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PLOS One logoLink to PLOS One
. 2023 Jun 29;18(6):e0287812. doi: 10.1371/journal.pone.0287812

Cost-effectiveness of mechanical thromboprophylaxis for cesarean deliveries in Brazil

Alex Veloz 1,*,#, Ubong Silas 2,#, Rhodri Saunders 2,#, Jody Grisamore 3,, André Luiz Malavasi 4,
Editor: Antonio Simone Laganà5
PMCID: PMC10309987  PMID: 37384744

Abstract

Objective

To evaluate the cost-effectiveness of using mechanical thromboprophylaxis for patients undergoing a cesarean delivery in Brazil.

Methods

A decision-analytic model built in TreeAge software was used to compare the cost and effectiveness of intermittent pneumatic compression to prophylaxis with low-molecular-weight heparin or no prophylaxis from the perspective of the hospital. Related adverse events were venous thromboembolism, minor bleeding, and major bleeding. Model data were sourced from peer-reviewed studies through a structured literature search. A willingness-to-pay threshold of R$15,000 per avoided adverse event was adopted. Scenario, one-way, and probabilistic sensitivity analyses were performed to evaluate the impact of uncertainties on the results.

Results

The costs of care related to venous thromboembolism prophylaxis and associated adverse events ranged from R$914 for no prophylaxis to R$1,301 for low-molecular-weight heparin. With an incremental cost-effectiveness ratio of R$7,843 per adverse event avoided. Intermittent pneumatic compression was cost-effective compared to no prophylaxis. With lower costs and improved effectiveness, intermittent pneumatic compression dominated low-molecular-weight heparin. The probabilistic sensitivity analyses showed that the probability of being cost-effective was comparable for intermittent pneumatic compression and no prophylaxis, with low-molecular-weight heparin unlikely to be considered cost-effective (0.07).

Conclusions

Intermittent pneumatic compression could be a cost-effective option and is likely to be more appropriate than low-molecular-weight heparin when used for venous thromboembolism prophylaxis for cesarean delivery in Brazil. Use of thromboprophylaxis should be a risk-stratified, individualized approach.

Introduction

Venous thromboembolism (VTE) is a disease condition that presents as a deep vein thrombosis (DVT) or in more severe cases, a pulmonary embolism (PE). It involves the development of blood clots (thrombi) inside the deep veins of the legs (DVT), and the potential movement of the thrombi to the pulmonary artery or its branches (PE) [1]. Bleeding-thromboembolism duality dilemma is a current challenge of obstetrics. Not long ago, the greatest concern of health care professionals was accidental hemorrhage during child birth, but today, this fear is compounded by VTE [2]. Pregnant individuals are at higher risk of experiencing a VTE event compared to non-pregnant populations, this is due to hypercoagulability, venous stasis, and endothelial injury [1, 3]. Consequently, embolism, according to research by the World Health Organization (WHO), is one of the main causes of global maternal death [2]. Covid-19 has been identified to have a potentially concerning thrombotic effect on pregnancy [4]. An increase in D-dimer, a protein associated with VTE, and a higher incidence of maternal vascular thrombosis have been reported in Covid-19 infected pregnant individuals compared to the non-infected group [5, 6]. Given this possible association, the International Society of Thrombosis and Hemostasis (ISTH) and Ministry of Health in Brazil recommends all pregnant individual receive a pharmacological thromboprophylaxis [7]. Additionally, birth through cesarean section has been identified as one of the leading risk factors for postpartum VTE events [1, 7]. Brazil is known to have the second highest cesarean section rates in the world after Dominican republic [8], with recent estimates that cesarean delivery accounted for 55.8% of all deliveries in the country between 2014 and 2017 [9].

To minimize the risk of VTE during cesarean delivery, it is the recommendation of several clinical guidelines that pregnant patients should receive thromboprophylaxis according to their VTE risk status [1013]. More specifically, the Brazilian Federation of Gynecology and Obstetrics Associations (Federação Brasileira das Associações de Ginecologia e Obstetrícia, FEBRASGO) recommends the use of anticoagulants (LMWH) as the drug of choice for the prevention of VTE in pregnancy [13]. But all anticoagulants have inherent bleeding risks which can result in serious clinical and cost consequences. A meta-analysis showed an increased risk of postpartum hemorrhage [Relative Risk (RR) 1.52, 95% CI; 1.22–1.88] with the use of prophylactic low-molecular-weight heparin (LMWH) compared to placebo or no treatment in cesarean delivery [14]. In an Argentinian study, the average medical costs of bleeding events associated with VTE prophylaxis have been estimated to range from approximately A$27,269 [2021 Brazilian Real = R$4,028] for minor bleeding to AR$223,606 [2021 Brazilian Real = R$36,729] for major bleeding [15].

An alternative approach of preventing VTE without increasing the risk of bleeding is by using mechanical means to improve venous blood flow velocity in the lower limbs. Intermittent pneumatic compression (IPC) is an example of a mechanical thromboprophylaxis. The American College of Obstetricians and Gynecologists (ACOG) recommends the use of pneumatic compression devices for all women undergoing cesarean delivery [10, 16]. According to a large registry study in the US, the use of IPC in all cesarean deliveries has seen a 85.95% reduction (p = 0.038) in postoperative PE death [17]. Furthermore, limb compression is also employed as a technique in reducing the risk of intraoperative hypotension during epidural anesthesia for cesarean delivery and has become the standard of care [18, 19]. According to a recent Cochrane review, leg compression during spinal anesthesia was shown to be an effective method to significantly reduce the risk of hypotension [RR 0.61, (95% CI; 0.47–0.78)] [20]. Therefore, using IPC during and after cesarean delivery might provide an added clinical advantage of reducing the risk intraoperative hypotension.

However, the absolute incidence of VTE after cesarean delivery is low. A large registry study of about 1.2 million cesarean sections reported an incidence of 0.21% [95% confidence interval (CI), 0.20–0.22%] between 2015 and 2017 in the United States [21]. Despite the low risk of VTE in cesarean delivery, the rate of VTE occurrence becomes significant when other risk factors are taken into consideration, risk factors such as history of VTE, thrombophilia, sickle cell disease, inflammatory bowel disease, cancer, obesity, preeclampsia and Covid-19 infection [7, 22]. Identification of at-risk individuals and subsequent selection of the most appropriate form of VTE prophylaxis is thus of paramount importance to providing cost-effective healthcare. Currently, there is no health economic comparison between IPC and standard of care during cesarean delivery in Brazil. Hence, there are open questions about the cost-effectiveness of the different prevention strategies in Brazilian hospitals. The primary objective of this analysis was to evaluate the cost-effectiveness of IPC compared to no prophylaxis or LMWH in patients undergoing a cesarean section.

Methods

A cost-effectiveness analysis was performed from the perspective of a Brazilian hospital using a decision-tree health economic model. The patient population considered were pregnant patients undergoing a cesarean delivery in Brazil. The modeled time horizon of the analysis was from receiving the cesarean section to discharge from hospital, reported to be two to three days in Brazil [23]. Our findings in this publication are reported according to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS 2022) checklist (see S1 Table in S1 File) [24].

Patient population

Included in this cost-effectiveness analysis was a theoretical cohort of pregnant patients requiring a cesarean delivery. The model used clinical data extracted from peer-reviewed studies as inputs; no primary clinical data was processed, and the analysis did not involve the use of human subjects. No exclusion criteria were applied in the model, though readers should familiarize themselves with the primary literature cited to understand any inclusion and exclusion bias that may be present in the literature inputs used.

Model structure

A decision-tree model was developed using TreeAge Pro® 2022 software (Healthcare version) to compare three different thromboprophylaxis strategies: mechanical prophylaxis (IPC), pharmacological prophylaxis (LMWH), and no prophylaxis (Fig 1). The events in the care pathway were assumed to be non-recursive and together with the short time horizon (three days) were the reason for adopting a decision-tree model structure [25]. Discounting of costs was deemed unnecessary due to the short time horizon.

Fig 1. Decision-tree model structure comparing three thromboprophylaxis strategies.

Fig 1

The pathways of LMWH and no prophylaxis strategies are the same as with IPC. Blue square node represents the initial decision node of each strategy; green circle nodes represent chance nodes; red triangle nodes represent terminal nodes. Abbreviations: IPC, intermittent pneumatic compression; LMWH, low-molecular-weight heparin; DVT, deep vein thrombosis, AE, adverse event, PE, pulmonary embolism.

Literature search

A structured literature search was performed on PubMed to identify relevant peer-reviewed studies for informing the model design and providing the input data. The search was initially conducted in April 2022 and further targeted searches were carried out for any identified data gaps. Data from meta-analyses and randomized controlled trials, as well as most recent publications from Central and South America were favored.

Clinical care pathway

The model simulates the clinical care pathway of a patient during and after cesarean delivery in the hospital. LMWH is the recommended thromboprophylaxis post cesarean section in Brazil and the no prophylaxis strategy was included because according to the FEBRASCO guideline on thromboprophylaxis, prophylaxis should be administered according to VTE and bleeding risk factors [13]. IPC can and is sometimes recommended to be used in the intraoperative setting (for prevention of intraoperative hypotension) as well as in the postoperative setting for VTE prophylaxis. In our model, intraoperative hypotension is not considered as a VTE or thromboprophylaxis-related adverse event, rather as an intermediate event highlighting the effect of intraoperative use of IPC.

Clinical effectiveness

A patient in the model may or may not have intraoperative hypotension during the cesarean section and may or may not have any of the postoperative adverse events (i.e., minor bleeding, major bleeding, DVT and PE). A patient with VTE, assumed to be DVT initially, has a risk of developing a subsequent PE.

The primary efficacy outcome in this analysis was the combined incidence of all cesarean sections not impacted by any VTE-related adverse event. Whereby, the value one means that all VTE-related adverse events were avoided, and the value zero means that every cesarean section was impacted by at least one adverse event. The expected effectiveness of each strategy was determined by calculating the respective probabilities and summing them across all the pathways. The probabilities of the adverse events (DVT, PE, minor bleeding, and major bleeding) were extracted from a previously published cost-effectiveness analysis comparing thromboprophylaxis with IPC versus no prophylaxis (see Table 1) [26]. A Cochrane review of preventing adverse events during spinal anesthesia for cesarean delivery provided the probability of intraoperative hypotension [20].

Table 1. Baseline clinical and cost input parameters for the model.

Parameters by measure Value (Variance)a Data source
Incidences, % e
 DVT post cesarean delivery 0.70 (0.10–3.0) [26]
 PE due to DVT 20.0 (15–25) [26]
 Minor bleed 6.80 (3–10) [26]
 Major bleed 1.40 (0.60–2.0) [26]
 Mortality 0.0026 [29]
 Hypotension 66.29 [20]
Costs, R$ b
 DVT 9,524 (7,486–12,036) [15]
 PE 10,618 (7,666–13,557) [15]
 Minor bleed 4,479 [15]
 Major bleed 36,730 [15]
 Hypotension 30 (20–40) [30]
 LMWH 50 [31]
 IPC 102 Data on filef
Relative efficacy, RR
 IPC versus LMWH on DVT or PE 0.87 (0.08–9.50) [32]
LMWH versus no treatment on DVT 0.33 (0.01–7.93) [33]
 LMWH versus no treatment on minor bleeding 2.12 (1.15–3.93) [33]
 LMWH versus no treatment on major bleeding 1.48 (0.25–8.72) [33]
 Lower limb compression versus control on hypotension d 0.36 (0.22–0.56)c [34]

Notes:

a 10% variation was assumed where variance was not provided;

b All cost data were inflated to 2021 Brazilian Real (R$);

c RR was estimated from the reported odds ratio;

dRelative efficacy of IPC on hypotension was estimated from that of lower limb compression, the event rate of hypotension with IPC was then calculated at 66.29% x 0.36 (RR) = 23.86%;

e Baseline incidences with no prophylaxis,

fIPC cost data provided by Cardinal Health

Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; LMWH, low-molecular-weight heparin; RR, relative risk; IPC, intermittent pneumatic compression.

Costs

All costs were estimated from the hospital payer perspective, therefore, only direct hospital costs of thromboprophylaxis and costs of managing associated adverse events were considered. Delivery-related costs, including the cost for a cesarean delivery were not modeled as they were assumed to be equal for all comparators. Cost data were mostly extracted from published studies, and, when unavailable, experts were consulted. Costs from previous years and currencies were converted to 2021 Brazilian Real (R$) using the respective exchange rates and Brazil’s Consumer Price Index [27, 28]. A summary of the all the cost data and their sources are presented in Table 1.

Cost per patient was calculated for each strategy. The incremental cost-effectiveness ratio (ICER), defined as the additional cost per adverse event avoided, was estimated for mechanical prophylaxis compared to no prophylaxis or pharmacological prophylaxis. The ICER is calculated as:

ICER=Costofstrategy1-Costofstrategy2Effectivenessofstrategy1-Effectivenessofstrategy2

Model assumptions

To estimate the cost-effectiveness of the three strategies over the time horizon of three days, the following assumptions were made:

  • The postoperative adverse events were assumed to be mutually exclusive except for PE which evolves from a DVT event; a patient could experience only one of the four adverse events.

  • As there is no consensus on an accepted willingness-to-pay threshold for Brazil, a previously reported willingness-to-pay value of R$15,000 per avoided AEs after thromboprophylaxis was used [35].

  • The non-AE related mortality of patients within the time horizon was assumed to be zero.

  • Only maternal outcomes were considered and no impact of the prophylaxis regimen on the infant was assumed.

  • Long-term VTE-related adverse events such as chronic thromboembolic pulmonary hypertension (CTEPH) and post-thrombotic syndrome (PTS) were assumed not to present within the time horizon of this model. As such, they are unlikely to influence a hospital payers’ determination of which method of VTE prophylaxis is optimal for the hospital to pursue.

Sensitivity analysis

One-way sensitivity, probabilistic sensitivity, and scenario analyses were performed to explore the uncertainty around model outcomes. The aim of the one-way sensitivity analysis was to identify the model inputs that have the greatest impact on the model outputs; results are presented as a tornado diagram. The impact of the risk of VTE on per patient cost of each strategy was also explored. For the probabilistic sensitivity analyses, a distribution was assigned to each parameter based on the mean and their corresponding variance: lognormal distribution for relative risks, gamma distribution for cost data and beta distribution for transition probabilities. In our analysis, the distributions of each parameter were randomly sampled over 1,000 Monte Carlo simulations to determine the overall proportion at which each thromboprophylaxis is cost-effective at a willingness-to-pay (WTP) value. A WTP threshold of approximately R$15,000 per avoided AEs was considered.

The scenario analysis considered the cost per patient in hypothetical situations where IPC is used only during or only after cesarean delivery.

Results

The cost per patient was estimated at R$914 with no prophylaxis. For the base case, the use of IPC and LMWH increased the cost to R$ 950 and R$1,301, respectively. For the effectiveness, the results of no prophylaxis and IPC prophylaxis were comparable (Table 2), with 91.2% and 91.6% of patients avoiding any adverse event. The effectiveness of LMWH was lower, with only 86.1% avoiding any adverse event. Given the lower cost and increased effectiveness associated with no prophylaxis and IPC prophylaxis, the use of these two strategies dominated the use of LMWH. The ICER for IPC prophylaxis versus “no prophylaxis” was calculated as R$7,843 per AEs avoided (Table 2), substantially below the WTP threshold (R$15,000 per avoided AEs).

Table 2. Model results.

Cost, R$ Incremental Cost, R$ Effectiveness Incremental Effectiveness ICER, R$
No prophylaxis 914 0.912
IPC 950 36 0.916 0.005 7,843
LMWH 1,301 351 0.861 -0.055 Dominated

Abbreviations: R$, Brazilian Real; IPC, intermittent pneumatic compression; LMWH, low-molecular-weight heparin; ICER, incremental cost-effectiveness ratio

According to the results of the one-way sensitivity analysis (see S1 and S2 Figs in S1 File), the cost-effectiveness result of IPC versus no prophylaxis was heavily influenced by the probability for DVT (estimate 0.03–0.001). On the other hand, the key drivers of the cost difference between IPC and no prophylaxis were the relative risks of LMWH on minor and major bleeding, the relative risk of IPC on DVT, and the probabilities of minor bleeding and major bleeding. This means that the cost-effectiveness of IPC versus LMWH was heavily influenced by bleeding events.

Considering only the incidence of VTE, a plot of its uncertainty estimates showed that the use of IPC is the more cost-saving strategy in comparison to no prophylaxis when the incidence of VTE is higher than 1.20% (Fig 2).

Fig 2. Illustrating the cost per patient of the three strategies with increasing incidence of VTE.

Fig 2

Abbreviations: R$, Brazilian Real; IPC, intermittent pneumatic compression; LMWH, low-molecular-weight heparin.

The results of the PSA were represented using a cost-effectiveness plane of 1,000 Monte Carlo simulations and a cost-effectiveness acceptability curve. Compared to no prophylaxis, IPC was superior in only 17.6% of the simulated cases and in 86.3% of cases compared to LMWH, which means that IPC has a higher likelihood of being cost effective in comparison to LMWH. The scatterplots in Fig 3 show the relationship between costs and effectiveness for all simulated strategy. At a WTP threshold of R$15,000 per VTE event avoided, the probability of being cost-effective was 0.49 for “no prophylaxis” 0.44 for IPC, and 0.07 for LMWH (Fig 4).

Fig 3. Cost-effectiveness plane showing the scattered plots of 1000 Monte Carlo simulated cost-effectiveness of IPC versus LMWH (A) and IPC versus No prophylaxis (B).

Fig 3

Each point in the graph represents a single simulated model calculation by plotting the incremental cost (x-axis) and incremental effectiveness (y-axis). The WTP line splits the graph into points that favor the comparator strategy—LMWH/no prophylaxis (below/right of line) and those that favor the baseline strategy—IPC (above/left of line). The green ellipsis shows the 95% confidence interval. Abbreviations: IPC, intermittent pneumatic compression; WTP, willingness-to-pay; LMWH, low-molecular-weight heparin.

Fig 4.

Fig 4

Cost-effectiveness acceptability curve showing the likelihood of cost-effectiveness of the three strategies: Abbreviations: R$, Brazilian Real; IPC, intermittent pneumatic compression; LMWH, low-molecular-weight heparin; WTP, willingness-to-pay.

The impact of using IPC intraoperatively and postoperatively is clear from the scenario analyses (see Table 3). That is, if used only during and only after cesarean delivery, IPC is likely to have a R$54 and R$13 higher cost per patient than the baseline cost respectively where the use of IPC is modeled until discharge from the hospital. The effectiveness was also shown to be comparable among the different scenarios.

Table 3. Results of scenario analyses.

Scenario comparison Cost, R$ Effectiveness
IPC—intra + post op 950 0.916
IPC—post op 963 0.916
IPC—intra op 1,004 0.912

Discussion

A current problem in obstetric practice is VTE, especially given the reductions in hemorrhagic complications and infections during pregnancy and puerperium observed in more developed settings. Mechanical and pharmaceutical preventative measures have been used to reduce the incidence of VTE and its immediate and long-term effects [36].

This cost-effectiveness study analyzed the cost-effectiveness of using a mechanical thromboprophylaxis compared to no prophylaxis or LMWH during cesarean delivery from a hospital perspective in Brazil. The result of our analysis showed that the cost of the prophylaxis strategies ranged from R$914- R$1,301 per patient. Our analysis also showed that IPC could be a cost-effective option compared to no prophylaxis as the calculated ICER of R$7,843 was lower than the estimated willingness-to-pay threshold of R$15,000 per avoided AEs. Furthermore, the PSA result showed that at the WTP threshold, probability of cost-effectiveness of no prophylaxis and IPC were comparable. Compared to LMWH however, the difference was substantial. With an ICER of -R$6,389, our model showed that the use of IPC during cesarean delivery avoided complications at a lower cost of hospital care. This may be due to the inherent risk of bleeding caused by administering LMWH, an adverse event which significantly increases the overall cost of complications. Although recommended by the Brazilian Federation of Gynecology and Obstetrics Associations (FEBRASCO) as the thromboprophylaxis of choice, LMWH may not be the most cost-effective option available for the prevention of VTE during cesarean delivery as shown by the results of our analysis [13].

Currently, there is insufficient evidence supporting the cost-effectiveness of mechanical thromboprophylaxis in obstetrics and gynecology. In orthopedics, however, the use of IPC alone or in combination with an anticoagulant have been reported as cost-effective strategies in the United States and Australia [37, 38]. The cost-effectiveness of mechanical thromboprophylaxis in gynecology was estimated by Casele and colleagues in 2006 [26]. In this study, a decision-tree with a Markov model was used to compare the cost and the quality adjusted life years (QALYs) of IPC versus no prophylaxis at the time of cesarean delivery from a healthcare system perspective [26]. Unlike in our study, the cost and consequences of long-term AEs such as post thrombotic syndrome and cardiovascular accident were also modeled alongside the VTE and bleeding events [26]. The ICER of routine use of a mechanical thromboprophylaxis during cesarean delivery was estimated at $39,545 per QALY [26]. Again, the results of this study are not fully comparable to our results because of the differences in the model setup and the included adverse events. Despite these differences, the results of both analyses support the cost-effectiveness of IPC use for cesarean delivery.

Generally, the risk of VTE is known to be increased after delivery, a risk further compounded when the delivery is via a cesarean section [7]. In Brazil, where there is a high proportion of cesarean deliveries, efforts are made to keep the risk of VTE at their lowest. For example, a VTE risk assessment model was introduced to designate the necessity and duration of thromboprophylaxis use. This has resulted in lower PE-related maternal death and an establishment of a risk stratification score [7]. However, the risk stratification and recommendations of the appropriate thromboprophylaxis are ongoing debates even among the different international guidelines [16]. Patients with a high risk of bleeding should avoid the use of anticoagulants such as LMWH, while patients with high risk of VTE without a high bleeding risk should be provided with the most cost-effective prophylaxis regimen. The results of our sensitivity analysis support the hypothesis that IPC would be a cost-effective option for cesarean delivery patients with high risk of VTE in Brazil, however, a risk-stratified individualized approach is recommended owing to the low absolute risk of VTE complications in obstetrics. The increasing rate of cesarean deliveries has not been justified by reduction in relevant clinical outcomes, and as indicated by Venturella et al. 2018, this trend may rather be linked to improper clinical practices and healthcare deficiencies [39]. Therefore, avoiding unnecessary cesarean deliveries could also reduce healthcare costs related to VTE in obstetrics practice in Brazil. A well-designed study comparing the clinical effectiveness of mechanical and pharmacological thromboprophylaxis could establish relative efficacy in this patient population and bring added validity to this model.

Our cost-effectiveness analysis has several limitations. As with any economic analysis, the results of the model are dependent upon the variables that are used. The relative efficacy of the two interventions, values that could materially alter the results, were derived from non-obstetric literature. The generalizability of its efficacy to an obstetric population is not well known. There is no direct comparison for mechanical and pharmacological VTE prophylaxis available for obstetrics and gynecology in Brazil. Relative efficacy comparing the two strategies was sourced from a study involving abdominoplasty surgical patients. Other data was sourced from international randomized control trials, which do not necessarily represent the Brazilian healthcare system. It is assumed that the efficacy and safety reported in those trials is comparable for all populations. Similarly, local cost data was not available for all inputs. The application of our study’s results will depend on local clinical practices, such as whether VTE prophylaxis is routinely employed or if the standard of care involves no prophylaxis. Although our analysis involved the use of a theoretical cohort of patients and not human subject, our findings will support healthcare providers in determining the most cost-effective approaches for VTE prophylaxis when the intervention is deemed necessary.

Conclusion

From the perspective of the hospital payer, the results of our analysis showed that the use of mechanical thromboprophylaxis could be a cost-effective alternative for preventing VTE-related complications in patients undergoing cesarean delivery in Brazil. For patients requiring thromboprophylaxis, providers should consider intra- and postoperative use of IPC.

Supporting information

S1 File

(DOCX)

Acknowledgments

We thank everyone that contributed to the research and the creation of this manuscript.

Data Availability

All relevant data are within the paper and its Supporting information files.

Funding Statement

This work was funded by Cardinal Health https://www.cardinalhealth.com/en.html The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Antonio Simone Laganà

25 Apr 2023

PONE-D-23-07556Cost-effectiveness of mechanical thromboprophylaxis for cesarean deliveries in BrazilPLOS ONE

Dear Dr. Veloz,

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Additional Editor Comments (if provided):

The topic of the manuscript is interesting. Nevertheless, the reviewers raised several concerns: considering this point, I invite authors to perform the required major revisions.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: N/A

Reviewer #3: Yes

Reviewer #4: No

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

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Reviewer #1: This is a paper that aim to demonstrate the cost-effectiveness of using a mechanical

thromboprophylaxis compared to no prophylaxis or LMWH during cesarean delivery in Brazil

the topic is relevant in the field, actual according to the everyday increasing rate of CS worldwide, Brazil moreover, as authors state is among the countries with the highest rate of CS,

the topic is original, due to a lack of evaluation in the available literature of cost effectiveness of such procedure in obstetrics and gynecology

I would like to suggest authors within the discussion to mention, at least briefly even just a sentence regarding the need to avoid unnecessary cesarean section, as this will be the most coast effective strategy to reduce thrombo embolism after birth, many of the CS we perform world wide have not even an obstetric indication(with this purpose I would suggest to cite PMID: 29560505, doi: 10.36129/jog.2022.20

references are appropriate

I would suggest also to ameliorate the images definitions and resolution

best regards

Reviewer #2: I read with great interest the Manuscript titled "Cost-effectiveness of mechanical thromboprophylaxis for cesarean deliveries in Brazil", which falls within the aim of this Journal.

In my honest opinion, the topic is interesting enough to attract the readers’ attention. Methodology is accurate and conclusions are supported by the data analysis. Nevertheless, authors should clarify some point and improve the discussion citing relevant and novel key articles about the topic.

Authors should consider the following recommendations:

- Inclusion/exclusion criteria should be better clarified.

- The Authors did not mention the sample size calculation for their study. It is essential to specify this data in order to guarantee an adequate significance of the results obtained by the Authors.

-The authors have not adequately highlighted the strengths and limitations of their study. I suggest clarifying these points.

- Was this study registered? I could not find any information about this point.

- I could not find any information regarding the approval of the Institutional Review Board. Did author this approval before the study start?

- I could not find any information regarding the informed consent of enrolled patients. Did author obtain informed consent for each patient? Conversely, this point may raise serious concern from the ethical point of view.

- I recommend to highlight, at least briefly, the higher thrombotic risk in case of pregnant women with covid-19 infection (authors may refer to: PMID: 32975205; PMID: 36143264)

Reviewer #3: Thank you for the opportunity to review this paper. The paper is well-structured and easy to understand, with a primary focus on evaluating the cost-effectiveness of using mechanical thromboprophylaxis for patients undergoing cesarean delivery in Brazil. However, I have one major issue and several minor suggestions of the manuscript.

Major issue:

1. In decision tree models, it is recommended to avoid multiple outcomes being presented side by side. For example, outcomes should be presented as DVT/no DVT, with 'no DVT' then being further divided into 'major bleeding/minor bleeding'.

Minor suggestions:

2. References should be provided lines 74-77 recommendations for Brazilian Federation of Gynecology and Obstetrics Associations

3. Please ensure consistency in the phrasing used in lines 79 and 96 for RR and 95% CI.

4. The introduction in the last paragraph discusses how the absolute risk of VTE is low, but becomes significant when considering risk factors. However, the authors did not mention what these risk factors are, nor did they provide data to indicate how important they are.

5. Lines 303-315 should be simplified or incorporated into the introduction.

6. Please remove the sentence 'Due to the low absolute risk of VTE complications in obstetrics, thromboprophylaxis should be considered through a risk-stratified individualized approach' as it is not a conclusion drawn by the authors based on their research.

7. Figure 3A and 3B are not clear. I would suggest the authors to merge Figure 3A and 3B using different color or shape.

8. Although the authors claim that the results of their one-way sensitivity analysis are presented in the supplementary material, I was unable to locate them.

9. The authors are missing the following relative efficacy values in Table 1: 'IPC versus LMWH on minor bleeding/major bleeding' and 'LMWH versus no treatment on DVT/PE'.

Reviewer #4: In this cost-effectiveness analysis, the authors compare no prophylaxis to LMWH to IPC use alone in the post-partum c section population in Brazil. In their results, they report that IPC use alone is the most cost-effective strategy, contrary to current societal recommendations for the use of LMWH. I have several significant concerns about the design of the model that need to be addressed prior to publication.

Major

*The composite outcome of any adverse event creates a false equivalence between the impact of post-partum hemorrhage, DVT, and PE. These events have different short and long-term implications for patients, and so I find the use of it problematic as the long-term consequences of DVT and PE, such as PTS and CTEPH, are not accounted for and major and minor bleeding are weighted equally in spite of having very different implications. In the discussion the authors note that a similar study in gynecologic patients (ref 23) did include long-term sequelae such as PTS and CTEPH and also was done from a systems perspective rather than hospital. These differences that they cite make that study stronger and should be considered for inclusion in this model to strengthen the conclusions.

*Please provide sources for the costs of LMWH and IPC. "Expert opinion" is not an acceptable source for a cost (doi 10.1097/XCS.0000000000000534).

*Please state an explicit time horizon, rather than "a few" days.

*Is hypotension considered an adverse event? Please be more explicit about how hypotension is considered.

Minor

*The second sentence of the introduction is redundant and should already be known by the readership, and thus should be deleted (lines 58-60, page 3).

*Please edit for grammar and punctuation.

*Line 176, page 6: please correct spelling in ICER formula.

*Why is hypotension a branch point in the decision tree? There are no different event probabilities cited based on the presence of hypotension. Please clarify.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: Yes: Kristina Nicholson

**********

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PLoS One. 2023 Jun 29;18(6):e0287812. doi: 10.1371/journal.pone.0287812.r002

Author response to Decision Letter 0


1 Jun 2023

Reviewer #1:

1. This is a paper that aim to demonstrate the cost-effectiveness of using a mechanical thromboprophylaxis compared to no prophylaxis or LMWH during cesarean delivery in Brazil the topic is relevant in the field, actual according to the everyday increasing rate of CS worldwide, Brazil moreover, as authors state is among the countries with the highest rate of CS, the topic is original, due to a lack of evaluation in the available literature of cost effectiveness of such procedure in obstetrics and gynecology.

Response: We appreciate the Reviewer’s acknowledgment of the significance of our study's rationale. This support reinforces our confidence in the study’s objectives.

2. I would like to suggest authors within the discussion to mention, at least briefly even just a sentence regarding the need to avoid unnecessary cesarean section, as this will be the most cost effective strategy to reduce thrombo embolism after birth, many of the CS we perform worldwide have not even an obstetric indication(with this purpose I would suggest to cite PMID: 29560505, doi: 10.36129/jog.2022.20 references are appropriate

Response: Thank you for this suggestion and for providing the references. We acknowledge that avoiding unnecessary cesarean deliveries should in general reduce the risk of venous thromboembolism. To highlight this, the following text has been added to lines 306-310 in the discussion section of the manuscript:

“The increasing rate of cesarean deliveries has not been justified by a reduction in relevant clinical outcomes, and as indicated by Venturella et al. 2018, this trend may rather be linked to improper clinical practices and healthcare deficiencies.[39] Therefore, avoiding unnecessary cesarean deliveries could also reduce healthcare costs related to VTE in obstetrics practice in Brazil.”

3. I would suggest also to ameliorate the images definitions and resolution

Response: We thank the reviewer for bringing this to our attention and the quality of all the figures has been improved.

Reviewer #2:

I read with great interest the Manuscript titled "Cost-effectiveness of mechanical thromboprophylaxis for cesarean deliveries in Brazil", which falls within the aim of this Journal. In my honest opinion, the topic is interesting enough to attract the readers’ attention. Methodology is accurate and conclusions are supported by the data analysis. Nevertheless, authors should clarify some point and improve the discussion citing relevant and novel key articles about the topic. Authors should consider the following recommendations:

1. Inclusion/exclusion criteria should be better clarified.

Response: Thank you for identifying this lack of clarity.

The following text has been added to lines 105-111 to address the patient population of interest in our analysis:

“Patient population

Included in this cost-effectiveness analysis was a theoretical cohort of pregnant patients requiring a cesarean delivery. The model used clinical data extracted from peer-reviewed studies as inputs; no primary clinical data was processed, and the analysis did not involve the use of human subjects. No exclusion criteria were applied in the model, though readers should familiarize themselves with the primary literature cited to understand any inclusion and exclusion bias that may be present in the literature inputs used.”

2. The Authors did not mention the sample size calculation for their study. It is essential to specify this data in order to guarantee an adequate significance of the results obtained by the Authors.

Response: While we appreciate the reviewer’s feedback, we wish to point out that the analysis carried out in our paper uses a health economic modeling approach, hence does not require a sample size calculation to guarantee an adequate significance of the results. This has been clarified in the original manuscript in line, but maybe we have not made this sufficiently clear. Therefore, we have now stressed this item earlier in lines 99-100:

“A cost-effectiveness analysis was performed from the perspective of a Brazilian hospital using a decision-tree health economic model”

3. The authors have not adequately highlighted the strengths and limitations of their study. I suggest clarifying these points.

Response: Thank you, we hope to have adequately addressed the strengths and limitations of the study in the appropriate manner now (see lines 313 -330)

4. Was this study registered? I could not find any information about this point.

Response: Thank you for highlighting this important point. Our study was not registered. To the best of our knowledge and according to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) best practice guidance, the registration of a health economic study is not mandatory.

5. I could not find any information regarding the approval of the Institutional Review Board. Did author this approval before the study start?

Response: The analysis in our study used a health-economic model with data from already published peer-reviewed studies. Therefore, our research did not involve the use of human subjects and did not warrant the approval of an Institutional Review Board.

6. I could not find any information regarding the informed consent of enrolled patients. Did author obtain informed consent for each patient? Conversely, this point may raise serious concern from the ethical point of view.

Response: Our research did not involve the use of human subjects, therefore did not involve the enrollment of patients and the signing of consent forms.

7. I recommend to highlight, at least briefly, the higher thrombotic risk in case of pregnant women with covid-19 infection (authors may refer to: PMID: 32975205; PMID: 36143264)

Response: We think this is an excellent suggestion and thank you for the references. We have added the following text to highlight the associated risk of VTE in pregnant women with Covid-19 infection and some recommendations (see lines 52-57):

“Covid-19 has been identified to have a potentially concerning thrombotic effect on pregnancy.[4] An increase in D-dimer, a protein associated with VTE, and a higher incidence of maternal vascular thrombosis have been reported in Covid-19 infected pregnant individuals compared to the non-infected group.[5, 6] Given this possible association, the International Society of Thrombosis and Hemostasis (ISTH) and Ministry of Health in Brazil recommends all pregnant individual receive a pharmacological thromboprophylaxis.[7]”

Reviewer #3:

Major issue:

1. In decision tree models, it is recommended to avoid multiple outcomes being presented side by side. For example, outcomes should be presented as DVT/no DVT, with 'no DVT' then being further divided into 'major bleeding/minor bleeding'.

Response: Many thanks for bringing this to our attention. The model design has been adjusted accordingly. See Figure 1. Please note that due to the change in the model design, there has been a slight change to the model results and results of the sensitivity analysis. However, the conclusion and the key message remain the same.

Minor suggestions:

2. References should be provided lines 74-77 recommendations for Brazilian Federation of Gynecology and Obstetrics Associations

Response: We apologize for this omission, the reference for the recommendation by the “Brazilian Federation of Gynecology and Obstetrics Associations” has now been included.

3. Please ensure consistency in the phrasing used in lines 79 and 96 for RR and 95% CI.

Response: Thank you for pointing out this inconsistency. This has now been amended. (See line 83)

4. The introduction in the last paragraph discusses how the absolute risk of VTE is low, but becomes significant when considering risk factors. However, the authors did not mention what these risk factors are, nor did they provide data to indicate how important they are.

Response: Thank you for pointing this out. The reviewer is right, outlining the risk factors in question gives a more balanced argument and well-informed hypotheses. Therefore, we have amended the texts in lines 88-91 and included the relevant references. It now reads:

“Despite the low risk of VTE in cesarean delivery, the rate of VTE occurrence becomes significant when other risk factors are taken into consideration, risk factors such as history of VTE, thrombophilia, sickle cell disease, inflammatory bowel disease, cancer, obesity, preeclampsia, and Covid-19 infection.[7, 22]”

5. Lines 303-315 should be simplified or incorporated into the introduction.

Response: Thank you for the recommendation. We made the decision to streamline the texts. The revised version now reads as follows (lines 286-299):

“Generally, the risk of VTE is known to be increased after delivery, a risk further compounded when the delivery is via a cesarean section.[7] In Brazil, where there is a high proportion of cesarean deliveries, efforts are made to keep the risk of VTE at their lowest. For example, a VTE risk assessment model was introduced to designate the necessity and duration of thromboprophylaxis use. This has resulted in lower PE-related maternal death and an establishment of a risk stratification score.[7] However, the risk stratification and recommendations of the appropriate thromboprophylaxis are ongoing debates even among the different international guidelines.[16]”

6. Please remove the sentence 'Due to the low absolute risk of VTE complications in obstetrics, thromboprophylaxis should be considered through a risk-stratified individualized approach' as it is not a conclusion drawn by the authors based on their research.

Response: We agree with Reviewer, the sentence was not drawn from our analysis, it was rather as a recommendation. Sentence has been removed from conclusion.

7. Figure 3A and 3B are not clear. I would suggest the authors to merge Figure 3A and 3B using different color or shape.

Response: We have enhanced the qualities of Figure 3A and 3B and have merged both to into one figure as suggested. Thank you!

8. Although the authors claim that the results of their one-way sensitivity analysis are presented in the supplementary material, I was unable to locate them.

Response: Thank you for the observation. The results of the one-way sensitivity analysis are presented as Tornado diagram in the supplementary material, but maybe we have not made this sufficiently clear. We have now changed the Figure Legends from “Tornado diagram analysis of…” to “One-way sensitivity analysis of…” to address this.

9. The authors are missing the following relative efficacy values in Table 1: 'IPC versus LMWH on minor bleeding/major bleeding' and 'LMWH versus no treatment on DVT/PE'.

Response: Thank you for pointing this out. It was an oversight on our part. The data and reference for relative efficacy of “LMWH versus no treatment on DVT” has now been added to Table 1. Unfortunately, there is no published data on the relative efficacy of IPC versus LMWH on minor/major bleeding in obstetrics and gynecology, therefore, a relative risk of 1 was assumed, that is no difference between IPC and no prophylaxis on minor/bleeding. However, the range of 0.9 -1.1 was tested in the sensitivity analysis of the results.

Reviewer #4:

In this cost-effectiveness analysis, the authors compare no prophylaxis to LMWH to IPC use alone in the post-partum c section population in Brazil. In their results, they report that IPC use alone is the most cost-effective strategy, contrary to current societal recommendations for the use of LMWH. I have several significant concerns about the design of the model that need to be addressed prior to publication.

Major

1. The composite outcome of any adverse event creates a false equivalence between the impact of post-partum hemorrhage, DVT, and PE. These events have different short and long-term implications for patients, and so I find the use of it problematic as the long-term consequences of DVT and PE, such as PTS and CTEPH, are not accounted for and major and minor bleeding are weighted equally in spite of having very different implications. In the discussion the authors note that a similar study in gynecologic patients (ref 23) did include long-term sequelae such as PTS and CTEPH and also was done from a systems perspective rather than hospital. These differences that they cite make that study stronger and should be considered for inclusion in this model to strengthen the conclusions.

Response: Thank you for the review of the model design. While we agree with the reviewer that bleeding, DVT and PE have long term implications for the patients, we would like to focus on the fact that our analysis was carried out from a hospital perspective. Although healthcare systems often look at a societal perspective, particularly for pharmaceutical purchases, this is not always the case for medical devices. Devices generally have no additional reimbursement, and their costs are accounted for in DRG payments for the procedure that the patient undergoes, in this case C-section. This means that the hospital must determine whether the purchase of IPC devices and their use in C-section makes economic and clinical sense in a time frame that is usually up to three days. If IPC is already used intraoperatively, then the question is whether maintaining its use to three days makes sense. As such, the model only accounts for the related costs and outcomes within this time frame. Long term adverse events such as chronic thromboembolic pulmonary hypertension (CTEPH) and post-thrombotic syndrome (PTS) are unlikely to be present within these three days, hence, our rationale for not including them in the model. Also, the costs of managing these long-term adverse events/complications are not covered by the hospital’s budget, therefore, outside the scope of our analysis. The perspective of the health economic evaluation is also the key difference between our analysis and the Casele et al., 2006 study. To further emphasize this, we have added the following text under model assumption (line 187-190):

“Long-term VTE-related adverse events such as chronic thromboembolic pulmonary hypertension (CTEPH) and post-thrombotic syndrome (PTS) were assumed not to present within the time horizon of this model. As such, they are unlikely to influence a hospital payers’ determination of which method of VTE prophylaxis is optimal for the hospital to pursue.”

Finally, please note that although minor and major bleed are presented side-by-side in the model diagram, they are not weighted equally. They both have different incidences and costs (see Table 1)

2. Please provide sources for the costs of LMWH and IPC. "Expert opinion" is not an acceptable source for a cost (doi 10.1097/XCS.0000000000000534).

Response: As pointed out by the reviewer, we have now provided a published reference for the cost of LMWH. The cost of IPC was provided by Cardinal Health (the manufacturer of IPC), a note explaining this point has been added to the manuscript (see line 198-199). These changes to the manuscript can be found in Table 1 “Baseline clinical and cost input parameters for the model”.

3. Please state an explicit time horizon, rather than "a few" days.

Response: The time horizon used for the model was three days. Accordingly, we have made this clear in the “Method structure” (Line 116) and “Model assumptions” (Line 176) sections of the manuscript.

4. Is hypotension considered an adverse event? Please be more explicit about how hypotension is considered.

Response: No, in our model, hypotension is not considered as an adverse event but as an intermediate event that can occur during cesarean delivery. As IPC is sometimes used intraoperatively to reduce the risk of intraoperative hypotension, the branching of hypotension allows the continued use of IPC postoperatively for VTE prophylaxis to be explored in the correct clinical context. To address this feedback, we have updated the Decision-tree model structure, changing the wording from “Delivery w/o complications” to “No VTE-related adverse event” (See Figure 1). The following the text have also been added to the methods (Line 138-140):

“In our model, intraoperative hypotension is not considered as a VTE or thromboprophylaxis-related adverse event, rather as an intermediate event highlighting the effect of intraoperative use of IPC”

Minor

5. The second sentence of the introduction is redundant and should already be known by the readership, and thus should be deleted (lines 58-60, page 3).

Response: Thank you for your suggestion. We agree that the sentence “It involves the development of blood clots (thrombi) inside the deep veins of the legs (DVT), and the potential movement of the thrombi to the pulmonary artery or its branches (PE)” may be redundant to certain readership, for example, medical professionals in the field of obstetrics and gynecology but to other readership of PLOS ONE journal, for example, health economists, this sentence may provide a bit of background context on the VTE topic. For this reason, we have decided to retain it in the manuscript.

6. Please edit for grammar and punctuation.

Response: Thank you for pointing this out. The manuscript has been reread and edited for grammar and punctuation by three native English speakers.

7. Line 176, page 6: please correct spelling in ICER formula.

Response: Thank you. The spelling error has been corrected (line 166).

8. Why is hypotension a branch point in the decision tree? There are no different event probabilities cited based on the presence of hypotension. Please clarify.

Response: Thank you. In our model, we consider hypotension as an intermediate event that could occur during cesarean section surgery. There is evidence that leg compression has been used to reduce the risk of hypotension. As IPC is sometimes used intraoperatively, the branching of hypotension allows the continued use of IPC postoperatively for VTE prophylaxis to be explored in the correct clinical context. There is a difference in the event probabilities as provided in Table 1, Incidence of hypotension without IPC -> 66.29%, Incidence of hypotension with IPC -> 23.86% (0.36*66.29%). This calculation was carried out directly in the model. To make this clearer in the manuscript, we have added the following text as one of the notes to Table 1: “Relative efficacy of IPC on hypotension was estimated from that of lower limb compression, the event rate of hypotension with IPC was then calculated at 66.29% x 0.36 (RR) = 23.86%”.

Attachment

Submitted filename: Response to reviewers.docx

Decision Letter 1

Antonio Simone Laganà

13 Jun 2023

Cost-effectiveness of mechanical thromboprophylaxis for cesarean deliveries in Brazil

PONE-D-23-07556R1

Dear Dr. Veloz,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Antonio Simone Laganà, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors performed the required corrections, which were positively evaluated by the reviewers. I am pleased to accept this paper for publication.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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Reviewer #2: (No Response)

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Reviewer #1: Yes

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Reviewer #1: Dear authors

thank you, all comments have been properly addressed

Congratulations, I would recommend It for publication

Reviewer #2: I carrefully evalutated the revised version of this manuscript. Authors have performed the required changes, iproving significantly the quality of the paper.

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Acceptance letter

Antonio Simone Laganà

20 Jun 2023

PONE-D-23-07556R1

Cost-effectiveness of mechanical thromboprophylaxis for cesarean deliveries in Brazil

Dear Dr. Veloz:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Antonio Simone Laganà

Academic Editor

PLOS ONE


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