A Cost-Effectiveness and Budget Impact Analysis of the Introduction of Heat Stable Carbetocin for Postpartum Hemorrhage Prevention in Nigeria

doi:10.21203/rs.3.rs-3416284/v1

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A Cost-Effectiveness and Budget Impact Analysis of the Introduction of Heat Stable Carbetocin for Postpartum Hemorrhage Prevention in Nigeria

https://doi.org/10.21203/rs.3.rs-3416284/v1

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Background

Nigeria contributes about 28.5% of the global maternal death burden and 22% of these deaths are attributable to postpartum hemorrhage (PPH). The World Health Organization recommends that the administration of a potent uterotonic agent within the first minute of birth is critical to preventing PPH. Studies reveal preponderance of low-quality oxytocin, misoprostol and other uterotonics in Nigeria due to substandard manufacturing practices, weak regulatory oversight, broken cold-chain systems, demanding climactic conditions (high heat; high humidity), inconsistent electricity and falsification of uterotonics. WHO, in its 2018 Recommendations, surmised heat-stable uterotonic agents may be more suitable options, depending on the context. This study evaluates the cost-effectiveness and budget impact of heat-stable carbetocin (HSC) compared to other uterotonic options for PPH prophylaxis.

Methods

This is a health-economic evaluation to compare the occurrence of PPH events, costs, and the cost-effectiveness of introducing heat-stable carbetocin versus oxytocin+/-misoprostol for PPH prevention among women delivering in public healthcare facilities in Nigeria. The study utilized a hierarchical decision-tree model, developed from the public healthcare system perspective, that had as inputs demographical, clinical, and economical information, and generated results related to PPH events (categorized as mild-moderate and severe), PPH-related deaths, DALYs (disability adjusted life-years) on account of PPH and PPH-related direct costs to the healthcare system.

Results

The cost-effectiveness analysis revealed that in a cohort of 2,548,136 deliveries in Nigeria, HSC can avert 111,652 PPH events, 12,873 severe PPH events, 31,442 DALYs, and 1,165 deaths when compared against oxytocin, at a 4.5% reduction in total cost to the health system. Similar favorable results are associated with heat-stable carbetocin when compared with misoprostol and oxytocin-misoprostol combination. The budget impact analysis revealed that HSC can lead to total cumulative savings of USD $325,114 (₦ 240,743,293¹) if scaled up over a 5-year period to 17% market share of prophylactic uterotonics administered in the country.

Conclusions

Introduction of HSC for PPH prevention is a cost-effective public health intervention in Nigeria. Health-economic modeling projects HSC to be associated with lower costs to the health system while conferring better maternal health outcomes when compared to oxytocin, misoprostol, or oxytocin-misoprostol combination.

[1] At a CBN rate of ₦740.49 to 1 USD (accessed 01/09/2023)

Postpartum Hemorrhage

Uterotonics

Economic evaluation

Cost-Effectiveness Analysis

Heat-Stable Carbetocin

Background to the Study

Nigeria records the highest burden of maternal deaths worldwide, with 28.5% (82,000) of global maternal deaths occurring in the country every year.¹ With a maternal mortality ratio of 1,047 deaths for every 100,000 live births, 1 in 5 Nigerian women are at a high risk of death during pregnancy.¹ Postpartum hemorrhage (PPH) remains the biggest overall contributor to maternal mortality and morbidity in Nigeria as it accounts for approximately 22% of total maternal deaths.^1,2 Progress towards attaining the Sustainable Development Goal of less than 70 global maternal deaths per 100,000 live births remains painfully slow, with a risk of not meeting the global set targets.³

A high proportion of mortalities and morbidities associated with PPH in Nigeria are preventable. Uterine atony is the leading cause of PPH and accounts for 70% of all PPH incidents.⁴ Simple, easily accessible methodologies such as prompt and consistent administration of quality uterotonics as part of the components of active management of the third stage of labor (AMTSL) have proven to be the most important approach and can reduce PPH-related deaths due to uterine atony.⁵

Oxytocin remains the gold standard uterotonic used in the third stage of labor globally and in Nigeria.⁶ However, there are concerns about the degradation of oxytocin quality in settings like Nigeria, where cold-chain infrastructure is weak, given that oxytocin must be stored and transported at 2–8°C.⁶ A study by Anyakora et al., found that on average, 74.5% of oxytocin and 33% of misoprostol from selected health care facilities and pharmaceutical outlets sampled and tested were of sub-optimal quality.⁷ In a study by Ejekam et. al., investigating clinicians’ experiences with oxytocin, 80% of respondents reported using oxytocin for augmentation of labor, 68% for induction of labor, 51% for stimulation of labor, and 78% for prevention of PPH. Of the 705 respondents, only 52% of healthcare workers were aware that oxytocin should be stored at 2˚C to 8˚C, and 41% reported using up to 20IU and 10% using 30IU to 60IU for prevention of PPH – dosing that is higher than the recommended prophylactic dose. Additionally, 13% of respondents were of the impression that the oxytocin brands in use were ineffective.⁸

Investment in the supply of Maternal and Newbornl Health (MNH) commodities by national and sub-national governments, health care facilities, partners, and individuals are determined by both independent and inter-related factors. These factors include availability of funds, cost, quality, safety, effectiveness, and affordability. Cost is a key determinant of procurement of commodities affecting the demand-side and supply-side cost-effectiveness thresholds, in correlation with other measures or drugs that are available for the management of the same conditions regardless of product quality⁹. Quality and assurance of efficacy of health technologies are determinants that are important to sustained use of a healthcare product as well as its appropriate use. As reported by Anyakora and Ejekam, the quality of oxytocin and misoprostol is suboptimal with geographical differences, and this has been associated with clinicians resorting to using increasing doses of oxytocin in an to attempt to achieve expected clinical responses.^7,8

The attainment of Sustainable Development Goals (SDG) 3.8 anchors on people having access to the full range of quality health services without financial hardship.¹⁰ Access to quality assured uterotonics at point-of-care for the prevention of PPH fully contributes to the realization and fulfilment of this goal. In line with this, the World Health Organization (WHO) in 2018 updated its recommendations on uterotonics for prevention of PPH with the inclusion of heat-stable carbetocin (HSC), an analogue of oxytocin, which does not require the stringent cold storage and transportation conditions that applies to oxytocin. Therefore, the use of HSC is recommended as appropriate and a suitable alternative in geographies where these conditions are not available, cannot be maintained in continuity, or wherein the quality and efficacy of oxytocin cannot be guaranteed.¹¹

Findings from the uterotonic agents for preventing postpartum hemorrhage network meta-analysis in 2018, following review of 196 trials involving 135,559 women across 53 high-, middle- and low-income countries, found ergometrine-oxytocin combination, oxytocin-misoprostol combination and carbetocin to be more effective than oxytocin related to the prevention of PPH (≥ 500mL of blood loss). The two-combination therapies were however found to be associated with important side-effects while the safety profile of carbetocin was similar to oxytocin.⁵ Included in the network meta-analysis was a high-quality randomized controlled trial comparing heat-stable carbetocin to oxytocin in the prevention of PPH for vaginal deliveries (CHAMPION trial).¹² Despite the non-inferiority result of the CHAMPION trial, the network meta-analysis results continue to favor carbetocin when combining efficacy and side-effects.

Study Aim

This study aims to determine the relative cost-effectiveness and budget impact of heat-stable carbetocin compared with the current standard of care for PPH prevention in Nigeria.

Contribution to Knowledge

Cost-effectiveness studies have typically focused on readily available uterotonics such as oxytocin and misoprostol¹³. This study evaluates the cost-effectiveness of heat-stable carbetocin, a new alternative, compared to commonly used uterotonic options for prevention of PPH, notably, oxytocin and misoprostol, including the oxytocin-misoprostol combination (which is used by clinicians to improve uterine contractility and reduce PPH events due to perceived poor quality and reduced efficacy of each uterotonic). The study used a predictive health economics model in order to generate evidence related to cost-effectiveness that can be used to buttress the business case for potential heat-stable carbetocin introduction in Nigeria and other low and middle-income countries (LMICs), in line with the updated 2018 WHO recommendations on uterotonics for prevention of PPH. Assessing the cost effectiveness, clinical impact, and cost and budget impact of using public access priced HSC compared to oxytocin, misoprostol, and oxytocin + misoprostol combination for PPH prevention in public facilities in Nigeria will help to set a precedence for similar assessment to support and inform policy makers, government officials, funders and health insurance schemes as they consider prioritization and inclusion in public health programming.

Study Design and Participants

This is a health-economic evaluation using a decision-analytic model developed for use in LMIC. The evaluation comprises a cost-effectiveness analysis and a budget impact analysis comparing uterotonics for PPH prevention in public health facilities. Data collection was conducted in six states in Nigeria: Kano, Lagos, Niger, Imo, Rivers, and Yobe. This represents a state from each of the six geopolitical zones of the country (see Figure 1 below). Three of the six states - Lagos, Niger, and Kano - are implementation states for the Smiles for Mothers project, which conducted this study as part of its project activities. Project states were selected based on the high burden of maternal mortality relative to other states in their regions, and the high probability of early adoption for new innovations given the strong government focus on reducing PPH, and co-existing maternal health investments that can support new product introduction.

The study included Clinicians practicing in public healthcare facilities (tertiary, secondary and primary), Heads of billing/administration units in secondary and tertiary healthcare facilities, Directors of Finance and Administration at the State Ministries of Health, Primary Health Care Boards/Agencies, Drug Management Agencies, and Hospital Management Boards. All study participants provided informed consent. The study excluded Private healthcare clinics and clinicians outside the field of obstetric care.

Methodology

We conducted this cost-effectiveness analysis data using a decision-tree model (see Fig. 2 below) constructed to compare outcome measures between heat-stable carbetocin and three other uterotonics in use for PPH prevention in Nigeria: oxytocin, misoprostol, and oxytocin-misoprostol combination. The expectation and practice are the administration of an uterotonic to a parturient within one minute of giving birth.¹⁴ Deliveries are either through the vaginal or abdominal (caesarean section) route, and the model provided for these two pathways. The occurrence of PPH, defined as blood loss from the genital tract of ≥ 500mL following delivery¹⁵ requires treatment depending on the cause. As uterine atony is the most common cause of PPH, the first line treatment approach is the administration of additional uterotonics before instituting other needed measures. The model classifies PPH into mild/moderate (500mL-1000mL of blood loss) and severe (≥ 1000mL blood loss), with women who undergo caesarean sections, and those with severe anemia, considered to be at higher risk of experiencing PPH with its associated complications. The treatment setting in Nigeria – primary, secondary, or tertiary level - significantly determines health outcomes related to PPH. Clinical practices and healthcare resources, especially availability of skilled birth attendants and funding, differ not only across the three tiers of health care (Primary, Secondary, Tertiary), but also differ across geographies.

Specific to the Budget Impact analysis, we also modeled gradual introduction of HSC, as depicted in Table 4. Table 3 presents the uterotonic administration mix presently estimated in the country. Oxytocin accounts for 65%, misoprostol 11.5% and oxytocin-misoprostol combination 23.5% of prophylactic uterotonics use in the country. A yearly increase of the proportion of HSC use for PPH prevention of about 3–5% up to a maximum of 17% by 2026 will reduce the proportion of each of the other uterotonics in the health benefits package in Nigeria to 54.5%, 9%, and 19.5% respectively, which is equivalent to a reduction of 14.8% for oxytocin, 18.2% for misoprostol, and 17.0% for oxytocin-misoprostol combination over a 5-year period (2022–2026) as seen in Table 4 below.

The data inputs collected from across the six states were entered into an Excel sheet and summarized into weighted averages to produce nationally representative data. The data inputs used were categorized as General inputs (population, healthcare setting), Clinical Inputs (uterotonic dosing, efficacy, PPH management, disability, mortality), and Economical Inputs (drug & drug administration costs, healthcare resource use, cold-chain costs). The weighted averages were then entered into the Excel-based decision analytic model to generate outcomes.

Model inputs

We used primary data collected from select health care facilities and key opinion leaders from across the six states and secondary data from literature as input into the hierarchical analytical decision-tree, with these stratified according to epidemiological inputs, uterotonics-related inputs, clinical outcomes inputs, and mortality risk inputs. The model allows for the investigation of the possible cost implications associated with the use of HSC as the uterotonic agent of choice for PPH prevention with oxytocin, misoprostol, and oxytocin+/-misoprostol combination[2] as comparators. Data was collected by trained interviewers using a structured questionnaire, which was available in electronic and paper versions. Data collection was conducted through a scoping exercise that included interviews with 84 key opinion leaders (doctors [Obstetricians and non-specialist doctors], nurses, midwives, pharmacists, and administrators) who provided informed consent. Data extraction from secondary data sources such as the Nigerian Demographic and Health Survey 2018 (NDHS 2018)¹⁶, and the District Health Information Software-2 (DHIS2).¹⁷ Other primary data sources included abstractions from registers in the facilities. Secondary data were collected through internet searches for article publications, results of meta-analysis, and systematic reviews. All identifiable information, such as names, telephone numbers, and email addresses, were kept separately, and not recorded on the questionnaire. The names of respondents were also not used in any of the results of the evaluation, and interview transcripts, and data entry Excel sheets were held securely and separately by interviewers and evaluation staff authorized to do so. The model is a simple decision tree that is based on a previous analytic decision model that investigated the cost-effectiveness of uterotonics for prevention of postpartum hemorrhage in India.¹⁸ Model parameters were informed by published literature, the opinion of key subject matter experts, local costing, and service utilization data.

Population and Delivery Characteristics

We considered a country-wide, public facility, birthing cohort of 2,548,136 as reported in the District Health Information System 2019.¹⁷ Facility-based birth distribution across healthcare settings shows that 40% of all deliveries occur at the Primary Health Care (PHC) level, 25% at the Secondary Health Care (SHC) level, and 35% at Tertiary Health Care (THC) level. Aggregate state and facility level indicators, such as the proportion of institutional births and the proportion of births in public sector facilities, were retrieved from the Nigerian Demographic and Health Survey and from the District Health Information Software-2.¹⁷ With an insignificant number of caesarean deliveries occurring in PHCs, the caesarean section rate at SHC and THC levels are 6% each, a situation probably reflecting the availability of specialist doctors at these levels of care. Estimates of anemia across the tiers of care show similar rates between 60–67% based on data collected from different health facilities that served as data collection centers.¹⁹ See Table 1 below.

Table 1

Population data for general setting
Variable	Value	Source
Total cohort size	2,548,136	DHIS-2 Data – 2019
Distribution of women giving birth per healthcare setting	PHC: 40%	DHIS-2 Data − 2019
	SHF: 25%
	THF: 35%
% of women with anemia per healthcare setting	PHC: 60%	NDHS 2018
	SHF: 63%
	THF: 67%
% of women with secondary infections after Spontaneous Vaginal Delivery (SVD)	PHC: 0%	KOL (Key Opinion Leader)
	SHF: 4%
	THF: 5%
% of women with secondary infections after C-section deliveries	PHC: 0	KOL
	SHF: 12%
	THF: 12%
Proportion of C-section births (%)	6%	DHIS-2 Data − 2019
Maternal Mortality Ratio	1047	WHO 2023. Trends in maternal mortality 2000 to 2020: estimates by WHO, UNICEF, UNFPA, World Bank group and the United Nations Population Division; Annex 4
PPH-related mortality as a % of MMR	22%	Federal Ministry of Health, Nigeria, 2019. Roadmap for the Accelerated Reduction of Maternal and Neonatal Mortality.
Willingness-to-pay threshold (in local currency)	₦ 1,013,605	World Bank Data (2019) CBN Exchange rate

Efficacy of Prophylactic Uterotonics

Model Input data on uterotonic efficacy was from the December 2018 Cochrane review on uterotonic use for preventing PPH.⁵ The Uterotonic Network Meta Analysis (U-NMA) focused on the relative effects and ranking of each uterotonic for the prevention of PPH using data from high-, middle- and low-income countries, including Nigeria, from 197 trials including 135,559 women.

Risk of Mortality

For the risk of mortality due to PPH, we considered differences in the healthcare setting and level of anemia. Women with severe anemia are at a high risk of developing PPH, and this is shown by Nyflot et. al. to be at an odds ratio of 4.27 (95% CI: 2.79–6.54).²⁰ A maternal mortality ratio of 1047 and the percentage of death resulting from PPH of 22% used in the model were results of the National Demographic Health Survey published in 2018¹⁶ and by the Nigerian Federal Ministry of Health in the Roadmap for the Accelerated Reduction of Maternal and Neonatal Mortality in 2019.²¹

Disability

The disability measure Disability Adjusted Life Years (DALYs) was employed for use in the model. Data from the Global Burden of Disease study was used as inputs to disability weights and outcome measures such as PPH events and disability-adjusted life years.²² Other studies that served as inputs include the work by Lubinga et al¹³. Non-availability of studies and difficulty in relating outcomes prevented the team from using Quality Adjusted Life Years (QALYs) as a measure of disability in this study.

Healthcare Resources Use and Costs

Clinical details on uterotonic administration in health facilities were obtained from key opinion leaders at each tier of the healthcare system (primary, secondary, and tertiary), as were healthcare resource use and drug and administration costs. Various cost drivers contribute to the cost of providing health care services in health systems. Analysis of these cost drivers in health care facility settings for each of the uterotonics in this study found, as shown in Table 2, that total cost was least for HSC and highest for health packages that have oxytocin as the uterotonic of choice for PPH prevention. Comparatively under each line item, while misoprostol comes with the least drug costs and administrative costs, when combined with associated costs for hospital stay, blood transfusion, and referrals, its total cost outstrips the total costs associated with HSC prophylactic use.

Table 2

Contributors to total treatment cost (in naira)
Cost Items	Heat-stable Carbetocin	Oxytocin	Misoprostol	Oxytocin+/-Misoprostol
Drug costs	1,331,851,234	1,754,253,467	834,242,807	1,851,962,958
Administration costs	225,299,526	242,278,828	75,929,088	258,011,037
Personnel costs	4,811,436,108	4,986,855,686	5,043,729,829	4,878,575,348
Hospital-stay costs	33,019,491,604	33,512,100,208	33,739,194,783	33,197,161,535
Blood transfusion costs	45,412,807	71,031,831	69,964,125	44,904,753
Referral costs	31,337,401	36,061,793	43,100,669	34,160,294
Follow-up costs	9,245,906,023	9,245,906,023	9,245,906,023	9,245,906,023
Cold-chain costs: logistics	34,919,656	689,391,060	81,153,035	672,414,872
Cold-chain costs: storage	7,274,928	143,623,138	16,906,882	140,086,432
Cold-chain storage: wastage	13,967,862	275,756,424	32,461,214	268,968,949
Total cost	48,766,897,149	50,957,258,457	49,182,588,456	50,592,149,201
Cost per woman	19,138	19,998	19,301	19,855

Model Output

Cost Effectiveness Analysis

The effect of HSC, as a prophylactic, versus the other uterotonics on postpartum hemorrhage on the health system (using a decision-tree model, see Fig. 2) is presented as PPH events averted – classified and disaggregated into the number of All PPH events, mild-moderate PPH events, severe PPH events – deaths from PPH, DALYs averted and total costs.

Budget Impact Analysis

In modelling the budget impact of incremental utilization of HSC for PPH prevention, we found that from 2022 through 2026, approximately USD $325,114 (₦240,743,294) accrues to the health system as budget savings with progressive integration of HSC to a conservative utilization rate of 17% of the uterotonics use for PPH prevention as against continuation of the current prophylactic oxytocin and misoprostol utilization pattern. This saving is driven by averting 11,041 PPH events.

Results of modeling from 2022 to 2026 are seen in Table 4 starting from current uterotonic utilization estimates as shown in Table 3.

Table 3

Current distribution of uterotonics utilization (excluding heat-stable carbetocin)
Intervention	2022	2023	2024	2025	2026
Heat-stable Carbetocin	N/A	N/A	N/A	N/A	N/A
Oxytocin	65.0%	65.0%	65.0%	65.0%	65.0%
Misoprostol	11.5%	11.5%	11.5%	11.5%	11.5%
Oxytocin+/-Misoprostol	23.5%	23.5%	23.5%	23.5%	23.5%

Table 4

Introducing heat-stable carbetocin with gradual increase in volume to uterotonic alternatives.
Intervention	2022	2023	2024	2025	2026
Heat-stable Carbetocin	1.5%	4.0%	8.0%	13.0%	17.0%
Oxytocin	64.0%	62.5%	60.0%	58.0%	54.5%
Misoprostol	11.0%	10.5%	10.0%	9.0%	9.0%
Oxytocin+/-Misoprostol	23.5%	23.0%	22.0%	20.0%	19.5%

Cost-Effectiveness Analysis

Incremental cost-effectiveness ratio (ICER), total and incremental costs, effectiveness, and incremental effectiveness were computed for each of the uterotonic agents under evaluation: heat-stable carbetocin, oxytocin, misoprostol and oxytocin and misoprostol combination. The primary outcome measure was cost per case of PPH avoided, and the secondary outcome measures, cost per case of mild and severe PPH.

Scenario Analyses

To better understand the contribution and impact of various inputs to results, we conducted analysis of different scenarios by modifying different variables and then comparing the cost-effectiveness of HSC to each of oxytocin, misoprostol, and oxytocin+/-misoprostol.

Sensitivity Analyses

We conducted both one-way sensitivity analysis (OWSA) and probabilistic sensitivity analysis (PSA) to assess the robustness of the study results. The pairwise comparison was conducted using oxytocin as the comparator to HSC at a willingness-to-pay threshold of ₦1,010,305. To assess the robustness of results obtained from the base case analysis, the modeling also included a probabilistic sensitivity analysis, which was run through 5,000 iterations. For the PSA, oxytocin and misoprostol were the comparators. In each analysis, DALYs averted was the parameter of interest.

Clinical Impact Results

Clinical impact analysis across prophylactic uterotonics as it relates to all PPH events and particularly severe PPH events and PPH deaths found that there will be a significant reduction in these with HSC introduction. There is a 39%, 50%, and 18% difference in All PPH events when HSC is administered prophylactically compared to oxytocin, misoprostol, and oxytocin+/-misoprostol combination, respectively, as shown in Table 5 below.

Table 5

Clinical effectiveness of HSC compared to Comparator Uterotonics in ALL PPH events.
Intervention (prophylactic)	Effectiveness All PPH Events	Incremental Effectiveness All PPH Events	% Additional All PPH Events (Comparator vs HSC)
Heat-stable Carbetocin	285,627
Oxytocin	397,279	111,652	39%
Misoprostol	429,366	143,739	50%
Oxytocin+/-Misoprostol	337,342	51,715	18%

When PPH events are analyzed at a more detailed level, findings as seen from Tables 6 and 7 are that of 15%, 38%, and 7% difference in severe PPH events and 21%, 41%, and 12% reduction in PPH deaths when HSC is administered prophylactically.

Table 6

Clinical effectiveness of HSC compared to Comparator Uterotonics in severe PPH events.
Intervention (prophylactic)	Effectiveness Severe PPH Events	Incremental Effectiveness Severe PPH Events	% Additional Severe PPH Events (Comparator vs HSC)
Heat-stable Carbetocin	85,388
Oxytocin	98,261	12,873	15%
Misoprostol	117,441	32,053	38%
Oxytocin+/-Misoprostol	91,095	5,707	7%

Table 7

Clinical effectiveness of HSC compared to Comparator Uterotonics in PPH related deaths.
Intervention (prophylactic)	Effectiveness Death	Incremental Effectiveness Death	% Additional Deaths (Comparator vs HSC)
Heat-stable Carbetocin	5,422
Oxytocin	6,587	1,165	21%
Misoprostol	7,643	2,221	41%
Oxytocin+/-Misoprostol	6,064	642	12%

Analysis of the clinical impact of HSC introduction and utilization over a five-year period, where HSC is introduced (new scenario) and reaches 17% utilization by 2026, shows a sustained decrease in the quantity of annual PPH events, i.e., PPH events averted. This is shown in Table 8.

Table 8

Yearly clinical impact analysis – Total PPH Cases
	2022	2023	2024	2025	2026
Total PPH Cases (current scenario – excludes HSC)	93,046	95,412	97,839	100,327	102,878
Total PPH Cases (new scenario – includes HSC)	92,574	94,304	95,770	97,223	98,591
Clinical impact (Total PPH cases averted)	473	1,108	2,069	3,104	4,287

Budgetary Impact Analysis

Cost impact analysis of HSC use for PPH prevention shows that there will be about 1–4% lower cost attributed to HSC compared to other uterotonics as seen from Table 9.

The introduction and use of HSC is associated with a reduction in annual expenditure to the health care system. The budget impact output shows that using HSC for PPH prevention versus each of the current prophylactic uterotonics translates to a budgetary savings to the health system in managing PPH. Aggregate cost savings are as result of lower input or expenditure costs and from prevention of more PPH events when we compared HSC with each other uterotonics.

Table 9

Total cost of PPH prevention with HSC compared to Comparator Uterotonics.
Intervention (prophylactic)	Total costs (in Naira)	Incremental costs vs heat-stable carbetocin	% Difference
Heat-stable Carbetocin	48,766,897,149
Oxytocin	50,957,258,457	2,190,361,308	4%
Misoprostol	49,182,588,456	415,691,307	1%
Oxytocin+/-Misoprostol	50,592,149,201	1,825,252,052	4%

Table 10 shows that the cost of PPH prevention per woman was found to be less with HSC compared to the other uterotonics. Evaluation of Incremental costs when comparing health delivery packages shows that as much as ₦860 higher cost per woman when oxytocin is chosen for PPH prophylaxis, ₦163 misoprostol and ₦717 with oxytocin-misoprostol combination.

Table 10

Cost of PPH prevention per woman
Intervention (prophylactic)	Costs/Woman (in Naira)	Incremental costs vs HSC	% Difference
Heat-stable Carbetocin	₦19,138
Oxytocin	₦19,998	₦860	4%
Misoprostol	₦19,301	₦163	1%
Oxytocin+/-Misoprostol	₦19,855	₦ 717	4%

Analysis of the budget impact of HSC introduction, where HSC uptake increases to 17% over a five-year period, shows an incremental annual increase in cost savings as HSC uptake increases (new scenario). See Table 11 below.

Table 11

Yearly total budget impact scenario analysis
	2022	2023	2024	2025	2026
Total costs (current scenario)	13,543,808,554	13,888,227,606	14,241,405,234	14,603,546,169	14,974,932,805
Total costs (new scenario)	13,537,300,301	13,868,608,334	14,198,371,394	14,532,187,028	14,874,728,017
Budget impact	6,508,253	19,619,272	43,033,840	71,359,141	100,204,789

Current scenario excludes HSC; New scenario includes HSC.

Cost-Effectiveness Analysis

Comparing HSC use for PPH prevention with each of the comparator uterotonics in this study, regarding health benefits and incremental costs, HSC was dominant in each case. As shown in Table 12, the highest health benefits (DALYs averted and death avoided) occur when HSC is compared to misoprostol, with the least favorable benefits when compared to oxytocin+/-misoprostol combination. Incremental costs for each health benefit gained is shown to be least compared to misoprostol and highest compared to oxytocin.

Table 12

Comparing health benefits and cost of introducing HSC for PPH prevention.
Intervention (prophylactic)	DALYs	DALYs Averted**	Deaths Avoided**	Incremental costs (in NGN) per woman*	ICER DALYs Averted
Heat-stable Carbetocin	145,013
Oxytocin	176,455	0.012	0.00046	-860	Heat-stable Carbetocin dominant
Misoprostol	204,549	0.023	0.00087	-163	Heat-stable Carbetocin dominant
Oxytocin+/-Misoprostol	162,085	0.007	0.00025	-716	Heat-stable Carbetocin dominant
*negative value means total costs are lower for Heat-stable Carbetocin;
**positive value means Heat-stable Carbetocin improves outcome

Sensitivity Analyses

In the OWSA, to assess the impact that changes in different input parameters have on the output results of our economic evaluation, we selected oxytocin as the pair-wise comparator to HSC with the focal point of DALYs averted. The most influential variables in order of importance are shown in Table 13. Based on this comparison, the parameters with the greatest impact on DALYs averted, where analyses results are similar to the primary analysis results, are predominantly related to mortality, referrals, and the proportion of C-section deliveries.

Table 13

Summary of the most influential variables: HSC vs. Oxytocin - OWSA
Parameter name	Lower bound	Upper bound	Difference
Odds ratio- risk of mortality with age between 20 and 35 years	0.005	0.010	0.005
Odds ratio- risk of mortality in PHC	0.006	0.010	0.004
Mortality due to severe PPH event	0.006	0.009	0.003
Proportion of referrals that get transferred	0.006	0.009	0.002
Odds ratio- risk of mortality in SHC	0.007	0.009	0.002
Odds ratio- risk of mortality due to referral	0.006	0.008	0.002
Mortality due to mild to moderate PPH event	0.007	0.008	0.002
Proportion of Caesarean section births	0.007	0.008	0.001
Proportion of women with anemia	0.007	0.008	0.000
Duration of disability- mild to moderate PPH events	0.007	0.008	0.000

Results from the PSA found convergence across a number of parameters following 5000 iterations as shown in Fig. 3. There is 99.8% probability that the results found in the base case are accurate (i.e., HSC has lower incremental cost and higher DALYs averted compared to oxytocin). HSC is dominant when compared to oxytocin, misoprostol, and oxytocin-misoprostol combination - see Tables 14 and 15.

Table 14

Incremental Analysis - Base case results
Intervention	Total costs per woman (Naira)	DALYs	Incremental costs (Naira)	DALYs averted	ICER (Cost per DALYs averted)
Heat-stable Carbetocin	19,138	0.035
Oxytocin	19,998	0.042	-860	0.007	HSC dominant
Misoprostol	19,301	0.049	-163	0.014	HSC dominant
Oxytocin+/-Misoprostol	19,855	0.039	-716	0.004	HSC dominant

Table 15

Incremental Analysis - PSA results
Intervention	Total costs per woman (Naira)	DALYs	Incremental costs (Naira)	DALYs averted	ICER (Cost per DALYs averted)
Heat-stable Carbetocin	19,186	0.034
Oxytocin	20,049	0.042	-863	0.007	HSC dominant
Misoprostol	19,351	0.048	-165	0.014	HSC dominant
Oxytocin+/-Misoprostol	19,904	0.038	-718	0.004	HSC dominant

This analysis shows nearly all (99.7%, 96.7%) of the PSA replicates indicate heat-stable carbetocin lowers costs and averts more DALYs compared to oxytocin and oxytocin-misoprostol and in the vast majority (86.6%) of PSA replicates compared to misoprostol – see Table 16 below.

Table 16

– Pair-wise Results – PSA
Intervention	Incremental Cost	DALYs Averted	Probability
Heat-stable Carbetocin vs Oxytocin	< 0	≥ 0	0.997
Heat-stable Carbetocin vs Misoprostol	< 0	≥ 0	0.866
Heat-stable Carbetocin vs Oxytocin+/-Misoprostol	< 0	≥ 0	0.967

Scenario Analyses

Results from changing key input assumptions are available under scenario analyses to assess the robustness of the base case model results. Across the base case, comparing incremental costs, deaths avoided, DALYs averted, PPH events avoided, severe PPH events avoided, ICER and net monetary benefit (NMB), heat-stable carbetocin outperformed oxytocin, misoprostol, and oxytocin+/-misoprostol, and thus is considered dominant, see Table 17 below. Specific to the scenario analysis where the key efficacy input was changed to using the CHAMPION trial data, HSC remained dominant over oxytocin, the sole direct comparator based on trial design. Across nearly all the other scenario analyses, where a different variable from the base-case was changed, the model found that HSC was also dominant compared with oxytocin and misoprostol. The only exception, specific to misoprostol, is where duration of hospital stay was changed using data from the CHAMPION trial. Here, total costs associated with misoprostol use (₦14,482) were slightly lower compared to costs associated with HSC use (₦14,500). HSC, however, performed better than misoprostol related to deaths, DALYs, and PPH events under this scenario.

Table 17

Scenario analyses outcomes
Intervention	ICER (DALYs)	NMB
Base Case
Oxytocin	HSC dominant	13,326
Misoprostol	HSC dominant	23,768
Oxytocin+/-Misoprostol	HSC dominant	7,485
Exclude cold-chain costs
Oxytocin	HSC dominant	12,913
Misoprostol	HSC dominant	23,739
Oxytocin+/-Misoprostol	HSC dominant	7,083
Exclude differential risk for anemia
Oxytocin	HSC dominant	12,689
Misoprostol	HSC dominant	22,449
Oxytocin+/-Misoprostol	HSC dominant	7,146
Duration of Hospital stay: CHAMPION
Oxytocin	HSC dominant	13,172
Misoprostol	772	23,587
Oxytocin+/-Misoprostol	HSC dominant	7,430
No higher average dose of oxytocin for prophylaxis to compensate for degradation of quality
Oxytocin	HSC dominant	13,108
Misoprostol	HSC dominant	23,768
Oxytocin+/-Misoprostol	HSC dominant	7,267

Dosing for misoprostol prophylaxis; 400mcg
Oxytocin	HSC dominant	13,326
Misoprostol	HSC dominant	23,718
Oxytocin+/-Misoprostol	HSC dominant	7,460
Costing method apply discount on drug costs of oxytocin and misoprostol
Oxytocin	HSC dominant	13,153
Misoprostol	HSC dominant	23,705
Oxytocin+/-Misoprostol	HSC dominant	7,304

Nigeria continues to account for the highest number of maternal deaths globally, with PPH its number one direct cause. Despite efforts to address maternal deaths, including PPH, such as the adoption of the 2009, 2012, and 2018 WHO recommendations on PPH management, launch of the Nigeria Reproductive, Maternal, Neonatal, Child, Adolescent and Elderly Health plus Nutrition Multi-stakeholder partnership Coordination platform (RMNCAEH + N), improved health sector care financing, capacity building in Nigeria, these systems changes have been inadequate and there has been limited success in achieving set maternal and newborn health targets. New approaches and tools are needed to invigorate the process for accelerated change.

The Smiles for Mothers consortium, recognizing the need to take a health systems approach in order to strengthen Nigeria’s response to PPH, implemented a broad number of activities – from supporting the Federal Ministry of Health (FMoH) to making updates to the National Essential Medicine List (NEML) and the life-saving skills (LSS) training manuals including HSC as an alternative uterotonic for PPH prevention, to developing comprehensive emergency obstetrics and newborn care (CEmONC) modules to improving delivery of respectful maternal and newborn care, validate and increase awareness of the availability of affordable public access priced HSC, to confirming the acceptability, feasibility and appropriate use of HSC via implementation research at secondary and primary care facilities. This led to this holistic health-economic assessment of introducing the newly recommended, public access priced HSC for PPH prevention into the Nigerian public health system.

On the clinical impact of using heat-stable carbetocin, our findings indicate a reduction in the incidence of all PPH events [Table 5], severe PPH events [Table 6] and PPH-related deaths [Table 7] when HSC was used as the prophylactic of choice compared to oxytocin, misoprostol, and oxytocin+/-misoprostol combination, respectively. In this study, the greatest reduction in PPH events is shown when HSC is used as a prophylactic compared to misoprostol, and smallest in comparison with the oxytocin+/-misoprostol combination. This finding of HSC preventing more PPH events when compared to oxytocin, misoprostol and oxytocin + misoprostol combination is similar to the finding by Matthijsse et al in a study conducted in the United Kingdom where in a cohort of 100 women, Carbetocin use compared to oxytocin use was associated with 3.42 less all PPH events disaggregated into 3.03 fewer mild/moderate PPH events and 0.39 fewer severe PPH events.²³ Our findings also suggest that as HSC scales, more favorable health outcomes (fewer PPH events and deaths) are achieved.

Our analysis of the costs and budgetary impact of HSC introduction for PPH prevention in Nigeria shows that overall, the use of HSC as the uterotonic of choice for the prevention of PPH comes at a lower total cost to the health system, at a lower cost to each woman and that cost savings to the health system increase as HSC scales. Comparatively, this cost savings in favor of HSC, is highest where oxytocin is used as the comparator prophylactic of choice. This is followed by oxytocin+/-misoprostol combination and least where misoprostol is used. Our finding is similar to Barrett et. al., which found that in PPH management of low-risk and high-risk PPH patients, replacing oxytocin with heat-stable carbetocin for PPH prevention could potentially provide annual savings to the Canadian health care system largely due to its greater efficacy in preventing the consequences of PPH.²⁴

Cost-effectiveness analyses help inform decision-makers on interventions with higher impact and benefits as they consider the contents of health care packages in any geography or health system.

Using a demand-side cost effectiveness threshold, we found in comparing HSC to oxytocin, misoprostol and oxytocin+/-misoprostol that when it comes to incremental effectiveness ratio, HSC dominated in each case. Simply stated, this means that not only is HSC more effective in preventing PPH events, but its scaling comes at a lower cost to the health care system when compared to each of the other uterotonics.

Our scenario analyses indicate a consistent dominance of HSC compared to oxytocin and oxytocin+/-misoprostol combination, while indicating a nearly consistent non-dominance of HSC compared to misoprostol with the exception of one scenario (duration of hospital stay based on CHAMPION data). Where this lack of dominance was found, HSC continued to reflect consistently favorable health outcomes, but at a higher total cost, compared to misoprostol. Considerations of prioritizing a woman’s health equity, quality of care and risk of long-term health morbidities/mortality may be warranted despite the higher incremental cost.

Heat-stable carbetocin’s efficacy and heat-stability characteristics, and thus preservation of its potency despite climatic and suboptimal cold-chain systems challenges in all the states favorably impacts the Nigerian health system in a number of ways: 1) aversion of PPH events; 2) cost-savings from reduced incidence of PPH events; 3) lower need for administration of extra uterotonics; 4) consistency in uterotonic quality builds trust among providers and patients; 5) promotes health equity by ensuring birthing women gain reliable access to a high-quality prophylactic uterotonic. Furthermore, our analysis suggests that as heat-stable carbetocin scales, its health outcomes and cost savings increase. These savings can be diverted to complement other areas of public health significance.

The wide-scale availability of HSC, which is suited to the current situation of sub-optimal uterotonic efficacy underpinned by fragile cold-chain infrastructure and poor electricity supply, as well as high heat/humidity, would help optimize PPH prevention efforts and complement other on-going interventions in the country to improve maternal and newborn care outcomes and facilitate progress in the attainment of SDG 3.1 and 3.8.

Limitations

The model considers direct costs to the healthcare system only. It does not consider indirect costs (e.g., healthcare provider training, etc. and for simplicity, non-pharmaceutical medical interventions such as UBT (uterine balloon tamponade), NASG (non-pneumatic antishock garment), hysterectomy, etc. are excluded, thus likely under-estimating the total economic costs and health outcomes across all the interventions.

Due to limitations with some data inputs because of the lack of readily available data (e.g., hospital and cold-chain costs, time required by healthcare providers to manage PPH, amount of blood units needed for transfusion, percentage of women receiving the oxytocin + misoprostol combination for prophylaxis, etc.), we relied on more subjective information provided by key opinion leaders for these inputs.

Ergometrine, as an alternative uterotonic for PPH prevention, was excluded due to limited use. Tranexamic acid alone or as part of the E-MOTIVE bundle to treat PPH was not included, suggesting an under-estimation of the total cost estimates and health outcomes across all the interventions. Poor-quality misoprostol (e.g., additional dosing, wastage) was excluded, despite a 2020 WHO systematic review that found “failures rates were …nearly 40% for … misoprostol (Torloni MR, 2016).”

The study outcomes provide relevant data and learnings for decision-makers as they consider the most appropriate uterotonics to optimize efforts to prevent PPH, to minimize complications and costs related to PPH events and to support more effective financial stewardship in healthcare provision.

Specifically, our findings show that HSC generates better health outcomes and lower costs compared to oxytocin and misoprostol. Health benefits come at a smaller cost to the health system, translating to a relative increase in available resources for health and the opportunity to channel these resources into other areas of intervention in the health sector.

With the introduction of HSC for PPH prevention, comparable disinvestments will occur across all other uterotonics to make room for HSC introduction and scaling, with no concomitant increase in the total health budget. The inclusion of HSC for PPH prevention in the package for healthcare not only serves to promote health equity through the provision of a product of consistent high quality but it also minimizes PPH-related health complications and maximizes the use of limited resources for more health benefits for the population while also addressing issues relating to evidence-based practice, quality of care, ethics and UHC principles.

AMTSL

Active Management of Third Stage of Labor

CBN

Central Bank of Nigeria

CEmONC

Comprehensive Emergency Obstetric and Newborn Care

Confidence Interval

section-Caesarean Section

DALY

Disability Adjusted Life Year

DHIS2

District Health Information Software 2

FMOH

Federal Ministry of Health

HSC

Heat Stable Carbetocin

ICER

Incremental Cost Effectiveness Ratio

International Units

KOL

Key Opinion Leader

LMIC

Low-and Middle-Income Country

LSS

Life Saving Skills

MMR

Maternal Mortality Ratio

MNH

Maternal and Newborn Health

₦

Naira (Nigerian)

NASG

Non-pneumatic Anti-Shock Garment

NDHS

Nigerian Demographic and Health Survey

NEML

National Essential Medicines List

NMB

Net Monetary Benefit

OWSA

One-Way Sensitivity Analysis

PHC

Primary Health Care/Clinic

PPH

Post Partum Hemorrhage

PSA

Probabilistic Sensitivity Analysis

QALY

Quality Adjusted Life Year

RMNCAEH + N

Reproductive, Maternal, Neonatal, Child, Adolescent, and Elderly Health plus Nutrition

SDG

Sustainable Development Goal

SHC

Secondary Health Care

SHF

Secondary Health Facility

SVD

Spontaneous Vaginal Delivery

THC

Tertiary Health Care

THF

Tertiary Health Facility

UBT

Uterine Balloon Tamponade

United Nations

UNFPA

United Nations Population Fund

NMA-Uterotonic Network Meta Analysis

USD ($)

United States Dollar

UHC

Universal Health Coverage

UNICEF

United Nations Children’s Fund

WHO

World Health Organization

Ethical Approval and Consent to Participate

The study team adhered to the highest ethical standards and obtained all required federal and state-level scientific research ethics approvals for this study. All methods were carried out in accordance with relevant guidelines and regulations. Ethical approvals obtained for this study included from the National Health Research Ethics Committee of Nigeria (NHREC Approval number NHREC/01/01/2007-16/04/2021), Kano state Health Research Ethics Committee (Ref No: MOH/off/797/T.I/2097), Lagos state Health Research Ethics Committee (Ref No: LREC/06/10/1499), Niger state Health Research Ethics Committee (Ref No: STA/495/vol/176) and

Study participants provided informed consent after careful perusal of the consent form. All information about the participants and health facilities have been anonymized and high protocol on confidentiality and safety maintained.

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Competing Interests

The authors declare that they have no competing interests.

Funding

The Smiles for Mothers program supports the Federal Ministry of Health in Nigeria and State governments of Kano, Lagos and Niger to reduce maternal deaths due to postpartum hemorrhage through innovations in Service Delivery and Supply Chain Management. This program is supported by funding from MSD, through MSD for Mothers, the company’s global initiative to help create a world where no woman has to die while giving life. MSD for Mothers is an initiative of Merck & Co., Inc., Rahway, NJ, U.S.A.

Authors’ contributions

Dr. Olatunde Amode contributed to the development of the research protocol, participated in the data collection and modeling process in Niger State, and led the development and revision of the manuscript.
Dr. Damilola Oyedele participated in the data collection and analysis process in Lagos State. She also led the process of data modeling for the 6 states included in the study and made significant revisions to the manuscript.
Hadiza Salele participated in the data collection and analysis process in Kano State and made significant revisions to the manuscript.
Olajumoke Adekeye developed the study protocol including data collection methodology and revisions of model outcomes.
Dr. Uchenna Igbokwe contributed to the development of the research protocol and revision of the manuscript.
Lola Ameyan contributed significantly to the revision of the manuscript.
Dr. Kayode Afolabi contributed to the development of the research protocol and revision of the manuscript.
Dr. Olufunke Fasawe contributed to the development of the research protocol and revision of the manuscript.
Dr. Owens Wiwa contributed to the development of the research protocol and revision of the manuscript.

Acknowledgements

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John R. Cook (Economic Modeling, Complete HEOR Solutions, LLC, PA, USA) and Dr. Kunal Saxena (Center for Observational and Real-World Evidence, Merck & Co., Inc, NJ, USA) for their foundational work on the economic model structure.

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2. The model used a weighted average of 51% of women received oxytocin + misoprostol as prophylaxis (Key Opinion Leaders). They estimated use as PHC (36%); SHC (37%) and THC (77%); the remaining 49% is oxytocin-alone.

No competing interests reported.

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A Cost-Effectiveness and Budget Impact Analysis of the Introduction of Heat Stable Carbetocin for Postpartum Hemorrhage Prevention in Nigeria

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Abstract

Figures

Background

Background to the Study

Study Aim

Contribution to Knowledge

Methods

Study Design and Participants

Methodology

Model inputs

Population and Delivery Characteristics

Efficacy of Prophylactic Uterotonics

Risk of Mortality

Disability

Healthcare Resources Use and Costs

Model Output

Cost Effectiveness Analysis

Budget Impact Analysis

Cost-Effectiveness Analysis

Scenario Analyses

Sensitivity Analyses

Results

Clinical Impact Results

Budgetary Impact Analysis

Cost-Effectiveness Analysis

Sensitivity Analyses

Scenario Analyses

Discussion

Limitations

Conclusion

List Of Abbreviations

Declarations

References

Footnotes

Additional Declarations

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