 study used isolated cleft palate as a proxy for these patients. 17he health impact of CL/P complications, i.e. fistula or lip/nose revision, was included in 2 studies.One study cited a disability weight of 0.05 for both the palatine fistula and the lip revision. 22he other study used isolated cleft lip as a proxy for complications and included this in the DALYs averted for CL/P. 17

Costs
All studies reported costs in international dollars (USD). Costs regarding whether NGOs used a center-or mission-based approach are outlined in Table 2. Eight articles provided an outline of cost components.Major cost components discussed in the articles were: staff salary and recruitment (88%), medical supplies (75%), staff accommodation (50%), staff transportation (50%), NGO overhead (50%), patient transportation (50%), patient hospital costs (50%), and patient food (50%).No articles reported patient or caregiver wages lost or time loss because all costs were reported from the NGO perspective.Finally, no article considered the costs associated with untreated cleft lip and/or palate.

Outcomes
Ten of the 11 articles valued health outcomes in terms of DALYs.DALYs averted per cleft lip or palate repair ranged from 1.2 to 10.7, dependent on the country (Table 2).The cost for primary CL/P repair ranged from $33.7 to 401.8, depending on the country and NGO (Table 2).The cost per DALY associated with surgery demonstrated that primary CL/P repair was cost-effective at the threshold of 51% of GDP per capita for all studies (Table 2).Only 1 study compared CL/P repair in relation to other interventions in Vietnam and found it to be cost-effective in comparison to human immunodeficiency virus/acquired immunodeficiency syndrome or tuberculosis treatment. 20ix cost-benefit analyses were reported, all of which used the human capital approach (Table 3).Using the human capital approach, the estimated economic benefit in USD for individual primary cleft lip repair ranged from $3191 (Indonesia) to $32,203 (Ecuador).The estimated economic benefit from individual cleft palate repair ranged from $4110 (Indonesia) to $87,393 (Ecuador).

Quality Appraisal
All articles met at least 1 of the 11 JBI criteria (Figure 2).However, only 1 study met at least 70% of JBI criteria.Nine of the 11 articles did not describe subsequent complications from primary CL/P repair or consider costs for patients without primary repair.Further, 10 of the 11 articles did not consider   disability weights for patients with untreated combined cleft lip and cleft palate which can be considered more severe than isolated cleft types.Furthermore, of the studies that accounted for the costs, none of the studies considered wages lost from the patient and caregiver perspective during care received.None of the studies used health outcomes from patient or societal populations in LMICs.Finally, multidisciplinary care was not considered.The data inputs for the economic evaluations make the results less relevant to local-decision makers and not generalizable to the affected patients in LMICs.

Discussion
This systematic review synthesizes the evidence on the economic value of CL/P repair in LMICs to date.All studies reported the costs of CL/P repair from the health care payer perspective, where the health care payer was the NGO.Local governments can assume the role of the health care payer and consider whether CL/P repair is cost-effective for their country.2][13] Based on this threshold, the cost per DALY for primary CL/P repair was cost-effective across all studies.However, several concerns were identified that could limit this implication.
First, it is suspected that GBD disability weights underestimate the disease severity and impact of treatment.7][28] Further, GBD descriptions do not include difficulties swallowing, malnutrition, and the extreme social stigma experienced by patients with CL/P in LMICs. 26Finally, disability weights for surgically treated CL/P were last estimated in 1990, by a small panel of elite international health experts and there is no consideration of multidisciplinary management. 26Second, all studies reported costs from the NGO perspective and thus the costs from the government perspective are unknown.Further, none of the studies considered opportunity costs for patients and their caregivers in receiving treatment.These context-specific costs can better inform cost-effectiveness analyses in these settings.Third, 10 of the 11 papers did not consider disability weights for untreated patients with combined cleft lip and palate.Cleft lip and palate is considered more severe than isolated cleft lip or cleft palate, and studies that omit this may further underestimate the burden of disease and cost-effectiveness of CL/P repair.Fourth, there was limited consideration of complications which may result from surgery, and finally, none of the articles considered multidisciplinary management.
Due to these concerns, existing CL/P cost-effectiveness analyses for LMICs may have underestimated the severity of CL/P and the impact of treatment.The main strength of this study is that it synthesizes existing evidence to highlight what is needed to better represent the cost-effectiveness of CL/P care and inform subsequent resource allocation decisions

Figure 1 .
Figure 1.Preferred reporting items for systematic reviews and meta-analysis (PRISMA) flow diagram.

Table 2 .
Summary of Costs per Procedure, DALYs Averted, Cost per DALY Averted, and Cost-Effectiveness Thresholds.Both refers to both patients with isolated cleft lip and patients with isolated cleft palate.Abbreviations: GDP, gross domestic product; DALY, disability-adjusted life year, NGO, Non-Governmental Organization. *

Table 3 .
Summary of Estimated Individual and Population Economic Benefit Using the Value of a Statistical Life Approach and Human Capital Approach.Individual economic benefit of cleft lip and cleft palate repair (2020 USD with 3% discounting)