Cost‐effectiveness of uterine tamponade devices for the treatment of postpartum hemorrhage: A systematic review

Abstract Background Uterine tamponade is widely promoted for treating refractory postpartum hemorrhage (PPH); however, its cost‐effectiveness may vary depending on unit costs and setting. Objective To review available data on cost‐effectiveness of uterine tamponade devices when used for PPH treatment. Search strategy PubMed and EMBASE were searched (1980 to January 2020), as well as the National Health Services Economic Evaluation database from inception (1995) to March 2015. Selection criteria Eligible studies were any type of economic evaluation, or effectiveness studies that provided cost or economic data. Data collection and analysis Two reviewers independently screened studies, extracted data, and assessed quality. Main results Eleven studies using a range of devices (condom catheter, uterine suction devices, Bakri, Inpress, Ellavi) were identified. Cost of condom catheter devices or kits ranged from US$0.64 to US$6, whereas purpose‐designed device costs were up to US$400. Two studies that took a health system perspective assessed the cost‐effectiveness of using uterine balloon tamponade and suggested that it was highly cost‐effective because of the low cost per disability‐adjusted life‐year averted, although both used effect estimates from case series. Conclusions Evidence on the cost‐effectiveness of uterine tamponade devices was limited and not generalizable. Rigorous economic evaluations based on updated effect estimates are needed.


| INTRODUCTION
Obstetric hemorrhage is the leading cause of maternal mortality, contributing to 27.1% (uncertainty interval 19.9%-36.2%) of maternal deaths worldwide. 1 The majority of these are postpartum hemorrhage (PPH), generally defined as blood loss of 500 mL or more within 24 hours after birth-a condition affecting an estimated 5% of all women who give birth. 2,3 Most maternal deaths due to PPH could be avoided by routine use of an effective uterotonic for PPH prophylaxis, as well as prompt and effective PPH management. 4 Interventions recommended by WHO to manage PPH include fluid replacement, treatment with uterotonics and tranexamic acid, and use of non-surgical (bimanual compression, uterine balloon tamponade [UBT], non-pneumatic anti-shock garment, external aortic compression) and surgical (compressive sutures, arterial ligation, or hysterectomy) interventions. 5,6 If bleeding persists despite treatment with uterotonic drugs, tranexamic acid, and non-surgical interventions, surgical intervention should be used without delay. 4 WHO's 2012 guidelines on PPH prevention and management recommended that if a woman with PPH due to uterine atony does not respond to treatment using uterotonics (i.e., refractory PPH), or if uterotonics are unavailable, then UBT should be used (weak recommendation, very-low-quality evidence). 5 In this situation, trained, skilled health personnel insert a balloon catheter inside the uterus that (when filled) applies hydrostatic pressure to reduce blood flow and facilitate clotting. In 2019, the WHO recommendation on UBT was prioritized for updating, in light of new evidence regarding the balance of risks and benefits of this intervention. 7,8 When guideline panels consider whether to recommend for or against the use of an intervention, consideration is given to a number of factors, including efficacy and safety, how feasible and acceptable the option is, whether it is cost-effective, and the resources required to provide it. 9 Cost-effectiveness may vary depending on the setting, device type and cost. Even where the cost of using UBT is high, its use may be reasonable if it can lead to equally large health gains.
Costs may also be offset by savings associated with a reduction in adverse outcomes.
To our knowledge, and at the date of submitting this manuscript, no previous systematic review has been conducted to identify and assess all available evidence related to the costs and cost-effectiveness of uterine tamponade. This review aimed to determine the incremental resource inputs and cost-effectiveness of using uterine tamponade as part of standard PPH care (versus comparators or usual measures) for the treatment of atonic PPH. By standard care, we mean the interventions recommended by WHO for PPH treatment. 5,6 However, we recognize that some studies may predate the WHO recommendation for a given intervention. The review was performed in the context of preparing the evidence base to update WHO's recommendation on UBT, 7 to summarize the available evidence related to cost-effectiveness of this intervention when used for the treatment of women with refractory PPH.

| Literature search
This systematic review was conducted according to a pre-specified protocol, in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (see PRISMA checklist in File S1). 10 As a review of publicly available literature, ethical approval was not required. We developed a search strategy (combining concepts and synonyms for the third stage of labor, uterine tamponade, PPH, and cost-effectiveness) and on January 15, 2020 searched PubMed (January 1, 1980 to date of search), EMBASE (January 1, 1980) and the National Health Services Economic Evaluation (NHS EED) database (inception in 1995 to April 2, 2015, database closure) (search strategy shown in File S2). We also screened the reference lists of any included studies for systematic reviews related to UBT effectiveness. 11 Eligible studies were economic evaluations (including full or partial economic evaluations, cost-benefit analyses, cost-effectiveness analyses, cost-utility analyses, cost analyses, cost description studies) or effectiveness studies (such as trials) that provide cost or economic data. Studies were included if they related to the use of uterine tamponade compared with standard care or other uterine tamponade devices for the treatment of women with PPH in the third stage of labor (after vaginal birth or cesarean section), in any healthcare setting. The incremental cost-effectiveness ratio was the primary outcome of interest, though we extracted all available data related to cost or cost-effectiveness. Cost data were reported as described in the paper; no standardization or cost adjustment was used.

| Data extraction
We adopted the Cochrane guidance for economic evaluations. 12 Two reviewers (JV and AW) independently assessed the eligibility of recovered citations using the Covidence platform, with disagreements resolved through discussion or consultation with a third reviewer. 13 A data extraction form was adapted from a 2019 systematic review of cost-effectiveness of uterotonics by Lawrie et al., 14 which was adapted from NHS EED guidance. 15 For each eligible study, two reviewers independently extracted data relating to study design (aim, design, setting, year, sources of costs and effectiveness data, analytical perspective, time horizon) and relevant outcomes (costs of treatment options considered, main findings). Quality of cost-effectiveness studies was assessed with the Consensus Health Economic Criteria (CHEC) checklist, with disagreements resolved through discussion or consultation with other reviewers (see File S3). 16 All extracted data and quality assessments were reviewed by a health economist (NS).

| Data synthesis
A conceptual framework was developed to clearly identify the role and possible cost consequences of using uterine tamponade in the management of atonic PPH (Fig. 1), informed by current WHO guidance on PPH prevention and management. 4 Extracted data were summarized using tables, and brief narrative summaries of principal results and differences between studies were constructed. The currency and price year applicable to measures of costs in each study are reported alongside measures of costs, incremental costs and incremental costeffectiveness. We originally planned to consider subgroups by mode of birth, high versus low-and middle-income countries and different uterine tamponade devices; however, these were not performed because of limited data.

| Characteristics of included studies
In total, 573 unique records were identified and screened, of which 550 were excluded at title and abstract screening (Fig. 2). Of the 23 full texts reviewed, 13 did not report on relevant economic outcomes and three did not relate to UBT use. A healthcare technology brief on UBT was potentially eligible 17 ; however, we were unable to obtain the full text of this report. Six studies were identified as eligible; on review of references a further five eligible studies were identified (11 studies in total) ( Table 1). [18][19][20][21][22][23][24][25][26][27][28] All studies provided some type of cost information on various tamponade devices. Four studies were case series, 18,21,26,28 three were randomized trials, 19,24,25 one was a nonrandomized interventional study, 23 one was a modelling study, 20 and two were cost-effectiveness analyses. 22 This study took a health system perspective; however, it included costs borne by patients and also took a societal perspective for the cost-benefit analysis (DALYs averted were converted to dollars based on GDP per capita). It used an Excel-based model (the details of which were not available) to estimate the cost-effectiveness of these interventions, and univariate deterministic sensitivity analyses were performed for different protection rates, coverage rates, and prices of drugs and products, with point estimates and ranges for parameters derived from international sources and consultation with country experts in four countries. The "protection rate" of UBT and catheter preconnected, sterilized, and packed" "No market price was available for the balloon tamponade. The estimated price ($6.00) is the sum of the price of a condom, catheter, 500 ml saline, and other materials. The price also accounts for the cost of prepackaging and sterilization."

Theron 2018 28
Prospective case series

South Africa
Provides cost of a device "The free-flow pressure controlled uterine balloon (Ellavi UBT; Sinapi biomedical)" "The device is affordable for use in lesser resourced countries with a sales price from the factory of approximately US$6." against death was assumed to be 75%, referencing two case series studies conducted in Bangladesh and the UK. 31,32 In the study in Bangladesh, a condom catheter was used in 23 women with hemorrhagic shock due to PPH following atonic uterus or placenta accreta, all of whom ceased bleeding within 15 minutes. 31 In the UK study, 27 women with uncontrolled PPH were managed by UBT using a Sengstaken-Blakemore esophageal catheter, and bleeding ceased in 22 (81%) of the women. 32 An estimated price of US$6 was used

| DISCUSSION
Limited evidence is available regarding the cost-effectiveness of UBT for the treatment of PPH, and no cost-effectiveness evidence was found for other tamponade devices, such as suction tamponade.
Some tamponade options cost between US$0.64 to US$6, including two purpose-designed devices (ESM-UBT and Ellavi), though other purpose-designed devices cost more (US$125 to nearly US$400).
The two cost-effectiveness analyses indicated that UBT using condom catheter is highly cost-effective from a health system perspec-  34 The trial authors reported that UBT introduction was associated with a significant increase in the composite outcome of PPH-related invasive procedures and/or maternal death. It is perhaps unsurprising that cost-effectiveness analyses based on optimistic estimates of benefits and harms would produce favorable results. Further research is evidently required, particularly the need for robust cost-effective analyses that are based on effect estimates derived from randomized trials of uterine tamponade interventions, for both improvised and purpose-designed devices. These analyses will need to consider the considerable differences in contexts and costs associated with introducing and/or scaling up uterine tamponade programs. Such findings would provide critical additional information to guide clinicians, policymakers, and other stakeholders.

| CONCLUSION
There is insufficient evidence to reliably determine the cost-effectiveness of uterine tamponade for the treatment of PPH. It is, however, likely that the cost-effectiveness of this intervention would differ in different settings and with different tamponade devices. In light of the widespread use of this intervention for refractory PPH, more rigorous economic evaluations based on reliable effect estimates are needed.

AUTHOR CONTRIBUTIONS
The concept for this article was conceived by JPV and OTO. The protocol was drafted by JPV, with input from ANW, NS, and OTO.
Literature screening, data extraction, and quality assessment were performed by JPV, ANW, and NS. All authors contributed to the analysis, interpretation, and write up. This article represents the views of the named authors only, and not the views of their institutions.